SPECIAL ARTICLE A Review of 12 Commonly Used Medicinal Herbs MaryAnn O’Hara, MD, MSt; David Kiefer, MD; Kim Farrell, MD; Kathi Kemper, MD, MPH 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. Arch Fam Med. 1998;7:523-536 More than one third of Americans use herbs • Your spouse has high cholesterol, your for health purposes, spending over $3.5 bil- child has recurrent ear infections, and lion annually.1,2 Yet patients (and physi- you have trouble relaxing after a hectic cians) often lack accurate information about day at the clinic. Prompted by your pa- the safety and efficacy of herbal remedies. tients’ questions, you wonder if any herbal Imagine the following are patients in your remedies might benefit your family. primary care practice. How would you ad- Popular use of medicinal herbs makes vise them? it necessary for physicians to become aware • Jane, who has chronic hepatitis C and of their health benefits, risks, and uncertain- receives medicine for both hyperten- ties so that they can educate their patients sion and schizophrenia, asks if she can about these issues. To assist clinicians in this take milk thistle to protect her liver. task, this article reviews existing data on the • John, who has the human immunode- history, safety, and efficacy of 12 of the most ficiency virus, has an increasing viral commonly used and best-studied medicinal load. He expresses fear of “medicine,” herbs (Table 1). In addition, it summarizes but requests information about St John’s general information about herbal therapies, wort (SJW) in hopes of “naturally” cur- including an overview of regulatory history ing his human immunodeficiency vi- (Table 2), important similarities and dif- rus and depression. ferences between medications approved by • Sam’s wife bought him valerian to help the Food and Drug Administration (FDA) him sleep, saw palmetto for his urinary and herbal therapies (Table 3), and the difficulties, and gingko to improve his nature of available data about medicinal memory. He is inclined to throw the herbs. Finally, lists of reliable introduc- herbs away but wants your opinion. tory resources (Table 4) and guidelines • After you inform Stephanie that she is 3 for patients (Table 5) are provided. months pregnant, she asks what effects the herbs she has taken for months will A HISTORICAL PERSPECTIVE have on her fetus (ginger for nausea, feverfew for headaches, and pen- Plants have been used medicinally through- nyroyal to induce a period). out history. Through the first half of this cen- From the Robert Wood Johnson Clinical Scholars Program, University of Washington Health Sciences Center (Dr O’Hara), and the University of Washington Family This article is also available on our Medicine Network, Swedish Family Medicine Residency (Drs Kiefer and Farrell), Seattle; and the Center for Holistic Pediatric Education and Research, The Children’s Web site: www.ama-assn.org/family. Hospital, Boston, Mass (Dr Kemper). ARCH FAM MED/ VOL 7, NOV/DEC 1998 523 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. Table 1. Twelve Common Medicinal Herbs* Herb Common Uses Scientific Name (Type of Evidence/ Part Used Recommendation)† Safety‡§ Dose¶ Cost** Chamomile Mild sedative (III-C) GRAS†† Tea as necessary $0.10 per tea Matricaria recutita, Mild spasmolytic (III-B) Rare allergic reaction and contact irritation. Compress as necessary bag Chamaemelum nobile Vulnerary (wound healing), (II.3-B) Avoid ocular preparations Flower Echinacea URI treatment (I-B) No serious side effects known Not standardized $0.25-$4 per Echinacea purpurea, URI prevention (I-C) Historically misidentified and contaminated Dried extract: day Echinacea Vulnerary (wound healing), (III-C) Long-term use may be immunosuppressive 300-400 mg tid angustifolia Immune stimulation (III-C) Tincture: 30-50 drops Leaf, stalk, root Antimicrobial (HIV), (IV-C [D]) (1 drop = 20 µL) tid Feverfew Headache prophylaxis (I-B) 5%-15% oral or GI irritation 25-75 mg (1-3 leaves) $0.10-$0.50 Tanacetum Rheumatoid arthritis (I-E) Rebound headaches possible bid, standardized to per day parthenium Avoid in pregnancy (traditional menses inducer) 0.2% parthenolide Leaf May potentiate platelet inhibitors Garlic 9% ↓ lipids (LDL, TG), (I-B) GRAS, including in pregnancy, lactation, and Fresh cloves: 0.5-1 qd $0.04-$0.70 Allium sativum Mild antihypertensive (I-B) childhood Pills: 600 mg-900 mg per day Cloves, root Antiplatelet (II.1-B) No serious side effects known qd, standardized to Antioxidant (I-B) Mild side effects: halitosis, body odor, topical 0.6%-1.3% allicin Antimicrobial (bacteria, fungus, and irritation, allergy (rare), GI upset Powder: 0.4-1.2 g viruses [HIV]), (III, IV-C [D]) May potentiate hypoglycemic and antiplatelet Cancer prevention (II.3-D) and therapy treatment (III-D) Ginger Antiemetic (I-B) (mildly prophylactic GRAS, including in pregnancy, lactation, and Capsules: 250-1000 mg $0.12 per Zingiber officinale and therapeutic against nausea childhood tid-qid dose Root from motion, chemotherapy, No serious side effects known Tea: steep powder or pregnancy, and surgery) May inhibit platelet aggregation fresh herb GI upset (mild) Allergy (rare) Ginkgo Dementia: slows cognitive No serious side effects known Use extract $0.30-$1.80 Ginkgo biloba deterioration (I-B) Mild side effects: GI upset, headaches, allergic standardized to 6% per day Leaf Mild effects, similar to tacrine skin reactions terpenoids, 24% Claudication: 50% ↑ in pain-free May inhibit platelet aggregation flavonoids walking distance (II.1-B) 40-80 mg bid-tid Ginseng Endurance/adaptation enhancer GRAS Root: 1-3g qd $0.30-$2.00 Panax ginseng, —Conflicting motor results (C) High cost without proven benefit Pills: 100-300 mg tid, per day Panax quinquefolius —↑ Cognitive function (I-C) Avoid use with other stimulants and in patients extract standardized Root —Resistance to stress (III-D) with cardiovascular disease (potential to 7% (“Siberian ginseng” —Androgenic and estrogenic hypertensive and chronotrope) ginsenosides is not a true (II.2-D) May increase digoxin levels ginseng) Enhances “quality of life” (II.1-D) Mastalgia and postmenopausal bleeding (rare) Immune/endocrine stimulant (III-D) Rare fatalities attributed to contaminants tury,manyherbswereconsideredcon- be considered drugs based on tradi- HERBS AND FDA-APPROVED ventional medicines and as such were tional use alone. A would-be manu- MEDICATIONS: SIMILARITIES included in medical curricula and for- facturer must gain FDA approval; the AND DIFFERENCES mularies (eg, United States Pharmaco- profit to be made from a patented poeia and The National Formulary). product is the motivating factor. Tra- Patients are often unaware of im- Twoimportantfactorsfosteredaschism ditional herbal therapies cannot be portant similarities and differences between mainstream drugs and herbal patented, and therefore lack spon- between medicinal herbs and FDA- therapies in the United States: the de- sors for the costly ($230 million) and approved medications. For ex- velopment of a pharmaceutical indus- lengthy (8-10 years)3 approval pro- ample, some mistakenly think of trycapableofmass-producingpurified cess. By default, many medicinal herbs as “natural” alternatives to chemicals, and regulatory changes by herbs are not legally considered drugs chemicals, failing to recognize that the FDA. and are not regulated as such by the herbs are composed of bioactive In 1962, thalidomide was found FDA. The FDA suggests but cannot chemicals, some of which may be to be teratogenic and Congress passed require that manufacturers of herbal toxic (see Table 6 for a list of com- an amendment to the Food and Drug therapies provide customers with sci- monly used herbs with toxic effects Act to increase assurance of drug entific data in support of advertis- that probably outweigh their poten- safety and efficacy. While successful ing claims. Furthermore, the FDA tial benefits). Also, patients are of- in general, the amendment initiated must prove that an herbal product is ten unaware that about 25% of mod- a regulatory dilemma regarding unsafe or ineffective before it can re- ern pharmaceutical drugs have herbal therapies in the United States quire the product to be removed from botanical origins, such as digoxin (Table 2). No longer can substances the market. from foxglove, morphine from pop- ARCH FAM MED/ VOL 7, NOV/DEC 1998 524 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. Table 1. Twelve Common Medicinal Herbs* (cont) Herb Common Uses Scientific Name (Type of Evidence/ Part Used Recommendation)† Safety‡§ Dose¶ Cost** Goldenseal Mask illicit drugs in urine (II.3-E) Generally well tolerated Use alternate sources of $0.45-$1.25 Hydrastis canadensis Berberine constituent effects: Traditional literature warns that huge berberine, 10 mg/kg per dose Root, rhizome Antidiarrheal in children (unspecified) doses can cause GI upset, per day (Escherichia coli, Giardia, and hypertension, cardiac inotropy, seizures, and cholera), (I-B) respiratory failure Antiseptic, topical (III-C) Avoid in pregnancy (uterotonic) and neonates (causes jaundice) May oppose anticoagulants Milk thistle Hepatoprotection against: No serious side effects known Capsules: 140 mg $0.44-$2.00 Silybum marianum —Acute hepatitis, ie, mushroom Rare: diarrhea, allergy bid-tid, standardized per day Fruit poisoning (II.3-B), drugs to 70% silymarin (oral) (III-C) IV silymarin in acute —Chronic active hepatitis (I-B) poisoning: 20-50 —Cirrhosis (I-B, conflicting data) mg/kg per day St John’s wort Mild-moderate depression (I-B) Photosensitization is rare, usually in fair-skinned Tablets: 300 mg tid of $0.17-$1.35 Hypericum perforatum (long-term use not yet studied) people taking large doses extract standardized per day Flower, leaf Antimicrobial (HIV), (III-C [D]) No clinical MAO-inhibition and/or related to 0.3% hypericin (oral) Vulnerary (III-C) drug/food interactions Topical Neoplastic inhibition (III-D) Avoid use with other antidepressants Saw palmetto Benign prostatic hypertrophy (B) Unlike finasteride, not associated with ↓ libido Tablets: 320 mg qd of $ 0.80-$1.20 Serenoa repens —↑ Flow, ↓ frequency, ↓ PVR or changes in PSA extract standardized per day Fruit (No. 7 II-1) No serious side effects or drug interactions to 85%-95% fatty —Efficacy = finasteride (I) known acids and sterols —↓ Androgen and estrogen Mild, rare effects: GI upset, headaches, diarrhea prostatic nuclear receptors (I) —5 reductase inhibition (IV) Valerian Somnogogue (sleep aid), (I-B) GRAS Capsules: 400 mg qhs $0.06-$0.19 Valeriana officinalis Spasmolytic (III-C) Mild, rare effects: headache, palpitations, as necessary ( 12 per dose Root insomnia years) Tea: 2-3 g = 1 tsp tid Tincture: 3-5 mL tid *GRAS indicates generally recognized as safe; URI, upper respiratory infection; HIV, human immunodeficiency virus; tid, three times daily; GI, gastrointestinal; bid, twice daily; LDL, low-density lipoprotein; TG, triglycerides; qd, every day; qid, four times daily; IV, intravenous; MAO, monoamine oxidase; PVR, post–void residual; PSA, prostate-specific antigen; qhs, every night. See text for more information and references. †Adapted from study reference system of the US Preventative Services Task Force (USPSTF), 1996, 2nd edition. Type of Evidence: I indicates randomized controlled trial; II, other human study (1 = placebo-controlled trial, 2 = cohort or case-controlled study, 3 = case series); III, animal study (vs expert opinion in USPSTF rating); IV, in vitro studies (not a category in USPSTF). Recommendation: A indicates safe and effective; B, probably safe and effective; C, probably safe, possibly effective; D, insufficient data; and E, unsafe or ineffective. ‡Data are often lacking on drug interactions and effects of long-term use. §Content and quality of commercial products are not regulated in the United States and can vary considerably. Safety in pregnancy, lactation, and childhood is unknown (and use in these groups therefore not recommended) unless specifically indicated. ¶ Patients should use standardized preparations, which are more reliable and cost-effective. **Range of costs for commercial products ( brands) in typical drug store. ††Generally recognized as safe as a food supplement by the FDA. pies, aspirin from willow bark, and age. In addition, herbs may be con- ably the best compendium of clini- tamoxifen from the Pacific yew tree.4 taminated or misidentified at any stage cal information about herbs in the Unlike the FDA-approved over- from harvesting through packaging. world, it does not disclose the sci- the-counter and prescription medi- entific basis for its conclusions. Nev- cations, medicinal herbs are not THE NATURE OF EVIDENCE ertheless, such guidelines provide required to demonstrate either safety ABOUT MEDICINAL HERBS hypotheses to prompt quality human or efficacy prior to marketing, nor are trials, optimally with randomized, they regulated for quality. Neverthe- Most research on medicinal herbs is double-blind, placebo-controlled less, herbal therapies are not neces- conducted in areas of the world (RDBPC) trials. Research in the sarily less expensive than patented where the use of medicinal herbs is United States will be bolstered by the drugs and are rarely covered by medi- mainstream, particularly in Asia and creation of the Office of Comple- cal insurance. In contrast to the pu- Europe. For the past 3 decades, the mentary and Alternative Medicine rified, standardized, and potent FDA- German Health Authority has sys- within the National Institutes of approved drugs, herbs contain an tematically reviewed the evidence on Health, Bethesda, Md. array of chemicals, the relative con- about 300 herbs and formulated Data about the safety and efficacy centration of which varies consider- clinical guidelines. An English trans- ofmedicinalherbsarelimitedinanum- ably depending on genetics, grow- lation of the resulting German Com- berofways.Insomecases,thebestdata ing conditions, plant parts used, time mission E Monographs is due for are years old, limited to in vitro or ani- of harvesting, preparation, and stor- release in 1998.5 Although argu- mal studies, and/or only available in ARCH FAM MED/ VOL 7, NOV/DEC 1998 525 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. Table 2. Genesis of a Regulatory Dilemma: US Legislation on Herbal Remedies Year Act/Agency Purpose/Details Effects on the Status of Herbal Therapies 1906 Food and Drug Act Outlawed misbranding and adulteration Therapeutic herbs continue to be included in the National Formulary and the United States Pharmacopoeia 1938 Federal Food, Drug and Required safety testing prior to marketing after Most traditional remedies with history of safe use Cosmetic Act new elixir killed 105 people are grandfathered in under law 1962 (Kefauver-Harris) Drug Required proof of safety and efficacy to be Most herbs not patentable and therefore Amendments marketed as a drug Lacked sponsor for costly approval process Considered only evidence presented to expert Never considered for approval, irrespective of panels, primarily by companies interested in efficacy or safety marketing a patentable (therefore profitable) Reassigned status to “foods or food drug supplements” No longer legally considered medications No longer regulated by Food and Drug Administration (FDA) Subject to confiscation if labeled like a drug, eg, with traditional indications, doses, or cautions ... FDA GRAS List FDA maintains a list of substances generally Includes about 250 herbs based on their use as food recognized as safe (GRAS) additives (eg, garlic and ginger) 1993 FDA Commissioner David Proposed removing herbal products from the More protest letters sent to Congress than about any Kessler, MD market given booming market despite issue since the Vietnam war, fueled by a unproven safety or efficacy multimillion-dollar industry campaign 1994 Dietary Supplement Health Shifted burden of proof to FDA (eg, that claims Ineffective assurance of safety, efficacy, or quality and Education Act are misleading or an herb is unsafe) Confusing guidelines about labeling: Altered restriction on labeling May state: effect on “structure or function of the body” or “mechanism” or “describe general well-being from consumption of the nutrient” May not state: false or misleading claims, or that the product can treat or prevent any specific disease May be accompanied by: balanced, nonpromotional literature 1997 Federal Commission on Recommended manufacturers provide Anticipate little effect, as lacks enforcement Dietary Supplements science-based evidence about product to capability consumers journalsoutsidetheUnitedStates.Some CHAMOMILE clusive results. A recent RDBPC clinically important types of informa- Matricaria recutita trial found no difference between tion are particularly sparse in the lit- chamomile and placebo in prevent- erature, such as the results of negative Common name: German chamo- ing mucositis in 164 patients trials, drug interactions, effects in spe- mile receiving fluorouracil, half of cialpopulations(eg,childrenandpreg- Chamaemelum nobile (English or whom used chamomile 3 times nantorlactatingwomen),andtoxicre- Roman chamomile) daily for 14 days).6 However, the actions. In some cases, good evidence Common uses: Sedative, spasmo- study was possibly too short to about short-term side effects comes lytic, anti-inflammatory, vulner- detect a difference, as mucositis is from well-controlled human trials. ary (wound healing) largely a result of immunosuppres- However,informationabouttheeffects Investigational uses: Antioxidant sion, and therefore takes weeks to oflong-termuseisusuallybasedoncase Side effects: Allergy (rare) develop. In another randomized, reports rather than prospective stud- Chamomile is a daisylike, placebo-controlled trial, radiation- ies.Asnotedearlier,traditionalusehas apple-scented flower that has been induced skin reactions were less revealedserioustoxiceffectsassociated used medicinally for thousands of frequent and appeared later in with some common medicinal herbs years. Anglo-Saxons believed it was chamomile-treated areas, but the (see Table 6). On the other hand, the 1 of the 9 sacred herbs given to hu- differences were not statistically FDA categorizes about 250 herbs as mans by the god Woden. In con- significant.7 “generally recognized as safe” (GRAS) temporary Germany, it is consid- Animal studies support cham- for consumption based on long-term ered a cure-all. Chamomile is omile’s traditional use as a vulner- and/orwidespreadtraditionalusewith- cultivated worldwide for use as a ary anti-inflammatory, spasmo- out significant side effects. This article sedative, spasmolytic, anti-inflam- lytic, and anxiolytic agent. The reviews several herbs on the FDA matory, and vulnerary (wound- flavonoid component apigenin GRASlist,includingchamomile,garlic, healing) agent. Few human studies exhibits dose-dependent, revers- ginger,ginseng,andvalerian.Evidence have evaluated these traditional uses. ible inhibition of irritant-induced about the safety and efficacy of these Only chamomile’s vulnerary skin inflammation8 and protects and 7 other commonly used medici- effects have been studied in a con- against gastric ulcers induced by nal herbs are reviewed below. trolled human trial, with incon- medications, stress, and alcohol.9 ARCH FAM MED/ VOL 7, NOV/DEC 1998 526 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. Table 3. Herbs and Food and Drug Administration (FDA)–Approved Drugs: Similarities and Differences Factor Legal Medications (FDA-Approved) Herbal Therapies Mechanism Biochemical Biochemical Origins 25% Plant origin Raw plants Efficacy Evidence required, but not always based on Proof not required well-controlled trials Safety Must be well studied, within acceptable limits, and Evidence of safety not required and often unavailable detailed on drug label or insert Burden of proof with FDA to show herbal therapies unsafe Dose Established, usually by dose-response studies Some guidelines exist, usually based on historical precedent or tradition, occasionally based on dose-response in clinical trials Standardized products are preferential and available for some herbs (eg, garlic, ginkgo, St-John’s-wort, saw palmetto, and valerian) Not necessarily standardized by content of active ingredients, which are often unknown Pharmacokinetics Usually well characterized Rarely known Potency Standardized Varies with genetics, growing conditions, time harvested, plant part used, preparation, and storage Proof of purity Required Varies greatly High potential for contamination; history of case reports Identification Some confusion possible with coexistence of Problematic, beginning with misidentification of plants at harvesting generic and multiple trade names Products should be labeled with and chosen by scientific name (genus species, eg, Echinacea purpurea is the most used and studied Echinacea species—many of its common names are shared by other plants) Quality control Required Not required Improving with self-regulation by herb industry Cost Wide range Highly variable Elevated for patented drugs Extracts are the most concentrated and cost effective Insurance coverage Often Rarely should not be taken in conjunction Table 4. Introductory References with other sedatives, such as ben- zodiazapines or alcohol. Books Blumenthal M, Gruenwald J, Hall T, Riggins C, Rister R. German Commission E Monographs: Medicinal Plants for Human Use. Austin, Tex: American Botanical Council; 1998. English ECHINACEA translation in press. Echinacea purpurea, Echinacea Duke JA, Emmanus PA. The Green Pharmacy. Emmaus, Pa: Trondal Press; 1997. angustifolia, and Echinacea pallida Murray M. The Healing Power of Herbs. 2nd ed. Rocklin, Calif: Prima Publishing; 1995. Tyler VE. Herbs of Choice: The Therapeutic Use of Phytomedicinals. Binghamton, NY: Pharmaceutical Products Press; 1994. Common name: Purple cone- Journals flower American Botanical Council, Austin, Tex. HerbalGram Common uses: Prevention and treat- Facts and Comparisons, St Louis, Mo. Lawrence Rev Nat Prod ment of colds, wound healing Online The American Botanical Council: http://www.herbalgram.org Investigational use: Anticancer The Phytochemical Database: http://www.ard-grin.gov/nfrlsb/ Side effects: Possible suppression of immunity with habitual use Echinacea is a purple cone- flower native to North America. Apigenin also binds the same remain to be definitively proven in Plains Indians valued this member receptors as benzodiazapines; it human trials, its beneficial effects of the daisy (Asteraceae) family for exerts anxiolytic and mild seda- seen in animals and its good safety its medicinal properties and intro- tive effects in mice10 and relaxes record in widespread traditional duced it to European settlers. By the intestinal spasms.11 In vitro, the use by humans make it an accept- 1920s, this acclaimed anti-infec- essential oil acts as an antioxi- able home remedy for soothing tious and vulnerary agent was listed dant12 and kills some skin patho- mild skin irritation, intestinal in the National Formulary and out- gens (some Staphylococcus and cramps, or agitated nerves. In the sold all other products of one ma- Candida species).13 United States, it is commonly con- jor pharmaceutical company. Its Chamomile is considered safe sumed as a tea or applied as a com- popularity dwindled after the ad- by the FDA, with no known press. Patients with severe allergies vent of antibiotics, only to experi- adverse effects in pregnancy, lacta- to ragweed should be warned ence a resurgence in recent years. It tion, or childhood. It caused no about possible cross-reactivity to is the most popular herb in the adverse reactions in the human tri- chamomile and other members of United States, generating more than als discussed earlier. While chamo- the aster family (eg, echinacea, $300 million in sales annually. 1 mile’s therapeutic effects and safety feverfew, and milk thistle). It Three of the 9 species of Echinacea ARCH FAM MED/ VOL 7, NOV/DEC 1998 527 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. In animal studies, echinacea af- Table 5. Medicinal Herbs: Patient Information Sheet fects several aspects of the immune system; components of echinacea in- • Plants have been used throughout history to improve health. crease the number of circulating white • Many modern medicines came from plants. Examples include aspirin (from willow bark), morphine (from poppies), and digoxin (from foxglove). Scientists are still discovering valuable blood cells,18 enhance phagocyto- medicines in ancient plants; eg, tamoxifen, which is used to treat breast cancer (from Pacific yew sis,19 stimulate cytokine production, trees). and trigger the alternate comple- • Herbs used for health purposes are drugs. They are chemicals that can affect the human body in ment pathway.20 In vitro, echinacea helpful or harmful ways. displays direct bacteriostatic and an- • Plant products are not necessarily safe. Hemlock, for example, was used to kill Socrates. Some commonly used herbal therapies are also unsafe. tiviral activity and stimulates the • Traditional herbal therapies are not necessarily effective. Only trials in humans comparing the production of cytokines (interferon, herbal product with a placebo (inert substance) can determine its effectiveness, appropriate tumor necrosis factor, interleukin 1, dose, and safety. and interleukin 6).3,15 Based on its • Individual reports of benefit from any drug, including herbs, are not reliable evidence. This is stimulation of cytokine production, because some people will feel better when treated with a medicine they believe will work, whether it does or not. echinacea is being investigated as a • Science is not opposed to nature, but rather is a tool to help distinguish natural products that are possible antineoplastic agent in pre- safe and effective from those that are not. liminary human trials.21 • Unlike medications approved by the Federal Drug Administration, herbal products Topical echinacea exhibits mul- 1. Are not required to prove claims about their safety or effectiveness. tiple vulnerary mechanisms, includ- 2. Are not regulated to ensure quality control. ing the anti-infective activity noted 3. Vary tremendously in concentration of active ingredients and other chemicals. • If you decide to use herbs for health purposes, the following recommendations can help above, stimulation of fibroblasts, and maximize the potential benefits and minimize the potential risks: inhibition of inflammation (metabo- 1. Discuss any drugs you use, including herbal remedies, with your doctor. lism of arachidonate to prostaglan- 2. If you experience side effects, stop taking the herb and notify your doctor. dins).22 In rodents, echinacea also 3. Avoid preparations containing more than one herb. decreases inflammation, protects 4. Be wary of commercial clalms about herbs; seek unbiased and scientifically based sources of against radiation-induced skin dam- information. Ask your doctor or pharmacist for suggested sources. 5. Preferentially use products that are standardized to contain a specific amount of active age, and hastens wound healing.23 ingredients. Such formulations are generally more reliable, effective, and economical. Availableevidenceonechinacea’s 6. Select herbal products carefully. In general, the highest quality products come from Europe or therapeuticpotentialisincomplete,but large companies in the United States with national reputations to protect. Only buy brands that does suggest a possible supportive role list the following information on the package: the herb’s common and scientific name, the in treating infections and wounds. name and address of the manufacturer, a batch and lot number, an expiration date, dosing guidelines, potential side effects, and details of how quality is ensured. However, well-designed clinical trials are needed to substantiate echinacea’s efficacy,clarifyappropriatedosages,and are used medicinally: E purpurea, E upper respiratory tract infections. In confirmsafety.Despitethefactthatthe angustifolia, and E pallida. Echina- one, echinacea extract demon- dosage has not been standardized and cea purpurea is the most commonly strated a statistically significant that preparations are frequently adul- used and extensively studied. decrease in symptoms and dura- terated,noserioussideeffectshavebeen In Germany, where most stud- tion of “flulike” illness (n = 180).15 reported in more than 2.5 million pre- ies have been conducted, echinacea The effects were dose dependent; scriptions per year in Germany and is approved by the Federal Health benefits were noted beginning on day morethanacenturyofuseintheUnited Agency as supportive therapy for up- 3 or 4 in patients taking 180 drops States.24 Toxicitystudiesfoundnomu- per respiratory tract infections, uro- (1 drop = 20 µL) of extract daily, tagenicityintissueculture,andnoclini- genital infections, and wounds.5 In whereas volunteers taking 90 drops cal or histologic side effects in rats the United States, echinacea is usu- per day showed no benefit. In the sec- treated with huge doses of echinacea ally marketed alone or in combina- ond RDBPC trial with 108 volun- (5 g/kg intravenously and acutely or 8 tion with other herbs as a purported teers who had a history of recurrent g/kgperdayorallyfor1month).24 Ger- immune booster, particularly for the URIs, prophylactic echinacea extract manguidelinesdiscourageuseofechi- prevention or treatment of colds. Al- was associated with less frequent nacea in place of antibiotics or for though 26 published controlled tri- (14% relative risk reduction) and less morethan8weeks(onestudysuggests als have evaluated echinacea’s thera- severe recurrences.16,17 In some stud- that long-term use may suppress im- peutic effects, none is of sufficient ies, immunocompromised patients munity).5 methodologic quality to be conclu- seemed to benefit the most.14 While sive.14 For example, in addition to provocative, interpretation of the FEVERFEW sharing the flaws of the best studies results is limited in both of the Tanacetum parthenium discussed later, most other controlled RDBPC trials by inadequate use or trials use formulations of echinacea description of the following: diag- Common use: Migraine prophylactic combined with other herbs. Treat- nostic criteria, randomization pro- Investigational use: Antiarthritic ment assignment is neither random cess, treatment interventions, meth- Side effects: Oral ulcers, rebound nor blind in most studies.14 ods for assessing outcome, assurance headaches, allergic reaction (rare) Only 2 RDBPC trials have of blinding, detail of results, and Feverfew is a daisylike peren- evaluated E purpurea’s effect on quality statistical analysis.14 nial found commonly in gardens and ARCH FAM MED/ VOL 7, NOV/DEC 1998 528 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. Table 6. Common, Potentially Toxic Herbs* Herb (Scientific Name) Purported Use Possible Toxic Reaction Arnica (Arnica montana) Anti-inflammatory, analgesic, antiseptic Ingestion associated with gastrointestinal and muscle damage Safe topically, excepting rare allergic reactions Belladonna (Atropa belladonna), Relaxant, antiulcer Central nervous system and respiratory depression; “deadly nightshade” anticholinergic Chaparral (Larrea tridentata) Anticancer Hepatotoxic, tumor trophic Coltsfoot (Tussilago farfara), Antitussive, salve Carcinogenic, hepatotoxic, genotoxic “cough wort” Cardiopulmonary stimulant Comfrey (Symphytum) Healing (wounds, ulcers, cancer) Carcinogenic, hepatotoxic, genotoxic Excreted in breastmilk Ephedra (Ma-huang) (Ephedra sinica) Anorectic, stimulant, bronchodilator Potent, highly variable -1 and receptor stimulation Associated with hypertensive strokes, palpitations, and nerve damage Fatalities reported European mistletoe (Viscum album) Antihypertensive, antitumor Central nervous system and cardiac toxic reaction Gastrointestinal bleeding Germander (Teucrium chamaedrys) Anorectic Hepatotoxic Licorice (Glycyrrhiza glabra) Expectorant, antiulcer High or prolonged doses cause pseudoaldosteronism (saline retention and potassium depletion) Life root (Senecio aureus) Emetic Hepatotoxic, carcinogenic Ease labor Pennyroyal (Hedoma pulegioides), Menstrual disorders, insect repellent Hepatotoxic “squawmint,” “mosquito plant” Neurotoxic Teratogenic (acetylcysteine is antidote) Pokeroot (Phytolacca) Tonic, anticancer, anti-inflammatory Gastrointestinal, neurologic, and hematologic toxic reaction May be fatal in children Sassafras (Sassafras albidum) Stimulant, tonic, antispasmodic, Carcinogenic anti-inflammatory Indian snakeroot (Rauvofilia serpentina) ... Neurotoxic reaction (sedation, depression) Tea tree oil (Malaleuca alternifolia) Antiseptic, salve Central nervous system toxic reaction if ingested Local irritation Yohimbe (Pausinystalia yohimbe) Impotence Cardiovascular stimulant, neurotoxic, emetic *Select list of herbs most likely to be used by family medicine patients. Adapted from Tyler.2,4 along roadsides. The name stems cently approved encapsulated well as the months of use needed for from the Latin febrifugia, “fever re- feverfew leaves as an over-the- clinical efficacy.25 ducer.” The first century Greek phy- counter medication for migraine In summary, some feverfew sician Dioscorides prescribed fever- prophylaxis. However, migraines preparations can prevent mi- few for “all hot inflammations.” Also were not prevented in a subse- graines, with efficacy that com- known as “featherfew,” its feathery quent randomized controlled trial pares favorably with -blockers and leaves are used commonly to treat (RCT) using a different formula- valproic acid.31 However, side ef- arthritis and prevent migraines.25 tion of feverfew (0.35% = 0.5 mg of fects may limit the use of feverfew, While feverfew did not reduce symp- parthenolide, a suspected active in- as 5% to 15% of users develop aph- toms in a double-blind, placebo- gredient).29 This highlights the po- thous ulcers and/or gastrointes- controlled (DBPC) trial among pa- tential variability of contents and ef- tinal (GI) tract irritation.25 Sudden tients with rheumatoid arthritis,26 it fects of different preparations of the discontinuation can precipitate re- has been shown to prevent mi- same herb, as well as the inad- bound headaches.28 Long-term safety graines in 2 of 3 DBPC trials. equacy of standardizing herbs to a data are lacking. Feverfew should The largest and best DBPC trial single ingredient when other bioac- not be used during pregnancy (his- was a crossover study in which fe- tive constituent(s) are not well char- torically it has been used to induce verfew use was associated with a acterized. menstrual bleeding) or in patients 70% reduction in migraine fre- Laboratory evidence indicates with coagulation problems (fever- quency and severity (n = 270).27 Side that feverfew causes vasodilation and few can alter platelet activity30). For effects were less frequent than with reduces inflammation. Feverfew’s patients who want to try feverfew, placebo. In a trial among feverfew constituents inhibit phagocytosis, expert herbalists recommend a users, subjects randomized to re- platelet aggregation, and secretion of gradual dose increase up to 125 mg/d ceive a placebo instead of continu- inflammatory mediators (arachidon- orally of encapsulated leaves (2-3 ing feverfew suffered a significant in- ic acid and serotonin).30 Feverfew is leaves) standardized to contain 0.2% crease in the frequency and severity thought to down-regulate cerebro- parthenolide. However, according to of headaches, nausea, and vomit- vascular response to biogenic a 1992 study, none of the commer- ing (n = 20).28 Based on these tri- amines, consistent with its ability to cially available North American als, Canadian health officials re- prevent but not abort headaches, as preparations contained even half of ARCH FAM MED/ VOL 7, NOV/DEC 1998 529 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. the recommended parthenolide con- due to a decrease in low-density li- at least 1.3% allicin (equivalent to centration.32 poprotein (LDL) ± decreased tri- approximately 3 g or 1 fresh clove glyceride levels.40-43 daily. Finally, the quality of com- GARLIC Of the factors that contribute to mercial preparations varies greatly, Allium sativum the discrepancies in data regarding a problem common to many herbal garlic’s antilipidemic effects, 2 are therapies. In an analysis of suppos- Common uses: Antiatherosclero- probably most important: publica- edly standardized preparations, sis (lipid lowering, antithrom- tion bias (the preferential publica- 93% were found to be so lacking in botic, fibrinolytic, antihyperten- tion of trials with positive findings) allicin that they were declared sive) and methodologic flaws. Both fac- expensive placebos.4 Investigational uses: Anticancer tors tend to overestimate the effect Side effects: Sulfuric odor, con- of a treatment. In contrast, exclud- GINGER tact irritation (rare) ing patients likely to benefit most Zingiber officinale Garlic’s historic and world- (patients with severe hyperlipid- wide medicinal use have made it emia or high-fat diets) might under- Common uses: Antiemetic one of the most extensively stud- estimate garlic’s effect. Side effects: Heartburn, allergic re- ied medicinal herbs. Nevertheless, Blood pressure has been action (rare) the actual therapeutic benefits of monitored in most recent studies Like garlic, ginger has been a this member of the Liliaceae fam- of garlic’s antilipidemic effects, popular culinary and medicinal herb ily is unclear. Louis Pasteur first showing a decrease (systolic and/or for thousands of years. For 2500 demonstrated garlic’s antiseptic diastolic) in the treatment group of years, the Chinese have used this activity.4 Both animal studies and some, but not all, trials. Previously, plant as a flavoring agent and anti- epidemiological analyses suggest a number of placebo-controlled tri- emetic. Ancient Greeks wrapped gin- anticancer effects.33 Most current als that focused on the antihyper- ger in bread and ate it after meals as research, popularity, and contro- tensive effects of garlic demon- a digestive aid. Ginger is now culti- versy relate to garlic’s use as a strated a modest (−5% to −7%) vated in Asia, Africa, and the Carib- putative antiatherosclerotic agent effect.44 Several small, nondefini- bean and is used worldwide as a nau- (via antithrombotic, antiplatelet, tive RCTs also corroborate garlic’s sea remedy. antihypertensive, and especially antiplatelet, antithrombotic, and The characteristic odor and fla- antilipidemic effects). fibrinolytic activity found in ani- vor of ginger root come from a vola- Mainstream medical interest in mal and in vitro studies.45 tile oil (1%-3% by weight) that is garlic’s potential lipid-lowering ef- Dozens of trials suggest, but composed of shogaol and gin- fects was stimulated by 2 meta- have not adequately proven, that gerols. In laboratory animals, the analyses of RPC trials that found a garlic can decrease the risk factors gingerols have analgesic, sedative, 9% to 12% decrease in cholesterol for atherosclerosis, particularly antipyretic, antibacterial, and GI in hyperlipidemic patients after at hypercholesterolemia. Pending tract motility effects.46,47 least 1 month of treatment with 600 conclusive evidence from addi- Ginger reduces nausea, accord- to 900 mg/d of garlic tablets.34,35 tional well-designed and ade- ing to some, but not all, controlled However, definitive conclusions quately powered studies, it is rea- human trials. In an RDBPC cross- were limited by methodologic flaws sonable for patients to choose to over trial of 30 women suffering in the trials analyzed. take garlic given that it is safe and from hyperemesis gravidarum, gin- Results of subsequent better- generally inexpensive. Garlic is ger (250 mg 4 times a day) signifi- designed RPC trials have been considered safe by the FDA, based cantly decreased the severity of nau- mixed, with most (4/7) failing to find on the lack of known serious sea (P=.04).48 Two RDBPCTs report a significant change in any lipopro- adverse outcomes despite culinary a significant decrease in periopera- tein component36-39 These studies ex- and medicinal use throughout tive nausea and vomiting in gyne- plicitly sought to overcome limita- human history (including daily use cological surgery patients who were tions of previous trials, such as by by pregnant or lactating women). given 1 g of ginger before sur- providing dietary stabilization prior Malodorous breath and skin can be gery.49,50 In one, ginger was as effec- to treatment and detailing methods diminished with enteric-coated tive as metoclopramide in reducing to ensure proper control processes tablets or by consuming garlic with the number of episodes of nausea or and laboratory standards. How- protein. Allergies and contact irri- emesis. 4 4 However, in another ever, 3 of the negative trials were tation occur rarely. Patients who RDBPCT, ginger was not found to relatively small (N 28), which in decide to use garlic medicinally be effective in preventing nausea af- one case yielded a marginal power should be aware of a few caveats. ter laparoscopic gynecologic sur- (80%) to detect the expected 9% re- The main purported active ingredi- gery.51 Regarding motion sickness, duction in cholesterol.38 Three RPC ent, allicin, is degraded by crush- ginger was more effective than di- trials support the positive findings ing, heat, and acid; thus, efficacy is menhydrinate in one controlled of the meta-analyses, finding a 6.1% optimized by consuming raw trial,52 but was not effective in an- to 11.5% cholesterol reduction in the cloves or enteric-coated tablets. other.53 Such inconsistency of re- garlic-treated patients. Similar to pre- The usual dose is 300 mg, taken 2 sults is found in studies of conven- vious studies, the lipid reduction was to 3 times per day, standardized to tional antiemetics as well, due in part ARCH FAM MED/ VOL 7, NOV/DEC 1998 530 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. to the difficulty in measuring symp- In 1997, the first US-based trial fects with tacrine. While G biloba toms such as nausea. In addition, the corroborated ginkgo’s efficacy in the leaves may cause mild GI tract irri- effect of antiemetics is often subtle treatment of dementia. In this year- tation, no serious adverse effects and difficult to discern unless tested long, RDBPC, multicenter study, have been noted in human or ani- in a homogeneous population with EGb 761 was found to stabilize and mal trials, including no mutagenic- a high prevalence of nausea. in some cases improve cognition and ity or teratogenicity.64 In contrast, G It is reasonable for patients to social functioning in patients with biloba seeds can cause fatal neuro- try ginger to treat nausea, not only mild to moderate dementia (Alzhei- logic and allergic reactions and are because data supports its efficacy, mer disease or multi-infarct demen- not used medicinally. 64 Patients but also because it is inexpensive, tia).56 In another trial, healthy geri- should use the extract studied in all readily available, and safe. Like gar- atric patients demonstrated better reported clinical trials, Egb 761. The lic, ginger is not known to cause any cognitive function after taking dose is 40 mg 3 times per day or 80 serious side effects, despite world- EGb 761.57 mg twice per day of an extract stan- wide culinary and medicinal use of EGb 761 improves perfusion dardized to 24% flavanoid glyco- ginger. Only 1 of the above con- peripherally as well as centrally. side and 6% terpenoids. Absorp- trolled human trials noted any side More than 15 European studies sug- tion is unaffected by food intake. The effect, which, ironically, was GI tract gest a reduction of claudication duration of benefit after discontinu- upset. It is on the FDA’s GRAS list. symptoms in patients treated with ation is unknown.65 The usual adult dose is 250 milli- EGb 761, including a 50% increase grams (1⁄4 tsp) to 1 g of powdered in pain-free walking distance.58 Si- GINSENG root several times per day. multaneous benefits on central and Panax ginseng peripheral perfusion are demon- Panax quinquefolius (American GINKGO strated in a randomized, placebo- ginseng, an endangered species) Ginkgo biloba controlled trial among 44 Hima- (Eleutherococcus senticosus, layan climbers.59 The 22 subjects so-called Siberian ginseng, is not Common uses: Intracerebral and pe- treated with 160 mg/d of EGb 761 in the Panax [true ginseng] genus) ripheral vascular insufficiency (de- developed significantly fewer cere- mentia and claudication) bral (0% vs 41.9%, P .002) and res- Common name: Korean ginseng Investigational uses: Mountain sick- piratory symptoms (13.6% vs 81.8%, Common uses: “Tonic,” perfor- ness P .001) of mountain sickness than mance enhancer, “adaptogen,” an- Side effects: Gastrointestinal tract climbers taking the placebo. EGb ticancer, aphrodisiac disturbance, headache, contact 761 also decreased vasomotor dis- Investigational uses: All common dermatitis (each is rare/mild) orders of the extremities, mea- uses are as of yet unproven but are One of the oldest surviving tree sured by plethysmography and under investigation species, G biloba has grown in China symptom scores. Side effects: Tachycardia, hyper- for more than 200 million years. For The mechanisms of ginkgo’s tension thousands of years, traditional Chi- therapeutic effects are not fully un- Ginseng is one of the most nese medicine has used ginkgo to derstood. They are attributed in part popular and expensive herbs in the treat brain disorders. In the past 20 to synergistic effects of its constitu- world. As in ancient China, gin- years, ginkgo has gained world- ents, particularly the flavonoids, ter- seng is still widely believed to be a wide popularity for similar pur- penoids, and organic acids. These act panacea; hence, its genus name poses, supported by evidence of its to varying degrees as scavengers of Panax. The common name ginseng ability to promote perfusion and in- free-radicals, chemicals implicated (“man-root”) stems from a belief that hibit oxidative damage. By 1988, in the pathophysiology of Alzhei- because this root is humanoid in ap- German physicians prescribed a mer disease.60,61 They also inhibit pearance, it can benefit all aspects standardized extract of ginkgo (Egb platelet activation factor and thereby of the human body. At least 6 mil- 761, Willmar Schwabe GmbH & Co, reduce thrombosis, dilate arteries lion Americans66 use the root of this Karlsruhe, Germany) more than any and capillaries, and block the re- slow-growing perennial. It is con- other medication. 4 Sales in the lease of chemotactic and inflamma- sidered a tonic or adaptogen that en- United States soared to $240 mil- tory mediators from phagocytes. hances physical performance (in- lion in 1997.1 In Germany, where Ginkgo’s antidementia effects cluding sexual), promotes vitality, most of the research has been con- are similar to that of the prescrip- and increases resistence to stress and ducted, the federal health authori- tion drugs donepezil and ta- aging. While in vitro and animal ties have concluded that treatment crine.62,63 While statistically signifi- studies suggest that it has benefi- with Egb 761 is safe and effective for cant, such modest effects are of cial effects on immune and endo- peripheral and cerebral circulatory uncertain clinical benefit. How- crine functions, evidence of its ef- disturbances, including claudica- ever, ginkgo may have other advan- fects on humans is limited and tion and memory impairment.5 Nu- tages, such as improvement of pe- contradictory. merous European clinical trials ripheral vascular circulation and One reason for lack of defini- report EGb 761’s efficacy in dimin- tolerance of altitude. In addition, tive data about ginseng’s health ef- ishing symptoms of cerebrovascu- ginkgo’s side effects are similar to fects is the inherent difficulty of lar insufficiency.54,55 placebo vs potential hepatoxic ef- quantifying intangible benefits such ARCH FAM MED/ VOL 7, NOV/DEC 1998 531 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. as “vitality” and “quality of life.” should be used. Patients should be tive than placebo and as effective as Nevertheless, a 3-month RCT warned that E senticosis, marketed as metronidazole (10 mg/kg 6 days) showed a significant increase in sub- “Siberian ginseng” for commercial in treating children with giardia.77 jective “quality-of-life” scores among reasons, contains no true ginseng. Berberine is thought to act in- ginseng users (n = 625).67 Some small Despite extensive use, adverse traluminally, as it is poorly ab- controlled trials report increased en- reactions to ginseng are rare and gin- sorbed and there is no clinical evi- durance, whereas others do not.68 In seng is on the FDA’s GRAS list. How- dence for systemic anti-infective an RDBPCT, college-aged volun- ever, at least 1 fatality has been at- activity.78 In vitro studies reveal pos- teers who took 100 mg of ginseng tributed to contamination of a sible mechanisms of berberine’s an- twice daily for 12 weeks experi- ginseng product with the potent and tidiarrheal effects. Berberine exerts enced a statistical improvement in unpredictable herbal stimulant ephe- antimicrobial activity against nu- the speed at which they were able to dra. While clear conclusions about merous bacteria, fungi, and proto- perform mathematical calcula- the safety of ginseng cannot be zoa.79 In addition, it blocks adhe- tions, but did not experience im- drawn from the uncontrolled 1979 sion of bacteria to epithelial cells,80 provement in motor function or case series that coined the term “gin- inhibits the intestinal secretory re- other cognitive functions; no ad- seng abuse syndrome,”74 ginseng can sponse of cholera and E coli toxins, verse effects were seen in this study.69 act as a mild stimulant and should and normalizes mucosal histology To our knowledge, no studies com- probably be avoided in association following cholera toxin damage.81 pare ginseng’s effect with that of in- with other stimulants or in patients Despite the antidiarrheal effi- expensive, widely available cogni- with cardiovascular disease. Rare en- cacy of the chemical berberine, we do tive stimulants such as caffeine, nor docrinologic effects include mastal- not recommend the use of the herb has an RCT confirmed aphrodisiac gia and postmenopausal bleeding, goldenseal for this purpose, both be- effects in humans. However, gin- both of which cease with discon- cause of this plant’s endangered sta- seng was associated with a signifi- tinuation of ginseng.75 tus and due to the possible toxicity cant increase in serum hormones of its other components. For ex- (testosterone, dihydroxytestoster- GOLDENSEAL ample, traditional herbal literature one, follitropin, and lutropin) and Hydrastis canadensis warns that large (unspecified) in sperm numbers and motility in 46 amounts of goldenseal (particularly men with oligospermia.70 A case- Common uses: Antidiarrheal and the alkaloid hydrastine) can cause control study suggests an associa- antiseptic (berberine compo- mucosal irritation, GI tract upset, tion (but not necessarily a causal re- nent) uterine contractions, neonatal jaun- lationship) between use of ginseng Investigational uses: Antineoplas- dice, hypertension, seizures, inotro- and lower cancer rates (n = 1987 tic and anti–human immunode- pic cardiac effects, and respiratory pairs matched for age, religion, mari- ficiency virus (berberine compo- failure.82 It may oppose heparin or tal status, education, sex, occupa- nent) coumadin anticoagulation.83 Gold- tion, and smoking status).71 Side effects (large doses): enseal should not be used by preg- In Asian cultures, ginseng is Mucocutaneous irritation, GI tract nant or lactating women, neonates, commonly consumed by pregnant upset, cardiac and uterine contrac- or patients with cardiovascular dis- women and is given to newborns in tility, vasoconstriction, central ner- ease, epilepsy, or coagulation prob- hopes of bolstering energy. A case- vous system stimulation, neonatal lems. No significant side effects have control study of 88 pairs of women jaundice (displaces bilirubin). been noted in clinical or animal stud- (matched only for age and parity) Cherokee Indians introduced ies of purified berberine. found a significantly lower rate of this member of the buttercup fam- pregnancy-induced hypertension, ily to European settlers. It is used MILK THISTLE but a 3-fold higher incidence of ges- topically for eye or skin irritation, Silybum marianum tational diabetes among ginseng con- and orally for infections. A recent sumers.72 We do not recommend surge in goldenseal’s popularity Common names: “Holy Thistle,” ginseng use for pregnant or lactat- stems from the erroneous but wide- “St Mary’s Thistle” ing women or for children until spread belief that it can mask illicit Common uses: Hepatoprotectant, safety and efficacy are proven in ran- drugs in urine toxicology screens. It antioxidant domized controlled trials. is a also a popular but unproven cold Investigational uses: Antihypergly- Patients who take ginseng risk remedy. However, one of its main cemic paying a high price without proven bioactive constituents, berberine, is Side effects: None known benefit. Commercial preparations of an effective antidiarrheal agent. For more than 2000 years, the ginseng cost up to $20 an ounce and In one RCT, a single 400-mg seeds of this prickly leafed, purple- vary tremendously in quality. In one dose of berberine sulfate signifi- flowered plant have been used to analysis of 54 available ginseng prod- cantly reduced stool volumes and treat liver disorders. In addition, all ucts, 85% were determined “worth- duration of diarrhea among pa- parts of this Kashmir native have less,” containing little or no gin- tients with enterotoxigenic Esche- been consumed historically as veg- seng. 73 To optimize quality and richia coli and Vibrio cholerae.76 In etables without report of toxic ef- chance of efficacy, only preparations another controlled trial, berberine (5 fects. Silymarin protects against a va- standardized to ginsenoside content mg/kg 6 days) was more effec- riety of hepatotoxic agents and ARCH FAM MED/ VOL 7, NOV/DEC 1998 532 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. processes in animal experiments. mon dose is a 140-mg capsule, stan- and efficacy compared with other Evidence of its effects in humans is dardized to 70% silymarin, 2 to 3 antidepressants.95 In response, the provocative but preliminary. times a day. A high first-pass effect Office of Complementary and The best human data deal with concentrates silymarin in the liver. Alternative Medicine of the Nat- silymarin’s effect on cirrhosis, with Silymarin is poorly absorbed, so con- ional Institutes of Health and the conflicting results from 2 RDBPC tri- centrated products (ie, extracts) are National Institute of Mental Health als.84,85 In the first, the 4-year mor- optimal. recently allocated $4.3 million for tality rate decreased by 30% in pa- the first clinical trial in the United tients treated for 2 years with 140 mg ST JOHN’S WORT States to address these issues. The of silymarin 3 times a day. Effects Hypericum perforatum 3-year multicenter trial beginning were greatest in alcohol-related cir- in 1998 will compare SJW with rhosis. In contrast, a recent multi- Common use: Antidepressant both placebo and fluoxetine hydro- center RDBPC trial in 200 patients Investigational uses: Anticancer, chloride. with alcoholic cirrhosis found no dif- antiviral (including human im- The mechanism of SJW’s anti- ferences in progression of disease or munodeficiency virus) depressant effects is only partially mortality after 2 years of treatment Side effects: Photosensitivity (rare, known. Some in vitro studies dem- with 150 mg of silymarin 3 times per with large doses) onstrated monoamine oxidase inhi- day.85 Interestingly, glycemic con- This 5-petalled yellow flower bition, but only at concentrations un- trol was significantly improved (lower grows wild in much of the world. attainable in vivo.96 Furthermore, SJW fasting blood glucose, glycosylated While reduced to 1% of its original is used extensively (66 million doses hemoglobins, and insulin require- population in the Pacific United in 1994 in Germany) without restric- ments) in a randomized, placebo- States by ranchers who consider it tion of tyramine-containing foods and controlled trial of 60 patients taking a bothersome weed, in Europe it is without reported side effects related silymarin for alcoholic cirrhosis.86 In highly valued as an antidepressant. to monoamine oxidase inhibition. Hy- another RCT of patients with chronic St John’s wort is by far the most com- pericin is the putative active ingredi- active hepatitis, 1 week of therapy mon antidepressant used in Ger- ent. It has a high affinity for - with oral silymarin (240 mg/d) re- many, where physicians prescribe it aminobutyric acid, the stimulation of sulted in decreased serum transami- 4 times more often as fluoxetine hy- which is known to have antidepres- nases and bilirubin values.87 Euro- drochloride.94 Sales in the United sant effects.87 Other studies indicate pean physicians routinely treat States increased 20-fold between that hypericin activates dopamine re- hepatotoxic mushroom poisoning 1995 and 1997, from $10 million to ceptors but inhibits serotonin recep- with intravenous silymarin (20-50 $200 million annually.1 St John’s tor expression.97 Altered receptor mg/kg per day), decreasing mortal- wort has been used for thousands of regulation is consistent with the sev- ity rates by more than half in several years for a myriad of conditions. It eral-week lag between drug initia- case series.88 is named after St John the Baptist be- tion and clinical efficacy, similar to In animal studies, silymarin cause it blooms around his feast day other antidepressants. protects liver cells against a variety (June 24) and exudes a red color In addition to SJW’s antidepres- of hepatotoxins, including drugs symbolic of his blood. Its scientific sant effects, evidence beyond the (acetaminophen, amitriptyline, and name derives from the Greek hyper scope of this article supports its his- erythromycin),89,90 toxins (a-aman- and eikon, “to overcome an appari- torical anti-inflammatory, anti- tin from deathcap mushrooms, al- tion,” relating to ancient belief in its infective, and vulnerary external appli- cohol, and carbon tetrachloride),91 ability to ward off evil spirits. The cations.96 Antineoplastic and antiviral hemosiderin,92 viruses, and radia- vulnerary and neurologic effects of applications are experimental. tion.88 Silymarin scavenges free radi- this herb were described by Galen, Existing data on the therapeu- cals, blocks toxin entry into cells by were repeated throughout the tic effects of SJW are provocative. competing for receptor sites, inhib- Middle Ages and by early Ameri- However, well-designed clinical tri- its inflammation, and stimulates liver can herbalists, and were recently als are needed to determine long- regeneration. As a result, it lowers supported by many clinical trials. term safety and therapeutic guide- serum transaminase levels, main- A 1996 meta-analysis of 23 lines for use of SJW for different tains coagulation factor produc- randomized, controlled clinical tri- depressive disorders. Prior to the tion, and limits necrosis.88-91 It also als of SJW concluded that it is sig- availability of such information, pa- prevents renal toxic reactions from nificantly more effective than pla- tients who choose to use SJW should cisplatin.93 cebo in treating mild to moderate use the regimen shown to be effec- Milk thistle warrants further in- depression. 95 The 8 studies that tive in the above clinical trials: 300 vestigation as a hepatoprotective and compared H perforatum with low- mg 3 times a day of an extract stan- regenerative agent. No adverse ef- dose tricyclics suggested equivalent dardized to 0.3% hypericin. St John’s fects have been reported. Diabetic efficacy, with significantly fewer wort is generally well tolerated, but patients taking silymarin should side effects. The authors noted the can cause photosensitivity, espe- carefully monitor their blood glu- need for further studies to deter- cially in fair-skinned persons tak- cose and may require reduction in mine optimal dosing, long-term ing large doses. It should not be used standard antihyperglycemic agents side effects, efficacy in mainte- during pregnancy (uterotonic) or to avoid hypoglycemia.86 The com- nance therapy, and relative safety with other psychoactive agents. ARCH FAM MED/ VOL 7, NOV/DEC 1998 533 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. SAW PALMETTO inflammatory activity (inhibition of mutagenic activity in vitro. Al- Serenoa repens cyclooxygenase and 5-lipoxygenase though these effects have not been pathways) are thought to be impor- reproduced in vivo even at high Common uses: Benign prostatic hy- tant in decreasing the edematous doses (1350 mg/kg), valerian prob- pertrophy (BPH), prostatitis component of BPH and prostatitis.4 ably should not be used by preg- Side effects: Gastrointestinal tract These studies support the use nant women. Valerian should not be upset, headache (each is rare and of SPE for BPH and show that its ef- taken with other sedatives or be- mild) ficacy is comparable to that of the fore driving or in other situations Extracts from the fruit of this 5 -reductase inhibitor finasteride when alertness is required. short, scrubby palm have been used with significantly fewer side ef- historically to treat urogential prob- fects. However, 1 antagonists are CONCLUSIONS lems. Many modern clinical trials more effective than both SPE106 and corroborate the ability of saw pal- finasteride.107 The usual dose of SPE Physicians need to know about me- metto extract (SPE) to improve the is 160 mg twice daily of an extract dicinal herbs because many pa- signs and symptoms of BPH, for standardized to contain 85% to 95% tients use them and are often guided which it is a first-line treatment in fatty acids and sterols. Side effects by misconceptions or inaccurate in- much of Europe.98 are rare ( 3%) and include mild formation. Whether or not physi- Seven of the 8 DBPC trials that headaches and GI tract upset.4 cians intend to prescribe herbal have evaluated SPE’s efficacy in treat- therapies, it is important that they ing BPH demonstrate significant ob- VALERIAN understand the potential associ- jective and subjective improve- Valeriana officinalis ated health consequences so that ment in BPH symptoms in patients they can help patients make in- taking 320 mg of SPE for 1 to 3 Common uses: Sleep-aid, anxio- formed decisions about their use. months.98,99 However, only 2 of these lytic, antispasmodic This review aimed to familiarize cli- trials are randomized, and their re- Side effects: Headaches (rare), heart nicians with available evidence on sults conflict. In the shorter ran- palpitations (rare), insomnia 12 commonly used herbs, as well as domized trial, SPE is no better than (rare) to indicate areas in need of further placebo in treating BPH (n = 70 The malodorous root of valer- research. Popular interest in herbal treated for 1 month).100 In the larger, ian, a pink-flowered perennial that therapies is stimulating research that randomized, multicenter trial grows wild in temperate areas of the will help clarify issues such as the (n = 176 treated for 2 months), and Americas and Eurasia, has been a indications, effective doses, and in the other 6 DBPC trials, SPE sig- popular calming and sleep-pro- safety of common medicinal herbs. nificantly increases urinary flow, moting agent for centuries. Ger- For patients who choose to use decreases nocturia, and decreases man health officials have approved herbal therapies, several guidelines postvoid residual.101 Saw palmetto ex- valerian for use as a mild sedative can help them to do so most safely tract worked as well as finasteride in and sleep aid, based on several Eu- and effectively (Table 5). Patients a randomized, 6-month study of 1098 ropean clinical trials that demon- need to understand that medicinal men, with similar significant im- strate these effects. herbs are drugs, and as such not only provements in the International Pros- In 2 randomized, blind, and pla- have potential benefits, but also the tate Symptom Score, quality of life, cebo-controlled crossover trials potential to interact with other drugs and peak urinary flow rate.102 Un- (n = 27 and n = 128), valerian (400- and to cause toxic reactions. Pa- like finasteride, SPE did not cause im- 450 mg before bedtime) resulted in tients should be informed about im- potence, decrease libido, or alter pros- significantly improved sleep quality portant similarities and differences tate-specific antigen levels. and decreased sleep latency, with no between FDA-approved drugs and A mechanism of SPE’s effect on residual sedation in the morn- herbal remedies, particularly that the BPH is demonstrated in an RDBPCT ing.108,109 In vitro, constituents of va- herbs are not required to be proven in which use of SPE for 3 months re- lerian mediate the release of - either safe or effective prior to mar- sults in a significant decrease in pros- aminobutyric acid110 and bind the keting (Table 3). Given the vari- tatic nuclear androgen and estrogen same receptors as benzodiazepines, able purity, potency, and quality of receptors.103 Prostate size decreased but with less affinity and milder clini- herbal products, they must be se- on serial ultrasounds in an open study cal effects.111 Habituation or addic- lected with care. In general, the best of 505 men with BPH.104 tion have not been reported. products are from Europe, where Like finasteride, SPE inhibits the In the United States, valerian is quality control regulations exist. In enzyme 5 -reductase (in vitro), approved for use in flavoring foods the United States, large stores with blocking the conversion of testoster- and beverages such as root beer. No national reputations to protect have one to dihydroxytestosterone, a ma- serious side effects have been re- particular incentive to ensure qual- jor growth stimulator of the prostate ported. However, a small percent- ity. Finally, patients should prefer- gland.105 Saw palmetto extract also age of consumers experience para- ably use standardized products and blocks the uptake of testosterone and doxical stimulation, including consult reputable sources for infor- dihydroxytestosterone by the pros- restlessness and palpitations, par- mation about appropriate indica- tate without affecting serum testos- ticularly with long-term use.112 Some tions, contraindications, and dos- terone levels.105 In addition, its anti- components display cytotoxic and ing (see Tables 4 through 6). ARCH FAM MED/ VOL 7, NOV/DEC 1998 534 Downloaded from www.archfammed.com on August 19, 2007 ©1998 American Medical Association. All rights reserved. Accepted for publication May 1, 1998. and clinical uses. HerbalGram.1994;30:33-47. a meta-analysis. J R Coll Physicians London. 17. Schoneberger D. Influence of the immunostimu- 1994;28:2-8. Thanks to the following for their lating effects of the pressed juice of Echinaceae 36. 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