INDEX, Original research papers presented in these continuing

Transcription

INDEX, Original research papers presented in these continuing medical education conferences The laboratory testing taught at these conferences is not “urinary neurotransmitter testing”, that model has been discredited in several peer‐reviewed papers listed below. The transporters which move neurotransmitters along with their precursors in and out of cells are responsible for the ultimate concentrations of neurotransmitters. This approach teaches Organic Cation Transporter Type‐2 (OCT‐2) functional status optimization. Once transporter function is optimized neurotransmitter levels and clinical results are optimal. Click on any of the links below to access the paper The effects of 5‐HTP and tyrosine on urinary serotonin and dopamine The dual gate lumen transporter model The invalidity of urinary serotonin and dopamine testing Differentiation of bipolar depression from major affective disorder with amino acids Amino acid responsive Crohn’s disease, a case study Amino acids with ADHD The invalidity of urinary norepinephrine and epinephrine testing Parkinson’s disease a case study The invalidity of the “urinary neurotransmitter testing model” Prolotherapy, a case study The Apical Regulatory Super System (APRESS) Neurotransmitter depletion by reuptake inhibitors (drug induced relative nutritional deficiency) Discrediting the monoamine hypothesis Relative nutritional deficiencies related to centrally acting monoamines and their precursors 5‐HTP efficacy and contraindications Administration of tyrosine with phenelzine The L‐dopa pill stop in the competitive inhibition state The paper that linked carbidopa to the increasing Parkinson’s death rate. Carbidopa induced dyskinesia and its need in the management of L‐dopa nausea Melanin steal induced dopamine and clinical fluctuations The depression chapter from the Ingrid Kolstadt, MD book. Return to index
ORIGINAL RESEARCH
Both stimulatory and inhibitory effects of dietary
5-hydroxytryptophan and tyrosine are found
on urinary excretion of serotonin and dopamine
in a large human population
George J Trachte 1
Thomas Uncini 2
Marty Hinz 3
Department of Physiology
and Pharmacology, University of MN
Medical School Duluth, Duluth,
MN, USA; 2 Chief Medical Examiner,
St. Louis County, Hibbing, MN, USA;
3
Clinical Research, NeuroResearch
Clinics, Inc., Duluth, MN, USA
1
Abstract: Amino acid precursors of dopamine and serotonin have been administered for decades
to treat a variety of clinical conditions including depression, anxiety, insomnia, obesity, and
a host of other illnesses. Dietary administration of these amino acids is designed to increase
dopamine and serotonin levels within the body, particularly the brain. Convincing evidence
exists that these precursors normally elevate dopamine and serotonin levels within critical brain
tissues and other organs. However, their effects on urinary excretion of neurotransmitters are
described in few studies and the results appear equivocal. The purpose of this study was to
define, as precisely as possible, the influence of both 5-hydroxytryptophan (5-HTP) and tyrosine
on urinary excretion of serotonin and dopamine in a large human population consuming both
5-HTP and tyrosine. Curiously, only 5-HTP exhibited a marginal stimulatory influence on urinary
serotonin excretion when 5-HTP doses were compared to urinary serotonin excretion; however,
a robust relationship was observed when alterations in 5-HTP dose were compared to alterations
in urinary serotonin excretion in individual patients. The data indicate three statistically discernible components to 5-HTP responses, including inverse, direct, and no relationships between
urinary serotonin excretion and 5-HTP doses. The response to tyrosine was more consistent but
primarily yielded an unexpected reduction in urinary dopamine excretion. These data indicate
that the urinary excretion pattern of neurotransmitters after consumption of their precursors is
far more complex than previously appreciated. These data on urinary neurotransmitter excretion
might be relevant to understanding the effects of the precursors in other organs.
Keywords: dopamine, serotonin, depression, urinary neurotransmitters excretion
Introduction
Correspondence: George J Trachte
Department of Physiology
and Pharmacology, University of MN
Medical School Duluth, 1035 University
Drive, Duluth, MN 55812, USA
Tel +1 218 726 8975
Fax +1 218 726 7906
Email [email protected]
Two critical neurotransmitters, serotonin (5-hydroxytryptamine; 5-HT) and dopamine,
are synthesized from the amino acids tryptophan and tyrosine, respectively.1,2 Serotonin
synthesis in vivo is accomplished by a two-step process converting tryptophan to
5-hydroxytryptophan (5-HTP), facilitated by the enzyme tryptophan hydroxylase, and
5-HTP is then decarboxylated by dihydroxyphenalanine (DOPA) decarboxylase to
form serotonin. Tyrosine is converted to dopamine by the combined action of tyrosine
hydroxylase to form DOPA and DOPA decarboxylase to form dopamine. The synthesis
of serotonin is commonly stimulated by dietary delivery of L-5-hydroxytryptophan
(5-HTP)3 and dopamine synthesis is stimulated by dietary administration of either
tyrosine or L-dihydroxyphenylalanine (L-DOPA).4 Protein-containing foods such as
meat and dairy products are good natural sources of both tyrosine and tryptophan.
Both 5-HTP and tyrosine are available in the United States as dietary supplements.
These agents are utilized as natural supplements to augment brain levels of either serotonin
Neuropsychiatric Disease and Treatment 2009:5 227–235
227
© 2009 Trachte et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.
Trachte et al
or dopamine. This study investigates the effects of 5-HTP
and tyrosine ingestion on urinary excretion of serotonin and
dopamine in a large sample of humans ingesting 5-HTP and
tyrosine. Curiously, the urinary excretion of these compounds
after ingestion of 5-HTP or tyrosine has only been reported in
human trials involving very small patient cohorts and the results
involve anomalous responses.5–7 Therefore, this study was
designed to critically test the hypothesis that increased ingestion
of 5-HTP or tyrosine elevates urinary excretion of serotonin
and dopamine, respectively. The purpose of the study was to
determine if urinary excretion of serotonin or dopamine reflect
the adequacy of supplementation with 5 HTP or tyrosine.
Methodology
The study included 824 individuals ingesting 5-HTP, tyrosine,
both 5-HTP and tyrosine, or neither. Multiple urine samples
were obtained from all of these individuals and most received
multiple doses of supplements to enable comparisons
between doses of supplements and urinary excretion of
mature neurotransmitters, as well as the relationship between
changes in doses and changes in urinary neurotransmitter excretion. The primary rationale for using the dietary
supplements was weight loss although a significant number of
patients were treated for diseases other than obesity that were
caused by, or associated with, serotonin and/or dopamine
dysfunction. The participants resided throughout the United
States. The dose range for 5-HTP ranged from 0 to 2700 mg
per day. Tyrosine was taken in doses of 0 to 17,000 mg per
day. The supplements were taken in divided doses two, three,
or four times a day depending on the dosing of amino acid
precursors administered.
Urine samples were collected six hours prior to bedtime
with 4:00 PM being the most frequent collection time point. The
samples were obtained in 6 N HCl to preserve dopamine and
serotonin. The urine samples were collected after a minimum
of one week at a specific dose of the precursor being consumed.
Samples were shipped to DBS Laboratories (Duluth, MN,
USA) under the direction of one of the authors (Dr Thomas
Uncini, a hospital-based dual board certified laboratory pathologist). Urinary dopamine and serotonin were assayed utilizing
commercially available radioimmunoassay kits (3 CAT RIA
IB88501 and IB89527; Immuno Biological Laboratories, Inc.,
Minneapolis, MN, USA). The DBS Laboratories are accredited as a high complexity laboratory by Clinical Laboratory
Improvement Amendments (CLIA) to perform these assays.
Statistical evaluations utilized either two-way ANOVA
to compare dose-response curves or regression analyses to
establish correlations between precursor doses and urinary
228
excretion of serotonin and dopamine. We also correlated
changes in precursor doses with changes in urinary neurotransmitter levels. These regression analyses were conducted to determine if a statistically definable relationship
existed between dose of precursor and excretion of the
resulting neurotransmitter. Comparison of mean values
was performed using Student’s t test. Data are presented as
individual data points or as means ± SE. A p value ⱕ 0.05
was considered statistically significant. JMP (SAS Institute,
Cary, NC, USA) software was used to perform the statistical
analysis.
Data were evaluated further by subdividing responses
into the following: 1) those representing inverse relationships
between dietary supplement intake and urinary excretion
of neurotransmitter, deemed phase 1; 2) those exhibiting
no relationship between dietary supplement intake and
neurotransmitter excretion, deemed phase 2; and 3) those
exhibiting a direct relationship between dietary supplement
consumption and neurotransmitter excretion in the urine
(phase 3). These groups were identified by dividing alterations in neurotransmitter excretion by alterations in supplement dose to obtain the slope of the relationship. Phases 1,
2, and 3 had negative, 0, and positive slopes, respectively.
These curves were compared by two-way ANOVA. They
also were compared with daily fluctuations in urinary neurotransmitter efflux in the absence of supplement ingestion
(ie, phase 0). This analysis was performed to determine if the
alterations in serotonin or dopamine excretion in phases 1,
2, or 3 could be accounted for by circadian rhythms and/or
daily fluctuations in neurotransmitter excretion resulting from
stress or other factors. The latter comparison involved the
Students t test comparing the absolute value of deviations
in neurotransmitter excretion in all groups. The conversion
to absolute values was necessary because samples contained
both positive and negative alterations in neurotransmitter
excretion that conformed to the appropriate response for a
specific phase. For instance, a reduction in precursor dose in
phase 3 resulted in a reduction in neurotransmitter excretion.
Although the change in neurotransmitter excretion was negative in this example, it represented the appropriate directional
change for samples in phase 3.
This study was exempt from Institutional Review Board
review at the University of Minnesota because it was a retrospective study of deidentified data.
Results
The dose response to 5-HTP on urinary serotonin excretion is
shown in Figure 1. The correlation between 5 HTP doses and
Neuropsychiatric Disease and Treatment 2009:5
Both stimulatory and inhibitory effects of dietary 5-hydroxytryptophan
urinary sertotonin excretion was not statistically significant
(r = 0.040; p = 0.09). All of these individuals also were
consuming tyrosine, therefore we sought an interaction with
tyrosine as well, but there was none (p = 0.50). Surprisingly,
the data from these experiments indicate only a marginal
relationship between administration of a serotonin precursor
and urinary excretion of serotonin.
We then sought a more convincing relationship by analyzing the effect of 5-HTP dosing alterations on changes
in urinary serotonin excretion in individual patients. These
experiments were conceived to ascertain whether individuals exhibited dramatically different basal levels of urinary
serotonin excretion but consistently responded to changes in
precursor administration with increased excretion of the serotonin. Figure 2 depicts a statistically significant relationship
between changes in 5-HTP administration and alterations in
urinary efflux of serotonin (p ⬍ 0.0001; r = 0.145). These
data indicate a relationship between ingested 5-HTP and
urinary serotonin excretion, but this effect remains modest
based on the regression coefficient.
Further examination of the data in Figure 2 indicated
that, of the 1671 individual data points, 390 demonstrated
an inverse relationship between changes in urinary serotonin
excretion and 5-HTP administration, 375 showed virtually no
change in urinary serotonin excretion (ie, an alteration of less
than 2000 μg/g creatinine) after altering the 5-HTP dose and
860 experienced the anticipated direct relationship between
changes in urinary serotonin excretion and 5-HTP dose.
Furthermore, 46 samples represented the random variation
in urinary serotonin excretion when no 5-HTP or tyrosine
dosing occurred. Thus the relationship between alterations
in 5-HTP dose and urinary serotonin excretion demonstrated
in Figure 2 appears to derive from three distinct responses
being summed in the data presented. The average value of
each of these three different responses, plus the random daily
fluctuation in the absence of precursors, is shown in Figure 3.
The results in the absence of any alteration in 5-HTP dose
(ie, normal circadian rhythms or other disturbances) are
compared to those representing the three different responses
when 5-HTP dosing was varied. This comparison was necessary to determine if there is a de facto statistical difference
between the different patterns of responses and whether the
responses are distinctly different than random fluctuations in
serotonin excretion. The data are presented as absolute values
of changes in serotonin excretion because the magnitude
of the change in serotonin excretion is the critical variable.
1,000,000
Urinary 5-HT (μg/g Creatinine)
y = 15161 + 5.7629x R = 0.04
N = 1671
800,000
600,000
400,000
200,000
0
0
1000
2000
3000
5-HTP (mg/day)
Figure 1 Relationship between 5-hydroxytryptophan (5-HTP) dose and urinary serotonin (5-HT) excretion.All data represent individual values from patients providing multiple
samples over time. N represents the total number of samples and the regression coefficient was not statistically significant (p = 0.09).
229
Trachte et al
Change in urinary 5-HT (μg/g Creatinine)
1,000,000
y = – 907 + 31.09 (² 5-HTP) R = 0.15
N = 1671
500,000
0
–500,000
–1,000,000
–2000
–1000
0
1000
2000
Change in 5-HTP dose (mg/day)
Absolute change in urinary 5-HT (μg/g Creatinine)
Figure 2 Relationship between change in 5-hydroxytryptophan (5-HTP) dose and change in urinary serotonin (5-HT) excretion. All values are individual points obtained
from patients providing multiple samples over time. A statistically significant relationship was identified by linear regression (p ⬍ 0.0001). The equation describing the linear
regression is provided in the figure.
***
40,000
***
30,000
20,000
10,000
0
46
390
***
860
0
1
2
3
Phase
Figure 3 Absolute change in serotonin (5-HT) excretion when responses are segregated by change in urinary serotonin excretion as follows: no 5-hydroxytryptophan (5-HTP)
dose (phase 0); inverse responses of urinary serotonin excretion to changes in 5-HTP (phase 1); no change in urinary serotonin excretion in response to changes in 5-HTP
dose (phase 2); and direct correlation between changes in urinary serotonin excretion and changes in 5-HTP dose (phase 3). All values are means + SE. Values in both phases 1
and 3 were greater than phases 0 (random fluctuation) or 2 (***p ⬍ 0.0001). Phase 2 responses were less than phase 0 (***p ⬍ 0.001) and the N was 375.
230
As shown in Figure 3, both phase 1 (inverse correlation
between altered 5-HTP dosing and serotonin excretion) and
phase 3 (direct correlation between altered 5-HTP dosing and
serotonin excretion) had much larger, statistically significant
variations in comparison to the values representing random
fluctuation of serotonin excretion (indicated as phase 0)
(p ⬍ 0.0001 both phases). Phase 2 responses (ie, indicative
of virtually no change in serotonin excretion in response to
a change in 5-HTP administration) also were statistically
different from either phases 0, 1, or 3 (p ⬍ 0.0001).
The dose-response curves for 5-HTP vs. urinary
serotonin excretion for the three phases are shown in Figure
4. The 5-HTP suppressed urinary serotonin excretion in the
phase 1 samples and augmented excretion in the phase 3
samples. The phase 0 and phase 2 samples had extremely
low urinary serotonin levels and the concentrations did not
fluctuate in response to alterations in 5-HTP dosing. Phase 2
values were significantly lower than urinary serotonin levels
in either phase 1 or phase 3 samples (p ⬍ 0.0001) and
the slopes of the curves for phases 1, 2, and 3 differed
significantly (p ⱕ 0.0022). Urinary serotonin excretion in
the absence of 5-HTP dosing was statistically higher in the
phase 1 samples than any of the other groups. This finding
is consistent with the phase 1 group demonstrating large
declines in urinary serotonin levels in response to increased
administration of 5-HTP. The stimulatory effect of 5-HTP
Phase 1 (390)
Phase 2 (375)
Phase 3 (860)
50,000
Urinary 5-HT (μg/g Creatinine)
observed in phase 3 samples occurred primarily in the dose
range of 150 to 900 mg 5-HTP. A maximal effect appeared
to be achieved at the 900 mg 5-HTP dose and no further
increment in urinary serotonin concentrations was observed
at higher 5-HTP doses.
Tyrosine ingestion produced a scenario starkly different from the 5-HTP data. Tyrosine consistently produced
a paradoxical effect to reduce urinary dopamine excretion.
The effect of tyrosine is shown in Figure 5. The inhibitory
effect of tyrosine was statistically significant and yielded a
concentration-dependent effect based on linear regression
analysis (p ⬍ 0.0001, R = 0.086).
As with the relationship between 5-HTP consumption and
serotonin excretion, the tyrosine effect on urinary dopamine
excretion represented a summation of responses exhibiting
one of the following: an inverse correlation; no effect; or a
direct correlation. These data are shown in Figure 6. Consistent with the data shown in Figure 5, the fluctuations in
dopamine excretion were smaller in samples obtained from
patients ingesting incrementally greater amounts of tyrosine; and this difference for the combined phases 1, 2, and 3
reached a high level of statistical significance (p ⬍ 0.0001)
when compared to phase 0 samples. The fluctuations in the
phase 2 samples were less than any other phase (p ⱕ 0.005).
The levels in phase 1 and 3 samples were not statistically
different from levels in phase 0 samples (p = 0.09 for both).
40,000
30,000
***
20,000
***
10,000
0
0
500
1000
1500
5-HTP (mg/day)
Figure 4 Influence of 5-hydroxytryptophan (5-HTP) dose on urinary excretion of serotonin (5-HT). All values are means ± SE. The number of samples in each phase is
indicated in parentheses. The slopes of the curves differed statistically for phases 1, 2, and 3 (p = 0.0022). Urinary serotonin levels for both phases 1 and 3 were significantly
greater than phase 2 by analyses of variance (***p ⬍ 0.0001), but did not differ from each other.
231
Trachte et al
4000
Urinary dopamine (μg/g Creatinine)
y = 249.56 – 0.0047 (Tyr) R = 0.12
N = 2154
3000
2000
1000
0
0
5000
10000
15000
20000
Tyrosine (mg/day)
Figure 5 Effect of tyrosine on urinary dopamine excretion. All values are individual data points from patients ingesting tyrosine. Tyrosine significantly suppressed urinary
dopamine excretion, resulting in a statistically significant regression (p ⬍ 0.0001).
These data add support to the surprising observation that
tyrosine ingestion suppresses urinary dopamine excretion.
The relationship between tyrosine doses and urinary
dopamine excretion in the three response phases is shown
in Figure 7. These data were presented as mean data with
standard errors for clarity necessitated by substantial overlap
of raw data points. Phase 1 responses were characterized by
decreasing excretion of dopamine as tyrosine doses increased.
The slope of this curve was negative and statistically different from the curves representing phases 2 or 3 (p ⬍ 0.0001).
Phase 2 and 3 did not exhibit statistically discernable slopes
(p = 0.32), but the urinary dopamine levels were statistically
greater in phase 3 samples (p = 0.0007).
Discussion
The data presented in this study indicate that consumption
of specific dietary precursors of serotonin or dopamine only
increases the urinary excretion of these neurotransmitters
approximately 50% of the time. Probably the most surprising
finding of this study is that 20% to 40% of these same individuals respond to the precursors with an unexpected reduction
in excretion of the neurotransmitters, particularly dopamine.
These observations indicate that the simplistic expectation
that increased ingestion of neurotransmitter precursors will
increase excretion of the mature neurotransmitters in the urine
232
is frequently not observed. In fact, the prominent response to
tyrosine was a suppression of dopamine excretion.
The uncoupling of neurotransmitter excretion from the
ingestion of precursors for the neurotransmitter is most likely
caused by the degradation of blood-borne neurotransmitter
in the kidney.8,9 Most of the serotonin or dopamine found
in the urine is synthesized in the kidney.9–12 Therefore, the
excreted neurotransmitters must be synthesized in the kidneys
and escape reabsorption into the blood in order to be excreted
in the urine. Most of the serotonin formed by the kidneys is
typically catabolized2 or reabsorbed and not excreted in the
urine.8,11,13 Alternatively, dopamine synthesized in the kidney
is secreted across the apical surface into the urine14 probably
by an organic cation transporter9,15 resulting in greater urinary
than interstitial dopamine concentrations.12,13 Larger doses
of tyrosine and 5-HTP have been observed to increase both
urinary dopamine and serotonin excretion.16–18 The array
of catabolic and reabsorptive events probably accounts for
the far more complex responses than expected to 5-HTP or
tyrosine ingestion observed in this study.
In spite of the complex sequence of renal events accounting for the appearance of neurotransmitter in urine, the presence of opposing responses (ie, phases 1 and 3) does not seem
possible without a direct effect of either the precursors or the
formed neurotransmitters to cause an aberration in the series
Absolute change in urinary dopamine (µg/g Creatinine)
300
200
100
0
46
874
**
0
1
2
1047
3
Phase
Figure 6 The average change in urinary dopamine excretion from baseline in the different phases including random fluctuation of dopamine excretion (phase 0). All values
are means + SE with the number of samples per group indicated except for phase 2 (N = 187). The fluctuation in phase 2 was significantly less than daily fluctuations in the
control (phase 0) group, as well as phases 1 and 3 (p ⬍ 0.001).
of events leading to the presence of urinary neurotransmitters.
Based on a large volume of studies in the literature, it is
likely that administration of 5-HTP increases the synthesis
of serotonin within the kidney.2,3,8 Transporters for serotonin
then transfer it into the blood stream to prevent it from being
excreted in the urine. The phase 1 response we observed for
serotonin could be explained by either a neurotransmitterinduced allosteric alteration of a reabsorptive transporter
to increase activity or an induction of the synthesis of the
transporter. Increased transport of the neurotransmitters out
of the region of the nephron would theoretically reduce urinary excretion of the neurotransmitter, as observed in phase
1. If the alteration or induction were great enough, essentially
all of the neurotransmitter would be reabsorbed and little
or none would appear in the urine, as observed in phase 2.
A conversion to phase 3 would be possible if the supply of
neurotransmitter eventually increased enough to saturate the
transport process and result in spillage of neurotransmitter
into the urine. All three phases have been observed in the
same individual and the three phases could represent different
stages of renal processing of 5-HTP. We currently have no
evidence explaining the different phases and the potential for
increased activity or induction of neurotransmitter transporters merely appears to be the most likely possibility explaining
these observations at this point in time.
The response to tyrosine was dominated by suppressed
urinary dopamine excretion. This scenario probably necessitates either an inhibition of dopamine secretion into the
nephron lumen or a reduction in renal dopamine synthesis.
Two reports indicate that newly synthesized dopamine is
normally secreted into the nephron,12,13 thus an inhibition
of this secretion could account for the inhibitory effect. It
is likely that tyrosine could interfere with the secretion of
dopamine into the lumen of the nephron but we are unaware
of any reports supporting this site of action.
Tyrosine appears to be an unlikely inhibitor of renal
dopamine synthesis because it is widely recognized as a
dopamine precursor. However, tyrosine suppresses L-DOPA
uptake into proximal tubule cells14,19 and L-DOPA uptake
is required for renal dopamine synthesis.20 L-DOPA is the
immediate precursor to dopamine in the synthetic pathway;
therefore, inhibition of its uptake could impair dopamine
synthesis. Proximal tubule cells accumulate tyrosine14 but
the kidney lacks extraneuronal tyrosine hydroxylase1,21,22 and
cannot convert it to dopamine. Thus, tyrosine could have a
paradoxical inhibition of dopamine synthesis in the kidney
by suppressing L-DOPA uptake into proximal tubule cells.
This scenario represents a potential mechanism accounting
for phase 1 responses to tyrosine. An alternative scenario
potentially accounting for phase 3 responses to tyrosine
233
Trachte et al
Urinary dopamine (µg/g creatinine)
900
800
700
Phase 1 (520)
Phase 2 (117)
Phase 3 (638)
600
500
400
300
200
***
100
0
0
5000
10000
15000
Tyrosine (mg/day)
Figure 7 The relationship between tyrosine administration and urinary dopamine excretion for the different phases of dopamine excretion.The number of samples per group
is indicated in parentheses. All values are means ± SE. The slope for phase 1 differed significantly from slopes for phases 2 or 3 (***p ⬍ 0.0001).
involves the peripheral conversion of tyrosine to L-DOPA
in neuronal tissue. The L-DOPA entering the kidney could
serve as a precursor to dopamine and result in increased
dopamine secretion observed in phase 3. The observation
of the inhibitory (ie, phase 1) response to tyrosine has not
been reported previously. A plethora of reports indicate that
phase 3 stimulatory effects of tyrosine on urinary dopamine
excretion is the predominant response in most studies in
rats4,22,23 and protein has been widely used as a tyrosine
source to increase dopamine excretion in humans.24 It is
possible that the phase 1 response to tyrosine in humans has
not been noted previously because of the limited number of
studies specifically investigating tyrosine effects on human
dopamine excretion.
The novel observations noted in this study include a
somewhat variable relationship between ingested 5-HTP and
urinary serotonin excretion and the unexpected inf luence
of tyrosine to reduce urinary dopamine excretion. The
description of the three phases demonstrating the relationship between 5-HTP and urinary serotonin excretion is also
novel and probably is a reflection of serotonin reabsorption
in the kidney. The consistent and statistically discernable
ability of tyrosine to dampen fluctuations in urinary dopamine excretion is also noteworthy. These processes might be
234
ref lective of similar processes occurring in other organs and
suggest that urine sampling for neurotransmitters requires
multiple samples to determine the direction of the response
and, potentially, the adequacy of dosing.
Disclosure
The authors report no conflicts of interest in this work.
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1986;78:1687–1693.
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O r i g i nal R e s e a r c h
The dual-gate lumen model of renal
monoamine transport
This article was published in the following Dove Press journal:
2 July 2010
Number of times this article has been viewed
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
Clinics, Inc. Cape Coral,
Florida, USA; 2Stein Orthopedic
Associates, Plantation, Florida, USA;
3
DBS Labs, Duluth, Minnesota, USA
1
Abstract: The three-phase response of urinary serotonin and dopamine in subjects
simultaneously taking amino acid precursors of serotonin and dopamine has been defined.1,2
No model exists regarding the renal etiology of the three-phase response. This writing outlines
a model explaining the origin of the three-phase response of urinary serotonin and dopamine.
A “dual-gate lumen transporter model” for the basolateral monoamine transporters of the kidneys
is proposed as being the etiology of the three-phase urinary serotonin and dopamine responses.
Purpose: The purpose of this writing is to document the internal renal function model that
has evolved in research during large-scale assay with phase interpretation of urinary serotonin
and dopamine.
Patients and methods: In excess of 75,000 urinary monoamine assays from more than
7,500 patients were analyzed. The serotonin and the dopamine phase were determined for
specimens submitted in the competitive inhibition state. The phase determination findings were
then correlated with peer-reviewed literature.
Results: The correlation between the three-phase response of urinary serotonin and dopamine
with internal renal processes of the bilateral monoamine transporter and the apical monoamine
transporter of the proximal convoluted renal tubule cells is defined.
Conclusion: The phase of urinary serotonin and dopamine is dependent on the status of the
serotonin gate, dopamine gate, and lumen of the basolateral monoamine transporter while in
the competitive inhibition state.
Keywords: serotonin, dopamine, basolateral, apical, kidney, proximal
Introduction
Correspondence: Marty Hinz
1008 Dolphin Dr., Cape Coral,
Florida 33904
Tel +1 218 310 0730
Fax +1 218 626 1638
submit your manuscript | www.dovepress.com
Dovepress
11704
The first step in development of the model was validation of peer-reviewed literature.
Scientific knowledge of the monoamines (serotonin, dopamine, norepinephrine, and
epinephrine) has grown significantly since 1990. Along with this growth in knowledge,
some of the science originally thought to be correct has been discredited. In contrast
to earlier writings it is now known that monoamines do not cross the blood-brain
barrier. Monoamines are not simply filtered at the glomerulous then excreted into the
urine. Urinary monoamine levels are not a direct assay of the peripheral or central
nervous system monoamine levels. Interpretation of urinary monoamine assays is more
complex than simply determining if urinary serotonin and dopamine levels found on
assay are high or low. Under normal conditions, significant amounts of serotonin and
dopamine filtered at the glomerulous do not make it to the final urine. Serotonin and
dopamine (herein referred to as “monoamines”) found in the final urine are newly
synthesized in the kidneys.1,2
© 2010 Hinz et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
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Hinz et al
The monoamines and their amino acid precursors are
filtered at the glomerulous then enter the proximal tubules
of the kidneys. They are transported by organic cation
transporters out of the proximal tubules into the proximal
convoluted renal tubule cells. The monoamines filtered at
the glomerulous are metabolized in the proximal convoluted
renal tubule cells. Very little of these monoamines filtered
at the glomerulous are found in the final urine of normal
subjects. Monoamine amino acid precursors filtered at the
glomerulous are synthesized in the proximal convoluted renal
tubule cells into new monoamines, which are then detected
in the final urine.2
Serotonin and dopamine exist in two states: the “endogenous
state” found when no additional amino acid precursors are
being administered, and the “competitive inhibition state”
found when the amino acid precursors of both serotonin and
dopamine are being administered.3
Prior to discussing the dual-gate lumen model, the following discussion of the three-phase urinary response is put
forth based on previous peer reviewed literature.2
Literature notes: “Urinary monoamine neurotransmitter
testing prior to initiation of serotonin and dopamine amino
acid precursors is of no value. There is no correlation between
PHASE 2
PHASE 3
Urinary neurotransmitter levels
PHASE 1
baseline testing and urinary neurotransmitter phases once the
patient is taking amino acid precursors. It is not necessary
or even useful to measure baseline urinary neurotransmitters
in treatment”.2,4
Urinary monoamine neurotransmitters are neurotransmitters that are synthesized by the kidneys and excreted
into the urine or secreted into the system via the renal
veins.1,2,5 With simultaneous administration of serotonin and
dopamine amino acid precursors, three phases of urinary
neurotransmitter response have been identified on laboratory assay of the urine (Figures 1 and 2). The three phases
of response apply to both serotonin and dopamine. In all
the life forms tested that have kidneys along with serotonin
and catecholamine systems, the three phases of urinary
neurotransmitter response exist.40 In reviewing the literature,
it would appear that the three phases of urinary response
to neurotransmitters were present in previous writings but
were not identified as such. For example, a 1999 article
notes that administration of L-dopa can increase urinary
dopamine levels (phase 3) and decrease urinary serotonin
levels (phase 1).2,6
To determine the phase of serotonin and dopamine with
certainty requires two urinary monoamine neurotransmitter
Increasing the daily balanced amino acid dosing
Figure 1 The three phases of urinary neurotransmitter excretion in response to amino acid dosing. The horizontal axis is not labeled with specific amounts; it reflects
the general trend seen in the population. Amino acid dosing needs are highly individualized. The dosing level needed to inflect into the next level varies greatly throughout
the general population. For example, some patients inflect into phase 3 on 37.5 mg of 5-HTP per day, while others need as high as 3,000 mg per day (source: DBS
Labs database).
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The dual-gate lumen model
Proximal
convoluted renal
tubule cell of the
kidneys
Urine
Proximal
convoluted renal
tubule cell of the
kidneys
System Urine
Phase 1 Response
Proximal
convoluted renal
tubule cell of the
kidneys
System
Phase 2 Response
Urine
System
Phase 3 Response
Figure 2 The three phases of urinary response to amino acid dosing (Two urinary neurotransmitter tests are required to determine the phase with certainty). PHASE 1: In
phase 1, as the amino acid dosing increases or decreases the urinary serotonin or dopamine decreases or increases respectively. In phase 1, there is inappropriate excretion
of neurotransmitters into the urine instead of the system where they are needed. PHASE 2: In phase 2, as the amino acid dosing increases or decreases the urinary serotonin
or dopamine is low (,80 µg/g creatinine for serotonin or ,300 µg/g creatinine for dopamine). In phase 2, there is no inappropriate excretion of neurotransmitters into the
urine. The neurotransmitters are being excreted appropriately into the system and the urine. PHASE 3: In phase 3, as the amino acid dosing increases or decreases the urinary
serotonin or dopamine increases or decreases respectively. In phase 3, there are adequate systemic serotonin and dopamine levels. The excess serotonin and dopamine are
appropriately excreted into the urine.
assays to be performed with the subject simultaneously
taking a different amino acid dosing of dopamine and/or
serotonin amino acid precursors on each test and comparing
the results.1,2
In phase 1, monoamine neurotransmitters synthesized
by the kidneys are excreted into the urine instead of being
secreted into the system via the renal vein where they
are needed (Figures 1 and 2). Increasing the amino acid
dose in phase 1 will correct the problem of urinary monoamine excretion into the urine at the expense of secretion into
the system. The amino acid precursor dosing of serotonin and
dopamine, where the individual patient is in phase 1 varies
widely in the population. The level at which the urinary serotonin is no longer in phase 1 ranges from 37.5 mg of 5-HTP
per day to 3,000 mg of 5-HTP per day. The level at which
the urinary dopamine is no longer in phase 1 ranges from no
L-dopa (with the use of L-tyrosine only in some subjects) to
540 mg of L-dopa per day in the subjects not under treatment
for Parkinsonism or Restless Leg Syndrome.1,2
By increasing the amino acid dosing of serotonin and
dopamine precursors above the dosing of phase 1, the phase
2 response is observed (Figures 1 and 2). In phase 2, urinary
monoamine levels are low (,475 micrograms dopamine
per gram of creatinine or ,80 micrograms serotonin per
gram of creatinine, the neurotransmitter – creatinine ratio
compensates for dilution of the urine), and the inappropriate excretion of neurotransmitters into the urine has ceased.
When in phase 2, serotonin and/or dopamine is being primarily secreted into the system and not excreted into the
urine. The model used to explain phase 2 is, “inappropriate
excretion of neurotransmitters has now ceased as the amino
acid precursor dosing is increased and systemic levels are
not increasing appropriately.”1,2
As serotonin and dopamine amino acid precursors are
increased above the phase 1 and the phase 2 levels, all subjects enter the phase 3 response (Figures 1 and 2). Further
increases in the amino acid dosing lead to increases in urinary
dopamine and serotonin neurotransmitter levels if they are
in phase 3. Phase 3 represents appropriate secretion into the
system and appropriate excretion of excess neurotransmitters
synthesized by the kidneys into the urine.1,2
Material and methods
Prior to this writing there has been no peer-reviewed publication setting forth an internal renal model to explain the
etiology of the three-phase response of urinary serotonin
and dopamine. This model is based on analysis of in excess
of 75,000 monoamine assays (serotonin, dopamine, norepinephrine, and epinephrine) from more than 7,500 human
subjects with samples obtained either in the endogenous state
or the competitive inhibition state under conditions covered
in previous writings on the three-phase response.1,2 The urinary phase of serotonin and dopamine was determined for
assay samples obtained in the competitive inhibition state.
Knowledge gained through large-scale phase interpretation
in correlation with peer-reviewed renal literature is the basis
for the model.
Urine samples were collected 6 hours prior to bedtime
with 4:00 PM being the most frequent collection time point.
The samples were obtained in 6 N HCl to preserve dopamine
and serotonin. The urine samples were collected after a
minimum of one week at a specific dose of the precursor
being consumed. Samples were shipped to DBS Laboratories
(Duluth, MN, USA) under the direction of one of the authors
(Dr T Uncini, hospital-based dual board certified laboratory
pathologist). Urinary dopamine and serotonin were assayed
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Hinz et al
utilizing commercially available radioimmunoassay kits
(3 CAT RIA IB88501 and IB89527, both from Immuno
Biological Laboratories, Inc., Minneapolis, MN, USA). The
DBS laboratory is accredited as a high complexity laboratory
by CLIA to perform these assays.
Results
When in the three-phase response, the two systems become
completely intertwined to the point that changes in one system will affect not just that system but the other system as
well.2 With administration of the dopamine precursor L-dopa
and the serotonin precursor 5-HTP there is no biochemical
feedback regulation in the synthesis of dopamine and/or serotonin, respectively. There is a direct proportion between the
amount of L-dopa and 5-HTP administered and the amount
of dopamine and serotonin synthesized.1,2
The three-phase response occurs only in the competitive
inhibition state. It is the response of the newly synthesized
renal serotonin and dopamine found in the urine to the
manipulation of serotonin and/or dopamine amino acid
precursor dosing. With each simultaneous urinary assay of
serotonin and dopamine in the competitive inhibition state,
a three-phase model for serotonin and dopamine must be
independently conceptualized. Serotonin and dopamine may
be in any one of the three phases simultaneously, with one
exception. Urinary serotonin and dopamine are never found
in phase 1 simultaneously.1,2
In Figure 1, increasing or decreasing one or both amino
acid precursors of serotonin or dopamine in the competitive
inhibition state allows for determination of the urinary phase
of both serotonin and dopamine.1,2
The following renal model is the basis for conceptualization of the dual-gate lumen model. While numerous transport
and cell wall crossing mechanisms exit in the proximal convoluted renal tubule cells, primary transport out of the proximal convoluted renal tubule cells for the newly synthesized
serotonin and dopamine is via the organic cation transporters
(OCT). Newly synthesized serotonin and dopamine exit the
proximal convoluted renal tubule cells primarily by one of
two routes. They are either transported across the basolateral
membrane via the basolateral transporter (an OCT transporter) or transported across the apical membrane via the
apical transporter (an OCT transporter).7,8 For the purpose of
this model, the basolateral membrane transporter (OCT) is
deemed as being dominant. Newly synthesized serotonin and
dopamine, not transported across the dominant basolateral
membrane, are transported out of the proximal convoluted
renal tubule cells by the apical transporters and detected
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in the final urine as waste. In reviewing urinary assays of
serotonin and dopamine in the competitive inhibition state,
the interpreter is viewing monoamines not transported by
the basolateral monoamine transporters (organic cation
transporters). While numerous other renal functions and
interactions have been described, these forces are viewed
as minor to insignificant in comparison to the dominating
force of the basolateral and apical transport on the newly
synthesized monoamines.
Discussion
Models of organic cation transporters of serotonin and dopamine have been defined in the past. One such model was
the “gate-lumen-gate model”.9–13 The gate-lumen-gate model
and other models do not explain the phenomenon observed
under the three-phase urinary response when both serotonin
and dopamine are in the competitive inhibition state.
It is purposed that the basolateral monoamine transporter is a “dual-gate lumen transporter” (Figure 3). The
transporter has a serotonin gate and a dopamine gate at
the transporter entrance, which function independently of
each other.
Primary forces affecting transport through the basolateral
monoamine transporter and the apical monoamine transporter
are the status of the basolateral monoamine transporter serotonin and dopamine gates, and lumen saturation. The serotonin
and dopamine gates at the entrance of the basolateral monoamine transporters can be either partially closed (impeding
transporter lumen access by the monoamines) or open (with
no impedance). The status of the basolateral monoamine
transporter lumen is either saturated or not saturated.
Correlations of the three-phase model and dual-gate lumen
model considerations are as follows. In phase 1 the monoamine gate is partially closed impeding access to the transporter
lumen. In phase 2 and phase 3 the monoamine gate is open
giving full access of the monoamine to the transporter lumen.
In phase 1 and phase 2 basolateral monoamine transport
through the lumen is not saturated. In phase 3 the basolateral
monoamine transport through the lumen is saturated. Opening and closing of a gate is not solely dependent on changes
in associated monoamine levels. The opening and closing of
the gates is dependent on the total amount of serotonin and
dopamine presenting at the transporter.
In the competitive inhibition state, a serotonin gate or a
dopamine gate in phase 1 (partially closed) can be opened
or closed by adding or subtracting the total amount of amino
acid precursors administered. This causes an increase or
decrease in the total amount of serotonin and dopamine
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The dual-gate lumen model
Dopamine
phase 2 or 3 at
the transporter.
Competitive
inhibition in
place
Gate open
To the
urine
OCT gate-lumen
regulation
Basolateral
monoamine
transporter
lumen
Serotonin
phase I at the
transporter. Gate
regulation in
place
To the
urine
Gate partially closed
Figure 3 The dual-gate lumen model. The basolateral monoamine transporters contain three key components: a serotonin gate, a dopamine gate, and a lumen.
presenting at the transporter. As the gate opens, more
monoamine has access to the transporter and is transported,
causing a drop in the amount of monoamine transported by
the apical transporter and found in the final urine.
In phase 2 the gate is open with full access to the transporter by monoamine. The transporter effectively transports
most of the monoamine through the lumen leading to a very
small amount of monoamine being transported by the apical
transporter and found in the final urine.
In phase 3 the gate is open and the transporter is saturated.
Increases or decreases in the total amount of the monoamine presenting at the transporter will lead to an increase or
decrease in the amount of monoamine found in the final urine.
When both serotonin and dopamine are in phase 3, increasing
the amino acid precursor dosing of one monoamine will cause
increased transport of the associated monoamine at both
the basolateral and apical transporters. Due to competitive
inhibition, transport of the other monoamine will decrease
at the basolateral transporter and increase at the apical transporter. Administration of one amino acid precursor with both
s erotonin and dopamine in phase 3 leads to an increase in
apical transport of both monoamines with associated increase
of urinary levels of both on assay.
Conclusion
Assay of the urinary monoamines, serotonin and dopamine,
in the competitive inhibition state is an assay of the newly
synthesized serotonin and dopamine of the kidneys not
transported by the basolateral monoamine transport. The
two primary forces affecting transport across the basolateral
membrane and responsible for the three-phase response are
the status of the basolateral monoamine transporter gates
and the saturation of the lumen. Proper assay interpretation
in the competitive inhibition state is a determination of
the states of serotonin and dopamine phases relative to the
basolateral monoamine transporter status. It is not the intent
of this writing to explore all known aspects of the basolateral monoamine transporter, apical monoamine transporter
properties, or renal properties in the context of the threephase response. The model presented here is intended to
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be used as a foundation and reference point for continuing
discussion, further studies, refinement of the model, and
future investigation of renal and urinary serotonin and
dopamine response to amino acid manipulation in the
competitive inhibition state.
Acknowledgment/disclosure
Marty Hinz and Thomas Uncini are owner and medical director of DBS Labs Duluth, Minnesota. Alvin Stein reports no
disclosure.
References
1. Trachte G, Uncini T, Hinz M. Both stimulatory and inhibitory effects of
dietary 5-hydroxytryptophan and tyrosine are found on urinary excretion
of serotonin and dopamine in a large human population. Neuropsychiatr
Dis Treat. 2009;5:228–235.
2. Hinz M. Depression. In: Kohlstadt I, editor. Food and Nutrients in
Disease Management. CRC Press; 2009;465–481.
3. Soares-da-Silva P, Pinto-do-O PC. Antagonistic actions of renal
dopamine and 5-hydroxytryptamine: effects of amine precursors
on the cell inward transfer and decarboxylation. Br J Pharmacol.
1996;117(6):1187–1192.
4. DBS Labs neurotransmitter data base, Tom Uncini, MD hospital base
dual board certified laboratory pathologist, medical director 8723 Falcon
St Duluth, MN 55808.
5. Ball SG, Gunn IG, Douglas IH. Renal handling of dopa, dopamine,
norepinephrine, and epinephrine in the dog. Am J Physiol. 1982;
242(1):F56–F62.
6. Garcia NH, Berndt TJ, Tyce GM, Knox FG. Chronic oral L-DOPA
increases dopamine and decreases serotonin excretions. Am J Physiol.
1999;277(5 Pt 2):R1476–R1480.
7. Wang Y, Berndt TJ, Gross JM, Peterson MA, So MJ, Knox FG. Effect
of inhibition of MAO and COMT on intrarenal dopamine and serotonin and on renal function. Am J Physiol Regul Integr Comp Physiol.
2001;280(1):R248–R254.
8. Vieira-Coelhe M, Soares-Da-Silva P. Apical and basal uptake of L-dopa
and L-5-HTP and their corresponding amines, dopamine and 5-HT,
in OK cells. Institute of Pharmacology and Therapeutics, Faculty of
Medicine, 4200 Porto, Portugal.
9. Schmitt B, Koepsell H. Alkali cation binding and permeation in the
rat organic cation transporter rOCT2. J Biol Chem. 2005;280(26):
24481–24490.
10. Lester H, Cao Y, Mager S. Listening to neurotransmitter transporters.
Neuron. 1996;17(5):979–990.
11. Sole M, Madapallimattam A, Baines A. An active pathway for serotonin
synthesis by renal proximal tubules. Kidney Int. 1986;29(3):689–694.
12. Cao Y, Mager M, Lester H. Amino acid residues that control pH
modulation of transport-associated current in mammalian serotonin
transporters. J Neurosci. 1998;18(19):7739–7749.
13. Pietig G, Mehrens T, Hirsch J, Etinkaya I, Piechota H, Schlatter E.
Properties and regulation of organic cation transport in freshly isolated
human proximal tubules. J Biol Chem. 2001;276(36):33741–33746.
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Open Access Journal of Urology
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O r i g i n al R e s e a r c h
Neurotransmitter testing of the urine:
a comprehensive analysis
6 October 2010
Marty Hinz 1
Alvin Stein 2
George Trachte 3
Thomas Uncini 4
Clinics, Inc., Cape Coral, FL, USA;
2
Stein Orthopedic Associates,
Plantation, FL, USA; 3Department
of Physiology and Pharmacology,
University of Minnesota Medical
School, MN, USA; 4DBS Labs, Duluth,
MI, USA
1
Abstract: This paper analyzes the statistical correlation of urinary serotonin and dopamine
data in subjects not suffering from monoamine-secreting tumors such as pheochromocytoma or
carcinoid syndrome. Peer-reviewed literature and statistical analyses were searched and monoamine (serotonin and dopamine) assays defined in order to facilitate their proper interpretation.
Many research findings in the literature are novel. Baseline assays completed with no monoamine
precursors differ from baseline assays performed on a different day in the same subject. There
is currently no scientific basis, value, or predictability in obtaining baseline monoamine assays.
Urinary assays performed while taking precursors can demonstrate a lack of correlation or
unexpected correlations such as inverse relationships. The only valid model for interpretation
of urinary monoamine assays is the “three-phase model” which leads to predictability between
monoamine assays and precursor administration in varied amounts.
Purpose: This paper reviews the basic science of urinary monoamine assays. Results of statistical
analysis correlating baseline and nonbaseline assays are reported and provide valid methods for
interpretation of urinary serotonin and dopamine results.
Patients and methods: Key scientific claims promoting the validity of the urinary neurotransmitter testing (UNT) model applications are discussed. Many of these claims were not supported
by the scientific literature. Matched-pairs t-tests were performed on several groupings. Results
of all statistical tests were compared with peer-reviewed literature.
Results: The statistical analysis failed to support the UNT model. Peer-reviewed literature
search failed to verify scientific clams made in support of applications of the UNT model in
many cases.
Keywords: serotonin, dopamine, urinary neurotransmitter testing
Introduction
1008 Dolphin Dr, Cape Coral,
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
Dovepress
DOI: 10.2147/OAJU.S13370
Three applications have evolved with regard to urinary monoamine assays. The first is
one of the older applications used in medicine. This is the use of monoamine assays for
screening and diagnosing tumors that secrete serotonin or dopamine (herein referred to
as the “tumor model”), such as pheochromocytoma (a catecholamine-secreting tumor)
and carcinoid syndrome (a serotonin-secreting tumor).1,2 The validity of this type of
monoamine testing application is well established in the scientific literature.
The second application is the use of monoamine assays for renal organic cation
transporter functional status determination (ie, the OCT model). Even though this
model is relatively new, having been developed in 2003, this approach and the urinary
serotonin and urinary dopamine applications developed according to this model are
Open Access Journal of Urology 2010:2 177–183
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Hinz et al
supported by the scientific literature, having been discussed
and documented in several articles since February 2009.3–5
The basis for the OCT model requires two or more serial
urinary serotonin and dopamine (ie, monoamine) assays
while taking varied amino acid precursor daily dosing
amounts. The results are then compared in order to determine the change in urinary serotonin and dopamine levels
in response to changes in dosing. A urinary serotonin or
dopamine value less than 80 or 475 µg of monoamine per
g of creatinine, respectively, indicates a Phase II response.
A urinary serotonin or dopamine value greater than 80 or
475 µg of monoamine per g of creatinine, respectively, is
interpreted as being in Phase I or Phase III. Differentiation
of Phase I from Phase III is as follows. If a direct correlation is found between amino acid dosing and urinary assay
response, it is referred to as a Phase III response. An inverse
correlation is referred to as a Phase I response.3–5 Unexpected results with matched-pairs t-test analysis revealed no
significant difference when comparing baseline monoamine
assays with assays performed while taking supplemental
amino acid precursors in the same subject.
Peer-reviewed scientific publications discussing urinary
serotonin and urinary dopamine phase analysis according
to the OCT model were first published in 20093,4 and 2010.5
These publications outlined the mechanics of the three-phase
model in connection with urinary serotonin and urinary dopamine under a novel renal transporter model. This transporter
model potentially describes the etiology of the three-phase
response of monoamine assays during the administration of
varied amino acid precursor daily dosing values.12
The third approach defining applications for the use of
monoamine assays is the urinary neurotransmitter testing
(UNT) model. This paper discusses the UNT model in depth
because it is the only model of the three that lacks valid
scientific literature discussing the model or supporting the
monoamine assay applications that are being promoted.
The goal of this writing is to assess monoamine assay
applications statistically and define the validity of monoamine assays in the absence or presence of supplemental
amino acid precursors. The premise of the UNT model is
that baseline monoamine assays correlate with and are a
good predictor of the peripheral and central nervous system
neurotransmitter functional status. The basic assumption
for this assertion is that serotonin and dopamine cross the
blood–brain barrier6–8 and are then filtered at the glomerulus and enter the urine without further interaction with the
kidneys.6,8 This argument is used on the basis of the UNT
model to justify the conclusion that monoamine assays, in
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the presence and absence of serotonin and dopamine amino
acid precursors, correlate with central nervous system and
peripheral neurotransmitter functional status. It also asserts
that baseline testing is the best approach to determine the
neurotransmitter functional status of the central and peripheral nervous systems.7,8,10
Other conclusions made in support of utilizing monoamine assays under the urinary neurotransmitter testing model
are as follows:
• Administration of amino acid precursors directly impacts
urinary monoamine levels; therefore, the results of monoamine assays merely need to be interpreted as being either
high or low values8,9,11
• Baseline testing of urinary monoamines prior to starting
supplemental amino acid precursors is required in order
to define the amino acid precursor starting dose needed
in treatment8–11
• Baseline monoamine assays in the absence of supplemental amino acid precursors are required to diagnose
and define the serotonin and dopamine imbalance in the
central and peripheral nervous systems6,10
• Baseline monoamine assays can serve as a reference
point to gauge treatment effectiveness after amino acid
precursors are started6,11
• Baseline monoamine assays can be used to reduce the
risk of side effects when amino acid precursor treatment
is started.10
Materials and methods
Statistical analysis was performed for each analyzed
grouping considered. The statistical analysis involved the
matched-pairs t-test. After initiation of supplemental amino
acid precursor administration or a change in daily dosing
levels was maintained constant, a minimum period of seven
days without missing one or more doses was required for
data to be considered valid. This time period allows the
amino acid precursors and the urinary monoamines to
achieve equilibrium in order to ensure that valid urinary
serotonin and urinary dopamine test results are obtained.
A P value #0.05 was considered statistically significant.
JMP software (SAS Institute, Cary, NC) was used to perform
the statistical analysis.
Processing, management, and assay of the urine
samples collected for this study were as follows. Urine
samples were collected six hours prior to bedtime, with
4 pm being the most frequent collection time point. The
samples were stabilized in 6 N HCl to preserve urinary
dopamine and urinary serotonin. The urine samples were
Open Access Journal of Urology 2010:2
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collected after a minimum of one week, during which time
the patient was taking a specific daily dose of amino acid
precursors of serotonin and dopamine. Samples were shipped
to DBS Laboratories. Urinary dopamine and serotonin were
assayed utilizing commercially available radioimmunoassay
kits (3 CAT RIA IB88501 and IB89527; Immuno Biological
Laboratories, Inc., Minneapolis, MN). The DBS laboratory is
accredited as a high complexity laboratory by Clinical Laboratory Improvement Amendments to perform these assays.
Results
Two approaches to analyze the validity of the UNT model
were undertaken. The first approach was a literature search
intended to test claims made in support of applications for
monoamine assays under the UNT model. After an exhaustive
search, no indepth valid peer-reviewed studies were found
documenting the UNT model. In most cases, the claims justifying use of urinary serotonin and urinary dopamine assays
according to the UNT model were contrary to the identified
scientific literature. The second approach was the statistical
analysis of baseline monoamine assays in the presence or
absence of supplemental amino acid precursors in order to
assess the UNT model critically.
Five significant divergences from the UNT model from
the existing scientific literature were identified. Specifically,
divergences were noted from the established science, ie, serotonin and dopamine do not cross the blood–brain barrier3,5,12,13
and peripheral serotonin and dopamine are filtered at the
glomerulus and then enter the proximal tubules.5 They are
then actively transported into the proximal convoluted renal
tubule cells where they are essentially completely metabolized.5 Due to the high efficiency of this metabolic process,
significant amounts of serotonin and dopamine filtered at the
glomerulus do not reach the urine in patients not suffering
from a tumor secreting serotonin or dopamine.3,5 From a
practical standpoint, urinary serotonin and urinary dopamine
represent serotonin and dopamine that have not previously
been in the central or peripheral nervous system.3,5 The literature notes that urinary serotonin and urinary dopamine
are monoamines that are newly synthesized from serotonin
and dopamine amino acid precursors by the kidneys in the
proximal convoluted renal tubule cells.3,5 These newly synthesized serotonin and dopamine molecules are then either
transported out of the proximal convoluted renal tubule cells
across the basolateral membrane and then into the peripheral
system via the renal vein or across the apical membrane
and then into the urine.3–5,14,15 It is noted that there are many
other renal interactions that exist between synthesis of
Neurotransmitter testing of the urine
serotonin and dopamine transported across the basolateral
membrane and the apical membrane prior to arriving at
the final destination of the renal vein or urine, respectively.
These interactions appear small in comparison with the
effects of the basolateral monoamine transporter and the
apical monoamine transporter under the three-phase model.5
There is also no correlation between urinary serotonin and
dopamine levels and the serotonin or dopamine levels within
the central and peripheral nervous systems.3–5 The renal
interaction of urinary serotonin, urinary dopamine, and their
amino acid precursors is counterintuitive. It is expected that
when serotonin and/or dopamine amino acid precursors are
administered, levels of the associated urinary serotonin or
urinary dopamine will increase or decrease with increases or
decreases in the amino acid precursor daily dosing levels, ie,
a direct relationship. The literature reveals that this is not the
predominant response. Outcomes are not intuitive because
the process is complex, and there is no simple, dominant,
direct relationship between serotonin and dopamine amino
acid dosing and monoamine assays. Instead, a complex
interaction is found, giving rise to the three-phase model,
as we have previously proposed.3–5 Furthermore, there is no
significant statistical difference between baseline monoamine
levels in the urine and those resulting from administration
of monoamine precursors. Given that support for this is not
found in the literature, the following statistical analysis is
put forth. The data for the following analysis was obtained
from the DBS Laboratories monoamine assay database. The
database was assembled according to the criteria discussed
in the Materials and methods section.
By definition, the laboratory baseline reference range for a
given assay is calculated by taking all baseline data generated for
that assay, then defining the group of values that are within two
SDs from the mean. This grouping size represents approximately
95% of the initial group data generated. In the following reports
of statistical analysis, when use of the reference range values
is referred to, the following values were used. A laboratory
promoting the UNT model has defined the urinary serotonin
reference range as 150–300 µg of serotonin per g of creatinine.
The same laboratory defined the urinary dopamine reference
range as 150–300 µg of dopamine per g of creatinine.9
Urinary serotonin at baseline versus
while taking 5-hydroxytryptophan
Matched-pairs groupings were queried from the database as
follows. Two urinary serotonin samples from the same subject were obtained, one sample while taking no supplemental
amino acid precursors and the other sample while taking
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Hinz et al
5-hydroxytryptophan (5-HTP), and these were match-paired
together. A group of these matched-pairs samples were then
defined for analysis, revealing a group of n = 167. The serotonin reference range values as reported above were used to
query the baseline urinary matched-pairs serotonin group
of n = 167 further, revealing a group of n = 103. The group
taking 5-HTP was then queried from the group of n = 103
using the parameter 5-HTP , 301 mg per day, to give a final
matched-pairs group of n = 78 for analysis.
The final matched-pairs group was then analyzed using a
t-test, and a P value of 0.0809 was found, indicating lack of
a significant statistical difference between baseline urinary
serotonin levels and serotonin levels when taking less than
301 mg of 5-HTP per day.
Urinary dopamine at baseline versus
while taking levodopa
Matched-pairs groups were queried from the database as
follows. Two samples from each subject, one sample taking
no supplemental amino acid precursors and the other sample
taking levodopa, were paired together. This revealed a group
of n = 617. The baseline assay portion of the entire matchedpairs group was queried with the dopamine reference range
values reported earlier, to give a population size of n = 230.
The group taking levodopa was then queried to find only
subjects taking less than 361 mg of levodopa per day, leading to a final population size of n = 166. This matched-pairs
group was then analyzed using a matched-pairs t-test, and
a P value of 0.0742 was found, indicating no significant
statistical difference between baseline dopamine assays and
dopamine assays performed while taking less then 361 mg
of levodopa per day.
Baseline serotonin assays from different
days in the same subject
Data were analyzed in the following manner, with the following numbers reported in µg of serotonin per g of creatinine. From a matched-pairs group of n = 146, the mean
(SD) for both baseline serotonin urinary assay groups was
determined. For Group 1, the mean serotonin value was
found to be 239.0 (±2282.8). For Group 2 (baseline testing performed on a different day after the first assay) the
mean serotonin value was found to be 273.2 (±8214.51). All
data greater than the value found in calculating the sum of
two SDs plus the mean were removed from consideration,
revealing a group of n = 134. The matched-pairs grouping was then analyzed using the matched-pairs t-test. The
baseline urinary serotonin assay grouping analysis revealed
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a P value of 0.0080. These findings indicate that baseline
urinary levels do differ in a statistically significant manner
when baseline assays are performed on different days for
the same subject and are not uniform or reproducible from
day to day.
Baseline dopamine assays from different
days in the same subject
Data were analyzed in the following manner, with numbers reported in µg of dopamine per g of creatinine. From
a matched-pairs group of n = 146, the mean SD for both
baseline serotonin urinary assay groups was determined. For
Group 1, the mean dopamine value was found to be 144.0
(±286.9). For Group 2 (baseline testing performed on a different day after the first assay), the mean dopamine value was
found to be 198.6 (±484.8). All data greater than the value
found in calculating the sum of two SD plus the mean were
removed from consideration, revealing a group of n = 138.
The matched-pairs grouping was then analyzed using the
matched-pairs t-test. The baseline urinary serotonin assay
grouping analysis revealed a P value of 0.0049. These findings indicate that baseline urinary dopamine levels do differ
in a statistically significant manner when baseline assays are
performed on different days in the same subject, and are not
uniform or reproducible from day to day.
Discussion
The focus of this research is the applications of urinary serotonin and dopamine assays, whereby three distinctly different
application models of monoamine assays are being promoted.
The basis of the tumor model is screening for a monoaminesecreting tumor. This methodology is well founded. The
OCT model is a relatively new application of monoamine
assays, but its validity is supported by the literature.3–5 The
third application model for monoamine assays, the urinary
neurotransmitter testing model, has no indepth, valid, peerreviewed scientific literature to support its use. The UNT
model distinguishes itself from the two other approaches
by requiring use of baseline urinary monoamine assays, and
advocates a direct relationship between urinary serotonin and
urinary dopamine when the serotonin and dopamine amino
acid precursor daily dosing levels are varied. The following
is a consolidation of the findings and scientific concepts
discussed in this paper with the claims and approach for use
of monoamine assay applications under the UNT model.
Significant challenges to the urinary neurotransmitter
testing model include the widely recognized finding that serotonin and dopamine do not cross the blood–brain barrier.16–19
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In support of applications for urinary serotonin and urinary
dopamine assays, the UNT model claims that serotonin and
dopamine do cross the blood–brain barrier.6–8 This assertion
is widely known to be untrue.16–19
No significant amount of serotonin and dopamine filtered
at the glomerulus reaches the urine. Serotonin and dopamine
found in the urine are newly synthesized in the kidneys, and
their levels are a function of the interaction between the
basolateral monoamine transporters and the apical monoamine transporters of the proximal convoluted renal tubule
cells.19 The UNT model claims that serotonin and dopamine
are merely filtered at the glomerulus, and then enter the urine
without further renal interactions.6 This assertion is not supported by review of the relevant science.
Urinary serotonin and urinary dopamine found in the
urine have no correlation with brain or peripheral serotonin
and dopamine levels. Significant levels of urinary serotonin
and urinary dopamine molecules assayed in the urine have
never been shown in the brain or peripheral nervous system.3,5
The UNT model, based on assertions that serotonin and
dopamine cross the blood–brain barrier and are then simply
filtered at the glomerulus and enter the urine, claims that
urinary monoamine assays represent the functional neurotransmitter status of the central nervous system, peripheral
nervous system, and urine.1 This assertion again is not supported by the relevant science.
There is no consistent direct relationship between serotonin and dopamine amino acid precursor daily dosing levels
and the amount of serotonin and dopamine that appears
in the urine on monoamine assays.3–5 The peer-reviewed
literature notes that there is no relationship between administration of the serotonin precursor, 5-HTP, in varied doses
and subsequent urinary serotonin levels.4 The literature also
notes that there is a correlation between administration of
L-tyrosine and urinary dopamine levels, but this is an inverse
relationship,4 and not the direct relationship predicted by
the UNT model.6,7 The UNT model advocates that there is a
dominant direct correlation between amino acid doses and
urinary serotonin and urinary dopamine found on assay.6,7
This leads to the assertion under the UNT model that simply
determining whether the urinary serotonin and urinary dopamine levels found on assay are high or low is the focal point
of proper monoamine assay interpretation.6,7 This assertion
is not supported on review of the science involved.
Statistical analysis of baseline monoamine assays reveals
that these assays do not predict the response to precursor
therapy. They differ significantly with subsequent baseline
assays undertaken on different days from the same subject,
and no significant difference exists with assays performed
when amino acid precursors are taken. These findings are
contrary to the assertions of the UNT model.6–8,11
The UNT model claims that baseline monoamine assays
obtained prior to ingestion of supplemental amino acid precursors can identify neurotransmitter imbalance in the central
nervous system, peripheral nervous system, and urine.6–8 Due
to the statistical difference in baseline monoamine assays in
the same subject from day to day, an unlimited number of
different neurotransmitter imbalances might theoretically
be diagnosed with serial assays performed on many different days from the same subject. There is a statistical
difference between baseline urinary serotonin and urinary
dopamine assays in subjects not harboring a monoaminesecreting tumor. The assertion that baseline monoamine
assays can diagnose central nervous system, peripheral
nervous system, and urinary neurotransmitter dysfunction is
not supported on review of the scientific literature.
The UNT model also claims that baseline assays of
urinary serotonin and urinary dopamine are required prior to
starting serotonin and/or dopamine amino acid precursors to
assist in selecting the optimal daily serotonin and dopamine
amino acid precursor doses.8–10 Using any laboratory criteria to
diagnose serotonin and dopamine imbalance prior to selecting
the starting point of amino acid dosing gives results that differ
statistically from day to day and are not reproducible. The assertion on the part of the UNT model that baseline monoamine
assays are needed to determine a starting point for serotonin and
dopamine amino acid precursor treatment is not supported.
The UNT model claims that baseline assays are required
to minimize side effects when treatment with amino acid
precursors is started. The results of baseline assays obtained
from the same subject on different days vary statistically,
and are not reproducible relative to the first baseline assay
obtained. The ability to minimize side effects claimed on
the basis of the UNT model is not supported by the reported
science.
The UNT model incorrectly asserts that baseline monoamine assays can serve as a reference point during treatment
to gauge effectiveness of treatment when serotonin and dopamine amino acid precursors are started.8,10 As noted already,
there is a significant statistical difference between values
found with baseline monoamine assays and baseline assays
performed on a different day in the same subject, leading to
a host of different reference points being generated when
baseline assays are obtained on multiple days. The baseline
assays cannot be used as a reference point to measure treatment progress or indicate results of treatment.
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Hinz et al
The only valid correlation that exists between monoamine
assays performed with and without administration of amino
acid precursors in subjects not suffering from a monoaminesecreting tumor is the three-phase model described in the
literature. When the three-phase model is applied correctly
to urinary serotonin and urinary dopamine assay results,
it leads to a predictable course of outcomes with urinary
serotonin and urinary dopamine assay interpretation. The
three-phase model is based on the interaction between the
newly synthesized serotonin and dopamine by the kidneys
with the basolateral monoamine (serotonin and dopamine)
transporters and the apical monoamine (serotonin and dopamine) transporters of the proximal convoluted renal tubule
cells of the kidneys, leading to the serotonin and dopamine
that is found in the urine on assay.3–5
Conclusion
The application and interpretation of baseline monoamine
assays according to the urinary neurotransmitter testing
model is not a valid approach because there is a significant
statistical difference between baseline monoamine assays
and monoamine assays obtained on a different day from
the same subject and no significant statistical difference in
subsequent monoamine assays performed while taking amino
acid precursors. The UNT model has no ability to diagnose
central or peripheral nervous system serotonin and dopamine
imbalance using baseline monoamine assays in subjects
not suffering from monoamine-secreting tumors. Urinary
serotonin and urinary dopamine assays are not assays of
serotonin and dopamine that have been in the central nervous
system. Serotonin and dopamine do not cross the blood–brain
barrier. Significant amounts of urinary serotonin and urinary
dopamine found on assay have not been in the brain or in the
peripheral system. Urinary serotonin and urinary dopamine
are filtered at the glomerulus and are then metabolized in
the kidneys, with no significant amounts of serotonin or
dopamine filtered at the glomerulus being found in the urine.
Levels of urinary serotonin and urinary dopamine found on
assay are newly synthesized in the kidneys, and are a function
of the interaction between the basolateral monoamine transporters and apical monoamine transporters of the proximal
convoluted renal tubule cells.
A simple direct relationship between the daily dosing
levels of amino acid precursors and monoamine assays does
not exist in most cases. Due to complex renal physiologic
interactions between serotonin and dopamine newly synthesized by the kidneys, a complex relationship is observed that
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is defined by the three-phase model described in the already
published peer-reviewed literature.
The goal of this paper is to spark interest, research, awareness, and scrutiny of the topics discussed. A laboratory assay
is only valid if properly interpreted. Correct interpretation
of monoamine assays while taking amino acid precursors is
complex, and not a direct linear relationship as predicted by
the UNT model.
Disclosure
TU and MH are director and owner of DBS Laboratories,
Duluth, Minnesota respectively. AS and GT have no conflicts
of interest to report in this work.
References
1. Oates JA, Sjoerdsma A. A unique syndrome associated with secretion
of 5-hydroxytryptophan by metastatic gastric carcinoids. Am J Med.
1962;32:333–342.
2. Szakacs JE, Cannon AL. Noreprinephrine myocarditis. Am J Clin Pathol.
1958;30:425–434.
Disease Management. CRC Press; 2009.
Dis Treat. 2009;5:227–235.
5. Hinz M, Stein A, Uncini T. The dual gate lumen model of renal monoamine transport. Neuropsychiatr Dis Treat. 2010;6:387–392.
6. Alts J, Alts D, Bull M. Urinary Neurotransmitter Testing: Myths and
Misconceptions. Osceola, WI: NeuroScience, Inc.; 2007.
7. Watkins R. Validity of urinary neurotransmitter testing with clinical applications of CSM (Communication System Management)
model. Asheville, NC: Sanesco International; 2009. Available at:
http://www.neurolaboratory.net/lab/neurolab%20pdf%20files/2009%20
Urinary%20NT%20White%20Paper.pdf. Accessed 2010 Aug 4.
8. Theirl S. Clinical relevance of neurotransmitter testing. The Original
Internist. Dec 2009. Available at: http://www.clintpublication.com/
documents/Dec_OI_2009.pdf. Accessed 2010 Aug 4.
9. Sanesco. Neurolab baseline sample repor t. Available at:
http://sanesco.net/images/files/resourcelibrary/baseline_sample_report.
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https://www.neurorelief.com/index.php?option=com_content&task=view&
id=131&Itemid=48. Accessed 2010 Jul 2.
11. Kellermann G, Bull M, Ailts J, et al. Understanding diurnal variation.
Technical Bulletin Issue 4. Osceola, WI: NeuroScience, Inc.; 2004: Jan 9.
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ntent&task=view&id=224&Itemid=48. Accessed 2010 Jul 2.
12. Carley C, Radulovacki M. Role of peripheral serotonin in the regulation
of central sleep apneas in rats. Chest. 1999;115:1397–1401.
13. Volkow N, Fowler JS, Gatley J, et al. PET evaluation of the
dopamine system of the human brain. J Nucl Med. 1996;37:
1242–1256.
14. Wang Y, Berndt T, Gross T, Peterson M, So M, Know F. Effect of
inhibition of MAO and COMT on intrarenal dopamine and serotonin
and on renal function. Am J Physiol Regul Integr Comp Physiol.
2001;280:R248–R254.
15. Vieira-Coelho MA, Soares-Da-Silva P. Apical and basal uptake of
L-dopa and L-5-HTP and their corresponding amines, dopamine and
5-HT, in OK cells. Am J Physiol. 1997;272(5 Pt 2):F632–F639.
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16. Pyle AC, Argyropoulos SV, Nutt DJ. The role of serotonin in panic:
Evidence from tryptophan depletion studies. Acta Neuropsychiatr.
2004;16:79–84.
17. Verde G, Oppizzi G, Colussi G, et al. Effect of dopamine infusion on
plasma levels of growth hormone in normal subjects and in agromegalic
patients. Clin Endocrinol (Oxf). 1976;5:419–423.
18. Gozzi A, Ceolin L, Schwarz A, et al. A multimodality investigation of
cerebral hemodynamics and autoregulation in pharmacological MRI.
Magn Reson Imaging. 2007;25:826–833.
19. Ziegler MG, Aung M, Kennedy B. Sources of human urinary epinephrine. Kidney Int. 1997;51:324–327.
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Return to index
A pilot study differentiating recurrent major
depression from bipolar disorder cycling
on the depressive pole
8 November 2010
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
2
Plantation, FL, USA; 3DBS Labs,
Duluth, MN, USA
1
Clinical Research, Neuro
Research Clinics, Inc., 1008 Dolphin
Drive, Cape Coral, FL 33904, USA
Tel +1 218 310 0730
Fax +1 218 626 1638
Dovepress
DOI: 10.2147/NDT.S14353
Purpose: A novel method for differentiating and treating bipolar disorder cycling on the depressive pole from patients who are suffering a major depressive episode is explored in this work.
To confirm the diagnosis of type 1 or type 2 bipolar disorder, the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) criteria require that at least one manic or hypomanic
episode be identified. History of one or more manic or hypomanic episodes may be impossible
to obtain, representing a potential blind spot in the DSM-IV diagnostic criteria. Many bipolar
patients who cycle primarily on the depressive side for many years carry a misdiagnosis of
recurrent major depression, leading to treatment with antidepressants that achieve little or
no relief of symptoms. This article discusses a novel approach for diagnosing and treating
patients with bipolar disorder cycling on the depressive pole versus patients with recurrent
major depression.
Patients and methods: Patients involved in this study were formally diagnosed with recurrent
major depression under DSM-IV criteria and had no medical history of mania or hypomania to
support the diagnosis of bipolar disorder. All patients had suffered multiple depression treatment
failures in the past, when evaluated under DSM-IV guidelines, secondary to administration of
antidepressant drugs and/or serotonin with dopamine amino acid precursors.
Results: This study contained 1600 patients who were diagnosed with recurrent major depression under the DSM-IV criteria. All patients had no medical history of mania or hypomania. All
patients experienced no relief of depression symptoms on level 3 amino acid dosing values of
the amino acid precursor dosing protocol. Of 1600 patients studied, 117 (7.3%) nonresponder
patients were identified who experienced no relief of depression symptoms when the serotonin
and dopamine amino acid precursor dosing values were adjusted to establish urinary serotonin
and urinary dopamine levels in the Phase III therapeutic ranges. All of the 117 nonresponders
who achieved no relief of depression symptoms were continued on this amino acid dosing
value, and a mood-stabilizing drug was started. At this point, complete relief of depression
symptoms, under evaluation with DSM-IV criteria, was noted in 114 patients within 1–5 days.
With further dose adjustment of the mood-stabilizing drug, the remaining three nonresponders
achieved relief of depression symptoms.
Conclusion: Resolution of depression symptoms with the addition of a mood-stabilizing drug
in combination with proper levels of serotonin and dopamine amino acid precursors was the
basis for a clinical diagnosis of bipolar disorder cycling on the depressive pole.
Keywords: depression, bipolar, serotonin, dopamine, mania, hypomania
Introduction
In order to make the diagnosis of type 1 or type 2 bipolar disorder under Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV) guidelines, the patient’s medical
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Hinz et al
h istory must include one or more manic or hypomanic
episodes, respectively.1 The history of mania or hypomania
may be obscure or nonexistent. For example, the bipolar
patient may be cycling heavily on the depressive pole with
the last manic or hypomanic episode having occurred many
years ago. This episode may have lasted for only 2 weeks,
during which time neither the patient nor others around the
patient ever appreciated its presence. This obscured medical
history represents a potential blind spot in the DSM-IV criteria for diagnosing bipolar disorder cycling on the depressive
pole. It is not uncommon in patients with bipolar disorder
cycling on the depressive pole, while looking for relief of
depression symptoms, to get caught in a seemingly endless
cycle of shopping for health care providers. These physicians may have prescribed most or all of the antidepressants
medically available for treatment without getting complete
relief of depression symptoms. This potential blind spot in
the DSM-IV criteria leads to a misdiagnosis of recurrent
major depression.
The novel approach described in this writing requires the
administration of serotonin and dopamine amino acid precursors with cofactors to reach the Phase III therapeutic ranges
(herein referred to as the target ranges) as guided by the use
of urinary serotonin and urinary dopamine organic cation
transporter (OCT) functional status determination (herein
referred to as ‘OCT assay interpretation’).2–5
The basis for the OCT assay interpretation model requires
two or more serial urinary serotonin and dopamine assays
while taking varied amino acid precursor daily dosing values.
Results of two or more assays are then compared in order
to determine the change in urinary serotonin and dopamine
levels in response to the change in dosing. A urinary serotonin or dopamine value ,80 or 475 µg of monoamine per
gram of creatinine, respectively, indicates Phase II responses.
A urinary serotonin or dopamine value .80 or 475 µg of
monoamine per gram of creatinine, respectively, is interpreted
as being in Phase I or Phase III. Differentiation of Phase I
from phase III is a follows. If a direct correlation is found
between amino acid dosing and urinary assay response, it
is referred to as a Phase III response. An inverse correlation
is referred to as a Phase I response. The Phase III therapeutic
range for urinary serotonin is defined as 80–240 µg of
serotonin per gram of creatinine. The Phase III therapeutic
range for urinary dopamine is defined as 475–1100 µg of
dopamine per gram of creatinine.2–5
Peer-reviewed scientific publications discussing urinary
serotonin and urinary dopamine phase analysis under the
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OCT model were published in 20092,4 and 2010.3,5 These
publications outlined the mechanisms of the ‘three-phase
model’ in connection with urinary serotonin and urinary dopamine under a novel renal transporter model. This transporter
model potentially describes the etiology of the ‘three-phase
response’ in monoamine assays during the administration of
varied amino acid precursor daily dosing values.3 Urinary
serotonin and dopamine levels are primarily dependent upon
the interaction of the basolateral monoamine transporters
with the apical monoamine transporters of the proximal
convoluted renal tubule cells of the kidneys.3
Most notable with this novel approach is the ability to
differentiate patients with bipolar disorder cycling on the
depressive pole from patients suffering from recurrent major
depression, and then implement effective treatment.
Processing, management, and assay of the urine samples
collected for this study were as follows. Urine samples were
collected 6 h prior to bedtime with 4:00 PM being the most
frequent collection time point. The samples were stabilized in
6 N HCl to preserve urinary dopamine and urinary serotonin.
The urine samples were collected after a minimum of 1 week
during which the patient was taking a specific daily dosing
of amino acid precursors of serotonin and dopamine where
no doses were missed. Samples were shipped to DBS Laboratories (Duluth, MN), which is operated under the direction
of one of the authors (Thomas Uncini, MD, hospital-based
pathologist, dual board certified in laboratory medicine and
forensic pathology). Urinary dopamine and serotonin were
kits (3 CAT RIA IB88501 and IB89527; Immuno Biological
Laboratories, Inc., Minneapolis, MN). The DBS laboratory
is accredited as a high complexity laboratory by Clinical
Laboratory Improvement Amendments to perform these
assays.3,6
The protocol
The protocol for treatment of depression consisted of the
amino acid dosing values found in Table 1. This protocol was
covered in previous peer-reviewed literature.2
The initial step of the protocol was the administration
of serotonin and dopamine amino acid precursors with no
OCT assay interpretation. Three dosing levels were available
as noted in Table 1. At the first visit, patients were started on
level 1 amino acid dosing. Patients were then seen weekly
for follow-up clinic visits.
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Differentiating recurrent major depression from bipolar disorder cycling on the depressive pole
Milligrams 5-HTP/Milligrams L-Tyrosine
AM
NOON
4 PM
7 PM
150/1,500
-----
150/1,500
-----
Level 1
300/1,000
300/1,000
----300/1,000
Level 2
Level 3
150/1,500
150/1,500
150/1,500
150/1,500
Table 1 Amino acid precursor dosing protocol. Subjects also received the following daily dosing values of cofactors: 1) 1000 mg vitamin C, 2) 220 mg calcium citrate, 3) 75
mg vitamin B6, and 4) 400 µg folate. Copyright © 2009, CRC Press. Adapted with permission from Hinz M. Depression. In: Kohlstadt I, editor. Food and Nutrients in Disease
Management. Boca Raton, FL: CRC Press; 2009:465–481.
The question to be answered in evaluating patients after
1 week of taking a specific amino acid dosing value was
‘What was the status of the depression symptoms yesterday?’
Since it takes up to 5 days for the maximum benefit of an
amino acid dosing change to be seen, secondary to equilibration of the amino acids, results from the day before the visit
were found to be more reliable than inquiring about the status
of depression symptom for the entire week.
Since the maximum benefit of any dosing change occurs
within 5 days, there is no purpose in waiting longer than 1 week
to see if an amino acid dosing change achieved additional relief
of symptoms. This only increases the amount of time needed to
find the proper dose leading to resolution of the symptoms.7
If there was no relief of depression symptoms at the
weekly visit, the amino acid dosing was adjusted upward
to the next dosing level (level 2 or level 3). The goal was
to obtain relief of depression symptoms or reach level 3
amino acid dosing with no relief of symptoms, whichever
occurred first.2
At the initial visit, all prescription drugs were continued.
Prescription antidepressant drugs were continued until full
relief of depression symptoms was obtained, and then tapered
to a stop, at the option of the caregiver. It was noted that
drugs may require being stopped sooner if drug side effects
emerge. As neurotransmitter levels increase with amino acid
precursor administration, drug side effects may occur in ∼5%
of patients. The emergence of drug side effects may be a
source of confusion for the caregiver. Since the last thing
changed in the patient’s treatment plan was the amino acid
dosing, there is a tendency to focus on the amino acids as the
source of side effects that were actually due to prescription
drug toxic side effects.
Failure to achieve relief of depression symptoms, on
evaluation with DSM-IV guidelines, after 1 week of taking
level 3 amino acid dosing of Table 1 was the indication for
initiation of OCT assay interpretation studies to guide further
amino acid precursor dosing value changes.
Subsequent to the interpretation of each urine sample
collected, the amino acid dosing was adjusted in response
to OCT assay interpretation findings. This was focused on
achieving both the urinary serotonin and dopamine in the
Phase III therapeutic ranges (the target ranges). The end
point of collecting samples for OCT assay interpretation
was whichever came first of the following: i) resolution of
depression symptoms, ii) obtaining both the urinary serotonin
and dopamine in the target ranges, or iii) the patient dropping
out of treatment.
If no relief of depression symptoms was observed with
the urinary serotonin and dopamine in the target ranges,
the amino acids were continued at that dosing value
and a mood-stabilizing drug was added. The choice of
mood-stabilizing drug was either lithium carbonate 300 mg
twice a day or divalprex sodium 250 mg 3 times a day at the
caregiver’s discretion.
l-Dopa and l-tyrosine have an ability to deplete sulfur
amino acids. Based on previous experience and peerreviewed literature, l-cysteine was added to the serotonin
and dopamine amino acid precursors in the amounts
of 4500 mg/day in adults in divided doses.2 Selenium
400 mcg/day was administered with the l-cysteine to address
concerns raised in the literature regarding l-cysteine facilitating neurotoxic insult by methylmercury.8 Other literature
notes that selenium irreversibly binds to methylmercury
rendering it nontoxic.9
Results
Patients selected had been formally diagnosed with depression under DSM-IV criteria and carried no previous diagnosis
or medical history supporting bipolar disorder.
The group studied consisted of 1600 patients diagnosed
with recurrent major depression who failed to respond to
treatment with amino acid precursors at the level 3 dosing
(outlined in Table 1) on evaluation under DSM-IV guidelines.
These 1600 patients had urine samples collected, and OCT
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assay interpretation was performed with amino acid dosing
adjustments focused on achieving urinary serotonin and
dopamine in the target ranges.
The status of depression symptoms was evaluated with
the DSM-IV criteria at each visit. Of the 1600 patients
starting the OCT assay interpretation, the following three
groupings of patients ultimately were defined: i) patients
who achieved relief of symptoms in response to amino
acid precursor dosing value adjustment guided by OCT
assay interpretation, ii) patients who achieved no relief of
symptoms with the amino acid precursor dosing required
for achieving urinary serotonin and dopamine in the target
ranges, and iii) patients who dropped out of treatment.
Patients achieving relief of symptoms with amino acid
dose adjustment and patients dropping out were not tracked
in this study. The goal of the study was to define a group of
patients who were nonresponders with urinary serotonin and
dopamine in the target ranges. Of the initial starting group
of N = 1600, a group of N = 117 (7.3%) was determined to
be nonresponders.
Demographics of the 117 nonresponders were as follows. There were 73 females in the nonresponder group
(62.4%). There were 44 males in the nonresponder group
(37.6%). The age range for the entire nonresponder group was
18.3–82.9 with a mean age of 55.2 and a standard deviation
of 13.2 years. The age range for the female nonresponder
group (N = 73) was 18.3–75.3 with a mean of 53.8 and a
standard deviation of 11.9 years. The age range for the male
nonresponder group (N = 44) was 25.0–82.9 with a mean of
55.2 and a standard deviation of 13.2 years.
Nonresponders were continued on the amino acid
dosing values needed to achieve the target ranges and a
mood-stabilizing drug was started. The choice and dose of
the mood-stabilizing drugs were lithium carbonate 300 mg
twice a day or divalprex sodium 250 mg 3 times a day, at the
caregiver’s discretion.
Of the 117 patients started on a mood-stabilizing drug
in combination with the amino acid dosing needed to establish the target ranges, 114 achieved full relief of depression
symptoms within 1–5 days of starting the drug. Of the
three patients who did not respond when the initial dose of
the mood-stabilizing drug was added, further adjustment
of the mood-stabilizing drug was guided by serum assays
of the drug levels with the goal of establishing lithium or
valproic acid serum levels in the therapeutic range. During the
process of serum-guided adjustment of the mood-stabilizing
drug, relief of depression symptoms was obtained in the
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final three patients. A positive response to adding the moodstabilizing drug to the amino acid dosing of the target ranges
was the basis for a clinical diagnosis of bipolar disorder
cycling on the depressive pole. The type was considered undifferentiated since no history of mania or hypomania existed.
The conclusion was that 100% of patients in whom a
mood-stabilizing drug was administered in conjunction with
amino acid precursors were clinically diagnosed with bipolar
disorder cycling on the depressive pole, while experiencing
complete relief of depression symptoms. A significant point
is the dramatic response of these patients to the starting
dose of the mood-stabilizing drug. Up until initiation of the
mood-stabilizing drug, none of the patients had experienced
any relief or improvement of depression symptoms. The starting dose of the mood-stabilizing drugs was well tolerated
with no reported start-up problems.
The choice of which mood-stabilizing drug to prescribe
was at the discretion of the caregiver; 71% of patients were
treated with lithium carbonate, and 29% of patients were
treated with divalprex sodium. Analysis of results revealed no
significant difference in outcomes with the mood-stabilizing
drug selected. Both mood-stabilizing drugs appear to
be equally effective with all patients achieving relief of
depression symptoms due to bipolar disorder cycling on the
depressive pole.
Review of group amino acid dosing values, where both
the urinary serotonin and dopamine were in the target ranges,
revealed daily dosing values were highly individualized with
no standard dosing apparent. In the group of 117 nonresponders to amino acids alone, the group amino acid dosing
values in the target ranges were as follows.
The group 5-HTP dosing range was 37.5–1800 mg/day
with a mean of 300 mg/day and a standard deviation
of 380.5 mg/day. l -Tyrosine group dosing range was
2500–13,000 mg/day with a mean of 7000 mg/day and a
standard deviation of 2148.5 mg/day. l-Dopa group dosing
range was 0–2940 mg/day with a mean of 240 mg/day and
a standard deviation of 285.8 mg/day.6
Treatment time to stabilization was as follows. All patients
at the start of the study had undergone 3 weeks of treatment
utilizing the amino acid dosing value adjustment under the
protocol of Table 1. Time to achieve urinary serotonin and
dopamine in the Phase III therapeutic ranges beyond level 3
dosing was 2–12 weeks with a mean of 6 weeks and a standard deviation of 2.23 weeks. In 114 of the patients started
on a mood-stabilizing drug, one additional week of treatment
time was required to achieve relief of symptoms. The average
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time of treatment from start of the amino acids in Table 1 to
relief of symptoms with the mood-stabilizing drugs was 10
weeks with a range of 6–16 weeks.
Physicians involved in this study reported no relapse of
depression symptoms as long as patients were compliant
with treatment prescribed. The longest follow-up period for
a patient in this study is currently 8 years.
Discussion
The clinical diagnosis of depression was made in the primary care setting. It was indicated that the diagnosis of
depression had been made under DSM-IV criteria. There
were no reports of structure interviews being performed
in these practices which may represent a limitation of this
depression care.
While the approach of administering l-tyrosine with
l-dopa may seem counterintuitive, the rationale for its use
is supported by the literature and the research experience
leading up to this article. Peer-reviewed literature notes
administering l-dopa without proper levels of l-tyrosine can
lead to significant fluctuations in urinary dopamine levels.
Dopamine fluctuations interfere with OCT assay interpretation, leading to inconsistent results. Dopamine fluctuations
can also decrease the efficacy of l-dopa, as the clinical
response fluctuates.4 It is also known that administration of
l-dopa can lead to depletion of l-tyrosine.10
The effects of mood-stabilizing drugs (lithium carbonate
or divalprex sodium) used in this study appear to be potentiated by the serotonin and dopamine amino acid precursor in
dosing values needed to establish the target ranges. There
appears to be a synergy. The mechanism of this potential
synergy is unknown. In this pilot study, patients who were
diagnosed with bipolar disorder cycling on the depressive
pole experienced no relief of symptoms in the past although
mood-stabilizing drugs were administered at various dosing values including levels verified as therapeutic by serum
assays. In this study, they obtained relief of symptoms
predominantly on the starting dose of drug when added to
amino acid precursors at dosing values required to establish
the target ranges.
The following patient profile exists for those patients
newly diagnosed in this study with bipolar disorder
cycling on the depressive pole under this protocol. The
typical patient has a history of being treated with antidepressants for recurrent major depression for many years
without relief of depression symptoms. Once symptoms
of depression are under control, with the addition of a
mood-stabilizing drug, it is not uncommon for patients to
report that their symptoms have been present since high
school or earlier in life. Patient reports of suffering since
high school are common and even more impressive when
it is realized that 80% of the patients in this study ranged
from 40 to 65 years of age, meaning years of suffering
without effective treatment.
Over the years, these patients have seen many physicians
while looking for relief of depression symptoms and
have taken most or all of the antidepressants available
without complete relief of symptoms.2 It is suggested
that future studies of this protocol which differentiates
bipolar depression from recurrent major depression should
incorporate the following screening in order to generate a
group with a higher percentage of previously undiagnosed
bipolar disorder cycling on the depressive pole. i) A history
of depression for over 10 years. ii) A history of having
seen five or more caregivers for treatment of depression.
iii) A history of having taken five or more antidepressant
drugs in the past without full relief of symptoms. It is also
suggested that in patients who meet this criteria, the amino
acid dosing simply be started on level 1 dosing of Table 1
and then a urine sample be obtained in 1 week and submitted
for OCT assay interpretation. This will decrease the time of
treatment by 3 weeks.
As noted previously, when this protocol was initiated,
any prescription drugs being taken were continued. Once the
patient with bipolar disorder cycling on the depressive pole
achieves relief of depression symptoms and the diagnosis of
bipolar disorder cycling on the depressive pole is made, any
antidepressants, which are not indicated for monotherapy for
treatment with bipolar depression under US Food and Drug
Administration (FDA) guidelines, should be stopped.6,7,11,12
However, it was found that many of these patients, finally
symptom free for the first time in years, are hesitant or even
highly resistant to giving up anything in their treatment plan
that has finally gotten them relief of symptoms, including the
antidepressants. These feelings on the part of the patient may
be exceptionally strong. An effective approach to eliminating
the antidepressants that are not indicated for monotherapy
in bipolar depression from the treatment plan, in the face
of strong patient resistance, is to simply wait 2–3 months
after relief of symptoms and then revisit the issue of slowly
tapering the antidepressants to a stop.
Implementation of this protocol is time intensive.
The amino acid dosing value OCT assay interpretation
cycle is 2 weeks. When the amino acid dosing value is
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Hinz et al
changed, it takes 1 week before urine can be collected in
the steady state, and then it takes another week to get the
test results of OCT assay interpretation reported back to the
physician in order to prescribe the next amino acid dosing
value. Patients at initial visit orientation and on follow-up
visits need to be prepared for the longest treatment time
possible (2–4 months), although some patients may find
relief of symptoms in 1–2 weeks. This is done to prevent
patients from dropping out of treatment due to perceived
lack of results after several weeks. Response time under
this approach varies greatly. Since there is no way of
predicting at which point in this process the patient will
achieve relief of symptoms, all patients need to be properly
oriented at the first visit to the indeterminate length of time
with reinforcement of this orientation at subsequent visits.
While weekly visits over a 4-month period may seem like
a long time to get relief of symptoms, in fact, most bipolar
disorder cycling on the depressive pole have suffered with
disease symptoms for 20–40 years or longer and the time
investment is relatively small compared to the prolonged
length of suffering and the cost due to ineffectiveness of
previous medical care.
As treatment under this protocol progresses, most patients
report no relief of depression symptoms until the proper
amino acid dosing or amino acid dosing with mood-stabilizer
dosing has been implemented. It was relatively rare for
patients to achieve gradual relief of symptoms from visit to
visit. Resolution of symptoms in patients can be and often is
dramatic and abrupt, analogous to a light switch being either
off (with symptoms) or on (without symptoms). It was not
uncommon for a patient who had been under treatment for
many weeks to return for a clinic visit and report the exact
day that relief of depression symptoms occurred. Waiting for
this dramatic effect to occur without the patient understanding the process involved may lead to an increased drop-out
rate of patients prior to relief of symptoms. For example, the
patient who has been under treatment for many weeks, with
no improvement of depression, may contemplate dropping
out of treatment when, in fact, they are on the doorstep of
dramatic improvement.
Conclusion
The novel approach of this pilot study clinically differentiates recurrent major depression from bipolar disorder cycling
on the depressive pole. Although this approach appears to
be effective in treatment of bipolar disorder cycling on the
depressive pole, more studies are needed.
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Bipolar disorder cycling on the depressive pole is frequently misdiagnosed by caregivers. One of the primary
stumbling blocks is the inability to elicit a proper medical
history of one or more manic or hypomanic episodes in
the patient’s past in order to satisfy the DSM-IV criteria.
This potential blind spot in the DSM-IV criteria leads to
antidepressants being prescribed to patients with bipolar
depression, a practice that is specifically not indicated as
monotherapy under FDA guidelines.6,7,11,12
The protocol of this study has been in use since 2004
with no reported failures in the treatment of bipolar disorder cycling on the depressive pole when the protocol was
followed properly. This is a pilot study. The intent of this
article is to disseminate some of the knowledge gained in
this research, spark interest leading to more research, refine
the protocol with more studies, and elicit scrutiny of these
observations.
Disclosure
Marty Hinz and Thomas Uncini are owner and medical
director of DBS Labs, respectively, Duluth, MN, USA. Alvin
Stein reports no disclosures.
References
1. American Psychiatric Association. Diagnostic and Statistical Manual
of Mental Disorder IV (DSM IV). 4th ed. Washington, DC: American
Psychiatric Association;1994:327–352.
Disease Management. Boca Raton, FL: CRC Press. 2009:465–481.
3. Hinz M, Stein A, Uncini T. The dual-gate lumen model of renal monoamine transport. Neuropsychiatr Dis Treat. 2010;6(1):387–392.
4. Trachte GJ, Uncini T, Hinz M. Both stimulatory and inhibitory effects of
Dis Treat. 2009;5:227–235.
5. Hinz M, Stein A, Trachte G, Uncini T. Comprehensive analysis of
urinary neurotransmitter testing. Open Access Journal of Urology.
2010; In press.
6. Wyeth Pharmaceuticals, Inc. Effexor XR(r) (velafaxine hydrochloride) Extended-Release Capsules. Prescribing information. July
2009. Philadelphia, PA: Wyeth Pharmaceuticals, Inc. Available from:
http://www.wyeth.com/content/showlabeling.asp?id=100. Accessed
2010 May 12.
7. Forest Labs. Lexapro(r) (escitalopram oxalate) prescribing information.
Jan 2009. St. Louis, MO: Forest Labs. Available from: http://www.frx.
com/pi/lexapro_pi.pdf. Accessed 2010 Jun 2.
8. Spindle A, Matsumoto N. Enhancement of methylmercury toxicity by L-cystine in cultured mouse blastocysts. Reprod Toxicol.
1987–1988;1(4):279–284.
9. Fair PH, Dougherty WJ, Braddon SA. Methyl mercury and selenium
interaction in relation to mouse kidney gamma-glutamyltranspeptidase,
ultrastructure, and function. Toxicol Appl Pharmacol. 1985;80(1):
78–96.
10. Karobath M, Diaz JL, Huttunen MO. The effect of L-dopa on the
concentrations of tryptophan, tyrosine, and serotonin in rat brain.
Eur J Pharmacol. 1971;14(4):393–396.
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11. GlaxoSmithKline. Wellbutrin XL(r) (bupropion hydrochloride
extended-release tablets). Dec 2008. Research Triangle Park, NC:
Glaxo SmithKline. Available from: http://us.gsk.com/products/assets/
us_wellbutrinXL.pdf. Accessed 2010 Jun 2.
12. Eli Lilly and Company. Prozac (fluoxetine hydrochloride) prescribing
information. Oct 2009. Indianapolis (IN): Eli Lilly and Company. Available from: http://pi.lilly.com/us/prozac.pdf. Accessed 2010 Jun 2.
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published authors.
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Clinical and Experimental Gastroenterology
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Return to index
C ase r epo r t
Amino acid-responsive Crohn’s
disease: a case study
6 December 2010
Alvin Stein 1
Marty Hinz 2
Thomas Uncini 3
1
Plantation, FL, USA; 2Clinical Research,
NeuroResearch Clinics Inc., Cape
Coral, FL, USA; 3Laboratory, Fairview
Regional Medical Center-Mesabi,
Hibbing, MN, USA
Purpose: This paper reviews the clinical course of a case of severe Crohn’s disease and discusses
the scientific ramifications of a novel treatment approach.
Patients and methods: A case study of a 37-year-old male with a 22-year history of Crohn’s
disease whose clinical course had experienced no sustained remissions. The patient was treated
with a protocol that utilized serotonin and dopamine amino acid precursors administered under
the guidance of organic cation transporter assay interpretation.
Results: Within 5 days of achieving the necessary balance of serotonin and dopamine, the
patient experienced remission of symptoms. This remission has been sustained without the use
of any Crohn’s disease medications.
Conclusion: In Crohn’s disease, it is known that there is an increase of both synthesis and
tissue levels of serotonin in specific locations. It is asserted that this is prima facie evidence
of a significant imbalance in the serotonin–dopamine system, leading to serotonin toxicity.
The hypothesis formulated is that improperly balanced serotonin and dopamine transport,
synthesis, and metabolism is a primary defect contributing to the pathogenesis of Crohn’s
disease.
Keywords: serotonin, dopamine, organic cation transporters, OCT
Introduction
Correspondence: Alvin Stein
6766 W Sunrise Blvd, Suite 100A,
Plantation, Florida 33313, USA
Tel +1 954 581 8585
Fax +1 954 316 4969
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DOI: 10.2147/CEG.S15340
Symptoms of Crohn’s disease in patients range on a spectrum from mild to very
severe. Symptoms include diarrhea, abdominal pain, intermittent fever, rectal bleeding,
loss of appetite, significant weight loss, arthralgias, fatigue, malaise, and headaches.
Involvement of other organ systems beyond the intestinal tract, such as eyes, skin,
and liver, may be present.1
As there is currently no known cure, treatment is focused on symptom control.
Complications secondary to medications prescribed for symptom control may occur.
When the disease fails to respond to the milder medications, more aggressive medications are prescribed. Medication complications can be severe, including infections,
serum sickness, drug-induced lupus, diabetes, cancers, and even death.2
This paper documents a case study of a patient with severe Crohn’s disease. The
patient had suffered with Crohn’s disease of progressing severity for 22 years, during which time no sustained remission of symptoms was noted. The patient suffered
profound complications from infliximab, 6-mercaptopurine, and prednisone. He
experienced no sustained response from mesalamine, low-dose naltrexone, or dietary
modification. The patient’s clinical course was complicated by steroid-induced insulindependent diabetes. He also suffered from severe weight loss, depression, fatigue, mal-
Clinical and Experimental Gastroenterology 2010:3 171–177
© 2010 Stein et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
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Stein et al
aise, headaches, purulent-mucinous diarrhea, rectal bleeding,
bilious vomiting, and diffuse arthralgias. Complaints of back
pain resulted in back surgery with negative operative findings
and no relief of symptoms. Exploratory gallbladder surgery
was done in response to abdominal pain. The pathologist’s
report of tissue submitted from the gallbladder surgery was
negative for any pathology. In February 2004, the patient had
progressed to the most severe state of his disease, losing 25%
of his body weight. The patient was fully disabled and unable
to work. He experienced constant symptoms of Crohn’s disease despite attempts at medication alteration. At all times
from his first confirmed attack of Crohn’s disease in 1990 at
age 19 years, he was on one or more prescription drugs to
try to control the disease symptoms.
The patient achieved full remission of symptoms in a
matter of days once the proper orally administered serotonin
and dopamine amino acid precursor dosing values were established with the guidance of urinary organic cation transporter
(OCT) functional status determination (herein referred to as
OCT assay interpretation).
The patient was treated with a novel treatment protocol developed by NeuroResearch Clinics (Duluth, Minnesota, MN,
USA). Peer-reviewed publications from 20093,4 and 20105–7
outlined a novel “three-phase model” of OCT response to
simultaneous administration of serotonin and dopamine
amino acid precursors in significant amounts, which is the
basis for OCT assay interpretation. Outlined in this paper
is a proposed novel OCT model that potentially describes
the etiology of the “three-phase response” of serotonin and
dopamine during simultaneous administration of their amino
acid precursors in varied daily dosing values.5
The protocol
Serotonin and dopamine exist in two states. The endogenous
state is found when no amino acid precursors are being
administered. The competitive inhibition state is found when
significant amounts of amino acid precursors of both serotonin
and dopamine are administered simultaneously. This novel
approach places serotonin and dopamine in the competitive
inhibition state and then optimizes their transport in proper
balance through the OCTs with OCT analysis interpretation.
The approach was developed by medical research that started
in 1997. Peer-reviewed research covering methodology, applications, and the scientific foundation of this novel approach
was published in 20093,4 and 2010.5–7 Optimization of the
serotonin–dopamine system has applications in any condition
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where an imbalance between serotonin and dopamine in
transport, synthesis, or metabolism is present. The potential
scope of applications is far-reaching.
The protocol utilized for treatment of Crohn’s disease
consisted of the amino acid dosing values listed in Table 1.
This protocol has been covered in previous peer-reviewed
research.3,7
The initial step of the protocol is the simultaneous administration of serotonin and dopamine amino acid precursors
with no OCT functional status determination in order to place
the system into a competitive inhibition state. Three dosing
levels were available, as noted in Table 1. At the first visit, the
patient was started on level 1 amino acid dosing. The patient
was then followed weekly for evaluation of response to the
start or change in amino acid dosing levels. As described in
the results section of this paper, dosing was implemented as
per Table 1. The patients took the amino acid dosing values
of each level at the times indicated in Table 1.
If the patient failed to achieve full relief of symptoms on
level 3 dosing, a urine sample was collected and submitted
for urinary serotonin and dopamine laboratory assay. This
was followed by OCT assay interpretation. Based on OCT
assay interpretation, the amino acid precursors of serotonin
and dopamine were adjusted in an effort to achieve full relief
of symptoms or a balance of urinary serotonin and dopamine
in the Phase 3 therapeutic range, whichever came first.3,7
OCT assay interpretation
The serotonin and dopamine filtered at the glomerulous are
metabolized by the kidneys, and significant amounts do not
make it to the final urine. Serotonin and dopamine found
in the urine are monoamines synthesized in the proximal
convoluted renal tubule cells and have never been found in
the central nervous system or peripheral system. Serotonin
and dopamine that are newly synthesized by the kidneys meet
one of two fates. Urinary serotonin and dopamine levels are
primarily dependent on the interaction of the basolateral
monoamine transporters (OCT2s) and the apical monoamine transporters (OCTN2s) of the proximal convoluted
Table 1 Individual dosing value: milligrams of L-tyrosine/milligrams
of 5-hydroxytryptophan*
Level
AM
Level 1
Level 2
Level 3
1500/150
1500/150
1500/150
Noon
4 PM
7 PM
1500/150
1500/150
1500/150
1000/300
1000/300
1000/300
Note: *The patient also received the following daily dosing values: 1000 mg of
vitamin C, 220 mg of calcium citrate, 75 mg of vitamin B6, 400 μg of folate, 4500 mg
L-cysteine, and 400 μg of selenium.
Clinical and Experimental Gastroenterology 2010:3
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Amino acid-responsive Crohn’s disease
renal tubule cells of the kidneys.5,8 The OCTN2s8 of the
proximal convoluted renal tubule cells transport serotonin
and dopamine that is not transported by the OCT2.5 While
in the competitive inhibition state, serotonin and dopamine
not transported by the OCT2s are found in the final urine as
waste.6 Although there are numerous other forces that interact with the newly synthesized renal monoamines, they are
small compared with the effects of these transporters.5 Proper
interpretation of urinary serotonin and dopamine levels in
the competitive inhibition state determines the functional
status of the OCT2s of the proximal convoluted renal tubule
cells of the kidneys, known as OCT assay interpretation.
The OCT2s exist in three different phases dependent on the
status of the entrance gate and lumen saturation.3–7 Table 2
outlines the correlation between entrance gate status and
lumen saturation.
The basis for OCT assay interpretation requires that the
system be placed into the competitive inhibition state and
then two or more urinary serotonin and dopamine assays
performed while taking serotonin and dopamine amino acid
precursors at significantly varied dosing values. The results
are then compared in order to determine the change in urinary
serotonin and dopamine levels in response to the change in
amino acid precursor dosing values.3–7
Urinary serotonin and dopamine values found on assay
were reported in micrograms of monoamine per gram of
creatinine in order to compensate for fluctuations in urinaryspecific gravity. A urinary serotonin or dopamine value
less than 80 or 475 µg of monoamine per 1 g of creatinine,
respectively, is defined as a Phase 2 response. A urinary
serotonin or dopamine value greater than 80 or 475 µg of
monoamine per 1 g of creatinine, respectively, is interpreted
as being in Phase 1 or Phase 3. Differentiation of Phase 1 from
Phase 3 is a follows. If a direct relationship is found between
amino acid dosing and urinary assay response, it is referred
to as a Phase 3 response. An inverse relationship is referred
Table 2 The following considerations exist with regard to
the basolateral monoamine organic cation transporters of the
proximal convoluted renal tubule cells*
Serotonin or dopamine
transporter entrance gates
Transporter lumen
saturation
Phase 1
Phase 2
Phase 3
Partially closed
Open
Open
Unsaturated
Unsaturated
Saturated
Note: *In Phase 1, the serotonin and dopamine gates are partially closed, restricting
access to the transporter. In Phases 2 and 3, the gates are open, allowing full
access to the transporter by serotonin and dopamine. In Phases 1 and 2, the lumen
of the transporter is not saturated with serotonin and dopamine. In Phase 3, the
lumen of the transporter is saturated with serotonin or dopamine.5
to as a Phase 1 response. The Phase 3 therapeutic range for
urinary serotonin is defined as 80–240 µg of serotonin per
1 g of creatinine. The Phase 3 therapeutic range for urinary
dopamine is defined as 475–1100 µg of dopamine per 1 g
of creatinine.3,5–7
collected 6 hours prior to bedtime with 4:00 PM being the
most frequent collection time point. The samples were stabilized in 6 N hydrochloric acid to preserve the dopamine and
serotonin. The urine samples were collected after a minimum
of 1 week, during which the patient was taking a specific daily
dosing of amino acid precursors of serotonin and dopamine.
No doses were missed. Samples were shipped to DBS Laboratories (Duluth, MN). Urinary dopamine and serotonin were
kits (3 CAT RIA IB88501 and IB89527, both from Immuno
Biological Laboratories, Inc., Minneapolis, MN). The DBS
laboratory is accredited by Clinical Laboratory Improvement
Amendments as a high-complexity laboratory. OCT assay
interpretation was performed. Results were reported in micrograms of monoamine per gram of creatinine to compensate
for specific gravity variances in the urine.
Results
An endoscopy examination, prior to treatment with amino
acids while the disease was active, was performed in
September 2005. Results revealed several apthous ulcers in
the terminal ileum. Tissue biopsy confirmed this diagnosis.
At the initiation of the amino acid protocol, the patient
was still taking mesalamine, low-dose naltrexone, and
escitalopram. The patient reported no relief of symptoms
after any of these drugs were started. The escitalopram was
discontinued at the start of amino acid treatment, and the
mesalamine and low-dose naltrexone were continued.
At the first visit, the patient was started on level 1
amino acid dosing as per Table 1. One week later there
was no change in symptoms, and the patient’s amino acid
dosing values were increased to level 2 (see Table 1). The
patient achieved lessening of the symptoms when he was
on level 2 amino acid dosing. At that point, the patient
revealed that he felt that this approach was the best treatment he had experienced during the course of his 22-year
illness. The amino acids were increased to level 3 dosing
(see Table 1), with no further change in symptoms. After
1 week of level 3 dosing, a urine sample was obtained and
analyzed. The reported values were then submitted for OCT
assay interpretation.
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Stein et al
When the first urine sample was collected for OCT assay
interpretation, the patient was taking level 3 dosing: 900 mg
5-hydroxytryptophan (5-HTP), 5000 mg L-tyrosine, and
4500 mg L-cysteine with cofactors.
The first urinary assay revealed serotonin to be in Phase 3
(Table 2) with a reported value of 5150.7 µg of serotonin
per 1 g of creatinine, and a dopamine in Phase 2 (Table 2)
with a reported value of 206.4 µg of dopamine per 1 g of
creatinine.
After the first OCT assay interpretation, the patient’s daily
amino acid dosing was increased by 1000 mg of L-tyrosine
and 240 mg of L-dopa. At that point, the patient was taking
the following in divided daily doses: 900 mg 5-HTP, 6000 mg
L-tyrosine, 240 mg L-dopa, and 4500 mg L-cysteine with
cofactors. After 1 week taking these new amino acid dosing
values, there was no change in the patient’s symptoms.
A second urine sample was submitted for analysis,
followed by OCT assay interpretation. This revealed that
the patient’s urinary serotonin was in Phase 3 (Table 2) at
12,611.1 µg of serotonin per 1 g of creatinine, and his dopamine was in Phase 3 (Table 2) at 741.3 µg of dopamine per
1 g of creatinine.
The recommendation was to decrease the daily 5-HTP
dosing by 300 mg per day, increase L-tyrosine by 1000 mg
per day, and continue other amino acids as before. The patient
was then taking the following in divided daily doses: 600 mg
5-HTP, 7000 mg L-tyrosine, 240 mg L-dopa, and 4500 mg
L-cysteine with cofactors.5 Within 1 week of this dosing
value change, the patient became asymptomatic, indicating that adequate OCT balance of the serotonin–dopamine
system had occurred. The patient’s response and remission
with amino acid treatment was very impressive and relatively
abrupt compared with the 22-year course of his disease. This
profound resolution of symptoms was achieved within 6
weeks of the first clinic visit.
The patient noted the return of solid stools, no further
vomiting, restored energy, increased motivation, and resolution of depression symptoms. All prescription medications
that the patient had been taking since the start of amino acid
treatment were discontinued after 6 weeks of amino acid
treatment, including mesalamine and naltrexone, with no
return of symptoms. The amino acid dosing values that had
induced relief of symptoms were continued.
Following remission of symptoms, the patient’s sedimentation rate returned to the normal range. His weight stabilized at approximately 20 pounds above the lowest weight
attained while disease symptoms were present. The patient
reported that he was very comfortable at that weight. The
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patient found that if he missed a dose of the amino acids,
some of the Crohn’s disease symptoms would return.
A third OCT assay interpretation was obtained 5 months
later with amino acid dosing values that induced relief of
symptoms. Urinary serotonin was reported as 9019.5 µg of
serotonin per 1 g of creatinine and urinary dopamine was
604.3 µg of dopamine per 1 g of creatinine; both were in
Phase 3 (Table 2). At this point, the patient was still asymptomatic. The recommendation was to decrease the daily
5-HTP dosage to 300 mg, decrease L-tyrosine dosing by
1000 mg per day, and continue other amino acids as before.
After this dosing value change, the patient was then taking
the following in divided daily doses: 300 mg 5-HTP, 6000 mg
L-tyrosine, 240 mg L-dopa, and 4500 mg L-cysteine with
cofactors. Following this change in amino acid dosing values,
the patient continued to be asymptomatic, a state that exists
to this day as long as he is compliant with the prescribed
amino acid dosing values.
Endoscopy subsequent to remission of symptoms was
performed in March 2010. This was 26 months after starting
the amino acid protocol guided by OCT assay interpretation and 24 months after achieving relief of symptoms. This
endoscopy was performed by the same gastroenterologist
that performed endoscopy prior to remission of symptoms.
At this endoscopy, the patient was taking his amino acids
daily with no prescription medications. He was taking no
insulin or oral hypoglycemic agents, and his HbA1c had
returned to normal. There were no signs of diabetes or other
illnesses. He had returned to full-time gainful employment,
after a period of over 4 years during which he was fully
disabled.
The gastroenterologist reported that for the first time in
10 years of caring for the patient, the Crohn’s disease was in
complete remission. This finding was verified by the pathologist after review of tissue samples submitted.
As of the time of writing this paper, the patient continues
to do well with no infections or adverse reactions. He is gainfully employed and living a normal life. All follow-up testing,
including sedimentation rates, have been normal.
Discussion
Scientific basis
The authors have documented a number of patients with
Crohn’s disease who experienced similar remission of symptoms with this approach. This case was selected for this paper
due to the severity of disease in the patient.
Serotonin and dopamine levels inside and outside of the
cell structures containing them are primarily a function of
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transporter status.5 The question raised is how OCT assay
interpretation of renal transporters relates to the OCTs of the
gastrointestinal (GI) tract. The hypothesis is that performing
OCT assay interpretation on one set of OCTs will give insight
into transport of serotonin, dopamine, and their precursors
at other OCTs throughout the body. Within 3–5 days of
starting or changing amino acid precursor dosing values,
serotonin, dopamine, and their precursors reach equilibrium
throughout the body.3,5–7 At equilibrium, amino acid precursors, serotonin, and dopamine exert similar effects at cation
transporters throughout the body.
In the competitive inhibition state, the serotonin and
dopamine systems function as one system in transport, synthesis, and metabolism. Affecting change to one system will
affect both systems in their functions. Serotonin, dopamine,
and their amino acid precursors compete for transport at the
OCTs. Significant increases in one monoamine will decrease
monoamine and precursor transport of the other system
through competitive inhibition. Transport of precursors into
the cells is required in order to place them in an environment
where synthesis takes place. The same enzyme, the L-aromatic
amino acid decarboxylase enzyme (AAAD), is responsible for
synthesis of serotonin and dopamine. Creating an environment
where precursors of one system are significantly increased
without significantly increasing the precursors of the other
system leads to decreased access to the AAAD by precursors
of the other system, with associated decreased synthesis or
depletion due to competitive inhibition. Both serotonin and
dopamine are metabolized by the monoamine oxidase (MAO)
enzyme system. A significant increase in levels of one system
will increase MAO activity, leading to increased metabolism
and depletion of the other system.2,5,6
In the intestinal tract of Crohn’s patients there is excessive synthesis with associated increased tissue levels of
serotonin.8,9 In Crohn’s disease, high levels of serotonin
dominate synthesis, metabolism, and transport, leading to
dopamine and catecholamine levels that are low relative to
the balance needed to function properly with the serotonin
levels present.3,5
As noted in previous peer-reviewed research by the authors,
OCT phase determination defines the status of the serotonin and dopamine gates at the entrance to the basolateral
monoamine OCT (open or partially closed) of the proximal
convoluted renal tubule cells of the kidneys and the status
of serotonin and dopamine saturation in these transporters
(see Table 2).5
Proper interpretation of the findings requires the following
explanation. Serotonin and dopamine both need to be in the
competitive inhibition state when OCT assay interpretation is
performed. This means that significant dosing values of both
serotonin and dopamine need to be administered simultaneously. When in the competitive inhibition state, serotonin and
dopamine are in full competition for transport, synthesis, and
metabolism.3,5 Testing of the urine is only done after amino
acid precursors of the monoamines are started in accordance
with the protocol, placing the serotonin–dopamine system
in the competitive inhibition state. Baseline testing in the
endogenous state prior to administration of amino acid
precursors is of no value, as these assay levels correlate
with nothing. As noted in previous peer-reviewed literature,
baseline testing of urinary serotonin and dopamine does not
correlate with baseline assays performed on subsequent days
in the same individual.6
Simply giving the patient one or more amino acid precursors is not the key to optimal outcomes. The OCT needs
to be challenged with serotonin and dopamine precursors
in significant amounts to place transport in the competitive
inhibition state so that proper OCT assay interpretation can
be realized.5
The OCTN
There is a known genetic defect of OCTN1 and OCTN2 in
the colon of patients suffering from Crohn’s diease.9 All
OCT and OCTN transporters are capable of transporting
organic cations, including serotonin, dopamine, and their
precursors.8 In Crohn’s disease, the serotonin content of
the mucosa and submucosa of the proximal and distal
colon is increased.10 Increased synthesis of serotonin is
known to be associated with Crohn’s disease.11 No reasonable explanation of the etiology of serotonin elevation in
the colon tissue of Crohn’s disease patients has been put
forth previously.
It is postulated that the known OCTN1 and OCTN2 genetic
deficit may be tied to the increased synthesis and tissue levels
of serotonin seen with Crohn’s disease. Based on OCT assay
interpretation, it appears that a severe imbalance between
serotonin and dopamine transport, synthesis, and metabolism
is at the heart of Crohn’s disease.
An imbalance of the serotonin–dopamine transport system has been linked to numerous diseases.3,5–7 It is proposed
that much of the clinical constellation found with Crohn’s
disease may be induced by a serotonin toxicity of the colon
exacerbated by relatively low levels of dopamine resulting
from defective OCTN transport.
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Stein et al
In the GI tract, serotonin is contained primarily in the
enteroendocrine cells (ECs). The serotonin–dopamine transporter balance of the ECs controls paracrine–autocrine and/or
endocrine mediators that modulate GI function.12 It is asserted
that proper treatment needs to include correct management of
the serotonin and dopamine imbalance in transport, synthesis,
and metabolism. The only definitive way to address these
problems optimally is with OCT analysis interpretation in
the competitive inhibition state that is established with proper
amino acid precursor administration.
It is postulated that the patient’s Crohn’s disease was
impacted in a positive manner as follows. It is known that
there is increased synthesis of serotonin with increased
serotonin levels in the proximal and distal colon.11 Levels
of the serotonin–dopamine system are impacted primarily
by synthesis, uptake, and metabolism. For serotonin and
dopamine to be synthesized, their amino acid precursors need
to be transported into the structures where this occurs. There
appears to be a defect in transport of serotonin precursors of
the colon. Serotonin precursors are transported preferentially
at the exclusion of dopamine precursors, leading to high
levels of synthesis, high levels of serotonin in portions of the
colon, and compromise of catecholamine synthesis. Properly
balancing the serotonin and dopamine precursor transport
leads to a decrease in serotonin synthesis, less serotonin in
the tissue of the proximal and distal colon, and an increase
in synthesis of dopamine, norepinephrine, and epinephrine.
Increased serotonin levels of Crohn’s disease lead to
increased MAO activity, which without reciprocal increases
of the catecholamines leads to increased metabolism of the
catecholamines, further exacerbating the imbalance.
Other implications
With a case study such as this there is always the possibility
that remission was coincidental to treatment. This patient had
a 22-year history of progressively worsening Crohn’s with no
remissions and has been free of Crohn’s disease symptoms
clinically and on biopsy for 2.5 years since the appropriate
dosing values of serotonin and dopamine amino acids were
established. We leave it to the reader to speculate as to the
odds of this being a spontaneous coincidental remission
versus a response to properly balanced amino acids.
One other aspect of the patient’s treatment needs to
be discussed. The patient was suffering from depression.
Previously published peer-reviewed literature by the authors
indicates that this same approach with OCT assay interpretation for treatment of depression is effective.3,7 In this case
study, the patient’s depression resolved when the serotonin
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and dopamine were balanced to the degree needed for relief of
Crohn’s disease symptoms. It is asserted that it was no coincidence that the patient’s depression resolved simultaneously
with the resolution of the symptoms of Crohn’s disease.
Conclusion
In recent years, a genetic defect of the OCTN1 and OCTN2 of
the colon has been identified in patients with Crohn’s disease.
The OCTN1 and OCTN2 are responsible for transport of cations, including the monoamines of the serotonin–dopamine
system and their precursors. It is known with Crohn’s disease
patients that there is a marked increased in serotonin levels
of the proximal and distal colon associated with a defect
in serotonin synthesis. It remains to be proven whether a
transport problem exists in the serotonin–dopamine system
induced by the OCTN1 and OCTN2 genetic defect found
in Crohn’s disease. For now, these observations cannot be
overlooked. Clearly, further studies relating to OCT analysis
interpretation and the OCTN transporters of the colon as they
relate to other abnormal findings associated with Crohn’s
disease are indicated.
This paper potentially opens the door to a new area of
treatment and study in Crohn’s disease patients. The goal
of the paper is to stimulate further interest in these findings
in order to duplicate, confirm, and invite scrutiny of these
results.
Disclosure
Dr Marty Hinz is President of Clinical Research, Neuro
Research Clinics, Inc., Cape Coral, Florida, USA. Dr Thomas
Uncini is Medical Director of DBS Labs, Duluth, Minnesota,
USA. Dr Alvin Stein reports no disclosures.
References
1. Greenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients.
Medicine (Baltimore). 1976;55(5):401–412.
2. Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI.
6-Mercaptopurine in the management of inflammatory bowel disease:
short- and long-term toxicity. Ann Intern Med. 1989;111:641–649.
Disease Management. FL: CRC Press; 2009:465–481.
Dis Treat. 2009;5:227–235.
5. Hinz M, Stein A, Uncini T. The dual-gate lumen model of renal monoamine transport. Neuropsychiatr Dis Treat. 2010;6:387–392.
6. Hinz M, Stein A, Trachte G, Uncini T. Neurotransmitter testing of the
urine, a comprehensive analysis. Open Access J Urol. In press 2010.
7. Hinz M, Stein A, Uncini T. A pilot study differentiating recurrent
major depression from bipolar disorder cycling on the depressive pole.
NeuroPsychiatr Dis Treat. In press 2010.
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8. Koepsell H, Schmitt B, Gorboulev V. Organic cation transporters.
Physiol Biochem Pharmacol. 2003;150:36–90.
9. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease
and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(7):
390–407.
10. Oshima S, Fujimura M, Fujimiya M. Changes in number of serotonincontaining cells and serotonin levels in the intestinal mucosa of rats
with colitis induced by dextran sodium sulfate. Histochem Cell Biol.
1999;112:257–263.
11. Minderhoud I, Oldenburg B, Schipper M, Ter Linde J, Samson M.
Serotonin synthesis and uptake in symptomatic patients with Crohn’s
disease in remission. Clin Gastroenterol Hepatol. 2007;5:714–720.
12. O’Hara J, Ho W, Linden D, Mawe G, Sharkey K. Enteroendocrine
cells and 5-HT availability are altered in mucosa of guinea pigs with
TNBS ileitis. Am J Physiol Gastrointest Liver Physiol. 2004;287(5):
G998–G1007.
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Return to index
Treatment of attention deficit hyperactivity
disorder with monoamine amino acid
precursors and organic cation transporter
assay interpretation
25 January 2011
Marty Hinz 1
Alvin Stein 2
Robert Neff 3
Robert Weinberg 4
Thomas Uncini 5
NeuroResearch Clinics Inc, Cape Coral,
FL; 2Stein Orthopedic Associates,
Plantation, FL; 3Mental Training Inc,
Dallas, TX; 4Department of
Kinesiology and Health, Miami
University, Oxford, OH; 5Laboratory,
Fairview Regional Medical CenterMesabi, Hibbing, MN, USA
1
Background: This paper documents a retrospective pilot study of a novel approach for treating
attention deficit hyperactivity disorder (ADHD) with amino acid precursors of serotonin and
dopamine in conjunction with urinary monoamine assays subjected to organic cation transporter
(OCT) functional status determination. The goal of this research was to document the findings
and related considerations of a retrospective chart review study designed to identify issues and
areas of concern that will define parameters for a prospective controlled study.
Methods: This study included 85 patients, aged 4–18 years, who were treated with a novel
amino acid precursor protocol. Their clinical course during the first 8–10 weeks of treatment
was analyzed retrospectively. The study team consisted of PhD clinical psychologists, individuals compiling clinical data from records, and a statistician. The patients had been treated with
a predefined protocol for administering amino acid precursors of serotonin and dopamine, along
with OCT assay interpretation as indicated.
Results: In total, 67% of participants achieved significant improvement with only amino acid
precursors of serotonin and dopamine. In patients who achieved no significant relief of symptoms
with only amino acid precursors, OCT assay interpretation was utilized. In this subgroup, 30.3%
achieved significant relief following two or three urine assays and dosage changes as recommended by the assay results. The total percentage of patients showing significant improvement
was 77%.
Conclusion: The efficacy of this novel protocol appears superior to some ADHD prescription
drugs, and therefore indicates a need for further studies to verify this observation. The findings
of this study justify initiation of further prospective controlled studies in order to evaluate more
formally the observed benefits of this novel approach in the treatment of ADHD.
Keywords: attention deficit hyperactivity disorder, 5-hydroxytryptophan, tyrosine, L-dopa,
organic cation transporter assay interpretation
Introduction
1008 Dolphin Drive, Cape Coral,
FL 363904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
Dovepress
DOI: 10.2147/NDT.S16270
A large meta-analysis (n = 171,756) published in 2007 involving the review of 303
literature articles placed the worldwide pooled incidence of attention deficit hyperactivity disorder (ADHD) at 5.29%. However, this review suggested that geographic
location plays only a limited role in the reasons for the large variability of ADHD/
hyperactivity disorder prevalence estimates worldwide.1 This paper documents the
results of a retrospective chart review relating to a novel serotonin and dopamine amino
acid precursor treatment approach to ADHD which integrates organic cation transporter
(OCT) assay interpretation.2–7 Our hypothesis was that this novel approach of adminNeuropsychiatric Disease and Treatment 2011:7 31–38
31
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Hinz et al
istering amino acid precursors of serotonin and dopamine
with OCT assay interpretation when indicated may have
efficacy that is superior to some of the prescription drugs
currently used in the treatment of ADHD.
The diagnosis of ADHD is dependent upon meeting the
Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV) criteria in the areas of inattention,
hyperactivity, and impulsivity which negatively affect performance in school and work, as well as in relationships
with others.8 It is a generally accepted premise that a primary
factor in development of ADHD is the status of the monoamine system to include serotonin, dopamine, norepinephrine, and epinephrine. In response, the pharmaceutical
industry has demonstrated, to the satisfaction of the US Food
and Drug Administration (FDA), that certain drugs that
impact the monoamine systems meet FDA efficacy standards.
Examples of these drugs include neutral sulfate salts of dextroamphetamine and amphetamine,9 methylphenidate,10
dexmethylphenidate,11 atomextine,12 and lisdexamfetamine
dimesylate.13
Side effects and adverse reactions associated with ADHD
prescription medications are significant, serious, and potentially life-threatening. The following is a limited list of these
events associated with the ADHD group of drugs as a whole,
which include, but are not limited to:9–13
• Black box warning of increased risk of suicidal ideation
• Severe liver injury
• Sudden death in cases with pre-existing structural cardiac
abnormalities or other serious heart problems
• Risk of stroke and myocardial infarction
• Exacerbation of symptoms of behavior disturbance and
thought disorder in patients with a pre-existing psychotic
disorder
• Induction of mixed/manic episodes
• Treatment by stimulants at usual doses can cause emergent psychotic or manic symptoms, eg, hallucinations,
delusional thinking, or mania in children and adolescents
without prior history of psychotic illness or mania
• Amphetamines may impair the ability of the patient to
engage in potentially hazardous activities such as operating machinery or vehicles
• Higher incidence of infection, photosensitivity reaction,
constipation, tooth disorders, emotional liability,
decreased libido, somnolence, speech disorder, palpitation, twitching, dyspnea, sweating, dysmenorrhea, and
impotence
• Integument disorders including, but not limited to, urticaria, rash, and hypersensitivity reactions, including
32
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angioedema and anaphylaxis; serious skin rashes,
including Stevens Johnson syndrome and toxic epidermal
necrolysis
• Lowering of seizure threshold
• Increased aggression and hostility
• Contraindicated in patients with marked anxiety, tension,
and agitation, because the drugs may aggravate these
symptoms
• Risk of drug dependence
• Development of leukopenia and/or anemia.
These drugs do not increase the total number of neurotransmitter molecules in the central nervous system. Their
primary mechanism of action is thought to be reuptake
inhibition which sets up conditions that move neurotransmitters from one place to another.4–8 However, previous writings
suggest that the process of reuptake inhibition may deplete
neurotransmitters throughout the body.4,14–19 The administration of amphetamine stimulants creates another potential area
of concern relating to neurotoxicity.20–22
There has been no previous peer-reviewed literature
published addressing the efficacy of amino acid precursors
of serotonin and dopamine simultaneously administered in
the treatment of ADHD. The immediate amino acid precursors of serotonin and dopamine are 5-hydroxytryptophan
(5-HTP) and L-3,4-dihydroxyphenylalanine (L-dopa),
respectively. They freely cross the blood-brain barrier and
are then synthesized into serotonin and dopamine without
biochemical feedback inhibition. L-tryptophan and L-tyrosine
are immediate precursors of 5-HTP and L-dopa, respectively.
L-tryptophan and L-tyrosine have the ability to be synthesized into serotonin and dopamine, respectively. They are
actively transported across the blood–brain barrier in competition with other amino acids. Synthesis of serotonin and
dopamine from L-tryptophan and L-tyrosine, respectively,
is regulated by biochemical feedback. Under the approach
of this pilot study, optimal results are dependent upon achieving a proper balance between the administered serotonin and
dopamine precursors. 2–7
This study reviews the effects of a novel method of
treatment involving the use of monoamine amino acid precursors that do what drugs are unable to do. This novel
approach has the ability to increase the total number of
neurotransmitter molecules in the central nervous system,3–7
leading to efficacy observations that appear greater than
those of prescription drugs without the potential for neurotransmitter depletion, neurotoxicity issues, and severe
potentially life-threatening drug side effects associated with
prescription drugs.
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ADHD treatment with monoamine amino acid precursors
Table 2 Adult protocol for patients 17 years of age and older
The study included 85 children aged 4–18 years who had
been diagnosed as having ADHD under the DSM-IV criteria
by a licensed PhD clinical psychologist. The patients were
then treated by a clinical psychologist. The medical charts
and treatment results were reviewed retrospectively. Patients
were evaluated twice during treatment with the ADHD Rating
Scale (ADHD-RS).17 Other variables assessed via a questionnaire included: taking/not taking ADHD medicine; previous
history of taking stimulant drugs; gender; age; perceived
amount of improvement as noted by a conversation between
the parent (or patient alone if an adult over 18 years) and the
psychologist; and number of comorbid factors (eg, depression,
cerebral palsy, chronic indigestion, hair pulling, seizures,
autism, obsessive compulsive behavior).
The time period covered in the review was 18 months.
The individual patients were treated for a period of 8–10 weeks
with staggered starting of treatment. If no relief of symptoms
was observed in the first 3–4 weeks of treatment, while
administering the amino acid dosing protocol values of
Tables 1 and 2, a urine sample was collected. Urinary serotonin and dopamine assay results were then subjected to OCT
assay interpretation in order to define the needed change in
amino acid dosing values. The goal of treatment was
resolution of symptoms or achieving urinary serotonin
and dopamine in the phase 3 therapeutic ranges, whichever
came first.3–7 The amino acid dosing values of the protocol
were developed by NeuroResearch Clinics Inc, Duluth, MN.3–7
The statistician performing data analysis had no exposure
to any aspects of active patient treatment, prior hypotheses,
treatment expectations, and anticipated results in the data
relating to the study. The researchers performing the charting were also blind to any hypotheses being evaluated.
A P value # 0.05 was considered statistically significant.
JMP (SAS Institute, Cary, NC) software was used to perform
the statistical analysis.
For the purposes of the study, participants 16 years of
age and younger were placed on the pediatric dosing protocol
(Table 1). Participants 17 years of age and older were placed
on the adult dosing protocol (Table 2).
mg 5-HTP/mg L-tyrosine
Table 1 Pediatric protocol for patients aged 16 years of age and
younger
mg 5-HTP/mg L-tyrosine
Level 1
Level 2
Level 3
Morning
4 pm
7 pm
75/750
112.5/1125
112.5/1125
75/750
112.5/1125
112.5/1125
–
–
112.5/1125
Level 1
Level 2
Level 3
Morning
Noon
4 pm
150/1500
225/2250
150/1500
–
–
150/1500
150/1500
225/2250
225/750
In addition to the basic amino acid dosing values, other
daily cofactors generally required for synthesis of the
monoamine and maximum benefit from the protocol were
administered. These included vitamin C 1000 mg, calcium
citrate 220 mg, vitamin B6 75 mg, folate 400 µg, L-lysine
500 mg, L-cysteine 4500 mg for adults and 2250 mg for
children, and selenium 400 µg for adults and 200 µg for
children. In general, L-dopa in the form of standardized
mucuna pruriens 40% was added when the recommendation
of the first urinary OCT assay interpretation demonstrated
its need, which was a frequent occurrence.4
Patients were seen weekly. The initiation of a treatment
prescription with amino acid precursors of serotonin and
dopamine was at the level 1 dosing values of Tables 1 and 2.
If the symptoms persisted after one week of treatment, the
dosing was advanced week to week to level 2, then level 3.
Patients who did not achieve relief of symptoms on level 3
dosing values had a urine sample collected after one week
on that dosage; serotonin and dopamine levels were determined
and reported in µg of monoamine per g of creatinine. Reported
values were then subjected to OCT assay interpretation.
Reporting of urinary monoamine levels as µg of mono
amine per g of creatinine compensated for the specific gravity
of the urine.3–7
Peer-reviewed publications from 2009 and 2010 outlined a
novel urinary “three-phase model” of urinary serotonin and
dopamine response to simultaneous administration of serotonin and dopamine amino acid precursors in significant
amounts. This three-phase model is the basis for OCT assay
interpretation.2–7 A 2010 paper proposed a novel renal organic
cation transporter model which potentially describes the
etiology of the “three-phase response” of serotonin and
dopamine during simultaneous administration of their amino
acid precursors in varied daily dosing values.3
The urinary neurotransmitter testing model should with
the OCT assay interpretation model used in this study. The
urinary neurotransmitter testing model merely attempts to
determine if urinary neurotransmitter levels are high or low,
making no provision for phase determination or OCT
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Hinz et al
f unctional status interpretation. The flawed science behind
the urinary neurotransmitter testing model was discussed in
a 2010 paper.6
The serotonin and dopamine filtered at the glomerulus
are metabolized by the kidneys, and significant amounts
do not reach the final urine. Serotonin and dopamine found
in the urine, in patients not suffering from a monoamine-
secreting tumor, primarily represent monoamines that are
newly synthesized in the proximal convoluted renal tubule
cells of the kidneys and have never been in the central nervous
system or peripheral system. The fate of the newly synthesized serotonin and dopamine inside the proximal convoluted
renal tubule cells is primarily dependent upon the interaction
of the basolateral monoamine transporters and the apical
monoamine transporters of these proximal tubule cells. The
basolateral monoamine transporter transports both serotonin
and dopamine to the renal interstitium where they ultimately
end up in the peripheral system via the renal vein. The apical
monoamine transporters transport the newly synthesized
serotonin and dopamine not transported by the basolateral
monoamine transporter to the proximal nephrons and, from
there, ultimately end up in the final urine as waste.3,24
Serotonin and dopamine are found in two states. The
endogenous state is found when no amino acid precursors
are administered. The competitive inhibition state is found
when significant amounts of both serotonin and dopamine
precursors are simultaneously administered. Proper OCT
assay interpretation requires that the serotonin and dopamine
systems be simultaneously placed in the competitive inhibition state prior to OCT assay interpretation.3–7,24
The basis for OCT assay interpretation requires that two
or more urinary serotonin and dopamine assays be performed
while taking serotonin and dopamine amino acid precursors
at significantly varied dosing values. The results are then
compared to determine the change in urinary serotonin and
dopamine levels in response to the change in amino acid
precursor dosing values.2–7
A urinary serotonin or dopamine value less than 80 µg
or 475 µg of monoamine per g of creatinine, respectively,
is defined as a phase 2 response. A urinary serotonin or
dopamine value greater than 80 µg or 475 µg of monoamine
per g of creatinine, respectively, is interpreted as being in
phase 1 or phase 3. Differentiation of phase 1 from phase 3
is a follows. If a direct relationship is found between amino
acid dosing and urinary assay response, it is referred to as a
phase 3 response. An inverse relationship is referred to as a
phase 1 response. The phase 3 therapeutic range for urinary
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serotonin is defined as 80–240 µg of serotonin per g of
creatinine. The phase 3 therapeutic range for urinary dopamine is defined as 475–1100 µg of dopamine per g of
creatinine.2–7
collected about six hours prior to bedtime, with 4 pm being
the most frequent collection time point. The samples were
stabilized in 6 N HCl to preserve the dopamine and serotonin.
The urine samples were collected after a minimum of one
week during which time the patient was taking a specific
daily dosing of amino acid precursors of serotonin and dopamine where no doses were missed. Samples were shipped
to DBS Laboratories (Duluth, MN) which is operated under
the direction of one of the authors (TU, hospital-based
pathologist, dual board-certified in laboratory medicine and
forensic pathology). Urinary dopamine and serotonin were
kits (3 CAT RIA IB88501 and IB89527, both from Immuno
Biological Laboratories Inc, Minneapolis, MN). The DBS
laboratory is accredited as a high complexity laboratory by
CLIA to perform these assays. OCT assay interpretation
was performed by one of the authors (MH, NeuroResearch
Clinics Inc).
Results
The retrospective chart review of this pilot study covered the
treatment of 85 children aged 4–18 years diagnosed under
DSM-IV criteria to have ADHD. The age distribution of the
study group was 4–8 years (n = 7), 9–12 years (n = 36), and
13–18 years (n = 22). The mean age of the subjects was
12.2 years. There were 51 boys and 34 girls evenly distributed
across the three age ranges.
Of the 85 patients, 62 (72.9%) had previously taken a
stimulant drug for ADHD, and 23 (27.1%) had no history of
treatment with an ADHD stimulant drug. There were
28 patients (30.0%) currently taking an ADHD drug while
57 (70.0%) were not. The breakdown of drugs taken at
the start of treatment was as follows: 14 were taking amphetamine enantiomers; five were taking methylphenidate; five
were taking atomoxetine; three were taking other drugs not
specifically defined; and one was taking a combination of
amphetamine enantiomers with atomoxetine. Parents sought
treatment under this novel approach primarily due to concerns
over lack of drug efficacy and/or drug side effects.
The ADHD-RS inventory was administered at the start
and end of treatment. Results indicated that group
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Table 3 Changes in Attention Deficit Hyperactivity Disorder
Rating Scale scores at initiation and end of treatment
Table 5 Percentage of the entire group (n = 85) achieving
complete relief of symptoms by weeks 5 and 8
Group ADHD-RS changes
2s
3s
Pre-Rx
End-Rx
t-test
P
4.6
8.3
1.2
2.3
8.42
12.26
,0.001
,0.001
Abbreviations: Rx, treatment; ADHD-RS, Attention-Deficit-Hyperactivity Disorder
Rating Scale.
scores (2 and 3) on the ADHD-RS scale (behavioral
symptoms of ADHD) decreased significantly (P , 0.001)
from the first to the second testing. ADHD-RS results are
shown in Table 3.
The decrease in 2 and 3 scores shown in Table 3 occurred
regardless of the variable being investigated, including age
and gender. This reduction in symptoms is noteworthy. Prior
to treatment, the number of significant ADHD behavioral
indicators that were displayed as “often” or “very often” were
in the 5–9 range. Only two post-treatment behavioral indicators
were noted. The only variable that approached significance
(P , 0.08) was gender. More males experienced a decrease
in symptoms in the ADHD-RS (3) from 8.9 to 2.3 versus
females in whom this score decreased from 7.1 to 2.2.
In addition to the statistical analysis parameters that were
identified on the DSM-IV, the following observations were
calculated relating to other issues. Some of the more compelling findings are included in the tables.
The results shown in Table 4 revealed that 67% of the
participants achieved significant improvement with only
amino acid precursors of serotonin and dopamine. Patients
who achieved no significant relief of symptoms with only
amino acid precursors represent a subgroup in whom urine
samples were collected and OCT assay interpretation was
utilized. In this subgroup, 30.3% achieved significant relief
of symptoms following two or three urine assays. The total
percentage of patients showing significant improvement
was 77%.
Referring to Table 6, a further 10% of patients who had
taken stimulant drugs in the past reported complete symptom
relief. There seems to be some advantage for the effectiveness of the amino acid supplement treatment when there is
a history of having taken stimulant drugs in the past.
Table 4 Percentage of the entire group (n = 85) achieving
significant relief of symptoms by weeks 3 and 8 (P , 0.05)
Significant relief
Week 3
Week 8
67%
77%
Complete relief
Week 5
Week 8
30%
33%
As noted in Table 7, a potential advantage was identified
with the administration of amino acid precursors relating to
taking ADHD drugs.
Urine tests did not typically occur until visit 4, and were
indicated if the patient did not show significant improvement
with relief of the majority of major ADHD symptoms after
one week taking level 3 dosing values of Table 1 or Table 2.
Those who experienced control of symptoms prior to or at
visit 4 were excluded from urine testing. Results of the
patients who had an OCT assay are shown in Table 8.
Therefore, it appears that urine testing with OCT assay
interpretation was beneficial because urinary serotonin and
dopamine assay interpretation defined the proper dosing
values. To establish urinary serotonin and dopamine phases
firmly requires two assays performed with varied amino acid
precursor dosing values. The significant relief values of 64%
prior to testing and 70% after two assays noted in Table 7 and
Table 8 represent only one amino acid dosing change, with
the confidence of knowing the serotonin and dopamine
phases.
Discussion
The data generated in the study were compared with data
generated in double-blind, placebo-controlled studies.
Tables 9 and 10 summarize the results of this literature
search. It would appear that the placebo effect is strong in
ADHD studies, because 28%–40% of placebo patients
achieved significant relief of symptoms in the atomoxetine
studies reviewed (Table 10), and 14%–31% had a placebo
benefit in the methylphenidate study (Table 9).
To meet the criteria for approval under FDA guidelines,
a drug has to demonstrate efficacy and safety.32 The amino
acids and cofactors used in this retrospective study are classified by the FDA as generally recognized and accepted as
Table 6 The percentage of patients with and without a history
of taking a stimulant for treatment of ADHD who experienced
complete relief of symptoms at weeks 5 and 8
No stimulant drug in past
Stimulant drug in past
Week 5
Week 8
22%
32%
28%
35%
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Hinz et al
Table 7 Effect of taking and not taking a prescription ADHD
drug on the endpoint of the study
Not taking a drug
Week 5
Week 8
Significant relief
Complete relief
64%
28%
safe (GRAS), in the same category as supplemental vitamins
and minerals.33 There are no safety concerns with the amino
acids based on this FDA position. All of the amino acids and
components used in the study are sold in the US over the
counter without a prescription.
The drugs prescribed for ADHD have potentially controversial concerns associated with them, including neurotransmitter
depletion, neurotoxicity, drug side effects, and adverse reactions;
this amino acid approach in comparison has none of these concerns associated with it. This gives a significant advantage to this
amino acid approach if studies continue to bear out that it is
similar or superior to prescription ADHD drugs in its efficacy.
This retrospective study was performed in order to focus
on the structure needed for a formal prospective study.
In the course of this study, the following observations and
considerations came to light. The administration of properly
balanced amino acid precursors of serotonin and dopamine
with OCT assay interpretation resulted in improvement that
appears to be superior to methylphenidate and atomoxetine
(Tables 9 and 10). This certainly provides encouragement to
undertake further studies.
Even if the finding was that use of serotonin and dopamine
amino acid precursors with OCT assay interpretation was
equal to reported efficacy values found with atomoxetine and
methylphenidate, it is asserted that this approach would be
superior because it does not share the adverse reactions,
Table 8 Approximately 59% of patients in the group achieved
relief of symptoms with administration of amino acids and no
testing
Urine test group
Two tests
Three tests
70%
78%
Notes: If no response was observed after treatment with the three amino acid
dosing levels of Table 1 or Table 2, organic cation transporte assay interpretation
was initiated leading to an increase in the number of patients in the study who
experienced significant relief of symptoms.
potential depletion of neurotransmitters, and neurotoxicity
concerns reported with the group of drugs prescribed for
ADHD treatment.
There is variance identified and reported in children who
were and were not taking drugs during this study. Future
studies need to be designed to address the impact of amino
acids on subgroups such as this. A further identified issue in
this study that needs to be corrected in future studies is the
timeline of the study. In response to the lack of amino acid
efficacy at visit 4 (taking level 3 dosing values for one week
from Tables 1 and 2), OCT assay interpretation was started.
For children in the study for 10 weeks, three urinary tests
were obtained. Experience leading up to this study suggested
that a significant number of patients with ADHD do not
achieve relief of symptoms until both urinary serotonin and
dopamine are in the phase 3 therapeutic ranges. Data analysis
revealed that it typically takes 2–8 urine tests with OCT assay
interpretation to achieve this goal. Provisions need to be made
in future studies to move away from rigid time guidelines
and position the studies as a process independent of time
where the endpoint is urinary serotonin and dopamine in the
phase 3 therapeutic ranges or relief of symptoms, whichever
comes first.
Table 9 Retrospective study results, significant improvement in patients (Table 4) versus reported results in double-blind, placebocontrolled studies taking methylphenidate
n
% improved
% placebo
improved
% drug
improvement
over placebo
Pilot study results
Methylphenidate studies
AA with OCT assay
interpretation
Study 126
Study 227
Study 328
85
77% (Table 4)
N/A
154
64%
27%
97
52%
31%
18
58%
14%
N/A
37%
21%
44%
Notes: The “% placebo improved” row represents percentage of subjects taking placebo who experienced significant remission of symptoms to the defined threshold of the
study or greater. The bottom row is the advantage of the drug over placebo in the study cited.
Abbreviations: AA, amino acid; OCT, organic cation transporter.
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Table 10 Retrospective study results, significant improvement in patients (see Table 4) versus reported results in double-blind,
placebo-controlled studies of patients taking atomoxetine
n
% improved
% placebo
improved
% drug
improvement
over placebo
Pilot study results
Atomoxetine studies
AA with OCT assay
interpretation
Study 129
Study 230
Study 331
85
77% (Table 4)
N/A
618
71%
28%
36
54%
40%
84
59%
31%
N/A
43%
14%
28%
Notes: The “% placebo improved” row represents percentage of subjects taking placebo who experienced significant remission of symptoms to the defined threshold of the
study or greater. The bottom row is the advantage of the drug over placebo in the study cited.
Abbreviations: AA, amino acid; OCT, organic cation transporter.
It is also suggested that the scrutiny of this retrospective
study be expanded to identify more phenotype traits.
Incorporation of expanded data fields such as this into further
studies would facilitate more indepth comparison with other
studies and statistical evaluation of subgroups.
This analysis does provide some initial evidence of the
efficacy of amino acids in significantly reducing symptoms
associated with ADHD. Tables 9 and 10 reveal the efficacy
of this treatment protocol to be potentially superior to results
seen with prescription drugs. Future studies are needed to
investigate the reliability of these observed effects. If these
results can be replicated in controlled studies, then such
important issues as cause and effect for the changes in ADHD
symptoms, potential mediating variables, and long-term uses
can be further investigated and clarified.
Conclusion
Based on the FDA guidelines, the amino acid precursors of
serotonin and dopamine, used in this study, are classified as
GRAS, meaning no significant safety concerns exist about
their use. The next question to ponder is whether the approach
is effective. The FDA has not set the bar very high in demonstrating efficacy of prescription drugs. There are numerous
examples of drugs being approved that are only 7%–13% more
effective than placebo.4 Under these conditions, it would appear
that the findings of this study have the potential to demonstrate
at least that level of efficacy in a prospective study based on
Tables 9 and 10.
The purpose of this paper was to document formally the
results and findings generated during the course of this retrospective pilot study involving 85 children, and define
parameters that allow focus on a future prospective study.
It is the goal of this paper to spark interest, research, awareness,
and scrutiny of these findings, and to raise awareness of
potential neurotransmitter depletion and neurotoxicity issues
relating to ADHD drugs.
Disclosure
This study was funded by an unrestricted grant from CHK
Nutrition, Duluth, MN. MH discloses his relationship with DBS
Labs Inc and NeuroResearch Clinics Inc. TU discloses his
relationship with DBS Labs. The other authors report no
disclosures.
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Return to index
Urinary neurotransmitter testing: considerations
of spot baseline norepinephrine and epinephrine
3 February 2011
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
Clinics Inc., Cape Coral, FL, USA;
2
Plantation, FL, USA; 3DBS
Laboratories, Duluth, MN, USA
1
Background: The purpose of this paper is to present the results of statistical analysis of spot
baseline urinary norepinephrine and epinephrine assays in correlation with spot baseline urinary
serotonin and dopamine findings previously published by the authors. Our research indicates a
need for physicians and decision-makers to understand the lack of validity of this type of spot
baseline monoamine testing when using it in the decision-making process for neurotransmitter
deficiency disorders.
Methods: Matched-pairs t-tests were performed for a group of subjects for whom spot baseline
urinary norepinephrine and epinephrine assays were performed on samples collected on different days then paired by subject.
Results: The reported laboratory test results for urinary serotonin, dopamine, norepinephrine,
and epinephrine, obtained on different days from the same subjects, differed significantly and
were not reproducible.
Conclusion: Spot baseline monoamine assays, in subjects not suffering from a monoaminesecreting tumor, such as pheochromocytoma or carcinoid syndrome, are of no value in
decision-making due to this day-to-day variability and lack of reproducibility. While there have
been attempts to integrate spot baseline urinary monoamine assays into treatment of peripheral
or central neurotransmitter-associated disease states, diagnosis of neurotransmitter imbalances,
and biomarker applications, significant differences in day-to-day reproducibility make this
impossible given the known science as it exists today.
Keywords: neurotransmitter testing, epinephrine, norepinephrine, dopamine, serotonin
Introduction
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
Dovepress
DOI: 10.2147/OAJU.S16637
A previously published paper by the authors of this paper discussed the reproducibility
of spot baseline urinary serotonin and dopamine assays. 1 This companion paper
discusses the reproducibility of spot baseline urinary norepinephrine and epinephrine
assays, and explores the feasibility and validity of using spot urinary norepinephrine
or epinephrine assays in subjects not suffering from a monoamine-secreting tumor
as a basis for decision-making. The paper then correlates the novel spot baseline
norepinephrine and epinephrine findings reported here with our earlier reports relating
to spot baseline urinary serotonin and dopamine.
Urinary neurotransmitter testing samples can be generated in several ways. “Spot
urine” is a single urine sample obtained at a specific time.1 A 24-hour urine sample is
a collection of all urine excreted in a defined time period, and is used when the total
daily excretion of a substance by the kidneys into the urine is to be studied. One application of the 24-hour urine test is in the diagnosis of monoamine-secreting tumors.
Open Access Journal of Urology 2011:3 19–24
19
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Hinz et al
ollection of a 24-hour urine sample is burdensome, and
C
requires the subject to carry sample collection materials
during all daily activities.2,14
Urinary monoamines exist in two states, ie, “the endogenous
state”, found when no amino acid precursors of the
monoamines are being administered, and “the competitive
inhibition state”, found when significant amounts of both
serotonin and dopamine amino acid precursors are being
administered simultaneously. Obtaining urine samples in the
endogenous state is known as “baseline testing”.3 The focus of
this paper is spot urine measurements obtained in the endogenous state, which is also known as “baseline urinary neurotransmitter testing”. Spot baseline urinary neurotransmitter testing
samples obtained in the endogenous state are of no value in
patients not suffering from a monoamine-secreting tumor,
such as pheochromocytoma or carcinoid syndrome, due to
a lack of reproducibility of the testing involved.1 Previously
published peer-reviewed literature has established the validity
and utility of OCT interpretation of monoamine assays in the
competitive inhibition state when performed under proper
conditions.1,3–5
Results of statistical analysis of spot baseline urinary neurotransmitter testing of serotonin and dopamine assays have
been discussed and published previously by the authors of
this paper.1 Novel statistical results of spot baseline urinary
neurotransmitter testing of norepinephrine and epinephrine
assays from a database accumulated by two of the authors
of this paper are reported here. Urinary norepinephrine and
epinephrine samples obtained on different days from the
same subject were statistically analyzed using a matchedpairs t-test. A P value #0.05 was considered to reveal
a significant difference between groupings. JMP (SAS
Institute, Cary, NC) software was used to perform the
statistical analysis.
collected six hours prior to bedtime, with 4 pm being the most
frequent collection time point. The samples were stabilized in
6 N HCl to preserve urinary dopamine and urinary serotonin.
Samples were shipped to DBS Laboratories, Duluth, MN.
Urinary norepinephrine and dopamine were assayed utilizing
commercially available radioimmunoassay kits (3 CAT RIA
IB88501 and IB89527; Immuno Biological Laboratories Inc,
Minneapolis, MN). DBS Laboratories is accredited as a high
complexity laboratory by Clinical Laboratory Improvement
Amendments to perform these assays.
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Results
In order for laboratory testing to be valid it needs to be
reproducible. The following is a discussion of the statistical
reproducibility of spot baseline urinary neurotransmitter
testing of norepinephrine and epinephrine performed on a
group of subjects in whom two urine samples were obtained on
different days. The matched-pairs t-test was used to evaluate
these spot baseline samples. To complete the serotonin and
catecholamine discussion, previously published data by the
authors relating to spot baseline urinary neurotransmitter
testing of serotonin and dopamine is included, because
norepinephrine and epinephrine production and balance are
related to balanced levels of serotonin and dopamine.
Spot baseline norepinephrine
matched-pairs t-test
The following norepinephrine data are novel. The laboratory
values are reported in µg of norepinephrine per g of creatinine.
From a matched-pairs group of n = 54, the mean and standard
deviation (SD) for both spot baseline norepinephrine urinary
assay groups was determined. For Group 1, the mean norepinephrine value was found to be 64.66 (±148.98). For Group 2
(spot baseline norepinephrine testing performed on a different
day after the first assay), the mean norepinephrine value was
found to be 42.01 (±173.39). All data greater than the value
found in calculating the sum of two SDs plus the mean were
removed from consideration, revealing a group of n = 44.
This matched-pair values group was then analyzed using the
matched-pairs t-test, revealing a P value of 0.0399. These
findings indicate that spot baseline urinary norepinephrine
levels do differ in a statistically significant manner when
spot baseline assays are performed on different days from
the same subject. This supports the assertion that spot urinary
norepinephrine values are not uniform or reproducible from
day to day. The epinephrine group (n = 44) comprised
21 females aged 48.22 (±13.34) years and 23 males aged
46.31 (±14.63) years.
Spot baseline epinephrine matched-pairs
t-test
The following epinephrine data are also novel. The laboratory
values are reported in µg of epinephrine per g of creatinine.
From a matched-pairs group of n = 135, the mean and the
SD for both spot baseline epinephrine urinary assay groups
was determined. For Group 1, the mean epinephrine value
was found to be 6.55 (±5.5). For Group 2 (spot baseline
testing performed on a different day after the first assay),
the mean epinephrine value was found to be 10.4 (±14.12).
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All data greater than the value found in calculating the sum
of two SDs plus the mean were removed from consideration,
leaving a group of n = 122. This matched-pair values group
was then analyzed using the matched pairs t-test, revealing
a P value of ,0.0001. These findings indicate that spot
baseline urinary epinephrine levels do differ in a statistically
significant manner when spot baseline assays are performed
on different days from the same subject. This supports the
assertion that spot urinary epinephrine values are not uniform
or reproducible from day to day. The epinephrine group
(n = 122) comprised 63 females aged 59.09 (±11.87) years
and 59 males aged 45.89 (±18.72) years.
Spot baseline serotonin matched-pairs
t-test
A 2010 peer-reviewed paper by the authors presented results
of a novel spot serotonin matched-pairs t-test (n = 134). Spot
baseline–baseline grouping of urinary serotonin samples
obtained on different days from the same patient revealed a
P value of 0.0080. This indicates that spot baseline urinary
serotonin levels differ in a statistically significant manner
when they are performed on different days from the same
subject. This supports the assertion that spot urinary serotonin values are not uniform or reproducible from day to
day.1
Spot baseline dopamine matched-pairs
t-test
A 2010 peer-reviewed paper by the authors of this paper
presented results of a novel spot dopamine matched-pairs
t-test (n = 138). Spot baseline–baseline grouping of urinary
dopamine samples obtained on different days from the same
patient revealed a P value of 0.0049. This indicates that spot
baseline urinary dopamine levels differ in a statistically significant manner when they are performed on different days
from the same subject. This supports the assertion that spot
urinary dopamine values are not uniform or reproducible
from day to day.1
Results of the four matched-pairs t-tests shown in
Table 1 reveal that there are significant differences between
spot baseline urinary neurotransmitter testing performed on
different days from the same subject for all four monoamines
under scrutiny.
Simply asserting that testing differs significantly and is
not reproducible from day to day in the same subject may not
have the impact of reviewing the data used for the statistical
analysis. The data in the accompanying tables illustrate
that the urinary neurotransmitter testing results are not
Urinary neurotransmitter testing
Table 1 Matched-pairs t-test values. A P value ,0.05 indicates
that a significant difference between the test 1 grouping and
test 2 grouping exists on different days in the same individual.
Spot baseline monoamine assays are not uniform and reproducible
from day to day in the same subject, and therefore the testing is
not reproducible or valid
Norepinephrine
Epinephrine
Serotonin
Dopamine
n
P value
44
122
134
138
0.0399
,0.0001
0.0080
0.0049
reproducible from day to day, and that spot baseline urinary
neurotransmitter testing is not a valid foundation for medical
decision-making. Tables 2–5 contain the paired results of
160 spot baseline urinary neurotransmitter tests. All values
are reported in µg of monoamine per g of creatinine.
The urine samples analyzed were collected approximately
six hours prior to bedtime, with 4 pm being the most common
time of collection. A review of all samples collected at other
times of the day revealed results that were similar to the aforementioned findings. Spot baseline urinary monoamine samples
differed significantly from day to day in the same subject,
regardless of the time collected, and were not reproducible.
Discussion
In the scientific world, there are two highly polarized views
regarding the validity of spot baseline urinary neurotransmitter
testing. One view advocates that baseline urinary neurotransmitter testing has no value in patients not suffering from a
Tables 2a, b Serial spot baseline–baseline norepinephrine assays
from the same subject. Some of the norepinephrine data used to
determine the norepinephrine matched-pairs t-test values found
in Table 1. Comparison of norepinephrine 1 with norepinephrine 2
from the same subject (by row) illustrates the lack of test
reproducibility. The number of days column is the number of days
between urinary sample collection dates
a) Sort: High-low by NE-1
b) Sort: High-low by NE-2
Days (n)
NE-1
NE-2
Days (n)
NE-1
NE-2
217
58
28
41
32
19
42
41
50
29
595.42
479.59
416.86
399.75
386.01
381.86
357.80
301.00
268.04
232.14
270.20
8.50
132.37
49.38
540.17
10.62
61.73
203.70
31.36
261.01
272
225
32
79
217
29
189
41
28
64
145.46
7.67
386.01
151.44
595.42
232.14
132.09
301.00
0.97
214.24
861.92
581.60
540.17
482.38
270.20
261.01
233.98
203.70
195.92
186.00
Abbreviation: NE, norepinephrine.
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Hinz et al
Tables 3a, b Serial spot baseline–baseline epinephrine assays
from the same subject, including epinephrine data used to determine
the epinephrine matched-pairs t-test values found in Table 1.
Comparison of EPI-1 with EPI-2 from the same subject (by row)
illustrates lack of test reproducibility. The number of days column is
the number of days between urinary sample collection dates
a) Sort: High-low by EPI-1
b) Sort: High-low by EPI-2
Days (n)
EPI-1
EPI-2
Days (n)
EPI-1
EPI-2
43
22
364
27
46
49
380
185
42
41
36.06
24.83
22.81
21.37
20.44
18.80
18.59
16.49
14.80
12.86
3.90
9.58
11.99
3.22
14.76
6.69
13.83
4.87
8.43
6.57
77
272
104
35
42
46
98
380
225
22
8.98
13.09
8.43
8.62
14.80
20.43
6.39
18.59
6.16
24.83
29.09
16.37
15.34
15.01
14.99
14.76
14.10
13.83
13.42
13.02
Abbreviation: EPI, epinephrine.
monoamine-secreting tumor.1,3–5 The other view advocates
that it is very beneficial, and that it has numerous applications
in medical decision-making, including diagnostic, therapeutic, and biomarker applications.6–12 The purpose of this
writing is to educate medical practitioners regarding the
selection of laboratory testing for neurotransmitter diseases
so that they do not use invalid testing methods.
The science supporting the view of the authors is as
follows. It is a well-known fact that norepinephrine, epinephrine, serotonin, and dopamine do not cross the blood–brain
barrier. These monoamines are filtered at the glomerulus and
are then metabolized by the kidneys. Significant amounts of
these monoamines filtered at the glomerulus do not reach the
final urine. Monoamines found in the urine of patients not
suffering from a monoamine-secreting tumor are primarily
synthesized by structures in the kidneys.1,3–5,13 Spot baseline
testing lacks reproducibility and is of no value in patients not
suffering from a monoamine-secreting tumor.1
Those who claim that spot baseline urinary neurotransmitter testing is valid assert that monoamines cross the
blood–brain barrier, are filtered at the glomerulus, and simply
excreted into the urine without further renal involvement.
They conclude that spot baseline urinary neurotransmitter
testing is a valid assay for peripheral and central nervous
system neurotransmitter levels.6–12
Spot baseline urinary neurotransmitter testing of norepinephrine, epinephrine, serotonin, and dopamine is not
reproducible from day to day in the same subject; therefore,
this type of testing is not valid. An infinite number of assays
performed on an infinite number of days would generate an
infinite number of differing test results.1 The following are
true, based on the statistics put forth in this paper and the lack
of reproducibility as demonstrated in this writing:
• Spot urinary neurotransmitter testing is not a reliable
assay for peripheral or central nervous system function;
the majority of serotonin and catecholamine molecules
found in the urine of patients not suffering from a
monoamine-secreting tumor have never been in the
peripheral or central nervous system, having been
synthesized by renal structures
• Spot urinary neurotransmitter testing does not correlate
with monoamine neurotransmitter-related disease states
in patients not suffering from a monoamine-secreting
tumor
• Spot urinary neurotransmitter testing, due to lack of
reproducibility, cannot assist the health care practitioner
in making informed decisions regarding the choice
Tables 4a, b Serial spot baseline-baseline serotonin assays from the same subject, including some of the serotonin data used to
determine the serotonin matched-pairs t-test values found in Table 1, from a previously published paper by the authors.1 Comparison
of serotonin 1 with serotonin 2 from the same subject (by row) vividly illustrates lack of testing reproducibility. The number of days
column is the number of days between urinary sample collection dates
a) Sort: High-low by Serotonin 1
b) Sort: High-low by Serotonin 2
Days
Serotonin 1
Serotonin 2
Days
Serotonin 1
Serotonin 2
42
28
32
41
98
42
79
29
217
19
9885.64
5178.39
3309.76
2451.00
2157.10
1569.16
1159.95
1005.58
828.22
763.47
179.65
415.45
1191.05
4049.95
368.47
432.35
5194.81
851.43
2275.38
31.14
272
79
41
41
103
217
204
47
383
32
307.07
1159.95
2451.00
96.77
9885.65
828.22
276.97
227.30
60.32
3309.76
6004.24
5194.81
4049.95
3655.97
3246.75
2275.38
2183.79
2000.00
1996.24
1191.05
22
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Urinary neurotransmitter testing
Tables 5a, b Serial spot baseline–baseline dopamine assays from the same subject, including dopamine data from a previous study
used to determine the dopamine matched-pairs t-test values found in Table 1.1 Comparison of dopamine 1 with dopamine 2 from the
same subject (by row) illustrates the lack of test reproducibility. The number of days column is the number of days between urinary
sample collection dates
a) Sort: High-low by dopamine 1
b) Sort: High-low by dopamine 2
Days (n)
Dopamine 1
Dopamine 2
Days (n)
Dopamine 1
Dopamine 2
46
41
204
28
77
27
58
168
28
29
7854.32
1129.58
1034.63
785.00
652.35
498.23
419.82
405.20
387.64
372.51
1884.93
2891.23
71.76
181
1288.47
68.80
88.41
180.51
169.78
208.49
41
98
6
103
46
28
77
314
47
383
1129.58
300.37
138.81
164.50
7854.32
785.00
652.35
197.72
785.00
289.88
2891.23
2623.79
2504.14
2109.03
1884.93
1806.00
1288.48
1220.54
853.00
430.71
of amino acids, or the dosing value for intervention
with a disease state associated with monoamine
neurotransmitters
• Spot urinary neurotransmitter testing, due to lack of reproducibility, does not have a place in clinical practice for
identifying biomarkers of peripheral or central nervous
system function and disease states
• Spot urinary neurotransmitter testing cannot determine
monoamine imbalances that exist in subjects because the
results are not reproducible
• Spot baseline monoamine assays cannot serve as a predictor of expected efficacy once amino acid precursors are
started due to lack of reproducibility.
There is evidence that urinary monoamines, such as
norepinephrine reported on 24-hour urine samples, may be
elevated in a specific group of patients with depression.15
However, these are group findings, and do not necessarily
translate to individual testing validity on spot testing due to
the lack of reproducibility of the test from day to day in the
same subject.
Conclusion
This research underscores the fallacy of the attempt to use
spot baseline urinary neurotransmitter testing as a potential
biomarker in the treatment of patients with presumed monoamine neurotransmitter-related diseases who are not suffering
from a monoamine-secreting tumor. Levels of urinary norepinephrine, epinephrine, serotonin, and dopamine, found in the
urine on spot baseline testing, differ significantly from day to
day in the same subject. Results are not reproducible, so spot
baseline urinary neurotransmitter testing in the endogenous
state in subjects not suffering from a monoamine-secreting
tumor is of no clinical value. Health care practitioners need
to understand this difference when selecting a form of testing
for their patients. It is hoped that this writing will spark
interest and scrutiny of the topic, leading to advancement
of the relevant science.
Disclosure
The authors report no conflicts of interest in this work.
References
urine, a comprehensive analysis. Open Access Journal of Urology.
2010;2:177–183.
2. Smythe G, Edwards G, Graham P, Lazarus L. Biochemical diagnosis
of pheochromocytoma by simultaneous measurement of urinary
excretion of epinephrine and norepinephrine. Clin Chem. 1992;38:
486–492.
5. Hinz M, Stein A, Uncini T. Amino acid responsive Crohn’s disease.
Clinical and Experimental Gastroenterology. 2010;3:171–177.
6. Alts J, Alts D, Bull M. Urinary Neurotransmitter Testing: Myths and
Misconceptions. Osceola, WI: NeuroScience Inc; 2007.
7. Watkins R. Validity of urinary neurotransmitter testing with clinical applications of CSM (Communication System Management)
model. Asheville, NC: Sanesco International; 2009. Available at:
http://www.neurolaboratory.net/lab/neurolab%20pdf.%20
files/2009%20Urinary%20NT%20White%20Paper.pdf. Accessed
November 24, 2010.
8. Theirl S. Clinical relevance of neurotransmitter testing. The Original
Internist. December 2009. Available at: http://www.clintpublication.
com/documents/Dec_OI_2009.pdf. Accessed November 24, 2010.
9. Sanesco. Neurolab baseline sample report. Available at: http://sanesco.
net/images/files/resourcelibrary/baseline_sample_report.pdf. Accessed
November 24, 2010.
10. Neuroscience. Assessing nutritional imbalances. Available at: https://
www.neurorelief.com/index.php?option=com_content&task=view&id=
131&Itemid=48. Accessed November 24, 2010.
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11. Kellermann G, Bull M, Ailts J, et al. Understanding diurnal variation.
Technical Bulletin Issue 4. Osceola, WI: NeuroScience Inc;
January 9, 2004. Available at: https://www.neurorelief.com/index.
php?option=com_content&task=view&id=224&Itemid=48. Accessed
November 24, 2010.
12. Marc D, Ailts J, Ailts-Campeau D, et al. Neurotransmitters excreted in
the urine as biomarkers of nervous system activity: validity and clinical
applicability. Neurosci Biobehav Rev. 2011;35:635–644.
Dis Treat. 2009;5:227–235.
14. Hughes J, Watkins L, Blumenthal J, Kuhn C, Sherwood A. Depression
and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom
Res. 2004;57:353–358.
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International Journal of General Medicine
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Return to index
C a s e r e po r t
Amino acid management of Parkinson’s disease:
a case study
25 February 2011
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
2
Duluth, MN, USA
1
Abstract: An extensive list of side effects and problems are associated with the administration
of l-dopa (l-3, 4-dihydroxyphenylalanine) during treatment of Parkinson’s disease. These
problems can preclude achieving an optimal response with l-dopa treatment.
Purpose: To present a case study outlining a novel approach for the treatment of Parkinson’s
disease that allows for management of problems associated with l-dopa administration and
discusses the scientific basis for this treatment.
Patients and methods: The case study was selected from a database containing 254 Parkinson’s
patients treated in developing and refining this novel approach to its current state. The spectrum
of patients comprising this database range from newly diagnosed, with no previous treatment,
to those who were diagnosed more than 20 years before and had virtually exhausted all medical
treatment options. Parkinson’s disease is associated with depletion of tyrosine hydroxylase,
dopamine, serotonin, and norepinephrine. Exacerbating this is the fact that administration of
l-dopa may deplete l-tyrosine, l-tryptophan, 5-hydroxytryptophan (5-HTP), serotonin, and
sulfur amino acids. The properly balanced administration of l-dopa in conjunction with 5-HTP,
l-tyrosine, l-cysteine, and cofactors under the guidance of organic cation transporter functional
status determination (herein referred to as “OCT assay interpretation”) of urinary serotonin and
dopamine, is at the heart of this novel treatment protocol.
Results: When 5-HTP and l-dopa are administered in proper balance along with l-tyrosine,
l-cysteine, and cofactors under the guidance of OCT assay interpretation, the long list of
problems that can interfere with optimum administration of l-dopa becomes controllable and
manageable or does not occur at all. Patient treatment then becomes more effective by allowing
the implementation of the optimal dosing levels of l-dopa needed for the relief of symptoms without the dosing value barriers imposed by side effects and adverse reactions seen in the past.
Keywords: Parkinson’s, Parkinsonism, Parkinson’s disease, l-dopa, 5-HTP
Introduction
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
Dovepress
DOI: 10.2147/IJGM.S16621
There is a need to effectively control and manage the problems associated with l-dopa
treatment in every Parkinson’s patient allowing full access to the l-dopa dosing level
needed by each Parkinson’s patient in order to achieve optimal relief of symptoms.1,2
This novel approach allows for the full access to the required l-dopa dosing values
through minimization or elimination of the undesirable l-dopa side effects. This is the
first attempt to formally document some of the results seen and the experience gained
in refining this novel protocol as applied to Parkinson’s disease.
Based on clinical experience gained with this novel protocol, it is asserted that
virtually all of the problems encountered in the administration of l-dopa for Parkinson’s
International Journal of General Medicine 2011:4 165–174
165
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Hinz et al
disease are caused by the improper management of systems
impacted by l-dopa and/or the concomitant use of carbidopa
with l-dopa.
This case study was selected as the focal point for a discussion of a novel Parkinson’s disease treatment protocol.
The case was not selected due to extraordinary results; it
was selected as an illustration of typical results seen with
this protocol. The purpose of this paper is to outline the basic
protocol as a reference point for future prospective studies.
The patient is a Vietnam veteran working as a computer
specialist who at the age of 55 years began to experience
tremor in the left upper extremity, which led to the diagnosis
of Parkinson’s disease. The patient was referred to the
practice of one of the authors of this paper for intravenous
(IV) glutathione treatment by a prominent neurologist. The
patient had exhausted virtually all nonsurgical medical
approaches in the treatment of his Parkinson’s disease. His
neurologist advised him that the only remaining option
available in the United States was deep brain stimulation.
This option was not agreeable to the patient.
This paper is based on research started in 1997 that
has consistently focused on the study, interactions, and
applications of serotonin, dopamine, and their amino
acid precursors. The hypothesis of this writing is that the
majority of side effects and problems observed during
treatment of Parkinson’s disease with l-dopa are caused by
mismanagement of the amino acid precursors and systems
affected by l-dopa.
Side effects and/or adverse reactions tend to be the
dose-limiting events associated with administration of
only l-dopa. These include but are not limited to nausea,
involuntary movements, and psychiatric problems. 1,2 In
order to address these l-dopa problems, medications that
potentiate l-dopa and/or dopamine are conventionally administered. These include decarboxylase inhibitors (carbidopa),3
dopamine agonists,4 glutamate (n-methyl-d-aspartic acid
[NMDA])-blocking drugs,5 anticholinergics, 6 MAO-B
inhibitors,7 and COMT inhibitors.8 All of these drugs are
second-line support drugs in comparison to the correctional
action and potential of l-dopa.9
This novel approach for the treatment of Parkinson’s
disease is dependent upon the administration of l-dopa in
adequate amounts to control symptoms through minimization
of side effects and adverse reactions by establishing a proper
balance between the dopamine and serotonin systems with
the concomitant use of 5-hydroxytyrptophan (5-HTP),
l-tyrosine, and a sulfur amino acid under the guidance of
organic cation transporter (OCT) assay interpretation.10–14
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The primary symptoms of Parkinson’s disease are the
result of degeneration of the post-synaptic neurons of
the substantia nigra. The very process of Parkinson’s disease
is associated with depletion of dopamine (DA), tyrosine
hydroxylase (TH), norepinephrine (NE), and serotonin
(5-HT).15–17 Parkinson’s disease depletion of these systems
is compounded by further depletion with l-dopa. As noted
in the literature, administration of only l-dopa or improperly
balanced l-dopa further depletes:
• l-tyrosine13,18,19
• serotonin10,14,18,20–25
• l-tryptophan18
• sulfur amino acids (glutathione and S-adenosylmethionine)10,13,14,26–28
• epinephrine29
l-dopa
depletion of l-tyrosine
Patients with Parkinsonism suffer from low levels of
tyrosine hydroxylase prior to treatment.15,17 The depressed
levels of tyrosine hydroxylase inhibit conversion of
l -tyrosine to l -dopa. It is known that l -dopa depletes
l-tyrosine.13,18,19 The interaction of l-tyrosine and l-dopa
is covered in the discussion section of this manuscript.
Other considerations of l-tyrosine depletion by l-dopa
that need to be explored are the impact on other systems
where l-tyrosine acts as a precursor, such as with thyroid
hormones.
l-dopa
depletion of serotonin
Patients with Parkinsonism suffer from inadequate levels of serotonin as a result of the disease state. 15,16 On
average, Parkinson’s disease patients have a 50% depletion of serotonin prior to starting treatment.16 Significant
dosing values of l-dopa induce the competitive inhibition state leading to further serotonin depletion through
processes relating to interaction of serotonin and dopamine in synthesis, transport, and metabolism.10,14,18,20–25
Definitive steps need to be taken during administration
of l -dopa to keep serotonin in proper balance with
dopamine.10,13,14
In the competitive inhibition state the serotonin and
catecholamine systems function as one single system (herein
referred to as the “serotonin–dopamine system”).10–14 While
in the competitive inhibition state changes to one component
of the serotonin–dopamine system will effect changes to all
components of both systems.11,14 The solution is concomitant
administration of 5-HTP along with l-dopa to prevent the
serotonin depletion.10,13,14
International Journal of General Medicine 2011:4
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l-dopa
Amino acid management of Parkinson’s disease
depletion of sulfur amino acids
It is known that administration of l-dopa depletes sulfur
amino acids.10,13,14,26–28 The implications of this are extensive.
Glutathione is a sulfur amino acid and a powerful antioxidant
that neutralizes neurotoxins that may cause Parkinson’s
disease and other neurotoxic events in the body.25 Implications
of sulfur amino acid depletion relating to Parkinson’s disease
include but are not limited to the depletion of:
• glutathione leading to progression of Parkinson’s disease
if the neurotoxic agents that are a component of the etiology
are still present and being absorbed into the system25
• the enzymes required to synthesize l -tyrosine to
l-dopa13,17,19
• s-adenosyl-methionine, the body’s one carbon methyl
donor10,13,14,26–28
• epinephrine29
Carbidopa in treatment
Carbidopa is a general decarboxylase inhibitor. It inhibits
l-aromatic amino acid decarboxylase (AAAD), the enzyme that
catalyzes synthesis of both serotonin and dopamine from 5-HTP
and l-dopa, respectively. Carbidopa does not cross the blood–
brain barrier. It exerts its actions peripherally. In Parkinson’s
disease it is administered to decrease peripheral conversion of
l-dopa to dopamine. This results in the need for a lesser dose
of l-dopa peripherally while still giving the higher level in the
CNS with fewer side effects, especially nausea. Carbidopa is
used to address the side effects seen when improperly balanced
l-dopa is administered; there is no direct therapeutic value of
carbidopa in treatment of Parkinson’s disease.30
Carbidopa’s inhibition of AAAD potentiates peripheral
serotonin, dopamine, norepinephrine, and e pinephrine
depletion as synthesis by AAAD is compromised.
N orepinephrine and acetylcholine regulate autonomic
nervous system function. The administration of carbidopa
with l-dopa is replete with peripheral autonomic dysfunction
problems that often develop.30
Administration of carbidopa/l-dopa preparations leads
to a “double depletion” of peripheral serotonin. One cause
of depletion is carbidopa inhibition of AAAD; the other
cause is improperly balanced administration of l-dopa
which decreases peripheral serotonin synthesis and transport
through competitive inhibition along with increasing the
metabolism of serotonin.10,13,14
Organic cation transporter functional status determination
(herein referred to as “OCT assay interpretation”) along
with the amino acid dosing values described in this paper
were developed by NeuroResearch Clinics, Inc (Duluth,
MN). All of the amino acid components, including l-dopa,
are available over the counter without a prescription in the
United States.
Treatment was initiated with administration of 5-HTP,
l-tyrosine, and l-dopa at the dose levels shown in Table 1.
In addition to the amino acids noted in Table 1, the following
cofactors were administered daily: 1) vitamin C 1,000 mg;
2) calcium citrate 220 mg; 3) vitamin B6 75 mg; 4) folate
400 mcg; 5) l-lysine 500 mg; 6) l-cysteine 4,500 mg;
7) selenium 400 mcg.
l-dopa in the form of mucuna pruriens 40% standardized
was used. Peer-reviewed literature suggests that l-dopa from
the mucuna pruriens source has more rapid onset of action
and a longer time of effectiveness leading to the conclusion
that it may be a superior source of l-dopa in treating
Parkinson’s disease.31
OCT assay interpretation overview
Serotonin and dopamine are found in two states. The
endogenous state exists when no amino acid precursors are
administered. The competitive inhibition state occurs when
significant amounts of the monoamine precursors are
simultaneously administered. Proper OCT assay interpretation
requires that both serotonin and dopamine be placed in the
competitive inhibition state prior to the assay interpretation
being performed for the results to be valid.
The scientific basis for OCT assay interpretation is novel
having been published in 2009 and 2010. At the heart of this
approach is the “3-phase model.”10–14,32
The goal of this novel approach is to keep the urinary
serotonin in the phase III therapeutic range, no higher
than 800 µg serotonin per gram of creatinine, through
proper manipulation of 5-HTP in combination with
l-dopa dosing values under the guidance of OCT assay
interpretation.3,7,8,19,20
Table 1 Parkinson’s dosing values at protocol initiation. Serotonin
and dopamine precursors initially administered. One week after
start of the second dosing level, a urine sample was obtained for
mg 5-hydroxytryptophan (5-HTP)/mg L-tyrosine/mg L-dopa
Morning
Initial visit
7 days into treatment
14 days into treatment
Noon
4 pm
150/1,500/120
–
150/1,500/120
150/1,500/360
0/0/240
150/1,500/360
Initiate organic cation transporter assay
interpretation
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Hinz et al
To facilitate replication of results the following data is
included. Processing, management, and assay of the urine
samples collected for this study were as follows. Urine
samples were collected about 6 hours prior to bedtime with
4:00 pm being the most frequent collection time point. The
samples were stabilized in 6 N HCl to preserve the dopamine
and serotonin. The urine samples were collected after a
minimum of 1 week during which time the patient was taking
a specific daily dosing of amino acid precursors of serotonin
and dopamine where no doses were missed. Laboratory
studies were conducted by DBS Laboratories under the
direction of Thomas Uncini, MD, one of the authors. The
assays were performed using commercially available radioimmunoassay kits from Immunol Biological Laboratories,
Inc (Minneapolis, MN). Assays were interpreted by Marty
Hinz of NeuroResearch Clinics.
Evaluation of treatment results
The Unified Parkinson’s Disease Rating Scale (UPDRS)
on presentation into the practice and before the start of the
protocol as compared to the results 2 years into the amino
acid treatment is seen in Table 2.
Results
The only portion of the patient’s history that seems relevant
to the etiological factors involved in the development of the
Parkinson’s disease was his exposure to Agent Orange during
the course of his tour of duty in Vietnam while serving in the
military. Agent Orange is a known neurotoxin.
Early in the patient’s clinical course the symptoms were
mild and untreated. As the symptoms increased in the left
upper extremity he was prescribed carbidopa–levodopa. The
patient was opposed to taking the carbidopa–levodopa at
that time and pursued alternative medicine options. Over the
next 18 months, the patient was treated with IV glutathione,
amantadine, trihexyphenidyl, primidone, and propranolol.
The amantadine gave no relief. The trihexyphenidyl
was given in an attempt to relieve the tremor, but the tremor
continued to progress extending into the patient’s left
Table 2 Unified Parkinson’s disease rating scale (UPDRS)33
Mentation behavior mood
Daily activities of living
Motor examination
Complications of therapy
Totals
168
Start of
treatment
2 years into treatment
with amino acids
9
16
16
1
42
0
3
0
0
3
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lower extremity compounded by severe balance and gait
issues. Primidone provided some relief from the tremor,
but it caused severe nausea requiring discontinuance of the
medication. Propranolol provided no relief. IV glutathione
was effective in diminishing the tremor, but results lasted
only about 30 hours.
The patient was then again prescribed carbidopa–
levodopa in combination, which was completely ineffective.
It was also suggested by that physician that the patient seek
out additional IV glutathione treatments nearer to his home
as that was the only approach that achieved some relief of
symptoms.
In October 2008, the patient presented at the practice of
one of the authors of this paper for IV glutathione treatment.
The patient was having increasing difficulty with every aspect
of life. He was very self-conscious of the constant tremor
in his left arm and left leg, which interfered with sleep and
sitting comfortably in a chair, and made him feel conspicuous
in public. He was having great difficulty working at his job
as a computer specialist for a large computer corporation
and found it almost impossible to type on a keyboard or
to maintain focus during conference calls. He was also
experiencing severe anxiety, depression, panic attacks, and
insomnia.
On the first visit it was apparent that IV glutathione had
not achieved any meaningful or lasting relief of symptoms in
the past and that it was another brief band-aid approach to the
disease. After obtaining a comprehensive medical history and
performing a physical examination the patient was offered
the novel treatment approach discussed in this report. The
use of comprehensive amino acid support in conjunction with
OCT assay interpretation was discussed with the patient and
he agreed to the treatment plan.
Within 4 months of initiating treatment the patient
experienced dramatic improvement in the tremor in both
the upper and lower extremities. He regained coordination
in his left hand and was once again able to use the computer
keyboard. He resumed his hobby of guitar playing and was
able to perform proficiently. His gait and balance were
restored. The depression improved significantly. Anxiety
was significantly relieved. The patient had lost his fear of
going out in public.
In the 2 years since initiation of treatment the patient has
continuously maintained the benefit of the treatment, with
no surgical intervention as previously recommended by his
neurologist and no prescription medications.
There appears to have been some progression of the
damage associated with the Parkinson’s neurons since
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initiation of treatment, as there has been a need for increasing
the dosage of the l -dopa. This has been managed by
increasing the l-dopa dosing value while continuing to monitor the balance of the levels with OCT assay interpretation.
The reason for asserting that this represented a progression
of disease state versus tachyphylaxis of l-dopa, which is
commonly seen during treatment of Parkinson’s disease, is
covered in the Discussion section.
The amino acid dosing that the patient was taking at the
initiation of this study, 2 years after starting on the program,
is found in Table 3.
The amino acid dosing values administered in treatment
were guided by OCT assay interpretation to assist in proper
titration of the levels of l-dopa, l-tyrosine, and 5-HTP. This
assured that the patient achieved proper therapeutic levels of
amino acids while keeping serotonin and dopamine in the
proper balance required for minimization of side effects and
adverse reactions while optimizing outcomes. The urinary
serotonin and dopamine levels obtained during stabilization
of the patient were as shown in Table 4.
At the April 29, 2010 collection date sample of Table 4,
the patient was suffering from nausea and on–off effect
secondary to serotonin imbalance and inadequate l-tyrosine
administration, respectively. The nausea improved by the May
18, 2010 collection date sample. Subsequent to the May 18,
2010 collection date the l-tyrosine was increased incrementally to 10,375 mg per day and the l-dopa was gradually
lowered. By mid-June, the nausea and on–off effect became
minimal.
Discussion
Etiology of the disease
The literature is clear that l-dopa holds the highest potential
for relief of symptoms, but dosing values in many patients
are limited by side effects.9 With administration of l-dopa,
side effects and adverse reactions may be the dose-limiting
event that prevents attaining optimal dosing values. The
following discussion is aimed at defining the basis for an
Table 3 The current amino acid dosing values that the patient
is taking, plus cofactors found in the discussion associated with
Table 1
Present daily amino acid dosing values in mg/day
L-dopa
5-HTP
l-tyrosine
l-cysteine
l-tryptophan
14,700
37.5
10,375
4,500
375
effective treatment that controls the problems associated with
administration.
There are a host of problems encountered in group
treatment with l-dopa that have not been displayed in this
patient’s course of treatment.1,30 Future prospective studies
under this protocol are indicated to define a more exact
incidence of each of these events and their impacts on
treatment.
While this is a case study report, the authors of this
paper possess data on the amino acid dosing needs of
over 254 Parkinson’s patients who have been treated
in the refinement of this novel approach to its current
state. At the core of this approach is the administration of l-dopa, which is approved by the US Food and
Drug Administration (FDA) for treatment of Parkinson’s
disease. Table 5 lists the group dosing ranges of 5-HTP and
l-dopa seen during refinement of this novel Parkinson’s
disease treatment approach with the guidance of OCT
assay interpretation.
As noted in Table 5, dosing value needs are highly
individualized. Group dosing value needs of l-dopa and
5-HTP to control the symptoms vary in exceptionally
large ranges. The l-dopa dosing value found in the “high”
column of Table 5 has not been described previously in the
literature for the treatment of Parkinson’s disease. It appears
that adverse reactions have precluded reaching these dosing
values in the past.
The chief dose-limiting factor tends to be nausea.2 Our
experience indicates that the only way a patient can safely
and effectively be titrated to the high l-dopa dosing values
found in Table 5 is with OCT assay interpretation guiding
amino acid dosing values.
In Table 3 of this case study the daily l-dopa dosing value
of 14,700 mg per day is large. The authors of this paper were
unable to locate previous literature discussing this type of
dosing value being routinely available to patients if needed
without seeing a problem significant enough to cut back the
treatment below the therapeutic threshold. Review of the
literature reveals that a significant group of patients develop
the gastrointestinal (GI) side effects that limit further increases
in l-dopa with dosing values in the 3,000 to 4,000 mg per
day range. Certainly there are Parkinson’s patients that need
much more than 3,000 to 4,000 mg per day of l-dopa, but
these patients are barred from the optimal treatment benefits
of l-dopa as a result of the side effects.1,2
The huge dosing variance seen during group treatment
of the Parkinson’s patients in Table 5 shows that one-size
dosing does not fit all.
l-dopa
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Hinz et al
Table 4 Serotonin and dopamine values reported in μg of monoamine per g of creatinine. Amino acid dosing values reported in mg/day
1
Date
2
Serotonin
3
Serotonin phase
4
Dopamine
5
Dopamine phase
6
5-HTP
7
L-tyrosine
8
L-dopa
10/23/2008
10/30/2008
11/6/2008
11/18/2008
12/11/2008
1/8/2009
1/22/2009
2/12/2009
3/19/2009
4/13/2009
6/1/2009
6/18/2009
7/28/2009
9/8/2009
1/7/2010
4/29/2010
5/18/2010
1,309.1
1,882.1
7,506.8
3,962.9
2,192.5
106.7
399.9
202.1
1,175.8
395.2
386.3
130.2
84.9
386.3
710.2
4,848.6
724.9
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
345.8
341.4
792.9
1,212.2
1,364.7
1,900.6
1,170.8
1,747.7
1,489.9
1,149.9
1,814.6
1,729.7
2,915.7
1,730.0
2,029.8
1,346.0
1,505.7
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
200.0
200.0
300.0
100.0
100.0
37.5
37.5
37.5
100.0
100.0
37.5
37.5
37.5
37.5
75.0
212.5
37.5
1,500
3,000
3,000
3,000
4,500
4,500
4,500
4,500
4,500
4,500
4,875
4,875
4,875
3,875
5,750
7,125
6,375
300
300
450
1950
3600
6300
6300
8400
15,750
12600
11,550
12,600
12,600
12,600
14,700
13,350
14,700
Notes: 1) Date of urine sample collection; 2) urinary serotonin reported; 3) serotonin phase; 4) urinary dopamine reported; 5) dopamine phase; 6) 5-HTP dosing value at
time of sample collection; 7) l-tyrosine dosing value at time of sample collection; 8) L-dopa dosing value at time of sample collection.
Management of L-dopa depletion
of serotonin
The serotonin depletion symptoms seen in Parkinson’s disease
and l-dopa administration fall into three categories: 1) disease
symptoms associated with inadequate serotonin levels;
2) side effects and adverse reactions; and 3) tachyphylaxis
of l-dopa.
Depression is a prominent disease associated with
inadequate serotonin levels in Parkinson’s disease patients
during treatment with l-dopa. Proof of this is the response to
the most selective serotonin reuptake inhibitor, citalopram.34
Other monoamine-related disease symptoms resulting from
depletion of serotonin by the disease and l-dopa are covered
in the following discussion.10–13
Simply administering some 5-HTP with l-dopa is not
optimal. When serotonin levels that are too high in phase
III depletion of dopamine may occur through competitive
inhibition.10,14,35,36 Nausea associated with the administration
of l-dopa is a sign of serotonin and dopamine imbalance. If
Table 5 5-HTP and L-dopa group dosing parameters based on OCT
assay interpretation during treatment N = 714. 5-HTP and L-dopa
dosing value range (low-high), mean, and standard deviation
5-HTP
L-dopa
Low
High
Mean
SD
37.5 mg
120 mg
2,100 mg
25,230 mg
300 mg
1,680 mg
330.3 mg
3,652 mg
Note: OCT assay interpretation refers to organic cation transporter functional status
determination.
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serotonin levels are too high or too low, nausea from l-dopa
can become a significant problem. When 5-HTP and l-dopa
are in proper balance and nausea associated with l-dopa displays, it is much milder and more easily manageable, resolving
in a matter of days in most cases. Additional management of
residual nausea may be through the implementation of smaller,
more frequent l-dopa dosing values. With proper serotonin–
dopamine balance nausea is no longer an l-dopa dose-limiting
event for virtually all patients and the use of carbidopa is no
longer needed. Since the development of nausea is the result
of serotonin levels that are either too high or too low and the
high or low status of the serotonin relative to dopamine cannot be distinguished clinically, OCT assay interpretation is
indicated to properly clarify and manage the problem.
Even with judicious and generous use of OCT assay
interpretation in this case study, this patient developed some
transient nausea, but it was not significant enough to avoid
maintaining the l-dopa dosing values at the level needed for
continued relief of Parkinson’s symptoms or the stopping
of the l-dopa, and within a matter of days the symptoms
resolved.10–14
Tachyphylaxis (where a drug stops working) of l-dopa
is associated with depletion of serotonin by l-dopa. When
serotonin levels become too depleted, any beneficial effects
of l-dopa will not be observed regardless of how high the
l-dopa dosing values are raised. When tachyphylaxis occurs,
the typical response is to increase the daily l-dopa dosing
value, which only further depletes serotonin. As treatment
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progresses, with further increases of the l-dopa dosing
values, the time between tachyphylaxis events decreases
and the patient’s l-dopa dosing values spiral ever higher.
The indicated approach is OCT assay interpretation in order
to balance serotonin and its precursors with the l-dopa and
dopamine, thereby managing the problem effectively.10–14
The results section noted a decrease in effectiveness
in the l-dopa in this patient in early 2009. In the results
section it was asserted, “There appears to have been some
progression of the damage associated with the Parkinson’s
neurons since the initiation of treatment, as there has been
a need for increasing the dosage of the l-dopa. This has
been managed by increasing the l-dopa dosing value while
continuing to monitor the balance of the levels with OCT
assay interpretation.” The decreased effectiveness of l-dopa is
primarily due to one of three events: 1) lack of patient compliance; 2) serotonin depletion leading to l-dopa tachyphylaxis;
or 3) further neuronal damage causing progression of the
disease. The patient’s medication journal ruled out concerns
in the area of compliance. OCT assay interpretation revealed
that the urinary serotonin was in phase III and in the desired
range, ruling out serotonin depletion concerns associated
with l-dopa tachyphylaxis. By exclusion, further progression of disease in the form of progression of neuronal damage had occurred. The three primary causes of decreased
response to prescribing l-dopa noted in this paragraph need
to be fully appreciated and implemented since the treatment
approach to the perceived decrease in efficacy of l-dopa is
very different.
Management of dopamine fluctuations
with l-tyrosine
As noted in previous writings by two of the authors of this
paper, urinary dopamine levels fluctuate on urinary assay significantly if proper levels of l-tyrosine are not co-administered
with l-dopa in the competitive inhibition state.37 This fluctuation in the competitive inhibition state is a direct reflection
of OCT2 activity of the basolateral monoamine transporters
of the proximal convoluted tubule cells of the kidneys.11,38
Research experience leading up to this writing has shown that
patients taking l-dopa required minimum administration of
5,000 to 6,000 mg per day of l-tyrosine to prevent significant
urinary dopamine fluctuations.10,13 It is a novel finding of this
research that l-tyrosine depletion and dopamine fluctuations
are associated with the on–off effect. The patient in this study
began to experience on–off effect. Instead of increasing the
l-dopa dosing, the l-tyrosine dosing values were increased
as noted in Table 3. The maximum required l-tyrosine dosing value encountered for control of on–off effect in all
patients studied leading up to the writing of this paper was
20,000 mg per day.
Management of sulfur amino acid
depletion by l-dopa
The sulfur amino acid l-cysteine was selected for use due
to its role in synthesis of enzymes that catalyze monoamine
synthesis. Theoretically, from the standpoint of enzymes
that catalyze monoamine synthesis, any sulfur amino acid,
with the exception of n-acetyl-cysteine and glutathione, may
serve as a sulfur donor in enzyme synthesis. From a database
developed by one of the authors of this article containing
over 1.931 million patient-days of amino acid treatment in
patients not suffering from Parkinson’s disease, objective
results revealed optimal l-cysteine dosing was 4,500 mg
per day. No objective changes were observed with the daily
dosing values of l-cysteine at or below 2,250 mg per day and
no additional response was seen in dosing values greater than
4,500 mg per day.10,13,14
Administration of proper levels of sulfur amino acids
prevents depletion of all of the following: glutathione; the
enzymes that catalyze amino acid precursors into monoamines;
S-adenosylmethionine; and epinephrine.10,13,14
It is asserted that metabolism of toxins utilizes a large
amount of sulfur amino acids in the form of glutathione
each day. Administration of IV glutathione is analogous
to temporarily plugging a hole in a bucket leaking sulfur
amino acids. The effect of IV glutathione is a temporary
band-aid approach, with sulfur amino acid levels returning
to the previous state and a relapse of symptoms within one to
two days of administration. A superior approach is the daily
administration of proper levels of sulfur amino acids from
the start of treatment so that sulfur amino acid depletion does
not have to be further addressed.10,13,14
Management of paradoxical amino acid
reactions
Most Parkinson’s disease patients treated under this novel
approach do not achieve gradual relief of symptoms as the
l-dopa dosing values are increased. Symptom cessation
tends to be abrupt, analogous to turning a light switch from
off to on.10,13,14
Paradoxical reactions with concomitant administration
of serotonin and dopamine amino acid precursors occur
in approximately 5% of patients. A paradoxical reaction is
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Hinz et al
defined as an outcome to treatment that is the opposite of what
is expected. In the Parkinson’s disease patients being treated
with balanced amino acid precursors, the most common
paradoxical reactions are agitation and confusion, although
any disease process related to monoamine diseases may be
exacerbated such as depression, insomnia, or anxiety. With
most Parkinson’s disease patients, paradoxical reactions occur
after many weeks or months when the l-dopa dosing value
is on the threshold needed for control of Parkinson’s disease
symptoms late in treatment.10,13,14
Achieving the results noted in this case study is
dependent upon proper management of any paradoxical
reactions that may develop and being able to differentiate
a paradoxical reaction from a side effect or adverse reaction. Proper management of paradoxical reactions in the
Parkinson’s patient is to adequately increase the l-dopa
dosing value. With a proper increase, the paradoxical
reaction will resolve in 1 to 2 days. Physicians who are
not properly oriented to the management of paradoxical
reactions may tend to inappropriately decrease the l-dopa
dosing when a paradoxical reaction displays, then increase
the l-dopa dosing slowly. This approach only leads to the
patient being exposed to the l-dopa dosing range that
induced the paradoxical reaction for a prolonged period
of time and may lead to failure when symptoms of a
paradoxical reaction are observed for a prolonged period
of time causing the l-dopa dosing value to be decreased
further or stopped.10,13,14
Categorizing symptoms associated
with carbidopa/l-dopa administration
The FDA-approved prescribing information for carbidopa/
l-dopa preparations was reviewed and a list of side effects,
adverse reactions, and problems associated with administration was generated.34 Each side effect was then placed
in one or more of the general categories listed below by
the authors of this paper. While the listing of each side
effect may be open to further discussion, these are the
categories that have evolved in this research project since
2001. The six categories of carbidopa/l-dopa side effects
are as follows:
Category 1: Problems caused by depletion of serotonin by
l-dopa: Tachyphylaxis (the l-dopa stops working).
Category 2: Problems caused by imbalance of serotonin
and dopamine: Nausea, vomiting, anorexia, weight loss,
decreased mental acuity, depression, psychotic episodes
including d elusions, euphoria, pathologic gambling,
impulse control, confusion, dream abnormalities including
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nightmares, anxiety, disorientation, dementia, nervousness,
insomnia, sleep disorders, hallucinations and paranoid
ideation, somnolence, memory impairment, and increased
libido.
Category 3: Problems caused by dopamine fluctuations
due to inadequate tyrosine levels: On-off effect, motor
fluctuations, dopamine fluctuations, implicated as an etiology
of dyskinesia.
Category 4: Problems caused by depletion of sulfur amino
acids by l-dopa: Bradykenesia (epinephrine depletion
implicated), akinesia, dyskinesia, dystonia, chorea,
extrapyramidal side effects, fatigue, abnormal involuntary
movements, and depletion of glutathione potentiating further
dopamine neuron damage by neurotoxins.
Category 5: Problems caused by paradoxical amino acid
reactions: Confusion, dizziness, headache, palpitations,
dyspnea, anxiety, agitation, increased tremor, faintness,
exacerbation of any disease related to the monoamine
(serotonin, dopamine, norepinephrine, and epinephrine)
neurotransmitters, and exacerbation of any central disease
process associated with the serotonin and catecholamine
systems.
Category 6: Peripheral problems caused by peripheral depletion
of serotonin and catecholamines by carbidopa: Glossitis, leg
pain, ataxia, falling, gait abnormalities, blepharospasm (which
may be taken as an early sign of excess dosage), trismus,
increased tremor, numbness, muscle twitching, peripheral
neuropathy, myocardial infarction, flushing, oculogyric crises,
diplopia, blurred vision, dilated pupils, urinary retention, urinary
incontinence, dark urine, hoarseness, malaise, hot flashes, sense
of stimulation, dyspepsia, constipation, palpitation, fatigue,
upper respiratory infection, bruxism, hiccups, common cold,
diarrhea, urinary tract infections, urinary frequency, flatulence,
priapism, pharyngeal pain, abdmoninal pain, bizarre breathing
patterns, burning sensation of tongue, back pain, shoulder pain,
chest pain (noncardiac), muscle cramps, paresthesia, increased
sweating, falling, syncope, orthostatic hypotension, asthenia
(weakness), dysphagia, Horner’s syndrome, mydriasis, dry
mouth, sialorrhea, neuroleptic malignant syndrome, phlebitis,
agranulocytosis, hemolytic and nonhemolytic anemia, rash,
gastrointestinal bleeding, duodenal ulcer, Henoch-Schonlein
purpura, decreased hemoglobin and hematocrit, thrombocytopenia, leukopenia, angioedema, urticaria, pruritus, alopecia,
dark sweat, abnormalities in alkaline phosphatase, abnormalities in SGOT (AST), SGPT (ALT), abnormal Coombs’ test,
abnormal uric acid, hypokalemia, abnormalities in blood urea
nitrogen (BUN), increased creatinine, increased serum LDH,
and glycosuria.
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Conclusion
The Parkinson’s disease process is known to be associated with
depletion of serotonin, tyrosine hydroxylase, norepinephrine,
and dopamine. l -dopa is known to deplete serotonin,
serotonin precursors, tyrosine, and the sulfur amino acids.
The dosing range of serotonin precursors needed for the
individual patient to achieve proper balance with l-dopa
administration appears to be in a relatively narrow range with
some of the side effects being displayed if the serotonin is
either too high or too low.
The most prominent dose-limiting events in the use of
l-dopa are the GI symptoms of nausea and vomiting along
with psychiatric problems. The patient in this case study had
the l-dopa, 5-HTP, l-tyrosine, and l-cysteine administered in
proper balance. OCT assay interpretation was implemented
early in order to get out in front of amino acid imbalance
problems before they occurred.
Everything used in the treatment of this patient is
recognized by the FDA as GRAS (generally regarded as
safe) and available over the counter without a prescription
in the United States.
This paper is the product of nine years of research in the
area of serotonin and dopamine precursor administration as
guided by OCT assay interpretation and statistical analysis
of numerous large databases. The protocol has been refined
since 2001 and appears ready for prospective studies. This
paper is an attempt to document what is known prior to
further studies.
The goal of this paper is to share some of the knowledge
gained prior to expanding group studies, spark interest in this
area of research, and hold these observations up to scrutiny
for Parkinson’s disease patients and their caregivers. The
administration of properly balanced amino acid precursors
used here for Parkinson’s disease does hold potential in
other research areas as evidenced by previous peer-reviewed
writings of the authors since 2009.
Disclosure
MH discloses ownership of DBS Labs, Duluth, MN, USA.
TU discloses directorship of DBS Labs, Duluth, MN, USA.
AS reports no conflicts of interest in this work.
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International Journal of Nephrology and Renovascular Disease
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Return to index
Review
Validity of urinary monoamine assay sales under
the “spot baseline urinary neurotransmitter
testing marketing model”
19 July 2011
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
1
Clinical Research, Neuro Research
Clinics Inc, Cape Coral, FL; 2Stein
Orthopedic Associates, Plantation,
FL; 3Laboratory, Fairview Regional
Medical Center-Mesabi, Hibbing,
MN, USA
Abstract: Spot baseline urinary monoamine assays have been used in medicine for over 50 years
as a screening test for monoamine-secreting tumors, such as pheochromocytoma and carcinoid
syndrome. In these disease states, when the result of a spot baseline monoamine assay is above
the specific value set by the laboratory, it is an indication to obtain a 24-hour urine sample to make
a definitive diagnosis. There are no defined applications where spot baseline urinary monoamine
assays can be used to diagnose disease or other states directly. No peer-reviewed published original
research exists which demonstrates that these assays are valid in the treatment of individual patients
in the clinical setting. Since 2001, urinary monoamine assay sales have been promoted for numerous applications under the “spot baseline urinary neurotransmitter testing marketing model”. There
is no published peer-reviewed original research that defines the scientific foundation upon which
the claims for these assays are made. On the contrary, several articles have been published that
discredit various aspects of the model. To fill the void, this manuscript is a comprehensive review
of the scientific foundation and claims put forth by laboratories selling urinary monoamine assays
under the spot baseline urinary neurotransmitter testing marketing model.
Keywords: monoamine, serotonin, dopamine, norepinephrine, epinephrine, urine, urinary
Introduction
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
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http://dx.doi.org/10.2147/IJNRD.S22783
About 10 years ago, a laboratory began selling urinary monoamine assays under the
“spot baseline urinary neurotransmitter testing marketing model”. It was claimed that
these assays had a direct relationship with the levels of the monoamine neurotransmitters in the brain and peripheral nervous system. The marketing model also made
numerous previously unknown claims regarding medical applications of urinary
monoamine assays. Attached to each monoamine assay report from the laboratory
were recommendations for treating monoamine neurotransmitter-related diseases,
such as depression and attention deficit hyperactivity disorder, using nutritional supplements in conjunction with the testing. The recommended nutritional supplements in
all cases were sold exclusively by those selling the laboratory assays.1–4 This medical
treatment methodology continues to be marketed today by several laboratories, physicians, other types of caregivers, and directly to the public over the Internet. In the
process, the scope of urinary monoamine assay marketing claims has increased.
This review examines the validity of this approach.
Without the benefit of published peer-reviewed research discussing or supporting
the scientific foundation of the testing, many physicians and caregivers have joined
laboratories in expanding the Internet marketing campaign for this type of testing
coupled with nutritional supplement sales.1–4
International Journal of Nephrology and Renovascular Disease 2011:4 101–113
101
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Hinz et al
This manuscript reviews and discusses the validity of
clinical applications promoted to enhance the sales of urinary
serotonin, dopamine, norepinephrine, and/or epinephrine
(herein referred to as “monoamine”) assays. The reference
point for this discussion and review is ten peer-reviewed
research papers relating to clinical applications of monoamine assays published by the authors of this manuscript since
2009 (as listed in Table 1).5–14
The topic is the rationale, validity, and clinical impact of
marketing claims used to sell urinary monoamine assays
under the “spot baseline urinary neurotransmitter testing
marketing model”. It is the hypothesis of this manuscript that
Table 1 Overview and summary of previous papers by the authors
of this paper
Authors
Comments
Hinz5
Use of serotonin and dopamine precursors guided
by organic cation transporter optimization in the
treatment of depression.
This is written by the chairman of the research
committee, University of Minnesota Medical School,
Duluth, MN, based on laboratory data provided by and
in collaboration with Marty Hinz. The paper documents
the response of urinary serotonin and dopamine to
administration of L-tyrosine in a large group.
Publishing of a new organic cation transporter model
relating to monoamine transport.
Discusses the validity of day to day reproducibility of
spot baseline urinary serotonin and dopamine samples
in the same subject. Findings were that testing differs
significantly from day to day in the same subject and is
not reproducible.
Differentiation of major affective disorder from
depression-dominant bipolar disorder and treatment
with serotonin and dopamine amino acid precursors,
guided by transporter assay optimization.
A treatment protocol for treatment of Crohn’s disease
with amino acids guided by organic cation transporter
functional status determination.
Treatment of attention deficit hyperactivity
disorder with serotonin and dopamine amino acid
precursors, guided by organic cation transporter assay
optimization.
Discusses the validity of day to day reproducibility of
spot baseline urinary norepinephrine and epinephrine
samples in the same subject. Findings were that testing
differs significantly from day to day in the same subject
and is not reproducible.
Management of Parkinson disease with organic cation
transporter optimization in a manner that allows for
management and control of all problems associated
directly and indirectly with L-dopa administration
during treatment.
A paper written in response to an editor invitation.
The paper reviews a paper titled, “Non-validity and
clinical relevance of neurotransmitter testing”.
Trachte et al14
Hinz et al6
Hinz et al7
Hinz et al8
Stein et al13
Hinz et al9
Hinz et al10
Hinz et al11
Hinz et al12
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the “spot baseline urinary neurotransmitter testing model”
is not a model based on science, but is a business marketing
tool, and a model formulated to drive laboratory sales of
urinary monoamine assays. There is no original research
published in scientific journals that discusses or defines the
scientific foundation of the model. It is hereby asserted that
the foundation upon which the model rests is clinically
unproven. The alleged scientific foundation put forth in
promotional sales material under this marketing model contradicts known science, especially in the areas of renal
physiology and blood–brain barrier permeability.
There is no formal laboratory test known as the “urinary
neurotransmitter testing”. From an objective scientific perspective, the proper nomenclature for the relevant laboratory testing
is “urinary monoamine assays”. The monoamines, ie, serotonin,
dopamine, norepinephrine, and epinephrine, do not function
exclusively as neurotransmitters. They carry out other major
neurotransmitter, neurohormonal, regulatory, autocrine, and
paracrine functions. The monoamines found in the urine have
not, do not, and will not function exclusively as neurotransmitters.
Therefore, it is not appropriate to refer to urinary monoamine
assays as “neurotransmitter testing” and ignore the other major
functions of these monoamines in the body.15
Urinary monoamines exist in one of two states. The
“endogenous state” is the normal day-to-day state. This occurs
when a subject is taking no amino acids. The “competitive
inhibition state” is found when significant amounts of both
serotonin and dopamine amino acid precursors are being
taken simultaneously.6,9–11,13 This clinical review is undertaken
exclusively to discuss the testing performed in the endogenous
state with spot baseline urine samples.
The following applications are direct quotes from a laboratory website7 that is promoting some of the alleged attributes of the spot baseline urinary neurotransmitter marketing
testing model. These include, but are not limited to:
• “…. baseline (urinary neurotransmitter) testing is the best
approach to determine the neurotransmitter functional
status of the central and peripheral nervous systems”
• “Administration of amino acid precursors directly impacts
urinary monoamine levels; therefore, the results of monoamine assays merely need to be interpreted as being either
high or low values with no need to make consideration for
other forces impacting urinary monoamine levels between
renal synthesis and showing up in the final urine”
• “Baseline testing of urinary monoamines prior to starting
supplemental amino acid precursors is required in order
to define the amino acid precursor starting dose needed
in treatment”
International Journal of Nephrology and Renovascular Disease 2011:4
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• “Baseline (urinary) monoamine assays in the absence of
supplemental amino acid precursors are required to diagnose and define the serotonin and dopamine imbalance
in the central and peripheral nervous systems”
• “Baseline (urinary) monoamine assays can serve as a
reference point to gauge treatment effectiveness after
amino acid precursors are started”
• “Baseline (urinary) monoamine assays can be used to
reduce the risk of side effects when amino acid precursor
treatment is started”.
The “spot baseline urinary neurotransmitter testing marketing model” (herein referred to as “the marketing model”)
claims that the clinical applications for the test are based on
science, yet when the alleged scientific claims supporting
the marketing model are examined, they are contradicted by
known science.
At present, the only clinically proven use for spot baseline
urinary monoamine assays is as a screening test for pheochromocytoma or carcinoid syndrome to determine if a
24-hour urine test is needed to diagnose these diseases
definitively. This application is hereby specifically excluded
from consideration in this manuscript.
Physician marketing claims
Physicians and other caregivers are promoting sales of urinary monoamine assays under the “spot baseline urinary
neurotransmitter testing marketing model” on the Internet.
It is easy to find this type of advertising. This section discusses how some physicians were induced to promote this
marketing model. The section ends with examples of marketing claims by physicians and caregivers currently found on
the Internet.
This “spot baseline urinary neurotransmitter testing
marketing model” has become known as the “pee in a cup
and we will determine the neurotransmitter levels in your
brain model”. It is asserted that the alleged scientific statements driving sales of urinary monoamine assays are deceptively simple and intuitively seductive.
The actual science required to support or contradict “the
marketing model” is found primarily in the renal physiology
literature and blood–brain barrier permeability. It is asserted
that this area of monoamine renal physiology is extraordinarily complex, especially for the uninitiated.
Physicians have implicit trust that the laboratory is giving
accurately reported results and advice. For most physicians,
this trust is cultivated by a history of dealing with only
hospital and/or clinic-based laboratories under the medical
direction of physicians who implement widely accepted
Urinary monoamine assay
treatment standards and testing policies. A basic flaw here
is that the laboratories selling urinary monoamine assays
under the “spot baseline urinary neurotransmitter testing
marketing model” are not clinic-based or hospital-based.
They are freestanding facilities directed and staffed by chemists who have no medical training or medical license.16–18
These laboratories are claiming, in their marketing, to
have the expertise to tell physicians how to treat their
patients, on a broad level, on the basis of the laboratory
studies they perform. These laboratories provide “technical
support” to assist physicians in treating their patients.
The quality of this technical support raises concerns. Routine
technical support is given by individuals with no formal
medical training, no first-hand experience in patient care,
and no medical licensure. In some cases, individuals with
only a high-school degree, who are trained only from a
marketing standpoint, advise physicians on how to treat their
patients with clinically unproven methods in order to optimize sales of nutritional supplement products sold by the
laboratory. While arguably it is the responsibility of the physician to implement or reject treatment advice, the whole
concept of laboratory owners and employees with no firsthand patient care training, experience, or medical licensure,
telling doctors how to treat their patients with clinically
unproven methods may be construed as the unlicensed practice of medicine by unqualified individuals. At the very least
it is a potential recipe for disaster.16–18
It is not hard to find physicians and other caregivers who
are advertising the sale of urinary monoamine assays under
the “spot baseline urinary neurotransmitter testing marketing
model”. Their numbers have grown in recent years. Some of
the examples of Internet marketing of urinary monoamine
assays under the “spot baseline urinary neurotransmitter
testing marketing model” by physicians and other caregivers
include the following assertions:
• “Neurotransmitter testing is now available to detect brain
neurotransmitter imbalances”19
• “Neurotransmitter testing is used to detect imbalances in
brain and body chemistry”20
• “We now have (urinary neurotransmitter) laboratory
tests that can accurately measure neurotransmitter levels
and greatly simplify the task of developing a proper
supplement plan, eliminating much of the guesswork
and trial and error. They are also affordable and noninvasive in that they use a simple urine sample. A baseline test is usually critical to understanding a person’s
unique patterns and designing the most appropriate
supplement program”21
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• “… approach is based on a baseline (urinary) measurement
of your neurotransmitter and/or hormone levels. The
initial testing of your levels from a urine or saliva sample
constitutes your baseline”22
• “Neurotransmitter testing to detect brain neurotransmitter
imbalances! Testing helps to determine exactly which
neurotransmitter levels are out of balance and helps to
determine which therapies are needed for an individualized treatment plan”23
• “For this to be most effective, it should include a specialized urinalysis test that provides a reliable means of
measuring excretory values of neurotransmitters. The
(name of company) neurotransmitter urinalysis panel can
be utilized to establish baseline, therapeutic, and maintenance protocols”24
• “Neurotransmitters are naturally occurring chemicals
within the brain that relay signals between the nerve cells
and are required for proper brain and body function. The
approach is based on a baseline (urinary) measurement
of your neurotransmitter and/or hormone levels”.25
Laboratory marketing claims
This section discusses how the marketing model arrived at
its current state, along with examples of the marketing claims
made to fuel urinary monoamine testing. The marketing
model is promoted primarily for disease states that have a
high positive placebo effect. In many studies, attention deficit
hyperactivity disorder and depression are associated with a
positive placebo effect of 40%–50%.5,9 Almost half of the
patients with these diseases improve significantly in 1 month
while being treated with placebo. However, under the marketing model, when this happens, those promoting the marketing model take credit for all cases that have improved.
Because almost half of the patients show significant improvement within 1 month, there is little upon which to challenge
the veracity of the laboratory claims of treatment efficacy
for the average physician not aware of the placebo statistics.
Indeed, physicians have said under questioning, “I like this
approach; at least half of my patients get better in the first
month”. This approach completely ignores the placebo effect
while quietly exploiting it in the background for the marketing of urinary monoamine assays.5,9
Virtually any properly licensed laboratory can perform
urinary monoamine assays. It is the clinical applications
promoted for these urinary monoamine assays that differentiate one laboratory from another. The following are direct
quotes from urinary monoamine assay marketing under the
urinary neurotransmitter marketing model.
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A 2007 marketing paper noted, “Studies have demonstrated
intact neurotransmitter transport out of the CNS, into the
periphery, via blood–brain barrier transporters. Renal filtration of neurotransmitters via specific transporters is welldocumented. Researchers have provided examples of urinary
neurotransmitter measurements that correlate with CNS
(central nervous system) tissue concentrations”.26
On September 22, 2010, a laboratory website27 promoting and selling urinary monoamine assay under the spot
baseline urinary neurotransmitter testing marketing model
on the Internet noted that baseline testing is recommended
with regard to urinary monoamine assays in marketing for
all neurotransmitter-related conditions for several
reasons:
• “First, it reveals imbalances that may be present in the
nervous system, thereby establishing a quantitative need
for intervention. Symptoms alone often do not provide
the information needed to effectively target the underlying neurotransmitter imbalances”
• “Next, baseline testing allows for more informed decisions to be made regarding intervention selection”
• “With neurotransmitter data in hand, practitioners can
choose products that target neurotransmitter imbalances”
• “Likewise, neurotransmitter testing shows which interventions may not be suitable for a particular individual,
reducing the chance of unwanted side effects”
• “Finally, the baseline test provides an important reference
point to monitor the effects of therapy. Retests can be
compared to baseline data to evaluate progress made in
the restoration process”
• “In addition to baseline testing, periodic retesting is used
to indicate a need for change in a patient’s dosing
regimen”.
The websites of other laboratories have posted the following on their web pages supporting sales of urinary monoamine assays under the spot baseline urinary neurotransmitter
testing marketing model:
• “(Company name) line of formulas designed to address
the communication system imbalances found through
testing. TNT formulations may be used as anchor products during the initial therapeutic phase, following a
baseline (urinary) test”28
• “For this to be most effective, it should include a specialized urinalysis test that provides a reliable means of
measuring excretory values of neurotransmitters. From
those findings an individualized protocol including transdermal amino acid supplementation is devised to improve
the quantity and ratios of neurotransmitters in the
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brain. The first step is to identify baseline (urinary)
neurotransmitter levels”2
• “The optimal range is suggested for the interpretation of
baseline (urinary neurotransmitter testing) values. If
neurotransmitter values fall above or below the optimal
range, your nervous system may be out of balance”29
• “In support of urinary neurotransmitter assessment, studies
have demonstrated that intact neurotransmitter is transported from the CNS to the periphery, via specific BBB
transporters, followed by renal filtration of neurotransmitters with subsequent excretion in the urine”.30
Scientific issues
There is a highly polarized divergence between published
peer-reviewed science and the “spot baseline urinary neurotransmitter testing marketing model”. In this section we
discuss the key points of this divergence. In order to enable
the reader to sort out which claims from caregivers and laboratories are correct, it is important to identify and discuss the
scientific foundation the marketing model is resting on. The
validity of the spot baseline urinary neurotransmitter testing
marketing model used to promote sales of urinary monoamine
assays rests on correct answers to the following questions.
What is the permeability of the blood–brain barrier regarding
the monoamines under normal conditions? Are significant
amounts of monoamines found in the final urine synthesized
by kidney structures under normal conditions? What is the
level of reproducibility of urinary monoamine testing results
from the same subject on a day-to-day basis?
Blood–brain barrier permeability
Some variations of “the marketing model” rest on claims that
measurement of urinary monoamines has a direct relationship
with the monoamine levels found in the brain. This gives
rise to the concept “pee in a cup and we will determine the
neurotransmitter levels of your brain model”.
Two specific considerations exist in the marketing model
when claiming that monoamines cross the blood–brain
barrier. The first assumption is that monoamines found in
the final urine contain monoamines that have been in the
central nervous system. The second requirement is that the
monoamines in the final urine are in constant equilibrium
with the monoamines found in the central nervous system
and peripheral nervous system. Embodied in the marketing
model is the concept that monoamines must cross the blood–
brain barrier then come to equilibrium with the peripheral
nervous system and final urine, leading to one large pool of
monoamines in constant equilibrium throughout the body.
The idea that monoamines do not cross the blood–brain
barrier under normal conditions has been widely accepted in
science for over 60 years. This fact has been referenced
heavily over time, as noted in the sampling of 104 references
noted in support of the following four bullet points:
• “Serotonin does not cross the blood–brain barrier”5–7,31–69
• “Dopamine does not cross the blood–brain barrier”70–93
• “Norepinephrine does not cross the blood–brain
barrier”94–107
• “Epinephrine does not cross the blood–brain barrier”.108–131
In order for claims made under the spot urinary neurotransmitter testing marketing model to be valid, monoamines must cross the blood–brain barrier. This is contrary to
the over 100 references cited above. When those promoting
the original laboratory marketing model, which is still promoted by some today, became cognizant that these monoamines did not freely cross the blood–brain barrier, the model
began to change. The new marketing argument asserts that
transporters move monoamines across the blood–brain barrier in amounts significant enough to affect equilibrium
between the central nervous system, peripheral nervous
system, and final urine. It continues to be asserted that monoamines in the final urine are composed of monoamines that
have been in the central nervous system.30
A review of transporter physiology is in order. The monoamines are primarily transported by organic cation transporters (OCT).132 It is recognized that the OCT of the liver,
intestines, kidneys, and brain are “identical and
homologous”.133 In 2010, the authors of this paper published
the most recent refinement to the monoamine OCT model.6
Even if there were transporters that transported monoamines out of the brain to the peripheral nervous system,
there would be no equilibrium or direct relationship, as
asserted by the marketing model, between the central nervous
system, peripheral nervous system, and final urine. The
amounts of monoamines that are transported vary greatly
over time. During transport, OCT affect monoamine gradients where the amount of monoamine on one side of the
transporter is not the same as the amount on the other side
of the transporter. In addition, monoamine concentrations
on either side of the transporter rise and fall independent of
each other. This leads to a situation where if transport did
occur, the monoamines in the central nervous system are not
in equilibrium and do not share a direct relationship with
levels in the peripheral nervous system and final urine, as
alleged by the marketing model.6
In the transporter version of the marketing model, the
laboratories involved continue to assert that urinary
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onoamine levels correlate with monoamines in the central
m
nervous system and are a measurement of monoamines that
have been in the central nervous system.7,19–30 A published
discussion of blood–brain barrier transport under one of the
current marketing models written by the staff of a laboratory
selling under the marketing model appeared in a 2010 review
article (ie, no original research was reported) published by a
psychology journal that had decided it had the expertise to
publish on peer-reviewed issues relating to monoamine renal
physiology and blood–brain barrier physiology.30 Figure 1
accompanying that review is a reproduction from Ohtsuki.134
The article claimed that both illustrations represent transport
of monoamines across the blood–brain barrier. Close
examination of the reference shows that the assertions of
Ohtsuki are contrary to the psychology review article in
noting that there is no known mechanism for these
monoamines that transports them across the blood–brain
barrier. The only thing that the figures from these two articles
illustrate is how the monoamines are transported into the
endothelial cells of the blood–brain barrier where they affect
regulation and that the monoamines are not transported across
the blood–brain barrier.30,134
There is no peer-reviewed published research that supports
the marketing model versions which expound that, under
normal conditions, monoamines cross the blood–brain barrier
and are in equilibrium with the peripheral nervous system,
urinary monoamine assays are of monoamines that have been
in the brain, and assays of monoamines found in the final
urine have a direct relationship with levels found in the brain.
There is no scientific support for any of these propositions.
Source of urinary monoamines
The second major issue reviewed is “the source of synthesis
of monoamines found in the urine under normal conditions”. The selling of urinary monoamine assays under the
“the marketing model” has made no scientific room for the
possibility that a significant source of synthesis of the
monoamines found in the final urine is from sources other
than the peripheral or central nervous systems. The marketing model claim is that urinary monoamines found in the
final urine are monoamines filtered at the glomerulus, and
measurement of monoamines in the final urine is a direct
assay of the monoamines of the peripheral and/or central
nervous systems. The marketing model fails to account for
known scientif ic facts that are contrary to these
assertions.30
Science notes that significant amounts of monoamines
found in the urine, under normal conditions, have never been
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in the central and/or peripheral nervous systems. The final
urine, under normal conditions, is composed of significant
amounts of monoamines synthesized by structures found in
the kidneys. The following referenced statements support
this set of facts:
• “Most of the serotonin or dopamine found in the urine is
synthesized in the kidney. Therefore, the excreted
neurotransmitters must be synthesized in the kidneys and
escape reabsorption into the blood in order to be excreted
in the urine”14
• “These findings provide further evidence that the increase
in urine serotonin after administration of both serotonin
precursors (5-HTP; glu-5-HTP) is largely due to serotonin
synthesized within the kidney”135
• “… free urine serotonin reflects actual biosynthesis by
the kidney”136
• “These results are consistent with the intrarenal formation
of serotonin by renal decarboxylase with attendant alterations in renal hemodynamics and salt and water
excretion”137
• “Dopamine and serotonin in the urine are believed to
reflect mainly the tubular decarboxylation of filtered or
circulating L-dopa and L-5-HTP, respectively”138
• “Intrarenal dopamine (3,4-dihydroxyphenethylamine; DA)
and serotonin (5-hydroxytryptamine; 5-HT) are synthesized
abundantly by renal proximal tubular cells from L-3,4dihydroxyphenylalanine and 5-hydroxy-L-tryptophan,
respectively”139
• “These data indicate that urinary free dopamine is mainly
derived from plasma dopa, which is converted by dopa
decarboxylase in the kidney”140
• “Urinary dopamine excretion was not diminished by
sympathectomy, was increased by L-dopa (but not
tyrosine or dopamine 4-Osulphate) in the perfusate and
was virtually abolished by prior treatment with the dopa
decarboxylase inhibitor, carbidopa. These results confirm
the importance of renal extraneuronal dopamine production, from circulating L-dopa, as a contributor to urinary
dopamine excretion”141
• “The data indicates that urinary free dopamine in a high
sodium diet is mainly derived from the renal tubular
cells”142
• “Plasma dopa is the main source of urinary dopamine”143
• “All of the components of a complete dopamine system
are present within the kidney”144
• “It is concluded that (urinary) dopamine and serotonin
are accumulated and likely formed within proximal
convoluted tubular cells”145
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Abluminal membrane
Luminal membrane
Endothelial
cell
BRAIN
BLOOD
Glutamine
Glutamate
EAAT1
EAAT2 1:3:6 ratio
EAAT3
NH4+
Low capacity
independent
carrier
system
Glutamate
aspartate
Glutamate
GABA
GAT2/BGT-1
Serotonin
SERT
GABA
transporter
GABA
NET
Serotonin
Norepinephrine
NET
Dopamine
Histamine
HA
transporter
HA
transporter
Histamine
Epinephrine
Agmatine
Agmatine
PEA
PEA
Figure 1 Serotonin, dopamine, norepinephrine, and epinephrine are transported across the abluminal membrane surface of the blood–brain barrier into the endothelial cells
where they affect regulatory function. They do not cross the blood–brain barrier since they do not cross the luminal membrane.
Reprinted from Neuroscience & Biobehavioral Reviews, Vol 35, Issue 3, Marc et al, Neurotransmitters excreted in the urine as biomarkers of nervous system activity: Validity
and clinical applicability, p 635–644, Copyright 2011, with permission from Elsevier.
Abbreviations: EAAT, excitatory amino acid transporter; GABA, γ-aminobutyric acid; GAT2/BGT-1, GABA/betaine transporter; HA, histamine; NET, norepinephrine
transporter; PEA, phenylethylamine; SERT, serotonin transporters.
• “... (urinary) dopamine is phosphaturic and is synthesized
by kidney proximal tubule”146
• “... urinary norepinephrine is not solely derived from
plasma by glomerular filtration but also arises from an
unidentified renal source”147
• “… the renal nerves were the main sites of the (urinary)
norepinephrine synthesis”148
• “Perfusion of L-dopa and free dopamine led to the
generation of norepinephrine in the kidney. This synthesis
was abolished when the kidney was denervated,
suggesting that the renal nerves were the main sites of
the (urinary) norepinephrine synthesis”148
• “Several recent studies have demonstrated that dopamine
can be generated from L-dopa in the isolated perfused
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rat kidney, and those findings led to the conclusion that
most of the urinary dopamine could be derived from
circulating L-dopa (in the kidneys)”148
• “Recent studies from our laboratory have suggested that
urinary NE (norepinephrine) may be derived, in part, from
intrarenal sources in man”149
• “We have previously reported that in standing humans a
significant portion of urinary norepinephrine is derived
from processes other than glomerular filtration”149
• “Net production was observed for NE (norepinephrine),
DA (dopamine), and NM (normetanephrine) in the renal
metabolic compartment, suggesting that a portion of these
compounds excreted in the urine may result from intrarenal synthesis or metabolism of these materials”149
• “… urinary epinephrine may not simply be filtered from
the bloodstream” and “urinary epinephrine was derived
from the kidney”150
• “We conclude that appreciable portions of renal and
urinary epinephrine are synthesized in the kidney by an
enzyme distinct from PNMT”.151
In reviewing the validity of the “spot baseline urinary
neurotransmitter testing marketing model” it is important to
determine what is being assayed and where it came from.
The first assertion of the model claims that it is urinary
neurotransmitters that are being assayed. Considering the
neurohormonal, regulatory, paracrine, and autocrine functions of monoamines, the monoamine population found in
the urine has not exclusively functioned as neurotransmitters.
This marketing model hinges on claims that the final urine
is composed of monoamines that have functioned only as
neurotransmitters, which have crossed the blood–brain barrier, and have been simply filtered at the glomerulus, and
then excreted directly into the final urine. Therefore, the
marketing model, has assumed that there is constant equilibrium between the monoamines of the central and peripheral
nervous systems and the monoamines found in the final urine
which have allegedly only functioned as neurotransmitters.
This marketing model is simply not valid. There is no direct
relationship between monoamines in the final urine and
monoamines in the peripheral or central nervous systems,
and under normal conditions, significant amounts of
monoamines found in the final urine have not been in the
peripheral or central nervous systems, but have been newly
synthesized by structures in the kidneys.
Day-to-day reproducibility of assays
The reproducibility of testing techniques in the laboratory, as
commonly addressed by precision and accuracy studies, is
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not what is being discussed here. It is the reproducibility of
urinary monoamine assay results obtained from the same
subject from one day to the next that is under discussion. It
would appear that none of the laboratories selling urinary
monoamine testing under this marketing model bothered to
verify the day-to-day reproducibility of testing in the same
subject. The authors of this paper published multiple original
research papers where the topic was “matched-pairs t-test”
analysis of baseline monoamine assays performed on different
days from the same subject. Each matched pair was made up
of a urine sample obtained from a subject on one day (test 1)
paired with a urine sample from the same subject on a different
day (test 2). These test 1 and test 2 matched pairs were then
grouped and analyzed using the “matched-pairs t-test”. It was
found that the urinary level of all four monoamines (serotonin,
dopamine, norepinephrine, and epinephrine) between test 1
and test 2 for the group differed significantly from day to day
(P , 0.05). The amount of each monoamine found in test 1
and test 2 urine samples was not consistent and reproducible
on a day-to-day basis in the same individual.7,10 The following
statement illustrates the impact of this finding: “It is asserted
that if one hundred baseline urinary monoamine assays from
the same subject were obtained on one hundred different days,
one hundred different laboratory values would be reported.
In the process, no firm reproducible laboratory data from one
day to another day would be generated and no reliable clinical
decision making could occur using this type of data”.7,10 These
findings invalidate the ability to use “baseline monoamine
assays” for anything more than a coarse screening tool, under
the only clinically proven applications known, for monoamine
hyperexcreting tumors,7,10 which is something we are not
discussing in this paper.
Unproven science of biomarkers
The alleged scientific foundation of the marketing model
continues to change. The marketing model still continues to
assert that all of the urinary monoamines found in the final
urine under normal conditions have been in the peripheral
and central nervous systems, despite the overwhelming
peer-reviewed published research evidence to the contrary.
The marketing model now asserts that urinary monoamines
can be used as biomarkers of common diseases, such as
attention deficit hyperactivity disorder and depression,
although these claims are clinically unproven with no published original research that would support or define treatment
of the individual patient in clinic. The only published original
research on the topic discredits the biomarker approach for
several of the reasons already discussed in this paper, not the
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least of which is the lack of day-to-day consistency of test
results in the same subject.30
The business model for the marketing of urinary monoamine assays as biomarkers of disease has certainly arrived.
The most extensive writing on the topic is a 2010 literature
review found in a psychology journal and containing no
original research.30 Contrary to the claims of the biomarker
marketing model cited, 30 the final urine being assayed
contains significant amounts of urinary monoamines
synthesized by the kidneys. The actual monoamine levels
found in the final urine when corrected for specific gravity
considerations by use of the monoamine to creatinine ratio
which compensates for dilution of the urine, is an assay of
the forces within the kidneys that impact the monoamines
between synthesis and the f inal urine. The OCTN2
transporters of the apical surface and the OCT2 transporters
of the basolateral surfaces of the proximal convoluted renal
tubule cells have a major impact on monoamine concentrations
found in the final urine.13 The marketing model is silent on
this interaction.
The most recent review of urinary biomarker applications
had numerous references citing group results of urinary
monoamine trends. The authors then made the jump, without
proper studies in place, to asserting that these group results
are valid for use in treatment of individual patients in the
clinical setting.30 Group study results cannot be used or
equated to treatment parameters in an individual. Even if a
group trend was found for a specific disease, the day-to-day
significant changes in urinary monoamine assays from the
same individual would invalidate the clinical applications of
the group trend finding.7,10
The question is raised, “What is the possible impact to
the medical community of laboratories selling clinically
unproven urinary biomarker tests?” One of the references
cited in the bibliography of the 2010 biomarker review
paper30 notes the following:
“Perhaps most worrisome is the problem of premature
clinical application (of biomarkers), both because of the risk
for harm to patients (misdirected in treatment decisions) and
for the cynicism about biomarkers in general this engenders;
still, the need for useful biomarkers is so great that sometimes
enthusiasm and optimism may overtake consideration of
results from carefully conducted controlled clinical trials. To
paraphrase the film Jerry Maguire, ‘show me the data!’ must
be the watchword if clinicians are to make prudent choices
for their patients”.152
The authors of this paper assert that the statement immediately above, in citing “premature clinical applications” of
biomarker testing,152 are discussing the exact problem associated with the urinary monoamine marketing model of biomarkers at this time. Careful review of the references cited
revealed no definitive clinical trials or support regarding use
of spot baseline urinary neurotransmitter testing in biomarker
applications for treatment of individuals in the clinical setting. The statement referenced above is correct in that premature use of an unproven biomarker application can risk
causing harm to the patient. Examples of the harm supported
under the statement include152 but are not limited to:
• A diagnosis of a false normal state when disease exists
• Misdiagnosis of disease states
• Medical treatment decisions that make the disease state
worse
• Initiation of unnecessary treatment
• Delay in implementing available beneficial treatment
• False hope given where no hope exists, leading to distress
when this is realized
• Interference with the doctor–patient relationship when
expected results promoted by the laboratory do not turn
out as advertised due to unrealistic expectations of care.
Conclusion
The “spot baseline urinary neurotransmitter testing marketing
model” used to promote sales of urinary monoamine assays
is not valid and has no scientific foundation. For the claims
of the marketing model to be valid, monoamines would need
to cross the blood–brain barrier and be in constant equilibrium with the peripheral nervous system and final urine. As
demonstrated by at least 100 citations, these monoamines do
not cross the blood–brain barrier. While one version of the
marketing model seems to recognize this and asserts that the
monoamines are transported out of the central nervous system, the very literature cited in making these transporter
assertions specifically illustrates that monoamines are not
transported out of the central nervous system to the peripheral
nervous system. For the marketing model to be valid, monoamines found in the final urine need to be composed primarily
of the monoamines from the peripheral system that are merely
filtered and placed in the final urine as claimed. A significant
amount of monoamines found in the final urine are synthesized by the kidneys. These monoamines perform other major
functions in the body. Therefore, identifying and calling these
monoamine assays of the final urine, “neurotransmitter testing” is not appropriate.
For the marketing model to be valid, urinary monoamine
assays obtained from the same subject need to be consistent
from one day to the next (P . 0.05 on the “matched-pairs
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t-test” using paired samples from the same subject obtained
on different days). Previous published literature indicates
that this is not the case; urinary monoamines differ significantly from day to day in the same subject.
The bottom line is that the “spot baseline urinary
neurotransmitter testing marketing model” used to sell urinary monoamine assays has not been clinically proven. The
original scientific research supporting the model, if it exists,
cannot be found in published science. It is postulated that
after 10 years of using this marketing model to sell urinary
monoamine assays it would be helpful if the first original
research scientific peer-reviewed paper outlining the foundation of the model would be formally written in order to
subject it to appropriate peer review.
It is the goal of this writing to spark interest and dialog
on the validity of the “spot baseline urinary neurotransmitter
testing marketing model” used in support of urinary monoamine assay sales. We hope that those using this marketing
model directly or indirectly in patient care will come forth
and enter into meaningful dialog. It is suggested that those
promoting this marketing model publish their original
research findings in order to facilitate a proper scientific
dialog on the topics of monoamine renal physiology and
blood–brain barrier permeability in relation to marketing
claims.
Disclosure
MH discloses ownership of NeuroResearch Clinics Inc. TU
discloses laboratory directorship of DBS Laboratories,
Duluth, MN.
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Open Access Journal of Sports Medicine
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Return to index
C as e R e port
Microperforation prolotherapy: a novel method
for successful nonsurgical treatment of atraumatic
spontaneous anterior sternoclavicular subluxation,
with an illustrative case
5 June 2011
Alvin Stein 1
Scott McAleer 2
Marty Hinz 3
1
Stein Orthopedic Associates, PA,
Plantation, FL, USA; 2University of
Central Florida, Orlando, FL, USA;
3
Clinical Research, Neuroresearch
Clinics, Inc, Cape Coral, FL, USA
Background: Surgical repair of an atraumatic spontaneous anterior subluxation of the sterno
clavicular joint (herein referred to as the “SCJ”) is often associated with poor outcome
expectations. With traditional treatment, successful conservative therapy usually incorporates
major lifestyle alterations. This manuscript discusses a novel approach known as “microperfo
ration prolotherapy”. To illustrate the technique, the care of a patient who benefitted from this
treatment is reviewed.
Purpose: To present a novel form of treatment with an illustrative case that demonstrates the
potential efficacy of microperforation prolotherapy of the SCJ.
Patient and methods: A novel approach to treatment of bilateral subluxation of the sterno
clavicular joint with microperforation prolotherapy is discussed. The clinical course of a 21-yearold male with bilateral subluxation of the SCJ, which seriously hampered the patient’s athletic
and daily living activities, is used as a backdrop to the discussion.
Results: Following microperforation prolotherapy, the instability of the SCJ was replaced
by full stability, complete range of motion, and the opportunity to engage in all of the athletic
endeavors previously pursued. There is no scar or other cosmetic defect resulting from the
treatment received.
Conclusion: Anterior sternoclavicular joint subluxation has a poor record of complete recovery
with surgical procedures or conservative measures with regard to providing restoration of full
lifestyle function. This manuscript documents a novel microperforation prolotherapy treatment
that induced healing and restored full stability to the ligament structures responsible for the
condition in a completely safe and effective fashion, allowing the patient to resume full lifestyle
activities without restriction. The exceptional response to treatment noted here is encourage
ment for further studies.
Keywords: sternoclavicular joint subluxation, shoulder pain, sternoclavicular instability,
spontaneous instability, anterior subluxation
Introduction
Correspondence: Alvin Stein
6766 West Sunrise Blvd, Suite 100A,
Plantation, FL 33313, USA
Tel +1 954 581 8585
Fax +1 954 316 4969
Dovepress
DOI: 10.2147/OAJSM.S20579
Presentation and documentation of this successful microperforation prolotherapy
outcome in the literature is novel, having never been previously done. The manuscript
is intended to discuss this novel microperforation prolotherapy method with an illus
trative patient history that documents the successful treatment of complete bilateral
spontaneous anterior subluxation of the sternoclavicular joints (herein referred to as
the “SCJs”) which occurred during the course of repetitive insult from powerlifting
and various martial arts.
Open Access Journal of Sports Medicine 2011:2 47–52
© 2011 Stein et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
47
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Stein et al
Understanding and mastery of anatomy is imperative
for successful outcomes. The lead author of this paper has
been performing prolotherapy for 16 years and orthopedic
surgery for over 30 years before that. During this time,
treatment of other cases of SCJ injury with surgery and then
with prolotherapy had not warranted a case report or other
paper documenting outcomes. Milder cases of SCJ instability
responded to prolotherapy with successful relief of pain and
return to full activity. A persistently painful postoperative
case was rendered pain-free by prolotherapy.
The degree of instability experienced by this patient was
so severe that its resolution by prolotherapy warranted a write
up of the case. It is felt that the dramatic result obtained was
due to the novel microperforation technique used.
Past medical history
The patient is a 21-year-old college student who gave a
history of being active in various forms of high impact
athletics, including powerlifting, Brazilian jiu-jitsu, mixed
martial arts, and a long history of freestyle bicycle motocross
(BMX), stemming from youth. No specific episode could
pinpoint the etiology for the presenting condition, but the
patient had crashed many times while engaging in freestyle
BMX. In addition, though not identifying any defining event
while powerlifting, there was suspicion that heavy bench
press exercises may have contributed to the problem affecting
the patient’s SCJs.
During the course of warm-ups for the various workout
sessions, the patient started to experience a clunking
sensation at the sternoclavicular joints bilaterally. The SCJs
would visibly sublux and then spontaneously reduce without
any discomfort. One day after a workout the patient came
home, laid down on the floor to play with his dog, placed his
right arm under his chest and, upon moving, experienced a
catching sensation followed by an audible ripping sound and
locking of the SCJ as forward flexion of the right arm was
attempted. The pain associated with this event was severe
and persisted for several weeks.
From that point on, the joints became increasingly
unstable and each subluxation event became excessively
painful. The painful sensation was isolated to the right SCJ,
while the left side continued to be hypermobile, but with
out any associated discomfort. Considering the degree of
reported instability and immense pain, it is probable that the
right SCJ suffered a complete dislocation with concomitant
injury to the articular disc.
Upon seeking medical attention, the patient had such
anxiety over the possibility of a painful episode that there
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was refusal to put the arm through a normal range of motion;
thus, the extent of instability was not fully appreciated by the
first examining physician. A subsequent consultation with
a second doctor revealed the true extent of instability, and
it was speculated that he had torn away the anterior capsule
of the SCJ. As the initial severe pain started to subside, the
splinting of the area associated with the initial injury also
subsided. This allowed the full extent of the instability to be
recognized clinically. This was a major instability with the
joint separation in excess of 2 cm on reclining and relaxing
the shoulder girdle tension. X-ray studies of the SCJs failed
to demonstrate any pathology.
The patient was advised by two separate competent
shoulder surgeons that surgical intervention for atraumatic
anterior SCJ instability was not recommended and carried
a large risk of complications. Unhappy over the prospect
of being unable to get relief of symptoms and the problem,
the patient actively researched other options for treatment.
This led to articles about prolotherapy and, eventually, to a
prolotherapist.
Methods and materials
The basic premise of joint instability can be attributed to liga
ments failing to keep the bones in proper approximation with
each other. Ligaments are avascular structures composed of
collagen that accumulate microtears when stretched from
4% to 8% of their original length. Macroscopic tears may be
observed when a ligament is stretched past 8%, with complete
rupture occurring around 12%.1–3 Under these parameters,
a 1-cm long ligament can stretch 1.2 mm and be completely
torn. In a joint such as the SCJ, where maximum strength
and complete restoration of physiological length is needed
to regain the full stability, conservative therapy, without
prololiferative stimulation, has little chance of regaining
this full strength and stability. The avascular nature of liga
ments decreases their healing potential and under the best
circumstances a damaged ligament may heal to its original
length, but only 50%–75% of its original tensile strength.1,2,4
Other tissues, such as muscle and bone, have an abundant
blood supply that enables them to bleed when injured. This
bleeding acts as a humoral message to the body which iden
tifies the area of damage and initiates the wound healing
cascade.1,2,4–13
The microperforation prolotherapy injection process
creates an acute, controlled local inflammation and an osmotic
type of bruise on the cells at the fibro-osseous junction
between the ligaments and the bony attachments and within
those ligamentous tissues themselves.1,2,4,5,9 This initiates
Open Access Journal of Sports Medicine 2011:2
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the healing process. The objective is to bring activity into
an indolent and unresponsive healing process that fails to
restore normal tissue turgor and strength to the damaged
areas.1–6,8,9,14–16
Multiple punctures of the fibro-osseous junction around
the joint at the sternal margins and on the clavicular
head at the attachments of the capsular ligaments were
done. The capsular tissues were also perforated. At each
perforation, enough proliferant solution was injected into the
tissues to create the inflammatory response to induce healing.
There is a clear attempt to get all of the tissues involved in
the healing process. A hiatus between treatments is usually
3 weeks to allow some tissue healing to take place and
then the process is reactivated until the desired healing has
occurred. It can be done more frequently or less frequently as
circumstances demand without losing the beneficial effects of
the treatment.9 The patient’s healing ability, including their
nutritional status and the extent of the damage, determines
the speed of resolution of the problem.
The solutions used are hypertonic osmotic proliferants
(dextrose and glycerin), irritants (dextrose, phenol, guaiacol,
tannic acid, and plasma quinine urea), particulates (pumice),
or chemotactics (sodium morrhuate arachadonic acid from
cod liver oil). The injections place the hypertonic solution
at the ligament level. The body attempts to neutralize the
hypertonic solution by adding more fluid to the area. This
creates the localized irritation and inflammation that sum
mons the reparative process to the area so that healing may
begin. The other additives serve to enhance the initiation
of the reparative process.1–5,9,16 The process activates the
normal physiological principles of wound healing where
the inflammation stimulates the migration of platelets with
their platelet-derived growth factors (PDGF). Neutrophils,
macrophages, and proteases become active debriding the
damaged tissues. These PDGFs represent cytokines that
stimulate the chemotaxis, mitosis, and the production of
extracellular matrix, angiogenesis, and cell proliferation
required to support healing. Other growth factors that are
part of any normal tissue healing process are, theoretically,
activated by this process.1–5,7,10,11,14,16 This phase lasts 3–5 days
and sets the stage for the proliferative stage to occur.5,10,11
In the proliferative stage, collagen is laid down.
Fibroblastic proliferation predominates and is oriented in
the direction of the ligaments that are healing. Movement
is encouraged, and it directs the fibroblastic proliferation
that forms the new ligaments.1–5,7,10,11,14,16 This proliferative
stage lasts from the end of the inflammatory stage upward
to 3 months.5,10,11
Microperforation prolotherapy
The third stage is the remodeling stage, where the new
ligament tissue increases its cross-linking and its fiber
orientation to form the new ligaments that are developing
to repair the damaged structures. Tissues contract to their
physiological length restoring the stability and integrity to the
joint treated.1–5,7,10,11,14,16 This stage can last up to 2 years.5,7,10,11
With prolotherapy, chronic indolent injuries are converted
into acute injuries that go on to heal the damaged area.
In treatment, platelet rich plasma (PRP) may be used. It is
a concentrate of the platelets in the patient’s own blood and is
harvested from a peripheral vein and concentrated to extract
platelets in a reduced quantity of plasma that is injected
back into the damaged tissues. This brings a high volume of
platelets into the area immediately instead of waiting for the
body to deliver platelets to the damaged area. This procedure
stimulates a greater healing response.3,12,13
A histological study of prolotherapy-treated ligaments
displayed an increased number of active fibroblasts, greater
amounts of collagen, and an increase in collagen size and
variation.14,17 These changes are accompanied by increased
thickness, mass, and ligament-to-bone-junction strength in
animal models.18,19
Results
At the patient’s first visit, approximately 4 months after
the painful subluxation-dislocation episode, examination
revealed extreme instability in the SCJs, especially on the
right side. The separation was in the vicinity of 2 cm with
abduction elevation movements of the right upper extremity.
In recumbency, the medial end of the clavicle moved anterior
approximately 2 cm confirming clinically that this was indeed
a major instability of these joints. The pectoralis muscle was
tight from the patient’s unwillingness to move the arm, and
it could not be stretched out without disrupting the SCJ on
the right side. The same movement on the left side caused
the joint to sublux.
Microperforation prolotherapy is indicated for ligament
laxity, degeneration, and disruption if the damage is in a
confined space. The patient’s SCJ constituted a confined
space, and the capsular and ligament tissues were readily
identifiable as to location for injection. The joint separation
made access to all parts of the joint capsule most acces
sible without any extraordinary techniques. The patient was
considered a candidate for this treatment.
The technique described above was employed by injecting
the hyperosmotic proliferant 22% dextrose and procaine
approximately 9 mL into each SCJ capsular and ligament
tissue. Heat and gentle exercise were recommended, and the
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Stein et al
patient was told to avoid any anti-inflammatory medication
during the healing process.
The patient had a very mild tightness in the SCJ area and did
not have any severe pain. After 5–6 weeks, he felt some reduction
in the popping and could realize more freedom of movement
without the anxiety associated with the subluxations.
The patient was a student, whose combined travel and
treatment time in clinic encompassed a full day away from
school. As a matter of convenience, he had three treatment
sessions with each of two different prolotherapists closer
to school who used a more traditional form of prolotherapy
treatment. The patient did not feel that he made an acceptable
amount of progress with those six treatments.
This lack of progress made the patient realize that the
more aggressive treatment yielded a better outcome and he
returned to the clinic 4 1/2 months later for reevaluation. The
right side was still hypermobile but was not popping. The left
side was popping. Both sides were still painful.
Platelet-rich plasma injection using the same micro
perforation technique was employed at this time. It was
obtained using the Harvest® method with 60 mL of blood
yielding 10 mL of PRP, which was injected into the ligament
structure around each SCJ following the same technique as
our original session.
Progressive improvement was observed at each sub
sequent visit with increasingly greater levels of stability
observed over the intervening weeks. Several additional
sessions of the microperforation prolotherapy treatment were
administered using hypertonic 22% dextrose plus 1 mL of
the chemotactic sodium morrhuate and procaine.
The sixth and final microperforation prolotherapy treat
ment was given 13 months after the initial injection session.
The patient had much more stability and experienced no
popping. When the patient was lying down, he felt that the
joints separated more than normal. This was confirmed on
examination. Close examination showed some tenderness at
the posterior part of the SCJ on palpation of that area. As a
result, another microperforation prolotherapy treatment was
given, especially injecting the SCJ posterior capsular area. To
easily and safely access this area, a bent needle technique was
utilized that allowed controlled access to the joint capsule from
the anterior direction with the needle directed anterior keeping
all vital structures safely out of harm’s way. A solution of
5 mL of 22% dextrose with procaine was used in each joint.
A 4-month hiatus of treatment was recommended to allow the
tissues to continue to heal without further stimulation.
The patient was last examined in February 2011,
20 months after he first presented in the clinic. At this visit
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he had complete stability of both sternoclavicular joints with
no evidence whatsoever of tendency to subluxation and no
weakness of the shoulder girdle or apprehension of upper
extremity movement. He was content with the treatment and
was pleased that he had not suffered any surgical incisions or
complications from a surgical procedure. From every point of
view the shoulder and the SCJs are completely normal with
no clinical evidence of a problem having existed.
Discussion
Treatment – the standard surgical
approach
Surgical treatment for atraumatic anterior dislocation/
subluxation of the SCJ remains controversial, with no published
studies demonstrating efficacy for a large sample size.20–31
Numerous authors have gone on the record recommending
avoidance of surgery, especially for the type of dislocation
described here.23–28,32–35 Complications reported by various
authors include, in no order of frequency, pneumothorax,
repeat surgery for bony erosions, hardware failure and/or
migration, severe postoperative pain and limited function,
persistent instability, cosmetic defects, and nonunion.21,26,28
Rockwood and Odor stated: “Operative treatment for
spontaneous anterior subluxation of the SCJ is rarely, if ever,
indicated”.28
Echlin et al stated: “Operative repair is reserved for either
posterior dislocation or nonremittent symptoms that signifi
cantly affect either daily or athletic activities”.23
Treatment – the standard conservative
approach
A case of a swimmer with bilateral SCJ subluxation reported
in the literature states that a successful resolution relied on
physical therapy and alternative sports like jogging and
cycling.23 The therapy was not described as curative, and the
patient continued to have instability of the SCJs, necessitating
the cessation of all sports requiring exaggerated overhead
movements. In a case report by DiFabio et al,22 they described
complete resolution of bilateral SCJ subluxation through
the use of immobilization followed by 9 months of physical
therapy. There was no mention of sporting activity.
Treatment – microperforation
prolotherapy
Wound healing follows physiological principals starting with
inflammation which serves to clear out the damaged tissue.
As vascularity increases, growth factors, enzymes, and other
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cells required for this debridement are summoned to the
area of damage. Cleansing takes place during the 3–5 days
of inflammation and is followed by a period of laying down
new collagen.1–5,7,10,11,14,16 The collagen process starts anywhere
from 3 to 5 days of inflammation upwards to 3 months.
Maturation of the collagen occurs over a period of time, pro
gressively upwards to almost 2 years as tissues become more
oriented, stronger, and contract to physiological length and
strength.5,7,10,11 The end result of the healing process stimulated
by prolotherapy techniques is the thickening of the ligament
structures and the return of the tensile strength to normal.
In 2002, Chen et al7 reported on a ligament healing
response technique called microperforation. In this article,
the authors demonstrated a technique for treating laxed liga
ments, especially the medial collateral ligament area of the
knee, with open surgery. The procedure uses a rake shaped
like a paddle with 14 sharp teeth to create multiple acute
rips and microperforations along the course of the medial
collateral ligament of the knee at the time of doing open sur
gery on an anterior cruciate ligament. The approach specified
that “the spikes must be driven into the bone to achieve a
better bleeding response”. Review of the approach indicated
that the patient should be advised of increased bruising and
ecchymosis and pain as a result of this type of surgery to
stimulate the medial collateral ligament into an acute healing
process. “Microperforation, despite its trauma remains less
invasive than conventional surgical procedures and avoids
their complications”. The positive ideas of this technique are
to avoid denervation of the ligament and devascularization
of the ligament tissue, preserve physiometric attachments,
and avoid pressure necrosis from hardware insertion.
The procedure would create an acute healing environment for
laxed ligaments and future developments could foresee using
this procedure for other weakened ligaments in the body. It
was advised that the procedure be reserved to certain classes
of injury to the medial collateral ligament, but that future
investigation may find other uses for the procedure.7
In actuality, the technique takes a relatively avascular
damaged structure and forces it into an acute inflammatory
response. These tissues then progress through the phases
of healing, which include inflammation, debridement, new
collagen lay down, and maturation. This is the body’s physi
ological response to damage.
Microperforation prolotherapy offers the opportunity to
do precisely what is described by this previous peer-reviewed
article. However, we do it in a far more elegant fashion with
much less necessity for bleeding and sheer tissue damage than
has been created by this type of surgical procedure.
Microperforation prolotherapy
It is performed elegantly with a fine needle inserted through
the skin and into the subcutaneous tissue. The needle is then
directed to the ligament structures where multiple perforations
accompanied by injection of the appropriate amounts and
types of solutions create the tissue injury that impels the final
healing. Multiple sessions without the need for open surgery
and anesthesia accomplish the same goals as the open surgery
described above. We accomplish regeneration and maturation
of ligaments, thereby eliminating instability, and we restore nor
mal function without surgical scars and without any prolonged
period of confinement. It is all done in a clinic setting.
Torretti and Lynch31 reviewed the current literature relat
ing to SCJ injuries. The authors analyzed many types of
treatments and clearly recognized the importance of the
posterior sternoclavicular capsular ligament as the main
anteroposterior component for stability. The authors reviewed
the relative strength of the various repairs and summarized
that “although there has been a small but significant advance
ment in the cumulative knowledge of the sternoclavicular
joint, there still remains a number of unanswered questions.
Controlled comparisons of a variety of treatment methods
will be needed to reliably assess clinical outcomes”.31
It is hypothesized that microperforation prolotherapy be
seriously considered as a proper treatment for the ligamentous
injuries of anterior sternoclavicular dislocation and other
applications where significant ligamentous injury is involved
in a confined space.
Conclusion
This manuscript describes and presents a novel form of
microperforation prolotherapy used to treat bilateral atraumatic
spontaneous anterior dislocation of the SCJ that was causing
severe morbidity. Results of this novel microperforation pro
lotherapy, applied to the capsular ligaments about the SCJ,
appear to be a completely satisfactory alternative to surgery.
The treatment has allowed the patient to return to full, normal
function with no residual observable findings indicating the
previous presence of this problem. This novel microperforation
prolotherapy has been able to accomplish a complete return to
full functional stability of the SCJs, without any scar or com
plication, in an acceptable time frame. Based on the positive
results obtained in this difficult case, further study and more
extensive use of microperforation prolotherapy are indicated.
It is the purpose of this writing to share observations and spark
interest in further studies of this technique.
Disclosure
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Stein et al
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33. Bicos J, Nicholson GP. Treatment and results of sternoclavicular joint
injuries. Clin Sports Med. 2003;22(2):359–370.
34. Garretson RB, Williams GR. Clinical evaluation of injuries to the acro
mioclavicular and sternoclavicular joints. Clin Sports Med. 2003;22(2):
239–254.
35. Lemos MJ, Tolo ET. Complications of the treatment of the acromio
clavicular and sternoclavicular joint injuries, including instability. Clin
Sports Med. 2003;22(2):371–385.
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APRESS: apical regulatory super system, serotonin,
and dopamine interaction
4 August 2011
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
Clinics, Inc, Cape Coral, FL, USA;
2
Duluth, MN, USA
1
Background: The monoamines serotonin and dopamine are known to exist in two separate
states: the endogenous state and the competitive inhibition state. The presence of the competitive
inhibition state has been known to science for many years, but from a functional standpoint it
has been noted in the literature as being “meaningless.”
Methods: A large database of monoamine transporter response to amino acid precursor
administration variations with clinical outcomes was accumulated. In the process, a new organic
cation transporter (OCT) model has been published, and OCT functional status determination
along with amino acid precursor manipulation methods have been invented and refined.
Results: Methodology was developed whereby manipulation of the OCT, in the competitive
inhibition state, is carried out in a predictable manner. This, in turn, has disproved the long-held
assertion that the monoamine competitive inhibition state is functionally meaningless.
Conclusion: The most significant aspect of this paper is the documentation of newly recognized relationships between serotonin and dopamine. When transport of serotonin and dopamine
are both in the competitive inhibition state, manipulation of the concentrations of one will lead
to predictable changes in concentrations of the other. From a functional standpoint, processes
regulated and controlled by changes to only serotonin can now be controlled by changes to
dopamine, and vice versa, in a predictable manner.
Keywords: catecholamine, monoamine, competitive inhibition state
Introduction
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
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http://dx.doi.org/10.2147/IJN.S22667
Serotonin and the catecholamines (dopamine, norepinephrine, and epinephrine) belong
to a group of chemicals herein known as “monoamines.” The monoamines function
independently, controlling and/or regulating bodily functions. These functions include,
but are not limited to, neurotransmitter, neurohormone, regulatory, autocrine, paracrine,
and autonomic control.1–3
This paper documents novel observations of the competitive inhibition state, which
was previously thought to be functionally meaningless. The physiologic observations
of this state are deemed the “apical regulatory super system” (APRESS), which occurs
with simultaneous administration of serotonin and dopamine amino acid precursors
in significant amounts.
“Super system” is defined as the fusion of two independent systems into one.
Changes to one or more components of either system affect changes to all components
in a predictable manner. In the balanced competitive inhibition state,3–8 serotonin and
catecholamines undergo super system fusion.
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Monoamines exist in one of three states: endogenous,
unbalanced competitive inhibition, and balanced competitive
inhibition.3–8 The “endogenous state” is achieved by dietary
intake alone when no supplemental monoamine amino acid
precursors are being administered.3–8
The competitive inhibition state cannot be achieved
through dietary modification; it is established when significant amounts of monoamine precursors are simultaneously
administered. 3–8 Competitive inhibition state literature
notes “… functional relevance of the competitive inhibitory effect … is most probably meaningless.”9 Functional
relevance is achieved with the ability to assay and regulate transport of the monoamines in a predictable manner
with organic cation transporter (OCT) functional status
determination. Except by random chance, it is impossible
to achieve the balanced competitive inhibition state without
OCT functional determination.3–8 Differentiating “unbalanced” and “balanced” competitive inhibition is discussed
later in this paper.
The foundation of APRESS is that in the competitive
inhibition state, transport changes to one monoamine lead to
predictable changes in all monoamines. These changes are not
intuitive. Endogenous state observations are not applicable to
APRESS (see Tables 1–4). This writing introduces APRESS
as a novel physiologic state adhering to unique transporter
properties that are counterintuitive to rules of the endogenous
state. This paper discusses only the following limited aspects
of monoamine interaction in APRESS.
• Functions impacted and/or controlled in the endogenous
state only by changes in serotonin concentrations may
also be impacted or controlled by changes in dopamine
concentrations in APRESS.
• Functions impacted and/or controlled in the endogenous
state only by changes in dopamine concentrations may
also be impacted or controlled by changes in serotonin
concentrations in APRESS.
Since 2009, the authors of this paper have published eleven
peer-reviewed original research papers relating to the simultaneous manipulation of the serotonin and catecholamine
systems with amino acid precursors under guidance of OCT
assay interpretation.3–8,10–14 APRESS embodies the common
thread of these writings: serotonin and catecholamine fusion
into one system. Previous publications outlined much of
the novel scientific foundation of APRESS, but its impact,
novel abilities and other considerations have not been fully
explored and documented.
Following are research components used to define the
novel physiologic attributes of APRESS in the body. These
components, observations, and networking applications
include, but are not limited to:
• Over 1000 monoamine databases relating to the
endogenous and competitive inhibition states.15
• A master database documenting over 2 million patient-days
of monoamine amino acid transporter manipulation.15
• Review and interpretation of over 100,000 urinary
monoamine assays in the endogenous or competitive
inhibition state.15
• Defining the three-phase monoamine transporter response
of serotonin and dopamine observed during simultaneous
administration of their precursors.3–8,10–14
• A network of over 1000 physicians manipulating nutrients
in APRESS.15
Serotonin and dopamine filtered at the glomerulous are
metabolized by the kidneys; significant amounts do not make
it into the final urine. Newly synthesized renal serotonin and
dopamine meet one of two fates, as illustrated in Figure 1.
The three-phase response of urinary monoamines is used to
determine the functional status of the basolateral OCT2 of the
proximal convoluted renal tubule cells.3–8,10–14 Urinary levels
are dependent upon the interaction of the basolateral OCT2
and the apical OCTN2 in transporting newly synthesized
monoamines out of the proximal convoluted renal tubule
cells (see Figure 1).3–8,11,12,16
Proper OCT interpretation requires obtaining two or
more urinary monoamine assays while taking significant
amounts of varied precursor dosing values consistently for
5 days minimum to achieve equilibrium. Serial assays are
then compared to determine the impact of precursor dosing
value changes.3–8,10–14
The following urinary monoamine values were reported
in µg of monoamine per g of creatinine to compensate for
specific gravity fluctuations. A urinary serotonin or dopamine
Table 1 Impact of increasing amino acid precursor dosing values of System A in phase 3
System A
System B
Amino acid intake
Synthesis
Metabolism
Transport
Post transporter
Urinary
Increased
Same
Increased
Decreased
Increased
Increased
Increased
Decreased
Increased
Decreased
Increased
Increased
Note: The response to increasing one monoamine precursor of serotonin or dopamine in competitive inhibition.
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APRESS
Table 2 Impact of decreasing amino acid precursor dosing values of System A in phase 3
System A
System B
Amino acid intake
Synthesis
Metabolism
Transport
Post transporter
Urinary
Decreased
Same
Decreased
Increased
Decreased
Decreased
Decreased
Increased
Decreased
Increased
Decreased
Decreased
Note: The response to decreasing one monoamine precursor of serotonin or dopamine in competitive inhibition.
value less than 80 or 475, respectively, is defined as a phase 2
response. A urinary serotonin or dopamine value greater than
80 or 475, respectively, is interpreted as being in phase 1 or
phase 3. If a direct relationship is found between amino acid
dosing and urinary assay response, it is a phase 3 response.
An inverse correlation is a phase 1 response. The phase 3
therapeutic range for urinary serotonin is 80–240. The phase 3
therapeutic range for urinary dopamine is 475–1100.3–8,10–14
Urine samples were collected 6 hours prior to bedtime
after a minimum of 1 week on a specific dosing value, with
no missed doses of amino acid precursors. The most frequent
collection time point was 4 PM. Samples were stabilized
in 6 N HCl to preserve the monoamines and shipped to
DBS Laboratories (Duluth, MN) which is operated under
the direction of one of the authors (Thomas Uncini, MD).
Urinary monoamines were assayed utilizing commercially
available radioimmunoassay kits (3 CAT RIA IB88501 and
IB89527, both from Immuno Biological Laboratories, Inc,
Minneapolis, MN). The DBS laboratory is accredited as a
high complexity laboratory by Clinical Laboratory Improvement Amendments. OCT assay interpretation was performed
by one of the authors (Marty Hinz).3–8,10–14
Results
Three primary functions affect intracellular and extracellular
serotonin and catecholamine levels: synthesis, metabolism,
and transport.3–5,7,8,10–12 These functions occur in either the
endogenous or competitive inhibition state.3–8
The relationship between serotonin and dopamine regarding synthesis, metabolism, and transport in the endogenous
state appears to be random. Matched pairs t-test analysis
of endogenous urinary monoamines reveals significant
day-to-day changes (P , 0.05) in a subject. In the competitive
Table 3 Urinary monoamine concentrations per phase
Phase 1
Phase 2
Phase 3
Serotonin
Dopamine
.80
,80
.80
.475
,475
.475
Phase 3 therapeutic ranges
Serotonin
Dopamine
80–240
475–1100
Note: Units are in μg of monoamine per g creatinine.
inhibition state, predictable changes occur to all monoamine
components with changes to individual precursor dosing
values of either system.6,10,12
Aromatic L-amino acid decarboxylase (AAAD) catalyzes
serotonin and dopamine synthesis. Monoamine oxidase
(MAO) catalyzes metabolism of serotonin and dopamine.
OCT transports monoamines and their precursors in and out
of proximal convoluted renal tubule cells. When significant
amounts of balanced serotonin and dopamine precursors are
administered simultaneously under guidance of OCT assay
optimization, the balanced competitive inhibition of APRESS
is established.6,10,12
Immediate precursors of serotonin and dopamine presenting at the AAAD need to be in balance. If not, precursors of
one system will dominate AAAD, compromising nondominant monoamine synthesis.6,10,11
Serotonin and dopamine need to be in balance or the
dominant monoamine increases MAO activity and metabolism of the nondominant system.6,10,12
Monoamine renal physiology is complex. Prior to the
authors writing this paper, the sequence of events from the
monoamines and their precursors being filtered at the glomerulous to them appearing in the system or final urine had
not been documented.
Until this research, direct clinical measurement and
evaluation of monoamine OCT functional status did not
exist, rendering the competitive inhibition state functionally
meaningless.9
Serotonin, dopamine, and their precursors filtered at the
glomerulous are taken up from the proximal tubules by OCT2
transporters into the proximal convoluted renal tubule cells
where the monoamines are metabolized. Significant amounts
do not make it to the final urine under normal conditions.3–8,11,12
Precursors are then synthesized into new monoamines, which
are preferentially transported by the basolateral OCT2 to the
system or excreted via the apical OCTN2 as urinary waste.
Interpretation of urinary monoamine levels in the competitive
inhibition state is an interpretation of the functional status of
the basolateral OCT2.3–8,11,12
Previous writings by the authors of this paper refined
the basolateral OCT2 transporter model.3 The OCT of
the liver, kidneys, bowels, and brain are “identical and
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Table 4 Effect of increasing only L-dopa dosing values in the competitive inhibition state
Day #
Urinary
serotonin
Urinary
dopamine
Serotonin
phase
Dopamine
phase
5-HTP mg/day
dosing value
L-dopa mg/day
dosing value
0 (test 1)
8 (test 2)
84
473
289
786
3
3
2
3
900
900
120
360
Notes: Serotonin phase 3/3; Dopamine phase 2/3; units are in μg of monoamine per g creatinine.
Abbreviation: HTP, hydroxytryptophan.
homologous.” Precursors cross the blood–brain barrier
then come to equilibrium throughout the body. 16 Under
the dual gate lumen transporter model, there are separate
serotonin and dopamine gates at the lumen entrance.
These gates independently regulate lumen access by the
respective monoamine. While either gate can be partially
closed, blocking access, both gates are never simultaneously partially closed.3
Serotonin and dopamine basolateral OCT2 transport
exists in three transport phases. In phase 1 the entrance gate
is partially closed, restricting access to the nonsaturated
lumen. If the gate at the lumen is partially closed (phase 1),
Serotonin newly
synthesized by
the kindey
it will open as the total amount of serotonin and dopamine
presenting at the transporter increases. In phase 2 the gate
of the nonsaturated lumen is open. In phase 3 the entrance
gate of the saturated lumen is open.3–8,10–14
Now the question becomes: how can functions controlled
only by serotonin or dopamine in the endogenous state be
controlled in a predictable manner by changes to either in
the competitive inhibition state?
Once the transporter is saturated with both serotonin and
dopamine (phase 3), an increase in one monoamine being
transported will cause the amount of the other monoamine
being transported to decrease. Tables 1 and 2 document the
Basolateral
transporters
(OCT2)
Dopamine newly
synthesized by
the kidney
Apical
transporters
(OCTN2)
To
renal
vein
The newly synthesized
serotonin and dopamine are
preferentially transported out of
the proximal convoluted renal
tubule cells by the basolateral
transporters (OCT2)
The serotonin and dopamine
not transported by the
basolateral transporter are
transported as waste to the
final urine via the apical
transporters (OCTN2)
To final urine
Figure 1 The interaction of OCT2 and OCTN2. Newly synthesized serotonin and dopamine are transported preferentially by the basolateral OCT2. Functional status of the
OCT2 is determined by assaying the urinary monoamines not transported by the OCT2, which are transported by the OCTN2 to the final urine as waste.3–8,11
Abbreviation: OCT, organic cation transporter.
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impact of placing both systems into competitive inhibition
as verified by OCT assay determination.3–8,10–14
In Tables 1 and 2, “System A” is either L-dopa or
5-hydroxytryptophan (immediate dopamine and serotonin
precursors respectively), with “System B” the opposite
precursor. With both systems in phase 3, a single precursor
increase leads to a decrease in the post-transporter levels of
the other system through competitive inhibition, just as a
decrease of one amino acid precursor leads to an increase in
post-transporter levels of the other system. In the competitive
inhibition state, these levels can be changed by making
changes to amino acid precursor dosing values of either
system.
Interpretation of urinary levels of serotonin and dopamine,
with amino acid dosing changes in the competitive inhibition state, are complex. In Table 1, the precursor increase
causes decreased synthesis of the nondominant monoamine
(system B) through AAAD competitive inhibition. Increased
activity of the MAO enzyme system is induced, leading to
increased metabolism of the nondominant monoamine.
The key to optimal balanced control is to place the
serotonin and dopamine in the therapeutic phase 3 ranges
of Table 3. This cannot be done empirically. The dosing
levels of 5-hydroxytryptophan (5-HTP) need to reach the
phase 2/phase 3 inflection point between 37.5 and 2400 mg
per day.15 The L-dopa dosing level to reach this inflection
point is between 30 and 2100 mg per day. Dosing values
of serotonin precursors are independent from dopamine
precursors, meaning any combination of precursors in a
large spectrum is possible. OCT assay to determine levels
of serotonin and dopamine not transported by the basolateral
OCT2 is required.3–8,10–14
In test 1 of Table 4, serotonin is phase 3 and dopamine
transport is phase 2. Between tests, L-dopa was increased to
360 mg per day, causing an increase in dopamine transported
by the OCT2 and in the urine. Less serotonin was then
transported by the OCT2 as dopamine transport increased,
excluding serotonin from the OCT2 transporter through
competitive inhibition, and more serotonin appeared in the
final urine as waste. In the first assay, serotonin was 84 µg of
serotonin per g creatinine and in phase 3. An increase in L-dopa
leads to a decrease in the serotonin phase 2/phase 3 inflection
point (inverse relationship). The same is true regarding 5-HTP
increases and the dopamine phase 2/phase 3 inflection point.
In test 2, APRESS effect is not optimal. The urinary
serotonin is too high, causing excessive exclusion of
dopamine transport even though the dopamine is in the
therapeutic range. Optimal serotonin and dopamine
APRESS
transport is seen only with both serotonin and dopamine in
their phase 3 therapeutic ranges. Even though on test 2 the
urinary dopamine is in the phase 3 therapeutic range, this
observation is meaningless until both serotonin and dopamine
are simultaneously in therapeutic ranges. If both systems are
not in therapeutic phase 3 ranges defined in Table 3, further
optimization is needed to maximize transporter balance.
With the lowering of daily 5-HTP dosing values due to
OCT2 transporter imbalance, the urinary dopamine levels
at the OCTN2 transporter entrance will drop secondary
to decreased serotonin transport, facilitating increased
dopamine transport. This causes less serotonin and dopamine
to show up in the final urine as waste. The general direction of
urinary serotonin levels in transport and final urinary levels
can be predicted in the competitive inhibition state; the exact
amount of movement secondary to amino acid precursor
changes, however, is individualized.3–8,10–14
Full interpretation of large-scale results may be quite
confusing at times for the uninitiated. Extraordinarily
complex relationships not covered in this writing exist
based on determination of OCT2 transporter status. These
complexities are beyond the scope of this paper.3–8,10–14
The unbalanced competitive inhibition
state, a pathologic state
The hallmark of the unbalanced competitive inhibition state
is “pathological depletion of monoamine components.”
When unbalanced amino acid precursors are administered,
one system dominates and the other is nondominant. The
dominant system overwhelms and depletes the nondominant
system. Most significant depletions occur in weeks or months
although some may take years.4,5,8,10,11
• L-tryptophan or 5-HTP depletes dopamine when domi
nant.4,5,8,10,11
• L-tyrosine or L-dopa depletes serotonin when domi
nant.4,5,8,10,11
L-dopa and 5-HTP are the immediate dopamine and serotonin precursors, respectively. Both are synthesized into the
monoamine without biochemical feedback regulation.7 The
following clinical situation illustrates unbalanced depletion
of a nondominant system.
In Parkinson’s disease, serotonin and dopamine are
depleted by the disease. L-dopa treatment alone leads to
serotonin depletion by inhibiting serotonin AAAD synthesis.
Administering only L-dopa increases the activity of the MAO
system, depleting the nondominant serotonin when balanced
levels of 5-HTP are not being administered. Side effects
associated with administration of only L-dopa, which are
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related to serotonin imbalance, include but are not limited
to tachyphylaxis due to serotonin depletion, problems of
improperly balanced monoamines, problems caused by
dopamine fluctuations, and problems resulting from sulfur
amino acid depletion.7
Problems associated with dominant levels of 5-HTP are a
mirror image of the L-dopa problems. The common practice
of administering only 5-HTP without properly balanced
dopamine precursors depletes dopamine.7
• Refractory depression can be successfully treated without
drug side effects.
• In Crohn’s disease, OCT genetic transporter defects that
cause Crohn’s symptoms and interstitial colonic serotonin
to be markedly elevated can be treated.4
• Attention deficit hyperactivity disorder preliminary
treatment studies (N = 85) published in 2011 reveal efficacy
results greater than atomoxetine or methylphenidate.5
Discussion
Serotonin and dopamine may exist in three basic states: the
endogenous state, the unbalanced competitive inhibition state,
and the balanced competitive inhibition state. Physiologic
observations in the endogenous state have no bearing or
relationship with the competitive inhibition state.
The balanced competitive inhibition state is the foundation
for APRESS. APRESS is a registry of the activities impacted
by manipulating the balanced competitive inhibition state.
The ability to affect and regulate bilateral serotonin or
dopamine concentration changes with a single monoamine
adjustment in a predictable manner is the foundation of
APRESS. This leads to the ability to define interactions and
gain control in a physiologic state that until now was thought
to be functionally meaningless.
APRESS is indeed based on a unique physiologic state
that is not meaningless. It is a new frontier that cannot be
achieved through dietary manipulation alone or without
OCT functional status determination, a procedure that can
be performed in medical clinics.
APRESS is not a state that can be optimally achieved by
empirical administration of amino acid precursors. Once in this
clinical competitive inhibition state, the scientific observations
of the endogenous state are no longer valid. APRESS is a new
physiological world in and of itself. It is in need of research to
define its far-reaching parameters and implications. It is the
goal of this writing to stimulate interest and discussion relating
to this novel state known as APRESS.
Functions dependent on only serotonin or dopamine
concentrations in the endogenous state can be impacted in
a predictable manner by changes in levels of either in the
balanced competitive inhibition state which is the foundation
of APRESS.4,5,8,10,11 APRESS physiology is not intuitive.
An intimate knowledge of monoamine physiology in the
endogenous state may even be a distraction to mastering
the complex state of APRESS. Observations and rules
formulated for the endogenous and unbalanced competitive
inhibition states are typically not valid in guiding amino acid
precursor adjustments.3–8,10–14
The physiological and clinical management observations
entered into the APRESS catalog have just started. It contains
the following:
• Functions controlled by dopamine in the endogenous
state can be controlled with changes to serotonin and vice
versa.
• The balanced approach does not deplete monoamines.3–8,10–14
• Administration of targeted and balanced amino acid
precursors leads to optimal results in disease and dysfunction
management.3–8,10–14
• The approach directly addresses and treats the cause of
problems, unlike the symptom management approach
with prescription drugs.3–8,10–14
• Properly balanced serotonin and dopamine does away
with side effect dosing value barriers providing the
opportunity to reach levels of needed amino acid intake
not possible in the unbalanced state.3–8,10–14
• Parkinson’s disease patients can be treated with L-dopa
levels needed to control symptoms without reaching a
side-effect induced dosing barrier.7
• Management of the extensive list of side effects
associated with L-dopa and carbidopa in treatment of
Parkinson disease.7
• Bipolar disorder cycling on the depressive pole can be
differentiated from major affective disorder then treated
effectively.11
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Conclusion
Disclosure
MH owns NeuroResearch Clinics, Inc; AS reports no
disclosures; TU reports a directorship of DBS Laboratories.
References
1. Pazos-Moura C, Ortiga-Carvalho T, Gaspar de Moura E. The autocrine/
paracrine regulation of thyrotropin secretion. Thyroid. 2004;13:2.
2. O’Hara J, Ho W, Linden D, et al. Enteroendocrine cells and 5-HT
availability are altered in mucosa of guinea pigs with TNBS ileitis. Am
J Physiol Gastrointest Liver Physiol. 2004;287:G998–G1007.
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4. Stein A, Hinz M, Uncini T. Amino acid-responsive Crohn’s disease:
a case study. Clin Exp Gastroenterol. 2010;3:171–177.
5. Hinz M, Stein A, Neff R, et al. Treatment of attention deficit
hyperactivity disorder with monoamine amino acid precursors and
organic cation transporter assay interpretation. Neuropsychiatr Dis
Treat. 2011;7:31–38.
Access J Urol. 2011;3:19–24.
7. Hinz M, Stein A, Uncini T. Amino acid management of Parkinson’s
disease: a case study. Int J Gen Med. 2011;4;165–174.
Disease Management. Boca Raton, FL: CRC Press; 465–481.
9. Soares-da-Silva P, Pinto-do-O PC. Antagonistic actions of renal
dopamine and 5-hydroxytryptamine: effects of amine precursors on
the cell inward transfer and decarboxylation. Br J Pharmacol. 1996;
117:1187–1192.
10. Hinz M, Stein A, Trachte G, Uncini T. Neurotransmitter testing of
the urine: a comprehensive analysis. Open Access J Urol. 2010;2:
177–183.
APRESS
12. Hinz M, Stein A, Uncini T. “Non-validity and clinical relevance of
neurotransmitter testing”: a review of the paper. Funct Neurol Rehabil
Ergon. 2011. In press.
Dis Treat. 2009;5:227–235.
14. Hinz M, Stein A, Uncini T. The validity of urinary monoamine assay
sales under the “spot baseline urinary neurotransmitter testing marketing
model.” Int J Nephrol Renovascular Dis. 2011;4:101–113.
15. NeuroResearch Clinics, Inc. Medical research, medical education databases and records. 1008 Dolphin Dr, Cape Coral, FL 33904, USA.
and brain. Annu Rev Physiol. 1998;60:243–266.
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published authors.
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Drug, Healthcare and Patient Safety
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Monoamine depletion by reuptake inhibitors
19 October 2011
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
Clinics Inc, Cape Coral, FL;
2
Plantation, FL; 3DBS Labs Inc, Duluth,
MN, USA
1
Background: Disagreement exists regarding the etiology of cessation of the observed clinical
results with administration of reuptake inhibitors. Traditionally, when drug effects wane, it is
known as tachyphylaxis. With reuptake inhibitors, the placebo effect is significantly greater than
the drug effect in the treatment of depression and attention deficit hyperactivity disorder, leading
some to assert that waning of drug effects is placebo relapse, not tachyphylaxis.
Methods: Two groups were retrospectively evaluated. Group 1 was composed of subjects with
depression and Group 2 was composed of bariatric subjects treated with reuptake inhibitors
for appetite suppression.
Results: In Group 1, 200 subjects with depression were treated with citalopram 20 mg per
day. A total of 46.5% (n = 93) achieved relief of symptoms (Hamilton-D rating score # 7), 37
(39.8%) of whom experienced recurrence of depression symptoms, at which point an amino
acid precursor formula was started. Within 1–5 days, 97.3% (n = 36) experienced relief of
depression symptoms. In Group 2, 220 subjects were treated with phentermine 30 mg in the
morning and citalopram 20 mg at 4 pm. In this group, 90.0% (n = 198) achieved adequate
appetite suppression. The appetite suppression ceased in all 198 subjects within 4–48 days.
Administration of an amino acid precursor formula restored appetite suppression in 98.5%
(n = 195) of subjects within 1–5 days.
Conclusion: Reuptake inhibitors do not increase the total number of monoamine molecules in
the central nervous system. Their mechanism of action facilitates redistribution of monoamines
from one place to another. In the process, conditions are induced that facilitate depletion of
monoamines. The “reuptake inhibitor monoamine depletion theory” of this paper offers a novel
and unified explanation for the waning of response seen after a reuptake inhibitor is started,
independent of a drug or placebo etiology.
Keywords: reuptake inhibitor, depletion, tachyphylaxis, relapse, serotonin, dopamine
Introduction
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
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http://dx.doi.org/10.2147/DHPS.S24798
Tricyclic antidepressants, nonspecific reuptake inhibitors, became available in 1956.1
They dominated depression treatment until the first selective serotonin reuptake inhibitor
(SSRI), fluoxetine, became available in 1988.1 The sympathomimetic anorectics, including phentermine, diethylproprion, and phendimetrazine, induce weight loss through
appetite suppression. Their mechanism of action is thought to include norepinephrine
reuptake inhibition.2 As with the rest of the reuptake inhibitors, the mechanism of
action of amphetamines is unknown. However, it is thought to be due to dopamine and
norepinephrine reuptake inhibition, which induces appetite suppression. Amphetamines
are also used in attention deficit hyperactivity disorder (ADHD).3 These classes of
Drug, Healthcare and Patient Safety 2011:3 69–77
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Hinz et al
reuptake inhibitors are also approved for other applications.
Fluvoxamine, an SSRI, is approved only for the treatment of
obsessive-compulsive disorder and social anxiety syndrome.4
Bupropion hydrochloride, a dopamine and norepinephrine
reuptake inhibitor, is indicated for smoking discontinuation.5
Reuptake inhibitors share the property of tolerance,
that is waning of the drug’s effects. In other classes of drugs
this effect is known as tachyphylaxis. Tachyphylaxis is formally defined as a “diminished response to later increments
in a sequence of applications of a physiologically active
substance”6 (ie, the drug stops working and its clinical effects
are no longer observed). The concept of reuptake inhibitor
tachyphylaxis is controversial. Double-blind, placebo-controlled studies reveal that in depression and ADHD treatment,
the placebo response is greater than the drug effect in relief
of symptoms.7,8 This leads to the argument that discontinuation of a drug’s clinical effects predominantly represents a
placebo relapse rather than drug tachyphylaxis.9,10
This paper presents the novel reuptake inhibitor monoamine depletion theory, which explains why symptoms that
are controlled at the start of treatment return, irrespective
of the cause of initial relief (placebo relapse or drug tachyphylaxis). Under this novel theory, a relative nutritional
deficiency occurs, a situation that can only be managed with
administration of proper levels of nutrients.
The following scientific facts exist. The monoamines –
serotonin, dopamine, norepinephrine, and epinephrine – do
not cross the blood–brain barrier. There are a finite number of
monoamine neurotransmitter molecules in the central nervous
system (CNS). Reuptake inhibitor drugs do not increase the
total number of these centrally acting monoamine molecules
in the CNS. The only way to increase the total number of
monoamine molecules in this finite CNS universe is through
a nutritional approach with administration of properly balanced serotonin and dopamine amino acid precursors. These
precursors cross the blood–brain barrier and are synthesized
in the CNS into new monoamine molecules.8,9,11–16
Serotonin, dopamine, norepinephrine, and epinephrine are
herein referred to as “monoamines”. A comprehensive search
of the literature was performed, specifically focusing on
depletion of monoamines by reuptake inhibitors, reuptake
inhibitor tachyphylaxis, and placebo relapse of depression
and ADHD symptoms.
Two pilot study groups were identified. Group 1 was
composed of 200 subjects taking the SSRI citalopram for
depression, which was screened initially with the Diagnostic
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and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) criteria17, then tracked with the Hamilton-D rating
scale for depression. The number of Group 1 subjects who
initially achieved relief of depression symptoms (Hamilton-D
≤ 7) was n = 93. Subjects who did not initially achieve relief of
depression symptoms on 20 mg of citalopram each morning
(Hamilton-D . 7) were excluded from the study. The next
criterion for inclusion was the return of depression symptoms
(n = 37) while taking the prescribed reuptake inhibitor drug.
Group 2 was composed of 220 patients taking a combination of citalopram and phentermine for appetite suppression
during bariatric treatment (see Table 2). Since tools do not exist
for evaluating drug-induced appetite suppression, the following
novel questions were used; a positive answer to any question
indicated inadequate appetite suppression. “Since your last
office visit have you: been inappropriately snacking on food,
been inappropriately nibbling on food, eaten more than your
calorie prescription, or needed to use willpower to stay away
from food in order to keep on your diet?” The number of Group
2 subjects who achieved initial control of appetite was n =
198. Subjects who did not initially achieve adequate appetite
control were excluded from the study. The next criterion for
inclusion was the loss of appetite suppression (n = 198) while
taking the prescribed reuptake inhibitor drugs.
Subjects were instructed to immediately report the return of
depression symptoms or loss of appetite control. Subjects were
then continued on the drug(s) and started on monoamine amino
acid precursors and cofactors in divided doses at the following
daily dosing values: L-cysteine 4500 mg, L-tyrosine 3000 mg,
vitamin C 1000 mg, L-lysine 500 mg, 5-hydroxytryptophan
(5-HTP) 300 mg, calcium citrate 220 mg, vitamin B6 75 mg,
folate 400 µg, and selenium 400 µg.
A full discussion of the scientific basis for each of these
amino acid and cofactor nutrients is covered in the authors’ previous writings.8,9,11–16,20–22 A brief overview is as follows. L-tyrosine
and 5-HTP are dopamine and serotonin precursors, respectively.
Vitamin C, vitamin B6, and calcium citrate are cofactors required
in the synthesis of serotonin and/or dopamine. L-cysteine is
administered to compensate for L-tyrosine-induced depletion of
sulfur amino acids. Folate is required for optimal sulfur amino
acid synthesis. Selenium is given in response to cysteine’s ability to concentrate methylmercury in the CNS. L-lysine prevents
loose hair follicles during bariatric treatment.
Results
Group 1: depression
A group of 200 patients who were positively diagnosed with
depression on DSM-IV depression criteria screening and had
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a Hamilton-D depression score . 7 (see row 1, Table 1) were
identified. All were started on citalopram 20 mg per day in
the morning. Two weeks after the initiation of treatment with
citalopram 20 mg, 93 subjects were diagnosed with remission
of depression (Hamilton-D # 7; row 2, Table 1). The remission
group continued citalopram 20 mg each morning. All were
instructed to immediately report if depression returned. They
were then followed in clinic every 2–4 weeks. In the 18 months
after symptom control had been achieved, 37 subjects experienced return of depression (Hamilton-D . 7; row 3, Table 1).
They were re-evaluated using the Hamilton-D depression scale
within 14 days of return of symptoms then started on the amino
acid formula discussed in the Materials and methods section.
On this amino acid formula, 36 of the 37 subjects reported
relief of symptoms, with a mean time of 1.9 days and a range
of 1 to 5 days (see Tables 3 and 4). Follow-up 6 months later
revealed no return of depression symptoms in those subjects
taking the amino acid formula.
Group 2: appetite suppression
Group 2, comprising 220 subjects, was started on 15 mg of
phentermine in the morning with 20 mg of citalopram at 4
pm for control of appetite in a bariatric medicine program.
One week later, independent of the appetite control in place,
all were increased to 30 mg of phentermine in the morning
with 20 mg of citalopram at 4 pm. One week later, 198 subjects were found to have adequate appetite suppression and
were then followed with weekly visits to monitor appetite
suppression. Novel questioning (as covered in the Methods
and materials section) revealed inadequate appetite control in
all subjects within 4–48 days, at which point the drugs were
continued and the amino acid formula outlined in the Methods and materials section was started. Within 1–5 days, 195
of the 198 subjects (98.5%) experienced return of adequate
appetite suppression.
A consistent phenomenon occurred with Group 2
participants. When the amino acid precursor formula was
added, each participant in Group 2 was able to retrospectively
identify the exact day that appetite suppression was restored.
This observation is consistent with a novel and sharply
demarcated monoamine threshold. When monoamine levels
were above the threshold, appetite suppression was observed.
When monoamine levels were below the threshold, appetite
suppression effects were not observed.
Discussion
The following definitions are put forth. Two basic types of
nutritional deficiencies may occur: a “deficiency of nutrient
Table 1 Hamilton-D rating scale scores for Group 1 (depression, n = 37)
n
Mean Hamilton
score
Hamilton score
ranges
Standard deviation
of Hamilton Score
Pretreatment score (.7)
200
10
8–21
3.39
Scores two weeks after
starting drug (#7)
93
5
1–7
1.76
Score when effects
no longer observed
37
12
7–23
3.61
Score one week after
starting amino acids
36
4
0–7
1.99
Demographics
Female
Demographics
Male
n (%)
Age range (years)
Mean age (years)
SD (years)
n (%)
Age range (years)
Mean age (years)
SD (years)
n = 126 (63.0%)
18.1–74.2
51.9
10.5
n = 60 (64.5%)
22.3–74.2
52.8
10.2
n = 24 (64.9%)
23.4–68.2
50.7
9.1
n = 23 (63.9%)
23.4–68.2
50.6
9.1
n = 34 (37.0%)
25.4–81.6
54.1
11.5
n = 33 (35.5%)
25.4–74.5
53.2
11.1
n = 13 (35.1%)
25.4–67.4
51.1
9.8
n = 13 (36.1%)
25.4–67.4
51.1
9.8
Notes: Row 1: Hamilton-D score prior to starting citalopram 20 mg in the morning. Row 2: Hamilton-D score after relief of depression achieved on citalopram 20 mg per
day. Row 3: Hamilton-D score when initial relief of symptoms after starting citalopram was no longer observed. Row 4: Hamilton-D score one week after the amino acid and
cofactor formulation was started in combination with citalopram 20 mg.
Abbreviation: SD, standard deviation.
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Table 2 Group 2 demographics of bariatric group by gender at start
of treatment and at evaluation of quality of appetite suppression
220 entering study
198 with adequate
appetite suppression
studied
Demographics
Female
Demographics
Male
n (%)
Mean age (years)
Age range (years)
Age SD (years)
n (%)
Mean age (years)
Age range (years)
Age SD (years)
173 (78.6%)
46.1
18.1–69.6
10.1
157 (79.3%)
46.1
18.8–68.2
9.7
47 (21.4%)
49.2
19.3–63.5
9.4
63 (20.7%)
49.2
19.3–63.5
9.3
Table 4 Group 1 subjects achieved relief of depression symptoms
after starting citalopram and then experienced a return of symptoms.
The amino acid precursor formula was then administered in
combination with citalopram, and the listed study parameters
were observed. Group 2 subjects achieved appetite suppression
after starting citalopram and phentermine in combination, then
experienced a return of appetite. The amino acid precursor
formula was then administered in combination with citalopram and
phentermine and the listed parameters were observed
n
Group 1
37
Group 2
198
Effects restored (n, [%])
Mean time to restore effects (days)
Range (days)
Standard deviation
36 (97.3%)
1.6 days
1–3
0.26 days
195 (98.5%)
1.9 days
1–5
0.39 days
Abbreviation: SD, standard deviation.
intake” and a “relative nutritional deficiency.” Relative nutritional deficiencies arise from changes in system status or from
system needs that give rise to increased nutrient dosing needs
that are beyond the limits of dietary modification.
The theoretical model of monoamine
depletion
The central theory of this paper rests on the following foundation: reuptake inhibitors facilitate conditions that deplete
monoamines, reuptake inhibitors will not function if monoamine depletion is significant enough, and when significant
monoamine depletion occurs, the placebo effect and/or drug
effect may no longer be observed.
The monoamines exist in one of two states. (1) The endogenous state is the normal day-to-day state found when no amino
acid precursors are administered. In this state, monoamine
levels are at or below the normal values of the reference range.
(2) The competitive inhibition state is observed when significant
amounts of serotonin and dopamine amino acid precursors are
simultaneously administered. In this state, monoamine levels
are higher than are normally found in the system.8,11,13–16
Table 3 Group 1 achieved relief of depression symptoms after
starting citalopram then experienced return of symptoms leading
to the listed observation. Group 2 achieved appetite suppression
then experienced a lapse in the control of hunger leading to the
listed observations
n
Group 1
37
Group 2
198
Mean (days to discontinuation
of effects after starting the drug[s])
Range (days to discontinuation
of effects after starting the drug)
Standard deviation
164
22
34–490
4–48
107.5
9.1
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The mechanism of action for reuptake inhibitors is only
theoretical; objective measurements do not exist. A debate
exists over drug tachyphylaxis versus placebo relapse when
there is a return of symptoms of depression or ADHD after
being controlled at the start of the drug. Relapse supporters
claim their argument makes room for recurrence of symptoms
in the presence of a large placebo effect combined with a
small drug effect.9,10
It is postulated that the following novel reuptake inhibitor
monoamine depletion theory is a viable explanation, especially in light of the amino acid observations summarized
in Tables 1, 3, and 4 plus the differentiation of synaptic and
postsynaptic electrical dysfunction. The reuptake inhibitor
monoamine depletion theory states that reuptake inhibitors
deplete the monoamines serotonin, dopamine, norepinephrine, and epinephrine in all subjects not ingesting adequate
amounts of balanced nutrients; when depletion is significant
enough, a point is reached where the effects of the drug and/
or the placebo effect are no longer observed.
The uniform and consistent response observed with
low-dose amino acid dosing values, which uniformly places
all subjects in the lower end of the competitive inhibition
state, supports the reuptake inhibitor monoamine depletion
theory.
The reported numbers (n) in rows 3 and 4 of Table 1 are
higher than expected based on expected drug response alone,
meaning that these subjects are a mix of placebo responders and drug responders. Note that >97% of this group
responded to the administration of amino acid precursors.
It is therefore concluded that this is a synaptic phenomenon
related to monoamine depletion by reuptake inhibitors,
which is the primary cause of placebo relapse and drug
tachyphylaxis.
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It is proposed that monoamine depletion is the correct
description of the event that occurs when drug or placebo
effects observed after the start of a reuptake inhibitor are no
longer present in the endogenous state. With monoamine
depletion, the synaptic monoamine levels decrease due to
a relative nutritional deficiency that is beyond the capabilities of dietary modification to correct. The effects of
placebo and/or drug efficacy will not be available if there
are not enough monoamines in the system. With significant
monoamine depletion by reuptake inhibitors, there may be
a return of the original disease symptoms or new onset of
disease symptoms.
Relapse versus tachyphylaxis
Some argue that, with reuptake inhibitor treatment of depression and ADHD, the placebo effect is the dominant force
facilitating the clinical response; therefore, the appropriate
term when symptoms return after a reuptake inhibitor response
is observed is “relapse,” rather than drug tachyphylaxis.9,10 The
placebo effect in depression ranges from 30% to 45%, and drug
efficacy over placebo ranges from 7% to 13%.7 Double-blind,
placebo-controlled depression studies reveal that the efficacy
of placebo is three to six times greater than that of reuptake
inhibitors. In these studies, the drug effect is so small that
87%–93% treated with a reuptake inhibitor can expect relief
of symptoms no greater than that provided by placebo.7
Double-blind, placebo-controlled ADHD studies of atomoxetine indicate placebo efficacy in the range of 28%–40%,
with drug efficacy 12%–26% greater than placebo. Studies
support the conclusion that 74%–88% of ADHD patients
treated with atomoxetine can expect relief of symptoms no
greater than that provided by placebo.8
Monoamines do not cross the blood–brain barrier. When
monoamine depletion of the CNS occurs, the only way to
address this relative nutritional deficiency and increase the
total number of monoamine molecules in the CNS is through
nutritional means, with the simultaneous administration of
properly balanced serotonin and dopamine amino acid precursors with cofactors. These precursors cross the blood–brain
barrier and are then synthesized, freely or with biochemical
feedback regulation depending on the amino acid, into new
monoamines, which, when levels are high enough, restore
the efficacy of the drug or placebo effect.8,9,11–16,21
Depletion of platelet monoamines:
peripheral evidence
Platelets contain 90% of the releasable serotonin stores.
Reuptake inhibitor studies demonstrate that 90% of platelet
serotonin is depleted in about 3 weeks. Over 80% of the total
releasable serotonin is depleted within 3 weeks after starting
reuptake inhibitors. The mechanism of platelet depletion is
attributed to blocking reuptake transport of serotonin into
platelets while allowing for transport out of the platelets.
Once outside the platelets, the serotonin is exposed to the
monoamine oxidase enzymes that affect metabolism at a
higher rate leading to depletion. This is the same mechanism
of action observed with monoamine transport in and out of
the presynaptic neurons of the CNS, as illustrated in Figures
1–3.23–30
Depletion in CNS
Do reuptake inhibitors facilitate CNS monoamine depletion? In excess of 80% of the releasable stores of serotonin
are depleted after 3 weeks of reuptake inhibitor treatment.
Monoamine depletion
The primary theory expounded by this paper is that when
symptomatic relief related to a drug or placebo wanes, it
is primarily due to drug-induced monoamine depletion.
Monoamine depletion studies done in conjunction with
amino acid precursor utilization have demonstrated that a
decrease in monoamine concentrations is associated with
the waning or outright discontinuation of the drug-induced
effects.18,19
Serotonin and dopamine are synthesized from the amino
acid precursors 5-hydroxytryptophan (5-HTP) and L-3,4dihydroxyphenylalanine (L-dopa), respectively. L-dopa is
synthesized from L-tyrosine and 5-HTP is synthesized from
L-tryptophan. Dopamine is the precursor of norepinephrine,
which, in turn, is the precursor of epinephrine.7,8,11–16,20–22
Figure 1 Inadequate levels of neurotransmitters in the synapse are associated with
compromised electrical flow in the postsynaptic neurons, leading to suboptimal
regulation of function and/or development of symptoms.34
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with reuptake inhibitor administration. These morphological
changes are found with all reuptake inhibitors reviewed. A
spectrum of depletion is concluded.31
Differentiating synaptic and postsynaptic
dysfunction
Figure 2 With administration of reuptake inhibitors, blockage of monoamine
transport back into the presynaptic neurons leads to a net redistribution of
neurotransmitter molecules from the presynaptic neuron to the synapse. Increased
levels of synaptic monoamines lead to increased flow of electricity which causes
adequate regulation of function and/or relief of symptoms.34
There is disagreement over the depletion of monoamines
by reuptake inhibitors in the CNS. Supporters of reuptake
inhibitors assert that there is no evidence of CNS monoamine
depletion by these drugs. Those in opposition, including the
National Institute on Drug Abuse, claim that reuptake inhibitors deplete CNS monoamines.23–30
One paper bridges the gap, its authors initially recognizing
articles claiming reuptake inhibitors do not deplete monoamines in the CNS. The article then identifies pathological
and morphological changes that occur with drug depletion
and goes on to explain that these same changes are seen
Figure 3 When the monoamines are in the vesicles of the presynaptic neuron they
are not exposed to the enzymes that catalyze metabolism (monoamine oxidase and
catechol-0-methyl transferase). They are safe from metabolism. When they relocate
outside the vesicles presynaptic neuron, they are exposed at a greater frequency to
these enzymes. Reuptake inhibitors create a mass migration of monoamines causing
increased metabolic enzyme activity and metabolism of monoamines. This leads to
monoamine depletion if significant amounts of balanced serotonin and dopamine
precursors are not coadministered with the reuptake inhibitor.34
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While the focus of monoamine reuptake inhibitor depletion is
on synaptic monoamine levels, there are other causes of electrical dysfunction, such as receptor desensitization and receptor
down regulation. While these may be valid topics, they do not
apply here. The phenomenon observed here is clearly electrical
dysfunction of synaptic origin, whereas receptor desensitization, receptor down regulation, bundle damage, and so forth, are
all postsynaptic processes linked to the postsynaptic neurons.
As discussed in the authors’ previous work, there are unique
observations that define synaptic electrical dysfunction versus
postsynaptic-driven electrical dysfunction. Considerations are
as follows. Correcting monoamine depletion-associated synaptic electrical dysfunction in the endogenous state involves
addressing the problem nutritionally to increase monoamine
concentrations from low to normal.7,8,11–16,20–22 Correcting
dysfunction associated with postsynaptic structures requires
nutritionally establishing monoamine levels in the competitive
inhibition state, where monoamine levels are higher than those
found in the endogenous (normal) state.7,8,11–16,20–22 Differentiation between synaptic and postsynaptic electrical dysfunction
is possible by observing the clinical response to group administration of nutrients (amino acid precursors with cofactors),
shown in Table 5.7,8,11–16,20–22
When dysfunction is due to low or inadequate synaptic monoamine levels associated with depletion, returning monoamine levels to the normal reference range of
the population in the endogenous state will correct the
problem.7,8,11–16,20–22 In Group 1 and Group 2, over 97% of
subjects who experienced waning of initial drug effects were
suffering from monoamine electrical dysfunction secondary
to developing a relative nutritional dysfunction. These subjects were placed on the lowest (starting) amino acid dosing
value required to induce the competitive inhibition state
leading to a positive and uniform response. As discussed
more thoroughly below, when synaptic monoamine electrical dysfunction is present, returning monoamine levels to
the normal range for the population or immediately above
normal restores the initial effects observed with administration of the drug.7,8,11–16,20–22
When the electrical dysfunction is due to postsynaptic
neuron structural impairment, the serotonin and dopamine
amino acid precursor dosing values required to fully
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Table 5 Observed differences between synaptic and postsynaptic
electrical dysfunction
Electrical dysfunction
is corrected with monoamines
in which state?
Returning monoamines
to normal levels
Uniform response to a
low-dose competitive inhibition
amino acid dosing value
Individualized amino acid
dosing value needed
Requires adjusting amino acid
dosing values for
optimal group results
Need to obtain organic
cation transporter functional
status determination
for optimal results
Synaptic
dysfunction
Postsynaptic
dysfunction
Endogenous
state
Competitive
inhibition state
Will restore
function
Yes
Will not
restore function
No
No
Yes
No
Yes
No
Yes
compensate for the dysfunction are not uniform and are
highly individualized.7,8,11–16,20–22
As the authors have previously discussed, the following
considerations exist while documenting the novel effects
of nutritional dosing value alterations on organic cation
transporter (OCT) function status in the competitive inhibition
state. The serotonin and dopamine precursor dosing values
needed to compensate for postsynaptic monoamine–associated electrical dysfunction in the competitive inhibition state
range from very low to very high. When optimal amino acid
precursor dopamine values in the competitive inhibition state
are achieved, as evidenced by properly balanced OCT serotonin and dopamine transport, the serotonin amino acid dosing
value is independent of the dopamine amino acid dosing
value. In addition, if OCT functional status interpretation
considerations are not affected, the dosing values of serotonin
and dopamine amino acid precursors needed to effectively
optimize and restore postsynaptic monoamine–related electrical function have been demonstrated to be random relative to
serotonin and dopamine assay levels. 7,8,11-16,20-22
In the case of reuptake inhibitor placebo relapse and/or
reuptake inhibitor tachyphylaxis, the amino acid dosing
values required to correct the relative nutritional deficiency
are relatively low, uniform, and constant. This is consistent
with synaptic monoamine electrical dysfunction in endogenous state. It is not consistent with the highly individualized group-dosing value needs observed in the competitive
inhibition state, which is linked to postsynaptic monoamine
electrical dysfunction (see Table 5).7,8,11–16,20–22
Neurotransmitter depletion
by reuptake inhibitors
It is known that the reuptake inhibitor methamphetamine
depletes dopamine,32 which facilitates the neurotoxicity.8
SSRIs are known to decrease serotonin synthesis.33 The
nonspecific reuptake inhibitor amitriptyline (a tricyclic
antidepressant) is known to deplete norepinephrine.34 The
National Institute on Drug Abuse has posted figures (Figures 1–3) on its website, which are in the public domain.
These figures illustrate how reuptake inhibitors deplete
monoamines.35
Other depletion-related problems
Monoamine depletion may explain other problems associated
with reuptake inhibitors. The US Food and Drug Administration requires that reuptake inhibitors display a black box
warning regarding the risk of suicidal ideation while taking
these drugs.4,5 It is postulated that this increased suicide risk
may be associated with monoamine depletion by reuptake
inhibitors.
Reuptake inhibitor discontinuation syndrome is an
exacerbation of symptoms or new onset of symptoms that
occurs when attempts are made to stop a reuptake inhibitor.
The patients typically, do not like the way they feel when
attempts to stop the drug are made; consequently they are
trapped into taking a drug that provides little relief of symptoms because they feel worse without the drug.37 It is postulated that reuptake inhibitor–induced monoamine depletion
plays a role in this phenomenon.
Customarily, when the clinical effect of a reuptake inhibitor stops, the response is to increase the daily dosing value
of the drug, start a second reuptake inhibitor, or stop the first
drug then substitute a second drug. It is postulated that all of
these actions further facilitate monoamine depletion.
General observations
It is postulated that if the reuptake inhibitor drug was introduced into an environment in which synaptic monoamine
homeostasis always existed, with no postsynaptic issues
arising, the drug would theoretically continue to function
indefinitely. However, this is not the case. It is well known
that these drugs, in the endogenous state, are associated with
return of symptoms, discontinuation syndrome, placebo
relapse, drug tachyphylaxis, suicidal ideation, reuptake
inhibitor discontinuation syndrome, induced relative nutritional deficiency, and a number of other problems. Reuptake
inhibitor monoamine depletion theory is the only model that
unifies and explains the phenomena described in this paper
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when the nutritional responses of Group 1 and Group 2 are
considered.
Reuptake inhibitors are a drug class that offer only 7%–13%
of patients relief of depression symptoms that is greater than
that provided by placebo.7 They make the disease cause worse
by depleting the centrally acting monoamine neurotransmitters
in all patients who do not ingest adequate amounts of serotonin
and dopamine amino acid precursors, which leads to a relative
nutritional deficiency. They also expose 100% of patients to
drug side effects and the economic costs of the drugs.
Worldwide annual sales of antidepressants coming off
patent between 2011 and 2016 is placed in excess of US$255
billion.37 If 87% of patients taking these drugs had no hope
of achieving relief of depression symptoms greater than
that provided by placebo, this would mean that US$221.9
billion is being spent annually for treatment that is no more
effective than a sugar pill. This number increases when the
cost of drugs already off patent are included.
The Internet is replete with claims that 5-HTP should not
be administered with reuptake inhibitors due to concerns of
serotonin syndrome. The authors firmly assert that this is not
correct. There are no reported cases of serotonin syndrome
resulting from concurrent use of 5-HTP with reuptake inhibitors in the literature. Since 1997, the authors have amassed
over 2 million patient-days of treatment experience using
5-HTP with reuptake inhibitors from over 1000 medical clinics, with not one case of serotonin syndrome documented.
Conclusion
SSRIs used in the treatment of depression and ADHD are
associated with low efficacy and high placebo response. This
leads to controversy in defining the cause for the discontinuation of symptomatic relief observed after starting a reuptake
inhibitor. Prior to this paper, the question was, “When depression symptoms return, is it due to drug tachyphylaxis or a
placebo relapse?” This paper puts forth the unified concept
of the reuptake inhibitor monoamine depletion theory.
Relative nutritional deficiency can exist when dietary
intake is normal and changes to the system occur that cannot be met through dietary modification alone. Increased
metabolism and inadequate synthesis of monoamines create
an environment where the relative nutritional deficiency associated with reuptake inhibitor treatment evolves. When this
happens, administration of serotonin and dopamine amino
acid precursors is the only course available to compensate for
CNS monoamine depletion by reuptake inhibitors.
The ability of reuptake inhibitors to induce a relative nutritional deficiency leading secondarily to depletion of monoamines
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has been overlooked and is of serious concern. When monoamine
depletion is extensive enough, placebo relapse occurs, drug
tachyphylaxis occurs, symptoms of disease return, new onset of
disease symptoms may occur, increased incidence of suicidal
ideation may be facilitated, and reuptake inhibitor discontinuation syndrome may be observed, regardless of the initial cause of
symptomatic relief (placebo effect versus drug effect).
Reuptake inhibitors do not increase the total number
of monoamines in the CNS. Their mechanism of action
facilitates redistribution of monoamines from one place to
another, which, in turn, sets up conditions that favor depletion of monoamines if proper levels of nutrients are not
administered.
Physicians currently prescribe reuptake inhibitor drugs
that are only 7%–13% more effective than placebo in treating
depression7 and only 12%–26% more effective than placebo
in treating ADHD.8 Reuptake inhibitors are known to further
deplete the very monoamines whose inadequate synaptic
levels are implicated in the etiology of numerous diseases
and conditions. This makes the cause of the disease (ie,
inadequate monoamine levels) worse. Monoamine depletion
is a relative nutritional deficiency that cannot be managed
adequately by dietary modification.
In the treatment of depression, 87%–93% of patients
taking these drugs cannot expect relief of symptoms that
is greater than that provided by placebo.7 In the treatment
of ADHD, 74%–88% of patients cannot expect relief of
symptoms greater than that provided by placebo.8 However, 100% of patients are subjected to the side effects,
the cost of the drugs, development of a relative nutritional
deficiency, and depletion of m onoamines by reuptake
inhibitors if simultaneous administration of properly
balanced serotonin and dopamine amino acid precursors
does not occur.
Reuptake inhibitors are the only class of drugs that the
authors are aware of that make the cause of the disease
(inadequate levels of monoamines) that is being treated
worse. With experience comes insight: the manufacturer of
citalopram reported that one of the authors of this article
was the largest private practice prescriber of this drug in
1999, the first full year after the drug became available in
the USA. This paper attempts to raise the level of awareness,
understanding, stimulate further studies, and facilitate dialog
regarding monoamine depletion by reuptake inhibitors.
Disclosure
MH discloses ownership of NeuroResearch Clinics Inc, Cape
Coral, FL. TU discloses laboratory directorship of DBS Labs,
Dovepress
Duluth, MN. AS declares no conflicts of interest in relation
to this paper.
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Return to index
O riginal R esearch
The discrediting of the monoamine hypothesis
13 February 2012
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
1
Clinics, Inc, Cape Coral, FL, 2Stein
Orthopedic Associates, Plantation, FL,
3
Fairview University Medical Center,
Hibbing, MN, USA
Background: The monoamine hypothesis has been recognized for over half a century as a
reference point to understanding electrical dysfunction associated with disease states, and/or
regulatory dysfunction related to synaptic, centrally acting monoamine concentrations (serotonin,
dopamine, norepinephrine, and epinephrine).
Methods: Organic cation transporters (OCT) are a primary force controlling intracellular and
extracellular (including synaptic) concentrations of centrally acting monoamines and their amino
acid precursors. A new type of research was analyzed in this paper (previously published by the
authors) relating to determining the functional status of the nutritionally driven organic cation
transporters. It was correlated with the claims of the monoamine hypothesis.
Results: Results of laboratory assays from subjects not suffering from a hyperexcreting tumor
show that centrally acting monoamine concentrations are indistinguishable in subjects with and
without disease symptoms and/or regulatory dysfunction. Analysis of centrally acting monoamine concentrations in the endogenous state reveals a significant difference in day-to-day assays
performed on the same subject with and without monoamine-related disease symptoms and/or
regulatory dysfunction. The day-to-day difference renders baseline testing in the endogenous
state non-reproducible in the same subject.
Conclusion: It is asserted that the monoamine hypothesis, which claims that low synaptic
levels of monoamines are a primary etiology of disease, is not a valid primary reference point
for understanding chronic electrical dysfunction related to the centrally acting monoamines.
Furthermore, the “bundle damage theory” is a more accurate primary model for understanding
chronic dysfunction. The “bundle damage theory” advocates that synaptic monoamine levels
are normal but not adequate in states associated with chronic electrical dysfunction and that
levels need to be increased to compensate for the chronic postsynaptic electrical dysfunction
due to existing damage. The monoamine hypothesis, in failing to accurately explain the etiology
of chronic neuronal electrical flow dysfunction in the endogenous state, is reduced to no more
than a historical footnote.
Keywords: monoamine hypothesis, monoamine theory, serotonin, dopamine, neuronal
dysfunction, bundle damage theory
Introduction
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
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http://dx.doi.org/10.2147/IJGM.S27824
This paper is the continuation of a series of original research papers published by the
authors on the topic of nutritionally driven organic cation transporter (OCT) functional
status determination (herein referred to as OCT assay[s]). This paper correlates original
research previously published by the authors on the topic of transporter-driven centrally
acting monoamine observations with the monoamine hypothesis.1–12
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Hinz et al
The centrally acting monoamines serotonin, dopamine,
norepinephrine and epinephrine (herein referred to as
“monoamine[s]”) exist in one of two states. The “endogenous
state” is present when no supplemental amino acids are being
administered, and the “competitive inhibition state” is found
when significant amounts of serotonin and/or dopamine
amino acid precursors are simultaneously administered.1–7
Previous literature described the competitive inhibition
state as “functionally meaningless.” The basis for this assertion was the inability to alter monoamine levels with amino
acid precursors and then objectively quantify the changes.7
With the perfection of the novel OCT assay analysis by the
authors, the competitive inhibition state is no longer functionally meaningless.1–12
Since the early 1960s, the monoamine hypothesis has
been a reference point for understanding the etiology of
the electrical defects associated with monoamine-related
disease and the mechanism of action of reuptake inhibitors. The monoamine hypothesis posits that depression is
caused by decreased monoamine function in the brain. The
hypothesis originated from early empirical clinical observations and has been generally recognized to mean that low
concentrations of synaptic monoamines are a primary factor in the etiology of depression, other monoamine-related
disease states, and regulatory dysfunction.13
The bundle damage theory was first published in 2009. It
advocates that although synaptic levels of monoamines are
normal in chronic monoamine-related disease states, these
levels are inadequate in compensating for postsynaptic damage to structures conducting electricity.8
In this manuscript, the new conclusions about
monoamine hypothesis and the bundle damage theory are
compared with the original research of the authors. When
inadequate levels of monoamines exist, the only way to
increase the total number of monoamine molecules in
the brain is through administration of their amino acid
precursors. This is because monoamines do not cross the
blood–brain barrier. The amino acid precursors can cross
the barrier, and are synthesized into new monoamines.
Whether the synaptic levels are lower than normal or
normal at the start of management, nutritional status is a
primary consideration in addressing problems associated
with inadequate monoamines.4,6,10
There are two primary types of nutritional deficiencies.
The monoamine hypothesis advocates that an absolute
nutritional deficiency (AND) is the core issue of monoaminerelated electrical dysfunction, whereas the bundle damage
theory advocates a relative nutritional deficiency (RND).8
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An AND occurs when not enough nutrients are included
in the diet, leading to nutritional concentrations that are not
adequate for establishing normal synaptic monoamine levels
(the monoamine hypothesis). A relative nutritional deficiency
occurs when synaptic levels are normal in the endogenous
state but not high enough to compensate for damage to the
postsynaptic neuronal structures that conduct electricity (the
bundle damage theory).
The organic cation transporters (OCT) are primary
determinants of intracellular and extracellular (including
synaptic) monoamine concentrations.13 Previously published
literature by the authors provides proof that in the endo
genous state transporter-dependent monoamine concentrations are indistinguishable in subjects with and without
monoamine-related disease and/or regulatory dysfunction.
These findings are an integral part of the challenge to the
validity of the monoamine hypothesis.4,6,10
Original research results by the authors1–12 outlined a novel
methodology for nutritionally driven OCT assay analysis that
defines the phase of monoamine transport, status of transporter entrance gates, transporter lumen saturation status, and
transporter balance status between the monoamines and their
amino acid precursors. These are all critical to determining
whether the relative concentrations of the centrally acting
monoamines are being effectively transported.1–12
Nutritionally driven OCT functional
status determination
Under normal conditions, serotonin and dopamine filtered
at the glomerulus are metabolized by the kidneys, which
prevent significant amounts of these peripheral monoamines
from being found in the final urine. Urinary serotonin and
dopamine, in subjects not suffering from a monoaminesecreting tumor, represent monoamines newly synthesized
in the proximal convoluted renal tubule cells of the kidneys.
These monoamines have never been in the central or
peripheral systems. Once synthesized, their fate is dependent upon the interaction of the basolateral monoamine
transporters (OCT2) and the apical monoamine transporters
(OCTN2). The OCT2 transports serotonin and dopamine
to the interstitium. These monoamines then end up in the
peripheral system via the renal vein. The OCTN2 of the apical
membrane transports the serotonin and dopamine not transported by the OCT2 to the proximal nephrons of the kidneys,
before sending them to the urine as waste. Proper OCT assay
requires that initially the serotonin and dopamine systems
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are placed in the competitive inhibition state simultaneously,
while administering adequate amounts of serotonin and
dopamine amino acid precursors. The assay results are then
compared in order to determine the change in urinary serotonin and dopamine concentrations associated with changes
in amino acid precursor dosing values.2,3,5,6,11
A urinary serotonin or dopamine value less than 80 µg or
475 µg of monoamine per gram of creatinine, respectively,
is defined as a phase 2 response. A urinary serotonin or
dopamine value greater than 80 or 475 µg of monoamine
per gram of creatinine, respectively, is interpreted as being
in phase 1 or phase 3. Differentiation of phase 1 from phase
3 is as follows. If a direct relationship is found between
amino acid dosing and urinary assay response, it is referred
to as a phase 3 response. An inverse relationship is referred
to as a phase 1 response. The phase 3 optimal range for
urinary serotonin is defined as 80–240 µg of serotonin per
gram of creatinine. The phase 3 optimal range for urinary
dopamine is defined as 475–1,100 µg of dopamine per g of
creatinine.2,3,5,6,11
are as follows: urine samples are collected about 5–6 hours
prior to bedtime, with 4:00 pm being the most frequent
collection time point. The samples are stabilized in 6 N HCl
to preserve the dopamine and serotonin. The urine samples
are collected after a minimum of 1 week, during which
time the patient has been taking a specific daily dosing of
amino acid precursors of serotonin and dopamine where no
doses are missed. Samples are shipped to DBS Laboratories
(Duluth, MN). Urinary dopamine and serotonin are assayed utilizing commercially available radioimmunoassay kits (3 CAT
RIA IB88501 and IB89527, both from Immuno Biological
Laboratories Inc, Minneapolis, MN). The DBS laboratory
is accredited as a high-complexity laboratory by Clinical
Laboratory Improvement Amendments (CLIA) to perform
these assays. OCT assay interpretation is performed by one of
the authors (Marty Hinz, MD, NeuroResearch Clinics, Inc).
Results
The authors previously published “matched pairs t-test”
results for the transporter-dependent, centrally acting monoamine concentrations in the endogenous state from the same
subject on different days. This current paper is a continuation
of this discussion based on original research that expands on
the scope and implications of these scientific findings within
the context of the monoamine hypothesis.4,6,10
In this previously published original research, spot
baseline urinary assays for each monoamine were obtained
for the first test on day one and for the second test on a
different day. Both occurred at the same time of the day
for each subject. The two tests from each subject were then
paired, and a statistically significant grouping of matched
pairs was subjected to the “matched pairs t-test.” The results
are a critical component in forming the foundation of the
conclusions in this paper.4,6,10
These original research studies reported that spot
baseline urinary serotonin, dopamine, norepinephrine, and
epinephrine concentrations in the endogenous state differ in
a statistically significant manner from day to day in the same
subject. This supports the conclusion that under normal conditions baseline urinary monoamine testing is not uniform or
reproducible from day to day in the same subject. The functional status of these organic cation transporters determines
intracellular and extracellular (including synaptic) concentrations of these monoamines. Furthermore, it was concluded
that it is virtually impossible to distinguish, via laboratory
assay interpretation, individuals with or without disease or
regulatory dysfunctions, even those dysfunctions that were
traditionally assumed to be associated with low levels of
synaptic, centrally acting monoamine levels.4,6,10
Discussion
The monoamine hypothesis holds that low concentrations of
synaptic monoamines are the primary etiology of monoamine-related chronic electrical dysfunction.13 The corollary to
this premise is that returning synaptic monoamine levels to
normal will resolve electrical dysfunction. In correlating the
perspective of the monoamine hypothesis with peer-reviewed
literature published by the authors since 2009, the following
considerations and conclusions exist.
Differentiation of those
with and without disease
There is no objective proof demonstrating that low in situ
levels of centrally acting monoamine concentrations in the
synapse are the primary etiology under normal conditions.14
There is no objective method that identifies individuals with
low concentrations of transporter-dependent monoamine concentrations in the endogenous state.13 Transporter-associated
concentration trends in groups of subjects have been
identified, but the day-to-day variability of monoamine
concentrations in each individual comprising the group
reveals that it is not possible to identify individuals with
electrical dysfunction on laboratory testing and/or transporter
analysis who are suffering from low levels of monoamines
relative to the normal reference range.4,6,11 Diets devoid of
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Hinz et al
critical amino acids will induce an AND with associated
disease symptoms, but diets such as this are not the normal
endogenous state of humans who develop monoamine or
regulatory dysfunction-related symptoms.15,16
Synaptic monoamine concentrations are primarily
dependent on the functional status of the nutritionally
driven organic cation transporters. The monoamines and
their amino acid precursors are “organic cations” that are
transported by the three primary electrogenic organic cation transporter types, each of which has several subtypes:
OCT1, OCT2, and OCT3. The OCT of the liver, brain,
kidney, and bowels are identical and homologous.17 Of the
three transporter types, the OCT2 has tissue expression
primarily in the kidney and the brain.
OCT assay analysis has led to the ability to define the
phases of monoamine transport, transporter saturation status,
the status of monoamine and precursor transporter balance,
the amount of waste (unneeded) monoamines the transporters
are excreting, and the status of transporter entrance gates.
After doing this OCT assay analysis, we can define the
individualized amino acid dosing values needed for optimal
flow of electricity through damaged postsynaptic bundles as
evidenced by clinical outcomes.12,13
There is no objective documentation that identifies individuals with low concentrations of transporter-dependent
monoamine concentrations in the endogenous state.
Transporter-associated concentration trends in groups of
subjects have been identified, but the day-to-day variability of
monoamine concentrations in each individual comprising the
group reveals that it is not possible to identify individuals with
electrical dysfunction on laboratory testing and/or transporter
analysis who are suffering from low levels of monoamines
relative to the normal reference range. 4,6,10
In the endogenous state, under the monoamine hypothesis,
low synaptic concentrations of monoamines are a primary
cause of electrical dysfunction.14 If this were true, the significant fluctuations in transporter-dependent monoamine
concentrations from day to day in the individual should lead
to clinical states where the findings would wax and wane in
a manner consistent with day-to-day observed fluctuations in
transporter-driven monoamine concentrations as documented
in same subject studies (matched pairs t-test). This is not the
case. The etiology of chronic problems is not low concentrations of monoamines that need to be returned to normal as
predicted by the monoamine hypothesis; it is concentrations
that are normal but not high enough to compensate for postsynaptic neuronal damage. Addressing this electrical defect
properly requires the system to be placed into the competitive
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inhibition state in order to be able to increase monoamine
levels to above normal to reach the threshold level needed to
establish the adequate electrical flow required. Analysis of
transporter-driven monoamine needs reveals that postsynaptic
electrical conduction damage in patients with chronic disease
is so high that the day-to-day monoamine fluctuations of the
endogenous state are below the threshold needed to attain
symptom relief. Therefore, chronic symptoms do not wax and
wane as might be predicted by the laboratory results obtained
in the endogenous state.5,8 Previous writings of the authors
demonstrated relative nutritional deficiencies in Parkinson’s
disease,5 chronic depression,9,12 Crohn’s disease,2 and attention deficit hyperactivity disorder without any findings that
would support an AND.3 Restoration of regulatory function
in these RND conditions is only possible when transporterdependent monoamine concentrations are elevated above
normal and properly balanced in the competitive inhibition
state (see Figure 1).1–12
Many disease states have been recognized as having a
common etiology of postsynaptic bundle damage associated with insult.1–12 Different areas of damage to the nerve
bundles result in different disease entities. These entities
all share a common pathology of inadequate levels of the
monoamine-driven electrical activity that is required to
power the functions of the body. This results in the relative nutritional deficiency that requires monoamine levels
higher than normally found in the synapse to overcome
the damaged areas of the nerve bundles. Parkinson’s
disease demonstrates this deficiency and the ability of
targeted amino acid precursor supplementation to restore
function.5
Parkinson’s disease as a prototype
Parkinson’s disease is a prototype disease that illustrates the
mechanism of action of postsynaptic neuron damage and its
compensation. Chronic damage to the postsynaptic dopamine
fibers of the substantia nigra induce an RND that is not just
dopamine related but is related to all of the centrally acting
monoamines. This RND causes Parkinson’s disease symptoms by compromising the flow of electricity regulating fine
motor control. The monoamine levels of Parkinson’s patients
prior to treatment are found to be in the normal range. Proper
management of Parkinson’s disease requires an increase in
the synaptic levels of dopamine with a higher than normal
administration of L-dopa. Increasing the synaptic neurotransmitter with L-dopa is analogous to turning up the voltage. It
causes more electricity to flow through the remaining viable
postsynaptic, electricity-conducting neuronal structures.
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When enough electricity is once again flowing, control of
symptoms is effected.5
Dietary management
The monoamines do not cross the blood–brain barrier.
The only way to increase the total number of monoamine
molecules in the brain – to a level that is higher than is possible
with dietary modification – is with supplemental nutritional
support through administration of properly balanced amino
acid precursors and cofactors. These cross the blood–brain
barrier and are synthesized into new monoamines.1–12
The immediate amino acid precursors of serotonin and
dopamine, 5-HTP and L-dopa, respectively, freely cross
the blood–brain barrier to synthesize into their respective
m onoamines without biochemical feedback inhibition
(Figure 2). At equilibrium the amino acid precursors have
a similar effect on all identical and homologous OCTs and
subtypes throughout the body.12
When synapse-related electrical compromise is present,
the monoamine hypothesis advocates that an AND exists,
ie, low synaptic monoamine levels are present and returning these levels to normal will restore adequate electrical
flow. This would predict that an optimized normal diet,
with no supplemental nutrients, will restore the low levels
of synaptic monoamines back to normal, leading to relief
of the electrical dysfunction that is causing the disease or
regulatory dysfunction. This does not happen. Literature has
not described dietary modification as a valid and/or effective
approach in management of monoamine-related synaptic
electrical dysfunction under normal conditions.
Under the bundle damage theory, as discussed in the next
section, when neuronal electrical compromise (due to postsynaptic damage) is significant, a relative nutritional deficiency
is concomitantly present. Proper compensation requires that
the system be placed in the competitive inhibition state where
synaptic monoamine levels are higher than normal; this cannot
be achieved with dietary modification alone. Administration
of properly balanced supplemental amino acid precursors
L-tryptophan
Depletes
L-tyrosine
Dopamine
Serotonin
Depletes
Sulfur amino acids
Depletes
Depletes
Depletes
Depletes
5-HTP
L-dopa
Figure 1 If dopamine precursors (L-tyrosine and/or L-dopa) are not in proper
balance with serotonin precursors (5-HTP and/or L-tryptophan), depletion of
serotonin or dopamine will occur. All components of the system need to be in
proper balance.
under the guidance of OCT assay analysis is needed. This
ensures proper amino acid and monoamine transport balance
and compensates for the electrical defect.
The balance between serotonin precursors, dopamine
precursors, and sulfur amino acids is critical, as profound
interactions exist between these substances. When administration of these substances is not in proper balance, an additional
amino acid-induced RND develops (see Figure 1).1–12
There are many things that can be gleaned out of Figure 1,
such as administering only 5-HTP facilitates depletion of
dopamine. Giving only L-dopa facilitates depletion of serotonin, sulfur amino acids, L-tyrosine, and L-tryptophan.
The administration of properly balanced 5-HTP with
L-dopa establishes transporter-dependent synaptic monoamine concentrations at levels higher than normal. These
levels compensate for the relative nutritional deficiency
and resultant electrical deficit.18 In contrast, the monoamine hypothesis has never demonstrated that under normal
conditions returning synaptic monoamine levels to normal
is effective.
The bundle damage theory
Under the bundle damage theory, relative nutritional deficiency is the cause of chronic electrical dysfunction observed
with centrally acting monoamine-related problems. This is
supported by the fact that in the endogenous state all subjects
with and without disease have similar and indistinguishable monoamine levels. The primary source of the chronic
electrical dysfunction under the bundle damage theory is
damage to the postsynaptic structural components involved
with electrical conduction. In this state, the levels of synaptic
monoamines are normal and an RND exists.8
A list of almost 1200 known neurotoxins found in the
environment serves as a backdrop for this discussion.19
Neurotoxins, trauma, biologics, and/or genetic predisposition contribute to postsynaptic structural damage which
compromises electrical flow when synaptic monoamine
levels are normal. This damage tends to be cumulative.
The flow of electricity between the pre- and postsynaptic
neurons is mediated by synaptic levels of centrally acting
monoamines. This causes electrically dependent functions
to be improperly regulated.5,8
Individual dendrite structures of postsynaptic neurons do not facilitate electrical flow as a single entity.
Multiple postsynaptic structures, functioning as bundles,
regulate function. The bundle damage theory states that a
significant factor in the development of monoamine-related
electrical dysfunction disease or regulatory dysfunction
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Hinz et al
Amino acids
Monoamine neurotransmitters
L-tryptophan
5-HTP
Serotonin
L-tyrosine
L-dopa
Dopamine
Norepinephrine
Epinephrine
Figure 2 The centrally acting monoamines with their amino acid precursors.
occurs when the electrical flow through the postsynaptic
neuron bundles regulating function is compromised by
damage. In order to optimally restore neuron bundle regulatory function, synaptic neurotransmitter levels involved
with transference of electrical flow across the synapse into
the remaining viable postsynaptic neuron structures must
be increased to levels higher than are normally found in
the system. This in turn results in restoration of adequate
electrical flow, relief of symptoms, and/or resolution of
regulatory dysfunction.8
Support for the bundle damage theory is that restoration
of normal neuronal electrical flow can be accomplished by
increasing monoamine concentrations into the competitive
inhibition state, where organic cation transporter-driven and
synaptic monoamine concentrations are higher than those
found in the endogenous state. The situation is managed as a
relative nutritional deficiency. Instead of ascribing the symptom etiology to low concentrations of transporter-dependent
synaptic monoamines in chronic states, it is more accurate
to attribute the cause to synaptic monoamine concentrations
being chronically inadequate to compensate for electrical
dysfunction induced by postsynaptic structural damage.
When chronic monoamine-related deficiency states exist, this
terminology more appropriately explains the need to increase
synaptic monoamine concentrations into the competitive
inhibition state.4,6,10
The World Health Organization’s observation, consistent
with the bundle damage theory, is that higher toxicant exposure (in developed countries) contributes to the higher rate of
depression and other monoamine-related disease.8
Relative nutritional deficiency, secondary to postsynaptic
structural damage, may be the only issue in which proper
management allows for removing the RND from the clinical
picture. This is to ensure that any other possible concomitant
disease and regulatory dysfunction etiologies or mechanisms
of action may be focused on more clearly.
Reuptake inhibitors
The mechanism of action of reuptake inhibitors is unknown,
but it is theorized that blocking of transporter reuptake leads
to increased concentrations of synaptic monoamines and
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restoration of electrical flow. Reuptake inhibitor efficacy in
the treatment of depression is low. Double-blind, placebocontrolled studies consistently reveal reuptake inhibitor
depression efficacy of 7% to 13% greater than placebo.
From another perspective, this means 87% to 93% of
patients treated with reuptake inhibitors for depression
can expect to achieve results no greater than placebo. The
authors previously reported the novel findings that the
effects of reuptake inhibitors on transporter-driven monoamine concentrations revealed serotonin concentrations
changed ,50 µg/gr creatinine. These very small OCTdriven changes in monoamine concentrations are consistent
with the low efficacy of the reuptake inhibitors. Group
analysis shows no statistical significance.9,18
If simply establishing synaptic monoamine concentrations in the normal range under an absolute nutritional deficiency approach as predicted by the monoamine hypothesis
were all that is required, it would be expected that reuptake
inhibitor efficacy would be higher than reported. This is
not the case. In previously published manuscripts by the
authors, subjects with depression were managed under the
relative nutritional deficiency approach using monoamine
precursor nutritional support with 5-HTP and L-dopa which
elevated the mean serotonin and dopamine concentrations
higher than normal into the desired competitive inhibition
phase 3 range, leading to restoration of electrical flow.
This procedure produced magnitudes of increased levels
of the transporter-driven serotonin and dopamine concentrations, far beyond the increases observed with reuptake
inhibitors alone.1–12
The required serotonin and dopamine precursor dosing
values are independent of each other in the competitive inhibition state. Optimal daily ranges exist when all monoaminerelated diseases are examined in the competitive inhibition
state. Some variances of the high end of the range may occur
when the individual diseases are examined. The 5-HTP
daily effective therapeutic range is .0 mg to 2400 mg. The
L-dopa daily effective therapeutic range (in subjects not suffering from Parkinson’s disease or Restless Leg Syndrome)
is .0 mg to 2100 mg. The tyrosine daily effective therapeutic
range is .0 mg to 14,000 mg.1–12
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Table 1 A comparison of the monoamine hypothesis and the bundle damage theory
Synaptic monoamine levels when
electrical dysfunction exits
Neuronal system status
Monoamine hypothesis
Bundle damage theory
Low
Normal
Normal
Postsynaptic structural damage leading to
compromised electrical flow
Higher than normal (competitive inhibition state)
Monoamine levels required
to restore electrical flow
Etiology
Nutritional deficiency
Conclusion on the
basis of the etiology
Absolute nutritional deficiency, dietary modification
(no supplements) will correct the problem
Laboratory observations
From a laboratory standpoint, in the endogenous state,
unable to distinguish those with and without disease
contrary to predictions of the monoamine hypothesis
Literature has never described dietary modification
that simply returns synaptic monoamine levels
to normal as a valid approach in management of
monoamine-related electrical dysfunction
Empirical observations that increasing synaptic
monoamine levels leads to clinical improvement
without proof that simply returning monoamine
levels to normal is what is happening
Undermining the concept
Support for the concept
Normal (endogenous state)
Recurrent damage due to neurotoxins, trauma,
biologics and/or genetic predisposition
Relative nutritional deficiency, properly
balanced supplementation needed to establish
monoamine levels higher than normal
OCT assay determination in the competitive
inhibition state allows for predictable outcomes
to nutritionally driven monoamine changes
None
Published literature on difficult to treat cases of
Parkinson’s disease, chronic depression, Crohn’s
disease, attention deficit hyperactivity disorder,
where synaptic levels are initially normal then
intentionally increased to higher than normal
to compensate for chronic electrical damage
Abbreviation: OCT, organic cation transporter.
Table 1 juxtaposes the monoamine hypothesis against the
bundle damage theory.
Conclusion
The authors of this manuscript have published more than a
dozen peer-reviewed papers on the topic of centrally acting
monoamines and administration of their precursors. This
paper correlates previous original research findings of the
authors with the monoamine hypothesis and is a continuation
of the scientific discussion.1–12 While there has been previous
literature that has discredited the monoamine hypothesis, this
paper sheds further light on the topic.
The monoamine hypothesis is based on the assumption
that synaptic concentrations of monoamines are lower than
normal in monoamine-related, central neuronal electrical
dysfunction states. This supports the assertion that addressing
the problem under an absolute nutritional deficiency strategy
by returning synaptic monoamine concentrations to normal
would be effective. The contents of this paper prove that this
does not happen.13
The bundle damage theory states that monoamine concentrations are normal but not adequate, due to an RND
in subjects with and without chronic disease. In order to
restore adequate electrical flow and compensate for postsynaptic damage, organic cation transporter-driven synaptic
monoamine levels must be increased to a level greater than
those concentrations found in the endogenous state, under a
monoamine amino acid RND approach outlined in previous
peer-reviewed original research publications.8
The key difference between the monoamine hypothesis
and the bundle damage theory is the perception that electrical dysfunction is caused by low synaptic concentrations
of monoamines versus normal synaptic concentrations of
monoamines that are not high enough to compensate for
postsynaptic structural damage.
Analysis of monoamine concentrations in subjects
in the endogenous state with and without the presence
of monoamine-related electrical dysfunction reveals that
it is impossible to differentiate these subjects based on
laboratory testing.4,6,10
Reuptake inhibitors have low efficacy in the treatment
of monoamine-related disease. Their focus is treatment of
the disease without addressing the proper balance of monoamines and precursors required under the relative nutritional
deficiency approach. This is consistent with findings that
reuptake inhibitors cause no statistically significant changes
in transporter-dependent monoamine concentrations.12
In chronic disease states the leading cause of electrical dysfunction is monoamine-related RND, secondary
to damage to postsynaptic neuronal structures caused by
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n eurotoxins, trauma, biologics, and/or genetic predisposition.
The only way to compensate for damaged electrical flow is to
properly balance serotonin and dopamine in the competitive
inhibition state through administration of amino acid precursors under the guidance of OCT assay determination.2,3,5,7,8
Postsynaptic electrical dysfunction may not be the only
etiology of monoamine-related dysfunction. Proper administration of serotonin and dopamine amino acid precursors,
under the guidance of OCT assay determination, removes concerns of RND from the clinical picture, facilitating the ability
to clearly focus on other possible etiologies as needed.
The monoamine hypothesis is simply not a valid concept.
It is the goal of this manuscript to stimulate interest and
dialogue regarding the etiology of synaptic monoamineassociated electrical dysfunction.
Disclosure
MH discloses ownership of NeuroResearch Clinics, Inc. TU
discloses lab directorship of DBS Labs, Duluth, MN. AS
reports no conflict of interest related to this paper.
References
2. Stein A, Hinz M, Uncini T. Amino acid responsive Crohn’s disease,
disorder with monoamine amino acid precursors and organic cation transporter assay interpretation. Neuropsychiatr Dis Treat. 2011;7:31–38.
4. Hinz M, Stein A, Uncini T. Urinary neurotransmitter testing: considerations of spot baseline norepinephrine and epinephrine. Open Access
Journal of Urology. 2011;3:19–24.
2011;7:1–7.
Disease Management Boca Raton: CRC Press; 2009:465–481.
Dis Treat. 2009;5:227–235.
urine; a comprehensive analysis. J Urol. 2010;2:177–183.
12. Hinz M, Stein A, Uncini T. Monoamine depletion by reuptake inhibitors.
Journal of International Drug, Healthcare and Patient Safety. 2011;3:
69–77.
13. Krishnan V, Nestler E. The molecular neurobiology of depression.
Nature. 2008;455:902–984.
14. Soares-da-silva P, Pinto-do-O PC. Antagonistic actions of renal
1996;117:1187–1192.
15. Young S, Smith S, Pihl R. Tryptophan depletion causes a rapid lowering
of mood in normal males. Psychopharmacology.1987;2:173–177.
16. Smith K, Fairburn C, Cowen D. Relapse of depression after rapid
depletion of tryptophan. Lancet. 1997;349(9056):915–919.
and brain. Annu Rev Physiol. 1998;60:243–266.
18. Scorecard.org. Neurotoxicants. Washington, DC: Green Media
Toolshed. Available from: http://scorecard.goodguide.com/healtheffects/chemicals-2.tcl?short_hazard_name=neuro&all_p=t. Accessed
December 16, 2011.
19. Koepsell H, Schmitt B, Gorboulev V. Organic cation transporters. Rev
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Return to index
O riginal R esearch
Relative nutritional deficiencies associated
with centrally acting monoamines
7 May 2012
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
1
Clinics Inc, Cape Coral, 2Stein
Orthopedic Associates, Plantation, FL,
3
DBS Labs, Duluth, MN, USA
Background: Two primary categories of nutritional deficiency exist. An absolute nutritional
deficiency occurs when nutrient intake is not sufficient to meet the normal needs of the system,
and a relative nutritional deficiency exists when nutrient intake and systemic levels of nutrients
are normal, while a change occurs in the system that induces a nutrient intake requirement that
cannot be supplied from diet alone. The purpose of this paper is to demonstrate that the primary component of chronic centrally acting monoamine (serotonin, dopamine, norepinephrine,
and epinephrine) disease is a relative nutritional deficiency induced by postsynaptic neuron
damage.
Materials and methods: Monoamine transporter optimization results were investigated, reevaluated, and correlated with previous publications by the authors under the relative nutritional
deficiency hypothesis. Most of those previous publications did not discuss the concept of a
relative nutritional deficiency. It is the purpose of this paper to redefine the etiology expressed
in these previous writings into the realm of relative nutritional deficiency, as demonstrated by
monoamine transporter optimization. The novel and broad range of amino acid precursor dosing
values required to address centrally acting monoamine relative nutritional deficiency properly
is also discussed.
Results: Four primary etiologies are described for postsynaptic neuron damage leading to a centrally
acting monoamine relative nutritional deficiency, all of which require monoamine transporter optimization to define the proper amino acid dosing values of serotonin and dopamine precursors.
Conclusion: Humans suffering from chronic centrally acting monoamine-related disease are
not suffering from a drug deficiency; they are suffering from a relative nutritional deficiency
involving serotonin and dopamine amino acid precursors. Whenever low or inadequate levels
of monoamine neurotransmitters exist, a relative nutritional deficiency is present. These precursors must be administered simultaneously under the guidance of monoamine transporter
optimization in order to achieve optimal relative nutritional deficiency management. Improper
administration of these precursors can exacerbate and/or facilitate new onset of centrally acting
monoamine-related relative nutritional deficiencies.
Keywords: nutritional deficiency, serotonin, dopamine, monoamine
Introduction
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Tel +1 218 626 2220
Fax +1 218 626 1638
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http://dx.doi.org/10.2147/IJGM.S31179
It is much more desirable to identify, address, and eliminate the cause of a disease than to
treat its symptoms. Until this research project defined the relative nutritional deficiencies
associated with disease and dysfunction of the centrally acting monoamines due to low
or inadequate levels of neurotransmitters, there was no awareness of these nutritional
deficiencies and no ability to address them properly and optimally.1 The authors of this
paper have published extensively on the topic of monoamine amino acid precursor
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management relating to various diseases and dysfunctions.
Further research in the areas covered in the previous writings
has revealed a relative nutritional deficiency (RND) etiology
not previously recognized or reported. The novel concept of a
monoamine-related RND is developed in this paper.1–13
Serotonin, dopamine, norepinephrine, and epinephrine
are “centrally acting monoamines” (herein referred to as
monoamine[s]), and are also involved in the control and
regulation of peripheral functions.
This novel concept hypothesizes the etiology of chronic
disease and/or regulatory dysfunctional symptoms to be
inadequate levels of monoamines as opposed to low levels
of synaptic monoamines. The RND described herein are
the most prevalent type of nutritional deficiency afflicting
humans. An extensive list of diseases, conditions, and dysfunctions has been identified in which synaptic monoamine
RND are recognized (see Appendix A and Appendix B).1–13
It is postulated that over 80% of humans suffer from symptoms relating to a serotonin and/or catecholamine RND.
Monoamine-related RND was unrecognized prior to this
research due to the inability to manage and verify results
of monoamine transporter manipulation objectively. The
organic cation transporters (OCT) are the primary determinants of intercellular and extracellular monoamine concentrations throughout the body.
Absolute nutritional deficiency
versus RND
Two primary categories of nutritional deficiency exist, ie,
absolute nutritional deficiency and RND.1 Insufficient dietary
nutrient intake causes absolute nutritional deficiencies. An
absolute nutritional deficiency can be corrected by optimizing nutrient intake in the diet. Management of the problem is
often enhanced by administration of nutritional supplements,
but they are not required.1
When an RND exists, nutritional intake and systemic
nutrient levels are normal. However, systemic needs are
increased above normal by outside forces and cannot be
achieved by dietary modification alone. Burns and postsurgical patients are examples where an RND may develop.1
In this paper, the authors discuss the novel finding that
an RND is the primary etiology whenever there is a chronic
disease or dysfunction relating to a compromise in the flow of
electricity through the presynaptic neurons (axons) across the
synapses then through the postsynaptic neurons (dendrites).
An extensive list of diseases, conditions, and dysfunctions
has been identified in which synaptic monoamine RND are
recognized (see Appendix A and Appendix B).1–13
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The monoamine-associated RND is by far the most
prevalent constellation of nutritional deficiencies found in
humans (see Appendix A and Appendix B). It is postulated
that over 80% of humans suffer from symptoms relating to a
serotonin and/or catecholamine RND. Conditions prior to in
situ monoamine transporter optimization (MTO, referred to
in some previous papers as OCT functional status optimization) made it impossible to achieve consistent results with the
administration of monoamine amino acid precursors. With
the invention and refinement of MTO, the ability to study,
manipulate, and optimally manage monoamine-related RND
became clinically possible.1–13
Four primary classes of monoamine-associated RND
have been identified by this research project:
• RND associated with monoamine disease or dysfunction
• RND induced by inappropriate administration of amino
acids
• RND induced iatrogenically or by the administration of
certain drug classes
• RND associated with genetic defects or predisposition.
Endogenous versus competitive
inhibition state
Serotonin and dopamine, and their precursors, exist in
one of two distinctly unique and physiologically divergent
states, ie, the endogenous state and the competitive inhibition
state.1–8,11–13 The monoamine hypothesis advocates that the
etiology of disease symptoms and/or regulatory dysfunction
in the endogenous state is low synaptic monoamine concentrations which induce trans-synaptic electrical defects.
Under this model, an absolute nutritional deficiency type
of approach is advocated, where simply returning synaptic
monoamine levels to normal corrects the electrical problem, leading to relief of disease symptoms. None of this
is true. There is no documentation illustrating that merely
establishing normal synaptic neurotransmitter levels is
effective in correcting an electrical defect.1
Subjects in the endogenous state, with and without
monoamine-related disease, if not suffering from a monoamine-secreting tumor, cannot be differentiated by laboratory
monoamine assays including MTO. Statistical distribution of
monoamine levels are the same in subjects with and without
disease.1,5,7,11
The term “competitive inhibition” refers primarily to interaction between monoamines and their amino acid precursors in
synthesis, metabolism, and transport. The competitive inhibition state occurs when significant amounts of serotonin and dopamine amino acid precursors are administered simultaneously.
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Nutritional deficiencies and centrally acting monoamines
The daily dosing values of serotonin and/or dopamine precursors
required for the system to enter into the competitive inhibition
state cannot be achieved by diet alone. When the etiology
of chronic symptoms is postsynaptic electrical compromise,
the system needs to be placed into the competitive inhibition
state in order to elevate synaptic monoamines high enough
to compensate for the postsynaptic damage. Optimization of
synaptic monoamine levels in order to facilitate optimal flow
of electricity is only possible with simultaneous administration
of serotonin and dopamine precursors guided by MTO.1–8,11–13
Etiologies of postsynaptic
neuron damage
Significant damage to the postsynaptic neurons of the serotonin and catecholamine systems may theoretically have
numerous etiologies. The most common1 are (in order of
frequency of occurrence):
• neurotoxin-induced
• trauma-related
• biology-related
• genetic predisposition.
These four categories interact and are interconnected. For
example, patients suffering from the genetic disease CharcotMarie-Tooth, which afflicts approximately 1 in 2500 humans,
have a list of over 50 drugs that are potentially neurotoxic in
the presence of this genetic state but are not toxic to patients
without the genetic disorder.14
In patients suffering from chronic monoamine-related
disease, there is permanent damage to the structures of
the postsynaptic neurons that conduct electricity, such as
occurs in Parkinson’s disease.1 This damage is permanent
and does not spontaneously reverse with time. Parkinson’s
disease is not the only monoamine-related disease where
humans suffer significant permanent postsynaptic damage.6
Based on MTO results, virtually all patients with chronic
monoamine-associated disease have permanent postsynaptic
damage caused by outside forces.1
Synaptic monoamine levels
These monoamines do not cross the blood–brain barrier. Drugs
do not increase the total number of monoamine molecules
Amino acids
in the brain; their mechanism of action only facilitates
movement of monoamines from one place to another. The
only way to increase the total number of monoamine molecules in the brain is by administration of their amino acid
precursors which cross the blood–brain barrier where they
are then synthesized into new monoamine molecules.1
Serotonin is synthesized from 5-hydroxytryptophan
(5-HTP) which is synthesized from L-tryptophan. Dopamine
is synthesized from L-dopa which is synthesized from
L-tyrosine. Epinephrine is synthesized from norepinephrine
which is synthesized from dopamine (see Figure 1).1,8
Prior to development of MTO, no method existed to manage properly and objectively the amino acid and monoamine
interaction problems found in Figure 2 that are observed in
the competitive inhibition state. The very act of administering amino acid precursors may cause amino acid and/or
monoamine depletion, leading to an RND. The administration
of improperly balanced amino acids may lead to an RND
environment with increased side effects, adverse reactions,
and suboptimal results.1,8
The key to addressing an amino acid precursor imbalance
during administration is the novel method of simultaneous
administration of serotonin and dopamine precursors, along
with sulfur amino acids in a proper balance, as defined by
MTO.1,8
Review of the chemical properties of the immediate
monoamine precursors, L-dopa and 5-HTP, shows that they
hold tremendous and extraordinary potential in the management of RND. L-dopa and 5-HTP are freely synthesized to
dopamine and serotonin, respectively, without biochemical
feedback inhibition. Each freely crosses the blood–brain
barrier. It is possible to achieve any required level of serotonin and dopamine to optimize synaptic monoamine levels
in the brain with these nutrients. MTO reveals that it is not
the concentration of monoamines that is critical for optimal
results; it is the balance between serotonin and dopamine in
the competitive inhibition state, as defined by MTO, that is
most critical in re-establishing and optimizing the postsynaptic flow of electricity.1,8
Even though 5-HTP has had increasing usage by physicians, the literature, dating back to the 1950s, has never
L-tryptophan
5-HTP
Serotonin
L-tyrosine
L-dopa
Dopamine
Norepinephrine
Epinephrine
Figure 1 Synthesis of serotonin and the catecholamines (dopamine, norepinephrine, and epinephrine).
Abbreviations: 5-HTP, 5-hydroxytryptophan; L-dopa, L-3,4-dihydroxyphenylalanine.
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Depletes
Depletes
Dopamine
Serotonin
Depletes
Sulfur amino acids
L-tyrosine
Depletes
L-tryptophan
Depletes
5-HTP
Depletes
L-dopa
Figure 2 Amino acid precursor-induced monoamine relative nutritional deficiency.
Administration of improperly balanced monoamine precursors and/or sulfur amino
acids may lead to far reaching relative nutritional deficiencies. This depletion of
amino acids and monoamines can only be corrected with proper administration of
nutrients as guided by monoamine transporter optimization.
supported truly successful, consistent, and reproducible use
of 5-HTP in management of nutritional deficiencies. MTO
clearly explains this problem, ie, the unbalanced approach
to the use of amino acid precursors.8
The literature on Parkinson’s disease demonstrates that
the L-dopa dosing value potential is limited due to side
effects and adverse reactions. In addition, the effectiveness of L-dopa wanes with time (tachyphylaxis). While
L-dopa is recognized as the most effective nutritional
management for Parkinson’s disease, it is common to use
other much less effective alternative Parkinson’s medications, such as agonists and metabolic enzyme inhibitors,
initially and for as long as possible in the management of
Parkinson’s disease, saving L-dopa for last due to all of the
problems and side effects associated with its unbalanced
administration. As noted in previous writings, utilizing
MTO technology will virtually eliminate all side effects and
problems associated with L-dopa administration which stem
from improper balance of serotonin, 5-HTP, L-tryptophan,
L-tyrosine, and sulfur amino acids.
Optimal 5-HTP and L-dopa results require MTO. It is only
under these conditions that efficacy increases significantly,
and side effects virtually resolve or are made manageable.6
Specific examples of the dominant monoamine depleting
the nondominant monoamine are listed here and illustrated
in Figure 2.1,8
•
•
•
•
•
•
•
•
•
•
5-HTP may deplete dopamine
L-tryptophan may deplete dopamine
L-dopa may deplete serotonin
L-dopa may deplete L-tryptophan
L-dopa may deplete L-tyrosine
L-dopa may deplete sulfur amino acids
L-tyrosine may deplete serotonin
L-tyrosine may deplete 5-HTP
L-tyrosine may deplete sulfur amino acids
Sulfur amino acids may deplete dopamine
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• Sulfur amino acids may deplete serotonin
MTO in the competitive inhibition state reveals that
effecting change to one component will effect change to all
components of the serotonin-catecholamine system, as depicted
in Figure 2, in a predictable manner. Unbalanced administration
of precursors causes the dominant monoamine to exclude the
nondominant monoamine in synthesis and transport, leading to
depletion and evolution of an RND relating to the nondominant
system in the process. A novel finding of this research is that
when depletion of the nondominant system is great enough,
the effects of the dominant system will no longer be observed
at any dosing value. This is a severe RND state.8
The L-aromatic amino acid decarboxylase enzyme
catalyzes conversion of 5-HTP and L-dopa to serotonin and
dopamine, respectively. Reviewing Figure 3, administration
of unbalanced enzyme-dominant dosing values of 5-HTP
or L-tryptophan will cause the serotonin side of the equation to dominate L-aromatic amino acid decarboxylase and
deplete the dopamine/catecholamine side of the equation
through compromise of synthesis. This causes an RND of
the nondominant dopamine/catecholamine systems. The
same is true in reverse with the administration of L-dopa.
When the dopamine side is dominant at the enzyme relative
to the serotonin side, a serotonin-related RND will occur (see
Figures 2 and 3).1–8,11–13
The activity of the monoamine oxidase enzyme system,
which catalyzes monoamine metabolism, is not static. If
levels of one system become dominant, monoamine oxidase
activity will increase, leading to depletion and an associated
RND of the nondominant system via accelerated metabolism
(see Figures 2 and 4).1–8,11–13
Tryptophan
5-HTP
Tyrosine
L-dopa
Aromatic
amino acid
decarboxylase
Serotonin
Dopamine
Figure 3 Improperly balanced amino acid precursor administration leads to
depletion of the nondominant system causing a relative nutritional deficiency of that
system through competitive inhibition at the L-aromatic amino acid decarboxylase
by the dominant system during synthesis of serotonin and dopamine.
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Dopamine
norepinephrine
epinephrine
Serotonin
MAO
COMT
HVA
5-HIAA
Figure 4 Domination of the monoamine oxidase enzyme system by one system
leads to increased enzyme activity resulting in depletion of the nondominant system
with an associated relative nutritional deficiency through increased metabolism.
Abbreviations: COMT, catechol-O-methyltransferase; MAO, monoamine oxidase;
5-HIAA, 5-hydroxyindoleacetic acid; HVA, homovanillic acid.
Synthesis (Figure 3) and metabolism (Figure 4) of
monoamines is dependent on OCT which regulates movement
of amino acids and monoamines in and out of cellular structures
where these functions take place. This functional status can only
be determined in situ with monoamine oxidase.1–8,11–13
OCT-dependent metabolism takes place both inside and
outside of cells. If one system dominates the transporter, the
nondominant system will be excluded from transport, leading
to suboptimal regulation of function secondary to increased
metabolism, and decreased synthesis of the nondominant system
(see Figure 5). When unbalanced amino acid precursors and/or
monoamines are present at the transporter entrance, systemic
monoamine concentrations, which are dependent on transport,
will not be optimal. This leads to an amino acid-induced RND
along with suboptimal regulation of function.1–8,11–13
Dopamine
phase 2 or 3 at
the transporter.
Competitive
inhibition in
place
Gate open
To the
urine
OCT gate-lumen
regulation
Basolateral
monoamine
transporter
lumen
Serotonin
phase I at the
transporter. Gate
regulation in
place
To the
urine
Gate partially closed
Figure 5 In the competitive inhibition state, organic cation transport of serotonin
and catecholamines needs to be in proper balance to ensure optimal regulation of
function and optimal synthesis of both systems and prevent monoamine-induced
and/or amino acid-induced relative nutritional deficiencies.
Abbreviation: OCT, organic cation transporters.
When the established effects of the dominant system
d issipate, secondary to depletion of the nondominant system, it
is caused by an amino acid-induced RND associated with the
nondominant monoamine system. This research has tracked the
etiology of L-dopa tachyphylaxis to a novel serotonin-related
RND, ie, serotonin is depleted due to serotonin precursor nutrient needs being greater than can be achieved with an optimal
diet in the face of L-dopa depletion of serotonin and serotonin
precursors. This is supported by the novel findings that administering proper levels of serotonin precursors as guided by
MTO can reverse L-dopa tachyphylaxis quickly.1–8
Centrally acting monoamine RND
The bundle damage theory notes that damage to the postsynaptic structural components involved with electrical
conduction is the primary cause of electrical dysfunction
associated with the monoamine-related diseases, not low
synaptic neurotransmitter levels. As previously noted, when
these electrical dysfunctions are present on a chronic basis,
monoamine levels and nutrient levels are in the normal
range on laboratory studies.1,8 The damage to the postsynaptic neurons leads to a compromise in the regulatory flow
of electricity. When the flow of electricity is compromised
enough, symptoms and dysfunction develop.1
Parkinson’s disease is a prototype in the study of monoamine-related RND. It is well known that in Parkinson’s disease
there is damage to the dopamine neurons of the substantia
nigra in the brain. L-dopa is administered in order to increase
dopamine levels to compensate for the compromised electrical flow that results from the damage.
MTO evaluation shows that the only viable explanation
for chronic electrical dysfunctional diseases that are present
in patients who have normal synaptic monoamine levels is
damage to the postsynaptic neuron structures (bundle damage theory). This is the classical presentation observed with
the Parkinson’s disease model where electrical dysfunction
secondary to postsynaptic neuron damage has been identified and has caused an RND problem related to inadequate
intake of the dopamine precursor. It is the novel findings
of this research project that, as with Parkinson’s disease,
postsynaptic neuronal damage with the associated RND is
common in all chronic monoamine-related illnesses for which
the etiology is electrical dysfunction.6
Prior to management of monoamine RND, the amount
of nutrients entering the brain is normal but it is not high
enough to facilitate synthesis of monoamines at the levels
needed to allow the OCT to function up to the required flow
potentials encoded in the transporter.
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The primary forces responsible for establishing monoamine
levels throughout the body are synthesis, metabolism, and
transport. Transport dominates with its control and regulation
over synthesis and metabolism.1,8 The first step in the RND management protocol is simultaneous administration of serotonin
and dopamine amino acid precursors in dosing values great
enough to place the monoamine system into the competitive
inhibition state. Then, 1 week later, a urine sample is obtained,
monoamine assays are performed, and MTO interpretation is
done. This enables a proper decision on the modification of
amino acid dosing values in order to achieve both the serotonin
and dopamine in the optimal phase 3 ranges.3,4,6,12
If the MTO-guided amino acid dosing value changes do
not yield the desired results in 1 week, another specimen is
obtained and submitted for additional MTO-guided dosing
change recommendations. The optimal phase 3 ranges of
serotonin and dopamine are achieved with the benefit of
MTO. This is a complex task because, in the competitive
inhibition state, changing one amino acid precursor changes
all components of the equation shown in Figure 2.3,4,6,12
Two or more urinary serotonin and dopamine assays,
performed on different days while taking different amino acid
dosing values, are required for absolute MTO verification of
phases and dosing recommendations. The patient must be
taking monoamine precursors in significantly varied doses
for five or more days continuously to allow for equilibration
of the system to the dosing change. The results of these serial
assays are then compared to determine the change in urinary
serotonin and dopamine levels in response to the change in
amino acid precursor dosing values.3,4,6,12
At the initial visit it is recommended that the following adult amino acid dosing values be initiated: L-cysteine
4500 mg, L-tyrosine 3000 mg, vitamin C 1000 mg, L-lysine
500 mg, 5-HTP 300 mg, calcium citrate 220 mg, vitamin B6
75 mg, folate 400 µg, and selenium 400 µg. The pediatric
dosing values (,17 years) are half the adult dosing values.
A full discussion of the scientific basis for each of these amino
acid and cofactor nutrients is covered in previous writings
by the authors. A brief overview is as follows:
L-tyrosine and 5-HTP are dopamine and serotonin precursors, respectively. Vitamin C, vitamin B6, and calcium
citrate are cofactors required in the synthesis of serotonin
and/or dopamine. Folate is required for optimal synthesis
of sulfur amino acids. Selenium is given in response to the
ability of cysteine to concentrate methylmercury in the central nervous system. L-lysine prevents loose hair follicles
in a bariatric medical practice. L-cysteine is administered
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to compensate for L-tyrosine-induced depletion of sulfur
amino acids.3,4,6,12
The literature verifies that baseline monoamine testing
in the endogenous state, prior to starting monoamine amino
acid precursors of serotonin and dopamine, is of no value
due to lack of reproducibility when monoamine testing is
performed on multiple days from the same subject. Therefore,
baseline testing has no place in monoamine-related RND
management.3,4,6,12
In the competitive inhibition state, laboratory testing
has reproducibility on successive test dates. MTO can
assist in selecting the appropriate dose of the respective
amino acid precursors to achieve the required transporter
flow of monoamines and amino acids for optimal RND
management.3,4,6,12
Three-phase transporter response
When postsynaptic damage compromises electrical flow at
that postsynaptic location, the OCT is encoded with optimal monoamine transporter configuration and flow rates to
compensate for the damage. When the monoamine flows are
optimized immediately above the phase 2/phase 3 inflection
point, as discussed in this section, there is optimal restoration
of postsynaptic electrical flow. However, when a significant
RND exists, encoded OCT needs cannot be met by dietary
intake alone, and this is the basis of the RND.1–13
In the competitive inhibition state, three phases of OCT
subtype 2 (OCT2) transporter response are observed. The
status of monoamines in the endogenous state may be referred
to as phase 0. In phase 0, the serotonin or dopamine entrance
gates are at maximum closure, although still partially open,
and the concentrations of monoamine presenting at the
transporter are too low for the entrance gate to impact access
of the monoamine to the transporter. In phase 0, the monoamines simply access the OCT2 without restriction. Since
urinary monoamine levels are a measurement of monoamines
not transported by the OCT2, urinary monoamine levels
are random in phase 0, not affected by the entrance gate or
transporter.1–13
Proper use of MTO deciphers the optimal flow of serotonin and dopamine as established by amino acid precursor
administration which is encoded in OCT2 by the damaged
system. Proper implementation of MTO revolves around
identification of the phase 1, phase 2, and phase 3 of both
urinary serotonin and dopamine responses during administration of varied amino acid precursor dosing values (the competitive inhibition state). While an experienced interpreter
may often be able to determine the serotonin and dopamine
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phases with one test, a high degree of certainty exists
only when two urinary monoamine assays are compared
while taking varied amino acid dosing values. Referring to
Figure 6, in phase 2, the urinary serotonin and dopamine
levels are low (serotonin ,80 µg and dopamine ,475 µg
of monoamine per g of creatinine). In phase 1, there is an
inverse relationship between amino acid dosing and urinary
monoamine levels. In phase 3, there is a direct correlation
between amino acid dosing values and urinary monoamine
levels on assay. The amino acid dosing values where the
phase inflection points occur is highly variable and unique
to each individual.1–13
Assayed urinary serotonin and dopamine values are
reported in µg of monoamine per g of creatinine in order
to compensate for fluctuations in urinary specific gravity.
The phase 3 optimal range for urinary serotonin is defined
as 80–240 µg of serotonin per g of creatinine. The phase 3
optimal range for urinary dopamine is defined as 475–1100
µg of dopamine per g of creatinine.1–13 Urine samples are usually collected 6 hours prior to bedtime, with 4 pm being the
most frequent collection time point. For most patients, 6 hours
before bedtime is the diurnal low point of the day.1–13
Organic cation transporters
The authors have published numerous peer-reviewed articles
on the topic of in situ MTO.1–13 These publications outlined the
novel first and only in situ methodology for OCT functional
status determination of encoded transporter optimization in
humans. This paper establishes the novel RND etiology and
traits associated with chronic monoamine-associated diseases
and regulatory dysfunctions, ie, postsynaptic damage-induced
electrical compromise and the resultant relative RND.
The monoamines and their amino acid precursors are
moved across cell walls by complex molecules known as
transporters. Depending on their orientation with the cell
Urinary monoamine levels
Phase 1
Phase 2
Phase 3
Optimal range
� � Increasing the daily balanced amino acid dosing � �
Figure 6 The core part of monoamine transporter optimization, ie, the three
phases of transporter response to varied amino acid precursor dosing values.
wall, transporters may move these substances in or out of
the cells.1
The three primary actions that determine monoamine
neurotransmitter levels everywhere in the body are synthesis, metabolism, and transport. Transporters dominate and
regulate synthesis and metabolism. Synthesis is dependent on
transport of amino acids into the cells. Metabolism depends
on transporters to move neurotransmitters into the environment where enzymes break them down. Ultimately, intercellular and extracellular (including synaptic) monoamine and
amino acid precursor levels are functions of and dependent
on transporters.1–8,11–13
The following key points establish synaptic monoamine
neurotransmitter levels. Monoamine neurotransmitters are stored
in storage vesicles found in the presynaptic neuron. When an
electrical pulse travels down the presynaptic neuron, it causes the
vesicles to fuse to the presynaptic neuron cell wall, at which point
neurotransmitters are excreted into the synapse. This is not the
controlling event that regulates synaptic neurotransmitter levels.
The synaptic monoamine levels are a function of simultaneous
interaction of two transporter types. High affinity transporters are
found on all neurons where monoamines are synthesized. The
OCT2 regulates synaptic neurotransmitter levels by transporting
neurotransmitters that escape high affinity transport. It is the
OCT2 that essentially fine tunes the intercellular and extracellular monoamine levels of the brain and kidneys. OCT2 are also
located on the cell membrane of the presynaptic neuron. The
OCT2 perform the reuptake function, whereby the neurotransmitters are returned back into the presynaptic neurons where
they are stored in the vesicles, waiting to be released anew on
impulse into the synapse.15
For many years, laboratories have attempted to decode
results found when neurotransmitters are assayed. The
primary approach has been to determine simply whether
levels were high or low. This did not work because it did not
take into account the effects of transporters. This high/low
approach to assay interpretation, as a guide to amino acid
dosing values, was no more effective than simply giving
amino acid precursors randomly.5,7,11
There are three specific items1–13 that allow for the validity
of MTO:
• The various subtypes of transporters are “identical and
homologous” throughout the body.
• OCT encoding occurs in an identical and homologous
manner that facilitates raising levels of monoamines to
establish levels high enough to relieve symptoms.
• Most importantly, OCT2 are found in only a few
places in the body, mainly the kidneys and synapses of
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the brain; they are encoded identically and enable MTO
determination to be an effective tool for establishing the
optimal levels of amino acid precursor administration.
Based on in situ OCT observations, when the patient is
suffering from chronic monoamine neurotransmitter-related
disease, MTO is the only method available that allows for
establishment of balanced serotonin and dopamine neurotransmitter levels needed to compensate optimally for the
defective electrical flow in the brain and to relieve the RND
induced by postsynaptic damage.1–13
Most patients, by history, are simultaneously suffering from
three or more monoamine deficiency diseases.9 This etiology
is consistent with multifocal RND. The entire clinical picture
presents as multiple monoamine-related disease, but needs to
be managed as a single problem with one etiology, ie, a monoamine RND relating to suboptimal function of OCT2.1,8
The MTO defines:
• The phase of serotonin and dopamine in OCT transport
in the competitive inhibition state;
• the status of the serotonin and dopamine OCT entrance
gates;
• the status of serotonin and dopamine OCT lumen
saturation; and
• the OCT balance status between the monoamines and
their amino acid precursors.1–13
All four of these functions are critical to determining the
following in the competitive inhibition state:
• Optimal dosing values of serotonin and dopamine amino
acid precursors.
• Facilitation of optimal transport of serotonin and
catecholamines.
Results
The results shown in the following tables are from urinary
monoamine assays which demonstrate the extreme individual
variability of serotonin and dopamine precursor needs in
monoamine-related RND management under the guidance
of MTO in order for both serotonin and dopamine to achieve
the phase 3 optimal ranges.
All three subjects in Tables 1–3 were suffering from
depression with no other monoamine-related RND states
present. In all three cases, when both serotonin and dopamine
were established in the phase 3 optimal ranges, relief of
depression symptoms was obtained. All three patients noted
no relief of symptoms until both the serotonin and dopamine
were established in these ranges.
The US Department of Agriculture recommended daily
allowances are intended for a normal population to meet
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inimal daily nutrient needs, ie, to prevent absolute nutritional
m
deficiencies. Proper management of RND is intended to be
under the care of a physician because achieving a balance of
neurotransmitters may require administration of nutrients in
dosing values which are well above the US Department of
Agriculture recommended daily allowances.16
Serotonin and dopamine amino acid dosing required to
meet encoded optimal monoamine transporter flow varies
greatly over large dose ranges. There is no relationship,
from patient to patient, between the ultimate dosing values
of serotonin and dopamine precursors required to establish
serotonin and dopamine concentrations at the optimal flow
encoded in the OCT.
The following ranges were extracted from a database
containing over 2.4 million patient-days of amino acid management experience where monoamine-related RND were
optimized with MTO. The effective therapeutic range was
defined as the amino acid dosing values, within two standard
deviations of the mean, that were associated with serotonin or
dopamine in the phase 3 optimal range. Excluded from the data
were patients suffering severe postsynaptic dopamine injury,
such as Parkinson’s disease and restless leg syndrome.
• The daily effective therapeutic range of 5-HTP as evidenced by a phase 3 serotonin in the 80 to 240 µg/g
creatinine range was found to be .0 mg to 2400 mg.
• The daily L-dopa effective therapeutic range as evidenced
by phase 3 dopamine in the 475 to 1100 µg/g creatinine
range was found to be .0 mg to 2100 mg.
• The daily effective therapeutic range of L-tyrosine as
evidenced by dopamine response to L-dopa administration was found to be .0 mg to 14,000 mg.
The dosing values of 5-HTP, L-dopa, and L-tyrosine are
independent of each other. Some variability in the high-end
range values may occur when individual RND-associated disease states are examined versus this entire group of diseases.
Using L-tyrosine as an example, dosing values of 14,000 mg
per day were unknown in the literature prior to this research.
However, when amino acid dosing values are established
with MTO, these seemingly high doses are uniformly well
tolerated by patients, because electrical flow and the system
revert back to normal.
Discussion
The OCT2 of the brain fine tunes monoamine neurotransmitter levels. The OCT2 of the brain and kidneys are identical
and homologous and share certain specific traits, including
being genetically identical with regard to DNA sequencing.16
In order to understand the significance of the amino acid
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Table 1 Patient with depression suffering from postsynaptic serotonin neuronal damage, as evidenced by the level of 5-HTP required
to control the RND
Urinary serotonin and dopamine reported in μg monoamine per g of creatinine
Amino acids (μg/day)
Date
Serotonin
Serotonin phase
Dopamine
Dopamine phase
5-HTP
L-dopa
L-tyrosine
11/1/2011
1/18/2011
12/4/2011
873
27
187
1
2
3
536
986
491
3
3
3
300
600
900
240
240
120
3000
4000
5000
Abbreviations: 5-HTP, 5-hydroxytryptophan; L-dopa, L-3,4-dihydroxyphenylalanine; RND, relative nutritional deficiency.
dosing value variables found in Tables 1–3, it is necessary to
review OCT2 transporter physiology.
Serotonin and dopamine transport across the basolateral
membrane of the proximal convoluted renal tubule cells is
identical to the mechanism of action in the brain. A high affinity
transporter is involved and the OCT2 transports and fine tunes
monoamine neurotransmitter levels not transported by the high
affinity transporters.17 The urinary assays of Tables 1–3 represent monoamines that are newly synthesized in the proximal
convoluted renal tubule cells and are not transported across the
basolateral membrane by the high affinity OCT2 system. These
newly synthesized monoamines, not transported by the basolateral transporter system, are transported via the OCTN2 through
the apical membrane, finally ending up in the urine.1,8
The high affinity OCT2 system in the brain primarily
functions as the monoamine reuptake transporters located
on the presynaptic neurons. Synaptic monoamine levels
represent monoamines that have not been transported into
the presynaptic neurons. This is a functional transporter
characteristic of the brain and is identical and homologous
to OCT2 function of the proximal renal tubule cells. The
synaptic monoamine levels are analogous to the monoamine
concentrations found in the urine. Monoamine reuptake
inhibitor drugs interact with OCT2 transporters.1–13
When postsynaptic damage associated with compromise
in the flow of electricity occurs leading to development of
disease symptoms:
• An increase in synaptic monoamine levels compensates
by facilitating the increased flow of electricity.
• OCT2 transporters are encoded to establish monoamine
concentrations required to compensate for the problem.
This is evidenced by the monoamine/amino acid dosing
value variability in correlation with the clinical response
of symptom resolution.
• Serotonin and dopamine amino acid precursor administration results in synaptic and urinary monoamine levels
following the three phase response.1–13
As noted in Figure 6, the optimal amino acid dosing values as identified by MTO places the serotonin and dopamine
in phase 3 just above the phase 2/phase 3 inflection point.
In the optimal phase 3 dosing range, the OCT2 entrance
gates are fully open, and the flow through the transporter has
become saturated with serotonin and dopamine. This occurs
at the phase 2/phase 3 inflection point as the total amount of
serotonin and dopamine presenting at the transporter entrance
increases. In the competitive inhibition state, the concentration of serotonin and dopamine reported on assay is not as
important as achieving proper balance of the monoamines in
the optimal phase 3 ranges as defined by MTO.1–13
For example, a serotonin concentration of 230 µg/g
creatinine may appear to be in the optimal range if only
concentration values are considered. However, when this
laboratory value is found to be in phase 1, a completely
different physiological state emerges, ie, one of suboptimal
synaptic function and restricted monoamine access to the
transporter because the system gives priority to elevating
synaptic monoamine levels at the expense of optimizing
monoamines stored in the presynaptic vesicles.1–13
Table 2 Patient with depression suffering from postsynaptic catecholamine neuronal damage as evidenced by the level of L-dopa
required to control the RND
Date
Serotonin
Serotonin phase
Dopamine
Dopamine phase
5-HTP
L-dopa
L-tyrosine
10/4/2011
10/22/2011
11/6/2011
3392
2343
216
3
3
3
554
283
694
1
2
3
300
150
37.5
240
480
720
3000
1500
375
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Table 3 Patient with depression suffering from postsynaptic serotonin and catecholamine neuronal damage as evidenced by the levels
of 5-HTP and L-dopa required to control the RND
Date
Serotonin
Serotonin phase
Dopamine
Dopamine phase
5-HTP
L-dopa
L-tyrosine
8/4/2011
8/22/2011
9/6/2011
10/4/2011
10/22/2011
11/6/2011
11/23/2011
12/9/2011
1496
1288
1213
761
364
168
64
161
1
1
1
1
1
1
2
3
362
178
86
152
187
248
417
513
2
2
2
2
2
2
2
3
300
600
900
1200
1500
1800
2100
2400
240
360
480
720
960
1200
1440
1440
3000
4000
5000
6000
7000
8000
9000
10,000
Synaptic monoamine levels and presynaptic vesicle monoamine levels are a function of OCT2 functional status. When
compromise in electrical flow is present, the OCT2 is encoded
with the monoamine transporter flow characteristics required for
optimal flow through the presynaptic, synaptic, and postsynaptic
systems. This novel transporter encoding variability is vigorously displayed in Tables 1–3, where MTO defines the required
optimal serotonin and dopamine amino acid precursors.1–13
A hypothesis of this research states that, in the endogenous state, when postsynaptic neuron damage occurs, a
point is reached where the transporters are unable to alter
the flow of available monoamines sufficiently to keep the
electrical flow at a level great enough for the system to
function normally and the patient to be symptom-free. When
the total monoamine concentration in the system is normal
but too low for the transporters to optimize synaptic levels,
it is the result of an RND of serotonin and/or dopamine;
this requires resolution with a nutrient-based amino acid
precursors approach any time low or inadequate levels of
monoamine neurotransmitters exist.1–13
One of the foundations for monoamine-associated RND
and the ability to compensate for this problem is illustrated
in Tables 1–3. The body responds to postsynaptic neuron
damage by encoding the OCT2 in a unique and individualized
manner that facilitates synaptic monoamine compensation.
However, monoamine levels that are high enough to allow
the OCT2 to compensate are not achievable on a regular diet,
so the system languishes in the phase 0 state.1–13
By administration of properly balanced nutrients (amino
acids), optimal synaptic monoamine levels are established
and relief of symptoms and/or proper regulation of function
occur. As discussed in the Results section, the amino acid
dosing values required to achieve optimal OCT2 function
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vary greatly and are very individualized. Once the proper
amino acid dosing needed to relieve symptoms is found, it
becomes that patient’s standard nutrient intake requirement
to compensate for the RND unless further postsynaptic damage is experienced.1–13
The site of postsynaptic neuron damage in the brain
dictates the nature of the RND and the monoamine-associated
disease symptoms that are manifest. With Parkinson’s disease,
damage occurs in the dopamine neurons of the substantia
nigra. Patients suffering chronic depression sustain postsynaptic damage to the regions of the brain that control affect
and mood. This could be a damage-associated RND of the
serotonin, dopamine, or norepinephrine postsynaptic neurons
or any combination thereof (Tables 1–3).1–13
The amino acid dosing values found in Table 3 deserve
some additional reflection. The dosing values of 5-HTP and
L-tyrosine are novel, and much larger than reported in the
previous literature. The dosing value of L-dopa for this nonParkinson’s patient is relatively large as well. Administration of
the novel amino acid dosing values needed to properly address
RND which are this large, with successful resolution of symptoms, would not be possible or considered without MTO.
Side effects and adverse reactions due to imbalanced
administration of amino acid dosing values of this magnitude
without MTO guidance would prohibit dosing values such
as this, effectively establishing an amino acid dosing barrier.
Further, without MTO, there is no objective amino acid dosing value guidance in addressing the RND; it is a random
event in an environment where individual needs vary on a
large scale and the dosing needs of serotonin and dopamine
precursors are independent of each other. When serotonin
and dopamine levels are increased to levels required to
address the RND and proper balance is achieved with MTO
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guidance, these amino acid dosing values, such as found in
Table 3, are exceptionally well tolerated and generate the
desired result of safely alleviating symptoms. The key is
proper balance. MTO reveals that if side effects and adverse
reactions occur during amino acid administration, they are
not due to a specific amino acid; rather, imbalance between
the serotonin and dopamine systems is the cause. The lack
of unmanageable side effects, such as those observed when
only L-dopa is administered for management of Parkinson’s
disease, is attributable to the balanced administration of the
precursors which restore neuronal electrical flow and system
function to normal.1–13
Administration of proper levels of amino acids does not
make the patient high or euphoric. In response to establishing
the serotonin and dopamine in the phase 3 optimal ranges,
symptoms resolve and the patient simply feels normal. What
matters is getting the required levels of balanced amino acids
into the system to compensate for the RND associated with
the electrical defect under the guidance of MTO without
regard to how large the amino acid dosing value has become,
as long as the need is indicated.1–13
Amino acid-induced RND
An RND of the nondominant system occurs when there
is an improper balance between the serotonin and dopamine
amino acid precursors. The three primary forces that
regulate concentrations of centrally acting monoamines
t hroughout the body are synthesis, metabolism, and
transport. The serotonin and catecholamine systems are so
heavily intertwined in the competitive inhibition state that
they need to be managed as one system under MTO guidance to achieve optimal results. Changes to one component
of either system will affect all components of both systems
in a predictable manner.8
Giving only 5-HTP or only L-dopa or improperly
balanced serotonin and dopamine amino acid precursors
(Figure 2) will, over time, create many problems which
result in needless patient suffering from suboptimal
monoamine levels, increased side effects, and false expectations during medical care.8
Unbalanced administration of serotonin and dopamine
amino acid precursors causes:
• One system to dominate over the other system in synthesis, transport, and metabolism (see Figures 3–5) leading
to depletion of the nondominant system.8
• Increased incidence of side effects due to administration
of improperly balanced amino acids.8
• The inability to achieve the amino acid dosing values
needed to optimize MTO fully, which prevents both
optimal management of the RND and restoration of
proper postsynaptic neuron flow.8
Iatrogenic or drug-induced RND
Depletion of monoamine neurotransmitters is known in the
literature to be associated with administration of reuptake
inhibitors. Reuptake inhibitors are not just prescription
drugs used for treatment of depression and attention-deficit
disorder, but are also available as street drugs, such as
amphetamines, “Ecstasy,” and methamphetamine. Reuptake
inhibitors deplete monoamines via their mechanism of
action, which induces an RND. All amphetamines also have
serious neurotoxic potential and are fully capable of inducing a neurotoxin-associated RND, with postsynaptic neuron
damage in addition to the reuptake inhibitor-driven RND.
Selective serotonin reuptake inhibitors are also known to
decrease serotonin synthesis, leading to a drug-induced RND.
The nonspecific reuptake inhibitor amitriptyline (a tricyclic
antidepressant) is known to deplete norepinephrine, leading
to a drug-induced RND.13
A series of illustrations (Figures 7–9) have been posted
on The National Institute on Drug Abuse’s website. These
f igures show how reuptake inhibitors deplete monoamine neurotransmitters leading to the induction of an
RND.13
Drugs that work with neurotransmitters do not function
properly if there are not enough synaptic neurotransmitters
available. The end stage of reuptake inhibitor-induced
Figure 7 Prior to reuptake inhibitor treatment, inadequate levels of
neurotransmitters in the synapse cause a disease-associated relative nutritional
deficiency leading to compromised electrical flow through the postsynaptic neurons
resulting in suboptimal regulation of function and/or development of symptoms.
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Figure 8 Administration of reuptake inhibitors blocks monoamine transport back
into the presynaptic neurons. This leads to a net redistribution of neurotransmitter
molecules from the presynaptic neuron to the synapse. The increased synaptic level
of monoamines increases post-synaptic flow of electricity leading to restoration of
adequate regulation of function and/or relief of symptoms.
RND occurs when there is severe depletion of the
neurotransmitters:
• Drug stops working.
• Discontinuation syndrome is so strong that the patient
cannot discontinue the drug even though there is no
perceived benefit.
• Suicidal ideation develops.
When this happens, administration of properly balanced
serotonin and dopamine amino acid precursors will correct
the RND, restore the effects of the drug, and restore the
normal functioning of the system.13
Disease-induced RND
Inadequate flow of postsynaptic electricity is associated
with virtually all chronic monoamine-related diseases.
Figure 9 The drug-induced relative nutritional deficiency. When the monoamines
are in the vesicles of the presynaptic neuron, they are not exposed to the enzymes
that catalyze metabolism (monoamine oxidase and catechol-O-methyltransferase).
They are safe from metabolism. When they are relocated outside the vesicles of
the presynaptic neuron, they are exposed to these enzymes at a greater frequency.
Reuptake inhibitors create a mass migration of monoamines causing increased
metabolic enzyme activity and metabolism of monoamines. This leads to the druginduced relative nutritional deficiency if significant amounts of balanced serotonin
and dopamine precursors are not coadministered with the reuptake inhibitor.
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In all cases where synaptic monoamine levels are normal but
not adequate such as states where low or inadequate levels of
monoamine neurotransmitters occur, there is a monoamineassociated RND. Even with the use of reuptake inhibitor drugs,
proper management of these problems involves addressing the
RND by administering the monoamines and their amino acid
precursors. Optimization can only be achieved with MTO.
The ability of MTO to address monoamine-related
RND is so definitive that proper implementation leads,
with absolute certainty, to determining whether monoamine neuronal electrical dysfunction is a component of the
disease picture. The examples below illustrate how proper
application of monoamine transport optimization can lead
to recognition and resolution of the RND and also allow
for observation of other problems not clearly anticipated as
disease etiologies.
Major affective disorder
Chronic major affective disorder (depression) has an RND
present which leads to monoamine levels in the central nervous system being too low to achieve optimal postsynaptic
flow of electricity. Properly balanced amino acid precursors
are necessary; dietary nutrient intake alone is not sufficient
to establish high enough monoamine levels to optimize
transporter-dependent synaptic monoamines.9,12
Contrary to the popular assertion that 5-HTP is indicated
for depression, MTO reveals that use of only 5-HTP for
depression is contraindicated. Many patients with depression
respond only to drugs with dopamine and/or norepinephrine
reuptake inhibition properties. Administration of only 5-HTP
leads to an amino acid-induced RND of the catecholamines
which leads to exacerbation of depression, especially in
patients whose depression is dominated by catecholamine
dysfunction. Use of only 5-HTP depletes catecholamines.
When catecholamine depletion is great enough, any clinical
benefits initially observed with the administration of 5-HTP
will be no longer present.1–13
Reuptake inhibitors have only marginal effectiveness in
addressing the symptoms associated with depression and
no ability to address the etiology of the RND. In doubleblind studies of major affective disorder, only 7%–13% of
patients achieve symptom relief greater than placebo. Drug
administration reveals subgroups of patients suffering from
major affective disorder who achieve greater efficacy with
a serotonin, dopamine, or norepinephrine reuptake inhibitor
or combination. The area of the brain that controls affect
involves interactions of all three of these monoamines. The
mechanism and site of action in the affected area of the
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brain will dictate which of these monoamines are primarily
involved. While recognizing that any of several monoamines
may be involved while displaying identical symptomatology, the exact determination of which ones are primarily
involved is not required. The MTO approach simultaneously optimizes levels of all three of these monoamines in
transport, based on interpretation of information encoded in
the transporters.9,12,13
Standard management for many patients with depression
includes prescribing reuptake inhibitor antidepressants. If
proper levels of nutrients are not administered concomitantly
with the drug, monoamine neurotransmitter depletion may
and often does occur, leading to a drug-induced RND.9,12
Two primary types of depression are recognized here,
ie, major affective disorder and bipolar disorder cycling on
the depressive pole (bipolar depression). As was previously
noted in the literature, when OCT serotonin and dopamine
levels were established with MTO in the optimal phase 3
ranges, all subjects whose depression did not resolve were
suffering from bipolar depression.12
A review of the clinical history prior to initiation of management revealed that these patients had no response to bipolar
medications in the past and had no response when amino acids
were optimized. These patients had all been treated with a
mood-stabilizing drug without success. This is an RND that
requires both serotonin and dopamine to be placed in the
phase 3 optimal ranges before the effects of mood-stabilizing
drugs are observed. When the amino acid dosing values
required for MTO were achieved and a mood-stabilizing drug
(lithium 300 mg twice a day or valproic acid 250 mg two or
three times a day) was added, .98% of cases experienced
resolution of depressive bipolar symptoms in 1–3 days. These
bipolar depressive patients were suffering from damage at a
central nervous system site distinctly different from that of
major affective disorder. Bipolar patients require addition of a
mood-stabilizing drug that had previously yielded no benefit
but became effective once the RND was properly addressed
with the aid of MTO.12
L-dopa is recognized as the most effective management
option for Parkinson’s disease, but is generally not used firstline due to the exceptionally large amount of iatrogenically
induced significant side effects and problems that evolve over
time. Previous literature published by the authors asserts that
virtually all of the problems associated with administration
of L-dopa and/or carbidopa are caused by iatrogenic mismanagement of the large number of RND associated with
the disease, L-dopa, and/or carbidopa. These RND involve
all three major classes of RND, ie, disease-associated, amino
acid-induced, and drug-induced.6
The Parkinson’s disease-associated RND is characterized by damage to the postsynaptic dopamine neurons of
the substantia nigra. The extremely high synaptic dopamine
levels required to restore normal flow of electricity cannot
be established by dietary intake alone.6
Parkinson’s disease-associated RND management may
require L-dopa dosing values up to 200 times greater than
the needs of other monoamine disease processes, as high as
25,000 mg per day. MTO reveals that the OCT2 are encoded
to elevate synaptic dopamine vigorously, to the point that
serotonin is excluded from the transporter leading to development of a Parkinson’s disease-associated serotonin RND.
Other Parkinson’s disease RND include norepinephrine and
epinephrine which are dependent on dopamine levels for
synthesis and are inadequate when the disease is present.6
The three primary monoamine RND associated with
Parkinson’s disease are shown in Figure 10. The only practical way to increase the depleted levels of monoamines and
amino acids noted in Figure 10 is by administration of amino
acid precursors guided by MTO.6
Administration of L-dopa is also known to induce RND
associated with L-tyrosine, sulfur amino acids, L-tryptophan,
Status in
Parkinson’s
disease
Status with
L-dopa Rx
Serotonin (Central)
Depleted
Further depleted
Dopamine (Central)
Depleted
Norepinephrine (Central)
Depleted
Parkinson’s disease
Epinephrine (Central)
Depleted
Serotonin (Peripheral)
Depleted
Standard medical management of Parkinson’s disease uses
L-dopa and carbidopa. This approach literally turns into a
case study of how many iatrogenic side effects and adverse
reactions can be amassed during amino acid mismanagement of patients. Under this approach, traditionally there
is a total disregard for the interactions of L-dopa and the
peripheral monoamine status induced by carbidopa (see
Figure 2).6
Dopamine (Peripheral)
Depleted
Further depleted
Norepinephrine (Peripheral)
Depleted
Further depleted
Epinephrine (Peripheral)
Depleted
L-tyrosine
Tyrosine Hydroxylase
Further depleted
Status with
Carbidopa Rx
Further depleted
Further depleted
Depleted
Depleted
L-tryptophan
Depleted
5-Hydroxytryptophan
Depleted
Sulfur amino acids
Depleted
Figure 10 Basis for multiple relative nutritional deficiencies associated with
Parkinson’s disease.
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5-HTP, and serotonin (see Figure 2).6 The following are
previously published categories of L-dopa-associated problems
that are now correlated with an L-dopa-associated RND.6
Serotonin-related RND induced by L-dopa
A serotonin RND is the primary reason the L-dopa quits functioning (tachyphylaxis, ie, L-dopa stops working).6 L-dopa
tachyphylaxis is precipitated by depletion of serotonin when
dominant levels of L-dopa are administered. Administration
of 5-HTP to restore the balance guided by MTO is required
to manage this RND properly.
RND-induced transport imbalance between
serotonin and dopamine
This RND-related problem is responsible for a number of
side effects associated with the administration of L-dopa in
a dominant manner, ie, nausea, vomiting, anorexia, weight
loss, decreased mental acuity, depression, psychotic episodes including delusions, euphoria, pathological gambling,
impulse control, confusion, dream abnormalities including
nightmares, anxiety, disorientation, dementia, nervousness,
insomnia, sleep disorders, hallucinations and paranoid
ideation, somnolence, memory impairment, and increased
libido.6
An imbalance in the administration of serotonin and
dopamine amino acid precursors is responsible for all of
the above listed side effects and adverse reactions. MTO is
required when serotonin precursors are started in combination with L-dopa. Several of the side effects, such as nausea,
may be caused by administering the serotonin amino acid
precursor at levels that are either too high or too low. Since
the status of serotonin could be too high or too low, the level
cannot be empirically determined and MTO is required.
L-tyrosine RND
L-tyrosine RND may contribute to the associated on-off
effect, motor fluctuations, or dopamine fluctuations.6 MTO
has identified fluctuations in dopamine transport that respond
to L-tyrosine administration. The etiology of this phenomenon remains unknown.
L-dopa-induced sulfur amino acid RND
L-dopa-induced sulfur amino acid RND is associated with
bradykinesia (epinephrine depletion implicated), akinesia,
dystonia, chorea, extrapyramidal side effects, fatigue, abnormal involuntary movements, and depletion of glutathione,
potentiating further the dopamine neuron damage done by
neurotoxins.6 Patients with Parkinson’s disease as a group have
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significantly depleted sulfur amino acid levels, leading to an
associated RND which is exacerbated by administration of
L-dopa. Neurotoxins are the leading etiology of postsynaptic
dopamine damage in Parkinson’s disease. Glutathione is the
body’s most powerful toxin-neutralizing agent and is synthesized from sulfur amino acids. When a sulfur amino acid RND
occurs, it may accelerate the progression of Parkinson’s disease
due to increased susceptibility to further neurotoxic insult.
Carbidopa-induced peripheral serotonin
and catecholamine RND
Carbidopa-induced peripheral serotonin and catecholamine
depletion cause RND that are associated with numerous
side effects and adverse reactions, ie, dyskinesia, glossitis,
leg pain, ataxia, falling, gait abnormalities, blepharospasm
(which may be taken as an early sign of excess dosage),
trismus, increased tremor, numbness, muscle twitching,
peripheral neuropathy, myocardial infarction, flushing,
oculogyric crises, diplopia, blurred vision, dilated pupils,
urinary retention, urinary incontinence, dark urine, hoarseness, malaise, hot flashes, sense of stimulation, dyspepsia,
constipation, palpitation, fatigue, upper respiratory infection, bruxism, hiccups, common cold, diarrhea, urinary
tract infections, urinary frequency, flatulence, priapism,
pharyngeal pain, abdominal pain, bizarre breathing patterns,
burning sensation of tongue, back pain, shoulder pain, chest
pain (noncardiac), muscle cramps, paresthesia, increased
sweating, falling, syncope, orthostatic hypotension, asthenia
(weakness), dysphagia, Horner’s syndrome, mydriasis, dry
mouth, sialorrhea, neuroleptic malignant syndrome, phlebitis, agranulocytosis, hemolytic and nonhemolytic anemia,
rash, gastrointestinal bleeding, duodenal ulcer, HenochSchonlein purpura, decreased hemoglobin and hematocrit,
thrombocytopenia, leukopenia, angioedema, urticaria,
pruritus, alopecia, dark sweat, abnormalities in alkaline
phosphatase, abnormalities in serum glutamic oxaloacetic
transaminase (aspartate aminotransferase), serum glutamic
pyruvic transaminase (alanine aminotransferase), abnormal
Coombs’ test, abnormal uric acid, hypokalemia, abnormalities in blood urea nitrogen, increased creatinine, increased
serum lactate dehydrogenase, and glycosuria.6
The problem in this category is a carbidopa-induced
RND of peripheral serotonin and catecholamines, and is
best managed by not using carbidopa in the first place. It is
not needed when MTO is properly utilized. Carbidopa was
originally employed in an effort to control the nausea associated with L-dopa administration, a side effect and RND
manageable by MTO.
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Carbidopa inhibits peripheral synthesis of serotonin and
catecholamines by L-aromatic amino acid decarboxylase.
In the process, peripheral monoamines develop an associated RND with a plethora of symptoms (see above). By far,
the largest group of RND-related side effects and adverse
reactions in the management of Parkinson’s disease are due
to carbidopa-induced RND. All of the reasons for which
carbidopa is added to L-dopa can be safely and easily managed with MTO.6
Attention-deficit hyperactivity
disorder RND
Double-blind, placebo-controlled studies of attention-deficit
hyperactivity disorder (ADHD) have revealed drug efficacy
(reuptake inhibitor and stimulant) greater than placebo in
14%–41% of patients studied.4
Drug treatment revolves around administration of reuptake
inhibitors, such as atomoxetine (a norepinephrine reuptake
inhibitor) and stimulants. The stimulants are divided into two
classes, ie, amphetamine and nonamphetamine. Both classes
have dopamine and norepinephrine reuptake properties, along
with the potential for neurotransmitter depletion.4 ADHD
patients are exposed to drug-induced RND:
• from reuptake inhibitors which deplete neurotransmitters
• from the amphetamines (neurotoxins) which cause brain
damage.
All of this is avoided with the amino acid administration
approach guided by MTO, because ADHD responds well to
this RND.4 A previous study indicated that pediatric ADHD
management with amino acid administration guided by MTO
which addressed the associated monoamine RND may be
more effective than methylphenidate and atomoxetine.4
Crohn’s disease RND
Crohn’s disease is a prototype for studying genetically
associated RND. There is a known genetic defect of OCTN1
and OCTN2 transporters in the proximal and distal colon of
patients suffering from Crohn’s disease. As with the OCT, the
OCTN is capable of transporting organic cations, including
serotonin, dopamine, and their precursors. In Crohn’s disease,
the serotonin content of the mucosa and submucosa of the
proximal and distal colon is significantly increased. The only
reasonable explanation, as verified by clinical response, is
that the OCTN1 and OCTN2 genetic deficits induce increased
synthesis and tissue levels of serotonin. Based on MTO
with Crohn’s patients, it appears that a severe imbalance
between high serotonin levels and RND-associated dopamine
transport, synthesis, and metabolism contributes significantly
to disease symptoms. The literature suggests that much of the
clinical constellation found with Crohn’s disease is induced
by serotonin toxicity in the colon exacerbated by dopaminerelated RND that exist simultaneously.3 Control of the disease
symptoms and resolution of all gut lesions has been shown to
occur with proper MTO-guided balanced amino acid dosing,
without the use of any drugs and in cases where conventional
drugs have had no positive effect.3
Other diseases
The rest of the diseases and regulatory functions listed
in Appendix A and Appendix B share the same basic
approach to diagnosis, etiology, and RND management.
If a monoamine-related RND is suspected where synaptic
monoamine levels are not high enough to compensate for
postsynaptic electrical defects, the amino acid dosing values
needed to correct the problem can be identified and achieved
with MTO.
Conclusion
The authors have published multiple papers relating to MTO.
In the course of further research and writing efforts, it was
realized that the most basic etiological factors relating to
monoamine disease had not been previously discussed, ie,
the presence of RND. The purpose of this paper is to clarify
how common an etiology RND is and why it needs to be
considered.
Neurotoxic, traumatic, biological, and genetic components that induce permanent brain damage are real. Without
an objective guidance tool such as MTO, specific problems
relating to the association of these RND with this damage
is not properly recognized or managed with either drugs or
amino acids. Most physicians do not recognize toxicity as
a cause of these diseases and few understand the existence
of the common RND-based etiology. The treatment of
symptoms with drugs, rather than addressing and resolving
underlying RND with nutrients, leads to gross failures during
management, prolonged unneeded disability, exacerbation
of the disease, and morbidity.
Many things are explained by becoming cognizant of
the role of chronic postsynaptic damage, as associated with
RND. In double-blind studies of the treatment of depression,
reuptake inhibitors are only 7%–13% more effective than
placebo. The monoamine RND model makes sense out of
that information. Reuptake inhibitors are only able to increase
transporter-driven synaptic monoamine levels minimally in
phase 0 which, in the longer term, may lead to monoamine
depletion after the response.
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Hinz et al
The RND models discussed in this paper have demonstrated
how the damage might be related to either dopamine, norepinephrine, or serotonin neurons, or a combination of
these. MTO defines the proper balance of amino acids in
order to establish adequate synaptic levels of monoamines
to compensate for postsynaptic damage and the electrical
deficit, while relieving the etiological RND. It is the goal of
this writing to stimulate interest and dialog based on these
novel observations. The ability to address the cause of a
problem with nutrients is more desirable than only treating
the symptoms with a drug.
Disclosure
References
1. Hinz M, Stein A, Uncini T. Discrediting the monoamine hypothesis. Int
J Gen Med. 2012;5:135–142.
3. Hinz M, Stein A, Uncini T. Amino acid-responsive Crohn’s disease:
disorder with monoamine amino acid precursors and organic cation transporter assay interpretation Neuropsychiatr Dis Treat. 2011;7:31–38.
5. Hinz M, Stein A, Uncini T. Urinary neurotransmitter testing: considerations
of spot baseline norepinephrine and epinephrine. Open Access Journal of
Urology. 2011;3:19–24.
disease: A case study. Int J Gen Med. 2011;4:1–10.
428
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8. Hinz M, Stein A, Uncini T. APRESS: apical regulatory super system,
serotonin, and dopamine interaction. Neuropsychiatr Dis Treat. 2011;
7:1–7.
Dis Treat. 2009;5:227–235.
urine: a comprehensive analysis. Open Access Journal of Urology.
2010;2:177–183.
Drug Healthc Patient Saf. 2011;3:69–77.
14. CMTA Charcot-Marie-Tooth Association [homepage on the Internet]. Glenolden, PA: Charcot-Marie-Tooth Association; 2006–2011.
Available from: http://www.cmtausa.org/index.php?option=com_con
tent&view=article&id=68&Itemid=42. Accessed February 12, 2012.
15. Andreas B, Ulrich K, Dagar M, et al. Human neurons express the
polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol.
1998;54:342–352.
16. Food and Nutrition Information Center [homepage on the Internet].
USDA National Agricultural Library; updated 2012. Available from:
http://fnic.nal.usda.gov/nal_display/index.php?info_center=4&tax_
level=1&tax_subject=620. Accessed February 12, 2012.
17. Wing-Kee L, Markus R, Bayram E, et. al. Organic cation transporters
OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital
dye ethidium in the kidney proximal tubule. Am J Physiol Renal Physiol.
2009;296:F1504–F1513.
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Appendix A
Partial listing of central nervous system
monoamine dysfunction-related diseases
Appendix B
Partial list of peripheral functions
regulated by serotonin and/or dopamine
Parkinson’s disease
Obesity
Bulimia
Anorexia
Depression
Anxiety
Panic attacks
Migraine headaches
Tension headaches
Premenstrual syndrome
Menopausal symptoms
Obsessive compulsive disorder
Obsessionality
Insomnia
Impulsivity
Aggression
Inappropriate aggression
Inappropriate anger
Psychotic illness
Fibromyalgia
Chronic fatigue syndrome
Adrenal fatigue/burnout
Hyperactivity
Attention-deficit hyperactivity disorder
Hormone dysfunction
Adrenal dysfunction
Dementia
Alzheimer’s disease
Traumatic brain injury
Phobias
Chronic pain
Nocturnal myoclonus
Irritable bowel syndrome
Crohn’s disease
Ulcerative colitis
Cognitive deterioration
Organ system dysfunction
Management of chronic stress
Cortisol dysfunction
Regulation of phosphate
Loss of serotonin transporters associated with irritable
bowel syndrome
Hyperammonemia
Hyperammonemia associated with retardation
Regulation alterations in diabetes
Regulation of renal function
Regulation of renal hemodynamics
Blood pressure regulation
Potassium regulation
Sodium regulation
ATP regulation
Regulation of receptors outside the central nervous system
including but not limited to:
• adrenal gland
• blood vessels
• carotid body
• intestines
• heart
• parathyroid gland
• kidney
• urinary tract
Regulation of renin secretion
Regulation by autocrine or paracrine fashion
Regulation in essential hypertension
Regulation of angiotensin II
Regulatory functions in shock
Regulatory functions in septic shock
Regulation of oxidative stress
Regulation of glomerular filtration
Regulation of functions that strengthen, examples include
but are not limited to:
• bone marrow
• spleen
• lymph nodes
Regulation of dopamine in bone marrow cells including
but not limited to:
• splenocytes
• lymphocytes from lymph nodes
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Hinz et al
Regulation of sympathetic nervous system
Regulation of platelet function
Regulation of function in prostate cancer
Regulation of syncope due to carotid sinus hypersensitivity
Regulation of dialysis hypotension
Regulation of cardiophysiological function
Regulation of adrenochromaffin cells
Regulation in hypoxia-induced pulmonary hypertension
Regulation in Tourette’s syndrome
Regulation of drug absorption and elimination
Regulation in pre-eclampsia
Regulation of fluid modulation and sodium intake via
actions including but not limited to:
• central nervous system
• gastrointestinal tract
Regulation of tubular epithelial transport
Regulation of modulation of the secretion and/or action
of vasopressin, which in turn causes changes in, but not
limited to:
• renin
• aldosterone
• norepinephrine
• epinephrine
• endothelin B receptors
Regulation of fluid and sodium intake by way of “appetite”
centers in the brain
Regulation in idiopathic hypertension
Regulation of alterations of gastrointestinal tract transport
Regulation of detoxification of exogenous organic cations
Regulation of prolactin secretion
Regulation affecting memory
Regulation of receptors in the central and peripheral
system
Regulation of fluid and electrolyte balance including but
not limited to:
• blood vessels
• gastrointestinal tract
• adrenal glands
• sympathetic nervous system
• hypothalamus
• other brain centers
Regulation of phosphorylation of DARPP-32
Regulation of dependent effects of psychostimulants and
opioids
Regulation of neuronal differentiation
Regulation of neurotoxicity
Regulation of transcription
Regulatory effects on fibroblasts
Regulation of melatonin synthesis in photoreceptors
Cyclic regulation of intraocular pressure
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Return to index
R e v ie w
5-HTP efficacy and contraindications This article was published in the following Dove Press journal:
18 July 2012
Marty Hinz 1
Alvin Stein 2
Thomas Uncini 3
Clinics, Inc, Cape Coral, 2Stein
FL, USA; 3University Medical Center
Mesabi Hibbing,
MN, USA
1
Abstract: L-5-hydroxytryptophan (5-HTP) is the immediate precursor of serotonin. It is readily
synthesized into serotonin without biochemical feedback. This nutrient has a large and strong
following who advocate exaggerated and inaccurate claims relating to its effectiveness in the
treatment of depression and a number of other serotonin-related diseases. These assertions are
not supported by the science. Under close examination, 5-HTP may be contraindicated for
depression in some of the very patients for whom promoters of 5-HTP advocate its use.
Keywords: 5-HTP, 5-hydroxytryptophan, L-5-HTP, L-5-hydroxytryptophan
Introduction
In the United States, the nutritional supplement 5-hydroxytryptophan (5-HTP) became
available over the counter in April of 1995.1 Previously, it was only available by
prescription. Its intuitively seductive appeal has encouraged its increasing use while
disregarding the actual science which stands in sharp contrast to the general perceptions
of the public and many physicians.2–15
The argument for using 5-HTP
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
Dovepress
http://dx.doi.org/10.2147/NDT.S33259
When placed in the proper context, the following basic chemical properties2–15 explain
the failure of 5-HTP to achieve consistent results. The following scientific facts are
generally accepted without dispute:
• In central nervous system disease states associated with synaptic serotonin dysfunction, synaptic serotonin levels in the brain must be increased to induce optimal
outcomes.
• Serotonin does not cross the blood–brain barrier.
• 5-HTP freely crosses the blood–brain barrier.
• 5-HTP is freely converted to serotonin without biochemical feedback inhibition.
• When infinitely high amounts of 5-HTP are administered, it is theoretically possible
to achieve infinitely high levels of serotonin. One limiting factor is the availability
of the enzyme L-aromatic amino acid decarboxylase (AAAD), which freely catalyzes the conversion of 5-HTP to serotonin.
The basic facts listed above form the basis of a very appealing and vehemently
defended scenario, “5-HTP is all that is needed when levels of serotonin need to be
increased effectively and safely.” Inadequate levels of serotonin in the brain have been
associated with numerous disease states and here is a nutrient that can theoretically
raise serotonin levels as high as needed.16–18
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Hinz et al
Short-term efficacy of 5-HTP alone
Generally, efficacy studies related to 5-HTP fall into one
of two categories: open (nonblinded) and double-blind,
placebo-controlled studies. One naturopathic physician, who
is considered by some to be a 5-HTP expert,17 interprets the
results from an open study on his web site as follows:18 He
reported one of his more impressive studies that involved
99 patients who were described as suffering from therapy
resistant depression. These patients had not responded to any
previous therapy including all available antidepressant drugs
as well as electro convulsive therapy. Specifically reported
was, “These therapy resistant patients received 5-HTP at dosages averaging 200 mg daily but ranging from 50 to 600 mg
per day. Complete recovery was seen in 43 of the 99.”18
There are two points that require further discussion. First,
the naturopath claims that only 5-HTP was administered to
patients in the study.18 A review of the entire study revealed that
a combination of 5-HTP with carbidopa was administered.19
Carbidopa is a general decarboxylase inhibitor that inhibits
peripheral synthesis of the centrally acting monoamines
(serotonin, dopamine, norepinephrine, and epinephrine).
It affects the response to 5-HTP dosing values by significantly
increasing the availability of 5-HTP in the central nervous
system.10 A comprehensive literature search of the use of
5-HTP for treating depression revealed that administration of 5-HTP alone is not very effective. To compensate for this efficacy problem, 5-HTP is often used in
combination with other drugs and/or substances. There
are more published studies examining the use of 5-HTP
in combination with another substance than the use of
5-HTP alone.
Second, according to the naturopath’s web site, 43 of
99 (43.4%) subjects taking 5-HTP and carbidopa achieved
relief of depression.18 The web site notes that “such significant
improvement in patients suffering from long-standing, unresponsive depression is quite impressive…”18 This illustrates
a second flaw: this magnitude of improvement is no greater
than that of a placebo.
Double-blind, placebo-controlled studies of depression
have consistently revealed that the placebo effect after
30 days of depression treatment ranges from 30%–45%.13
It is inaccurate to describe the referenced study as “One
of the more impressive studies…” 18 when the efficacy
rate was only 43.4%. This statement reveals a lack of
understanding of the complex and large impact the
placebo effect has in treating patients with depression.13
A review of peer-reviewed studies does not support the
effectiveness of 5-HTP as follows:
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1. “Trials performed do not provide evidence for an
antidepressant effect of 5-HTP.”20
2. 2009 meta-analysis of 111 (one hundred eleven) 5-HTP /
depression studies concluded, “Further studies are needed
to evaluate the efficacy and safety of 5-HTP and tryptophan
before their widespread use can be recommended.”21
3. “While there is evidence that precursor loading may be of
therapeutic value, particularly for the serotonin precursors
5-HTP and tryptophan, more studies of suitable design
and size might lead to more conclusive results.”22
4. “The immediate serotonin precursor, 5-HTP, has been
given to depressed patients either alone or in combination
with a MAO inhibitor. The results are conflicting and,
in the main, do not provide convincing evidence for an
antidepressant effect for 5-HTP.”23
While there are some published pilot studies relating
to small groups of subjects, the majority of these smaller
studies conclude by noting that more studies are needed.
The peer-reviewed literature supports the assertion that use
of 5-HTP alone in the management of depression is associated with efficacy no greater than placebo and that its use is
controversial.19–23
While those strongly advocating the use of 5-HTP alone
believe that depression is due to serotonin dysfunction,
depression may also be associated with catecholamine dysfunction, including dopamine and/or norepinephrine, or a
combination of serotonin and catecholamine dysfunction.24,25
Administration of 5-HTP alone facilitates depletion of dopamine, norepinephrine, and epinephrine (see Discussion).
When catecholamine neurotransmitter levels influence
depression, administration of 5-HTP alone is contraindicated since it may deplete dopamine and norepinephrine,
thereby worsening the disease and its underlying cause. This
contraindication is not exclusive to depression, but extends
to all other disease processes for which dysfunction of a
catecholamine component has been implicated, including
attention-deficit hyperactivity disorder (ADHD),26 seasonal
affective disorder,27 obesity,28 generalized anxiety disorder,25
and Parkinson’s disease.29
5-HTP alone contraindicated
for long-term use
The most significant side effects and adverse reactions
may occur with long-term use (many months or longer).
Administration of 5-HTP alone depletes catecholamines
(dopamine, norepinephrine, and epinephrine).12,15 When
dopamine depletion is great enough, 5-HTP will no longer
function.15 If other centrally acting monoamine-related
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disease processes involving catecholamines are present,
administration of 5-HTP alone may deplete dopamine,
norepinephrine and epinephrine thereby exacerbating these
conditions.15
Based on monoamine transporter optimization (MTO)
studies, managing depression and other centrally acting
monoamine-related diseases requires a combination of
properly balanced dopamine and serotonin amino acid
precursors.2–15
Synthesis of serotonin from 5-HTP and dopamine from
l-dopa is catalyzed by the same enzyme, L-aromatic amino
acid decarboxylase (AAAD). Dopamine and serotonin amino
acid precursor administration must be in proper balance. If
only 5-HTP or 5-HTP that dominates dopamine at the enzyme
is administered, it will block dopamine synthesis at the AAAD
enzyme through competitive inhibition, leading to depletion
of dopamine and the rest of the catecholamines.6,9,12,15,30
Metabolism of serotonin and dopamine is catalyzed by
monoamine oxidase (MAO). The activity level of MAO is not
static. With increasing doses of 5-HTP, which lead to increased
serotonin levels, MAO activity increases. Without a properly
balanced increase in dopamine there will be increased metabolism of dopamine leading to depletion.1,3,4,6,9,12,15
The synthesis, metabolism, and transport of serotonin
and dopamine, along with their amino acid precursors, are
primarily controlled by the functional status of transport,
which is carried out by organic cation transporters (OCT).
Serotonin, dopamine, and their amino acid precursors
must be transported by OCT across cell walls. Transport
dominates, controls and regulates synthesis and metabolism.
Administration of 5-HTP alone leads to increased unbalanced
transport of serotonin. Competitive inhibition at the transporters will inhibit movement of dopamine and its precursors into
areas that affect synthesis and metabolism, compromising
and depleting dopamine (catecholamine) levels. Long-term
administration of 5-HTP alone, or in an unbalanced manner,
facilitates depletion of catecholamines, negatively affecting
neurotransmitter-related disease processes.3–15,31
Use of 5-HTP with a general
decarboxylase inhibitor
A literature review revealed that more studies have been
reported using 5-HTP in combination with another substance
than using 5-HTP alone due to the lack of efficacy of 5-HTP
alone. One combination examined includes the use of 5-HTP
with carbidopa. Carbidopa inhibits peripheral conversion of
5-HTP to serotonin and l-dopa to dopamine.32 Carbidopa
was originally used in combination with l-dopa to control
5-HTP efficacy and contraindications
symptoms associated with serotonin and dopamine imbalance
that occur when only l-dopa was administered to manage
Parkinson’s disease. The following problems have been
reported with use of carbidopa to treat Parkinson’s disease.10
• “Most of the side effects observed in the management
of Parkinson’s disease with the combination l-dopa and
carbidopa are attributed to the carbidopa.”10,15
• “Due to the lack of specificity of l-aromatic amino acid
decarboxylase, 5-HTP administration results in 5-HT
(serotonin) production in dopaminergic as well as in
serotonergic neurons.”23
Additionally, a previous study reported that in animals
5-HTP caused increased turnover of both dopamine and
norepinephrine. They hypothesized that 5-HTP is taken up
by catecholaminergic neurons, transformed into 5-HT that,
in turn, could act as a false transmitter, possibly increasing the turnover of catecholamines. “The net functional
result of the two opposite processes, ie, formation of a false
transmitter and increased synthesis of catecholamines, is
unknown. In other words, it is unknown whether 5-HTP augments or reduces catecholaminergic neuronal functions.”26
Monoamine depletion
by amino acid precursors
Serotonin and dopamine systems exist in two distinctly
different and separate states. The endogenous state occurs
when no supplemental amino acid precursors (Figure 1) are
administered. The competitive inhibition state occurs when
at least one serotonin and one dopamine amino acid precursor (Figure 1) are administered simultaneously. Competitive
inhibition states have been described for many years, but
until the publication of MTO technology, this competitive
inhibition was considered to be “probably meaningless.”12,14,30
Competitive inhibition occurs during the balanced and unbalanced state. In the unbalanced state, amino acid precursors
of serotonin or dopamine dominate the opposite system in
synthesis, metabolism, and transport, leading to depletion of
nondominant monoamine neurotransmitters (Figure 2).3,6–15
Numerous studies published since 2009 document the
need to administer serotonin amino acid precursors simultaneously in proper balance with dopamine precursors in order
to prevent depletion (Figures 1 and 2).2–15
Amino acids
L-tryptophan
5-HTP
Serotonin
L-tyrosine
L-dopa
Dopamine
Norepinephrine
Epinephrine
Figure 1 Synthesis pathway of serotonin and catecholamines.
Abbreviation: 5-HTP, 5-hydroxytryptophan.
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Hinz et al
L-tryptophan
Depletes
L-tyrosine
Dopamine
Serotonin
Sulfur amino acids
Depletes
Depletes
Depletes
Depletes
5-HTP
L-dopa
Depletes
Figure 2 When an amino acid precursor of serotonin or dopamine is administered
alone or in a manner that dominates the synthesis, metabolism, and/or transport of
the other system, depletion may occur.12–15
Abbreviation: 5-HTP, 5-hydroxytryptophan.
Specific examples of a dominant monoamine depleting
a nondominant monoamine and/or amino acid precursor are
listed here and illustrated in Figure 2.
• 5-HTP may deplete dopamine.33–37
• l-tryptophan may deplete dopamine.35
• l-dopa may deplete serotonin.2–15,38–42
• l-dopa may deplete l-tryptophan.42
• l-dopa may deplete l-tyrosine.42
• l-dopa may deplete sulfur amino acids.4,6,43–45
• l-tyrosine may deplete serotonin.46,47
• l-tyrosine may deplete 5-HTP.47
• l-tyrosine may deplete sulfur amino acids.4,6,43–45
• Sulfur amino acids may deplete dopamine.48
• Sulfur amino acids may deplete serotonin.49
Effects of 5-HTP when administered
in an unbalanced manner
Amino acid precursors of serotonin and dopamine in the
competitive inhibition state are intertwined during synthesis,
metabolism, and transport to the point that they function as
one system. This is a deep-seated interaction as discussed
in the novel concept of apical regulatory super system
(APRESS), published in 2011. The paper discusses how
the serotonin and dopamine systems, when properly balanced in the competitive inhibition state, function as one
system. In this state, functions regulated only by serotonin
in the endogenous state can be regulated by manipulating
dopamine levels, and functions regulated only by dopamine
in the endogenous state can be regulated by manipulating
serotonin.12
Improperly balanced administration of serotonin and
dopamine precursors (Figures 1 and 2) leads to decreased
efficacy and increased incidence of side effects. Most importantly, if only one precursor of the serotonin and dopamine
system is administered or it is administered in a manner that
dominates the other system (either serotonin or dopamine)
in synthesis, metabolism and transport, neurotransmitter
depletion of the dominated system will occur. When this
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depletion of the nondominant system is great enough,
any effects observed with administration of the single or
dominant amino acid will no longer be observed. An amino
acid precursor no longer functioning can be observed in the
management of Parkinson’s disease in which the effects of
l-dopa are no longer observed over time due to serotonin
depletion.7–15
A study involving properly balanced serotonin and dopamine amino acid precursor dosing values guided by MTO
published in 2009 and 2010 documents that administration
of properly balanced serotonin and dopamine precursors
is not only highly effective for managing depression, but
can also be used to differentiate bipolar depression cycling
heavily on the depressive pole from unipolar depression
(major affective disorder).2,6 Proper balancing of serotonin
and dopamine amino acid precursors, which can only be
optimized using MTO, is critical.2–15
Administration of 5-HTP
in a properly balanced manner
To achieve optimal efficacy, minimal side effects, and prevent
depletion of other amino acids and neurotransmitters, 5-HTP
must be administered in proper balance with dopamine
amino acid precursors along with proper levels of sulfur
amino acids.
Synthesis and metabolism are controlled by transporter
function. Transporters move serotonin, dopamine and their
amino acid precursors into and out of cells to sites where
synthesis and metabolism occur. Most important is the
transporter’s ability to establish specific levels of serotonin
and dopamine in numerous locations, including the synapses
between pre- and post-synaptic neurons.12,15,31
MTO is an in situ method for determining the functional
status of OCT responsible for establishing serotonin and dopamine levels throughout the body. Optimization requires establishing serotonin in the Phase 3 optimal range while dopamine
is in its Phase 3 optimal range. The Phase 3 optimal ranges of
serotonin and dopamine are independent of one another. When
both serotonin and dopamine are in their respective phase 3
optimal ranges, optimization has occurred.5,7,10,11,13,15
Optimal group results cannot be obtained without
MTO. The following are group effective therapeutic ranges
defined by MTO during simultaneous administration of
serotonin and dopamine precursors:
• 5-HTP daily dosing values . 0 to 2,400 mg per day.14,15
• l-tyrosine daily dosing values . 0 to 14,000 mg per
day.14,15
• l-dopa daily dosing values . 0 to 2,100 mg per day.14,15
Dovepress
The effective therapeutic ranges listed above are independent of each other. For example, in one patient, a daily
5-HTP dosing value of 2,400 mg per day with an l-dopa
dosing value of 30 mg per day may be required for proper
balance of transport to place both serotonin and dopamine in
their respective Phase 3 optimal ranges. Another patient may
require 25 mg per day of 5-HTP with 2,100 mg of l-dopa for
Phase 3 optimization. Dosing values required for transporter
optimization are highly individualized.15
To understand the extreme variability in the dosing levels
of 5-HTP and the other amino acid precursors, it is important
to understand why these transporters react so differently
from one individual to the next. Neurotransmitters facilitate the flow of electric signals across the synapse between
the pre- and post-synaptic neurons. When a change in the
overall flow of electricity across the synapse is needed, a
signal is sent throughout the body that encodes the identical
transporters to regulate and control neurotransmitter flow
in the specific manner required to optimize this flow. When
permanent damage from neurotoxins, trauma, biologicals,
and/or genetic predisposition occurs to postsynaptic neurons,
the electrical flow that regulates function is compromised.
This process may damage areas regulating affect and mood,
leading to depression. With this sequence of circumstances,
a signal goes out encoding the OCT2 to increase or decrease
synaptic levels of serotonin and/or dopamine in order to
compensate for the electrical deficit being experienced across
the synapse.2,13–15,31
Since serotonin and dopamine do not cross the blood–brain
barrier, the total number of serotonin and dopamine molecules
present in the brain is a function of the amount of nutrients
(amino acid precursors) available to be synthesized into new
neurotransmitter molecules. If the amount of neurotransmitter
molecules is low or inadequate, a relative nutritional deficiency exists. Inadequate monoamine levels can only be
elevated to levels required for optimal transporter function
through administration of supplemental nutrient precursors
guided by “Monoamine transporter optimization” (MTO).15
Optimal efficacy and minimized side effects are not a
function of achieving sufficiently high amino acid dosing
levels; they are a function of achieving a proper balance
between serotonin and dopamine.2–15
Conclusion
5-HTP in the treatment of depression has languished for
years. Intuitively, the potential is extraordinary, but from
a practical level efficacy is no better than placebo. In
review of the science, effective integration of 5-HTP into
5-HTP efficacy and contraindications
a patient management plan is much more complicated than
simply giving some 5-HTP in order to have more serotonin
throughout the system.
Administration of 5-HTP alone is contraindicated for
depression and any process involving a catecholamine
component due to its ability to facilitate depletion of these
neurotransmitters. 5-HTP should be administered carefully in
patients because depletion of dopamine and norepinephrine
may exacerbate existing disease processes or precipitate
onset of catecholamine-related problems.
Administering serotonin or dopamine amino acid
precursors should never involve administration of only one
amino acid. Improperly balanced amino acid precursors are
associated with decreased efficacy, increased side effects,
and depletion of the nondominant system.
Disclosure
MH discloses his ownership of DBS Labs. TU discloses his
medical directorship of DBS Labs. AS has no disclosures
to reveal.
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Clinical Pharmacology: Advances and Applications
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Return to index
Review
Administration of supplemental L-tyrosine
with phenelzine: a clinical literature review
22 July 2014
Marty Hinz 1
Alvin Stein 2
Ted Cole 3
Patricia Ryan 4
2
Plantation, FL, USA; 3Cole Center for
Healing, Cincinnati, OH, USA; 4Family
Wellness Center, Omaha, NE, USA
1
Abstract: The subject of this literature review is the alleged relationship between L-tyrosine,
phenelzine, and hypertensive crisis. Phenelzine (Nardil®) prescribing information notes:
“The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated
with NARDIL should not take […] L-tyrosine […]”. Interest in the scientific foundation of
this claim was generated during routine patient care. A comprehensive literature search of
Google Scholar and PubMed revealed no reported cases of hypertensive crisis associated with
concomitant administration of L-tyrosine and phenelzine. Review of current US Food and
Drug Administration nutritional guidelines relating to ongoing phenelzine studies reveals no
mention and requires no consideration of L-tyrosine ingestion in combination with phenelzine.
This paper is intended to provide an objective review of the science to then allow the reader
to formulate the final opinion.
Keywords: hypertensive crisis, phenelzine, tyrosine, tyramine, stroke, phenelzine
Introduction
L-Tyrosine
L-Tyrosine is a normal component of protein foods. It is a neutral amino acid and the
precursor of the catecholamines dopamine, norepinephrine, and epinephrine. “Animal
studies indicate that systemic administration of tyrosine in pharmacological quantities can reduce physiological and behavioral decrements induced by highly stressful
conditions.”1
Phenelzine
NeuroResearch Clinic, Inc.,
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
Nardil® (phenelzine) (Pfizer, Inc., New York, NY, USA) is a potent inhibitor of monoamine oxidase (MAO). Phenelzine sulfate is a hydrazine derivative. It has a molecular
weight of 234.27 and is chemically described as C8H12N2 · H2SO4.
Phenelzine prescribing information specifically notes: “The potentiation of
sympathomimetic substances and related compounds by MAO inhibitors may
result in hypertensive crises (see WARNINGS). Therefore, patients being treated
with NARDIL should not take sympathomimetic drugs […] or related compounds (including methyldopa, L-dopa, L-tryptophan, L-tyrosine, and phenylalanine).”2 In humans, L-tyrosine is metabolized to tyramine, L-dopa, dopaquinone, and
3-iodo-L-tyrosine. The literature is clear that the problem of phenelzine-associated
hypertension is due to concomitant administration with tyramine (not tyrosine).3
107
Clinical Pharmacology: Advances and Applications 2014:6 107–110
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© 2014 Hinz et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on
how to request permission may be found at: http://www.dovepress.com/permissions.php
http://dx.doi.org/10.2147/CPAA.S67271
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Hinz et al
Results
No cases of L-tyrosine-induced
hypertensive crisis have been
documented
A comprehensive literature search of Google Scholar and
PubMed revealed that the first phenelzine studies were published in 1959.4 There have been no documented cases of
L-tyrosine-associated hypertensive crisis. Conversely, several
articles were found illustrating that when normal blood pressure exists or the subject is hypertensive, L-tyrosine lowers
blood pressure.4–12 The assertion that ingestion of L-tyrosine
with phenelzine induces hypertensive crisis is without scientific literature verification.
When Google Scholar was searched for articles containing the exact phrase “L-tyrosine induced hypertensive crisis”,
no articles were found; however, the exact phrase “tyramine
induced hypertensive crisis” identified 50 articles. PubMed
is the recognized “gold standard” for peer-reviewed scientific publication certification. A search there using the query
“L-tyrosine, phenelzine, hypertensive crisis” failed to reveal
any peer-reviewed literature.
Avoidance of all L-tyrosine is not possible
Phenelzine prescribing information advises against tyrosine
ingestion. It makes no recommendations regarding the level
of L-tyrosine restriction. The only specific food restriction
guidelines are for foods high in tyramine.2
With L-tyrosine found in virtually all protein foods,
the prescribing information poses a confounding problem.
The United States Department of Agriculture (USDA)
nutrient database lists 4,889 foods that contain L-tyrosine.
There are 1,962 foods listed that have over 500 mg of
L-tyrosine per serving. In reviewing the USDA recommendation, the established serving sizes are small. For example, the
serving size for fish or beef is 3 oz, which typically contains
between 600 mg and 900 mg of L-tyrosine. Most patients eat
more than 3 oz of these proteins as a serving. The average
meal contains more than 1,500 mg of L-tyrosine.13
Complying with the phenelzine prescribing information would induce a significant nutritional deficiency by
completely eliminating all tyrosine-containing protein
foods.
It is impossible for any human to comply with the
phenelzine prescribing information and avoid all L-dopa,
L-tryptophan, L-tyrosine, and phenylalanine. Completely
eliminating these four amino acids from the human diet
would leave no protein-containing food to consume and
would induce a significant nutritional deficiency.
108
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Phenelzine tyrosine safety record
Drug safety is not established by double-blind, placebocontrolled studies. The most reliable safety (side effect)
data are collected over time through prescribing to large
populations. The earliest peer-reviewed literature located
discussing phenelzine, by Saunders et al,4 was published on
1 July 1959. Phenelzine has been prescribed for 55 years.
There are no documented cases of hypertensive crisis being
induced by concomitant administration of L-tyrosine and
phenelzine. Until the first case is documented in the literature,
there is no scientific basis for asserting in the prescribing
information that concomitant administration of L-tyrosine
and phenelzine may be a problem.
It appears that the warning regarding L-tyrosine found in
the phenelzine prescribing information may have been placed
there for a reason other than one that is found in the known
scientific literature. When a significant interaction between
two administered substances occurs, both substances are
required to carry a warning. The US Food and Drug Administration (FDA) considers L-tyrosine ingestion so safe that it
does not require it to carry a warning regarding concomitant
ingestion with phenelzine. This raises the question of why
phenelzine has a tyrosine warning when tyrosine is not
required to carry a phenelzine warning.
Current FDA guidelines
Phenelzine is the subject of ongoing clinical studies under the
FDA guidelines. In 2011 the FDA defined the current protocols for ongoing phenelzine drug studies, which address only
foods containing tyramine. The FDA places no restriction on
L-tyrosine intake in subjects involved in current phenelzine
(Nardil) studies. There appears to be a divergence between
the phenelzine prescribing information, which originated
in the 1950s, and current phenelzine study guidelines. The
updated study guidelines have not been reflected in the
current prescribing information.14
Author experience
The two primary authors of this paper have a database
c ontaining over 3 million patient-days of experience
administering L-tyrosine with virtually all prescription drugs.
The authors possess L-tyrosine treatment data from over
1,400 medical practices from primarily the US and Canada,
as well as many other countries around the world. Administration of MAO inhibitors is uncommon with the exception of
southern California. Total phenelzine with L-tyrosine medical
record data on file are approximately 43,532 patient-days.
This database was started in 1999, and up to the time of this
Clinical Pharmacology: Advances and Applications 2014:6
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writing no concerns have been raised regarding concomitant
administration of L-tyrosine with phenelzine.15–29
The primary cause of phenelzineassociated hypertensive crisis
The literature notes numerous documented cases of
phenelzine-associated hypertensive crisis. The primary etiology of these events is patient noncompliance with restriction of high-tyramine foods.30–32 If a patient experiences a
hypertensive crisis while taking phenelzine, the prescribing
information offers a protocol to follow. “NARDIL should
be discontinued immediately and therapy to lower blood
pressure should be instituted immediately”.2 In a significant
number of hypertensive crisis episodes the patient has been
noncompliant with the following required restrictions.2
Phenelzine prescribing information notes:
Hypertensive crises during NARDIL therapy may also be
caused by the ingestion of foods with a high concentration of
tyramine or dopamine. Therefore, patients being treated with
NARDIL should avoid high protein food that has undergone
protein breakdown by aging, fermentation, pickling, smoking,
or bacterial contamination. Patients should also avoid cheeses
(especially aged varieties), pickled herring, beer, wine, liver,
yeast extract (including brewer’s yeast in large quantities), dry
sausage (including Genoa salami, hard salami, pepperoni,
and Lebanon bologna), pods of broad beans (fava beans),
and yogurt. Excessive amounts of caffeine and chocolate
may also cause hypertensive reactions.2
The phenelzine prescribing information takes a position
with regard to L-dopa, L-tryptophan, and L-tyrosine and
phenylalanine. The formal recommendation found in the
prescribing information regarding these four amino acids is
“[…] should not take [...]”.2 Regarding tyramine ingestion,
for which there is ample scientific literature supporting the
position that ingestion with phenelzine is a problem, a less
restrictive warning is noted; “Hypertensive crises during
NARDIL therapy may also be caused by the ingestion of
foods with a high concentration of tyramine or dopamine.
Therefore, patients being treated with NARDIL should
avoid high protein food […]”.2 The warning for tyramine
appears to be less stringent, despite the fact that according
to the literature it is the primary amino acid known to induce
hypertensive crisis when ingested with phenelzine.
Conclusion
Physicians are trained to treat patients in accordance with
known science. Intuitively, it may seem that the proper thing
Administration of supplemental L-tyrosine with phenelzine
to do is place the patient on an L-tyrosine-free diet while
administering phenelzine as suggested by the prescribing
information. A diet truly free of L-dopa, L-tryptophan, and
L-tyrosine and phenylalanine in accordance with phenelzine
prescribing information raises concerns relating to nutritional
deficiency, a problem that is well documented in the literature.
With 55 years of prescribing experience there are no reported
cases in the formal scientific literature of L-tyrosine administration with a MAO inhibitor inducing hypertensive crisis.
On the contrary, numerous articles exist demonstrating how
L-tyrosine actually lowers blood pressure. Although phenelzine prescribing information published years ago asserts that
concomitant administration of L-tyrosine with phenelzine is
a problem, recent FDA guidelines on phenelzine studies no
longer mention or require L-tyrosine considerations to be
made when prescribing phenelzine.
The real problem is not the amino acids; it is the drug side
effects that may be enhanced with amino acid administration.
If the drug were not prescribed, this paper would not have
been written.
This article is intended to serve as a literature review,
a foundation for opinion formulation, and a reference for
future discussion regarding L-tyrosine, phenelzine, and
hypertensive crisis.
Disclosure
MH discloses his relationship with DBS Labs, Inc., and
NeuroResearch Clinics, Inc. The other authors report no
conflicts of interest in this work.
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Clinical Pharmacology: Advances and Applications is an international,
peer-reviewed, open access journal publishing original research, reports,
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Original Research
Management of L-dopa overdose
in the competitive inhibition state
22 July 2014
Marty Hinz 1
Alvin Stein 2
Ted Cole 3
2
Plantation, FL, USA; 3Cole Center for
Healing, Cincinnati, OH, USA
1
Abstract: The amino acid L-3,4-dihydroxyphenylalanine (L-dopa) is prescribed for conditions
where increased central and/or peripheral dopamine synthesis is desired. Its administration can
establish dopamine concentrations higher than can be achieved from an optimal diet. Specific
indications include Parkinson’s disease and restless leg syndrome. The interaction between
serotonin and dopamine exists in one of two distinctly different physiologic states: the endo
genous state or the competitive inhibition state. Management with L-dopa in the competitive
inhibition state is the focus of this paper. In the past, control of the competitive inhibition state
was thought to be so difficult and complex that it was described in the literature as functionally
“meaningless”. When administering L-dopa without simultaneous administration of serotonin
precursors, the patient is in the endogenous state. Experience gained with patient outcomes
during endogenous L-dopa administration does not allow predictability of L-dopa outcomes in
the competitive inhibition state. The endogenous approach typically increases the daily L-dopa
dosing value in a linear fashion until symptoms of Parkinson’s disease are under control. It is
the novel observations made during treatment with the competitive inhibition state approach
that L-dopa dosing values above or below the optimal therapeutic range are generally associated
with the presence of the exact same Parkinson’s disease symptoms with identical intensity. This
recognition requires a novel approach to optimization of daily L-dopa dosing values from that
used in the endogenous state. This paper outlines that novel approach through utilization of a
pill stop. This approach enhances patient safety through its ability to prevent L-dopa overdose,
while assisting in the establishment of the optimal therapeutic L-dopa daily dosing value.
Keywords: L-3,4-dihydroxyphenylalanine, L-dopa, levodopa, Parkinson’s disease
Introduction
NeuroResearch Clinics, Inc., 1008
Dolphin Dr, Cape Coral,
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
5-hydroxytryptophan (5-HTP) is a metabolite of L-tryptophan and the immediate
precursor of serotonin. L-3,4-dihydroxyphenylalanine (L-dopa) is a metabolite of
L-tyrosine and the immediate precursor of dopamine. Dopamine does not cross the
blood–brain barrier.1 L-dopa freely crosses the blood–brain barrier, then is synthesized
into dopamine without biochemical feedback inhibition.2 Greater amounts of L-dopa
need to be administered if increased synthesis of dopamine in the central nervous
system is required.3–12 L-tyrosine does not have this ability, due to norepinephrine
biochemical feedback inhibition of tyrosine hydroxylase.
To understand the discussions contained herein, the concepts of the endogenous
state and competitive inhibition state need to be defined.1,12–20
Humans taking no supplemental serotonin or dopamine amino acid precursors
are in the endogenous state. The endogenous state also exists when L-dopa or 5-HTP
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http://dx.doi.org/10.2147/DHPS.S67328
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Hinz et al
is administered without adequate amounts of serotonin or
dopamine precursors, respectively. The amino acid intermediates 5-HTP and L-dopa do not occur in the normal
diet in amounts sufficient to produce a significant metabolic
effect. The competitive inhibition state does not occur with
normal or optimal food intake due to biochemical feedback
inhibition of L-tyrosine and L-tryptophan. Their respective
conversion to L-dopa and 5-HTP in a normal or optimal
diet are inadequate to establish competitive inhibition. This
limits the amount of dopamine and serotonin synthesized
to levels less than are required to place the system into the
competitive inhibition state.12–20 When daily dopamine and
dopamine amino acid requirements are higher than can be
achieved in a normal or optimal diet, the state is known as a
relative nutritional deficiency.12
The concept of competitive inhibition between serotonin
and dopamine is well known to science. Competitive inhibition is the interaction of serotonin and dopamine that may
occur in synthesis, transport, and metabolism only when
adequate and properly balanced amounts of serotonin and dopamine amino acid precursors are administered simultaneously.
Full optimization of the competitive inhibition state
requires simultaneous administration of properly balanced
5-HTP, L-dopa, L-tyrosine, a thiol (L-cysteine, glutathione,
S-adenosylmethionine, or L-methionine), and cofactors
(vitamin C, pyridoxal phosphate, or calcium carbonate). To
date, the only published methodology for optimization of the
competitive inhibition state is Organic Cation Transporter
Type 2 (OCT2) functional status determination.12–20
The focus of this paper is not L-dopa efficacy, which
has been firmly established by numerous past studies; this
paper focuses on management of L-dopa dosing utilizing a
novel technique that identifies overdose in the competitive
inhibition state relative to optimal daily dosing, and assists
in identifying the optimal dosing range.
Administration of L-dopa in Parkinson’s disease has
been studied since the early 1960s.21 Since then, numerous
side effects and adverse reactions have been documented.2,12
Most agree with the Mayo Clinic’s observations that L-dopa
is the most effective Parkinson’s disease treatment available.22
Typically, other less effective drugs are used to control symptoms as long as possible prior to prescribing L-dopa. This
delays the inevitable onset of progressive side effects and
adverse reactions associated with concomitant administration
of L-dopa and carbidopa (or benserazide).21
Past research documented the use of general decarboxylase inhibitors such as carbidopa and benserazide for the
management of L-dopa-induced nausea.23,24 These drugs have
no direct benefit in the management of Parkinson’s disease
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symptoms. The primary reason for administering carbidopa
or benserazide is to decrease daily L-dopa dosing requirement, thereby decreasing L-dopa-induced nausea. During
L-dopa monotherapy (administration without a decarboxylase inhibitor), these side effects may prevent the patient from
ingesting enough L-dopa to control symptoms.2
The enzyme L-aromatic amino acid decarboxylase
(AAAD) catalyzes synthesis of serotonin and dopamine
from 5-HTP and L-dopa, respectively. Through competitive
inhibition of AAAD, carbidopa or benserazide compromises
peripheral synthesis of serotonin and dopamine. This druginduced inhibition of peripheral AAAD–L-dopa metabolism
leaves more L-dopa unmetabolized and available to freely
cross the blood–brain barrier into the central nervous system.
As a result, when carbidopa or benserazide is administered,
lower L-dopa daily intake values are required to achieve the
same central nervous system results.2
Carbidopa and benserazide also inhibit peripheral metabolism of 5-HTP to serotonin and can cause a drug-induced
depletion of peripheral serotonin. Dopamine is metabolized
to norepinephrine, which, in turn, is metabolized to epinephrine. The inhibition of dopamine synthesis may also deplete
norepinephrine and epinephrine. Physicians may fail to
recognize the signs, symptoms, adverse reactions, and side
effects that result from this drug-induced peripheral depletion
of serotonin, dopamine, norepinephrine, and/or epinephrine
by carbidopa. It is known that inhibition of AAAD with drugs
may induce life-threatening side effects, including myocardial
infarction, neuroleptic malignant syndrome, agranulocytosis,
hemolytic and nonhemolytic anemia, gastrointestinal bleeding, thrombocytopenia, and hypokalemia (Table 1).2,12
Hinz et al2,12 previously published papers demonstrating
that L-dopa-induced nausea can be nutritionally managed
by addressing serotonin and dopamine imbalance. Proper
administration of 5-HTP with L-dopa effectively controls
nausea, eliminates the need for carbidopa, and, as they are no
longer required, removes the signs, symptoms, side effects, or
adverse reactions associated with carbidopa or benserazide
in virtually all patients. With the removal of carbidopa, the
risks and problems associated with peripheral depletion of
the centrally acting monoamines are eliminated, which is a
great safety advantage.
L-dopa is an amino acid that may be classified by the
US Food and Drug Administration (FDA) as a drug, a medical food, or a nutritional supplement, depending upon the
application. As a nutritional supplement, L-dopa is classified
by the FDA as Generally Recognized As Safe (GRAS), with
a side effect profile safe enough to allow for over-the-counter
sales. The combination of L-dopa with carbidopa is only
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Management of L-dopa overdose in the competitive inhibition state
Table 1 Previously published side effects and adverse reactions
associated with carbidopa
Carbidopa side effects
Glossitis
Leg pain
Ataxia
Falling
Gait abnormalities
Blepharospasm (which may be taken as an early sign of excess dosage)
Trismus
Increased tremor
Numbness
Muscle twitching
Peripheral neuropathy
Myocardial infarction
Flushing
Oculogyric crises
Diplopia
Blurred vision
Dilated pupils
Urinary retention
Urinary incontinence
Dark urine
Hoarseness
Malaise
Hot flashes
Sense of stimulation dyspepsia
Constipation
Palpitation
Fatigue
Agranulocytosis
Hemolytic and nonhemolytic anemia
Rash
Gastrointestinal bleeding
Duodenal ulcer
Henoch–Schonlein purpura
Decreased hemoglobin and hematocrit
Thrombocytopenia
Leukopenia
Angioedema
Urticaria
Pruritus
Alopecia
Dark sweat
Abnormalities in alkaline phosphatase
Abnormalities in serum glutamic oxaloacetic transaminase
(aspartate aminotransferase) or serum glutamic pyruvic transaminase
(alanine aminotransferase)
Abnormal Coombs test
Abnormal uric acid
Hypokalemia
Abnormalities in blood urea nitrogen
Increased creatinine
Increased serum lactate dehydrogenase
Glycosuria
Note: Data from Hinz et al.
L-dopa. It is the experience of Hinz et al2,12 that few physicians are aware of the availability of the nutritional supplement form of standardized L-dopa over the counter in the
US, and even fewer understand the management of L-dopainduced nausea without the use of carbidopa.
Table 1 is a previously published list of side effects and
adverse reactions associated with peripheral depletion of centrally acting monoamines (serotonin, dopamine, norepinephrine, and epinephrine) due to carbidopa administration.2,12
The current standard of care for Parkinson’s disease is
based on the endogenous state perspective. There is no consideration that nausea is caused by the imbalance between the
serotonin and dopamine systems. The depletions of serotonin,
thiols, L-tyrosine, L-tryptophan, and other monoamines
associated with the clinical course of Parkinson’s disease,
L-dopa monotherapy, and the use of general decarboxylase
inhibitors are not addressed (see Table 2).2,12
Under the current standard of care, the etiology of the
signs and symptoms associated with these depletions is not
adequately recognized, understood, or controlled. Standard
treatment of Parkinson’s disease under endogenous conditions is to simply increase L-dopa/carbidopa if symptoms of
Parkinson’s disease are not optimally under control.
Competitive inhibition research has identified the causes
of the depletion and previously published the steps required
to increase the synthesis in a properly balanced manner,
Table 2 Depletions of centrally acting monoamines (serotonin,
dopamine, norepinephrine, and epinephrine), thiols, L-tyrosine,
and L-tryptophan associated with Parkinson’s disease, L-dopa
administration, and administration of a general decarboxylase
inhibitor
Serotonin
Dopamine
Norepinephrine
Epinephrine
Thiols
2,12
classified as a drug; it is not listed as GRAS by the FDA.
Currently, in the US, if a patient experiences a carbidopa side
effect, the only available form of L-dopa without carbidopa
is a nutritional supplement product containing standardized
L-tyrosine
L-tryptophan
Parkinson’s
disease
L-dopa
administration
General
decarboxylase
inhibitor
Depletion
known
Depletion
known
Depletion
known
Depletion
known
Depletion
known
Depletion
known
Depletion
known
Depletion known
Peripheral
depletion known
Peripheral
depletion known
Peripheral
depletion known
Peripheral
depletion known
Depletion known
Depletion known
Depletion known
Note: Adapted with permission from Dove Medical Press. Hinz M, Stein A, Uncini T.
Relative nutritional deficiencies associated with centrally acting monoamines.
Int J Gen Med. 2012;5:413–430.12 Copyright © 2012.
Abbreviation: L-dopa, L-3,4-dihydroxyphenylalanine.
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Hinz et al
leading to optimal functional results. The properly balanced
competitive inhibition approach avoids the extensive depletion of serotonin, thiols, L-tyrosine, and L-tryptophan that is
known to exist with L-dopa monotherapy. It also eliminates
the nausea dosing barrier that may occur when L-dopa is
administered without the need for a general decarboxylase
inhibitor.2,12
A total of 813 medical patients with a diagnosis of Parkinson’s
disease were queried from a database owned by DBS Labs
(Duluth, MN, USA). These were patients who had collected
urine samples in the competitive inhibition state and then
submitted them for serotonin and dopamine assay followed
by OCT2 functional status determination.1,2,13–20
The Parkinson’s disease patients’ diagnostic evaluations
were performed under the care of a licensed medical doctor or doctor of osteopathic medicine and then entered as
a working diagnosis on submission of laboratory samples.
The diagnosis of Parkinson’s disease was then added to the
database without further diagnostic verification.
Patient demographics are as follows. Total number of
Parkinson’s disease patients included for consideration in
this paper: N=813 of which males were N=554 (68.14%) and
females were N=259 (31.86%). The male age range was 42–95
years with a mean of 70 years and a standard deviation of 10.0
years. The female age range was 28–91 years with a mean of
66 years 8 months and a standard deviation of 10.6 years.
Amino acid formulas were obtained from CHK Nutrition
(Duluth, MN, USA). The following formulas were utilized:
• NeuroReplete (eight pills containing 5-HTP 99% + pure
300 mg, L-tyrosine 3,000 mg, L-lysine 500 mg, vitamin C
1,000 mg, vitamin B6 75 mg, calcium carbonate 220 mg,
and folate 400 µg)
• D5 Mucuna 300 mg pills of 40% L-dopa standardized
(each pill containing 120 mg L-dopa)
• D5 Mucuna powder (one level tablespoonful [2.4 g]
containing 840 mg L-dopa)
• CysReplete (six pills containing L-cysteine 4,500 mg,
selenium 400 µg, and folate 400 µg).
The patients were started on one pill of NeuroReplete
in the morning and at 4 pm to achieve 5-HTP control of
L-dopa-induced dopamine and serotonin depletion symptoms, including nausea and/or vomiting. If nausea and/or
vomiting become a problem, the 5-HTP daily dosing value
is addressed by adjusting the NeuroReplete within the range
of 37.5–600 mg per day until the symptoms are controlled.
As 5-HTP levels can be either high or low relative to L-dopa
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for nausea control, the first adjustment is to decrease the
5-HPT intake by 37.5 mg per day. If that change is not
effective, at 3-day intervals the 5-HTP level is increased in
daily incremental values going up to 112.5 mg/day, then up
150 mg per day, then 300 mg per day, then up to a maximum
of 600 mg per day. No patients (N=813) experienced nausea
that was refractory to this 5-HTP approach.
With regard to L-dopa administration, patients were
started on two pills of D5 Mucuna 40% in the morning, noon,
and at 4 pm. The D5 Mucuna 40% was then increased weekly
in six-pill increments (L-dopa daily dosing value increases
of 720 mg) until symptoms were brought under control or
an L-dopa daily dosing value of 6,720 mg was achieved,
whichever came first. If there was no symptom relief at
6,720 mg per day, a pill stop, as outlined in the following
section, was started in order to identify whether the daily
L-dopa dosing value was overdosed or underdosed relative
to optimal therapeutic dosing. The optimal therapeutic range
for the daily L-dopa dosing was from 720 mg to 16,800 mg
per day with a mean of 5,880 mg per day and a standard
deviation of 1,190 mg.
All patients were started on two pills of CysReplete
three times a day, with the first dose at noon to prevent
and/or reverse thiol depletion associated with Parkinson’s
disease and/or the administration of L-dopa. The daily
L-cysteine dose was static and not adjusted. For a discussion
of the establishment of the static dosing requirements of the
CysReplete formula, the reader is referred to prior writings
of Hinz et al (2009).12
The pill stop protocol
If the patient was experiencing residual symptoms associated with Parkinson’s disease when the daily dosing value of
L-dopa was established at 6,720 mg per day (equal to 56 pills
each containing 120 mg of L-dopa), a 2-day pill stop of all
amino acids was implemented. This was utilized to define
whether the patient’s daily L-dopa intake was too high or too
low relative to the optimal therapeutic dosing value.
With each pill stop, one of three general outcomes was
typically observed:
1. If in the morning following the first day of a complete pill
stop the patient’s Parkinson’s disease symptoms, from
the patient’s perspective, were markedly improved, it was
interpreted that the patient was overdosed relative to the
optimal daily dosing value requirements.
2. If in the morning following the first day of a complete pill
stop the patient’s Parkinson’s disease symptoms were the
same or worse, it was interpreted that the patient’s daily
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L-dopa dosing value was too low relative to the optimal
therapeutic requirements.
3. If a patient experienced a deterioration of symptoms the
same day that the pill stop was initiated, all amino acids
should be restarted immediately at the previous daily
dosing values, as the patient was underdosed.
A patient’s daily L-dopa dosing value was considered
to be optimal when it corresponded with the greatest relief
of symptoms. At that point, no further pill stops were
required.
For those patients who did not achieve optimal symptom relief after the first pill stop, subsequent pill stops were
undertaken. The patient who reported relief of symptoms
the morning following the pill stop was designated as
being given an L-dopa overdose relative to the optimal
dosing needs. The overdosed value was then referenced
against the daily L-dopa dosing value of the most recent
previous pill stop where the patient underdosed. With
these high and low values recorded, the optimal L-dopa
dosing was then defined. The patient was placed on the
higher daily L-dopa dosing value minus 240 mg per day
of L-dopa and evaluated again in 7 days. If symptoms
were not at the level experienced the morning after the
pill stop when the L-dopa was overdosed, the daily dosing
value was decreased another 240 mg per day. This combination of pill stops with decreases of 240 mg L-dopa
daily dosing values was continued until optimal relief of
Parkinson’s disease symptoms was achieved. Symptomatic
relief should be on a par with the marked improvement
experienced the morning after the initial pill stop where
the L-dopa overdose relative to optimal therapeutic needs
was identified.
Those patients who failed to show improvement the
morning after the pill stop were interpreted as having been
administered L-dopa daily dosing values that were too low
relative to the required optimal dosing needs. The L-dopa
daily dosing value was then increased by 720 mg and another
pill stop was performed in 1 week.
The pill stop criteria require answering the following
questions from the patient’s perspective with regard to
overall Parkinson’s disease symptoms: whether symptoms
were better, whether symptoms were worse, or whether
symptoms were the same.
A patient’s response to a question is not always direct.
When the caregiver is not confident in the response to the
questions, it is recommended that another pill stop be performed. One physician reported performing three pill stops
with a patient on the same daily L-dopa dosing value before
being convinced that the proper clinical data were in place
to make a dosing change decision.
Results
The pill stop concept evolved from initial observations where
Parkinson’s disease patients taking higher daily dosing values
of L-dopa (.10,800 mg) had either missed pills or stopped
their pills during treatment. Physicians reported patients
who in the morning of the day following the stopping of all
amino acid pills experienced what turned out to be a period
of optimal symptom relief. A brief period of time (3–6 hours)
was noted with a remarkable improvement from the patient’s
perspective. These patients spontaneously volunteered
comments such as “This is the best I have felt in years” or
“For 20 years I have wanted to feel this good”. The comments were definitive. They clearly indicated that from the
patient’s perspective an abrupt dramatic and positive change
in the patient’s symptoms had occurred. It was subsequently
determined that in these patients the daily L-dopa dosing
value in the competitive inhibition state prior to the L-dopa
pill stop was too high. These patients had been unknowingly
overdosed. When all amino acids are stopped, systemic
L-dopa and dopamine levels decrease through the levels that
are required for optimal control of symptoms. A period of
optimal symptom relief occurs approximately 24 hours after
the pill stop where the first L-dopa dosing was missed.
Most surprising was the novel observation in the competitive inhibition state. Identical Parkinson’s disease symptoms
of the same intensity were present when L-dopa daily dosing
values were too high or too low relative to optimal daily dosing value. Typically, it is clinically impossible to determine
whether the patient’s daily L-dopa dosing value is too high
or too low without a pill stop. An L-dopa overdose cannot
be determined based on traditional signs and symptoms
observed in the endogenous state. These novel clinical overdose observations do not exist in the endogenous state, and
observations in the endogenous state do not have predictability with regard to outcomes of amino acid administration in
the competitive inhibition state. When administering properly
balanced L-dopa with 5-HTP, L-tyrosine, and thiols in the
competitive inhibition state, this novel pill stop approach
is required to prevent L-dopa overdose and to assist in
identifying the optimal therapeutic dosing range.12
As noted in Figure 1, there is an L-dopa daily dosing
value range where symptoms are optimally controlled.
This dosing range is very narrow: ±240 mg relative to the
optimal therapeutic value. The point of optimal symptom
relief is indicated with an “X”. Figure 1 also illustrates the
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Hinz et al
Symptom intensity
Optimal relief of Parkinson’s
disease symptoms ±240 mg
Daily dosing value of L-dopa
Figure 1 The typical dose–response curve observed with administration of
L-dopa in the competitive inhibition state (concomitant administration of L-dopa,
5-hydroxytryptophan, a thiol, and L-tyrosine).
Notes: There is an abrupt cessation or return of symptoms when the daily dosing
value of L-dopa is too high or too low. The dosing value associated with these abrupt
changes is small, generally 120 mg per day or less. The range associated with optimal
relief of symptoms is narrow: ±240 mg from the mean.
phenomenon observed with this narrow optimal dosing value
range where symptoms abruptly resolve or return with small
increases or decreases of the daily L-dopa dosing value
(#120 mg). When these inflection points are reached, it is
not a gradual resolution or return of symptoms. The change
in symptoms tends to be abrupt.
Changing the daily L-dopa dosing value by 120 mg can
have dramatic clinical results. In general, this is independent
of the size of the daily L-dopa dose. For example, a patient
was taking 10,800 mg of L-dopa per day (equivalent to
90, 120 mg L-dopa pills) in the competitive inhibition state.
The patient reported being frozen in the chair and unable
to stand. After a pill stop the patient was placed on 89 pills
per day (10,680 mg of L-dopa). After a daily decrease in
the L-dopa dosing value of only 120 mg, the patient was
able to rise without assistance and ambulate. These results
are common, not rare.
No L-dopa discussion relative to Parkinson’s disease would be complete without touching on the topic of
dyskinesias. In the competitive inhibition state, no problems
or concerns were noted with dyskinesias under this approach
in the 10 years of implementation. Further discussion is
reserved for other papers.
Discussion
The novel focus of this paper is that in the competitive
inhibition state L-dopa daily dosing values that are too
high or too low relative to the optimal therapeutic range
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manifest the same symptoms with identical intensity. This
phenomenon is so pervasive that pill stop evaluation needs to
be conducted with all patients if optimal relief of symptoms
is not achieved when the daily dosing value is increased to a
specific set point. The pill stop should be performed if relief
of symptoms has not been achieved at L-dopa daily dosing
values $6,720 mg per day, or if a question exists regarding the direction of the next change in the L-dopa daily dosing
value. It is impossible to empirically determine with absolute
certainty whether patients in the competitive inhibition state
are taking too much or too little L-dopa without a pill stop.
The only exception is if the L-dopa daily dosing value happens to be established at the optimal therapeutic value during
a dosing adjustment. Blindly increasing the daily L-dopa
dosing values in a linear manner based on endogenous reference points (status of symptoms) in the competitive inhibition
state has a high potential for L-dopa overdose relative to the
optimal therapeutic dosing value.
In the competitive inhibition state, the daily L-dopa dosing value range where optimal relief of symptoms is obtained
is as narrow as ±120 mg of L-dopa in some patients. With
L-dopa daily dosing value increases of 720 mg or more, it
is common to exceed the optimum dosing value, leading to
an overdose situation.
Conclusion
This paper is about safety, not efficacy, of L-dopa. Efficacy
has been established by numerous studies over the last
50 years it has been administered. The enhanced safety
margin is related to L-dopa overdose management.
This paper reports a novel observation relating to L-dopa
in the competitive inhibition state. L-dopa daily dosing values
that are either excessive or insufficient relative to the optimal
therapeutic requirements are clinically associated with the
exact same symptoms of Parkinson’s disease, each with identical intensity. These novel findings document that there are
no clinical signs or symptoms for the physician to formulate
a conclusion that the patient is overdosed on L-dopa and is
above the optimal therapeutic dosing range.
From a safety standpoint, the pill stop is required in the
competitive inhibition state to prevent L-dopa overdose and
facilitate realization of the therapeutic dosing value. It has
been previously documented how depletions of serotonin,
L-tyrosine, and thiols are associated with Parkinson’s disease
and potentiated by L-dopa monotherapy with or without a
general decarboxylase inhibitor in the endogenous state.
Peripheral depletion of serotonin, dopamine, norepinephrine,
and epinephrine is facilitated by administration of carbidopa
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or benserazide. If these depletion issues are to be addressed
properly, the patient has to be placed in the competitive
inhibition state, and L-dopa daily dosing value needs to be
guided by pill stops.
The purpose of this paper is to outline a novel safety concern identified with administration of L-dopa in the competitive inhibition state that has not been previously described in
the literature and to facilitate discussion of these findings.
Disclosure
Marty Hinz discloses his relationship with DBS Labs, Inc.
and NeuroResearch Clinics, Inc. The other authors report no
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dailymed/lookup.cfm?setid=69e575b9-f8a5-494f-b736-2520ef505cb0.
Accessed July 1, 2014.
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PERSPECTIVES
The Parkinson’s disease death rate: carbidopa
and vitamin B6
21 October 2014
Marty Hinz 1
Alvin Stein 2
Ted Cole 3
2
Plantation, FL, USA; 3Cole Center
for Healing, Cincinnati, OH, USA
1
Abstract: The only indication for carbidopa and benserazide is the management of
L-3,4-dihydroxyphenylalanine (L-dopa)-induced nausea. Both drugs irreversibly bind to and
permanently deactivate pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, and PLPdependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually
every major system in the body is impacted directly or indirectly by PLP. The administration of
carbidopa and benserazide potentially induces a nutritional catastrophe. During the first 15 years
of prescribing L-dopa, a decreasing Parkinson’s disease death rate was observed. Then, in 1976,
1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug, the Parkinson’s disease death rate started increasing. This trend has continued to the
present, for 38 years and counting. The previous literature documents this increasing death rate,
but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute
to the increasing Parkinson’s disease death rate and to the classification of Parkinson’s as a
progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis.
Keywords: L-dopa, levodopa, vitamin B6, pyridoxal 5′-phosphate
Introduction
NeuroResearch Clinics, Inc.,
FL, USA 33904
Tel +1 218 626 2220
Fax +1 218 626 1638
Parkinson’s disease is classified as a progressive neurodegenerative disease.1 L-3,4dihydroxyphenylalanine (L-dopa) is the most effective treatment for Parkinson’s
disease.2 Many patients who take it experience profound nausea, which may prevent
them from reaching higher dosing values required for symptom relief.3 On May 2,
1975, the US Food and Drug Administration (FDA) approved carbidopa (MK-486),4,5
a drug whose only indication was the management of L-dopa-induced nausea. The
Centers for Disease Control and Prevention (CDC) noted an increasing Parkinson’s
disease death rate. In 2003, Parkinson’s disease was added to the top 15 causes of
death; it entered the list as the 14th leading cause of death.6
The following questions are examined in this review:
1. Is carbidopa linked to the increasing Parkinson’s disease death rate?
2. Are the attributes of the nutritional collapse associated with Parkinson’s disease,
L-dopa, and/or carbidopa being misdiagnosed as progressive neurodegeneration?
3. Is carbidopa involved in L-dopa tachyphylaxis?
Insight into these questions required the review of Parkinson’s disease, relative
nutritional deficiencies, pyridoxal 5′-phosphate (PLP) (the active form of vitamin B6),
L-dopa, carbidopa, carbidopa’s side effects, the CDC-reported Parkinson’s disease death
rates, the biochemistry of L-dopa-induced nausea, and of the documented alternatives
to carbidopa and benserazide.
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Hinz et al
Benserazide
Benserazide and carbidopa have identical mechanisms of action
and indications. Any reference to benserazide means, “Benserazide and/or its metabolite trihydroxybenzylhydrazine.”7
While the focus of this paper is on carbidopa, the attributes
shared by benserazide are noted.
Drug nutrient perspective
The following definition for a nutrient is utilized: A nutrient
is any substance that facilitates normal system function.
A drug is any substance that induces abnormal system function. A nutrient may become a drug. A drug may not become
a nutrient.
5-hydroxytryptophan (5-HTP) is a nutrient. When it is
administered as a single agent, dopamine depletion may
occur.8–21 If it induces dopamine depletion, then 5-HTP no
longer functions as a nutrient; it is a drug. L-dopa may be
administered as a nutrient. When it is administered as a single
agent, serotonin depletion may occur.10–18,22–29 If it induces
serotonin depletion, then L-dopa no longer functions as a
nutrient; it is a drug.
Vitamin B6
Over 300 enzymes and proteins require PLP to function properly. 30 The f ive PLP-dependent enzymes –
glutamate decarboxylase, arginine decarboxylase, histamine
d ecarboxylase, aromatic L-amino acid decarboxylase
(AADC), and sulfoalanine decarboxylase – are:
[...] unrivaled in the variety of reactions they catalyze and
the highly diverse metabolic pathways they are involved
in, including the conversion of amino acids, one-carbon
units, biogenic amines, tetrapyrrolic compounds, and amino
sugars […] sulfur assimilation, incorporation in cysteine,
biotin, and S-adenosyl methionine.31
L-dopa
The primary pathology demonstrated in Parkinson’s disease is
progressive degeneration of the substantia nigra of the brain.12
The primary etiology of Parkinson’s disease is postsynaptic
dopamine neuron damage caused by neurotoxins. Progressive
neuron damage induces the collapse of the electrical conduction
that regulates fine motor control.12 L-dopa crosses the blood–
brain barrier and it is then freely synthesized to dopamine without feedback regulation. The administration of L-dopa increases
synaptic dopamine levels.32–55 It is analogous to turning up the
voltage; more electricity flows through the remaining viable
postsynaptic neurons. Restoration of postsynaptic electrical
flow optimizes regulation of fine motor control.10,56
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The only major advancements in Parkinson’s treatment
occurred in the 1950s and involved the amino acid, L-dopa.
This research was awarded the Nobel Prize in Medicine in
200057,58 and the Nobel Prize in Chemistry in 2001.59 Sweet
and McDowell60 attributed the decreasing Parkinson’s death
rate that occurred between 1958 and 1975 to L-dopa (from
2.9/100,000 to 1.6/100,000 of the standard population,
age-adjusted).61
The National Parkinson Foundation notes that 89% of
the 1 million Parkinson’s patients in the US take L-dopa/
carbidopa daily.62 While L-dopa is the most effective treatment, it is not usually the drug of choice.2 Side effects have
positioned it to be one of the last drugs started in many
cases.2
Parkinson’s disease is associated with the depletion of
serotonin, dopamine, norepinephrine, epinephrine, thiols
(homocysteine, L-methionine, S-adenosyl-L-methionine,
S-adenosyl-homocysteine, cystathione, L-cysteine, and glutathione), L-tyrosine, and L-tryptophan, and these depletions
represent relative nutritional deficiencies (RNDs) where systemic nutritional synthesis requirements cannot be achieved
on a normal or optimal diet.12,13,28,63–68
L-dopa may induce its own unique RND and exacerbate the Parkinson’s disease RND. When administered
singularly or with an improper nutrient balance, it has the
ability to induce RNDs of serotonin, thiols, L-tyrosine, and
L-tryptophan.12,13 We hypothesize that if the Parkinson’s disease patient is being evaluated for the signs and symptoms of
progressive neurodegenerative disease without considering
the potential for, as well as the existence and ramifications
of RNDs associated with the disease itself, L-dopa, and/or
carbidopa, then nutritional collapse components will erroneously be attributed to progressive neurodegeneration.
Carbidopa
Efficacy and safety concerns must be addressed before US
FDA drug approval. Conceptualize a drug that has no treatment efficacy claims under US FDA guidelines. Its sole
indication is the management of the side effect of nausea
induced by improperly balanced nutrient administration.3 It
irreversibly binds to and permanently deactivates free PLP
and PLP-dependent enzymes while inducing PLP reserve
pool depletion.7 It negatively impacts the function of over
300 enzymes and proteins.30 Administering vitamin B6 counteracts its mechanism of action.3 Drugs with these attributes
are being prescribed. (2S)-3-(3,4-dihydroxyphenyl)-2hydrazino-2-methylpropanoic acid (carbidopa) is being
prescribed in the US and (RS)-2-amino-3-hydroxy-N′-(2,3,
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6.5
5.5
4.5
All ages – age-adjusted
all ethnic groups
male and female
328.7% increase in the
death rate between
1976 and 2011
3.5
2.5
2010
2005
2000
1995
1990
1985
1.5
1980
Rate per 100,000 US standard population, age-adjusted
7.5
Figure 1 Parkinson’s disease death rates in the United States between 1976 and
2011, all ages, age-adjusted, male and female.
Notes: Graph generated from multiple data sources.62,84,89
point that prescription L-dopa as a single ingredient is no longer
available (Table 1). Prior to 1999, three pharmaceutical companies distributed a US FDA-approved brand name prescription forms of L-dopa as a single-ingredient drug: Bendopa®
(Valent Pharm Intl); Dopar® (Shire plc, St Helier, Jersey); and
Larodopa® (Hoffman-La Roche Ltd, Basel, Switzerland).22
There is no public documentation explaining the reasoning
80
Rate per 100,000 US, age-adjusted
70
60
White males age 65 years
and older, age-adjusted
311.0% death rate
increase between 1981
and 2010
50
40
30
All ages, age-adjusted, male
and female
300.1% death rate increase
between 1981 and 2010
20
White males all ages,
age-adjusted
233.2% death rate
increase between 1981
and 2010
10
2010
2000
1990
0
1981
4-trihydroxybenzyl) propanehydrazide (benserazide) is being
prescribed outside the US.2,69
L-dopa-induced nausea is a peripheral phenomenon.
C arbidopa and benserazide inhibit peripheral L-dopa
metabolism by AADC. 3 This increases the amount of
L-dopa available to cross the blood–brain barrier. Decreasing peripheral L-dopa levels through decreased ingestion,
while maintaining its levels in the central nervous system,
effectively controls nausea.12 Carbidopa and benserazide
control nausea by identical mechanisms.2,69 Carbidopa and
the active metabolite of benserazide, trihydroxybenzylhydrazine, irreversibly bind to and permanently deactivate PLP
and PLP-dependent enzymes.18,19,70–74 Normally, a Schiff
base aldamine reaction catalyzes the irreversible hydrazine
binding of PLP with the core protein of AADC to produce
the active enzyme.5 Benserazide is completely metabolized
to trihydroxybenzylhydrazine before it reaches the arterial blood. Carbidopa and trihydroxybenzylhydrazine are
substrate analogues endowed with irreversible substituted
hydrazine function.7
PLP is noncovalently (reversibly) bound to approximately
300 enzymes and proteins forming the PLP reserve pool.30 The
molecular weight of PLP is 247.142 g/mol75 and that of carbidopa is 244.244.76 Carbidopa irreversibly binds to PLP in a
1:1 ratio.7 The recommended dietary allowance of vitamin B6
is about 1 to 2 mg/day depending on age.77 If the lowest daily
dose of carbidopa (10 mg) is administered, then the system is
placed into a PLP-induced RND state on the first day.
Systemic vitamin B6 concentrations inversely correlate
with mortality induced by coronary artery disease, colorectal
cancer, stroke, heart failure, and atherosclerosis.78–83 We
hypothesize that if carbidopa and benserazide significantly
deplete PLP, then an increased death rate will be observed.
During the first 15 years of prescribing L-dopa (1960–1975)
it was administered without carbidopa, a practice that was
associated with a decreasing death rate.61 On May 9, 1975,
the US FDA approved carbidopa for concomitant administration with L-dopa.3 Between 1976 and 2011, the there has
been an increase in the general Parkinson’s disease death
rate. While numerous etiologies have been postulated to
explain the increasing Parkinson’s death rate, none have
impacted this 38-year trend. Parkinson’s disease is most
prevalent in white males. Figures 1 and 2, when viewed
together, demonstrate that the Parkinson’s death rate
increase is occurring across all ages, sexes, and ethnic
groups.
Concomitant L-dopa/carbidopa preparations have been
positioned by the manufacturers to permeate treatment to the
Parkinson’s disease death rate
Figure 2 Parkinson’s disease death rates in the United States between 1981–2010,
in comparison to white males of all ages, and white males aged 65 years and older.
Note: Graph generated from the following data source: Centers for Disease Control
and Prevention. National Center for Health Statistics. Health Data Interactive.
www.cdc.gov/nchs/hdi.htm.84
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Hinz et al
Table 1 The timeline of significant events
L-dopa/carbidopa timeline
1958–1975: The Parkinson’s disease death rate decreased from
2.9/100,000 to 1.6/100,000 and was attributed to L-dopa.61
1967: The first four studies on the administration of a general
decarboxylase inhibitor for the management of L-dopa-induced nausea
were documented.86
1975: The original brand of L-dopa with carbidopa (Sinemet®) was
approved by the US FDA.62,86
1976–2011: The Parkinson’s disease death rate increased by 328.7%.61,84
1977: The first paper demonstrating significant peripheral and central
PLP depletion by carbidopa was submitted for publication.5
1999: Pharmaceutical companies discontinued distributing the
prescription form of L-dopa (a single-ingredient drug leaving L-dopa/
carbidopa combinations the only prescription options).87
2003: The CDC added Parkinson’s disease to the top 15 causes of
death; it entered at number 14.6
2012: Paper that asserts that carbidopa irreversibly binds to PLP
and PLP-dependent enzyme molecules was published. Prior to this,
carbidopa depletion of PLP was viewed as a side event, not the
mechanism of action.7
Abbreviations: L-dopa, L-3,4-dihydroxyphenylalanine; US FDA, United States
Food and Drug Administration; PLP, pyridoxal 5′-phosphate; CDC, Centers for
Disease Control and Prevention.
behind the virtually simultaneous discontinuation of these
drugs by the three companies.
When these drugs were approved, each was described
as a decarboxylase inhibitor. Documentation submitted in
1997 noted significant central and peripheral PLP depletion after limited ingestion time of carbidopa.5 Now the full
mechanism of action of PLP is known, giving rise to more
serious concerns. It is documented that PLP freely crosses
the blood–brain barrier.84 Carbidopa prescribing information
states that it “[…] does not affect the metabolism of levodopa
within the central nervous system.”3 This is not correct. If PLP
freely crosses the blood–brain barrier allowing a peripheral
and central equilibrium to exist, then both peripheral and central PLP depletion will be induced by carbidopa and benserazide. Theoretically, complete PLP depletion of the central
and peripheral systems may occur. If carbidopa-induced PLP
depletion is great enough for compromise of central AADC
function to occur, then there will be an impairment of central
dopamine synthesis. This is a previously undocumented
potential etiology of L-dopa tachyphylaxis.
Carbidopa prescribing information lacks full disclosure.3
There is no reference to PLP, PLP depletion, irreversible
binding to and permanent deactivation of PLP and PLPdependent molecules, depletion of PLP reserve pools, risks
induced by PLP depletion, potential functional compromise
of over 300 enzymes and proteins, or RND induction. Simply
describing carbidopa and benserazide as decarboxylase
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inhibitors is analogous to describing a nuclear blast as a
window breaker. Chronic administration affects virtually
every system in the body.30
The mechanism of action of carbidopa and benserazide
is PLP depletion.18,19,70–74 Carbidopa prescribing information only notes, “Pyridoxine hydrochloride (vitamin B6),
in oral doses of 10 mg to 25 mg, may reverse the effects
of levodopa by increasing the rate of aromatic amino
acid decarboxylation. Carbidopa inhibits this action of
pyridoxine.”3 PLP depletion is an RND event. PLP can
reverse the nausea control of carbidopa and ameliorate the
clinical effects of L-dopa, requiring caution during concomitant administration. We hypothesize that if these drugs are
stopped and then ample vitamin B6 is administered, PLP
function, PLP-dependent enzyme function, and PLP reserve
pools will return to normal.
The exact size of the PLP reserve pool, which is reversibly bound to about 300 enzymes and proteins, is a matter
of speculation. We postulate that when normal PLP pool
reserve function exists at the start of treatment, it may take
5 or more years of chronic carbidopa or benserazide ingestion, depending on the daily dosing value, before progressive
clinical deterioration is demonstrated. We further postulate
that without a PLP reserve pool, carbidopa or benserazide
ingestion would induce PLP collapse in days.
Carbidopa side effect profile
L-dopa active ingredient products may be administered
as a nutritional supplement or a drug. Nutritional supplements are generally recognized as safe (GRAS), allowing
over-the-counter sales.12 Due to side effects, carbidopa is
not GRAS.3 It may induce life-threatening events including
myocardial infarction, neuroleptic malignant syndrome,
agranulocytosis, hemolytic and nonhemolytic anemia, gastrointestinal bleeding, thrombocytopenia, and hypokalemia
(Table 2).12,13 While carbidopa side effects require its discontinuation when the continuation of L-dopa is indicated,
nutrient products are the only option. Most physicians are
unaware of the availability of this L-dopa form.
The carbidopa side effects and adverse reactions listed in
Table 2 are a direct result of irreversible drug-induced PLP
depletion, irreversible PLP-dependent enzyme binding, PLP
reserve pool collapse, along with RND-induced collapse
of serotonin and catecholamine synthesis.12,13,18,19,70–74,78–83
If, when equilibrated, central PLP depletion occurs as a result
of peripheral PLP depletion, then central compromise, side
effects, and adverse reactions are inevitable – a phenomenon
not previously documented.
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Table 2 Side effects and adverse reactions associated with
carbidopa
Glossitis
Leg pain
Ataxia
Falling
Gait abnormalities
Blepharospasm (which
may be taken as an early
sign of excess dosage)
Trismus
Increased tremor
Numbness
Muscle twitching
Peripheral neuropathy
Myocardial infarction
Flushing
Oculogyric crises
Diplopia
Blurred vision
Dilated pupils
Urinary retention
Urinary incontinence
Dark urine
Hoarseness
Malaise
Hot flashes
Sense of stimulation
Dyspepsia
Constipation
Palpitation
Fatigue
Upper respiratory
infection
Bruxism
Hiccups
Common cold
Diarrhea
Urinary tract
infections
Urinary frequency
Flatulence
Priapism
Pharyngeal pain
Abdominal pain
Bizarre breathing
patterns
Burning sensation of
tongue
Back pain
Shoulder pain
Chest pain
(noncardiac)
Muscle cramps
Paresthesia
Increased sweating
Syncope
Orthostatic
hypotension
Asthenia
(weakness)
Dysphagia
Horner’s syndrome,
mydriasis
Dry mouth
Sialorrhea
Neuroleptic
malignant syndrome
Phlebitis
Agranulocytosis
Hemolytic and
nonhemolytic
anemia
Rash
Gastrointestinal
bleeding
Duodenal ulcer
Henoch–Schonlein
purpura
Decreased
hemoglobin and
hematocrit
Thrombocytopenia
Leukopenia
Angioedema
Urticaria
Pruritus
Alopecia
Dark sweat
Abnormalities
in alkaline
Phosphatase
Abnormalities in
SGOT (AST)
SGPT (ALT)
Abnormal
Coombs’ test
Abnormal uric acid
Hypokalemia
Abnormalities
in blood urea
nitrogen
Increased
creatinine
increased serum
LDH
Glycosuria
Note: Data from Hinz et al.12,13
Abbreviations: SGOT, serum glutamic oxaloacetic transminase; AST, aspartate
aminotransferase; SGPT, serum glutamic pyruvic transminase; ALT, alanine
transaminase; LDH, lactate dehydrogenase.
Nutritional management of nausea
It was previously documented that L-dopa-induced nausea, along
with Parkinson’s disease, L-dopa-associated, and carbidopaassociated RND, is definitively controlled with properly balanced
administration of the nutrient 5-HTP, along with L-tyrosine, a
thiol (L-cysteine, glutathione, S-adenosylmethionine, or
L-methionine), and cofactors (vitamin C, vitamin B6, and
calcium carbonate), as facilitated by organic cation transporter
type-2 functional status analysis.12,13
AADC inhibition may be reversible or irreversible.
The irreversible inhibition of AADC is the mechanism
of action whereby carbidopa and benserazide control
L-dopa-induced nausea.3,18,19,70–74 Reversible inhibition of
AADC in the competitive inhibition state is the mechanism of action whereby 5-HTP controls L-dopa-induced
nausea. If 5-HTP effectively controls L-dopa-induced
nausea, then carbidopa or benserazide is no longer indicated, and all detrimental effects discussed herein no
longer apply. If 5-HTP is not administered in proper balance with amino acid precursors of other systems, then
it will become a drug due to its depletion of dopamine.12,13
Due to the increased frequency of the onset of new druginduced side effects, carbidopa, monoamine oxidase inhibitors, and catechol-O-methyl transferase inhibitors need to be
stopped as 5-HTP and other nutrients are started under the
nutrient protocol. If carbidopa is administered with expectations of controlling L-dopa-induced nausea, then vitamin
B6 cannot be replenished while taking the drug since PLP
reverses the drug effects. If there is a patient history of carbidopa or benserazide ingestion, then vitamin B6 (100–300 mg/
day) is indicated at the initiation of the nutrient protocol.
Discussion
Responsible physicians create an environment where
optimal symptom control nurtures healing. Two medications with no efficacy claims have been prescribed for the
iatrogenic mismanagement of a nutrient, L-dopa , turning
it into a drug which depletes other systems.3,12,13,69 Their
only indication is to alleviate nausea, a benign condition,
while having the ability to profoundly compromise hundreds of system functions.3,69 In our opinion, use of these
medications is a violation of the physician’s oath to first,
do no harm. These drugs can create fatal events, clinical
deterioration, drug-induced sequelae, and risks where none
previously existed due to profound multisystem nutritional
collapse.12,13,18,19,70–74,78–83 Nausea induced by improper administration of the nutrient L-dopa should not be addressed with
drugs whose mechanism of action is system-wide vitamin
B6 RND, which is especially true when a drug-free nutrient
management approach is available.
In 1941, almost 20 years before the dawn of L-dopa,
Baker described a subgroup involving 25% of Parkinson’s disease patients who achieved “definite objective
improvement” with vitamin B6 administration.85 In 2012, the
literature noted, “Multifactorial neurological pathologies such
as […] Parkinson’s disease […] have also been correlated
to inadequate intracellular levels of PLP.”25 Administration
of carbidopa and benserazide should be contraindicated in
these patients.
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Hinz et al
Conclusion
Between 1960 and 1974, the only prescription form of L-dopa
available was the single-ingredient form that was associated
with a decreasing death rate.61 In 1975, the original combination L-dopa/carbidopa drug (Sinemet®) was approved by the
US FDA. Between 1976 and 2011, the CDC documented a
progressive increase of 328.7% in Parkinson’s disease deaths
that crossed age, sex, and ethnic boundaries.61,84 In addition,
no effective way has been discovered to truly stop what has
been described as neurodegeneration.
The mechanism of action for carbidopa and benserazide
induces irreversible binding to and permanent deactivation
of PLP and PLP-dependent enzyme molecules, potentially
inducing a negative impact on over 300 enzymes and
proteins. Without the induction of PLP deficiency, the clinical effects of carbidopa and benserazide are not observed.
It is a documented fact that these drugs may induce systemwide PLP depletion, representing an RND that is reversed
with vitamin B6 administration. Administration of carbidopa
may play a role in the escalating Parkinson’s disease death
rate, the exacerbation of symptoms exclusively attributed
to progressive neurodegeneration, and L-dopa tachyphylaxis. The full list of biochemical compromises can only be
speculated due to the ability of carbidopa and benserazide
to induce hundreds of intertwined peripheral and central
PLP function collapses, many of which may not be fully
understood at present. It is illogical to assert that an increased
carbidopa-induced death rate will not occur under these
circumstances. In an attempt to control a benign condition
(nausea – caused by the improperly balanced administration
of a nutrient, L-dopa), the patient has been exposed to the
devastating consequences of these drugs. While a formidable number of studies may still be needed to define all of
the PLP depletion ramifications, they become unnecessary
in the effective management of Parkinson’s disease when
the nutrient protocol is implemented, since carbidopa and
benserazide are no longer indicated.
The administration of properly balanced nutrients,
under a documented nutritional protocol for the definitive
control of L-dopa-induced nausea, should raise no more
concern with the caregiver or patient than administration
of a multivitamin; all are GRAS. Physicians should fully
understand the mechanism of action of the drugs they
prescribe rather than relying on the described indications
provided by the drug company. Efficacy concerns relating
to the discontinuation of carbidopa and benserazide are
unfounded since they have no efficacy; they only deal with
L-dopa side effects. Before 1976, in the precarbidopa era,
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ample studies were published documenting the efficacy of
L-dopa without carbidopa.
Three questions are raised: 1) Is progressive neurodegeneration observed with Parkinson’s disease intrinsic to the
disease, or may some symptoms be attributed to carbidopa
or benserazide-induced RND? 2) Does iatrogenic druginduced poisoning, which may result in irreversible binding
to and permanent deactivation of PLP and PLP-dependent
enzyme molecules throughout the system, play a role in the
increasing death rate noted by the CDC since 1976? 3) Is
carbidopa or benserazide potentially involved in L-dopa
tachyphylaxis? If the answer to these questions is yes, or
even maybe, a greater focus on nutrition is indicated while
discontinuing drugs such as carbidopa or benserazide. The
doctrine of res ipsa loquitur (the thing speaks for itself)
applies.
There is much fertile ground presented here for furthering
this research started in 1997. The authors encourage continued investigation, along with dialogue, into the ramifications
of carbidopa and benserazide use and the known RNDs that
plague the Parkinson’s disease patient.
Disclosure
MH discloses his relationship with DBS Labs, Inc. and
NeuroResearch Clinics, Inc. The other authors report no
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Return to index
PERSPECTIVES
Parkinson’s disease: carbidopa, nausea,
and dyskinesia
14 November 2014
Marty Hinz 1
Alvin Stein 2
Ted Cole 3
Clinics, Cape Coral, FL, 2Stein
FL, 3Cole Center for Healing,
Cincinnati, OH, USA
1
Abstract: When l-dopa use began in the early 1960s for the treatment of Parkinson’s disease,
nausea and reversible dyskinesias were experienced as continuing side effects. Carbidopa or
benserazide was added to l-dopa in 1975 solely to control nausea. Subsequent to the increasing
use of carbidopa has been the recognition of irreversible dyskinesias, which have automatically
been attributed to l-dopa. The research into the etiology of these phenomena has identified
the causative agent of the irreversible dyskinesias as carbidopa, not l-dopa. The mechanism
of action of the carbidopa and benserazide causes irreversible binding and inactivation of
vitamin B6 throughout the body. The consequences of this action are enormous, interfering with
over 300 enzyme and protein functions. This has the ability to induce previously undocumented
profound antihistamine dyskinesias, which have been wrongly attributed to l-dopa and may be
perceived as irreversible if proper corrective action is not taken.
Keywords: vitamin B6, PLP, irreversible, pyridoxal 5’-phosphate
Introduction
Clinics, 1008 Dolphin Drive,
Cape Coral, FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
Serotonin, dopamine, norepinephrine, and epinephrine are centrally acting monoamines.
The immediate amino acid precursor of serotonin is 5-hydroxytryptophan (5-HTP);
l-3,4-dihydroxyphenylalanine (l-dopa) is the immediate amino acid precursor of
dopamine. The aromatic l-amino acid decarboxylase (AADC; EC 4.1.1.28) enzyme
catalyzes the synthesis of serotonin, dopamine, and histamine.1,2
Side effects may position l-dopa as one of the last drugs administered, despite
the fact that it has the highest efficacy in the treatment of Parkinson’s disease.3 Two
prominent l-dopa side effects are nausea and dyskinesias. Carbidopa is listed as
a decarboxylase inhibitor and is sold in the US. It is administered in combination
with l-dopa to alleviate nausea.4 It irreversibly binds to and permanently deactivates
pyridoxal 5′-phosphate (PLP) and PLP-dependent enzymes and depletes PLP reserve
pools.5 The first documentation of novel carbidopa-induced dyskinesias was in 2012.1
Research into the phenomenon led to the formulation of the hypothesis that if significant depletion of histamine induces dyskinesias, then carbidopa is capable of inducing
dyskinesias, which if not managed properly may be perceived as irreversible.
Benserazide is a decarboxylase inhibitor sold outside of the US. The term
“benserazide” refers to the drug or its metabolite trihydroxybenzylhydrazine. No
efficacy claims have been approved by the US Food and Drug Administration (FDA)
for carbidopa or benserazide.6 Their only indication is management of l-dopa-induced
nausea, a side effect.4,6 Double-blind studies are used to demonstrate efficacy, but are
not appropriate for developing comprehensive side-effect profiles. Fatal events, which
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can occur at a rate of one in 10,000, may not be observed
during a limited-population and limited-duration study.
Endogenous versus competitive
inhibition
The endogenous state relating to serotonin and dopamine exists when no amino acid precursors are taken, or
when inadequate or improperly balanced precursors are
administered. Competitive inhibition is the interaction
of serotonin and dopamine that may occur in synthesis,
transport, and metabolism only when adequate and properly
balanced amounts of serotonin and dopamine amino acid
precursors are administered simultaneously. Organic cationtransporter type 2 functional status analysis verifies the
existence of the serotonin/dopamine competitive inhibition
state under the apical regulatory supersystem model. When
competitive inhibition under this system exists, changes to
either serotonin or dopamine concentrations individually
will affect both serotonin and dopamine concentrations in
a predictable manner.1,7–16
Relative nutritional deficiency
A relative nutritional deficiency (RND) exists when optimal nutrient intake cannot meet system needs. Parkinson’s
disease may induce many RNDs associated with depletions
of serotonin, dopamine, norepinephrine, epinephrine, thiols
(homocysteine, l-methionine, S-adenosyl-l-methionine,
S-adenosyl-homocysteine, cystathione, l-cysteine, and glutathione), l-tyrosine, and l-tryptophan.1,7,17,18–23
l -dopa may induce depletions of serotonin, thiols,
l-tyrosine, and l-tryptophan, resulting in RNDs (Figure 1).1,7
Carbidopa may induce depletions of peripheral serotonin,
dopamine, norepinephrine, and epinephrine, along with
system-wide depletion of niacin and vitamin B6, resulting
in multiple system RNDs. Over 300 enzymes and proteins
require vitamin B6 for normal function.1,7,24–29
L-dopa
Drug/nutrient perspective
A nutrient is any substance that facilitates normal system
function. A drug is any substance that induces abnormal system function. A nutrient may become a drug. A drug may not
become a nutrient. When the nutrient 5-HTP is administered
as a single agent, dopamine depletion may occur. If dopamine
depletion is induced, 5-HTP is no longer functioning as a
nutrient; it is a drug.1,7–22 When l-dopa is administered as
a single agent, it may deplete serotonin, and would then be
considered a drug, not a nutrient.1,7,30–34
l-dopa-induced
Depletes
Sulfur amino acids
Serotonin
Depletes
Depletes
Depletes
Dopamine
L-tyrosine
Depletes
nausea
The only indication for carbidopa and benserazide is control
of nausea resulting from improper l-dopa administration.
The enzyme l-aromatic amino acid decarboxylase (AADC)
catalyzes the synthesis of serotonin and dopamine by metabolizing 5-HTP and l-dopa, respectively. Through irreversible
inhibition of AADC, carbidopa or benserazide compromises
peripheral synthesis of serotonin and dopamine. This druginduced inhibition of peripheral metabolism of l-dopa by
AADC leaves more l-dopa unmetabolized and available
to freely cross the blood–brain barrier into the central nervous system. As a result, when carbidopa or benserazide is
administered, lower l-dopa daily intake values are required
to achieve the same central nervous system results.4,6
It is documented that 5-HTP controls l-dopa-induced
nausea, utilizing the same basic chemical mechanism as
carbidopa and benserazide: AADC inhibition. Carbidopa and
benserazide inhibition is irreversible while 5-HTP inhibition is reversible. The use of 5-HTP is superior, since under
proper administration it is a nutrient that does not deplete
systems or induce abnormal system functions when properly
administered.1,7,35–37
If the goal of administering 5-HTP for the control of
l-dopa-induced nausea is to have it function as a nutrient, this
is not merely a simple substitution. It requires concomitant
L-tryptophan
5-HTP
Depletes
Figure 1 Administering any of the illustrated components in a dominant manner will facilitate the associated depletion.
Notes: Copyright © 2012. Dove Medical Press. Adapted from Hinz M, Stein A, Uncini T. The discrediting of the monoamine hypothesis. Int J Gen Med. 2012;5:135–142.15
Abbreviation: HTP, hydroxytryptophan.
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administration of l-dopa with 5-HTP, along with the “core
nutrients”: l-tyrosine, a thiol (l-cysteine, glutathione, S-adenosyl
methionine, or l-methionine), and cofactors (vitamin C, vitamin
B6, and calcium carbonate). Administration of properly balanced
core nutrients needs to be guided by organic cation-transporter
type 2 functional status analysis, in order to achieve a balance
that does not convert the nutrients into a drug.1,7,37
All l-dopa single-ingredient products were discontinued by the pharmaceutical companies in the US in 1999.38
Concomitant l-dopa/carbidopa products became the only
prescription form of l-dopa available. If an indication for
l-dopa as a single ingredient is identified, it is available
only as a nutritionally sourced product, such as Mucuna
cochinchinensis (which is defined by the US Department
of Agriculture as a synonym for Mucuna pruriens).38,39 Few
physicians are aware of the existence of this product.
Carbidopa dyskinesias
Abnormal or impaired voluntary movements are dyskinesias.40
Movement disorders associated with Parkinson’s disease
include tremors, and other uncoordinated motions. These
are often seen when there are inadequate levels of l-dopa
available in the system. For over 50 years, all dyskinesias
experienced while taking l-dopa or concomitant carbidopa/
l -dopa preparations were described as l -dopa-induced
dyskinesias.41–48 It is common for dyskinesia studies that
reference administration of concomitant l-dopa/carbidopa
to refer to the combination as l-dopa.49
Novel observations reporting a group of 17 Parkinson’s
disease patients led to identification of carbidopa-induced
dyskinesias, which had not been documented prior to 2012.1
These patients had been ingesting prescribed concomitant
l-dopa/carbidopa preparations for 1–7 years. Their drugs
were continued as the core nutrients were started. The mean
daily dosing value of l-dopa/carbidopa was 1,000 mg and
250 mg, respectively, at the initiation of the core nutrients.
The mean duration of previous drug treatment was 3 years,
7 months. Onset of dyskinesias began within the first week
of treatment when the core nutrients were added. Dyskinesias
were generally described as facial twitching and head bobbing
due to peripheral muscle-control problems within the neck
and upper shoulders. When dyskinesias developed, the l-dopa/
carbidopa was immediately discontinued and the nutritionally sourced l-dopa increased fivefold to compensate for the
loss of the carbidopa effect on the central nervous system by
blocking peripheral conversion of l-dopa to dopamine. This
conversion to higher-dose l-dopa was monitored using the
previously published pill-stop technique.37 Following this
Parkinson’s disease: carbidopa, nausea, and dyskinesia
protocol, all patients achieved full resolution of dyskinesias
within 4 days. This led to the hypothesis that the dyskinesias
that resolved after applying the new protocol had been induced
by the carbidopa and were not related to the l-dopa. There
were no refractory dyskinesias experienced.
PLP
Histidine decarboxylase (HDC) and AADC are PLP-dependent
enzymes that catalyze the metabolism of histidine to
histamine.50 Each contains an apoprotein core requiring
irreversible hydrazine–PLP binding for activation. PLP then
becomes the active site for catalyzing reactions.5 Carbidopa
and benserazide induce permanent deactivation and irreversible binding of PLP, PLP-dependent enzymes, and depletion
of PLP reserve pools.1,24 While PLP freely crosses the blood–
brain barrier,51 carbidopa and benserazide do not.4,6 If carbidopa and benserazide deplete peripheral PLP, then central
PLP is also depleted when the system reaches equilibrium.
Over 300 enzymes and proteins may be adversely affected
by this extensive PLP collapse.24
Semantic change and neologisms
Dyskinesias are classified as either reversible or irreversible.
Between 1960 and 1975, when only the single-ingredient
l-dopa was available, no l-dopa-induced irreversible dyskinesias were documented.52 In 1975, the FDA approved
the combined formulation of l-dopa with carbidopa for
Parkinson’s disease treatment. The neologism “ l-dopainduced irreversible dyskinesias” first appeared in the literature after 1975.53 A semantic change had occurred: the
term “l-dopa-induced dyskinesias” was expanded to include
l-dopa-induced irreversible dyskinesias.
A 1971 article noted: “Transitory adventitious movements are the commonest dose-limiting adverse reaction
to levodopa in parkinsonian patients. Prompt resolution of
dyskinetic symptoms usually attends reduction in levodopa
dosage or the administration of pyridoxine hydrochloride.”54
A 1999 article noted: “As Parkinson’s disease progresses, the
dosage and frequency of levodopa needs to be increased to
maintain control. As a result, most patients develop irreversible dyskinesias.”55 A 2012 article noted: “The most effective
pharmacologic treatment for PD, levodopa, has a limited
period of effectiveness (7–12 years) and is associated with
irreversible dyskinesias.”56
Antihistamine dyskinesias
To formulate the following observations, Hinz et al treated
over 800 Parkinson’s disease patients primarily with Mucuna
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pruriens-sourced l-dopa, with and without carbidopa. An
antihistamine is a substance that inhibits the histamine
agonist, inhibits histamine synthesis, or induces physiologic
antihistamine effects.57 Antihistamine effects may be exerted
by 5-HTP (weak), l-dopa (strong), and carbidopa (potentially
profound). AADC or HDC is exclusively responsible for
catalyzing histamine synthesis. If 5-HTP induces a reversible
inhibition of AADC, then a weak antihistamine effect may be
present.1,16 This is a novel documentation of 5-HTP having a
potential antihistamine effect.
l-dopa may induce both strong and weak antihistamine
effects. Dopamine metabolism to epinephrine is without
biochemical regulation. Synthesis of epinephrine shares
a direct relationship with dopamine. A strong physiologic
antihistamine effect is associated with increased epinephrine synthesis induced by administration of l-dopa. The
rapid power of epinephrine to reverse acute life-threatening
histamine collapse is well known in medicine.57 l-dopa also
induces a second weaker antihistamine effect through reversible inhibition of AADC.1
Carbidopa and benserazide have the ability to induce a
previously undocumented profound antihistamine effect.
These drugs irreversibly bind to and permanently deactivate
the two PLP-dependent enzymes responsible for histamine
synthesis: AADC and HDC.5,58,59 This is exacerbated by
depletion of their PLP substrate and PLP reserve pools.5
Dyskinesias may be induced by prolonged high-dose antihistamine ingestion or overdose.60–63 If carbidopa is administered
in high-enough and/or long-enough concentrations to cause
significant collapse of histamine synthesis, then carbidopainduced antihistamine dyskinesias will occur.
Discussion
l-dopa-induced
dyskinesias have not been observed or
documented in the serotonin/dopamine competitive inhibition state. Prior to 1976 and the introduction of carbidopa,
there was no documentation of “l-dopa-induced irreversible
dyskinesias.”52
The molecular weight of PLP is 247.142.63 Carbidopa
has a molecular weight of 244.244.64 Molecular binding of
carbidopa to PLP is in a 1:1 ratio. Free adult male PLP is
placed at 167 mg.65 The PLP that is noncovalently bound to
about 300 enzymes and proteins represents the PLP reserve
pool, which is at equilibrium with free PLP.24 The amount of
PLP bound and unbound system-wide is not agreed upon.
Assume carbidopa ingestion of 250 mg per day over a 4-year
period, while ingesting the US-recommended daily allowance
of about 2 mg of vitamin B6 per day. This reveals a potential
192
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irreversible carbidopa PLP-induced deficiency of 0.36208 kg
(0.78 lb). If PLP depletion is great enough, then administration of 2 mg per day of vitamin B6 will never reverse the
profound drug-induced PLP RND and the carbidopa-induced
antihistamine dyskinesias in the patient’s lifetime. The
observed dyskinesias will be perceived as irreversible.
Effective control of reversible l-dopa-induced dyskinesias
with PLP was documented in the 15-year precarbidopa era.54
It is documented that administration of adequate amounts of
PLP will reverse the AADC and HDC effects from carbidopa
when it is stopped.66 If discontinuation of carbidopa with
administration of ample vitamin B6 is effective over time at
reversing the effects of irreversible binding of carbidopa to
AADC and HDC as new molecules of these enzymes are
synthesized, then the approach will be effective in reversing carbidopa-induced antihistamine dyskinesias. The PLP
reserve pool is much larger than previously realized. It is
made up of about 300 enzymes and proteins that are noncovalently bound to PLP. If the PLP reserve pool is significantly
greater than anticipated, then adequate reversal of carbidopa
PLP collapse may take administration of PLP-dosing values
in excess of those previously associated with restoration of
PLP collapse. For optimal restoration of PLP collapse, carbidopa or benserazide needs to be discontinued.
Conclusion
This paper discusses the mechanism of action whereby
5-HTP controls l-dopa-induced nausea. It also discusses
the previously undocumented potential of carbidopa and
benserazide to induce profound antihistamine dyskinesias
that are irreversible if ample vitamin B6 replacement is not
provided.
During the 15 years prior to 1975, when l-dopa was
prescribed without carbidopa, there was no documentation of irreversible dyskinesias. After the FDA approval of
carbidopa/l-dopa, the neologism “l-dopa-induced irreversible dyskinesias” began to appear in the literature as a semantic change. After carbidopa was approved by the FDA in 1975
for concomitant administration with l-dopa, all new-onset
dyskinesias have continued to be wrongly attributed to l-dopa
alone. Documentation of carbidopa-induced dyskinesias did
not exist until 2012. Irreversible antihistamine dyskinesias
are a function of carbidopa’s mechanism of action, which
causes collapse of histamine synthesis that is exacerbated by
PLP collapse and PLP reserve-pool depletion.
The possible hesitation of the medical community
to embrace the nutritional approach by giving up the
drugs (carbidopa or benserazide) is without foundation.
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The efficacy of l-dopa without the drugs carbidopa or
benserazide has been amply documented in double-blind
studies since 1960. There are no efficacy claims for these
drugs approved by the FDA. Properly administering the
nondrug protocol that incorporates the core nutrients definitively controls l-dopa-induced nausea and avoids irreversible
dyskinesias. No carbidopa or benserazide is utilized in this
regimen, thereby eliminating the massive vitamin B6 depletion experienced by patients taking the combined l-dopa/
carbidopa formulation. This nutritional approach should
raise no concern, as all of the ingredients are classified by the
FDA as being safe enough for over-the-counter sales.
Disclosure
MH discloses his relationship with CHK Nutrition, which
was wholly divested in June 2011, along with current affiliations with DBS Labs and NeuroResearch Clinics. The other
authors report no conflicts of interest in this work.
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Return to index
Perspectives
Parkinson’s disease-associated melanin steal
10 December 2014
Marty Hinz 1
Alvin Stein 2
Ted Cole 3
2
Plantation, FL, USA; 3Cole Center
for Healing, Cincinnati, OH, USA
1
Abstract: Urinary dopamine fluctuations in the competitive inhibition state were first
documented in 2009. At that time, it was noted that progressively higher daily dosing values
of L-tyrosine decreased the magnitude of these fluctuations. While extensive statistical analysis
has been performed by the authors since 2004, it was not until 2012 that a plausible explanation
was formulated. In the process, correlations with L-tyrosine administration and the on/off effect
of Parkinson’s disease were defined. This paper documents the current knowledge with regard
to the management of retrograde phase 1 dopamine fluctuations and investigates the hypothesis
that they are caused by a melanin steal phenomenon.
Keywords: fluctuations, L-dopa, dopamine, melanocyte
Introduction
In 2004, during interpretation of urinary serotonin and dopamine amino acid load
testing, retrograde phase 1 urinary dopamine fluctuations were defined. By 2005, it
was noted that increasing the daily L-tyrosine consumption significantly decreased
fluctuations. The phenomenon was formally documented in 2009:
[…] the fluctuations in dopamine excretion were smaller in samples obtained from
patients ingesting incrementally greater amounts of tyrosine; and this difference for the
combined phases 1, 2, and 3 reached a high level of statistical significance (p , 0.0001)
when compared to phase 0 samples.1
A potential etiology of dopamine fluctuations was not defined until 2012. This
paper documents the current knowledge regarding this phenomenon as associated
with the treatment of Parkinson’s disease. The primary hypothesis is that if significant
retrograde phase 1 urinary dopamine fluctuations exist in the competitive inhibition
state, then the primary force causing this phenomenon is melanin steal, which causes
dopaquinone to preferentially utilize L-tyrosine and L-3,4-dihydroxyphenylalanine
(L-dopa), leading to an inconsistency of dopamine synthesis.
The three-phase response
Clinical Research, NeuroResearch Clinics,
Inc., 1008 Dolphin Dr, Cape Coral,
FL 33904, USA
Tel +1 218 626 2220
Fax +1 218 626 1638
L-tryptophan is metabolized to 5-hydroxytryptophan (5-HTP), which in turn is
metabolized by aromatic L-amino acid decarboxylase (AADC) to serotonin. L-tyrosine
is metabolized to L-dopa, which in turn is metabolized by AADC to dopamine.2–8
Competitive inhibition between serotonin and dopamine exists in transport, synthesis,
and metabolism when precursors of both are administered simultaneously in levels
that are high enough and properly balanced.5,6 Objective verification of the competitive inhibition state is under the apical regulatory super system (APRESS) model.
Under APRESS, changes in only serotonin concentrations will affect changes in
dopamine concentrations in a predictable manner. The inverse is also true: changes
to only dopamine concentrations will affect serotonin concentrations in a predictable
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http://dx.doi.org/10.2147/NDT.S74952
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Hinz et al
manner. Functions exclusively controlled by manipulation
of serotonin in the endogenous state may be regulated by
dopamine and/or serotonin manipulation in the competitive inhibition state. Functions exclusively controlled by
manipulation of dopamine in the endogenous state may be
regulated by dopamine and/or serotonin manipulation in the
competitive inhibition state.5,6
Figure 1 illustrates the three phases of correlation between
urinary serotonin or dopamine with the total daily dosing
values of serotonin and dopamine precursors in competitive
inhibition: inverse (phase 1), no (phase 2), and direct (phase 3)
correlation.1 These responses are generated by the basolateral
organic cation transporters type-2 (OCT-2) of the proximal
convoluted renal tubule cells’ (PCT) S3 segment. Under
normal conditions, serotonin and dopamine filtered at the
glomerulus are transported into the PCT and then metabolized, and are not found in the final urine. The serotonin and
dopamine (which are centrally acting monoamines) in the final
urine represent monoamines that are newly synthesized by the
kidneys. The monoamines newly synthesized in the PCT are
preferentially transported by serotonin transporters (SERT)
and OCT-2 across the S3 basolateral border of the PCT to the
peripheral circulation via the renal vein. SERT is responsible
for bulk transport, while OCT-2 is responsible for fine tuning
the exact final amount of monoamines transported to the system. The monoamines not transported to the peripheral system
are carried across the apical PCT S3 surface by organic cation
transporters novel type-2 (OCT-N2), then onto the final urine
as waste.2,9 The importance of renal OCT-2 functional status
analysis to the central nervous system is documented:
The current knowledge of the distribution and functional
properties […] of cation transport measured in intact plasma
membranes is used to postulate identical or homologous
transporters in intestine, liver, kidney, and brain.10
Urinary monoamine levels
Phase 1
Phase 2
Phase 3
Optimal range
→→Increasing the daily balanced amino acid dosing→→
Figure 1 The three-phase response of serotonin or dopamine in the competitive
inhibition state.
Note: Copyright © 2013. Dove Medical Press. Adapted from Hinz M, Stein A,
Uncini T. The dual-gate lumen model of renal monotransport. Neuropsychiatr Dis
Treat. 2010;6:387–392.9
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Serotonin and dopamine both need to be conceptualized
independent of each other, each with its own three-phase model.
The phases illustrated in Figure 1 correlate with specific configurations which, in the competitive inhibition state, define the
functional status of the OCT-2 in the transport of serotonin and
dopamine. Phase 1 correlates with the transporter entrance gate
inhibiting full monoamine access to the unsaturated transporter
lumen. Entrance gate restriction of monoamine access to the
transporter lumen dissipates as the sum total of serotonin and
dopamine presenting at the gate increases. This causes increasing amounts of monoamine to be transported to the peripheral
system, while decreasing concentrations observed in the final
urine. Phase 2 correlates with full monoamine access to the
unsaturated lumen as the effects of the entrance gate restriction
are no longer present. Phase 3 correlates with full transporter
lumen access as the entrance gate effects are no longer a factor
while the lumen transporter is saturated. This leads to the phenomenon whereby increases in serotonin or dopamine concentrations presenting at the saturated transporter lead to increased
excretion of these monoamines in the final urine.2,5,6,9
Fluctuations
It takes 5 days to achieve equilibrium when the daily dosing
value of a serotonin or dopamine amino acid precursor is
started or changed.5,6 Urinary dopamine levels that are higher
than can be achieved in phase 3 at the equilibrium of a specific
amino acid dosing value are definitive evidence that urinary
dopamine fluctuations are present. For example, while ingesting 120 mg of L-dopa per day, the phase 3 urinary dopamine
response limit is defined as 1,500 µg of dopamine per gram of
creatinine (µg/g cr). Urinary levels higher than 1,500 µg/g cr
are not a phase 3 response, but represent retrograde phase 1
dopamine fluctuations, as illustrated in Figure 2.
These fluctuating retrograde phase 1 urinary dopamine
assay results are not reproducible. They are also revealed with
repeat assays on different days with the same L-dopa dosing values. In studying this phenomenon, it is apparent that
there is a force variably compromising dopamine synthesis,
pulling dopamine back into phase 1, which then fluctuates.
These variations are a random occurrence in the laboratory
assay. The urinary dopamine assay is a single snapshot of
the fluctuating urinary dopamine level in the competitive
inhibition state. Serotonin levels vacillate in response to
dopamine fluctuations, a phenomenon that is explained by
the APRESS model.5
Methodology
Table 1 is based on statistical analysis of urinary serotonin
and dopamine amino acid precursor load testing performed
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Phase 1
Phase 2
h igh-complexity laboratory testing that is accredited by
Clinical Laboratory Improvement Amendments (CLIA).
Phase 3
120 mg L-dopa maximum phase 3 =1,500 µg/g cr
x
Parkinson’s disease melanin
steal model
When taking 120 mg of L-dopa
daily, a urinary dopamine level of
2,000 µg/g cr represents a
phase 1 retrograde fluctuation.
→→Increasing the daily balanced amino acid dosing→→
Figure 2 Retrograde phase 1 dopamine fluctuation.
Notes: At a dose of 120 mg of L-dopa, urinary phase 3 dopamine levels higher
than 1,500 µg/g cr are not observed. Under these conditions, levels higher than
1,500 µg/g cr represent a phase 1 retrograde fluctuation. Copyright © 2013. Dove
Medical Press. Adapted from Hinz M, Stein A, Uncini T. The dual-gate lumen model
of renal monotransport. Neuropsychiatr Dis Treat. 2010;6:387–392.9
Abbreviations: cr, creatinine; L-dopa, L-3,4-dihydroxyphenylalanine.
on Parkinson’s disease patients by DBS Laboratory Services, Inc. (Duluth, MN, USA) between January 1, 2014
and September 4, 2014.
Laboratory sample processing was as follows. After
1 week on a specific amino acid dosing, a urinary sample was
obtained 6 hours prior to onset of the sleep cycle; 4 pm was
the most frequent time of collection. After stabilization with
6 N HCl for preservation of the monoamines, the samples
were shipped to DBS Laboratory Services, Inc. Commercial
kits for radioimmunoassay were used (3 CAT PIA IC88501
and IB89527; Immuno Biological Laboratories, Inc, Minneapolis, MN, USA). DBS Laboratory Services, Inc. performs
With the induction of suboptimal L-tyrosine and/or L-dopa
concentrations, retrograde phase 1 fluctuations can and will
occur.1,5,6 Dopamine fluctuations may be intermittent. It is
common to observe initial assays wherein the dopamine
and serotonin are following the three-phase model prior
to the occurrence of retrograde phase 1 dopamine fluctuations. It has been previously documented that, in the
competitive inhibition state, increasing L-tyrosine daily
dosing decreases dopamine fluctuations.1 Prior research
has revealed that administration of progressively higher
amounts of L-tyrosine can move the urinary dopamine out
of phase 1, through phase 2, and into phase 3. This research
further revealed that L-tyrosine alone will not establish
urinary dopamine concentrations higher than 475 µg/g cr
going into phase 3.5,6
The prototype for understanding the etiology of dopamine
fluctuations is the exaggerated response seen in Parkinson’s
disease. Retrograde phase 1 urinary dopamine levels of 20,000
to 200,000 µg/g cr are common, while levels above 2 million
µg/g cr are occasionally observed. Exacerbation of dopamine
fluctuations may occur as the serotonin and dopamine daily
amino acid precursor dosing levels (not including L-tyrosine)
increase and/or as time passes on a static dose.
Table 1 Group amino acid parameters associated with the reported urinary dopamine amino acid load testing results in patients
diagnosed with Parkinson’s disease
N
Mean 5-HTP
Median 5-HTP
Standard deviation 5-HTP
5-HTP dosing range
Mean L-dopa
Median L-dopa
Standard deviation L-dopa
L-dopa dosing range
Mean tyrosine
Median tyrosine
Standard deviation tyrosine
Tyrosine dosing range
Mean urinary dopamine
Median urinary dopamine
Standard deviation urinary dopamine
Urinary dopamine range
All subjects
Subjects with 2 tests
168
80
75 mg
123.8 mg
76.0 mg
37.5–300 mg
4,200 mg
4,505 mg
3,169 mg
480–12,600 mg
3,000 mg
9,345 mg
13.015 mg
375–46,500 mg
52,461 μg/g cr
83,144 μg/g cr
95,020 μg/g cr
2,047–528,840 μg/g cr
112.5 mg
127.9 mg
71.4 mg
37.5–300 mg
5,040 mg
5,595 mg
2,874.4 mg
0.0–14,280 mg
16,500 mg
18,064 mg
13,784 mg
750–46,500 mg
71,197 μg/g cr
99,086 μg/g cr
111,994 μg/g cr
6,265–528,840 μg/g cr
Notes: All data are based on the last test submitted and include all subjects tested between January 1 and September 4, 2014. In the right column, subjects with fewer than
three tests performed were excluded.
Abbreviations: 5-HTP, 5-hydroxytryptophan; cr, creatinine; L-dopa, L-3,4-dihydroxyphenylalanine.
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Hinz et al
While carbidopa/L-dopa combinations are the current
standard in medicine, 5-HTP, as documented in Table 1, was
administered in place of carbidopa based on the following
considerations. Carbidopa has no efficacy in the treatment
of Parkinson’s disease symptoms. Its only indication is
management of the L-dopa-induced side effect nausea.11
It is documented that carbidopa irreversibly binds to and
permanently deactivates the active form of vitamin B6
(pyridoxal 5′-phosphate [PLP]), PLP-dependent enzymes,
and depletes B6 reserves.12 Depletion of B6 by carbidopa
and benserazide adversely affects over 300 enzymes and
proteins that depend on B6 for their function.13 Both are
effective in controlling L-dopa-induced nausea by the same
mechanism of action, AADC inhibition.5,6,11 The inhibition
caused by carbidopa is irreversible, while 5-HTP inhibition
is reversible.5,6,12 A primary advantage of 5-HTP over carbidopa is that it does not irreversibly bind to nor permanently
deactivate or deplete PLP, PLP-dependent enzymes, and PLP
reserves, thereby avoiding system-wide nutritional deficiency
and collapse of B6.12 Both Parkinson’s disease and administration of L-dopa are associated with serotonin depletion.4,14–17
5-HTP is freely metabolized to serotonin without biochemical
feedback regulation. This means that it is the most powerful
precursor available for serotonin synthesis in compensating
for the known serotonin depletion associated with Parkinson’s disease and its treatment.5,6
L-tyrosine administration has not been previously documented at the daily dosing levels found in Table 1. It is asserted
that daily L-tyrosine dosing, greater than 5,000 mg, needs to be
started or increased only in response to a confirmed laboratory
indication in the competitive inhibition state. Previous research
by the authors has revealed that, when the laboratory indications
exist, virtually all patients tolerate L-tyrosine administered at
the individualized levels reflected in Table 1. The hypothesis is
that if there is a tolerance to the nutrients being administered,
then there was a need in the body for these nutrients.
Table 2 presents real-life data from one subject. While
the daily dosing value of L-dopa was decreased by 33.3%
between the first and second assays, the urinary dopamine
levels increased more than 16-fold. L-cysteine is administered to compensate for the ability of L-dopa to deplete
thiols.5,6 The next recommended step in treatment would be to
start L-tyrosine 3,750 mg twice a day for control of dopamine
fluctuations and to continue adjusting the L-dopa daily dosing
with pill stops consistent with previous documentation.8
L-tyrosine is an amino acid synthesized from phenylalanine.
The recommended dietary allowance (RDA) for phenylalanine is 3,000 to 5,000 mg per day.18 In humans, L-tyrosine is
metabolized to one of five metabolites: tyramine, 3-iodo-Ltyrosine, 4-hydroxyphenylpyruvate, dopaquinone, or L-dopa.19
Fluctuations of tyramine, 3-iodo-L-tyrosine, and 4-hydroxyphenylpyruvate have not been documented. By default, this
leaves the melanin system, with its precursor dopaquinone,
as the prime candidate for generating L-dopa/dopamine
fluctuations in the competitive inhibition state. Both melanin
and dopamine fluctuations have been documented.1,4,20–25
The inverse association between the increasing daily L-dopa
dosing value with the magnitude of dopamine fluctuations in
the competitive inhibition state has also been documented.1,4
Not documented until now are the interactions of L-tyrosine,
L-dopa, and dopaquinone, with regard to the previously documented dopamine variances.1
As noted in Figure 3, two enzymes catalyze metabolism
of L-tyrosine to L-dopa: tyrosinase and tyrosine hydroxylase.
Tyrosinase also catalyzes metabolism of both L-tyrosine and
L-dopa to dopaquinone, the critical precursor of melanin synthesis (Figure 3).19,26 Tyrosinase is known to have higher efficacy in the conversion of dopamine to dopaquinone than in the
conversion of L-tyrosine to L-dopa.27 In Parkinson’s disease,
there is a 50% to 90% loss of tyrosine hydroxylase-containing
cells and a 33% to 80% loss of neuromelanin-containing neurons in the substantia nigra.28 As a result, the system attempts
to synthesize more melanin by increasing concentrations of
β-melanocyte-stimulating hormone (MSH).29 An increase in
MSH induces increased activity in tyrosinase. Increases in
tyrosinase activity, up to 90-fold, secondary to MSH stimulation have been reported.30 Melanin fluctuations have been
documented in vivo and in vitro.20–22 The hypothesis is that if
decreasing tyrosine hydroxylase activity and increasing tyrosinase activity is more effective in the synthesis of dopaquinone than dopamine, then this leaves melanin synthesis and
fluctuations in a more primary position, while the melanininduced fluctuations of L-tyrosine and L-dopa are reflected as
dopamine fluctuations on laboratory assay.
Table 2 One patient’s laboratory results
Date
Dopamine μg/g cr
5-HTP
L-tyrosine
L-dopa
L-cysteine
July 5, 2014
September 10, 2014
2,391
42,174
75 mg
75 mg
750 mg
750 mg
2,160 mg
1,440 mg
4,500 mg
4,500 mg
Notes: These data are from one subject. The dopamine of 9/10/2014 demonstrates a retrograde phase 1 dopamine fluctuation. Testing was done at the same time each day.
Note the higher dopamine level with a lower L-dopa dose.
Abbreviations: 5-HTP, 5-hydroxytryptophan; cr, creatinine; L-dopa, L-3,4-dihydroxyphenylalanine.
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Dopaquinone
Tyrosinase
Tyrosinase
Tyrosine
Melanin synthesis
Tyrosinase
L-dopa
Dopamine
Tyrosine
hydroxylase
Figure 3 Tyrosinase enzyme metabolism of tyrosine and L-dopa to dopaquinone along with metabolism of tyrosine to L-dopa by tyrosinase and tyrosine hydroxylase.
Note: Data from Stansley and Yamamoto.14
Implications
The on/off effect is defined as symptoms of Parkinson’s
disease that wax and wane and are not fully controlled with
L-dopa. With classic on/off effect, Parkinson’s disease
patients have better control early in the day, decreased
control 6 to 12 hours after rising, then better control prior
to onset of sleep.31,32 The results reported herein adhered to
the retrograde fluctuation model and L-tyrosine was only
administered for the control of fluctuations when urinary
dopamine levels exceeded 40,000 μg/g cr. This paper is
based on accumulated data, which reveal control of the on/
off effect in over 800 Parkinson’s disease patients treated
with L-tyrosine, administered only when indicated, with
no refractory cases reported. Curiously, low-protein diets
have been reported to have a positive effect in the management of the on/off effect, yet this laboratory-guided amino
acid administration approach ameliorates the phenomenon
completely.33
In Parkinson’s disease patients, the correlation between
motor fluctuations and dopamine fluctuations has been documented for several years.23–25 Until this novel approach, there
was no objective, laboratory-based method for addressing
the problem of dopamine-driven motor fluctuations. Observations also support the assertion that patients not exhibiting the on/off effect who are more difficult to control with
L-dopa may benefit from administration of L-tyrosine in
response to laboratory indications. Once enough L-tyrosine
is administered to compensate for and meet dopaquinone
synthesis needs, further administration of L-tyrosine optimizes dopamine synthesis by meeting some of the dopamine
precursor needs (Figure 3).
Discussion
The need for higher levels of L-tyrosine is not absolute.
Administration needs to be guided by laboratory indication.
When laboratory indication exists, there is a tolerance of the
higher dosing of L-tyrosine. Bearing in mind that the melanin
system has the ability to preferentially steal the precursors
of dopamine, the following question was posed: “What is
the melanin system involved with that is so important that
it has the ability to assume priority in the metabolism of
amino acid precursors over the catecholamine system?”
Melanin regulates cytokines. If optimization of melanin
synthesis occurs using this approach, then this approach may
be the foundation for regulating and optimizing cytokine
function.34,35 No evidence has been found to support the
concept that cytokine function is important enough to preferentially steal the precursors required for catecholamine
synthesis and optimal function. A more compelling argument
is that the various forms of melanin are DNA protective.
Ultraviolet (UV) radiation may cause melanoma and other
deadly events. Melanin has the ability to establish a protective
barrier around DNA, protecting it from toxin damage.36,37 It is
documented that “[…] melanin binds directly to DNA, it acts
as a direct photosensitizer of mtDNA damage during UVA
irradiation.”38 The hypothesis is that if the momentary load
of toxins or UV protection fluctuates, then melanin needs
will also fluctuate.
Conclusion
Urinary dopamine fluctuations have been recognized since
2004, but were first documented in 2009.1 Melanin concentrations are known to fluctuate under normal conditions. In
Parkinson’s disease patients, there is a defect of the postsynaptic dopamine neurons found in the substantia nigra of the brain.
The dark color of the substantia nigra is from neuromelaninrich cells. As the disease progresses, the substantia nigra turns
progressive shades of lighter gray with the loss of neuromelanin. There is diminished tyrosine hydroxylase activity and
an increase in MSH which increases tyrosinase activity. The
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Hinz et al
enhanced tyrosinase activity is more effective at synthesizing
dopaquinone than L-dopa. The model is that dopaquinone/
melanin synthesis has priority in utilization of L-tyrosine
and L-dopa at the expense of stable dopamine synthesis and
concentrations. As a result, dopamine synthesis fluctuates as
the needs of melanin synthesis are preferentially met.
The diagnosis of dopamine fluctuations in the competitive
inhibition state is a novel approach for determining whether
there is adequate L-tyrosine supplementation in the stabilization of Parkinson’s disease patients and may be a powerful
tool for the management of the on/off effect and for the
control of cytokines.
Disclosure
MH discloses his relationship with DBS Laboratory Services,
Inc. and NeuroResearch Clinics, Inc. MH also discloses his
relationship with West Duluth Distribution Company, which
ended in June 2011. The authors report no other conflicts of
interest in this work.
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Dovepress
Neuropsychiatric Disease and Treatment is an international, peerreviewed journal of clinical therapeutics and pharmacology focusing
on concise rapid reporting of clinical or pre-clinical studies on a
range of neuropsychiatric and neurological disorders. This journal
is indexed on PubMed Central, the ‘PsycINFO’ database and CAS,
and is the official journal of The International Neuropsychiatric
Association (INA). The manuscript management system is completely
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29 Depression
Marty Hinz, M.D.
I. INTRODUCTION
Since amino acids obtained from dietary sources are the precursors of mood-regulating neurotransmitters such as serotonin and dopamine, amino acids are considered to hold potential in treating
depression. Neurotransmitter precursors are the subject of ongoing research.
So why is this topic relevant to primary care medicine? Patients have taken matters into their own
hands. Patients are self-treating their depression with amino acid supplements and appear to be motivated by a perceived benefit in their mood and overall health. The amino acid precursors tryptophan,
tyrosine, 5-hydroxytryptophan, and L-dopa are readily available as supplements at doses that exceed
feasible dietary intake. Amino acids supplements have less potential for harm and larger therapeutic
effect when their use is physician-guided.
This chapter presents the bundle damage theory of depression to probe the biologic basis of amino
acid therapy. It offers primary care physicians a treatment protocol that implements laboratory testing to
guide dosing; explains the potential side effects and how these can be minimized; offers quality regulation in product selection; and presents a protocol for simultaneous use of medication and nutrients in
the treatment of clinical depression.
II.
EPIDEMIOLOGY
Depression is a global problem. The World Health Organization notes:32
Nearly 5–10% of persons in a community at a given time are in need of help for depression. As much
as 8–20% of persons carry the risk of developing depression during their lifetime. The average age of
the onset for major depression is between 20 and 40 years. Women have higher rates of depression than
men. Race or ethnicity does not influence the prevalence of depression. World wide depression is the
fourth leading cause of disease burden, accounting for 4.4% of total Disability-Adjusted Life-Years
(DALYs) in the year 2000. It causes the largest amount of non-fatal burden. Disability from depression
world wide is increasing. In 1990, the total years lived with disability (YLD) was 10.7%. By 2000, the
YLD had increased to 12.1% worldwide.33 Mental health conditions have a tendency to move upwards
in ranking, while ranked as the fourth leading cause of disease burden in 2000, it is expected that
depression will move to second place by 2020, second only to heart disease.34
Population surveys suggest that while the incidence of depression is higher in the developed
countries of North America and Europe than in other regions, it is nonetheless a common condition
throughout the world.38 The rate difference is often attributed to underdiagnosis, but newer data
suggest that the Western diet, stressful lifestyle, and higher toxicant exposures contribute to the
prevailing high rates in Westernized countries.32
The monoamine theory fails to explain why the incidences of depression are increasing on a
worldwide basis and is more prevalent in developed countries.1
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Food and Nutrients in Disease Management
III. PATHOPHYSIOLOGY
THE MONOAMINE THEORY
The monoamine theory of depression has long been the major framework against which the treatment of depression has been examined and developed due to the fact that the theory attempts to
provide a pathophysiologic explanation for depression and the actions of antidepressants. The central premise of the monoamine theory states that it may be possible to restore normal function in
depressed patients by targeting the catecholamine and/or serotonin systems with antidepressants.
This theory is based on evidence that depression symptoms can be improved by administering
compounds that are capable of increasing monoamine concentrations in the nerve synapses. Early
research focused on deficits in the catecholamine system with specific emphasis on noradrenalin
as a potential cause for depression. With further research, the theory was expanded to include the
serotonin system as a cause for depression. This research has led to the use of drugs for treatment of
depression that affect changes in monoamine uptake and enzymatic metabolism.1
While many of the depression treatments based on the monoamine theory appear to be initially
useful, many of them lack the short-term and long-term efficacy needed for relief of symptoms in
most patients. In several studies of reuptake inhibitors administered, only 8% to 13% of subjects
obtained relief of symptoms greater than placebo. Remission rates for escitalopram compared to
placebo in adults was studied (48.7% vs. 37.6%, P = 0.003). Here, 11.1% of subjects obtained relief
greater than placebo.35 Remission rates for citalopram versus placebo in another study were studied (52.8% vs. 43.5%, P = 0.003). Here, 9.4% of patients obtained relief greater than placebo.35
Venlafaxine-XR was similar to escitralopram and citalopram (P = 0.03).35
Treatment of the elderly in the primary care setting under the monoamine theory reveals no relief
of symptoms versus placebo. In the elderly (79.6 years, SD = 4.4, N = 174), it was concluded that
citalopram, “was not more effective than placebo for the treatment of depression.”27 In treatment of
depression in patients over 60 years of age with a mean age of 68 years, “Escitalopram treatment
was not significantly different from placebo treatment” (N = 264).29
Depression treatment of children and adolescents ages 7 to 17 (N = 174) with citalopram, under
a double-blind 20 mg/day, 40 mg/day option, found 24% of patients treated with placebo showed
improvement versus 36% of patients taking citalopram.28
Other studies of other reuptake inhibitors revealed similar results.50–55
Reuptake inhibitors are effective in treating other disorders than those for which they were initially developed, such as obesity, panic disorder, anxiety, migraine headaches, ADHD/ADD, premenstrual syndrome, dementia, fibromyalgia, psychotic illness, insomnia, obsessive-compulsive
disorder, and bulimia/anorexia; yet not all drugs that increase serotonin or catecholamine transmission are effective when treating depression.1
Treatment with reuptake inhibitors is based on the monoamine theory, which does not explain
why most subjects studied achieve results no better than placebo and why treatment is much less
efficacious in the elderly. Neither does it explain the efficacy of treating other conditions. In sum,
the mechanism and corresponding medication for the treatment of depression suggest there may be
more to the underlying pathophysiology.
PARKINSONISM MODEL
Insights into the pathophysiology of depression can be gained from understanding another monoamine neurotransmitter disease, Parkinson’s disease. Parkinsonism is caused by damage to the
dopamine postsynaptic neurons of the substantia nigra at levels that result in clinical compromise of
fine motor movement.
Parkinson’s disease has a study model of neurotoxin damage.49 A great deal of understanding about
Parkinson’s disease has resulted from research and case studies involving the neurotoxin MPTP (1-methyl
4-phenyl 1,2,3,6-tetrahydropyridine). In 1982, the first writings on MPTP appeared in the medical
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literature after several heroin addicts administered synthetic heroin (MPPP) that contained the byproduct of synthesis, MPTP.9 Since that time, the MPTP mechanism of action has become the prototype in
the study of Parkinson’s disease. At present, most medical school students study the ability of MPTP to
quickly induce advanced Parkinson’s symptoms in patients without prior history of the disease.
MPTP is a free radical neurotoxin, which interferes with mitochondrial metabolism and leads
to cell death (apoptosis). It freely crosses the blood-brain barrier and has an affinity for the postsynaptic dopamine neurons of the substantia nigra, which it destroys. MPTP is chemically similar
to MPPP (synthetic heroin) and may be produced as a byproduct during the illegal manufacturing
of MPPP and other narcotics.9 The MPTP model of Parkinson’s disease has taught us a lot about
the dopamine neurons of the substantia nigra. The main point is that if enough dopamine neurons
are damaged, the flow of electrical impulses is compromised and Parkinson’s symptoms will occur.
The way to compensate for neurotoxin-induced damage is to increase neurotransmitter levels higher
than is normally found in the system.9
Consistent with the findings of the MPTP model, the pharmacologic treatment is dopamine
agonists, which raise the existing levels of this neurotransmitter above population norms in order to
boost damaged neurons. Dopamine agonists, such as bromocriptine, pergolide, ropinirole, pramipexole, and cabergoline can be used as a monotherapy or in combination with L-dopa. L-dopa crosses
the blood-brain barrier and is freely synthesized into dopamine without biochemical regulation.3
The elevation of dopamine in the central nervous system stimulates the remaining viable dopamine
neurons of the substantia nigra by increasing the electrical flow, which results in restoration of the
regulator function of the dopamine bundles and improvement of disease symptoms.7 The shortcoming is tachyphylaxis, where the dopamine agonist and/or L-dopa become ineffective.
With Parkinson’s patients, establishing dopamine levels in the reference range reported by the
laboratory does not provide relief of symptoms. For example, the reference range of urinary dopamine reported by the laboratory is 40 to 390 micrograms of dopamine per gram of creatinine (the
neurotransmitter-creatinine ratio compensates for dilution of the urine). In our years of research,
we have not observed a patient with Parkinson’s who was able to achieve relief of symptoms with
dopamine levels in this range. For treatment of patients with Parkinson’s, the therapeutic range of
urinary dopamine is 6000 to 8000 micrograms of dopamine per gram of creatinine. Dopamine
levels of this magnitude can be achieved by administration of the amino acid precursor, L-dopa.
Amino acid supplementation can reduce the tachyphylaxis generally associated with pharmacologic
interventions. Once the synaptic levels of dopamine are high enough and the flow of electricity is
once again adequate to regulate fine motor control, clinical resolution of the Parkinsonian tremor
and other symptoms are seen.40
As with Parkinsonism, the damage to other neuron bundles of the serotonin/catecholamine pathways as seen in depression can be dealt with effectively by increasing the neurotransmitter levels
higher than is normally found in the system. This has led our group to propose the Bundle Damage
Theory of Depression.
THE BUNDLE DAMAGE THEORY
The bundle damage theory states:
Neurotransmitter dysfunction disease symptoms, such as symptoms of depression, develop when the
electrical flow through the neuron bundles that regulate function is compromised by damage to the
individual neurons or the neuron components composing the neuron bundle which conducts electricity
to regulate or control function. In order to optimally restore neuron bundle regulatory function, synaptic neurotransmitter levels of the remaining viable neurons must be increased to levels higher than is
normally found in the system, which restores adequate electrical outflow resulting in relief of symptoms
and optimal regulatory function.
Bundles of neurons convey electricity that regulates and/or controls numerous functions in the
body. If enough of the individual neurons of a bundle become damaged the flow of electricity through
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the bundle is diminished, leading to the function being controlled and/or regulated not controlling
properly, causing symptoms of disease to develop. Technically synaptic neurotransmitter levels prior
to treatment in patients with disease due to neuron bundle damage are in the normal range for the
population.
The bundle damage theory and the monoamine theory are not mutually exclusive of each other.
Instead these two theories can be viewed a complementary in that they address different mechanisms of action leading to neurotransmitter dysfunction and compromised electrical flow out of
the postsynaptic neuron. The monoamine theory addresses low levels of neurotransmitters in the
synapse as the etiology of impedance of electrical flow needed to regulate function and keep
disease symptoms under control. The bundle damage theory addresses damage to the primarily
postsynaptic neuron structures that impede the flow of electricity needed to regulate function
and keep disease symptoms under control. With the monoamine theory and the bundle damage
theory the flow of electrical energy needed to regulate function is not adequate. Differentiation
of the two theories lies in the etiology of the dysfunction. Under monoamine theory returning
neurotransmitter levels to normal will relieve disease symptoms. Under the bundle damage theory
synaptic neurotransmitter levels need to be established that are higher than the reference range of
the population.
It is the mechanical damage to the postsynaptic neurons as suggested by the bundle damage
theory and not the synaptic neurotransmitter levels that is the primary cause of monoamine disease.
This subset is composed of about 88% of adult patients and 100% of the elderly patients with depressive symptoms—the nonresponders from the depression studies above.
Neurons are intended to function for life. Loss of a neuron to apoptosis is permanent, although
in limited areas of the brain neurons may regenerate to replace the neurons that have undergone
apoptosis.58 As neurons go into apoptosis in the postsynaptic neuron and become completely nonfunctional they tend to go through an agonizing death where the electrical brilliance with which
they function slowly fades until the electrical flow through the neuron regulating function decreases
and stops over time.
The only way to increase neurotransmitter levels in the central nervous system is to administer
amino acid precursors that cross the blood-brain barrier and are then synthesized into neurotransmitters. Increasing neurotransmitter levels in the synapse is analogous to increasing the voltage in
an electrical wire, whereby turning up the voltage you get more electricity out of the other end of the
wire. Turning up the voltage increases the electrical potential (pressure) of the electrons entering a
partially damaged wiring connection, leading to more electrons (electricity) flowing out of the other
end. In the case of neurotransmitter disease where the neurons of the neuron bundles are damaged
to the point that the electricity flowing out of the neuron bundles is diminished disease develops.
Increasing neurotransmitter levels will effectively increase voltage in the remaining viable neurons
in the bundle, causing electrical flow out of the damaged neuron bundles to increase to the point that
normal regulation and/or control is once again observed. In this state, from a clinical standpoint, the
symptoms of disease are under control.
ETIOLOGY OF BUNDLE DAMAGE
Bundles of monoamine neurons can be impaired from neurotoxin exposures, trauma, or biological insult.56 Neurotoxin exposures are poorly defined and ongoing exposures are in contrast to
the MPTP study model of Parkinsonism. The most comprehensive listing located reveals 1179
known neurotoxins.39 Susceptibility of individuals based on genetic predisposition, environmental
influences, synergy between chemicals or other predisposing factors suggest that some individuals
may experience neurotoxicity from many unlisted substances and at lower than threshold doses
of known neurotoxins, and so was not considered. Under the bundle damage theory it is assumed
that neurotoxins are the leading cause of monoamine bundle damage leading to the following
speculation:
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The bundle damage’s theory of repeated insult during a lifetime can explain the lack of efficacy seen
in the treatment of elderly with reuptake inhibitors who presumably have greater cumulative lifetime
effects from neurotoxins and other events that cause neuron damage. In the end these patients need
to have neurotransmitter levels established that are much higher than can be achieved with reuptake
inhibitors alone.
With repeated insult more damage occurs, which is cumulative. When the damage is at the point
where the neurotransmitter levels needed to control disease symptoms cannot be achieved with the
use of reuptake inhibitors alone, from a clinical standpoint it appears that the drug is not working.
This may explain why about 90% of adults treated with reuptake inhibitors achieve results no better
than placebo.
The bundle damage theory may also explain why developed countries have a higher rate of
depression as the population is exposed at a higher rate to neurotoxins.
Since insult exposure may be ongoing in patients with depression, optimizing nutritional status
is important. Improving neuronal ability to minimize and recover from toxic insult form the basis
of the antioxidant nutrients Dr. David Perlmutter explains in Chapter 28, “Parkinson’s Disease,” and
the membrane-stabilizing nutrients Dr. Patricia Kane explains in Chapter 24, “Seizures.”
IV. PHARMACOLOGY
AMINO ACIDS
Treatment of depression, as well as any other monoamine neurotransmitter diseases, is not possible
through the direct administration of monoamine neurotransmitters. This is due to the fact that monoamine neurotransmitters do not cross the blood-brain barrier, as depicted in Figure 29.1.2,3,4,5 The
only way to increase the levels of central nervous system monoamine neurotransmitter molecules is
to provide amino acid precursors, which cross the blood-brain barrier and are synthesized into their
respective neurotransmitters by presynaptic neurons.6,7
REUPTAKE INHIBITOR DEPLETION OF MONOAMINE
PERIPHERAL
SYSTEM
Serotonin, Dopamine,
Norepinephrine, Epinephrine
Tryptophan, 5-HTP,
L-tyrosine, L-dopa
X
Blood Brain Barrier
The National Institute of Drug Abuse presents a detailed discussion on its website on how reuptake
inhibitors deplete neurotransmitters.22 Medicines used to treat depression are not the only drugs
that block reuptake; cocaine and amphetamines block reuptake as well.22 Reuptake inhibitors block
CENTRAL
NERVOUS
SYSTEM
X
Serotonin, Dopamine,
Norepinephrine, Epinephrine
Tryptophan, 5-HTP,
L-tyrosine, L-dopa
FIGURE 29.1 The monoamine neurotransmitters serotonin, dopamine, norepinephrine, and epinephrine
do not cross the blood-brain barrier; therefore, peripheral administration of these neurotransmitters will not
increase central nervous system neurotransmitter levels. The amino acid precursors of these neurotransmitters
do cross the blood-brain barrier. The only way to increase central nervous system neurotransmitter levels is
through administration of amino acid precursors.
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FIGURE 29.2 The effects of reuptake inhibitors on neurotransmitter levels, reuptake inhibition may deplete
neurotransmitters. In the left picture, prior to treatment, neurotransmitter levels are not high enough to prevent
symptoms of disease. In the center picture, reuptake is blocked, neurotransmitters move from the vesicles of
the presynaptic neuron to the synapse. In the right picture, the neurotransmitters are depleted, the increase in
synaptic neurotransmitter levels results in an increase in MAO and COMT metabolism (From The National
Institute of Drug Abuse).
the uptake of neurotransmitters back into the presynaptic neuron. In doing so, synaptic levels are
increased. As synaptic neurotransmitter levels rise, relief of symptoms is observed.
Monoamine Oxidase (MAO) and the Catecholamine O-Methyl Transferase (COMT) enzymes
metabolize serotonin, dopamine, norepinephrine, and epinephrine. The monoamine neurotransmitters are relatively stable and are not metabolized until they come in contact with the MAO
and COMT enzymes. When neurotransmitters are in the vesicles of the presynaptic neuron, they
are not exposed to metabolism by the MAO and COMT enzymes; they are safe and stable. When
neurotransmitters are in the synapse between the presynaptic and postsynaptic neuron, they are
exposed to enzymatic metabolism, which leads to the depletion of neurotransmitters if proper levels
of amino acid precursors are not administered to compensate for this process.24
In depressed patients, synaptic neurotransmitter levels are not high enough to prevent disease
symptoms, as illustrated in Figure 29.2. Treatment with reuptake inhibitors leads to a decrease
in presynaptic neurotransmitter levels (where they are safe from enzymatic metabolism) and an
increase in the number of neurotransmitters in the synapse. The blocking of neurotransmitter
reuptake increases synaptic levels and the probability that neurotransmitters will experience enzymatic metabolism.
With regards to Figure 29.2, the net effect of enzymatic metabolism is the depletion of neurotransmitter levels in the central nervous system. Neurotransmitters do not cross the blood-brain
barrier. Therefore, the only way to increase central nervous system levels or to prevent the overall depletion of neurotransmitters when administering prescription drugs that block reuptake is to
provide amino acid precursors, which are then synthesized into neurotransmitters. Administering
L-tyrosine (not phenylalanine or n-acetyl-tyrosine) or L-dopa is the only way to predictably raise
dopamine, norepinephrine, and epinephrine. Administering tryptophan or 5-hydroxytryptophan
(5-HTP) is the only way to predictably raise serotonin levels in the central nervous system. It is
noted that 5-HTP, L-dopa, and tyrosine are available in the United States without a prescription.
The ability of tryptophan to raise serotonin levels is limited because it is a rate-limited reaction.
The effects of neurotransmitter depletion by drugs may have far-ranging implications. It has been
found in studies that depletion of serotonin by drugs may also lead to a reduction in the number of
serotonin synapses in the hippocampus.43
MONOAMINE SYNTHESIS FROM AMINO ACIDS
The synthesis of serotonin and the catecholamines is illustrated in Figure 29.3. Peripheral administration of only 5-HTP (serotonin system) or only L-dopa (dopamine system) will decrease the synthesis of the other system (dopamine or serotonin respectively).57. With administration of only one amino
acid precursor, the administered amino acid precursor dominates the enzyme and compromises
proper synthesis of the other system’s neurotransmitters. This is due to the fact that the same enzyme
catalyzes the conversion of 5-HTP to serotonin and L-dopa to dopamine everywhere in the body.
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OH
OH
OH
OH
OH
Aromatic
Amino Acid
Decarboxylase
Tyrosine
Hydroxylase
NH2
C
COOH NH2 C
COOH
CH2
Dopa
C
HN
OH
HC
NH2
COOH
Tryptophan
FIGURE 29.3
precursors.
C
H
NH
CH3
Adrenaline
Aromatic Amino
Acid Decarboxylase
HN
HN
CH2
CH2
HO
CH2
H2N
Noradrenaline
OH
Tryptophan
Hydroxylase
H
CH2
H2N
Dopamine
H
H
Tyrosine
HO
OH
Phenylethanoamine
N-methyltransferase
Dopamine
-hydroxylase
CH2
CH2
CH2
OH
OH
OH
HC
CH2
NH2
CH2
COOH
NH2
5-Hydroxytryptophan
Serotonin (5-HT)
The synthesis of serotonin, dopamine, norepinephrine, and epinephrine from amino acid
The aromatic L-amino acid decarboxylase enzyme is also known as 5-HTP decarboxylase
enzyme or L-dopa decarboxylase enzyme, as well as the general decarboxylase enzyme, is illustrated
in a kidney in Figure 29.4 (bottom right). The implications of this fact are profound.10 The administration of only 5-HTP or L-dopa will compete with and inhibit the synthesis of the opposite precursor
(dopamine and serotonin, respectively) at the enzyme.
In patients with Parkinson’s, the long-term administration of L-dopa with insufficient serotonin
precursor will result in depression. The literature is very clear that this depression is a serotonindependent depression, which responds optimally to the most serotonin specific reuptake inhibitor,
citalopram.11
AMINO ACIDS AND MONOAMINE METABOLISM
The MAO and COMT enzymes metabolize serotonin and the catecholamines, as illustrated in
the kidney in Figure 29.4 (bottom left).12 The implications are that the levels of these two enzyme
systems are not static; they fluctuate in response to changing neurotransmitter levels. When neurotransmitter levels are increased, enzymatic activity also increases.14,23–26
If you administer L-dopa or 5-HTP, the activity of MAO and COMT increases due to the increase
in dopamine or serotonin levels, respectively. The problem occurs when L-dopa is administered
without 5-HTP, both dopamine and serotonin will be subjected to increases in metabolism by these
two enzyme systems. However, serotonin will not experience an increase in production, which leads
to further depletion. The same rule is true of 5-HTP administered without the use of dopamine
precursors. The bottom line is that the administration of 5-HTP or L-dopa that is unopposed or
improperly balanced with the amino acid precursors of the other system will deplete the other system as a result of the increased metabolism of MAO and COMT, decreased synthesis, and uptake
competition (as covered in the next section).
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Renal arterial blood Glomerulous
Amino acids and
Neurotransmitters
Proximal Tubule
Cation
uptake
port
Neurotransmitter
metabolized
dopamine
norepinephrine
epinephrine
serotonin
monoamine
Oxidase
catecholamineO-methyl
transferase
Homovanillic
acid
Amino acids
synthesized to
neurotransmitters
Proximal
convoluted
Tyrosine
renal Tryptophan
5-HTP
L-dopa
tubules
Aromatic
cell
amino acid
decarboxylase
Serotonin
Dopamine
5-hydroxyindolacetic
acid
Final concentrated
urine
Renal vein into
the system
FIGURE 29.4 The neurotransmitters and amino acids are filtered as the glomerulous are uptaked in the
proximal renal tubules by the cation ports of the proximal convoluted renal tubule cells. The proximal convoluted renal tubule cells then further filter the neurotransmitters and amino acids into separate areas where the
neurotransmitters are metabolized and the amino acids are synthesized into new neurotransmitters that are
then either excreted into the urine or secreted into the system via the renal veins.
AMINO ACID UPTAKE
In order for the synthesis of monoamine neurotransmitters to occur, the amino acid precursors must
undergo uptake into the cells performing synthesis. This process occurs in numerous places throughout
the body including the central nervous system, kidneys, liver, gastrointestinal tract, mesentery, lungs,
and peripheral nerves. The “cation uptake ports” found in the proximal convoluted renal tubule cells are
a prototype for amino acid uptake (see Figure 29.4 at the top center).16
Neurotransmitters synthesized by the kidneys are the source of urinary serotonin and
catecholamines.16–19 Serotonin and the catecholamines are synthesized by the kidneys, then excreted
into the urine or secreted into the system via the renal veins.20 Uptake is affected by administration
of a single amino acid precursor or improperly balanced amino acid precursors as may overwhelm
and compete with uptake of the other amino acids. Administration of only L-dopa inhibits uptake
of 5-HTP.44 Administration of only 5-HTP has the same effect on L-dopa uptake.
V.
TREATMENT
It is not possible to design a diet where the patient can obtain enough amino acids to affect even
level 1 amino acid dosing (see Table 29.1), since the amino acid dosing requirement is higher than
can be achieved with diet alone. Amino acid precursors of serotonin and dopamine have two primary
applications. First, proper use of amino acid precursors will keep drugs that work with neurotransmitters
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TABLE 29.1
The “Generic Amino Acid Dosing Protocol” (milligrams of 5-HTP/milligrams
tyrosine) If relief of symptoms is not obtained with level 3 dosing, obtain
urinary neurotransmitter testing. Use of proper levels of cofactors and sulfur
amino acids is required for optimal results
LEVEL
1
2
3
from depleting neurotransmitters, thus allowing the drugs to keep functioning and functioning optimally. Second, proper use of amino acids can also serve as the treatment modality.
The generic protocol developed for treatment of neurotransmitter dysfunction disease relating to
the catecholamine system and/or serotonin system involves the use of tyrosine, 5-HTP, and cofactors.
Results do not appear to be dependent on taking the amino acids with or without food. The following
cofactors need to be used along with the amino acid precursors:
• Vitamin C 1000 mg/day
• Vitamin B6 75 mg/day
• Calcium 500 mg 500 mg/day
In addition
• Cysteine 4500 mg/day in equally divided doses
• Selenium 400 mcg/day
• Folic acid 2000 to 3000 mcg/day
should also be used to prevent depletion of the methionine-homocysteine cycle (Figure 29.5) by
L-dopa and presumably by L-tyrosine from which L-dopa is synthesized from, the immediate precursor of L-dopa. Administration of L-dopa leads to depletion of S-adenosyl-methionine (SAMe), a
component of the methionine-homocysteine cycle that is the one carbon methyl donor of the body;
proper levels of SAMe are needed in order for norepinephrine to be methylated to epinephrine.
Long-term use of L-dopa without proper administration of amino acids of the methionine-homocysteine cycle leads to depletion of epinephrine.37
There is a “total loss” of sulfur amino acid associated with treatment of Parkinsonism with
L-dopa as evidenced by the loss of total glutathione that occurs.41
Glutathione is synthesized in a side chain reaction off the methionine-homocysteine cycle (see
Figure 29.5). The loss of total glutathione leads to a state where the body’s most powerful detoxifying
agent (glutathione) is no longer functioning properly and is unable to neutralize further toxic insult
leaving the patient in a state where more toxic damage is facilitated. All patients taking L-dopa and/
or L-tyrosine need to be supplemented with adequate levels of sulfur amino acid to prevent depletion of the methionine-homocysteine cycle, depletion of glutathione, depletion of epinephrine, and
the other components dependent on the methionine-homocysteine cycle. While administration of
any of the sulfur amino acids in the cycle is adequate if the dosing is high enough, cysteine is chosen
since it costs only about 11 cents per day wholesale.
Selenium 400 mcg/day needs to be administered with cysteine to prevent cysteine (sulfur amino
acids) from creating an environment that contributes to central nervous system neurotoxicity from
methylmercury. Administration of cysteine can potentially facilitate concentration of methylmercury
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Methionine
Norepinephrine
Folic Acid
(Folate) Cycle
Methionine Homocysteine
Cycle
Proper levels of B6
and B12 are also
needed
SAMe
Epinephrine
S-Adenosyl
homocysteine
Homocysteine
Glutathione
FIGURE 29.5
Cysteine
The methionine–homocysteine cycle, the heart of the sulfur amino acids.
into the central nervous system.46 Selenium binds irreversibly to methylmercury in the central nervous system rendering the methylmercury biologically inactive and nontoxic.47
Folic acid is required in order to provide optimal function of the folic acid cycle, which in turn
prevents hyperhomocysteinemia from preventing the methionine-homocysteine cycle from functioning properly. As noted previously, without proper administration of amino acids of the methionine-homocysteine cycle there will be depletion of epinephrine. It would appear the second factor
driving epinephrine levels beyond methionine-homocysteine cycle depletion is hyperhomocysteinemia. It can take 3 to 6 months for hyperhomocysteinemia to return to normal when proper levels
of folate, vitamin B6, and vitamin B12 are provided for. It appears to be no coincidence that it can
take 3 to 6 months for epinephrine levels to return to normal—a fact that appears to parallel homocysteine improvement.
When the goal of treatment is to prevent depletion of neurotransmitters by prescription drugs or
in associated situations where prescription drugs are no longer working effectively during treatment
due to the neurotransmitter levels falling too low from depletion due to circumstance set up by the
drug,45 the patient should be placed on the level 1 amino acid dosing (see Table 29.1) along with the
prescription drug, cysteine, selenium, and folate. While amino acid precursors when used alone and
properly are highly effective, a drug/amino acid combination may be desirable with severe disease,
such as the suicidal patient, the catatonic patient, or the patient unable to take part in normal day-today functions such as work. Supplementing with amino acid precursors allows reuptake inhibitors
to continue to function optimally without tachyphylaxis.
When amino acids are used as the initial therapy, start all patients on the level 1 dosing protocol
of Table 29.1 along with cofactors and proper methionine-homocysteine cycle support at the first
visit. Patients should return in 1 week, at which time focus on how the patient’s symptoms were
the previous day. Asking about the previous day’s symptoms is more indicative of changes in the
system brought about by amino acid therapy since it takes 3 to 5 days for the full effects of starting
or changing an amino acid dosing to be displayed.
If symptoms are not fully under control in 1 week, increase to the level 2 dosing along with cofactors and proper sulfur amino acid support and instruct the patient to return in 1 week. At the 3rd visit,
if symptoms are not under control, increase to the level 3 dosing along with cofactors and proper sulfur
amino acid support and have the patient return to the clinic in 1 week. If in 1 week symptoms are not
under control, continue the level 3 dosing and obtain a urinary neurotransmitter test of the caliber
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provided by a laboratory under the direction of a hospital-based laboratory pathologist.40 Follow the
amino acid dosing recommendations generated after review of testing preformed under the supervision of a board-certified laboratory pathologist. Patients should return in 1 week to discuss results
and amino acid dosing changes that may be needed. Any time an amino acid dosing change occurs,
patients should return in 1 week to evaluate the results. Over 60% of patients tested needed only one
neurotransmitter test. This is consistent with complete resolution of symptoms after adjusting the
amino acid dosing in accordance with the consultant recommendations on the test.
When treating depression, if amino acid dosing changes establish both the serotonin and dopamine in the phase 3 therapeutic range (see urinary neurotransmitter testing in the following) and
no relief of symptoms is achieved, consider the possibility of depressive bipolar disorder. Under
treatment with the amino acid protocol approximately 2% of patients are found to suffer from
depressive bipolar disorder that has not been previously diagnosed. The primary care physician at
this point should continue the amino acids and initiate a psychiatric referral in order to affect starting of a mood-stabilizing bipolar drug. It is noted that as long as the amino acids are continued,
over 99% of patients started on mood-stabilizing drugs such as lithium, Depakote, or Lamictil find
complete resolution of depression on the standard starting dose.
VI.
SAFETY
The following is a side effect profile developed from approximately 50 patient-years of databased
treatment in hand at NeuroResearch Clinics, Inc. The following results were obtained from patients
taking only amino acids with no prescription drugs:
Dry mouth
Insomnia
Headache
Nausea
Dizziness
Constipation
34 (2.1%)
14 (0.9%)
12 (0.7%)
10 (0.6%)
6 (0.4%)
6 (0.4%)
All other side effects were reported at a rate of less than 1 in 500 visits (0.02%). No irreversible
side effects were noted.
Amino acid precursors are safe to administer with any prescription drug, but amino acid precursors
can also cause the side effects of the prescription drugs to be displayed. Any side effect associated with
the drug can be triggered. For example, a patient was taking an SSRI with the side effect of malignant
neuroleptic syndrome listed. As the amino acids were started, the patient developed new onset malignant neuroleptic syndrome. When drug side effects occur, it is necessary to manage the situation as
you would with any other prescription drug side effect, which in general means decreasing or stopping
the drug not the amino acid.
With regards to pregnancy there is nothing in the literature indicating that the amino acid precursors
are a problem. Nor is there anything in the literature indicating studies have been performed indicating
they are safe. In this light it is recommended that amino acid precursors not be used in the first trimester
of pregnancy.
VII. SYSTEMS PRIORITY
The serotonin and/or catecholamine system has a role, either directly or indirectly, in controlling
most of the other systems and functions in the body. For example, cortisol synthesis is controlled
in part by norepinephrine. Hormone synthesis is dependent on norepinephrine. The sympathetic
nervous system is controlled by norepinephrine. Other neurotransmitter systems are partially controlled by the serotonin and/or catecholamine systems. For example, the GABA neurotransmitter
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system is associated with control of anxiety and panic attacks. Yet when the serotonin and/or catecholamine neurotransmitter levels are brought to proper levels, as confirmed by lab testing, these
diseases may be fully under control. This would indicate control of GABA by the serotonin/catecholamine system even though at this time we have been unable to identify a chemical pathway for
such in the literature.
VII.
PATIENT EVALUATION: URINARY NEUROTRANSMITTER
TESTING MONOAMINES IN THE KIDNEYS
Urinary neurotransmitter testing prior to amino acid therapy is of no value. There is no correlation between baseline testing and urinary neurotransmitter phases once the patient is taking amino
acid precursors. It is not necessary or even useful to measure baseline urinary neurotransmitters in
treatment.40
Urinary monoamine neurotransmitters do not cross the blood-brain barrier.2–5 Urinary monoamine neurotransmitters are not neurotransmitters filtered by the glomerulous of the kidneys and
excreted into the urine. They are neurotransmitters that are synthesized by the kidneys and excreted
into the urine or secreted into the system via the renal veins.20 With simultaneous administration of
serotonin and dopamine amino acid precursors, three phases of urinary neurotransmitter response
have been identified on laboratory assay of the urine (see Figures 29.6 and 29.7). The three phases of
response apply to both serotonin and dopamine. In all the life forms tested that have kidneys along
with serotonin and catecholamine systems, the three phases of urinary neurotransmitter response
exist.40 In reviewing the literature it would appear that the three phases of urinary response to
neurotransmitters were present in previous writings but were not identified as such. For example, a
1999 article notes that administration of L-dopa can increase urinary dopamine levels (phase 3) and
decrease urinary serotonin levels (phase 1).42
The goal of treatment is to establish both urinary serotonin and dopamine levels in the phase 3
therapeutic range. To determine the phase of serotonin and dopamine with certainty requires two
urinary neurotransmitter tests to be performed with the patient simultaneously taking a different
amino acid dosing of dopamine and serotonin amino acid precursors on each test and comparing
the results. Not all patients will need to have the urinary serotonin and dopamine levels in the phase
3 therapeutic range for relief of symptoms. In many cases, adjusting the amino acids so that the
patient moves closer to the phase 3 therapeutic range of urinary serotonin and dopamine induces
relief of symptoms. Then, no further amino acid adjustments or testing are needed unless disease
symptoms return. If the patient misses one or more amino acid doses in the week prior to testing,
wait until 1 week has passed with the patient properly taking all of their amino acids.
In phase 1, neurotransmitters synthesized by the kidneys are inappropriately excreted into the
urine instead of being secreted into the system via the renal vein where they are needed (see Figures
29.6 and 29.7). Increasing the amino acid dose in phase 1 will correct the problem of inappropriate
neurotransmitter excretion. The amino acid precursor dosing of serotonin and dopamine, where
the individual patient is in phase 1 varies widely in the population. The level at which the urinary
serotonin is no longer in phase 1 ranges from 37.5 mg of 5-HTP per day to 3000 mg of 5-HTP per
day. The level at which the urinary dopamine is no longer in phase 1 ranges from no L-dopa (with
the use of L-tyrosine only in some patients) to 540 mg of L-dopa per day in the patients not under
treatment for Parkinsonism or Restless Leg Syndrome.
Administration of proper levels of tyrosine with L-dopa is known as a “tyrosine base.” Proper
use of the tyrosine base greatly reduces wild fluctuations in dopamine levels found with administration of L-dopa alone and greatly decreases the need for L-dopa. It is postulated that the tyrosine
hydroxylase enzyme is not completely shut down with the administration of L-dopa, leading to
fluctuations in the L-dopa produced from tyrosine synthesized to L-dopa then dopamine, which
ultimately causes fluctuations of dopamine. By providing ample tyrosine with administration of
L-dopa, these fluctuations of dopamine cease and the overall dosing needs of L-dopa decrease.
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EFFECTIVE
NOT EFFECTIVE
PHASE 1
PHASE 2
Phase 1 range
PHASE 3
Phase 3 range
Increasing the daily balanced amino acid dosing
FIGURE 29.6 The three phases of urinary neurotransmitter excretion in response to amino acid dosing.
The horizontal axis is not labeled with specific amounts; it reflects the general trend seen in the population.
Amino acid dosing needs are highly individualized. The dosing level needed to inflect into the next level varies greatly throughout the general population. For example, some patients inflect into phase 3 on 37.5 mg of
5-HTP per day, while others need as high as 3000 mgday (From DBS Labs database).
Proximal
convoluted renal
tubule cell of the
kidneys
Urine
Proximal
convoluted renal
tubule cell of the
kidneys
Proximal
convoluted renal
tubule cell of the
kidneys
System Urine
PHASE 1 RESPONSE
System Urine
PHASE 2 RESPONSE
System
PHASE 3 RESPONSE
FIGURE 29.7 The three phases of urinary response to amino acid dosing (Two urinary neurotransmitter tests
are required to determine the phase with certainty). PHASE 1: In phase 1, as the amino acid dosing increases
or decreases the urinary serotonin or dopamine decreases or increases respectively. In phase 1, there is inappropriate excretion of neurotransmitters into the urine instead of the system where they are needed. PHASE 2:
In phase 2, as the amino acid dosing increases or decreases the urinary serotonin or dopamine is low (<800 μgr/
gr creatinine for serotonin or <300 μgr/gr creatinine for dopamine). In phase 2, there is no inappropriate excretion of neurotransmitters into the urine. The neurotransmitters are being excreted appropriately into the system
and the urine. PHASE 3: In phase 3, as the amino acid dosing increases or decreases the urinary serotonin or
dopamine increases or decreases respectively. In phase 3, there are adequate systemic serotonin and dopamine
levels. The excess serotonin and dopamine are appropriately excreted into the urine.
By increasing the amino acid dosing of serotonin and dopamine precursors above the dosing of
phase 1, the phase 2 response is observed (see Figures 29.6 and 29.7). In Phase 2, urinary neurotransmitter levels are low (<300 micrograms dopamine per gram of creatinine or <800 micrograms
serotonin per gram of creatinine, the neurotransmitter-creatinine ratio compensates for dilution of
the urine) and the inappropriate excretion of neurotransmitters into the urine has ceased. When in
phase 2, neurotransmitters are being appropriately secreted into the system and not into the urine.
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The model used to explain phase 2 is, “inappropriate excretion of neurotransmitters has now ceased
as the amino acid precursor dosing is increased and the system is now filling up appropriately.”
As serotonin and dopamine amino acid precursors are increased above the phase 1 and the phase
2 levels, all patients enter the phase 3 response (see Figures 29.6 and 29.7). Further increases in the
amino acid dosing lead to increases in urinary dopamine and serotonin neurotransmitter levels if
they are in phase 3. Phase 3 represents appropriate secretion into the system and appropriate excretion of excess neurotransmitters synthesized by the kidneys into the urine.
In the case of chronic depression, research has shown neurotransmitter levels need to be established
at levels that are in phase 3 and higher than the reference range reported by the laboratory in order to
achieve optimal relief of group symptoms.40 In the case of serotonin, the reference range reported by
the research lab is 48.9 to 194.9 micrograms of serotonin per gram of creatinine. The therapeutic range
of urinary serotonin for the treatment of chronic depression is defined as 800 to 2400 micrograms of
serotonin per gram of creatinine in phase 3. The reference range reported by the research lab of urinary
dopamine reported by the laboratory is 40 to 390 micrograms of dopamine per gram of creatinine. The
therapeutic range of urinary dopamine for the treatment of chronic depression is defined as 300 to 600
micrograms of dopamine per gram of creatinine in phase 3.
It would appear that in depression, the same mechanism of action may be at work as is found in
Parkinson’s disease. There is damage to dopamine and/or serotonin neuron bundles controlling affect,
which can be compensated for by increasing serotonin and dopamine neurotransmitter levels higher
than is normally found in the system. Just as with Parkinson’s disease, the bundle damage in chronic
depression is permanent. In most patients simply returning neurotransmitter levels to normal or the
reference range reported by the lab, as suggested by the monoamine theory, will not lead to relief
of symptoms. As with Parkinsonism, treatment of depression may require long-term use of amino
acids to control symptoms. After symptoms associated with monoamine neurotransmitter diseases are
controlled with the proper administration of amino acid precursors, the need for ongoing amino acid
therapy may present if symptoms have not been addressed fully under the monoamine theory.
Urinary monoamine neurotransmitter testing is used only when the patient has not responded to
the levels 1 through 3 of the dosing protocol. Over 80% of patients will achieve relief of depression
symptoms without laboratory testing.
GENERALIZABILITY
Laboratory-guided supplementation with amino acid precursors is also associated with clinically
favorable outcomes in RLS and peroxismal limb movement disorder, where dopamine agonists
are also the first line of therapy and clinical response is readily observable by patients and documented with sleep studies. The dosing level of L-dopa at which dopamine is no longer in phase 1, in
patients not suffering from RLS, ranges from 0 milligrams of L-dopa per day to 6000 mg of L-dopa
per day. With a proper “tyrosine base” in place, L-dopa dosing in these patients range from 10 to
1040 mg/day.
VIII. CONCLUSIONS
The bundle damage theory creates a framework by which to offer patients new treatments for clinical depression. The theory underscores the importance of minimizing toxic exposures, through
avoidance where possible, through diminished uptake, and through adequate nutrients. Similarly
patients who have inadequate substrate for neurotransmitter synthesis may need cofactors, nutrients
involved in sulfur pathways, and amino acid precursors. Patients may also receive benefit from
amino acid precursors beyond what can be obtained from diet alone.
There are three primary considerations in the use of amino acids for treating depression.
First, proper levels of amino acids should be administered with the drugs to prevent depletion of
neurotransmitters. Second, proper use of amino acids will keep the drug functioning properly,
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avoiding tachyphylaxis. Third, the use of amino acids may cause a drug side effect to become
active. In summary, amino acids hold more therapeutic potential and less potential for harm when
administration is physician-guided.
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INDEX, Original research papers presented in these continuing

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