Low-Dose Naltrexone (LDN)

Low-Dose Naltrexone (LDN)
by
Mark J Donohue
Naltrexone / Naltrexone Hydrochloride (C20H23NO4-HCl) - is a pharmacologically active opioid antagonist that
blocks the opioid receptor, thereby inhibiting the two main effects of opioids – pain relief and euphoria. It is a
non-selective antagonist, with strong effects on the mu opioid receptor (MOR) and delta opioid receptors
(DOR), with less antagonism of kappa opioid receptors (KOR).
Naltrexone, a “designer drug”, was approved by the FDA (at a 50-200mg dosage) in 1984 for the treatment of
opiate (opium, morphine, heroin, etc.) addiction, and again in 1995 for alcohol abuse. Unfortunately, naltrexone
treatment for these conditions had a high non-compliance rate due to the increased incidence of side effects
such as: anxiety, depression, irritability, poor sleep and an inability to handle minor stressors.
Currently the patent on naltrexone has expired and is therefore categorizes as a “generic drug”.
Low-Dose Naltrexone (LDN) - is an “off label” use of naltrexone, which is formulated by a compounding
pharmacy at a much lower dosage ranging from 1.5 to 4.5 mg. At this dose LDN continues to act as an opioid
antagonist, though only briefly, and yet just long enough to trick the body into elevating its own endogenous
opioids - endorphins. Most importantly the elevated endorphins act to boost or modulate the immune system.
LDN is gaining attention as an immune modulator and is being used more and more to treat patients with
dysfunctional immune system and central nervous system disorders such as:
Multiple Sclerosis (MS)
Parkinson’s Disease
ALS (Lou Gehrig’s Disease)
Alzheimer’s Disease
Lupus
Autism
Rheumatoid Arthritis
Hashimoto’s Thyroiditis
Lyme Disease
Crohn’s Disease
Celiac Disease
Ulcerative Colitis
Hepatitis
HIV/AIDS
Cancers
Fibromyalgia
Chronic Fatigue Syndrome
And Other Disorders
“Low-Dose Naltrexone (LDN) may well be the most important therapeutic
breakthrough in over fifty years. It provides a new, safe and inexpensive method of
medical treatment by mobilizing the natural defenses of one’s own immune system”
(Dr. Gluck)
Many of the disorders listed above (and others not listed) are categorized as autoimmune disorders.
Interestingly, people with autoimmune disorders are considered to have an aggressive over active
immune system which attacks its own organ tissues, and are generally treated with immune
suppressants. Therefore, prescribing an immune boosting drug such as LDN would appear to be
contradictory.
However, more and more data is emerging that suggests that autoimmune disorders may in fact be due
to a weakened and ineffective immune system. Therefore, rather than indicating that a person has
either an overactive or underactive immune system, it is now commonly being indicated that a person’s
immune system (with such disorders) is simply dysfunctional. LDN is being shown to be able to modulate
and rebalance such dysfunctional immune systems. And this may explain why LDN works so well for
autoimmune disorders.
The LDN Theory
As mentioned, Low-Dose Naltrexone (LDN) is an opioid antagonist, which not only blocks the reception
of opiates, but also the body’s own endogenous opioids – endorphins. However, because LDN is
administered in such a “low dose” it is believed that LDN only briefly (for 3-4 hours) obstructs the effects
of endorphins. Sensing an endorphin deficit, the hypothalamus signals for increased production of
endorphins in what is called “the rebound effect”. The rebound effect results in three things happening:
1. Opioid receptor production increases in order to try and capture more endorphins.
2. Opioid receptor sensitivity increases, also to try and capture more endorphins.
3. Production of endorphins is increased in order to compensate for the perceived shortage.
Once LDN is metabolized by the liver and eliminated from the body (after 3-4 hours), the elevated levels
of endorphins produced as a result of the rebound effect can now interact and bind with the moresensitive and more-plentiful opioid receptors. These opioid receptors, as we have learned earlier, are
found through out the body, including virtually every cell of the body’s immune system.
“This ‘‘rebound phase” may release the increased density of mu and delta opioid
receptors for endogenous opioid stimulation with the increasingly available betaendorphins and met-enkephlins. The general principle operative here may be that
the increased concentrations of beta-endorphines and met-enkephlins that gain
access to increased density of MOR and DOR receptors may ‘‘functionally
supersensitize” endogenous opioid functions throughout the body with beneficial
downstream effects on various body parameters, especially immune-competence.”
(Dr. Brown)
The elevated levels of endorphins will usually last around 18-20 hours. During this time the elevated
endorphins act by up-regulating vital elements of the body’s immune cells. By doing so it has been
shown that elevated levels of endorphins, due to the administration of LDN is responsible for:
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Down regulating inflammatory cytokines
Reducing inflammation and oxidative stress
Facilitating tissue repair and wound healing
Restoring T-helper/CD4 levels
Restoring the balance between Th1 & Th2 lymphocytes
Increasing cytotoxic T cells and natural killer (NK) cells
Regulating cell growth & inhibiting tumor growth
Reducing excitotoxicity and microglial activation
Reducing apoptosis of the myelin-producing oligodendrocytes
Stimulating mucosal healing (lining of bowel)
 RADIO – Dr. David Gluck is interviewed on The Mary Bradley Show, May 2009, blogtalkradio
(29:37) Link
“… instead of the medication actually doing the work, the medication is going into
the body and essentially tricking the body… and forcing the body to double and
triple its output of endorphins and met-enkephalins… and those in turn cause your
immune system to strengthen…
… A nice way to think of low-dose naltrexone is not like any other medication what
so ever but as a way to have a strong immune system or strengthen the immune
system and the reason why that is vital is because in all the studies that have ever
been done on any autoimmune disease they have always been found to be marked
by a weak dysfunctional immune system… the moment that immune system is
strengthened by the low-dose naltrexone then it remembers that its first important
thing to do is to never attack self… the moment you are stuck with a weak
dysfunctional immune system that’s how you get these autoimmune diseases. By
taking LDN the diseases then stops progressing because the immune system is now
strengthened and no longer attacks self.” (Dr. Gluck)
 RADIO – Dr. Jaquelyn McCandless is interviewed on The Mary Bradley Show, October 2009,
blogtalkradio (65:51) Link
“… a decade ago we didn’t know that immunity was so tied in with endorphins but
the endorphins actually contribute to both humoral and acquired immunity…
“… the main situation is that it (LDN) heightens the immune system and I learned in
some of my studies that the CD4 count which is a regulatory cell is increased…
… Restoration of the body’s normal production of endorphins in those with cancer
and autoimmune diseases is the major therapeutic action of LDN.” (Dr. McCandless)
 RADIO – Dr. Jarred Younger is interviewed by The LDN Research Trust (2012), YouTube (12:51) Link
“There are immune system cells in the brain called microglia and those cells are
normally floating around and they are normally looking for problems and if there is a
virus they will help fight that off and they basically protect the brain from damage.
One of the side effects when they become activated they release cytokines that make
people feel sick and they can actually if they are around too long can start to destroy
neurons so they are neuro-degenerative…
… an example is if you get the flu and you feel really horrible and sick and you really
don’t want to do anything… you just want to lay in bed… that’s actually caused by
your own immune system… the microglia are producing chemicals that make you feel
sick and the reason they do that is to get you In bed so your body can devote all of its
resources to fight off the infection. But what we think in a lot of conditions is that
these microglia have become chronically activated… they are producing these
cytokines in the brain and they are causing fatigue and chronic pain….
… and so I think low-dose naltrexone can block those microglia from producing the
cytokines… it essentially calms them back down… and that can happen in the brain
and it can also happen in the spinal cord… and so its keeping microglia from
producing chemicals that can destroy neurons and cause lesions or cause pain and
fatigue and flu like symptoms…
… naltrexone has two halves, it has a left side and a right side… the left side is
responsible for blocking opioids and the right side which we call dextro… dextronaltrexone is responsible for blocking the microglia.” (Dr. Younger)
Opioid Growth Factor (OGF)
We have established that Low-Dose Naltrexone exerts its primary effects by increasing levels of
endogenous opioids such as beta-endorphins, enkephalins and dynorphins. In particular, researchers at
Penn State (Dr. Ian Zagon’s team) discovered that increased production of Met-5-Enkephalin
(methionine enkephalin / met-enkephalin) and its receptor account for some of the most significant
effects associated with LDN.
Dr. Zagon’s team discovered that the axis between met-enkephalin and its receptor functions to
regulate cell growth of both normal and abnormal cells. Dr. Zagon named or re-named Met-5Enkephalin (met-enkephalin) to - opioid growth factor (OGF) to better reference its functional
properties and to distinguish it from its neuromodulatory function. They also identified the receptor
activated by OGF – the zeta opioid receptor and re-named it as well to - opioid growth factor receptor
(OGFr).
“… we eventually discovered that the endogenous opioid involved with LDN action
is called opioid growth factor (OGF) (chemical term - methionine encephalin). The
OGF receptor (OGFr) mediates the activity of OGF. Treatment with exogenous OGF
allows magnitudes more of this potent peptide to react with the OGF receptors, and
this substance is currently in Phase 2 clinical trials for therapy of pancreatic cancer,
squamous cell carcinoma of the head and neck, and hepatocellular carcinoma.” (Dr.
Zagon)
In humans, the OGF receptor is highly expressed in the heart and liver, moderately expressed in skeletal
muscle and kidney tissue and to a lesser extent in brain and pancreas. Many cancer cells have been
found to have OGF receptors. It was also found that OGF/met-enkephalin has potent antiviral and
antitumor properties due to its ability to increase production of interleukin-2, natural killer lymphocytes,
CD4 lymphocytes and CD8 lymphocytes.
 VIDEO – Low Dose Naltrexone: How it Works, YouTube (4:49) Link
Dr. Ian Zagon PhD – LDN Pioneer
Dr. Ian S. Zagon PhD (Link) - is considered to be the discoverer of Low-Dose Naltrexone, the OGF-OGFr
axis and their ability to control cell growth. Below are excerpts from an interview given by Dr. Zagon. To
view the entire interview, go to this Link.
“We had observed that if naltrexone blocked the opioid receptors for the entire 24
hours, endogenous opioids were blocked from the receptors and cancers grew
rapidly. If the blockade was for only 4-6 hours, the cancers either did not appear or
were markedly delayed. This indicated to me that 1) endogenous opioids were
really regulating the growth of these cancers and were antitumor agents, 2)
endogenous opioids are tonically active - they work all the time and if you block
them from receptors all the time then cancer growth is less controlled, 3) opioid
antagonists can be used to modulate this process, 4) if you block opioid receptors
part of the day, you get an exaggerated action of the opioids after the blockade…
… We also knew from previous scientific literature on the action of naltrexone that
opioid receptor blockade by such an opioid antagonist causes cells to have a
compensatory increase in endogenous opioids and opioid receptors because they
sense they are deprived of these elements. After the opioid antagonist (naltrexone)
is no longer present (having been metabolized by the liver), there is a period of
super-sensitivity of the elevated levels of receptors to the increased levels of the
endogenous opioids and one sees a more pronounced functional effect…
… So, in the 4-6 hour period each day, we elicited what we call an up-regulation in
endogenous opioids and opioid receptors, and cell division was increased. But in
the remaining 18-20 hours when the naltrexone was no longer present, cell
proliferation was greatly diminished by the high levels of opioids interfacing with
the increased number of receptors.” (Dr. Zagon)
 RADIO – Dr. Ian Zagon is interviewed on The Mary Boyle Show, June 2009, BlogTalkRadio (59:19)
Link
 Dr. Ian S. Zagon Introduction to Low Dose Naltrexone, LDN Research Trust, Oct. 2009 Link
“During this interval (blockage), these native opioids are prevented from interacting
with the opioid receptors present on cells in the body; these cells depend on opioids
to govern metabolic processes and to regulate cellular replication. The body and
cells react by compensating for this blockade by making more opioids and opioid
receptors. Of course, this excess in opioids and opioid receptors still cannot interact
with each other while the opioid antagonist is present. However, after 4-6 hours
when the opioid antagonist disappears and the blockade is removed because LDN
has been metabolized by the liver the elevated levels of opioids and greater number
of receptors interact with each other causing a heightened biological reaction…
… Pertaining to cell growth, this opioid-opioid receptor system in essence acts to
keep in check the number of cells through a tonically active inhibitory mechanism
(in other words the system is in a constant dynamic state that maintains cell
number by carefully monitoring - and restraining if necessary - the number of cells
produced). In cancer, for example, an intermittent blockade by opioid antagonists
has a profound effect on delaying replication of these deadly cells.” (Dr. Zagon)
 Zagon I.S., et al., Duration of Opiate Receptor Blockade Determines Tumorigenic Response in Mice
with Neuroblastoma: a Role for Endogenous Opioid Systems in Cancer, Life Sciences, 1984 Jul
23;35(4):409-416 Link
 Zagon I.S., et al., Naltrexone Modulates Body and Brain Development in Rats: a Role for
Endogenous Opioid Systems in Growth, Life Sciences, 1984 Nov 12;35(20):2057-2064 Link
Dr. Bernard Bihari MD – LDN Pioneer
Dr. Bernard Bihari MD (Link) - is considered a pioneer in the use of Low-Dose Naltrexone with patients
in a clinical environment. Below are excerpts from two interviews Dr. Bahari gave.
 VIDEO – Interview with Dr. Bernard Bihari (2002) YouTube, (1:19:37) Link
“I knew that the immune system was regulated almost entirely by endorphins, and
that also the endorphin production was markedly increased by naltrexone. My
colleagues and I worked to find some way of using that ability of naltrexone to raise
endorphins, but without the downside of naltrexone blocking the endorphins, the
purpose being to find a way to raise endorphins to boost immune function. Along
the way, we tested endorphin levels in ten people with AIDS and found they were
extremely low—less than 30% of normal. So the hormones that people with AIDS
need the most, to have the immune system fight the virus—those hormones are
lacking. So, what we did was to do what's called a “dose ranging trial” to find the
best dose of the drug to use to raise endorphins without blocking them at the same
time…
… The reason the hour is important is that 90% of the endorphins are made in the
middle of the night, between 2 and 4 in the morning. If a small dose of naltrexone is
taken in the late evening, generally at bedtime, generally endorphin production is
boosted as much as threefold, 300%. The naltrexone itself is gone in about 3 hours,
but the endorphins remain elevated all the next day. So the naltrexone doesn't
significantly block the endorphins but does cause them to rise. If someone with low
endorphin levels starts taking low dose naltrexone every night, their endorphin
levels will triple and stay tripled as long as they're taking the drug…
… there's been a lot of research studying the relationship between endorphins and
cancer in laboratory animals and in the test tube. There are a large number of
studies, and the studies that involve giving beta-endorphin (the endorphin from the
pituitary gland), met-enkephalin (an endorphin made in the adrenal gland), and low
dose naltrexone. The low dose naltrexone works by inducing the body to make more
of both endorphins, so they work similarly to the direct injection of endorphins. All
three are effective in markedly reducing the number of cancers that take in mice. Or,
once the cancer has been injected and has started growing, in producing remission.
That’s been true of almost every cancer that has been studied in mice…
… The person doing the bulk of that research—the investigator doing it—is a PhD
(Dr. Zagon) who believes that all cancers have opioid receptors. He’s gotten
responses with all the cancers that he’s treated with endorphins or low dose
naltrexone in laboratory animals. The question arose as to whether the effect on
cancer was a direct effect of the endorphins on the tumor, or worked through the
intermediary effect on the immune system because it’s well known in scientific
circles that endorphins boost immune function…
… In order to separate that out, he did two studies in which he grew cancer cells in
the test tube, where there is no immune system. One was colon cancer, and the
other was pancreatic cancer. And in both settings the cancer was grown in a
nutrient solution, and the cancers were growing rapidly, adding small amounts of
met-enkephalin, the adrenal endorphin, to a petri dish, in both cases, led to cell
killing in cancer cell death. Both cancers were destroyed by the endorphins. So, in
that case, there was no immune system intermediary. That supported his belief that
endorphins work by activating the opioid receptors and producing what's called
apoptosis, which is the term for programmed cell death, induced in this case by
endorphins…
… One of the factors involved is that all the studies that have been done that I’m
aware of, endorphin levels in people with cancer, show that endorphin levels are
quite low—generally less than 30% of normal, just as they are in people with AIDS.
So, the hormone that the body most needs to fight the cancer is lacking. And giving
endorphins, or low dose naltrexone to raise endorphins, serve as a means of
restoring normal endorphin levels in people with cancer. And that appears to have
the possibility of producing remissions in some cancers—even restoration to
relatively normal levels…
… One of the implications is that one of the causes of cancer may be a drop in
endorphin levels. The endorphin levels may first drop, and by dropping, deprive the
body of its most important defense against cancer, which is direct cell-killing by
endorphins, indirectly depriving the body of another defense against cancer, which
is through immune system cells, called killer cells—natural killer cells, what are
called CD8, cytotoxic killer cells. Both are low when endorphins are low. Both are
enhanced by the presence of normal levels of endorphins as are all immune
functions. So a drop in endorphins would reduce the immune system’s surveillance
against cancer and its ability to kill cancer cells as they arise, and the lack of
endorphins would also deprive the body of the direct cell-killing effect on cancer
cells of endorphins…
… It (naltrexone) blocks the receptors for opiates for endorphins in the
hypothalamus, the structure in the base of the brain. And when it blocks those, the
hypothalamus begins producing larger amounts in the middle of the night of a
complex pro-hormone called proopiomelanocortin. That’s a hormone that breaks up
eventually into three hormones, and goes down a small stalk into the pituitary gland
in the night, and in the pituitary gland, it’s broken down by enzymes into betaendorphin, a hormone called ACTH and a melanin-stimulating hormone. So that we
know for sure. So it induces the adrenal gland to make more enkephalin through a
prohormone called proenkephalin. It causes the increase by blocking. What the
blocking does is it gives the body a false message that the body doesn't have enough
endorphins, and so the body responds with exquisite sensitivity by making more…
… Beta-endorphin has a very long life in the body. The term that’s used with
hormones and drugs is “half life,” which means how long it takes for half of a
substance—a hormone or a drug—for the body to get rid of it; to leave. And the half
life of beta-endorphin is about twenty hours. That means if you raise betaendorphin levels between 2 and 4 in the morning, you still have much higher levels
all the next day into the next evening. Met-enkephalin is harder to measure because
when it’s produced, unlike beta-endorphin, it immediately goes into cells. It
stimulates the opioid receptors, goes inside the cells. And the levels that we measure
are not as reliable the next day. Presumably the cells of the body contain larger
amounts of met-enkephalin, but you wouldn't be able to tell easily by doing blood
levels…
… But the two most important ones for enhancing immune function and for killing
cancer cells are endorphins that have what are called delta opioid receptor effects.
There are several different kinds of opioid receptors. The mu receptors are the pain
receptors—Mu named after morphine. Those are in the brain. The delta receptors
are the receptors present primarily in small amounts in the brain, but present in
many tissues in the body—in most tissues. The delta receptors play very little role, if
any, in pain relief, but they do play a major role in not only controlling cancer, but in
many of the effects that I described before that endorphins have—for example, the
receptors in the immune system cells are primarily delta receptors. Most of the
peripheral, systemic effects of endorphins are mediated through the delta
receptors… (Dr. Bihari)
Below are excerpts from an interview, conducted by Dr. Kamau Kokayi on Sept. 23, 2003. For full
interview go to Multiple Sclerosis Resource Centre Link
“We then started a little foundation and did a placebo-controlled trial in which half
the patients got the drug and half got sugar pills. A year later when we broke the
code, we discovered that people with HIV who took the drug (LDN) had only an
eight percent death rate in the year, while people who were on the placebo had a
thirty-three percent death rate. And of course they had many more infections and
their immune system declined. That was a startling discovery…
… It’s more that the autoimmune diseases are beginning to look more and more like
they’re diseases of endorphin deficiency. Models of all the diseases I mention that
can be bred in mice, the endorphin levels are always fifteen to twenty percent of
normal compared with normal mice…
… There’s only three or four ways that I know (to increase endorphins). First,
Naltrexone increases them substantially, two to three hundred percent in people
with low levels. Second, aerobic exercise increases them, but not as much. If you do
an hour of exercise four or five times a week it will last three, four hours, and that’s
one of the reasons that exercise helps prevent cancer. A third way, oddly, is
acupuncture. Acupuncture, especially when used in treating addicts, increases
endorphin levels in the blood and the spinal fluid. And chocolate increases it…
… Chocolate has a substance in it called phenylalanine, which slows endorphins
from being broken down in the body…
… The endorphins are the hormones centrally involved in regulating the immune
system. About 95% of the regulation or orchestration comes from endorphins…
… Well, first one of the things we discovered was that almost all cancers have a lot of
receptors for endorphins on the cell surface….
… It’s an endorphin deficiency which weakens the immune system, so that certain
cells in the body forget to distinguish between the body tissues and bacteria or
viruses, so when these cells are activated by an infection they attack the bacteria
and they attack you. Restoring the immune function to normal stops that. So far, the
drug (LDN) works dramatically in all the diseases that are labeled autoimmune
diseases.” (Dr. Bihari)
LDN: Informative Videos
 VIDEO – Dr. Phil Boyle on LDN, YouTube (9:26) Link
 VIDEO – Dr. David Gluck: Autoimmunity & LDN, YouTube (7:23) Link
 VIDEO – Dr. Chris Steele on LDN, YouTube (5:46) Link
 VIDEO – Dr. Aristo Vojdani, Vimeo (44:07) Link
LDN Treatment: What to Expect.
Low-Dose Naltrexone is not a cure and hardly a magic bullet. However, LDN is reported (antidotal) to
halt disease progression in a number of different conditions, and in some cases it has improved
symptoms remarkably. This is due to the simple fact that each individual is different – genetics - and
because of this the effects of LDN will be different from person to person. There are several other
factors which will determine how LDN affects an individual person such as:
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What is the actual disorder being treated
How long has the person had the disorder
What level of severity has the disorder reached
Age of person
Environmental factors such as – stress level, diet, level of exercise, quality of sleep, consumption
of alcohol, sugar, cigarettes, etc.
“I don’t think LDN is a stand alone medicine… you do have to consider diet and you
have to make sure the person is in good health and not eating a lot of sugar and a lot
of things that would impair the immune system.” (Dr. McCandless)
“I have found that LDN works best when the following three conditions have been
addressed prior to its use: (1) vitamin D deficiency has been corrected, (2) food
sensitivities have been corrected, and (3) adrenal stress or adrenal fatigue has been
properly corrected.” (Dr. Singleton)
Though LDN does not work for everyone, meaning some patients have no relief or change in their
symptoms. In general, around two-thirds of patients report some symptom improvement within the first
few days. Other patients report improvement over the course of several weeks or even months. The
types of improvements a person might experience are:
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Autoimmune disorders - disease progression halts and symptoms such as fatigue, pain, muscle
weakness and cognitive problems are alleviated.
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Multiple Sclerosis – most patients have a reduction and termination of attacks. And some
patients with MS actually report significant improvement in their symptoms.
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Degenerative illnesses like ALS and Alzheimer's - the illness progression is slowed down. People
with ALS may even regain already lost function, but this apparently does not happen in
Alzheimer’s, so it is crucial to begin the treatment as early as possible.
LDN and Cancer
 Donahue R.N., et al., Low-Dose Naltrexone Targets the Opioid Growth Factor-Opioid Growth
Factor Receptor Pathway to Inhibit Cell Proliferation: Mechanistic Evidence From a Tissue Culture
Model, Experimental Biology and Medicine, 2011 Sept., 236(9):1036-1050 Link
“Systemic exposure to a high dose of Naltrexone (HDN) or a low dose of Naltrexone
(LDN), given multiple times each day, continuously blocks opioid receptors and
accelerates cell proliferation and growth .In contrast, intermittent or short-term
opioid receptor blockade, achieved by daily administration of LDN blocks opioid
peptide–opioid receptor interactions for a short term each day (e.g. 4–6 h), and
inhibits cell proliferation and growth in the interval when the opioid antagonist is
no longer present…
… In the case of neoplasia (abnormal growth of tissue/tumor), for example,
persistent blockade of opioid receptors from endogenous opioids has a profound
effect on oncogenesis (causation of tumors) by accelerating tumor appearance and
growth. However, a temporary blockade of opioid receptors from native opioids
markedly suppresses the onset and progression of carcinogenesis (formation of
tumors).”
 Smith J.P., et al, Opioid Growth Factor Improves Clinical Benefit and Survival in Patients with
Advanced Pancreatic Cancer, Open Access Journal of Clinical Trials, 2010 March; 2010(2): 37-48
Link
“Opioid growth factor (OGF; Met-enkephalin) is a natural peptide that has been
shown to inhibit growth of pancreatic cancer in cell culture and in nude mice. The
purpose of this study was to evaluate the effects of OGF biotherapy on subjects with
advanced pancreatic cancer who failed chemotherapy.
Clinical benefit response was experienced by 53% of OGF-treated patients
compared to historical controls of 23.8% and 4.8% for gemcitabine and 5fluorouracil, respectively. Of the subjects surviving more than eight weeks, 62%
showed either a decrease or stabilization in tumor size by computed tomography.
The median survival time for OGF-treated patients was three times that of untreated
patients (65.5 versus 21 days). No adverse effects on hematologic or chemistry
parameters were noted, and quality of life surveys suggested improvement with
OGF.”
 Berkson B.M., et al, The Long-Term Survival of a Patient With Pancreatic Cancer With Metastases
to the Liver After Treatment With the Intravenous Alpha-Lipoic Acid/Low-Dose Naltrexone
Protocol, Integrative Cancer Therapies, 2006; 5(1):83-89 Link
“In summary, the integrative therapy described in this article may have the
possibility of extending the life of a patient who is customarily considered terminal.
This was accomplished with a program of universal antioxidants, one that
bears known antitumor activity (alpha-lipoic acid/ALA) and an opiateblockading agent that can stimulate an endogenous immune response (low-dose
naltrexone/LDN). The authors believe that biomedical science will one day develop
a cure for metastatic pancreatic cancer, per-haps via gene therapy or another
biological-type plat-form. But until such protocols come to market, and moreover
evolve and become realized, the ALA/LDN therapy should be considered given its
lack of toxicity at levels reported herein…”
 Berkson B.M., et al, Reversal of Signs and Symptoms of a B-Cell Lymphoma in a Patient Using Only
Low-Dose Naltrexone, Integrative Cancer Therapies, 2007; 6(3):293-296 Link
“This case report describes the treatment of a 61-year old man with biopsy-proven
FL (follicular lymphoma). His initial physical examination and PET/CT scan showed
multiple large, metabolically active, pathologic lymph nodes that impressively
demonstrated complete resolution within 6 months of commencing therapy with
nocturnally administered LDN… T.M. (patient) remains asymptomatic from his
disease, now 1 year after his last CT/PET imaging.”
LDN and Human Immunodeficiency Virus (HIV)
HIV is a retrovirus that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in
which progressive failure of the immune system allows life-threatening opportunistic infections and
cancers to thrive.
 Traore A.K., et al, Single cohort study of the effect of low dose naltrexone on the evolution of
immunological, virological and clinical state of HIV+ adults in Mali, Journal of AIDS and HIV
Research, 2011 Oct; 3(10):180-188 Link
“In this study’s patients, who all had HIV infection but whose CD4 levels were not
yet low enough to warrant antiretroviral (ARV) drug therapy, the mean CD4 %
count remained unchanged throughout the study. This is in contrast to the usual
outcomes in all other similar groups in the past, who were untreated, whose CD4%
continued to decline month after month inexorably. The researchers concluded that
for HIV+ individuals “LDN might offer a simple, relatively safe, inexpensive and
easily monitored treatment alternative.” (Dr. Gluck’s interpretation)
 Traore A.K., et al, Impact of low-dose naltrexone (LDN) on antiretroviral therapy (ART) treated
HIV+ adults in Mali: A single blind randomized clinical trial, Journal of AIDS and HIV Research, 2011
Oct; 3(10):189-198 Link
“It has been demonstrated that a treatment program which used three antiretrovirals reduced progression to AIDS or death by about 40%... we found that
adding LDN to the three-antiretroviral regime used in our study improved the
recovery rate of CD4 count significantly by 37.06% at six months… these immune
system benefits of LDN are encouraging.”
 Low-Dose Naltrexone in the Treatment of HIV Infection (1996) – this Link (to webpage) provides a
brief summary of the history of Dr. Bernard Bihari’s work into the development of low dose
naltrexone as an immune-enhancing agent in the treatment of HIV/AIDS. Dr. Bihari has shown that
LDN treatments can either raise or stabilize CD4 counts, accompanied by a reduction in
opportunistic infections and death in his patients with HIV.
LDN and Multiple Sclerosis (MS)
Multiple Sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central
nervous system in which pain, fatigue and spasticity are among the more disabling symptoms.
 Gironi M., et al, A Pilot Trial of Low-Dose Naltrexone in Primary Progressive Multiple Sclerosis,
Multiple Sclerosis, 2008 Sept.; 14(8): 1076-1083 Link
“Because LDN is supposed (but never documented) to exert its efficacy by triggering
the release of beta-endorphin, we serially measured beta-endorphin concentration
in the PBMC (peripheral blood mononuclear cells) of our patients. We were able to
provide the first in-vivo demonstration that LDN treatment is able to increase the
intracellular concentration of beta-endorphin in PBMC of patients with MS. Betaendorphin concentration started increasing 3 months after the beginning of the
therapy and remained elevated up to 1 month after therapy discontinuation. At this
stage, we might only speculate that the symptom improvement is related to the
increased circulating concentration of beta-endorphin. Nevertheless, it is interesting
to note that symptom amelioration paralleled increasing beta-endorphin
concentration during the trial and persisted 1 month after treatment
discontinuation when beta-endorphin level peaked.”
 Agrawai Y.P., Low-Dose Naltrexone Therapy in Multiple Sclerosis, Medical Hypothesis,
2005;64(4):721-724 Link
“There is overwhelming anecdotal evidence, that in low doses naltrexone not only
prevents relapses in MS but also reduces the progression of the disease. It is
proposed that naltrexone acts by reducing apoptosis of oligodendrocytes. It does
this by reducing inducible nitric oxide synthase activity. This results in a decrease in
the formation of peroxynitrites, which in turn prevent the inhibition of the
glutamate transporters. Thus, the excitatory neurotoxicity of glutamate on neuronal
cells and oligodendrocytes via activation of the… glutamate receptor is prevented.”
LDN and Crohn’s Disease
Crohn’s disease is an autoimmune disease marked by chronic and remitting inflammation of the
gastrointestinal tract which manifest as – abdominal cramps, fever, fatigue, diarrhea, painful bowel
movements and loss of appetite.
 Smith J.P. et al, Therapy with the opioid antagonist naltrexone promotes mucosal healing in active
Crohn’s disease: a randomized placebo-controlled trial. Digestive Diseases and Sciences, 2011 July;
56(7):2088-2097 Link
“This clinical trial is the first randomized double-blind placebo controlled study
demonstrating that naltrexone improves clinical activity index scores and improves
gastrointestinal mucosal inflammation in subjects with moderate to severe Crohn’s
disease. Over a 12-week period of time, subjects were treated with either placebo or
naltrexone in a blinded fashion, and mucosal healing was evaluated by endoscopic
appearance and histology from biopsies obtained during colonoscopies. Only those
patients treated with naltrexone showed significant reversal of gastrointestinal
inflammation by histology, whereas, placebo-treated subjects had no improvement.
Thus, using a medication that alters the interaction of endogenous opioids at their
receptors to decrease inflammation provides an innovative approach that utilizes
native biological pathways…
… Evidence for efficacy of naltrexone for Crohn’s disease is further supported by the
extension study which followed the double blind protocol. Those subjects that were
in the placebo arm of the study that subsequently were treated with naltrexone in
an open-labeled fashion showed significant improvement both in clinical activity
and in colonoscopy scores.”
 Smith J.P., et al, Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease, The American
Journal of Gastroenterology, 2007 Apr; 102(4):820-828 Link
… The results of this pilot study are the first to show that LDN therapy significantly
decreases symptoms and improves quality of life in patients with active Crohn’s
disease. In fact, two-thirds of enrolled patients achieved remission at some point
during LDN treatment.”
LDN, Fibromyalgia & Pain Management; the Paradoxical Effect
 Younger J., Mackey S., Low-Dose Naltrexone Reduces the Symptoms of Fibromyalgia: A DoubleBlind and Placebo-Controlled Crossover Study, Presented at the 2012 AAPM Meeting, (abstract
only) Link
“Pain was reduced significantly more in the LDN condition (43%) versus the placebo
condition (33%).”
 Younger J., Mackey S., Fibromyalgia Symptoms are Reduced by Low-Dose Naltrexone: A Pilot
Study, Pain Medicine, 2009 May-Jun; 10(4):663-672 Link
“Overall symptom severity was significantly reduced in the drug condition, as
contrasted to baseline and placebo conditions. In the entire group of participants,
LDN reduced fibromyalgia symptoms by 30.2% over and above placebo.”
WebMD – Naltrexone May Ease Fibromyalgia Symptoms (2009) - An article that explains the above
Fibromyalgia Stanford Study in simple layman’s terms. Link
 VIDEO – An Update on Fibromyalgia with Dr. Sean Mackey MD, PhD (2009), Stanford Health Video
Library; Research Channel (1:15:11) Link
(Dr. Mackey is one of the authors of the Fibromyalgia Stanford Study. In this video he speaks about
the mechanisms of fibromyalgia and how LDN may be helpful)
Pain Treatment Topics (2009) – This article explains how LDN has a “paradoxical” effect in the
treatment of difficult conditions such as fibromyalgia or neuropathies. Link
“Opioid antagonists — in particular, naloxone and naltrexone — have been available
and studied for decades as agents that displace opioid molecules from their neuroreceptors, and block opioids from attaching to and activating those receptors…
Laboratory research and clinical trials have demonstrated the unexpected,
paradoxical effects of opioid antagonists as adjuvants for enhancing rather than
attenuating analgesic effects of opioids like morphine, oxycodone, and others.
Further benefits of opioid antagonists, as monotherapy, for better managing certain
chronic pain conditions also have been discovered…
… Studies in opioid-free animals have shown that, by causing a transient blockade of
opioid receptors, low doses of antagonists stimulate increased production, or
upregulation, of mu opioid receptors in regions of the brain that control pain
responses. Therefore, it seems plausible that after antagonist effects wear off
greater numbers of opioid receptors are available to bind with pain-relieving
opioids in the circulatory system, whether externally administered (eg, morphine)
or endogenous peptides (eg, endorphins). At the same time, it has been noted that
the body responds to the temporary opioid-receptor blockade by producing
substantially increased amounts of beneficial natural endorphins…
… The ultimate effects of these mechanisms, demonstrated in animal studies and
human trials, appears to be an enhancement by low- or ultralow-dose naloxone or
naltrexone of opioid agonist antinociceptive (pain relieving) efficacy. Essentially,
appropriately low doses of opioid antagonists have been postulated to “reset” the
opioid-receptor system for a period of time…
… More recently, neuroimaging studies found that patients with fibromyalgia had
significantly reduced availability of mu-opioid receptors in specific brain regions
known to modulate pain, as compared with healthy control subjects. The
investigators suggested this as a possible explanation for why exogenous opioids
generally have reduced effectiveness in fibromyalgia. Low-dose naltrexone, by
upregulating the opioid-receptor system, might increase the body’s responsiveness
to endogenous opioid peptides in helping to relieve fibromyalgia pain.”
Cure Together – is a website that surveys and charts symptoms and treatments. Their charts indicate
that LDN is still relatively unknown, but those who have used it give it high ratings for reducing
symptoms. Fibromyalgia treatment chart - Link
LDN and Chronic Fatigue Syndrome (CFS)
Phoenix Rising – is a popular CFS website and here they nicely describe how and why LDN might be
helpful for those with CFS. Link
Herald Scotland, Saturday 25 April 2009 Link
Dr. Gilhooly from Rutherglen (Scotland) has around 200 patients at his clinic who
are currently receiving LDN and he said he had recorded “a lot of success” in those
who had taken the drug.
Dr Gilhooly said that around half of his patients who receive LDN had been
prescribed it for chronic fatigue syndrome and fibromyalgia.
Dr Gilhooly said: "We have used it for both with great success. I have been treating
chronic fatigue syndrome for years but we have been incredibly limited in
treatments. To find something like this that is working is great for the patients.”
The Essential Health Clinic – Chronic Fatigue Syndrome Link
“We have also started to use Low Dose Naltrexone (LDN), a drug which works well
in MS patients. This appears to work by reducing oxidative stress, particularly a free
radicals called perioxynitrites which are neurotoxic. So far CFS patients are
responding very well and so this is an area for future research.”
Cure Together – is a website that surveys and charts symptoms and treatments. Their charts indicate
that LDN is still relatively unknown, but those who have used it give it high ratings for reducing
symptoms. Chronic Fatigue Syndrome treatment chart - Link
LDN and Multiple Chemical Sensitivity (MCS)
Allergy Center.com – LDN for Immune Modulation Link
“Individuals with HIV, chronic fatigue syndrome, fibromyalgia, multiple chemical
sensitivities, autism and Hepatitis C are being treated with LDN…with promising
results…
… Chemically sensitive individuals have responded favorably to LDN noting a
decrease in reactivity and improvement in energy and mood.”
Cure Together – is a website that surveys and charts symptoms and treatments. Their charts indicate
that LDN is still relatively unknown, but those who have used it give it high ratings for reducing
symptoms. MCS treatment chart - Link
LDN & Lyme Disease
Cure Together – is a website that surveys and charts symptoms and treatments. Their charts indicate
that LDN is still relatively unknown, but those who have used it give it high ratings for reducing
symptoms. Lyme Treatment Chart - Link
LDN Testimonials
MCS – LDN Testimonial Link
Fibromyalgia – LDN Testimonial Link
 LDN Research Trust YouTube Channel – this channel has almost 300 videos which mostly are
testimonials from patients whose lives have greatly improved since taking LDN. Link
LDN: How to Take IT
The usual adult dosage of LDN is 1.5 - 4.5mg taken orally once daily at bedtime on an empty stomach.
Because of the natural rhythms of the body’s hormone production; meaning the body produces most of
its endorphins between 2 – 5 AM, LDN is best taken between 9pm and 2am.
Though it is recommended to take LDN at night and on an empty stomach it is not necessary. Food is not
known to affect the absorption of naltrexone; therefore LDN can be taken with or without food. Also,
taking LDN at night may disturb sleep in some individuals and for these people taking it in the morning is
preferred.
However a note of caution if one feels they need to take LDN in the morning - endogenous opioids are
important for our well-being, blocking them for 4 to 6 hours during the daytime may cause very
bothersome side effects. I personally can attest to this when I experimented by taking my LDN in the
morning with breakfast. Four hours after taking it I developed a pretty good headache which was
followed by extreme fatigue and a sense of spacyness which lasted the entire day.
“… initially try taking it in the evenings before bedtime to avoid discomfort brought
on by deprivation of the body’s endogenous opioids with opioid receptors – and if
this has repercussions (disturbing dreams) take it in the morning.” (Dr. Zagon)
Also, Naltrexone is cleared by the liver, and an impaired liver function may slow the clearance of the
drug from the body. If this is the case each additional dose might be adding to the load in the body. In
such cases dosing should take place every other night or every third night, rather than nightly.
“… one of the things we’re learning is, we were giving low-dose naltrexone and OGF
(opioid growth factor) every day. We’ve got a study right now that shows you can
give the opioid growth factor once a week and you can get a better effect than you
get every day… that’s what research is all about. That’s going to translate to the fact
that people don’t have to take this growth factor everyday… they don’t have to take
low-dose naltrexone everyday…
… and we’re also finding out that some people… they’re actually taking too much
low-dose naltrexone. In fact what they will do is they are going to feel that they are
having a very positive effect but maybe 6 months to a year down the road they’re
going to say I’m losing that effect. And I’ve already had to help about a dozen people
so far about that… they reach me… and it’s not working anymore… what’s
happening? Well the reason why it’s not working is because there building up too
much naltrexone so their effects are not going to be as great. So what was the result
of that… they had to take the naltrexone every other day and in some cases some of
them are taking it every third day now… and the first thing that comes back is… oh
it’s working beautifully again.” (Dr. Zagon)
“… I do adjust the dosages… some patients do need to take a drug break… I think
there are patients that aren’t so endorphin deficient and need a break of a day or
two every now and again… if somebody is going down is it that they are not taking
the drug or is it the case that they’ve got too much… it’s a new idea… consider the
possibility that we are over treating consider a bit of a break from the treatment and
that might work.” (Dr. Boyle)
LDN: Side Effects
Low-Dose Naltrexone is considered, by medical professionals (MDs, PhDs) to be extremely safe.
Interestingly, many of the medical professionals who specialize in the treatment of LDN take the drug
themselves prophylactically. And have also encouraged their family and friends to do the same.
LDN is not addictive and all sources indicate that LDN has virtually no side effects. What side effects
have been reported usually only last 1-2 weeks and then clear. Some side effects of LDN are:
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Disruptive Sleep – due to the endorphin surge after LDN is metabolized.
Vivid Dreams – due to the endorphin surge after LDN is metabolized.
Dry Mouth - due to the endorphin surge after LDN is metabolized.
Stiffness
Fatigue
Spacyness
Headaches – LDN crosses the blood brain barrier
Diarrhea, gas, bloating
Irritability, Agitation
Loss of Appetite
Changes in Blood Pressure
“…over the counter aspirin would have a longer list of side effects than what
naltrexone has.” (Dr Boyle)
LDN: Contraindications
Because LDN is an opioid antagonist and blocks opioid receptors, people using opioid/narcotic
medications should not take LDN until such medicine is completely out of the system.
Those taking thyroid hormone ought to begin LDN at the lowest range. LDN may lead to prompt
decrease in the autoimmune disorder Hashimoto’s thyroiditis. This may require a rapid reduction in the
dose of thyroid hormone in order to avoid symptoms of hyperthyroidism.
Steroids would counteract the effects of LDN and should not be combined.
LDN should not be used by people receiving interferon. Because LDN stimulates the immune system and
interferon suppresses it.
At this moment, there is no known reason to avoid taking LDN with any medication, drug, vitamin, or
supplement other than opiate-type drugs usually used for treating pain.
LDN: Compounding Considerations
Low-Dose Naltrexone can only be acquired through a compounding pharmacy. Several things need to
be considered when ordering LDN from a compounding pharmacy.
Avoid slow-released or timed-released naltrexone. You want to be sure the LDN you receive is in
unaltered form that allows you to receive the full dose quickly. Slow-release formulas may not give you
the full therapeutic effects.
An empty capsule (size #3) can hold approximately 225mg of powder. A dose of 4.5mg of naltrexone is a
very small amount that fills about 2% of the capsule. Therefore, the remaining space (98%) is filled with
inert filler. The most common fillers used are:
o
o
o
o
Lactose (milk sugar)
Avicel (microcrystalline cellulose/plant base filler)
Calcium Carbonate – may interfere with LDN absorption
Acidophilus
Some pharmacies add B-2 (yellow) to make sure the compounded LDN is evenly mixed.
When mixing your own LDN in to a liquid - naltrexone is stable in water for up to 60 days when
refrigerated. The dose can also further be mixed with additional water or even juice.
 VIDEO – How to compound your own low dose Naltrexone (LDN), YouTube (4:53) Link
Manufacturing of Naltrexone
Presently, Naltrexone is manufactured by a number of different companies from around the world and
go under the following trade names:
-
Antaxone - manufactured by Pharmazam in Spain
Celupan - manufactured by Lacer in Spain
Nalorex - manufactured by Bristol-Myers-Squibb in the UK
Nodict - manufactured by Sun Pharma in India
Naltima - manufactured by INTAS in India
Narpan - manufactured by Duopharma in Malaysia
Narcoral - manufactured by Siton in Italy
Nemexin, Revez, Naltrexona, and Naltrexonum - manufactured by Bristol-Myers-Squibb in
Germany
References
Books:

Enkephalins and Endorphins; Stress and the Immune System, by Dr. Nicholas Plotnikoff, Plenum Press (1986)
Link

Immunosuppression – Role in Health and Diseases: Chapter 1 Role of Opiodergic System in Humoral
Immune Response by Dr. Suman Kapur, InTech, (2012) Link

Messengers of Paradise; Opiates and the Brain, by Dr. Charles F. Levinthal, Anchor Press (1988) Link

The Lyme Disease Solution, by Dr. Kenneth Singleton, Brown Books, (2008) Link

The Opiate Receptors, by Dr. Gavril Pasternak, The Humana Press (1988) Link

The Promise of Low Dose Naltrexone Therapy: Potential Benefits in Cancer, Autoimmune, Neurological and
Infectious Disorders, by Elaine A. Moore and Samantha Wilkinson, McFarland & Company Inc. Publishers
(2008) Link
Articles:

Introduction to Low-Dose Naltrexone (LDN), by Dr. Ian S. Zagon, LDN Research Trust, 2009 Oct. 22nd Link

Low-Dose Naltrexone as a Treatment for Multiple Sclerosis, by Dr. Tom Gilhooly, British Journal of
Neuroscience Nursing, 2009 Nov., 5(11):494 Link

Low-Dose Naltrexone (LDN): Tricking the body to heal itself, Experimental Biology and Medicine, Sept. 2011,
236(9) Link

Low-Dose Naltrexone (LDN) for Mood Regulation and Immunomodulation in ASD (Autism Spectrum
Disorders), by Dr. Jaquelyn McCandless, lowdosenaltrexone.org, April 2006 LInk

Opioids Antagonists, Naloxone & Naltrexone – Aids for Pain Management, by Stewart Leavitt PhD, Pain
Treatment Topics, March 2009 Link
Research Publications:
Research publication links are included within the text of this report
Videos:
Videos and video links are included within the text of this report
Radio:
-
Mary Bradley Show interviews Dr. Chris Steele Link
Mary Bradley Show interviews Dr. Ian Zagon Link
Mary Bradley Show interviews Dr. Tom Gilhooly Link
Mary Bradley Show interviews Dr. David Gluck Link
Mary Bradley Show interviews Dr. Bob Lawrence Link
Mary Bradley Show interviews Dr. Skip Lenz Link
Mary Bradley Show interviews Dr. Jaquelyn McCandless Link
Mary Bradley Show interviews Dr. Burt Berkson Link
Mary Bradley Show interviews Dr. Phil Boyle Link
WWW:
o
o
o
o
o
Allergy Center Link
Cure Together Link
Fiikus – Low dose naltrexone: an overview LInk
HealClick – Most Effective Treatment for Autoimmune Illness? Link
Heal Yourself At Home – Low Dose Naltrexone Link
o
o
o
o
o
o
o
o
o
o
o
o
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Herald Scotland – Life changing benefits for patients using addiction drug Link
LDN Aware Link
LDN Research Trust Link
LDN Science Link
Low Dose Naltrexone Link
Multiple Sclerosis Resource Centre – Interview with Dr. Bihari Link
Medical News Today – Opioid-Induced Constipation Link
NCBI Bookshelf - Signaling Molecules and their Receptors Link
Phoenix Rising Link
Society for Experimental Biology and Medicine– Low Dose Naltrexon: Tricking the Body to Heal Itself Link
Stress Tips – The Users Guide to Brain Chemicals Controlling Stress, Mood & Emotions Link
Suboxone Assisted Treatment – All About Opiates Link
The Compounder – What is Low Dose Naltrexone Link
o
o
o
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The Essential Health Clinic – Chronic Fatigue Syndrome LInk
WebMD – Naltrexone May Ease Fibromyalgia Symptoms Link
Western Anaesthesia Society Ireland Link
Wise GEEK – What is a Neuropeptide Link