A. Overview

1. These agents are typically sold in the USA as dietary supplements
2. In Europe, some of these agents are licensed for specific indications
3. Good clinical evidence for efficacy exists in some cases
4. Side effects and drug interactions are important for many agents [2]
5. Manufacturing (purity, process) standards do not exist for many agents
6. Physicians need to inquire frequently into use by patients in non-confrontational manner
7. Estimated 15-20% of adults in USA use herbal supplements [3]
8. Policosanol, a mixture of sugar cane wax derived alcohols, has no effect on lipids [22]
9. Regulation of these agents is likely to become more stringent in the near future

B. Ginkgo

1. Derived from Ginkgo biloba
2. Putative Clinical Uses
   1. Memory Impairment - possible benefit on memory; no improvement in cognition
   2. Dementia - good evidence for slowing of progression of dementia (Alzheimer's Disease)
   3. Tinnitus - undetermined value; large study of 50mg po tid x 12 weeks no effect [2]
   4. Intermittent Claudication - not as effective as regular walking exercises
3. Doses
   1. Therapeutic window likely 120-320mg/d
   2. Usually given in 40-80mg doses tid or qid
   3. Quality extracts 22-27% flavone glycosides and 5-7% terpin lactones
   4. Four weeks usually required to observe effects
   5. However, no benefit in randomized trial in patients >60 years after 6 weeks [4]
4. Side Effects
   1. Usually mild, transient, reversible
   2. Bleeding and seizures have been reported
   3. Caution in patients on anticoagulants (ginkgo has antiplatelet effects)

C. Saint John's Wart

1. Derived from Hypericum perforatum
2. Putative Clinical Use: antidepressant
   1. St. John's Wart extract 1050mg/d equivalent to 100mg/d imipramine
   2. Side effects are generally less than any prescription antidepressant
   3. Questionable efficacy in some studies [10]
   4. No benefit over placebo in adolescents with attention deficit hyperactivity disorder [25]
3. Doses
   1. Standard extract 900mg is most often studied
   2. Standard extract has 0.3% hypericin content
4. Side Effects
   1. Excellent safety profile as monotherapy
   2. Only serious adverse event is photosensitization (very rare)
   3. Induces hepatic P450 metabolism and P-glycoprotein (mdr1)
   4. Specifically induces CYP3A4 but not CYP2D6 [15]
   5. Increases elimination of other drugs by metabolism and drug efflux pumping
   6. Do not combine with serotonin reuptake inhibitors (can cause serotonin syndrome)

D. Ginseng

1. Derived from Panax ginseng
2. Putative Clinical Uses
   1. Improve "general well being" - clinical data are very week
   2. Improve wakefullness - insomnia is side effect; efficacy questionable
   3. Epidemiologic evidence suggest reduction in cancer risk
   4. Overall, no convincing evidence to recommend use
3. Doses
   1. Dry ginseng root: 0.5-2.0gm per day (1.0gm chronically)
   2. Extract: 200-600mg per day
   3. Highly variable production methods
   4. Low quality agents may be contaminated
4. Side Effects
   1. Severe side effects are not uncommon
   2. Include insomnia, diarrhea, vaginal bleeding, severe headache
   3. Schizophrenia and Stevens-Johnson Syndrome have been reported
   4. Likely interaction with warfarin

E. Saw Palmetto

1. Derived from Serenoa repens
2. Putative Clinical Use
   1. Reported to improve symptoms of benign prostatic hyperplasia (BPH)
   2. No improvement on BPH symptoms or urinary flow rates versus placebo over 1 year [6]
   3. No change in prostate size or residual urinary volume after 1 year versus placebo [6]
3. Dose is typically 160mg po bid liposterolic extract daily (equivalent to ~20gm crude berries)
4. Side Effects
   1. Only mild and infrequent adverse effects occur
   2. Long term safety is not known

F. Echinacea [17]

1. Derived from Echinacea species (E. angustifolia, E. palida, E. Purpurea)
2. Putative Clinical Uses
   1. Best studied are prevention and treatment of upper respiratory infections (URI)
   2. In a randomized study in early adult common cold, had no effect compared with placebo [9]
   3. No prophylactic or therapeutic effect on induced rhinovirus infection in adults [19]
   4. In randomized study in treating URIs in healthy children age 2-11 years, no efficacy [16]
   5. No efficacy demonstrated for treatment or prevention of URI
3. Doses
   1. Typically ~1000mg po tid (up to 1000mg po 6 times per day on day 1, then tid)
   2. Quality of supplements in USA is variable and generally poor
4. Side Effects
   1. Mainly allergic reactions
   2. Hepatitis, asthma, rash, myalgia, sollen tongue, anaphylaxis
   3. May contain organochlorine pesticides [5]
   4. Generally rare frequency overall

G. Ephedra [11,12]

1. Originally traditional Chinese Medicine herbal formula
   1. Initially to treat asthma and other respiratory diseases
   2. Increasingly a component of dietary supplements in USA
   3. May also be used for weight loss and as a stimulant in athletic performance [12]
2. Ephedra alkaloids include ephedrine and smaller amounts of related compounds
   1. Pseudoephedrine
   2. Phenylpropanoloamine
   3. Methylephedrine
   4. Methylpseudoephedrine
   5. Cathine (norpseudoephedrine, a controlled substance)
3. Ephedra alkaloids are stimulants and adrenergic agonists
4. Relatively high risk of adverse events
   1. Accounts for 64% of all adverse events to herbs due to ephedra
   2. Relative risk of adverse event due to ephedra versus other herbs >100 fold
   3. Psychiatric, autonomic, gastrointestinal symptoms and heart palpitations [12]
5. Strong caution in use of this agent

H. Melatonin [7,20]

1. N-acetyl-5-methoxytryptamine) synthesized exclusively in the pineal gland
2. In normal persons, the hormone is secreted at night (peaking at 2-4 AM)
3. Melatonin 5mg taken at bedtime x 3 weeks relieved nocturnal insomnia in blind persons
4. Some data to support use in jet lag treatment AFTER arrival in new time zone
5. Mild hypnotic effects 1-2mg given at bedtime reduced time to fall asleep by 10 minutes
6. No suppression of REM sleep
7. Agent is sold in health food stores and is not FDA approved to date
8. If purchased, brands which use "good manufacturing practices" (GMP) should be sought
9. A number of uncharacterized contaminants have been detected in most preparations [5]

I. Kava

1. Derived from dried rhizome of kava plant
2. Putative Clinical Use
   1. Mainly for anxiolytic effects
   2. Possible enhancement of gamma-aminobutyric acid effects
   3. Similar efficacy as oxazepam (Serax®) for anxiety in short term study
3. Doses: 70-240mg po qd (dried root extract); up to 330mg/d without side effects
4. Side Effects
   1. Generally similar to placebo groups
   2. Toxic (severe) liver damage has been reported and may be life threatening [5]
   3. Long term, high dose use associated with dry, flakey, yellow skin, ataxia, hearing loss

J. Hawthorn

1. Derived from Crataegus monogyna and C. oxyacantha
2. Oligomeric procyanidins and flavonoids
3. Putative Clinical Use
   1. Advocated for mild congestive heart failure (CHF, New York Heart Association Class II)
   2. In animal models, shows inotropic action, vasodilation, increased coronary blood flow
   3. Randomized trials have shown some improvement in subjective symptoms in 8 weeks
   4. In NYHA Class III, 900mg bid showed increase in maximal tolerated workload in 16 weeks
   5. Meta-analysis of randomized trials (692 patients) showed significant benefits in patients with CHF NYHA Classes I-III [13]
4. Doses: 450-900mg po bid
5. Side Effects
   1. Gastrointestinal symptoms
   2. Palpitations and chest pain
   3. Circulatory disturbances

K. Airborne® Herbal Supplement [18]

1. Contains:
   1. 7 herbal extracts
   2. 3 vitamins
   3. 2 amino acids
   4. Selenium
   5. Zinc
   6. Other ingredients
2. Being promoted for prevention or treatment of colds
3. Long term selenium supplements do not prevent type 2 diabetes, and may increase risk [24]
4. No efficacy has been demonstrated for any of the ingredients
5. Overall safey has not been established

L. Conenzyme Q10 [21]

1. Fat soluble antioxidant, also called ubidecarenne, ubiquinone, CoQ10
2. Present in mitochondria from human cells
3. Mainly found in organs with high metabolism (heart, liver, kidney, muscle)
4. Primary deficiency described: autosomal recessive disorder with myopathy, encephalopathy
5. Has shown some benefit in Parkinson's disease
6. May reduce cardiotoxicity of doxorubicin
7. Dose 100-300mg/day diveded into 2-3 doses in most efficacy studies
8. Different forms are available, but lots have variable potency

M. Guggul [14]

1. Extract from Commiphora mukul (guggul)
2. Guggulsterones claimed to reduce lipid levels
3. Action through farnesoid X receptor and bile acid receptor
4. No significant change in total, HDL, LDL, VLDL cholesterol or triglycerides versus placebo
5. Causes dermatologic hypersensitivity in some patients

N. Menopausal Symptoms [8]

1. Reported efficacy of black cohosh and foods containing phytoestrogens
2. Randomized study of black cohash ± soy showed no efficacy compared with placebo [23]
3. No herbal supplement improved menopausal vasomotor symptoms [23]
4. Dong quai, primrose oil, vitamin E, acupuncture not effective

References

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2. De Smet PAGM. 2002. NEJM. 347(25):2046
3. Ernst E. 2002. Ann Intern Med. 136(1):42
4. Solomon RR, Adams F, Silver A, et al. 2002. JAMA. 288(7):835
5. Problems with Dietary Supplements. 2002. Med Let. 44(1140):84
6. Bent S, Kane C, Shinohara K, et al. 2006. NEJM. 354(6):557
7. Brzezinski A. 1997. NEJM. 336(3):186
8. Kronenberg F and Fugh-Berman A. 2002. Ann Intern Med. 137(10):805
9. Barrett BP, Brown RL, Locken K, et al. 2002. Ann Intern Med. 137(12):939
10. Hypericum Depression Trial Study Group. 2002. JAMA. 287(14):1807
11. Bent S, Tiedt TN, Odden MC, Shlipak MG. 2003. Ann Intern Med. 138(6):468
12. Shekelle PG, Hardy ML, Morton SC, et al. 2003. JAMA. 289(12);1537
13. Pittler MH, Schmidt K, Ernst E. 2003. Am J Med. 114(8):665
14. Szapary PO, Wolfe ML, Bloedon LT, et al. 2003. Lancet. 362(9379):765
15. Markowitz JS, Donovan JL, DeVane CL, et al. 2003. JAMA. 290(11):1500
16. Taylor JA, Weber W, Standish L, et al. 2003. JAMA. 290(21):2824
17. Echinacea. 2002. Med Let. 44(1127):29
18. Airborne. 2005. Med Let. 47(1199):1
19. Turner RB, Bauer R, Woelkart K, et al. 2005. NEJM. 353(4):341
20. Melatonin. 1995. Med Let. 37(962):111
21. Coenzyme Q. 2006. Med Let. 48(1229):19
22. Berthold HK, Unverdorben S, Degenhardt R, et al. 2006. JAMA. 295(19):2262
23. Newton KM, Reed SD, LaCroix AZ, et al. 2006. Ann Intern Med. 145(12):869
24. Stranges S, Marshall JR, Natarajan R, et al. 2007. Ann Intern Med. 147(4):217
25. Weber W, Stoep AV, McCarty RL, et al. 2008. JAMA. 299(22):2633