Herbal Medicine

1. Herbal Medicine David Hilmers MLK Clinic Lecture Series March 31, 2008

2. Objectives • To discuss the efficacy and use of some common herbal remedies • To learn about the regulation and safety of herbal medicines in the US • To discuss some of the drug interactions and common side effects of herbal medicines

3. Background • In 1997, 12.1% of Americans used herbal medications with out-of-pocket costs of $5.1 billion • In Europe there has been more regulation and more formal licensing of products than in the USA • Many traditional remedies are not considered “medicines” by patients and may be part of social norms (e.g. “azarcon” or “greta” for stomach ailments in Mexican infants contain high levels of lead)

4. Case 1 • A 65 year old male patient tells you that he is using saw palmetto for his “prostate problems”. He tells you that the salesman at the health food store says that it is guaranteed to meet the same quality standards as any other drug. He asks your opinion. What do you tell him?

5. Regulation of herbal remedies • Herbal remedies are exempt from rigorous regulation in the United States • Must have some evidence for claims that are made on the packaging, but not asked to provide it before marketing begins • May be considerable variation in the composition of an herbal remedy among manufacturers and lots, as well as discrepancies between label information and actual content.

6. Manufacturing of herbal products • For commonly used herbal remedies the U.S. Pharmacopeial Convention is developing standards for product quality and monographs that review chemical, pharmacologic, and therapeutic data. • When an herbal product is labeled “U.S. Pharmacopeia” or “National Formulary,” the Dietary Supplement Health and Education Act of 1994 (DSHEA) requires that the product comply with the standards for product quality. • System of standards is entirely voluntary and leaves the door open for inferior products.

7. Does it work? • The patient asks you about whether saw palmetto really works. What is your response?

8. Efficacy of saw palmetto • Double-blind trial randomly assigned 225 men over 49 years with symptoms of benign prostatic hyperplasia to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo • Primary outcome measures were changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate. Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values, and adverse effects. • No significant difference between the saw palmetto and placebo groups in AUASI scores, maximal urinary flow rate, prostate size, residual volume after voiding, quality of life, or PSA during the one-year study. • The incidence of side effects was similar in the two groups. • N Engl J Med. 2006 Feb 9;354(6):557-566

9. Case 2 • You are seeing a 75 year old patient with history of a mitral valve replacement with a mechanical valve. He says that he would like to take some herbal medications that he was told would help increase his energy and his memory. His wife tells him all herbal medicines are safe. He asks your opinion. • Are all herbal medicines safe? • To what herbal medicines might he be referring? • What might be some consequences of these in this patient?

10. Safety of herbal medications • Problems include: • Adulteration of product during manufacturing • Different formulations giving inconsistent doses • Drug-drug interactions • May contain other active ingredients (digoxin-like molecules in herbal teas, for example) • Most herbal medications have not been adequately tested for long-term side effects (kava and hepatotoxicity)

11. News flash from last week: FDA Warns Against Unapproved Erectile Dysfunction Supplements The FDA is warning consumers not to take the Blue Steel or Hero dietary supplements, marketed over the Internet to treat erectile dysfunction, after a chemical analysis showed they contain undeclared ingredients that could adversely affect a person's blood pressure. The supplements, distributed by Active Nutraceuticals or the Marion Group, contain substances similar to sildenafil (Viagra). These ingredients may interact with nitrates in prescription medications and cause one's blood pressure to drop to unsafe levels. March 26, 2008

12. Difference in content of ginseng in various formulations.

13. Herbal remedies for memory and energy • Gingko biloba has long been thought to improve memory • A well-designed double-blind trial investigated gingko for memory enhancement in cognitively intact elderly adults. • Randomly assigned 230 community dwelling men and women over the age of 60 with MMSE scores greater than 26 to receive ginkgo biloba 40 mg three times daily or placebo for six weeks. • There was no improvement in memory with ginkgo treatment as measured by standard neuropsychological tests, self-reported memory function, or global rating by spouses, friends, and relatives. • Ginseng has been used for its alleged aphrodisiac, antidepressant, and diuretic activity. It is often recommended to improve stamina, concentration, vigilance, and well-being • No evidence to support improved well-being in clinical trials

14. Case 3 • A 65 year old man presents to your office with complaints of fatigue, difficulty falling asleep, loss of appetite, and a loss of interest in his hobbies over the past 3 months. His current medications include coumadin, verapamil, HCTZ and glipizide. For the past week he reports having a URI for which he has been taking Vitamin C and Echinacea. His wife suggested he take St. John’s Wort, ginseng root and ginkgo for his problems and general health.

15. What should you advise him regarding the use of St. John’s Wort?

16. St. John’s Wort • There are data, predominantly from Europe, that support the efficacy of standardized extracts of St. John's wort in the short-term treatment of mild to moderate depression. • These data also suggest that St. John's wort is comparable in efficacy to tricyclic antidepressants and SSRIs. • However, data from the US have not confirmed the benefits of St. John's wort for depression. • There are only relatively limited data on the efficacy of St. John's wort for severe depression. • A Cochrane systematic review concluded that the evidence on St. John's wort is inconsistent and confusing

17. For what adverse events is he at risk with his combination of prescription and herbal remedies?

18. Side effects • St. John’s Wort hastens the metabolism of verapamil and warfarin, resulting in lower levels of both • Gingko biloba can cause platelet dysfunction leading to increased bleeding tendencies • Ginseng has been noted to reduce the levels of warfarin, resulting in subtherapeutic INR’s

19. He has read in a health magazine that ginkgo can help male impotence – what do you tell him?

20. Gingko biloba and sexual function • A small study of men with erectile dysfunction secondary to decreased blood flow found that those treated with ginkgo biloba extract had an improvement in penile blood flow in six weeks. After six months, 50 percent of patients treated were noted to regain potency. • In an open trial, 37 male and female patients with selective serotonin reuptake inhibitor (SSRI) associated sexual dysfunction were treated with ginkgo biloba extract. Significant improvement was noted after four weeks in 86 percent of patients. A small randomized trial failed to show similar benefits. • A proprietary combination product containing ginkgo biloba improved libido in a randomized trial of 108 women ages 22 to 73

21. What is the medical data regarding Echinacea in the treatment of the common cold?

22. Echinacea and URI’s • There is controversy over the best echinacea species, plant part, active component(s), and dosage. • In contrast to other herbal medicines, echinacea products are often not standardized. • Several controlled trials of echinacea for URI prior to 2000 showed a decrease in symptom intensity and duration. These studies varied greatly in their quality and the type of echinacea used. • Since then, several well-designed studies have found that it is no better than placebo for the treatment of URI • Well-designed studies have not generally found it to be efficacious for the prevention of URI: • Experimental studies have also generally not found that it is effective in preventing URI after challenge with rhinovirus

23. Problems studying effects of herbs • Randomization and blinding are difficult; for herbs that have a distinctive taste or smell, concealing the treatment assignment can be problematic. • Results obtained with one product may not apply to other preparations from the same herb; few trials have compared different preparations from the same plant source. • In the case of products that contain a mixture of herbal ingredients, the relative contribution of each may not be known. • Trial reports are often limited to the statistical significance of a mean difference between herb and placebo, whereas they could also present the number needed to treat for a minimal clinically important difference.

24. More problems with studies • Intermediate outcomes (e.g., the effects of hawthorn on cardiac performance in CHF) instead of hard end points (e.g., effects on cardiovascular mortality) are often reported. • Most trials compare an herb with placebo but not with medications that have well-established safety and efficacy. When an herbal remedy is compared with an established compound, adequate doses of each are needed. • Few trials have considered the combined use of an herbal medication and a conventional drug, but such use is common. • Positive results may be reported more often than negative results, leading to an overestimate of the treatment effect (publication bias)

25. What general advice should you give patients interested in taking remedies?

26. Cautions for patients • Speak with your physician before taking herbal remedies or even herbal teas • Be sure to list all medications, including herbal remedies, on drug lists • Choose reliable manufacturers of herbal meds • There are many different formulations, use form and dose that has been tested in clinical trials • Consider cost of herbal medications, sometimes can be much more expensive than conventional medication

27. Cautions for doctors • Need to specifically ask patients if they are taking any herbs, teas or traditional medicine treatments. They might not consider these “medicines”. • Look carefully at side effect profile • Look for drug-herb interactions • Do not dismiss herbal medicine automatically as ineffective • May have a strong placebo effect • May damage patient-provider relationship • Some herbs have been found to be very effective drugs (artemesins were Chinese herbs used for malaria and now have been shown to be most effective treatment available for malaria)

28. Summary • Herbal medicines are considered supplements and are not subject to strict regulation • There are no standard formulations of many herbal medicines • There is little conclusive clinical data supporting a benefit for most herbal meds • Like conventional meds, herbals can have dangerous side effects and significant drug-drug interactions • Randomized prospective trials are difficult to perform and are rarely done

29. Resources for herbal medicine data • Cochrane reviews • www.cochrane.org/reviews • Physicians' Desk Reference for Herbal Medicines • Up To Date • The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines • De Smet P. HERBAL REMEDIES N Engl J Med, Vol. 347, No. 25. December 19, 2002