From the Center for Women’s Health, Department of Medicine, Columbia University Medical Center, New York, New York
Because the use of herbs and herbal therapies in the United States is increasing, it is essential to be aware of their clinical effects, safety, doses, and potential drug interactions. In 1998, a consumer poll showed that nearly one third of respondents use botanical remedies.1 Moreover, nearly one in five individuals taking prescription medications uses herbs, high-dose dietary supplements, or both,2 suggesting an estimated 15 million adults are at risk for adverse interactions involving prescription drugs, herbs, or vitamin supplements. Many physicians, however, have little knowledge of herbal treatments or their adverse effects.
Herbal products are marketed without the confirmation of efficacy or safety that the Food and Drug Administration (FDA) requires of drugs. The Dietary Supplement and Health Education Act (DSHEA) of 1994 assigned responsibility for ensuring safety and efficacy to manufacturers, but they are under no obligation to present evidence of product testing or standards for quality control. DSHEA also does not require approval before supplements enter the marketplace.3 Manufacturers may not make claims for treatment or cure of a disease, but they may state a product’s physiologic effects. Thus, consumers have little information on which to base decisions about effectiveness, safety, contraindications, or interactions and must rely on the manufacturers’ labels or physicians for data.
Reports of adverse effects exist almost entirely as case reports and thus may be underreported. Lack of quality control regulation and product standardization has hindered the determination of safe doses. Contaminants and unpredictability of active compounds between and among manufacturers are common.5,6 The National Center for Complementary and Alternative Medicine (NCCAM), established in 1998 at the National Institutes of Health, is mandated to conduct and advocate research into complementary medicines and techniques.7 NCCAM, however, reviews only a small percentage of the therapies and techniques currently being practiced.7
Experience in other countries
In Germany, the Ministry of Health established Commission E—a committee of physicians, pharmacists, scientists, and herbalists—to evaluate the safety, quality, and efficacy of herbs.8 Commission E approves new remedies and publishes recommendations on doses, indications, contraindications, interactions, and mechanisms of action.8 Both the American Botanical Council8 and the PDR for Herbal Medicines9 reference Commission E reports. In China, two parallel systems of medicine exist: traditional Chinese medicine, composed of alternative remedies including herbs, acupuncture, acupressure, and other techniques; and Western medicine.10 Patients often seek care from both types of practitioners.11 Research in each system is supported by the government; however, controlled trials are lacking because use of placebo is considered unethical.10
Common herbal remedies
Garlic (Allium sativum). The third National Health and Nutrition Examination Survey listed garlic as the most frequently used dietary supplement.3 Estimated garlic sales from 1998 were $84 million.1 Garlic is believed to thin the blood, reduce cholesterol, decrease blood pressure, inhibit atherosclerosis, and improve circulation.
Studies of garlic are plagued by methodologic problems related to active compounds. Garlic’s odor is associated with its activity and limits blinding in clinical trials.12 The active substance, allicin, is formed when garlic is crushed and may vary in amount depending on preparation methods.13 Most studies use commercially available dried garlic powder standardized for allicin content, in doses of 300 to 900 mg per day; however, even standardized products may yield different quantities of allicin owing to differences in tablet composition.14
In vitro evidence suggests that garlic reduces blood pressure by inhibiting platelet nitric oxide synthase.15 Studies involving hypertensive subjects report a modest reduction in diastolic pressure.16,17 A meta-analysis reported a modest systolic reduction of 7.7 mm Hg and a diastolic reduction of 5.0 mm Hg,17 but only two trials involved hypertensive subjects. To date, however, there is insufficient evidence to support a role for garlic in treating blood pressure (table 1).18
Garlic is generally safe and well tolerated; however, serious adverse events including central nervous system bleeding23 and skin burns from topical application have been reported, as well as flatulence, dyspepsia, allergic dermatitis, and asthma.24 Garlic may also potentiate the effect of warfarin (table 2).26
Ginseng. Ginseng refers to the root of the Panax species. The most commonly examined species are Panax ginseng (Asian ginseng), P quinquefolius (American ginseng), and P japonicus (Japanese ginseng).27 The terms red and white refer to different methods of ginseng preparation, not to different species.41 Siberian ginseng, the root of an unrelated species, Eleutherococcus senticosus, does not contain similar compounds.42 Ginseng is thought to promote vigor, potency, well-being, and longevity and is used for angina, myocardial infarction (MI), heart failure, and blood pressure. It is administered as a whole dried root, extract, tea, or capsule. The active compounds are heterogeneous triterpene saponin glycosides, collectively termed ginsenosides. Ginsenosides vary by Panax species,27 root age, and preparation method (ie, red or white).42 The actions of specific ginsenosides vary, and in some instances are inconsistent. Of note, many products that claim ginseng content have no ginsenosides.43 Typical doses are 100 to 400 mg of ginseng extract daily. The Commission E recommends a dose of 1 to 2 g of root daily.25
Ginseng has been shown to have both hypertensive and hypotensive effects in animal studies and clinical trials.42 Hypotensive effects are attributed to enhanced synthesis of nitric oxide.42 An open trial of 4.5 g of red ginseng daily found systolic blood pressure decreased after 8 weeks.44 In contrast, a ginseng abuse syndrome has been described wherein hypertension, behavioral changes, and diarrhea occur.19 In a study of 133 chronic ginseng users, 22 developed elevated blood pressure.45 Subjects reported using varied preparations, including Siberian ginseng, which has been separately linked with hypertension.45 These conflicting effects are attributed to various actions of individual ginsenosides.42
Possible interactions with warfarin and digoxin have been reported but monopreparations of gin-seng are relatively safe.28 Adverse effects include headache as well as sleep and gastrointestinal (GI) disturbances.28 Some ginseng preparations are contaminated with germanium, which has led to a report of ginseng-related diuretic resistance and renal failure.46
Hellebore (Veratrum species). A variety of hellebore species grow in North America, Europe, and Asia and contain active veratrum alkaloids.21 Hellebore’s use as an antihypertensive agent is precluded by nausea and vomiting. Cardiac arrhythmias also occur, particularly in association with digitalis. Hellebore toxicity often results from accidental ingestion, particularly when white hellebore (Veratrum album) is mistaken for gentian to produce gentian wine.30 Toxicity is associated with vomiting, hypotension, and bradycardia, but is rarely fatal.29
Ma huang (Ephedra sinica). Ma huang (ephedra) is a natural source of ephedrine and has potent sympathomimetic activity. Herbal remedies and soft drinks used for energy or weight loss often contain ephedra. Its pharmacokinetics and bioavailability are similar to standard doses of ephedrine,47 but because it is considered a dietary supplement under the DSHEA of 1994, the FDA had not regulated it for safety and efficacy. Ma huang is a prime example of
an herb’s potential for widespread harm and the need for more rigorous regulatory efforts. Adverse case reports and the announcement of
a voluntary recall of ephedra-containing products by Health Canada in January 2002 prompted a federally sponsored study in the United States. The RAND Corporation reviewed over 1,500 adverse events due to ephedra and another 15,000 reports supplied by Metabolife International, makers of ephedra-based products.48 Side effects ranged from palpitations, hypertension, psychiatric and GI disturbances, tremor, and insomnia to arrhythmias, seizures, stroke, MI, and death.34 Many reports concerned healthy, young people and linked the adverse response of ma huang to concurrent use of caffeine, guarana (a source of caffeine and theoph-
ylline35), or strenuous exercise. A case report of eosinophilic myocarditis possibly associated with ephedra has also been reported.49 This compelling data led the FDA and the Department of Health and Human Services to seek action for consumer protection concerning health risks of, information on, and the need for warning labels on ephedra-based products in February 2003. On December 30, 2003, the FDA advised consumers to stop using all products containing ephedra and most recently banned the sale of all supplements containing ephedra owing to unreasonable risk.50
Yohimbine (Pausinystalia yohimbe). Yohimbine is isolated from yohimbe, the bark of the tree Pausinystalia yohimbe, and is used for erectile dysfunction.36 It is a competitive alpha2-antagonist that increases central sympathetic outflow and raises blood pressure, heart rate, and norepinephrine levels.38,39 It may exacerbate elevated blood pressure in hypertensive patients, as well as cause arrhythmias and tremors.38,39 Yohimbine has been evaluated for postural hypotension associated with autonomic dysfunction.22 As an alpha2-antagonist, yohimbine opposes the effects of clonidine.38 It also interacts with tricyclic antidepressants, enhancing pressor effects at lower doses, and may potentiate the alpha-adrenergic blocking properties of phenothiazines.40 Adverse reactions include mania, bronchospasm, a systemic lupus-like syndrome, and agranulocytosis.51-54 The recommended dose is 5.4 mg three times daily; pressor effects are associated with doses of 15 to 20 mg.40
Licorice (Glycyrrhiza glabra). Licorice, a root extract, is used as a sweetening and flavoring agent and as a remedy for gastritis and upper respiratory tract infections.31-33 A me-tabolite, glycyrrhetinic acid, inhibits renal 11b-hydroxysteroid dehydrogenase causing mineralocorticoid excess by impeding the inactivation of cortisol.32 Case reports link licorice to hypertension, hypertensive encephalopathy, pulmonary edema, edema, hypokalemia, arrhythmias, congestive heart failure, muscle weakness, acute renal failure,31 and dilated cardiomyopathy.33 Fifty to 100 g of confectionary licorice, or
50 to 300 mg of glycyrrhetinic acid, over weeks may cause adverse effects.55 A study of 30 healthy, normotensive volunteers reported that 100 g per day of licorice (270 mg glycyrrhizic acid) over 4 weeks increased systolic blood pressure
6.5 mm Hg and decreased plasma potassium 0.24 mmol/L from baseline.56 Susceptibility to licorice varies; women and hypertensive patients may be more sensitive,32,56 and adverse effects may take weeks to reverse due to suppression of the renin-angiotensin-aldosterone axis and the large volume of distribution of glycyrrhetinic acid.32 It is noteworthy that most licorice candies in the United States do not contain licorice.
Other herbs. Clinical trials of hawthorn (Crataegus species) describe decreased symptoms of heart failure as well as improved cardiac performance. Hawthorn is a spiny shrub native to Europe and North America whose proposed actions include antioxidant, inotropic, vasodilatory, and antihyperlipidemic actions.25 An open trial of 1,011 subjects showed an increased ejection fraction and decreased arrhythmias.20 Oleander, a common flowering shrub ubiquitous in North America, contains cardiac glycosides that can potentiate digoxin.36 Cases of oleander toxicity have been treated effectively with digoxin-specific antibodies.37 Belladonna, often used to treat GI symptoms, is a source of atropine and may cause tachycardia.
Conclusion Investigating the effects of herbal therapy is complex because many contain mixtures of compounds and exist in varied forms. Resources on efficacy, dose, toxicity, contraindications, and drug interactions are constrained by limited research and information. The controversy over ephedra makes a case for closer monitoring of product safety and effectiveness than what currently exists under the DSHEA of 1994. Considering the widespread use of herbal remedies, physicians must recognize their effects and guide patients about the potential for cardiovascular risk from what may be perceived as completely benign therapy.