MEDICAL GRAND ROUNDS WILLIAM S. WILKE, MD, EDITOR TAKE-HOME POINTS FROM EDUCATIONAL PRESENTATIONS BY CLEVELAND CLINIC FACULTY AND VISITING Fear or distrust of physicians. One pam- PROFESSORS The herbal phlet touts "health secrets your doctor doesn't want you to know," and hints that physicians medicine boom: and pharmaceutical companies are conspiring to suppress information about unconventional Understanding what therapies. "Natural is better." Popular mythology holds that allopathic medicine is unnatural patients are taking and therefore bad, while herbal cures are nat-

ANA VANN, PharmD ural and therefore good. Natural cures help Drug information clinical pharmacist, Cleveland Clinic. one "build resistance" to disease, according to this thinking. F PHYSICIANS WERE TO ASK every patient Disappointment with allopathic care. if he or she is taking herbal medica- Many persons who seek alternative therapies tions, one in three would answer yes, accord- have chronic conditions for which there is no ing to a 1993 survey.1 Sales of herbal medi- effective cure; they often use herbal prepara- cines are booming, totaling $2.5 billion in tions as an adjunct to allopathic therapies. For 1996 and growing 25% per year.2 such persons, taking an herbal medication is a Unfortunately, the herbal medicine indus- way of helping themselves while exerting more try is not sufficiently regulated to guarantee control over their own health care. that an herbal preparation is safe for con- Other influences. Some cultures have a sumption. Although some herbal prepara- tradition of using herbal medicine. Other peo- tions, such as homeopathic remedies, contain ple may be swayed by false advertising, word- no active ingredients at all, others contain of-mouth, and peer influences prevalent in substances that do produce effects—including their society. adverse reactions and interactions with pre- In the world scription drugs. Claims of efficacy are unsub- • WHAT PRODUCTS DO PEOPLE TAKE? of herbal stantiated, based mostly on anecdotal evi- dence. Worse, there is frequently no way to Data compiled from manufacturers indicate that medicine, let ascertain exactly what an herbal preparation ginseng accounts for 20% of herbal medications the buyer contains, as labeling is often inadequate or taken, garlic preparations for 18%, ginkgo for inaccurate, and some manufacturers continue 10%, melatonin (which is not an herb) for 19%, beware to use potentially dangerous herbs. and all others for 33%.4-6 However, hundreds of Obtaining information about the effects substances are available, and many products of herbal medications is difficult. Herbs often contain multiple substances. have several different names, and herbs with The following section lists some common similar or even identical names sometimes herbal medications, their reputed effects, and belong to different species entirely. There is what is known about possible side effects and no regulation of the purity of the substances, drug interactions. and no standardization of dosages. They are If a physician has questions about an sold over-the-counter with no instructions as unfamiliar herbal medicine, he or she should to possible side effects or interactions. call a local drug information center, the FDA consumer hotline (800-FDA-4010), or the • WHY DO PEOPLE TAKE HERBAL MEDICINES? National Institutes of Health Office of Alternative Medicine (888-644-6226). The There may be a number of explanations, from Lawrence Review of Natural Products, published a failure to understand the scientific process3 by Facts and Comparisons in St. Louis, to skepticism about modern medicine. Among Missouri, is a reliable reference of herbal med- factors that may be at work: icines' known therapeutic and adverse effects.

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Garlic Ginkgo (Panax schinseng) (Allium sativum) (Qinkgo biloba, maidenhair)

Ginseng is sold as an "adaptogen" to "normal- Garlic reduces total and LDL cholesterol and ize" the body and build resistance to stress, and triglycerides and raises HDL. It may have also as an aphrodisiac. However, its effective- antibacterial, antifungal, antithrombotic, hypo- ness is not adequately documented. It may tensive, hypoglycemic, antihyperlipidemic, lower total and low-density lipoprotein (LDL) anti-inflammatory, and anticancer activity.14 cholesterol levels. Some ingredients raise Precautions and interactions. Garlic has blood pressure, and some lower it.7 been shown to inhibit platelet aggregation Complicating the issue: there are eight species and therefore may interact with anticoagu- of ginseng, and one of them—Siberian gin- lants. It reduces blood sugar, and may there- seng—is completely different from the others. fore affect glucose control. Rarely, it causes For questions These issues may be moot for some products allergic reactions.15 about herbal labeled as ginseng: one study looked at 10 "gin- seng" products and found that seven contained Ginkgo has been used in China since ancient products, call no ginseng at all.8 A study from the late 1970s times.16'17 It dilates arteries, capillaries, and the NIH Office analyzed 54 ginseng products; of these, 60% veins, and has been shown to have significant contained less than the therapeutically effec- beneficial effects on cognitive function, of Alternative tive levels, and an astounding 20% contained enhance various CNS functions such as short- Medicine at no active ingredient.9 term memory, concentration, and alertness,18 Precautions and interactions. Nervous- and improve cognition in Alzheimer's dis- (888)644-6226 ness and excitation can occur for the first few ease.19 There are data in animals that ginkgo days of intake. Overuse can cause headache, protects against cerebral ischemic damage, and insomnia, and palpitations. Patients with may enhance blood flow to the brain.20.21 hypertension should be cautious of ginseng People are also using it to treat varicosity, cere- because of its unpredictable effect on blood bral vascular insufficiency, dementia, tinni- pressure. One case10 has been reported of an tus,22 vertigo, and sexual dysfunction induced interaction between ginseng and furosemide by selective serotonin reuptake inhibitors. (decreased diuretic effect probably caused by Precautions and interactions. Ginkgo- germanium contamination), which resulted in lide is a selective antagonist of platelet aggre- hospitalization. Estrogenic effects have caused gation. A few case reports of bilateral subdural vaginal bleeding and mastalgia; patients should hematomas have been reported. These cases not take ginseng with hormonal therapy in were all linked with prolonged use of this light of cases of uterine bleeding.11-13 Patients herbal remedy (longer than 2 years).23 It may should be discouraged from using ginseng long- cause minor GI disturbances. Rarely, ginkgo term (more than 3 months). causes headache, dizziness, or vertigo.24

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Saw Palmetto (Echinacea uugustifolia, purple coneflower) (Serenoa repens)

Echinacea, also known as purple coneflower Lipid extracts of saw palmetto contain and snakeroot, has been promoted for pre- fatty acids and sterols that have antiandro- venting cold and flu symptoms. Although its genic activity in vitro. However, human stud- mechanism of immune stimulation is ies have been inconclusive. These studies also unknown, it may work by stimulating the used very high doses of the extracts; therefore, production of phagocytes.25 the levels of active ingredient may be exces- Precautions and interactions. This herb sive in humans.27 may cause immunosuppression with continu- Precautions and interactions. Side effects ous use (6 to 8 weeks).26 It is contra indicated are minimal. Saw Palmetto may, in theory, in patients with autoimmune diseases. have a synergistic effect with the hormonal therapy used in BPH. Always ask if Ma huang (Ephedra sinica and others). the patient More than 40 species of Ephedra are known, St. John's wort is pharmacologically similar some of which contain alkaloids including to monoamine oxidase inhibitors, and is used is taking any ephedrine and pseudoephedrine. It is used in as an antidepressant and to treat menopausal herbal asthma and to treat colds. It is used alone and premenstrual symptoms. The FDA lists it and in combination with St. John's wort in as a new investigational agent (it was previ- medicines weight-loss products, although it has not ously listed as unsafe). Several small studies been shown to be safe or effective for this found St. John's wort to be more effective purpose. than placebo for treating mild to moderate Precautions and interactions are similar depression.28 to those for ephedrine and pseudoephedrine. Precautions and interactions. To avoid Doses used in herbal weight-loss products and the risk of a hypertensive crisis, patients tak- herbal cold preparations containing ma huang ing St. John's wort should observe the same are typically excessive, and the range of side precautions as with the monoamine oxidase effects is unpredictable. Patients are strongly inhibitors, avoiding not only foods that con- discouraged from taking any herbal remedy tain tyramine (eg, aged meats and cheese), but containing this herb. also sympathetic amines (eg, amphetamine, phenylpropanolamine, pseudoephedrine). In Saw Palmetto is widely used in Europe to treat addition, serotonergic agents (ie, selective benign prostatic hyperplasia (BPH). In fact, up serotonin reuptake inhibitors such as fluoxe- to 90% of patients with BPH in Europe take tine, venlafaxine, nefazodone, , tra- herbal medications, and 50% of European zodone; some tricyclic antidepressants; lithi- urologists prefer herbs to alpha blockers. um; meperidine; and dextromethorphan)

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St. John's wort Valerian (Hypericum perforatum) (Valeriana officinalis)

should be avoided to minimize the risk of sero- uct should be used only under the supervision tonin syndrome. is char- of a physician. Only the prescription product acterized by confusion, shivering, agitation, should be used, as herbal doses may be exces- fever, diaphoresis, diarrhea, myoclonus, hyper- sive. It is contraindicated in patients with reflex ia, and tremor. However, no study of sys- renal insufficiency. temic interactions with drugs or food has been conducted. • HERBAL MEDICINE SHOULD BE REGULATED Phototoxicity has occurred in animals grazing on the , but is unlikely within Federal drug laws govern prescription and therapeutic doses. In addition, some orthosta- over-the-counter drugs but exclude herbal Observe tic hypotension has been reported.29 preparations, which cannot be patented. The the same Health and Education Valerian has sedative and hypnotic effects. (DSHE) Act of 1994 defines herbal medica- precautions Precautions and interactions. Cases of tions as dietary supplements, and therefore with severe liver damage have been reported.^0 these supplements are treated more like foods Valerian can cause morning drowsiness, atax- than drugs. In fact, a can of tomato sauce is St. John's wort ia, and fatigue. Cytotoxic activity has raised subject to more scrutiny than are herbal med- as with MAO concern about long-term use. It is not syner- ications. Under the law, packages of herbal gistic with alcohol, but has not been studied remedies must carry the disclaimer: "This inhibitors with opiates or other central nervous system product has not been evaluated by the FDA depressants. and is not intended to diagnose, treat, cure or prevent any disease." In other words, let the Yohimbe ( johimbe). A sympa- buyer beware. thicolytic and mydriatic, yohimbe is available Further, there is no restriction on placing both as a prescription drug and as an herbal pamphlets, books, and posters in proximity to product. It is used to treat male erectile dys- the products, and these often carry biased, mis- function. leading, and false information. When herbal Precautions and interactions. Yohimbe products, which undergo no testing or inspec- has a high risk-to-benefit ratio. It can cause tion, are displayed for sale in licensed pharma- central nervous system stimulation, hypoten- cies, adjacent to products that are rigorously sion or hypertension, tachycardia, nausea, tested, they gain an aura of respectability by vomiting, and psychoses. It may have association. Consumers may be misled into monoamine oxidase inhibitory activity, and believing they are purchasing something that may interact with antidepressants. This prod- has been proven safe and effective.

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TABLE 1 ADVICE ON HERBAL MEDICINES 2. Grauds C. Botanicals: Strong medicine for health and profit. The Source. Association of Natural Medicine Pharmacists, 1997; 3(1). Common-sense advice to patients 3. Sagan C. The demon-haunted world. Science as a candle in the dark. New York: Random House, 1996. about herbal medicines 4. A.C. Nielsen Surveys. (Prepared for Pharmaton Natural If you are ill, see a doctor or other health care professional. health Products Division) January 1997. 5. Foster S. Ginseng plays big part in driving growth of Do not take herbs if you are pregnant or attempting homeopathic medicine. Chain Drug Review Nov 21 1994; to become pregnant. 16:22. Do not take herbs if you are nursing. 6. Brevoort P. The U.S. botanical market—an overview. HerbalGram 1996;36:49-51. Do not give herbs to a baby. 7. Hammond TG, Whitworth JA. Adverse reactions to gin- Do not take large quantities of any one herbal preparation. seng (letter). Med J Aust 1981; 1:492. 8. Herbal roulette. Consumer Reports. November 1995. Do not take any herb on a daily basis. 9. Ziglar W. The Ziglar report: an analysis of 54 ginseng Buy only preparations in which the are listed on the packet. products. Whole Foods 1979; 2(4):48-53. (Note: there is no guarantee attached to any herbal product.) 10. Becker BN, Greene J, Evanson J, et al. Ginseng-induced diuretic resistance (letter). JAMA 1996; 276:606-607. Do not take herbal medicines if you have allergies to plants. 11. Greenspan EM. Ginseng and vaginal bleeding (letter). Always tell your doctor about any herbal remedy or alternative JAMA 1983; 249:2018. medicine you may be taking. 12. Palmer BV, Montgomery A, Montero J. Ginseng and mastalgia (letter). Br Med J 1978; 1:1284.

ADAPTED FROM HUXTABLE RJ. THE HARMFUL POTENTIAL OF HERBAL AND OTHER PLANT 13. Punnonen R, Lukola A. Oestrogen-like effect of ginseng. PRODUCTS. DRUG SAFETY 1990; 5(SUPPL 11:126-136. Br Med J 1980; 281:1110. 14. Gray MA. Herbs: Multicultural folk medicines. Orthopedic Nursing 1996 15(2)49-57. 15. Garlic. The Lawrence Review of Natural Products. St. Louis: Facts and Comparisons, April 1991. We need a better system to protect the 16. Heinerman J. Heinerman's Encyclopedia of Healing Herbs public. For starters, the names of substances and Spices. West Nyack, NY: Parker Publishing Co, need to be standardized, as do the formula- 1996:255-257. 17. Morris J, Burke V, Mori TA, et al. Effects of garlic extract tions and doses. Some regulatory body should on platelet aggregation: A randomized placebo-con- be given the power to truly regulate herbal trolled double-blind study. Clin Exp Pharmacol Physiol drugs, requiring manufacturers to ensure the 1995; 22:414-417. 18. Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insuf- standarization, purity, and consistency of ficiency. Br J Clin Pharm 1992; 34:352-358. manufacture of all herbal preparations. 19. LeBars PL, Katz MM, Berman N, et al. A placebo-con- As part of implementing the DSHE Act trolled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 1997; (if 1994, a commission composed of leaders in 278:1327-1332. the field of herbal medicines has been created. 20. Ramassamy C, Clostre F, Christien Y, et al. Prevention by a The primary goal of this commission is to Ginkgo biloba extract (GBE 761) of the dopaminergic neu- rotoxicity of MPTP. J Pharm Pharmacol 1990; 42:785-789. reform labelling laws and provide additional 21. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992; needed information regarding these remedies, 340:1136-1139. particularly for the public. In addition, the 22. Holgers KM, Axelsson A, Pringle I. Ginkgo biloba extract for treatment of tinnitus. Audiology 1994; manufacturing practices of these manufactur- 33(2):85-92. ers of dietary supplements will be analyzed. 23. Rowin J, Lewis SL. Spontaneous bilateral subdural The Commission report is scheduled to be hematomas associated with chronic Ginkgo biloba inges- tion. Neurology 1996; 46:1775-1776. published this year. 24. Gilbert GJ. Ginkgo biloba (letter). Neurology 1997; In the meantime, health-care providers 48:1137. should ask patients if they are taking herbal 25. Hobbs C. Echinacea: a literature review. HerbalGram 1994; 20:33-48. medicine and should be prepared to offer com- 26. Echinacea. The Lawrence Review of Natural Products. St. mon-sense advice (TABLE 1). Louis: Facts and Comparisons, December 1996. Physicians should report adverse events 27. Lowe FC, Ku JC. Phytotherapy in treatment of benign pro- static hyperplasia: a critical review. Urology 1996; 48:12-20. due to herbal medications to the FDA (800- 28. Linde K, Ramirez G, Mulrow CD, et al. St. John's wort for FDA-1088), just as with other medications. H! depression—an overview and meta-analysis of random- ized clinical trials. Br Med J 1996; 313:253-258. • REFERENCES 29. Wincor MZ, Gutierrez MA. St. John's wort and the treat- ment of depression. U.S. Pharmacist 1997 (August):88-97. 1. Eisenberg DM, Kessler RC, Foster C, et al. Unconventional 30. MacGregor FB, Abernethy VE, Dahabra S, et al. medicine in the United States. Prevalence, costs, and pat- Hepatotoxicity of herbal remedies. Br Med J 1989; terns of use. N Engl J Med 1993; 328:246-252. 299:1156-1157.

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