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A Review of 12 Commonly Used Medicinal Herbs
MaryAnn O'Hara, MD, MSt;
David Kiefer, MD;
Kim Farrell, MD;
Kathi Kemper, MD, MPH
Arch Fam Med. 1998;7:523-536.
ABSTRACT
A large and increasing number of patients use medicinal herbs or seek the advice of their physician regarding their use. More than one third of Americans use herbs for health purposes, yet patients (and physicians) often lack accurate information about the safety and efficacy of herbal remedies. Burgeoning interest in medicinal herbs has increased scientific scrutiny of their therapeutic potential and safety, thereby providing physicians with data to help patients make wise decisions about their use. This article provides a review of the data on 12 of the most commonly used herbs in the United States. In addition, we provide practical information and guidelines for the judicious use of medicinal herbs.
INTRODUCTION
More than one third of Americans use herbs for health purposes, spending over $3.5 billion annually.1-2 Yet patients (and physicians) often lack accurate information about the safety and efficacy of herbal remedies. Imagine the following are patients in your primary care practice. How would you advise them?
- Jane, who has chronic hepatitis C and receives medicine for both hypertension and schizophrenia, asks if she can take milk thistle to protect her liver.
- John, who has the human immunodeficiency virus, has an increasing viral load. He expresses fear of "medicine," but requests information about St John's wort (SJW) in hopes of "naturally" curing his human immunodeficiency virus and depression.
- Sam's wife bought him valerian to help him sleep, saw palmetto for his urinary difficulties, and gingko to improve his memory. He is inclined to throw the herbs away but wants your opinion.
- After you inform Stephanie that she is 3 months pregnant, she asks what effects the herbs she has taken for months will have on her fetus (ginger for nausea, feverfew for headaches, and pennyroyal to induce a period).
- Your spouse has high cholesterol, your child has recurrent ear infections, and you have trouble relaxing after a hectic day at the clinic. Prompted by your patients' questions, you wonder if any herbal remedies might benefit your family.
Popular use of medicinal herbs makes it necessary for physicians to become aware of their health benefits, risks, and uncertainties so that they can educate their patients about these issues. To assist clinicians in this task, this article reviews existing data on the history, safety, and efficacy of 12 of the most commonly used and best-studied medicinal herbs (Table 1). In addition, it summarizes general information about herbal therapies, including an overview of regulatory history (Table 2), important similarities and differences between medications approved by the Food and Drug Administration (FDA) and herbal therapies (Table 3), and the nature of available data about medicinal herbs. Finally, lists of reliable introductory resources (Table 4) and guidelines for patients (Table 5) are provided.
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Table 1. Twelve Common Medicinal Herbs*
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Table 2. Genesis of a Regulatory Dilemma: US Legislation on Herbal Remedies
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Table 3. Herbs and Food and Drug Administration (FDA)–Approved Drugs: Similarities and Differences
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Table 4. Introductory References
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Table 5. Medicinal Herbs: Patient Information Sheet
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A HISTORICAL PERSPECTIVE
Plants have been used medicinally throughout history. Through the first half of this century, many herbs were considered conventional medicines and as such were included in medical curricula and formularies (eg, United States Pharmacopoeia and The National Formulary). Two important factors fostered a schism between mainstream drugs and herbal therapies in the United States: the development of a pharmaceutical industry capable of mass-producing purified chemicals, and regulatory changes by the FDA.
In 1962, thalidomide was found to be teratogenic and Congress passed an amendment to the Food and Drug Act to increase assurance of drug safety and efficacy. While successful in general, the amendment initiated a regulatory dilemma regarding herbal therapies in the United States (Table 2). No longer can substances be considered drugs based on traditional use alone. A would-be manufacturer must gain FDA approval; the profit to be made from a patented product is the motivating factor. Traditional herbal therapies cannot be patented, and therefore lack sponsors for the costly ($230 million) and lengthy (8-10 years)3 approval process. By default, many medicinal herbs are not legally considered drugs and are not regulated as such by the FDA. The FDA suggests but cannot require that manufacturers of herbal therapies provide customers with scientific data in support of advertising claims. Furthermore, the FDA must prove that an herbal product is unsafe or ineffective before it can require the product to be removed from the market.
HERBS AND FDA-APPROVED MEDICATIONS: SIMILARITIES AND DIFFERENCES
Patients are often unaware of important similarities and differences between medicinal herbs and FDA-approved medications. For example, some mistakenly think of herbs as "natural" alternatives to chemicals, failing to recognize that herbs are composed of bioactive chemicals, some of which may be toxic (see Table 6 for a list of commonly used herbs with toxic effects that probably outweigh their potential benefits). Also, patients are often unaware that about 25% of modern pharmaceutical drugs have botanical origins, such as digoxin from foxglove, morphine from poppies, aspirin from willow bark, and tamoxifen from the Pacific yew tree.4
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Table 6. Common, Potentially Toxic Herbs*
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Unlike the FDA-approved over-the-counter and prescription medications, medicinal herbs are not required to demonstrate either safety or efficacy prior to marketing, nor are they regulated for quality. Nevertheless, herbal therapies are not necessarily less expensive than patented drugs and are rarely covered by medical insurance. In contrast to the purified, standardized, and potent FDA-approved drugs, herbs contain an array of chemicals, the relative concentration of which varies considerably depending on genetics, growing conditions, plant parts used, time of harvesting, preparation, and storage. In addition, herbs may be contaminated or misidentified at any stage from harvesting through packaging.
THE NATURE OF EVIDENCE ABOUT MEDICINAL HERBS
Most research on medicinal herbs is conducted in areas of the world where the use of medicinal herbs is mainstream, particularly in Asia and Europe. For the past 3 decades, the German Health Authority has systematically reviewed the evidence on about 300 herbs and formulated clinical guidelines. An English translation of the resulting German Commission E Monographs is due for release in 1998.5 Although arguably the best compendium of clinical information about herbs in the world, it does not disclose the scientific basis for its conclusions. Nevertheless, such guidelines provide hypotheses to prompt quality human trials, optimally with randomized, double-blind, placebo-controlled (RDBPC) trials. Research in the United States will be bolstered by the creation of the Office of Complementary and Alternative Medicine within the National Institutes of Health, Bethesda, Md.
Data about the safety and efficacy of medicinal herbs are limited in a number of ways. In some cases, the best data are years old, limited to in vitro or animal studies, and/or only available in journals outside the United States. Some clinically important types of information are particularly sparse in the literature, such as the results of negative trials, drug interactions, effects in special populations (eg, children and pregnant or lactating women), and toxic reactions. In some cases, good evidence about short-term side effects comes from well-controlled human trials. However, information about the effects of long-term use is usually based on case reports rather than prospective studies. As noted earlier, traditional use has revealed serious toxic effects associated with some common medicinal herbs (see Table 6). On the other hand, the FDA categorizes about 250 herbs as "generally recognized as safe" (GRAS) for consumption based on long-term and/or widespread traditional use without significant side effects. This article reviews several herbs on the FDA GRAS list, including chamomile, garlic, ginger, ginseng, and valerian. Evidence about the safety and efficacy of these and 7 other commonly used medicinal herbs are reviewed below.
CHAMOMILE
Matricaria recutita
Common name: German chamomile
Chamaemelum nobile (English or Roman chamomile)
Common uses: Sedative, spasmolytic, anti-inflammatory, vulnerary (wound healing)
Investigational uses: Antioxidant
Side effects: Allergy (rare)
Chamomile is a daisylike, apple-scented flower that has been used medicinally for thousands of years. Anglo-Saxons believed it was 1 of the 9 sacred herbs given to humans by the god Woden. In contemporary Germany, it is considered a cure-all. Chamomile is cultivated worldwide for use as a sedative, spasmolytic, anti-inflammatory, and vulnerary (wound-healing) agent. Few human studies have evaluated these traditional uses.
Only chamomile's vulnerary effects have been studied in a controlled human trial, with inconclusive results. A recent RDBPC trial found no difference between chamomile and placebo in preventing mucositis in 164 patients receiving fluorouracil, half of whom used chamomile 3 times daily for 14 days).6 However, the study was possibly too short to detect a difference, as mucositis is largely a result of immunosuppression, and therefore takes weeks to develop. In another randomized, placebo-controlled trial, radiation-induced skin reactions were less frequent and appeared later in chamomile-treated areas, but the differences were not statistically significant.7
Animal studies support chamomile's traditional use as a vulnerary anti-inflammatory, spasmolytic, and anxiolytic agent. The flavonoid component apigenin exhibits dose-dependent, reversible inhibition of irritant-induced skin inflammation8 and protects against gastric ulcers induced by medications, stress, and alcohol.9 Apigenin also binds the same receptors as benzodiazapines; it exerts anxiolytic and mild sedative effects in mice10 and relaxes intestinal spasms.11 In vitro, the essential oil acts as an antioxidant12 and kills some skin pathogens (some Staphylococcus and Candida species).13
Chamomile is considered safe by the FDA, with no known adverse effects in pregnancy, lactation, or childhood. It caused no adverse reactions in the human trials discussed earlier. While chamomile's therapeutic effects and safety remain to be definitively proven in human trials, its beneficial effects seen in animals and its good safety record in widespread traditional use by humans make it an acceptable home remedy for soothing mild skin irritation, intestinal cramps, or agitated nerves. In the United States, it is commonly consumed as a tea or applied as a compress. Patients with severe allergies to ragweed should be warned about possible cross-reactivity to chamomile and other members of the aster family (eg, echinacea, feverfew, and milk thistle). It should not be taken in conjunction with other sedatives, such as benzodiazapines or alcohol.
ECHINACEA
Echinacea purpurea, Echinacea angustifolia, and Echinacea pallida
Common name: Purple coneflower
Common uses: Prevention and treatment of colds, wound healing
Investigational use: Anticancer
Side effects: Possible suppression of immunity with habitual use
Echinacea is a purple coneflower native to North America. Plains Indians valued this member of the daisy (Asteraceae) family for its medicinal properties and introduced it to European settlers. By the 1920s, this acclaimed anti-infectious and vulnerary agent was listed in the National Formulary and outsold all other products of one major pharmaceutical company. Its popularity dwindled after the advent of antibiotics, only to experience a resurgence in recent years. It is the most popular herb in the United States, generating more than $300 million in sales annually.1 Three of the 9 species of Echinacea are used medicinally: E purpurea, E angustifolia, and E pallida. Echinacea purpurea is the most commonly used and extensively studied.
In Germany, where most studies have been conducted, echinacea is approved by the Federal Health Agency as supportive therapy for upper respiratory tract infections, urogenital infections, and wounds.5 In the United States, echinacea is usually marketed alone or in combination with other herbs as a purported immune booster, particularly for the prevention or treatment of colds. Although 26 published controlled trials have evaluated echinacea's therapeutic effects, none is of sufficient methodologic quality to be conclusive.14 For example, in addition to sharing the flaws of the best studies discussed later, most other controlled trials use formulations of echinacea combined with other herbs. Treatment assignment is neither random nor blind in most studies.14
Only 2 RDBPC trials have evaluated E purpurea's effect on upper respiratory tract infections. In one, echinacea extract demonstrated a statistically significant decrease in symptoms and duration of "flulike" illness (n=180).15 The effects were dose dependent; benefits were noted beginning on day 3 or 4 in patients taking 180 drops (1 drop=20 µL) of extract daily, whereas volunteers taking 90 drops per day showed no benefit. In the second RDBPC trial with 108 volunteers who had a history of recurrent URIs, prophylactic echinacea extract was associated with less frequent (14% relative risk reduction) and less severe recurrences.16-17 In some studies, immunocompromised patients seemed to benefit the most.14 While provocative, interpretation of the results is limited in both of the RDBPC trials by inadequate use or description of the following: diagnostic criteria, randomization process, treatment interventions, methods for assessing outcome, assurance of blinding, detail of results, and quality statistical analysis.14
In animal studies, echinacea affects several aspects of the immune system; components of echinacea increase the number of circulating white blood cells,18 enhance phagocytosis,19 stimulate cytokine production, and trigger the alternate complement pathway.20 In vitro, echinacea displays direct bacteriostatic and antiviral activity and stimulates the production of cytokines (interferon, tumor necrosis factor, interleukin 1, and interleukin 6).3, 15 Based on its stimulation of cytokine production, echinacea is being investigated as a possible antineoplastic agent in preliminary human trials.21
Topical echinacea exhibits multiple vulnerary mechanisms, including the anti-infective activity noted above, stimulation of fibroblasts, and inhibition of inflammation (metabolism of arachidonate to prostaglandins).22 In rodents, echinacea also decreases inflammation, protects against radiation-induced skin damage, and hastens wound healing.23
Available evidence on echinacea's therapeutic potential is incomplete, but does suggest a possible supportive role in treating infections and wounds. However, well-designed clinical trials are needed to substantiate echinacea's efficacy, clarify appropriate dosages, and confirm safety. Despite the fact that the dosage has not been standardized and that preparations are frequently adulterated, no serious side effects have been reported in more than 2.5 million prescriptions per year in Germany and more than a century of use in the United States.24 Toxicity studies found no mutagenicity in tissue culture, and no clinical or histologic side effects in rats treated with huge doses of echinacea (5 g/kg intravenously and acutely or 8 g/kg per day orally for 1 month).24 German guidelines discourage use of echinacea in place of antibiotics or for more than 8 weeks (one study suggests that long-term use may suppress immunity).5
FEVERFEW
Tanacetum parthenium
Common use: Migraine prophylactic
Investigational use: Antiarthritic
Side effects: Oral ulcers, rebound headaches, allergic reaction (rare)
Feverfew is a daisylike perennial found commonly in gardens and along roadsides. The name stems from the Latin febrifugia, "fever reducer." The first century Greek physician Dioscorides prescribed feverfew for "all hot inflammations." Also known as "featherfew," its feathery leaves are used commonly to treat arthritis and prevent migraines.25 While feverfew did not reduce symptoms in a double-blind, placebo-controlled (DBPC) trial among patients with rheumatoid arthritis,26 it has been shown to prevent migraines in 2 of 3 DBPC trials.
The largest and best DBPC trial was a crossover study in which feverfew use was associated with a 70% reduction in migraine frequency and severity (n = 270).27 Side effects were less frequent than with placebo. In a trial among feverfew users, subjects randomized to receive a placebo instead of continuing feverfew suffered a significant increase in the frequency and severity of headaches, nausea, and vomiting (n = 20).28 Based on these trials, Canadian health officials recently approved encapsulated feverfew leaves as an over-the-counter medication for migraine prophylaxis. However, migraines were not prevented in a subsequent randomized controlled trial (RCT) using a different formulation of feverfew (0.35% = 0.5 mg of parthenolide, a suspected active ingredient).29 This highlights the potential variability of contents and effects of different preparations of the same herb, as well as the inadequacy of standardizing herbs to a single ingredient when other bioactive constituent(s) are not well characterized.
Laboratory evidence indicates that feverfew causes vasodilation and reduces inflammation. Feverfew's constituents inhibit phagocytosis, platelet aggregation, and secretion of inflammatory mediators (arachidonic acid and serotonin).30 Feverfew is thought to down-regulate cerebrovascular response to biogenic amines, consistent with its ability to prevent but not abort headaches, as well as the months of use needed for clinical efficacy.25
In summary, some feverfew preparations can prevent migraines, with efficacy that compares favorably with  -blockers and valproic acid.31 However, side effects may limit the use of feverfew, as 5% to 15% of users develop aphthous ulcers and/or gastrointestinal (GI) tract irritation.25 Sudden discontinuation can precipitate rebound headaches.28 Long-term safety data are lacking. Feverfew should not be used during pregnancy (historically it has been used to induce menstrual bleeding) or in patients with coagulation problems (feverfew can alter platelet activity30). For patients who want to try feverfew, expert herbalists recommend a gradual dose increase up to 125 mg/d orally of encapsulated leaves (2-3 leaves) standardized to contain 0.2% parthenolide. However, according to a 1992 study, none of the commercially available North American preparations contained even half of the recommended parthenolide concentration.32
GARLIC
Allium sativum
Common uses: Antiatherosclerosis (lipid lowering, antithrombotic, fibrinolytic, antihypertensive)
Investigational uses: Anticancer
Side effects: Sulfuric odor, contact irritation (rare)
Garlic's historic and worldwide medicinal use have made it one of the most extensively studied medicinal herbs. Nevertheless, the actual therapeutic benefits of this member of the Liliaceae family is unclear. Louis Pasteur first demonstrated garlic's antiseptic activity.4 Both animal studies and epidemiological analyses suggest anticancer effects.33 Most current research, popularity, and controversy relate to garlic's use as a putative antiatherosclerotic agent (via antithrombotic, antiplatelet, antihypertensive, and especially antilipidemic effects).
Mainstream medical interest in garlic's potential lipid-lowering effects was stimulated by 2 meta-analyses of RPC trials that found a 9% to 12% decrease in cholesterol in hyperlipidemic patients after at least 1 month of treatment with 600 to 900 mg/d of garlic tablets.34-35 However, definitive conclusions were limited by methodologic flaws in the trials analyzed.
Results of subsequent better-designed RPC trials have been mixed, with most (4/7) failing to find a significant change in any lipoprotein component36-39 These studies explicitly sought to overcome limitations of previous trials, such as by providing dietary stabilization prior to treatment and detailing methods to ensure proper control processes and laboratory standards. However, 3 of the negative trials were relatively small (N 28), which in one case yielded a marginal power (80%) to detect the expected 9% reduction in cholesterol.38 Three RPC trials support the positive findings of the meta-analyses, finding a 6.1% to 11.5% cholesterol reduction in the garlic-treated patients. Similar to previous studies, the lipid reduction was due to a decrease in low-density lipoprotein (LDL) ± decreased triglyceride levels.40-43
Of the factors that contribute to the discrepancies in data regarding garlic's antilipidemic effects, 2 are probably most important: publication bias (the preferential publication of trials with positive findings) and methodologic flaws. Both factors tend to overestimate the effect of a treatment. In contrast, excluding patients likely to benefit most (patients with severe hyperlipidemia or high-fat diets) might underestimate garlic's effect.
Blood pressure has been monitored in most recent studies of garlic's antilipidemic effects, showing a decrease (systolic and/or diastolic) in the treatment group of some, but not all, trials. Previously, a number of placebo-controlled trials that focused on the antihypertensive effects of garlic demonstrated a modest (-5% to -7%) effect.44 Several small, nondefinitive RCTs also corroborate garlic's antiplatelet, antithrombotic, and fibrinolytic activity found in animal and in vitro studies.45
Dozens of trials suggest, but have not adequately proven, that garlic can decrease the risk factors for atherosclerosis, particularly hypercholesterolemia. Pending conclusive evidence from additional well-designed and adequately powered studies, it is reasonable for patients to choose to take garlic given that it is safe and generally inexpensive. Garlic is considered safe by the FDA, based on the lack of known serious adverse outcomes despite culinary and medicinal use throughout human history (including daily use by pregnant or lactating women). Malodorous breath and skin can be diminished with enteric-coated tablets or by consuming garlic with protein. Allergies and contact irritation occur rarely. Patients who decide to use garlic medicinally should be aware of a few caveats. The main purported active ingredient, allicin, is degraded by crushing, heat, and acid; thus, efficacy is optimized by consuming raw cloves or enteric-coated tablets. The usual dose is 300 mg, taken 2 to 3 times per day, standardized to at least 1.3% allicin (equivalent to approximately 3 g or 1 fresh clove daily. Finally, the quality of commercial preparations varies greatly, a problem common to many herbal therapies. In an analysis of supposedly standardized preparations, 93% were found to be so lacking in allicin that they were declared expensive placebos.4
GINGER
Zingiber officinale
Common uses: Antiemetic
Side effects: Heartburn, allergic reaction (rare)
Like garlic, ginger has been a popular culinary and medicinal herb for thousands of years. For 2500 years, the Chinese have used this plant as a flavoring agent and antiemetic. Ancient Greeks wrapped ginger in bread and ate it after meals as a digestive aid. Ginger is now cultivated in Asia, Africa, and the Caribbean and is used worldwide as a nausea remedy.
The characteristic odor and flavor of ginger root come from a volatile oil (1%-3% by weight) that is composed of shogaol and gingerols. In laboratory animals, the gingerols have analgesic, sedative, antipyretic, antibacterial, and GI tract motility effects.46-47
Ginger reduces nausea, according to some, but not all, controlled human trials. In an RDBPC crossover trial of 30 women suffering from hyperemesis gravidarum, ginger (250 mg 4 times a day) significantly decreased the severity of nausea (P=.04).48 Two RDBPCTs report a significant decrease in perioperative nausea and vomiting in gynecological surgery patients who were given 1 g of ginger before surgery.49-50 In one, ginger was as effective as metoclopramide in reducing the number of episodes of nausea or emesis.44 However, in another RDBPCT, ginger was not found to be effective in preventing nausea after laparoscopic gynecologic surgery.51 Regarding motion sickness, ginger was more effective than dimenhydrinate in one controlled trial,52 but was not effective in another.53 Such inconsistency of results is found in studies of conventional antiemetics as well, due in part to the difficulty in measuring symptoms such as nausea. In addition, the effect of antiemetics is often subtle and difficult to discern unless tested in a homogeneous population with a high prevalence of nausea.
It is reasonable for patients to try ginger to treat nausea, not only because data supports its efficacy, but also because it is inexpensive, readily available, and safe. Like garlic, ginger is not known to cause any serious side effects, despite worldwide culinary and medicinal use of ginger. Only 1 of the above controlled human trials noted any side effect, which, ironically, was GI tract upset. It is on the FDA's GRAS list. The usual adult dose is 250 milligrams ( tsp) to 1 g of powdered root several times per day.
GINKGO
Ginkgo biloba
Common uses: Intracerebral and peripheral vascular insufficiency (dementia and claudication)
Investigational uses: Mountain sickness
Side effects: Gastrointestinal tract disturbance, headache, contact dermatitis (each is rare/mild)
One of the oldest surviving tree species, G biloba has grown in China for more than 200 million years. For thousands of years, traditional Chinese medicine has used ginkgo to treat brain disorders. In the past 20 years, ginkgo has gained worldwide popularity for similar purposes, supported by evidence of its ability to promote perfusion and inhibit oxidative damage. By 1988, German physicians prescribed a standardized extract of ginkgo (Egb 761, Willmar Schwabe GmbH & Co, Karlsruhe, Germany) more than any other medication.4 Sales in the United States soared to $240 million in 1997.1 In Germany, where most of the research has been conducted, the federal health authorities have concluded that treatment with Egb 761 is safe and effective for peripheral and cerebral circulatory disturbances, including claudication and memory impairment.5 Numerous European clinical trials report EGb 761's efficacy in diminishing symptoms of cerebrovascular insufficiency.54-55
In 1997, the first US-based trial corroborated ginkgo's efficacy in the treatment of dementia. In this year-long, RDBPC, multicenter study, EGb 761 was found to stabilize and in some cases improve cognition and social functioning in patients with mild to moderate dementia (Alzheimer disease or multi-infarct dementia).56 In another trial, healthy geriatric patients demonstrated better cognitive function after taking EGb 761.57
EGb 761 improves perfusion peripherally as well as centrally. More than 15 European studies suggest a reduction of claudication symptoms in patients treated with EGb 761, including a 50% increase in pain-free walking distance.58 Simultaneous benefits on central and peripheral perfusion are demonstrated in a randomized, placebo-controlled trial among 44 Himalayan climbers.59 The 22 subjects treated with 160 mg/d of EGb 761 developed significantly fewer cerebral (0% vs 41.9%, P<.002) and respiratory symptoms (13.6% vs 81.8%, P<.001) of mountain sickness than climbers taking the placebo. EGb 761 also decreased vasomotor disorders of the extremities, measured by plethysmography and symptom scores.
The mechanisms of ginkgo's therapeutic effects are not fully understood. They are attributed in part to synergistic effects of its constituents, particularly the flavonoids, terpenoids, and organic acids. These act to varying degrees as scavengers of free-radicals, chemicals implicated in the pathophysiology of Alzheimer disease.60-61 They also inhibit platelet activation factor and thereby reduce thrombosis, dilate arteries and capillaries, and block the release of chemotactic and inflammatory mediators from phagocytes.
Ginkgo's antidementia effects are similar to that of the prescription drugs donepezil and tacrine.62-63 While statistically significant, such modest effects are of uncertain clinical benefit. However, ginkgo may have other advantages, such as improvement of peripheral vascular circulation and tolerance of altitude. In addition, ginkgo's side effects are similar to placebo vs potential hepatoxic effects with tacrine. While G biloba leaves may cause mild GI tract irritation, no serious adverse effects have been noted in human or animal trials, including no mutagenicity or teratogenicity.64 In contrast, G biloba seeds can cause fatal neurologic and allergic reactions and are not used medicinally.64 Patients should use the extract studied in all reported clinical trials, Egb 761. The dose is 40 mg 3 times per day or 80 mg twice per day of an extract standardized to 24% flavanoid glycoside and 6% terpenoids. Absorption is unaffected by food intake. The duration of benefit after discontinuation is unknown.65
GINSENG
Panax ginseng Panax quinquefolius (American ginseng, an endangered species)
(Eleutherococcus senticosus, so-called Siberian ginseng, is not in the Panax [true ginseng] genus)
Common name: Korean ginseng
Common uses: "Tonic," performance enhancer, "adaptogen," anticancer, aphrodisiac
Investigational uses: All common uses are as of yet unproven but are under investigation
Side effects: Tachycardia, hypertension
Ginseng is one of the most popular and expensive herbs in the world. As in ancient China, ginseng is still widely believed to be a panacea; hence, its genus name Panax. The common name ginseng ("man-root") stems from a belief that because this root is humanoid in appearance, it can benefit all aspects of the human body. At least 6 million Americans66 use the root of this slow-growing perennial. It is considered a tonic or adaptogen that enhances physical performance (including sexual), promotes vitality, and increases resistence to stress and aging. While in vitro and animal studies suggest that it has beneficial effects on immune and endocrine functions, evidence of its effects on humans is limited and contradictory.
One reason for lack of definitive data about ginseng's health effects is the inherent difficulty of quantifying intangible benefits such as "vitality" and "quality of life." Nevertheless, a 3-month RCT showed a significant increase in subjective "quality-of-life" scores among ginseng users (n=625).67 Some small controlled trials report increased endurance, whereas others do not.68 In an RDBPCT, college-aged volunteers who took 100 mg of ginseng twice daily for 12 weeks experienced a statistical improvement in the speed at which they were able to perform mathematical calculations, but did not experience improvement in motor function or other cognitive functions; no adverse effects were seen in this study.69 To our knowledge, no studies compare ginseng's effect with that of inexpensive, widely available cognitive stimulants such as caffeine, nor has an RCT confirmed aphrodisiac effects in humans. However, ginseng was associated with a significant increase in serum hormones (testosterone, dihydroxytestosterone, follitropin, and lutropin) and in sperm numbers and motility in 46 men with oligospermia.70 A case-control study suggests an association (but not necessarily a causal relationship) between use of ginseng and lower cancer rates (n = 1987 pairs matched for age, religion, marital status, education, sex, occupation, and smoking status).71
In Asian cultures, ginseng is commonly consumed by pregnant women and is given to newborns in hopes of bolstering energy. A case-control study of 88 pairs of women (matched only for age and parity) found a significantly lower rate of pregnancy-induced hypertension, but a 3-fold higher incidence of gestational diabetes among ginseng consumers.72 We do not recommend ginseng use for pregnant or lactating women or for children until safety and efficacy are proven in randomized controlled trials.
Patients who take ginseng risk paying a high price without proven benefit. Commercial preparations of ginseng cost up to $20 an ounce and vary tremendously in quality. In one analysis of 54 available ginseng products, 85% were determined "worthless," containing little or no ginseng.73 To optimize quality and chance of efficacy, only preparations standardized to ginsenoside content should be used. Patients should be warned that E senticosis, marketed as "Siberian ginseng" for commercial reasons, contains no true ginseng.
Despite extensive use, adverse reactions to ginseng are rare and ginseng is on the FDA's GRAS list. However, at least 1 fatality has been attributed to contamination of a ginseng product with the potent and unpredictable herbal stimulant ephedra. While clear conclusions about the safety of ginseng cannot be drawn from the uncontrolled 1979 case series that coined the term "ginseng abuse syndrome,"74 ginseng can act as a mild stimulant and should probably be avoided in association with other stimulants or in patients with cardiovascular disease. Rare endocrinologic effects include mastalgia and postmenopausal bleeding, both of which cease with discontinuation of ginseng.75
GOLDENSEAL
Hydrastis canadensis
Common uses: Antidiarrheal and antiseptic (berberine component)
Investigational uses: Antineoplastic and anti–human immunodeficiency virus (berberine component)
Side effects (large doses): Mucocutaneous irritation, GI tract upset, cardiac and uterine contractility, vasoconstriction, central nervous system stimulation, neonatal jaundice (displaces bilirubin).
Cherokee Indians introduced this member of the buttercup family to European settlers. It is used topically for eye or skin irritation, and orally for infections. A recent surge in goldenseal's popularity stems from the erroneous but widespread belief that it can mask illicit drugs in urine toxicology screens. It is a also a popular but unproven cold remedy. However, one of its main bioactive constituents, berberine, is an effective antidiarrheal agent.
In one RCT, a single 400-mg dose of berberine sulfate significantly reduced stool volumes and duration of diarrhea among patients with enterotoxigenic Escherichia coli and Vibrio cholerae.76 In another controlled trial, berberine (5 mg/kg x 6 days) was more effective than placebo and as effective as metronidazole (10 mg/kg x 6 days) in treating children with giardia.77
Berberine is thought to act intraluminally, as it is poorly absorbed and there is no clinical evidence for systemic anti-infective activity.78 In vitro studies reveal possible mechanisms of berberine's antidiarrheal effects. Berberine exerts antimicrobial activity against numerous bacteria, fungi, and protozoa.79 In addition, it blocks adhesion of bacteria to epithelial cells,80 inhibits the intestinal secretory response of cholera and E coli toxins, and normalizes mucosal histology following cholera toxin damage.81
Despite the antidiarrheal efficacy of the chemical berberine, we do not recommend the use of the herb goldenseal for this purpose, both because of this plant's endangered status and due to the possible toxicity of its other components. For example, traditional herbal literature warns that large (unspecified) amounts of goldenseal (particularly the alkaloid hydrastine) can cause mucosal irritation, GI tract upset, uterine contractions, neonatal jaundice, hypertension, seizures, inotropic cardiac effects, and respiratory failure.82 It may oppose heparin or coumadin anticoagulation.83 Goldenseal should not be used by pregnant or lactating women, neonates, or patients with cardiovascular disease, epilepsy, or coagulation problems. No significant side effects have been noted in clinical or animal studies of purified berberine.
MILK THISTLE
Silybum marianum
Common names: "Holy Thistle," "St Mary's Thistle"
Common uses: Hepatoprotectant, antioxidant
Investigational uses: Antihyperglycemic
Side effects: None known
For more than 2000 years, the seeds of this prickly leafed, purple-flowered plant have been used to treat liver disorders. In addition, all parts of this Kashmir native have been consumed historically as vegetables without report of toxic effects. Silymarin protects against a variety of hepatotoxic agents and processes in animal experiments. Evidence of its effects in humans is provocative but preliminary.
The best human data deal with silymarin's effect on cirrhosis, with conflicting results from 2 RDBPC trials.84-85 In the first, the 4-year mortality rate decreased by 30% in patients treated for 2 years with 140 mg of silymarin 3 times a day. Effects were greatest in alcohol-related cirrhosis. In contrast, a recent multicenter RDBPC trial in 200 patients with alcoholic cirrhosis found no differences in progression of disease or mortality after 2 years of treatment with 150 mg of silymarin 3 times per day.85 Interestingly, glycemic control was significantly improved (lower fasting blood glucose, glycosylated hemoglobins, and insulin requirements) in a randomized, placebo-controlled trial of 60 patients taking silymarin for alcoholic cirrhosis.86 In another RCT of patients with chronic active hepatitis, 1 week of therapy with oral silymarin (240 mg/d) resulted in decreased serum transaminases and bilirubin values.87 European physicians routinely treat hepatotoxic mushroom poisoning with intravenous silymarin (20-50 mg/kg per day), decreasing mortality rates by more than half in several case series.88
In animal studies, silymarin protects liver cells against a variety of hepatotoxins, including drugs (acetaminophen, amitriptyline, and erythromycin),89-90 toxins (a-amantin from deathcap mushrooms, alcohol, and carbon tetrachloride),91 hemosiderin,92 viruses, and radiation.88 Silymarin scavenges free radicals, blocks toxin entry into cells by competing for receptor sites, inhibits inflammation, and stimulates liver regeneration. As a result, it lowers serum transaminase levels, maintains coagulation factor production, and limits necrosis.88-91 It also prevents renal toxic reactions from cisplatin.93
Milk thistle warrants further investigation as a hepatoprotective and regenerative agent. No adverse effects have been reported. Diabetic patients taking silymarin should carefully monitor their blood glucose and may require reduction in standard antihyperglycemic agents to avoid hypoglycemia.86 The common dose is a 140-mg capsule, standardized to 70% silymarin, 2 to 3 times a day. A high first-pass effect concentrates silymarin in the liver. Silymarin is poorly absorbed, so concentrated products (ie, extracts) are optimal.
ST JOHN'S WORT
Hypericum perforatum
Common use: Antidepressant
Investigational uses: Anticancer, antiviral (including human immunodeficiency virus)
Side effects: Photosensitivity (rare, with large doses)
This 5-petalled yellow flower grows wild in much of the world. While reduced to 1% of its original population in the Pacific United States by ranchers who consider it a bothersome weed, in Europe it is highly valued as an antidepressant. St John's wort is by far the most common antidepressant used in Germany, where physicians prescribe it 4 times more often as fluoxetine hydrochloride.94 Sales in the United States increased 20-fold between 1995 and 1997, from $10 million to $200 million annually.1 St John's wort has been used for thousands of years for a myriad of conditions. It is named after St John the Baptist because it blooms around his feast day (June 24) and exudes a red color symbolic of his blood. Its scientific name derives from the Greek hyper and eikon, "to overcome an apparition," relating to ancient belief in its ability to ward off evil spirits. The vulnerary and neurologic effects of this herb were described by Galen, were repeated throughout the Middle Ages and by early American herbalists, and were recently supported by many clinical trials.
A 1996 meta-analysis of 23 randomized, controlled clinical trials of SJW concluded that it is significantly more effective than placebo in treating mild to moderate depression.95 The 8 studies that compared H perforatum with low-dose tricyclics suggested equivalent efficacy, with significantly fewer side effects. The authors noted the need for further studies to determine optimal dosing, long-term side effects, efficacy in maintenance therapy, and relative safety and efficacy compared with other antidepressants.95 In response, the Office of Complementary and Alternative Medicine of the National Institutes of Health and the National Institute of Mental Health recently allocated $4.3 million for the first clinical trial in the United States to address these issues. The 3-year multicenter trial beginning in 1998 will compare SJW with both placebo and fluoxetine hydrochloride.
The mechanism of SJW's antidepressant effects is only partially known. Some in vitro studies demonstrated monoamine oxidase inhibition, but only at concentrations unattainable in vivo.96 Furthermore, SJW is used extensively (66 million doses in 1994 in Germany) without restriction of tyramine-containing foods and without reported side effects related to monoamine oxidase inhibition. Hypericin is the putative active ingredient. It has a high affinity for  -aminobutyric acid, the stimulation of which is known to have antidepressant effects.87 Other studies indicate that hypericin activates dopamine receptors but inhibits serotonin receptor expression.97 Altered receptor regulation is consistent with the several-week lag between drug initiation and clinical efficacy, similar to other antidepressants.
In addition to SJW's antidepressant effects, evidence beyond the scope of this article supports its historical anti-inflammatory, anti-infective, and vulnerary external applications.96 Antineoplastic and antiviral applications are experimental.
Existing data on the therapeutic effects of SJW are provocative. However, well-designed clinical trials are needed to determine long-term safety and therapeutic guidelines for use of SJW for different depressive disorders. Prior to the availability of such information, patients who choose to use SJW should use the regimen shown to be effective in the above clinical trials: 300 mg 3 times a day of an extract standardized to 0.3% hypericin. St John's wort is generally well tolerated, but can cause photosensitivity, especially in fair-skinned persons taking large doses. It should not be used during pregnancy (uterotonic) or with other psychoactive agents.
SAW PALMETTO
Serenoa repens
Common uses: Benign prostatic hypertrophy (BPH), prostatitis
Side effects: Gastrointestinal tract upset, headache (each is rare and mild)
Extracts from the fruit of this short, scrubby palm have been used historically to treat urogential problems. Many modern clinical trials corroborate the ability of saw palmetto extract (SPE) to improve the signs and symptoms of BPH, for which it is a first-line treatment in much of Europe.98
Seven of the 8 DBPC trials that have evaluated SPE's efficacy in treating BPH demonstrate significant objective and subjective improvement in BPH symptoms in patients taking 320 mg of SPE for 1 to 3 months.98-99 However, only 2 of these trials are randomized, and their results conflict. In the shorter randomized trial, SPE is no better than placebo in treating BPH (n = 70 treated for 1 month).100 In the larger, randomized, multicenter trial (n = 176 treated for 2 months), and in the other 6 DBPC trials, SPE significantly increases urinary flow, decreases nocturia, and decreases postvoid residual.101 Saw palmetto extract worked as well as finasteride in a randomized, 6-month study of 1098 men, with similar significant improvements in the International Prostate Symptom Score, quality of life, and peak urinary flow rate.102 Unlike finasteride, SPE did not cause impotence, decrease libido, or alter prostate-specific antigen levels.
A mechanism of SPE's effect on BPH is demonstrated in an RDBPCT in which use of SPE for 3 months results in a significant decrease in prostatic nuclear androgen and estrogen receptors.103 Prostate size decreased on serial ultrasounds in an open study of 505 men with BPH.104
Like finasteride, SPE inhibits the enzyme 5 -reductase (in vitro), blocking the conversion of testosterone to dihydroxytestosterone, a major growth stimulator of the prostate gland.105 Saw palmetto extract also blocks the uptake of testosterone and dihydroxytestosterone by the prostate without affecting serum testosterone levels.105 In addition, its anti-inflammatory activity (inhibition of cyclooxygenase and 5-lipoxygenase pathways) are thought to be important in decreasing the edematous component of BPH and prostatitis.4
These studies support the use of SPE for BPH and show that its efficacy is comparable to that of the 5-reductase inhibitor finasteride with significantly fewer side effects. However, 1 antagonists are more effective than both SPE106 and finasteride.107 The usual dose of SPE is 160 mg twice daily of an extract standardized to contain 85% to 95% fatty acids and sterols. Side effects are rare (<3%) and include mild headaches and GI tract upset.4
VALERIAN
Valeriana officinalis
Common uses: Sleep-aid, anxiolytic, antispasmodic
Side effects: Headaches (rare), heart palpitations (rare), insomnia (rare)
The malodorous root of valerian, a pink-flowered perennial that grows wild in temperate areas of the Americas and Eurasia, has been a popular calming and sleep-promoting agent for centuries. German health officials have approved valerian for use as a mild sedative and sleep aid, based on several European clinical trials that demonstrate these effects.
In 2 randomized, blind, and placebo-controlled crossover trials (n=27 and n=128), valerian (400-450 mg before bedtime) resulted in significantly improved sleep quality and decreased sleep latency, with no residual sedation in the morning.108-109 In vitro, constituents of valerian mediate the release of -aminobutyric acid110 and bind the same receptors as benzodiazepines, but with less affinity and milder clinical effects.111 Habituation or addiction have not been reported.
In the United States, valerian is approved for use in flavoring foods and beverages such as root beer. No serious side effects have been reported. However, a small percentage of consumers experience paradoxical stimulation, including restlessness and palpitations, particularly with long-term use.112 Some components display cytotoxic and mutagenic activity in vitro. Although these effects have not been reproduced in vivo even at high doses (1350 mg/kg), valerian probably should not be used by pregnant women. Valerian should not be taken with other sedatives or before driving or in other situations when alertness is required.
CONCLUSIONS
Physicians need to know about medicinal herbs because many patients use them and are often guided by misconceptions or inaccurate information. Whether or not physicians intend to prescribe herbal therapies, it is important that they understand the potential associated health consequences so that they can help patients make informed decisions about their use. This review aimed to familiarize clinicians with available evidence on 12 commonly used herbs, as well as to indicate areas in need of further research. Popular interest in herbal therapies is stimulating research that will help clarify issues such as the indications, effective doses, and safety of common medicinal herbs.
For patients who choose to use herbal therapies, several guidelines can help them to do so most safely and effectively (Table 5). Patients need to understand that medicinal herbs are drugs, and as such not only have potential benefits, but also the potential to interact with other drugs and to cause toxic reactions. Patients should be informed about important similarities and differences between FDA-approved drugs and herbal remedies, particularly that the herbs are not required to be proven either safe or effective prior to marketing (Table 3). Given the variable purity, potency, and quality of herbal products, they must be selected with care. In general, the best products are from Europe, where quality control regulations exist. In the United States, large stores with national reputations to protect have particular incentive to ensure quality. Finally, patients should preferably use standardized products and consult reputable sources for information about appropriate indications, contraindications, and dosing (see Table 4, Table 5, and Table 6).
AUTHOR INFORMATION
Accepted for publication May 1, 1998.
Thanks to the following for their thoughtful comments and assistance: Lisa Butters, Maureen Brown, MD, Chris Vincent, MD, and the Swedish Medical Center Library staff.
Corresponding author: MaryAnn O'Hara, MD, Robert Wood Johnson Clinical Scholars Program, University of Washington Health Sciences Center, 1959 NE Pacific, Room H-220, Box 357183, Seattle, WA 98195 (e-mail: maryanno{at}u.washington.edu).
From the Robert Wood Johnson Clinical Scholars Program, University of Washington Health Sciences Center (Dr O'Hara), and the University of Washington Family Medicine Network, Swedish Family Medicine Residency (Drs Kiefer and Farrell), Seattle; and the Center for Holistic Pediatric Education and Research, The Children's Hospital, Boston, Mass (Dr Kemper).
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