Handouts - College of Pharmacy

Herbal Supplement Usage in the U.S.
Herbal Dietary Supplements:
The Good, the Bad, and the Ugly

Bill J. Gurley, Ph.D.
UAMS College of Pharmacy
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UAMS, College of Pharmacy
Continuing Education Course
Little Rock, AR
December1, 2013
Approx. 60% of U.S. population take dietary supplements
(vitamins, minerals & botanicals)
Sales of dietary supplements exceeded $30 billion in 2011.
Products range from conventional dosage forms containing
crude botanical material (i.e. capsules, tablets, transdermal
patches) to “nutraceuticals” and “functional foods” (i.e.
ginkgo potato chips, ginseng candy bars).
Disclosure
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Chief Science Officer for Balm Innovations, LLC.
(makers of Omnibalm™)
Member of the USP Expert Panel on Dietary Supplements
Expert witness (plaintiff) in numerous Ephedra-related
litigations
Principal ingredients:
Epimedium brevicorum
Tribulus terrestris
Both E. brevicorum and T. terrestris
are sources of icariin, a natural
phosphodiesterase b5a inhibitor.
Icariin is about 80 times less potent
than sildenafil
Hoodia gordonii
Indication:
Weight-loss aid
“P57” purported active cpd.
Efficacy:
Good for Kalahari natives
No effect as marketed extract
More Hoodia on the market than
can be grown in S. Africa
(Most Hoodia products are bogus!)
Enzyte® and “Smiling Bob”
What’s in Enzyte?
Tribulus terrestris: purported natural testosterone stimulant
Yohimbe extract: purported aphrodisiac, source of yohimbine an
alpha-2 receptor blocker (synthetic yohimbine impotence treatment)
Niacin: peripheral vasodilator
Epimedium brevicorum: purported natural treatment for erectile dysfunction. Contains
icariin,natural phosphodiesterase b5a inhibitor, 80 times less potent than sildenafil
Avena sativa: natural source of vitamins, “has been shown to stimulate genital organs”
Maca: Peruvian plant with natural stimulant properties
Ginkgo biloba: Tree whose leaves contain ginkgolides, which are mild anticoagulants
L-arginine: amino acid substrate for NO synthase, which produces NO, a vasodilator
Saw Palmetto: Plant indigenous to U.S. used for mild prostatic hyperplasia
Recent Actions: Criminal

FTC Case 2006: Enzyte’s
“Smiling Bob” ad campaign;
also Rogisen and Avlimil

“Free” samples led to
unauthorized auto-shipping
Herbal Supplement Usage in the U.S.

Best selling and most heavily promoted supplements
are associated with:
Mood
Food
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Criminal Case 2008: DOJ, USPS, FBI, IRS, FDA

Ordered to forfeit $459,540,000; prison sentences as high as 25
years
Company and 4 execs convicted on 93 criminal counts of mail
fraud, bank fraud, money laundering, obstruction of FTC/FDA
cases
Berkeley Premium Nutraceuticals (2008)
Sleep
Sex
Demographics and viewpoints
of supplement users.
Dietary Supplement Health & Education Act
(DSHEA)
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Enacted in 1994.
Defines dietary supplements as distinct from drugs or
food additives...“a product (other than tobacco) added to the total
diet that contains at least one of the following: vitamin, mineral,
herb, or botanical, amino acid, metabolite, extract, or combination
of ingredient described above.”
Limits the role of FDA: made dietary supplements exempt
from premarket approval. Places burden of proof for safety on
FDA.
Efficacy of Dietary Supplements
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Average consumer is college-educated, 40-55 years of age,
female, and Caucasian. Use in children and the elderly is
increasing.
Many consumers don’t consider herbal supplements as
drugs even though many herbs contain active drug
ingredients.
Consumers less likely to link herbal supplements to
adverse health events.
Safety of Botanicals
Clinical trials conducted or ongoing for:

feverfew (Type 2 diabetes, migraine & rheumatoid arthritis)

St. John’s wort (depression)

garlic (hypertension & hyperlipidemia)
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ginseng (Type 2 diabetes, fatigue & cancer prevention)
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ginkgo biloba (circulatory disturbances, dementia)
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saw palmetto (benign prostatic hyperplasia)
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Potentially safe botanicals (when used singly):
echinacea, feverfew, garlic, ginkgo biloba, ginseng, saw palmetto,
St. John’s wort, valerian

Unsafe botanicals:
coltsfoot, comfrey, sassafras, chaparral, germander, licorice,
ephedra (ma-huang), aristolochia.
valerian (insomnia)
echinacea (immune stimulant)
Safety of Botanicals
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Safety of Botanicals
(adulteration with Rx medications)
Misidentification of plant species:
Digitalis lanata, Aristolochia fangii
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Adulterants: (Chinese herbal medicines) benzodiazepines,
caffeine, corticosteriods, digitialis, ephedrine,
hydrochlorothiazide, indomethacin, phenobarbital,
phenylbutazone, phenytoin, salicylates, theophylline, thyroid
hormones,
Contaminants: Bacteria, fungi, pesticides, heavy metals
(Hg, Pb, Cd, As)
Evaluation of 634 nutritional supplements in 13 countries between 2000-2001
Geyer et al., Int J. Sports Med. 25, 124-129; 2004
Safety of Botanical Weight-loss aids
(adulteration with synthetic steroids)
Safety of Botanicals
(adulteration with Rx medications)
October 2009, FDA warned consumers not to use
body building supplements marketed to increase
muscle mass as they contain undeclared anabolic
steroids (Tren Xtreme, Mass Xtreme, HMG Xtreme)
Sleepees™, one of five Canadian “natural” sleep-aid products found to
contain estazolam (benzodiazepine). Removed from market in August 2007.
2007-2013, many herbal sex-enhancing products in U.S. recalled after they
were found to contain tadalifil (Cialis®), sildenafil (Viagra®), or analogues of
sildenafil.
http://www.fda.gov/bbs/topics/NEWS/2008/NEW01933.html
Safety of Botanical Weight-loss aids
Heavy metals in
dietary supplements
(adulteration with Rx medications)
Extrim Plus  phenytoin
JAMA. 2008; 300:915-923
(AugustJ 27)
Venom Hyperdrive  sibutramine
Starcaps  bumetanide
February 2009, FDA found 80 internet weight-loss
products contained undeclared prescription drugs.
Phyto Shape  rimonabant
http://www.fda.gov/bbs/topics/NEWS/2008/NEW01933.html
Potential for Herb-drug Interactions
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“An estimated 15 million adults in 1997 took
prescription medications concurrently with
herbal remedies and/or high dose vitamins
(18.4% of all prescription users).”
“This estimate includes nearly 3 million adults
aged 65 years or older.”
JAMA 280:1569, 1998
Herbal Supplement Usage in the U.S.
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Recent surveys indicate that 20% of Rx users
take botanical supplements concomitantly;
32-61% of hospital patients use botanical
supplements regularly.
Less than 40% of patients reveal use of herbal
dietary supplements to health care
professionals.
Herbal supplement usage among surgery patients.
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1,017 patients (pre-op.) surveyed by Dept. of Anesthesiology at Texas Tech
Supplement
Vitamins
Garlic
Ginkgo biloba
St. John’s wort
Echinacea
Aloe
Cascara
Licorice
Percent Usage
90%
43%
32%
30%
18%
10%
8%
3%
Factors contributing to herb-drug interactions
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Products containing multiple herb components.
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Formulations utilizing concentrated plant extracts.
Presence of multiple phytochemicals that have not
been characterized for pharmacological activity.

(e.g. ~ 500 phytochemicals identified in Panax ginseng)
Kaye et al. J. Clin. Anesthesia. 2000;12:468-471
Partial Listing of Known Constituents
of typical St. John’s wort Extracts
Naphthodianthrones
hypericin
pseudohypericin
protohypericin
protopseudohypericin
cyclopseudohypericin
Xanthones
1,3,6,7-tetrahydroxyxanthone
kielcorin
Phloroglucinol derivatives
hyperforin
hydroperoxycadiforin
adhyperforin
Potential mechanisms for herb-drug interactions
Flavonoids
luteolin
13, II8-biapigenin
amentoflavone
hyperin
catechin derivatives
epicatechin derivatives
quercitin
kaempferol
hyperoside
quercitrin
isoquercitrin
rutin
myricetin
Pharmacodynamic interactions:

Botanicals having pharmacological properties
similar to or opposite of conventional medications.
Essential Oils
methyl-2-octane
pinenes
terpineol
geraniol
limonene
caryophyllene
humulene
Ephedra Alternatives (“Ephedra-free”)
Case reports with merit: Ephedra-free
Ephedra Alternatives
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Natural sources of caffeine are now the most
frequently used substitutes for Ephedra.
Caffeine sources: Guarana, Green tea, Kola nut, Yerba
maté, combinations of each.
Typical recommended servings can contain as much
caffeine as 2-5 cups of regular coffee, sometimes
more.
Are high dose caffeine products safer?
UAMS C.O.P. Study of “Ephedra-free” products
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Ephedra-free
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Dietary restrictions (no caffeine intake), no
medications
Randomized to receive Guarana, Zantrex 3,
Xenadrine EFX, and Metabolift
(2 capsules, 3 times daily for 3 days)
Monitored for hemodynamic and electrocardiographic effects (Holter monitor) at baseline
and days 1 & 3.
UAMS C.O.P. Study Results
UAMS C.O.P. Study of “Ephedra-free” products
Holter monitor placement
12 healthy male volunteers
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Mean systolic BP increased by 10 mm Hg
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Mean diastolic BP increased by 6 mm Hg
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EKGs demonstrated abnormal heart rhythms in
certain individuals (e.g. atrial flutter, SVT, inverted T waves).
Other side effects: insomnia, chest pain, anxiety, nausea*,
tinnitus, diuresis, sweating, indigestion, loss of appetite, etc.
One product contaminated with 5 Bacillus spp.
Foster et al, Clin. Pharmacol. Ther. 2013;93:269-274
UAMS C.O.P. Study Results
Pharmacodynamic herb-drug interaction
considerations of “Ephedra-free” Study
Systolic blood pressure
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Consumers of “ephedra-free” supplements may be
obese with underlying cardiovascular disease.
Such consumers may take antihypertensive and
other cardiovascular medications concomitantly.
Study suggests that “ephedra-free” may not be
“trouble-free” in certain consumers.
Foster et al, Clin. Pharmacol. Ther. 2013;93:269-274
Potential mechanisms for herb-drug interactions
P-gp
Pharmacokinetic mechanism:
Affect drug absorption, distribution, metabolism,
excretion.

Modulation of drug metabolizing enzymes in small
intestine and liver. (e.g. Cytochrome P-450 enzymes)

Modulation of drug transporting proteins in small
intestine, liver, blood brain barrier.
(e.g. P-glycoprotein, OATP, other transporters)
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Pharmacokinetic Effect of CYP and/or P-gp Modulation
Rx Plasma Conc.(ng/mL)
Inhibition
of CYP or P-gp
P-gp
St. John’s wort
Hypericum perforatum
Indication:
MSC
MEC
Induction
of CYP or P-gp
Antidepressive
Efficacy:
Good
Rx Interactions?
Yes
Time (hours)
St. John’s wort
St. John’s wort
Indications:
Mechanism of action:
•Mild–moderate depression
• Hyperforin, hypericin, and other phytochemicals:
Evidence:
inhibit 5-HT, NE, DA uptake?
GABAA & GABAB receptor ligands?
Other ?
• Numerous randomized placebo-controlled clinical trials.
• Performed mainly in Germany and U.S.
• 2 NIH-sponsored trials—mixed results.
Drug interaction risk:
Efficacy:
• Superior to placebo in most studies of mild depression.
• As efficacious as tricyclics. SSRI comparisons ongoing.
• Well tolerated, few adverse side effects (no loss of libido).
• Results are often product-specific.
• HIGH !!
• Potent inducer of CYP drug metabolizing enzymes and
drug transporters
Effect of SJW on Cyclosporine Trough Concentrations
Effect of SJW on CYP3A4 Phenotype
Young: [Average increase = 98%] (Range = 17%-240%)
(OHMDZ / MDZ) Plasma Ratio
Elderly: [Average increase = 141%] (Range = 58%-725%)
Young
(~25 y.o.)
Elderly
(~67 y.o.)
**
**
GW Barone, BJ Gurley, et al. Transplantation 71:239, 2001
Reported SJW/Cyclosporine Interactions
in Transplant Recipients
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What makes St. John’s wort so problematic?
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Hyperforin is responsible for CYP3A4 and P-gp induction.
(Moore et al. PNAS. 97:7500, 2000)
Heart TXP with rejection
(Ruschitzka et al. Lancet 355: 548, 2000)

Liver TXP with rejection
(Karliova et al. J. Hepatol. 33: 853, 2000)
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Kidney TXP with rejection
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(Barone et al. Transplantation 71:239, 2000;
Hyperforin is a potent ligand for the nuclear receptor, SXR, which induces
CYP3A4 and ABCB1 gene expression.
(Wentworth et al. J. Endocrinol. 166:R11, 2000.)
Breidenbach et al. Transplantation 69:2229, 2000)

Hyperforin is more potent than rifampin with regard to CYP and P-gp
induction. Hyperforin Ki for SXR ≈ 25 nM
What makes St. John’s wort so problematic?
What makes St. John’s wort so
problematic?
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24 mg/day
(hyperforin)
600 mg/day

CYP3A4 and P-gp responsible for metabolism and transport
of ≥50% of conventional drugs.
Hyperforin responsible for antidepressive activity.
SJW products standardized for hypericin (0.3%), yet hypericin
exhibits no anti-depressive activity nor does it affect CYP.
Hyperforin content not a label requirement.
600 mg/day rifampin (C) similar to 24 mg/day hyperforin (D)
with regard to effects on digoxin pharmacokinetics.
Gurley et al, Mol. Nutr. Food Res.. 2008;52:772-79
St. John’s wort
Hyperforin Content of SJW
Product
A1*
A2
B
C
D
E
F
Hyperforin (mg/g) Hypericin (mg/g)
13.6
0.25
3.8
0.30
5.3
0.30
10.0
0.30
7.4
0.28
1.1
0.35
1.1
0.24
Interaction mechanism:
Induces CYP3A4, CYP2E1, CYP2C9, and P-gp
Interactions:
Cyclosporine, digoxin, warfarin, BCPs, simvastatin,
indinavir, midazolam, verapamil, irinotecan,
omeprazole, many others…
Consequences:
Numerous!! Renders most medications ineffective!
Effect of Goldenseal on CYP3A4 & 2D6 Phenotype
Goldenseal
(~40% reduction)
Hydrastis canadensis
mask urine drug screens)
Efficacy:
Poor
Rx Interactions?
Yes
**
Debrisoquine Urinary Recovery Ratios
Numerous
(Colds, URTIs, GI disorders,
Effect on CYP2D6
Effect on CYP3A4
OH-MDZ/MDZ Serum Ratios
Indication:
Gurley et al., Clin. Pharmacol. Ther., 2005; 77:415-426
Gurley et al., Clin. Pharmacol Ther., 2008; 83:61-69
Gurley et al., Mol. Nutr. Food Res., 2008; 52:755-763
**
Goldenseal isoquinoline alkaloids
What makes Goldenseal problematic?
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(broken circle = methylenedioxyphenyl moiety)
In vivo activity of CYP3A4 & 2D6 reduced by 40%
(clinically relevant).
CYP3A4 & 2D6 responsible for metabolism of ≥75% of
conventional drugs.
Two isoquinoline alkaloids (hydrastine and berberine)
inhibit CYP isoforms.
Gurley et al., Clin. Pharmacol Ther., 2008; 83:61-69
Historical perspective of goldenseal’s
effect on CYP3A4
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Other MDP-containing botanicals
Piper longum & Piper nigrum (Black pepper)
During the American Civil War quinine (Cinchona bark) was one
of the few effective febrifuges available to both armies.
Quinine was in especially short supply to the Confederate army.
Goldenseal was often administered with quinine to prolong its
antipyretic effects and reduce its dose.
Quinine is a CYP3A4 substrate.
Other MDP-containing botanicals
Other MDP-containing botanicals
Piper longum & Piper nigrum (Black pepper)
Schizandra chinensis
Other MDP-containing botanicals
Schizandra chinensis
Miscellaneous
dietary supplements
Schizandra extract increases
tacrolimus absorption
Ginkgo biloba
Ginkgo biloba
Indications:
Indications:
•Mild dementia, early-stage Alzheimer’s disease, peripheral
claudication
Mild dementia
Evidence:
Efficacy:
• Numerous randomized placebo-controlled clinical trials
• Performed mainly in Europe and U.S. Large NIH trial ongoing
Mixed
Rx Interactions:
???
Efficacy:
• Superior to placebo in most studies of mild dementia
• Generally well tolerated, few adverse side effects
• Mixed results in Alzheimer’s disease
• Results are often product-specific
Ginkgo biloba
Mechanism of action/Interaction mechanism:
Garlic
Allium sativum
Terpene lactones: inhibit platelet-activating factor
Flavonol glycosides: antioxidants, free radical scavengers
Indication:
Side effects:
Antihyperlipidemic
Spontaneous bleeding described in several case reports.
Efficacy:
Rx Interactions:
Mixed
Several prospective in vivo studies suggest that ginkgo
biloba does not interact with warfarin, aspirin, or
clopidogrel, and does not affect CYP activity.
Rx Interactions:
Can inhibit CYP2E1
Of minimal clinical relevance
Milk Thistle
Black Cohosh
Silybinum marianum
Cimicifuga racemosa
Indications:
Indications:
Hepatoprotectant
Menopausal symptoms
Efficacy:
Mixed
Efficacy:
Fair to good, product specific
Rx Interactions:
Minimal effects on CYPs
and P-gp
Rx Interactions:
Unlikely
Echinacea
Echinacea purpurea
Indications:
Immune stimulant
Efficacy:
Mixed
Rx Interactions:
Unlikely
Allergic reactions!
Saw Palmetto
Serenoa repens
Indications:
Benign prostatic
hyperplasia
Efficacy:
Good
Rx Interactions:
Unlikely
Tea Tree Oil
Tea Tree Oil
Melaleuca alternifolia
Melaleuca alternifolia
Indications:
Natural antifungal,antibacterial,
anti-inflammatory properties
Efficacy:
Good
Safety:
Avoid pure oil in clear glass containers,
oxidation products can produce dermatitis
Developed at UAMS
College of Pharmacy
Efficacy:
Burns (sunburns)
Itching (poison ivy)
Severely cracked skin
Diabetic foot care
Minor bed sores
Summary
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Botanical supplements can interact with
conventional medications.
Keeping it in perspective

Mechanism(s) may be pharmacodynamic (similar
pharmacology) or pharmacokinetic (e.g. induction or
At present only a few botanical supplements
appear to pose significant herb-drug
interaction risks; however, only a small
number have been thoroughly evaluated.
inhibition of drug metabolizing enzyme activity).
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
Caution must be used when mixing drugs and
botanical supplements.
Information Resources
What can health care professionals do?
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More vigilance regarding herbal supplement use is
necessary.
Medical histories should include queries about herbal
supplement use.
Herb-drug interactions are not as prevalent
as conventional drug-drug interactions. They
complicate an already complex problem.

Internet:
www.nccam.nih.gov
www.ods.od.nih.gov
Health care professionals must educate themselves
about herb-drug interactions and their clinical
consequences.
www.naturaldatabase.com
Patients must become better educated about the
potential risks of herbal supplements and the need to
report such use to their physician and pharmacist.
www.consumerlab.com
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