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CLINICAL TRIALS OF HERBS
COMPLEMENTARY AND ALTERNATIVE THERAPIES IN PRIMARY CARE
00954543 /97 $0.00
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CLINICAL TRIALS OF HERBS Adriane Fugh-Berman, MD
The use of plants as medicine predates even the existence of humans: great apes consumed specific medicinal plants when they are In Eisenberg's 1990 study, herbal medicine was found to be used by 3% of the U.S. population in 1990.19This widely invoked survey almost certainly underestimated the actual prevalence of use, as it was limited to Englishspeaking participants with telephones. There is certainly higher utilization of herbs by immigrants from Asian, African, Caribbean, and Central and South American cultures. About one quarter of our pharmaceuticals originally were derived from plantsF4and only a tiny fraction of plants have been screened for medicinal compounds. Plant-derived products used regularly by primary care physicians include oral contraceptives (the progestin component is derived from Diascorea villosa, the Mexican yam); digoxin from foxglove (Digitalis lanata); cephalosporins, derived from a marine fungus (Cepkalosporium acremonium); cromolyn sodium, a khellin derivative from the Ayurvedic herb A m m i uisnaga; and the statins, which are derived from the fungus Aspergillus terreus. Recently there has been renewed interest from both large and small pharmaceutical companies in searching for novel molecules from plants. In 1991Merck contracted with Costa Rica's Instituto Nacional de Biodiversidad for a supply of biological samples. Since then, Bristol MeyersSquibb, Smith-Kline, Glaxo, and Pfizer have negotiated arrangements in various countries, including China, Surinam, Peru, Argentina, Mexico, Chile, Nigeria, and Cameroon.' While the larger companies usually depend on high-throughput random screening programs, a few companies rely on an ethnobotanical approach. Shaman Pharmaceuticals, a small company founded in 1990, typifies this more directed, low-tech approach, in which close relationships are established with local herbalists and only plant species historically used medicinally are tested. From the National Women's Health Network, Washington, DC PRIMARY CARE
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VOLUME 24 * NUMBER 4 DECEMBER 1997
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Although the extraction of discrete active compounds from plants is a laudable goal, it is often an elusive one. Many herbs lose their activity when purified. This may be because the wrong compound was identified (each species contains hundreds or even thousands of ingredients), but it is more likely that an unknown number of compounds may be acting synergistically. There is growing openness within both the research and regulatory communities to clinical testing of whole herbs or even herb mixtures and a growing number of clinical trials of herbs. A sampling of clinical trials of interest to primary care practitioners follows.
PAIN Mastalgia
Evening primrose oil, high in the essential fatty acids linoleic and gamma-linolenic acid, may be effective for mastalgia. A Welsh series of 414 patients with either cyclic or noncyclic mastalgiaZ5found that evening primrose oil, in a dose of 3g daily (containing 240 mg of gamma-linolenic acid), equalled bromocriptine in effectiveness. Neither treatment was as effective as danazol. The evening primrose oil group experienced fewer side effects than did other groups; 30% of the danazol group and 35% of the bromocriptine group reported significant adverse events, compared with 4% of those taking evening primrose oil.
Migraines
Several trials indicate that feverfew (Tanaceturn partheniurn) may be effective in migraine prophylaxis. A small study tested feverfew withdrawal in regular users. Seventeen patients who ate fever few leaves daily to prevent migraine were randomized to either dried feverfew leaves or placebo.38Those who received placebo had a significant increase in the frequency and severity of headache, nausea, and vomiting; those in the feverfew group showed no change in the incidence of their migraines. In a larger, cross-over study:2 72 migraine patients were given either one capsule of dried feverfew or placebo daily for 4 months, then received the other therapy for 4 more months. Patients receiving feverfew had fewer migraines, less severe attacks, and less emesis, although the duration of migraines that did occur remained the same. Feverfew can cause aphthous ulcers, oral edema, or loss of taste.4 Taking the herb in capsules reduces but does not eliminate these effects.
Arthritis
One double blind controlled study of 21 patients57found that capsaicin cream applied topically reduced tenderness and pain of osteoar-
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thritis patients by 40% but had no effect on patients with rheumatoid arthritis. Evening primrose oil may help rheumatoid arthritis patients to reduce their use of painkillers; one study6 found that 60% of rheumatoid arthritis patients were able to reduce or stop their painkillers. A study of 37 patients with rheumatoid arthritis" compared gammalinoleic acid (a fatty acid found in evening primrose, black currant seed, and borage seed oil) with cottonseed oil and found that in patients who completed 24 weeks of treatment, GLA improved pain, ability to perform tasks, and global assessment by physician. Another study that used an olive oil placebo found evening primrose oil equivalent to the placebo and neither very effe~tive.'~
Fibromyalgia
Of 45 patients treated with topical capsaicin or placebo for fibromyalgia,56those receiving capsaicin reported less tenderness at their trigger points. A significant increase in grip strength also was noted.
Vulvar Vestibulitis
Topical capsaicin (.025%)also has been tested in a vehicle-controlled trial of 14 subjects with vulvar vestibulitiss7;the nine subjects who had completed the study at the time of its presentation experienced a 77% reduction of pain.
Neuropathy
Topical capsaicin may be useful for diabetic neuropathy; one study of 252 patients with diabetic neuropathy15 found that 69.5% of patients treated with the capsaicin cream reported pain improvement to their physicians compared with 53.4% of those on placebo. Intensity of pain also was lessened in the capsaicin group. A controlled trial of 32 elderly patients with postherpetic neuralgia7 found that almost 80% of the capsaicin-treated patients experienced some relief from their pain after 6 weeks. A small, controlled study of 23 patientss3found that capsaicin cream is helpful in postmastectomy pain syndrome. Five of 13patients receiving the capsaicin cream reported good to excellent results compared with one out of ten patients in the placebo group. Capsaicin cream can cause a brief local burning or stinging sensation: this effect usually disappears after a few doses. Patients should be counseled to wash their hands after applying the cream and to avoid touching their eyes.
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CARDIOVASCULAR DISEASE
Hypercholesterolemia Garlic (Allium safivum) may have beneficial cardiovascular effects. Alliums (which also include onions) lower blood lipid levels, and may have anticoagulant and antioxidant effects as well. A placebo-controlled trial'" with 88 participants found that garlic decreased total cholesterol in both healthy volunteers and patients with coronary heart disease. After taking garlic for 6 to 8 months, total cholesterol fell 20% in the healthy volunteers and 18% in those diagnosed with cardiovascular disease; triglycerides and low-density lipoprotein also fell while high-density lipoprotein rose. Another double blind study of 40 patients with hypercholesterolemias' found that after 4 months, the group taking garlic had a 21% reduction in total cholesterol, compared with a 3% reduction in the control group. Triglycerides also decreased 24% in the garlic-treated group, compared with a 5% reduction in the control group. A more recent doubleblind, placebo-controlled found a more modest effect: garlic tablets reduced LDL cholesterol 11%and total cholesterol about 6%; cholesterol levels went down 1%in the placebo group. A meta-analysiss2of five trials that examined the effect of garlic on cholesterol found that the equivalent of one half to one clove of garlic lowered cholesterol about 9% in the groups of patients studied. The rise in blood lipid levels that occurs within a few hours of consuming fat is reduced by garlic or onion." Two studies found that alliums inhibit platelet aggregation in human b l o ~ d ~ another , ~ * ; laboratory study found allicin, one of the components in garlic, had the same effect. Garlic also appears to have some antioxidant qualities.26 Amla, an ayurvedic herb, is used to treat hypercholesterolemia. In an 50g of raw uncontrolled study with a number of methodologic Amla (Emblica oficinalis), also called Indian gooseberry, was found to lower cholesterol in 35 men (some of whom were hypercholesterolemic and some of whom had normal cholesterol levels). After a month, there was significant reduction in total cholesterol as well as LDL cholesterol.
Hypertension Garlic may have an effect on mild hypertension, but studies have been mixed. In one double blind trial of 47 patients with mild hypertension,2diastolic blood pressure was reduced from 102 to 89 mm Hg after 12 weeks in the garlic group; no significant changes occurred in the placebo group. Decreased cholesterol and triglycerides also were noted in the garlic-treated group. An analysis of eight trials with a total of 415 subjects found the general quality of trials poor; only three of the trials were limited to hyper-
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tensive patients. Four of the seven placebo-controlledtrials found an effect on diastolic blood pressure.74
Intermittent Claudication
Of 15 controlled trials on intermittent claudication, only two were deemed to be of acceptable Both of these trials showed a benefit, as did all of the poorer quality trials.
ENDOCRINE EFFECTS Hyperprolactinemia
Chaste-tree berry (Vitex agnus castus) may have profound hormonal effects. In a double blind placebo-controlled trial of 52 women with luteal phase defect due to latent hyperprolactinemia, one 20-mg capsule of Vitex daily reduced prolactin levels, normalized the length of luteal phases, and normalized luteal phase progesterone levels.60A case of ovarian hyperstimulation apparently due to ingestion of Vitex has been reported (REF TK).
Diabetes
A double blind, placebo-controlled study of 36 newly diagnosed NIDDM patients76compared two doses of standardized ginseng with placebo and found that ginseng reduced fasting blood glucose and (in the 200 mg but not 100 mg group) reduced HbAlc. Mood, psychomotor performance, and physical activity also improved in patients receiving ginseng.
PSYCHIATRIC CONDITIONS Depression
The herb St. John’s wort (Hypericum perforaturn) is an effective treatment for mild to moderate depression. A meta-analysis of 23 randomized controlled trials with a total of 1757 outpatients found that St. John’s wort was almost three times more effective than placebo and comparable when tested against standard antidepressant^.^^ St. John’s wort also may cause photosensitivity. St. John’s wort has mild MA0 inhibition effects, but its antidepressant effects are not exclusively due to this mechanism. Still, patients using St. John’s wort probably should observe MA01 precautions.
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Dementidcerebral Insufficiency
Ginkgo bilboa is very promising for the treatment of dementia. A placebo-controlled double blind study of a standardized ginkgo extract (EGb761)in 216 patients with Alzheimer’s or multi-infarct dernentia4Oadministered 240 mg of the extract daily for 24 weeks after a 4-week placebo run-in. Patients who received ginkgo did better on tests of attention, memory, and psychopathologic assessment. Another placebo-controlled trial of 40 Alzheimer’s patients32given 80 mg of ginkgo extract three times daily found that patients given ginkgo improved in tests on memory, attention, psychopathologic disorder, and functional dynamics over those given placebo. A third trial of 31 patients67with mild to moderate memory impairment found a benefit of a standardized extract on cognitive function at 24 weeks. The dose in this trial was 40 mg three times daily. About 40 studies have been done on the use of ginkgo for the illdefined diagnosis of cerebral insufficiency; a m e t a - a n a l y ~ i sfound ~ ~ , ~ that ~ in seven of the eight best placebo-controlled trials, ginkgo was more effective than placebo for a variety of patient complaints, including memory and concentration problems, headaches, depression, and dizziness. UROLOGIC CONDITIONS Sexual Dysfunction
Ginkgo may help sexual dysfunction. An open trial of ginkgo was conducted in 37 male and female patients with serotonin reuptake inhibitor associated sexual problems, including erectile difficulty, delayed ejaculation, anorgasmia, and decreased libido.’*All patients had previously attempted to address sexual difficulties through the use of cyproheptadine, yohimbine, amantadine, buspirone, or dosage adjustment. After 4 weeks of taking 60 mg of ginkgo biloba extract three or four times a day, 86% reported significant improvement. In another uncontrolled trial of 60 men with unsuccessfully treated impotence secondary to arterial flow problems,73ginkgo extract improved blood flow within 8 weeks. After 6 months half of the men had regained potency. Benign Prostatic Hypertrophy
A double blind studyI6of saw palmetto (Serenoa repens) extract in 110 patients in France found that flow rate improved by 50%, and the number of nighttime bathroom trips also decreased significantly. In an uncontrolled trial of saw palmetto in 305 men with mild to moderate symptoms of BPH,12 improvements in International Prostate Symptom Scores, quality of life scores, urinary flow rates, and residual urinary volume were seen after 45 days of treatment. PSA levels were not
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affected. Prostatic volume (measured by transrectal echography) decreased by a mean of 9% at 45 days. At 3 months, 88% of patients considered the therapy effective; and equal percentage of physicians agreed. The herb was administered in a dose of 160 mg twice daily for 3 months. Five percent of patients experienced side effects; more than half of these were gastrointestinal. Other effects reported included dizziness, dry mouth, tachycardia, angina, and testicular pain.
IMMUNE EFFECTShNFECTIOUSDISEASE
Echinacea (Echinacea augustifoh or E. purpurea) appears to enhance both cellular and humoral immunity. It is popular in Europe, especially in Germany, where more than 300 preparations of Echinacea are available. A review of 26 controlled clinical trials58(18 randomized, 11 double blind) of pure or mixed Echinacea preparations found positive results claimed for 30 of the 34 treated groups. Nineteen trials studied whether the preparation prevented or cured infections (most commonly upper respiratory infections), four trials the reduction of side effects of cancer therapies, and three looked at the effect of echinacea on immune measures. Authors of the review, however, note that although the evidence points to a positive effect of Echinacea on the immune system, most of the trials were of poor methodologic quality and do not provide enough information to make clear recommendations on how much of which preparation to use and under what circumstances it should be used.
Bronchiolitis
An herbal mixture was effective in the treatment of acute bronchiolitis in children with respiratory syncytial virus. In a single-blind 96 children were randomized to antibiotics, herbs, or a combination of both; those receiving the herbs, with or without antibiotics, had earlier resolution of fever, cough, and wheezing.
Malaria
Long an herbal remedy for parasites, including those that cause malaria, wormwood (Arternisia annua), also called quinghao, is staging a comeback, perhaps owing to the emergence of drug-resistant types of malaria. Several studies show its e f f e c t i v e n e ~ s .One ~~,~ study ~ of artemisinin in 638 malaria patients in Vietnam7*showed a dramatic success rate; parasites in the blood decreased more than 98% within 24 hours and were cleared by 48 hours. Recurrence of symptoms was high with short-term artemisinin, but the herbal extract works faster than known drugs. The ideal treatment for malaria probably is a combination of wormwood and a pharmaceutical agent. No acute toxicity was apparent.
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UTI
Cranberry juice acidifies the urine but also decreases bacterial adhere n ~ eIn. ~ one ~ study? 153elderly women drank 300 mL a day of cranberry juice or a placebo juice matched for taste, appearance, and vitamin C content. Those who drank the placebo drink had more than twice the incidence of bacteriuria and pyuria as those who drank the cranberry juice. The effect of a number of fruit juices on the adhesive ability of E. coli has been tested; only Vaccinia species (which includes both cranberry and blueberry) were benefi~ial.~~ HEPATIC DISEASE
Milk thistle, (Silybum marianum) appears to protect the liver. Intravenous preparations of milk thistle are used in Germany to treat Amanita mushroom ("Deadly Angel") poisoning. Although clinical studies on this herb are problematic, results are intriguing enough that more research should be done on milk thistle, especially given the dearth of effective treatments for liver disease. In a double blind study of patients admitted to a Finnish military hospital for hepatitis,68the 47 patients who received silymarin had a greater decrease in liver enzymes than 50 controls. Some patients had preand post- liver biopsies: treated patients showed more histologic improvement than did controls. No distinction was made among various causes of increased liver enzymes. A better study compared silymarin to placebo in 170 patients with cirrhosis.22Patients in the treated group were less likely to die; the treatment appeared to be more effective in those with alcohol-induced cirrhosis or less severe forms of cirrhosis. DERMATOLOGIC CONDITIONS Psoriasis
A double blind, placebo-controlled trial of topical aloe Vera extract in 60 patients with mild to moderate chronic psoriasis ~ u l g a r i found s ~ ~ that after 4 weeks, 83.3% of aloe-treated patients were cured, versus 6.6% of the placebo treated group. The preparation used was aloe Vera extract 0.5% in hydrophilic cream, applied three times daily without occlusion for 5 days a week for a maximum of 4 weeks. Eczema
Chinese herbs, traditionally used in often complex mixtures, have been shown to be effective in both children and adults with atopic eczema. In a double-blind crossover study, 40 adults with long-standing, refrac-
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(Reglan), ginger equalled metoclopramide in preventing postoperative nausea and vomiting. A small trial of 11 patients who regularly experienced nausea after taking 8-MOP prior to photopheresis found that ginger reduced nausea scores by two thirds (several patients complained of a feeling of heartburn).59 Ginger also has been shown to be superior to dimenhydrinate (Dramamine) for preventing laboratory-induced motion sickness. In one study, 36 undergraduates ingested capsules of dimenhydrinate, powdered ginger, or a placebo herb, and then were blindfolded and placed in a tilted rotating chair for whichever of the following came first: 6 minutes; emesis; three triplings in the magnitude of nausea; or pleas for freedom. None of the subjects in the placebo and dimenhydrinate groups could stay in the chair for 6 minutes, but half of those in the ginger group did.61Another laboratory study of eight volunteers found ginger more effective than placebo in controlling induced dizziness.30 The effect of ginger in real-life, roiling seas is less clear. A placebocontrolled trial of 80 naval cadets in heavy seas found that ginger reduced the number of vomiting episodes and cold sweats but did not significantly reduce nausea or dizziness. A recent study of 28 volunteers compared ginger with scopolamine or placebo and found ginger ineffecti~e.~~ Hot Flashes
Evening primrose oil, a good source of gamma linolenic acid, has been evaluated in a double blind controlled trial of 56 women and found to be no more effective than placebo for hot flashes.I7 Symptomatic HIV Infection
A 12-week, placebo-controlled trial of a Chinese herb mixture in 30 symptomatic HIV infection found no significant differences between the two groups in terms of symptoms, perceived health, or life satisfa~ti0n.l~ Insomnia
In one trial, a preparation containing VaZerian officinalis with other ingredients was compared with an extract containing only ~ a l e r i a nboth ~~: were tested against placebo. Both valerian preparations had a significant positive effect on sleep latency and subjective quality of sleep. patients received two pills In a study of 27 patients with and took one pill on the first night and the other on the second night. Both pills contained hops (Flores kumuli) and, apparently, lemon balm (Melissa officinalis, misnamed in the text), but one pill contained only 4 mg of valerian while the other contained a full dose of 400 mg of valerian. (Both hops and lemon balm are mild sedatives; valerian is considered
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tory atopic dermatitis were randomized to receive a Chinese herbal mixture or an inactivated herb placebo, and then were crossed over to the other group. Itching, erythema, and surface damage improved significantly during the time patients were on active treatment.72Forty-seven children in a similar trial responded ~ i m i l a r l y . ~ ~ Fatty acids were used in the 1930s and 1940s for eczema, but are not generally used today. Several studies of evening primrose oil, which contains the omega-6 fatty acid gamma-linolenicacid, indicate a possible benefit for eczema. In one study of 99 patients with atopic adults taking 8 to 12 capsules a day and children taking four capsules a day of evening primrose oil experienced improvement in itch, scaling, general severity, and physician assessment of the condition. Lower doses improved only itching, and adults responded better than children. Another study of 17 children and 15 adults with found that evening primrose oil was more effective than placebo by both physician and patient assessment. A third also found a beneficial effect on eczema. Peristomal Skin Integrity A small study of 13 urostomy patients found that daily ingestion of 160 to 320 g of cranberry juice resulted in improvement in five of the six patients who started the study with peristomal skin conditions, even though urine did not become more acidic.80 RESPIRATORY DISEASE Fifteen patients with severe respiratory illness requiring home oxygen treatment were given a standardized ginseng extract in a dose of 200 mg, twice daily.31After three months PFTs, ABGs, and walking distance increased dramatically. FVC increased from 32.1% to 72.8%; FEVl increased from 34.75% to 47.3%; PEFR increased 37.5% to 47.2%; Pao2from 47.0 torr to 69.3 torr. Six-minute walking distances increased from 600 meters to 1123 meters. MISCELLANEOUS SYMPTOMS Emesis Ginger (Zingiber officinale) may be a useful therapy for nausea and emesis of assorted causes. In a double blind crossover trial of 30 women with morning sickness, each woman received ginger capsules or placebo for four days.23After a two-day washout period, she was crossed over to the other group for four days. Seventy percent of the women preferred the ginger, which reduced both emesis and the degree of nausea. Ginger also is helpful in postoperative nausea and vomiting. In a double blind study8 that compared ginger, placebo, and metoclopramide
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much stronger). Twenty-one of 27 patients rated the full-dose valerian preparation as better; two subjects rated the preparations as equally good, and four preferred the control preparation. The difference was statistically significant.
ADVERSE EFFECTS OF HERBS
Most plant-related poisonings are due to accidental consumption of toxic ornamental plants, not herbs.55Mistaking poisonous plants for beneficial herbs has resulted in deaths (poison hemlock, for instance, has a superficial resemblance to parsley), but even correctly identified herbs may have both mild and severe side effects.34Herbs also can interact with drugs, and caution should be used when combining herbal and pharmaceutical treatments. The most dangerous medicinal herbs are those that contain pyrrolizidine alkaloids. Comfrey (Symphytum officinale), coltsfoot (Petasites hybridus), and members of the Heliotropiurn, Senecio, and Crotalaria species, among others, contain pyrrolizidine alkaloids, which have been associated with hepatitis, hepatic failure, hepatic veno-occlusive disease, and possibly cirrhosis. External use of coltsfoot or comfrey (commonly used as a compress for injuries) probably is not a problem; in rats, percutaneous absorption of alcohol-extracted comfrey is only 2% to 5% that of oral ab~orption~~). Senecio and Crotolaria species often are used in herbal teas in Africa, Jamaica, and South and Central America. Liver toxicity also has been as~~,~~ (Teucrium chasociated with chaparral (Larrea d i u u r i ~ a t a )germander47 maedrys), and a Chinese herbal product called Jin Bu H ~ a n . * ~ Licorice (Glycyrrhiza glabra) an important herb in Chinese medicine, affects the metabolism of cortisol, apparently by inhibiting the 11B-hydroxysteroid dehydrogenase system;*lthis can result in a pseudoprimary aldosteronism with edema, hypertension, and hypokalemia,2°J and there is one case of nonfatal cardiac a r r e ~ t . ~ It bears noting that all of the reported cases of licorice-induced problems were from licorice-containing candies, gum, laxatives, or chewing tobacco: not from the medicinal use of licorice. Most "licorice" candies manufactured in the United States are actually flavored with anise; imported candies usually contain real licorice. However, licorice tinctures and extracts, capsules, lozenges, etc., are available in the United States, so it is useful to know about possible side effects. In terms of drug interaction, hypokalemia due to licorice may be potentiated by the use of diuretics, and it would be expected that side effects of systemic steroids and licorice might be additive. Ginseng can cause estrogenic effects, although the plant does not actually contain phytoestrogens. Several cases of postmenopausal uterine bleeding after ingesting ginseng have been reported;28,66 another case occurred after use of a face cream that contained ginseng.33Mastalgia has also been rep0rted.~6,6~ Ginseng may cause hypertension in some individ-
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uals, and there are two cases of possible interactions between ginseng and phenel~ine.”,~~ Ephedra (Ephedra sinicu), also called ma huang, is an herb used most often for asthma (one component, ephedrine, is the primary ingredient of OTC asthma drugs, and another component, pseudoephedrine, is commonly used in OTC decongestant products). All of these may cause tachycardia, anxiety, hypertension, and arrhythmias. Ephedra should not be combined with theophylline; thyroid hormone, tricyclic antidepressants, methylphenidate, or any other drugs that can cause tachycardia or hypertension. Effects of herbal medications (or pharmaceutical medications, for that matter) vary according to age, weight, genetics, sex, and biochemical individuality. At the same time, just because a plant contains a toxin does not mean that the herb is toxic. Cabbage, for instance, contains a substance that can cause goiter, but unless one is subsisting on Cole slaw and sauerkraut, no harm results. Poison is always a question of dose. CONCLUSION
Primary care practitioners should be aware of the literature on phytotherapies because these preparations are in wide use and may interact with conventional medications. There may be a place for the use of herbal medications in primary care, especially in light of clinical studies indicating efficacy in alleviating symptoms and enhancing function in patients with chronic diseases. There is also intriguing evidence for therapeutic efficacy in several conditions (including neuropathy, dementia, and sexual dysfunction) for which conventional treatments are inadequate. More research needs to be done on phytotherapies as both alternatives and adjuncts to conventional treatment.
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9. Bordia A: Effect of garlic on human platelet aggregation in vitro. Atherosclerosis 30:355360,1978 10. Bordia A: Effect of garlic on blood lipids in patients with coronary heart disease. Am J Clin Nutr 34:2100-2103,1981 11. Bordia A, Bansal HC, Arora SK, et al: Effect of the essential oils of garlic and onion on alimentary hyperlipemia. Atherosclerosis 21:15-19, 1975 12. Braeckman J: The extract of Serenoa repens in the treatment of benign prostatic hyperplasia: A multicenter open study. Curr Ther Res 55(7):776-85, 1994 13. Brzeski M, Madhok R, Capell HA: Evening primrose oil in patients with rheumatoid arthritis and side effects of non-steroidal anti-inflammatory drugs. Br J Rheumatol 30:370-372,1991 14. Burack JH, Cohen MR, Hahn JA, et al: Pilot randomized controlled trial of Chinese herbal treatment for HIV-associated symptoms. J AIDS Hum Retro 12:386-393,1996 15. Capsaicin Study Group: Treatment of painful diabetic neuropathy with topical capsaicin. Arch Intern Med 151:2225-2229,1991 16. Champault G, Pate1 JC, Bonnard AM: A double-blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia. Br J Clin Pharmacol 18:461-462, 1984 17. Chenoy R, Hussain S, Tayob Y, et al: Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. Br Med J 308:501-503,1994 18. Cohen AJ, Bartlik BD: Ginkgo biloba for drug-induced sexual dysfunction. Presented at the American Psychiatric Association Annual Meeting, San Diego, May 1997 19. Eisenberg DM: Unconventional medicine in the United States. N Engl J Med 328:246252,1993 20. Epstein MT, Espiner EA, Donald RA, et al: Effect of eating liquorice on the renin-angiotensin aldosterone axis in normal subjects. Br Med J 11:488490, 1977 21. Farese RV, Biglieri EG, Shackleton CHL, et al: Licorice-induced hypermineralocorticoidism. N Engl J Med 325:1223-7,1991 22. Ferenci P, Dragosics 8, Dittrich H, et al: Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol9:105-113, 1989 23. Fischer-Rasmussen W, Kjaer SK, Dahl C, et al: Ginger treatment of hyperemesis gravidarum. Eur J Ob Gynecol Repro Biol38:19-24,1990 24. Foster S, Duke JA: Eastem/Central Medicinal Plants (Peterson Field Guides). Boston, Houghton Mifflin, 1990, vii 25. Gately CA, Miers M, Manse1RE, et a 1 Drug treatments for mastalgia: 17 years experience in the Cardiff mastalgia clinic. J R SOCMed 85:12-15, 1992 26. Gibbs WW: Jungle medicine. Sci Am 20, 1996 27. Gordon DW, Rosenthal G, Hart J, et al: Chaparral ingestion: The broadening spectrum of liver injury caused by herbal medications. JAMA 273(6):489-490,1995 28. Greenspan EM: Ginseng and vaginal bleeding. JAMA 249:2018,1983 29. Grontved A, Brask T, Kambskard J, et al: Ginger root against seasickness: A controlled trial on the open sea. Acta Otolaryngol 105:4549, 1988 30. Grontved A, Hentzer E: Vertigo-reducing effect of ginger root: A controlled clinical study. J Otorhinolaryngol48:282-286, 1986 31. Gross D, Krieger D, Efrat R, et al: Ginseng extract G115 for the treatment of chronic respiratory diseases. Schweiz Z Ganzheits Med 95:29-33, 1995 32. Hofferberth B: The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type, a double-blind, placebo-controlled study on different levels of investigation. Hum Psychopharmacol9:215-22, 1994 33. Hopkins MO, Androff L, Benninghoff A S Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol159:1121-1122, 1988 34. Huxtable RJ: The harmful potential of herbal and other plant products. Drug Safety 5:126, 1990 35. Jacob A, Pandey M, Kapoor S, et al: Effect of the Indian gooseberry (Amla) on serum cholesterol levels in men aged 35-55 years. Eur J Clin Nutr 42:939-944, 1988 36. Jain AK, Vargas R, et al: Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med 94632-635,1993 37. Jiang J-B, Li G-Q, Guo X-B, et al: Antimalarial activity of mefloquine and quinhaosu. Lancet ii:285-288,1982
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38. Johnson ES, Kadam NP, Hylands DM, et al: Efficacy of feverfew as prophylactic treatment of migraine. Br Med J 291:569-73, 1985 39. Jones BD, Runikis AM: Interaction of ginseng with phenelzine. J Clin Psychopharmacol 7(3):201-202, 1987 40. Kanowski S, Herrmann WM, Stephan K, et al: Proof of efficacy of the Ginkgo biloba extract EGb761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 29:4756,1996 41. Katz M, Saibil F: Herbal hepatitis: Subacute hepatic necrosis secondary to chaparral leaf. J Clin Gastroenterol 12:203-206,1990 42. Kiesewetter H, Jung EM, Mrowietz C, et al: Effect of garlic on platelet aggregation in patients with increased risk of juvenile ischemic attack. Euro J Clin Pharmacol45:333336, 1993 43. Kleijnen J, Knipschild P: Ginkgo biloba. Lancet 340:1136-39, 1992 44. Kleijnen J, Knipschild P: Ginkgo biloba for cerebral insufficiency. Br J Clin Pharmacol 34:352-358,1992 45. Kong X-T, Fang HT, Jiang GQ, et al: Treatment of acute bronchiolitis with Chinese herbs. Arch Dis Child 68:468471, 1993 46. Koriech OM: Ginseng and mastalgia. Br Med J 1:1556, 1978 47. Larrey D, Vial T, Pauwels A, et al: Hepatitis after germander administration: Another instance of herbal medicine hepatotoxicity. Ann Intern Med 117(2):129-132, 1992 48. Leathwood PD, Chauffard F, Herck E, et al: Aqueous extract of valerian root improves sleep quality in man. Pharmacol Biochem Behav 1765-71,1982 49. Leventhal LJ, Boyce EG, Zurier RB: Treatment of rheumatoid arthritis with gammalinolenic acid. Ann Intern Med 119(9):867-873, 1993 50. Li G-Q, Arnold K, Guo X-8, et al: Randomized comparative study of mefloquine, quinghaosu and pyrimethamine-sulfadoxine in patients with falciparum malaria. Lancet ii:1360-1361,1984 51. Lindahl 0,Lindwall L: Double blind study of a valerian preparation. Pharmacol Biochem Behav 32:1065-1066,1989 52. Linde K, Ramirez G, Mulrow CD, et al: St John’s wort for depression-an overview and meta-analysis of randomized clinical trials. Br Med J 313:253-58, 1996 53. Love11 CR, Burton JL, Horrobin DF: Treatment of atopic eczema with evening primrose oil. Lancet i:278, 1981 54. Mayeux PR, Agrawal KC, Tou J-S H, et al: The pharmacological effects of allicin, a constituent of garlic oil. Agents Actions 25(1-2):182-190,1988 55. McCaleb RS: Food ingredient safety evaluation. Food Drug Law J 47(6):657-663,1992 56. McCarty DJ, Csuka M, McCarthy G, et al: Treatment of pain due to fibromyalgia with topical capsaicin: A pilot study. Semin Arthritis Rheum 23(6), 3:4147, 1994 57. McCarthy GM, McCarty DJ: Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol 19:604-607, 1992 58. Melchart D, Linde K, Worku F, et al: Immunomodulation with Echinacea-a systematic review of controlled clinical trials. Phytomedicine 1:245-254, 1994 59. Meyer K, Schwartz J, Crater D, et al: Zingiber officinale (Ginger) used to prevent 8-MOP associated nausea. Dermatol Nurs 7(4):24244, 1995 60. Milewicz A, Gejdel E, Sworen H, et al: Vitex agnus-castus-extrakt zur Behandlung von Regeltempoanomalien infolge latenter Hyperrolaktinamie. Arzneim-Forsch/Drug Res 43(II), 7752-56, 1993 61. Mowrey DB: Motion sickness, ginger, and psychophysics. Lancet:655-657, 1982 62. Murphy JJ, Heptinsall S, Mitchell JRA: Randomized double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet ii:189-92, 1988 63. Ofek I, Goldhar J, Zafriri D, et al: Anti-escherichia coli adhesion activity of cranberry and blueberry juices. N Engl J Med 324(22):1599,1991 64. Palmer BV, Montgomery ACV, Monteiro JCMP: Ginseng and mastalgia. Br Med J 1:1284, 1978 65. Phelps S, Harris WS: Garlic supplementation and lipoprotein oxidation susceptibility. Lipids 28(5):475477, 1993 66. Punnonen R, Lukola A: Oestrogen-like effect of ginseng. Br Med J 281:1110,1980 67. Rai GS, Shovlin C, Wesnes KA: A double-blind, placebo controlled study of Ginkgo
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biloba extract (’Tanakan’)in elderly outpatients with mild to moderate memory impairment. Curr Med Res Opin 12(6):350-355,1991 Salmi HA, Sarna S:Effect of silymarin on chemical, functional, and morphological alterations of the liver. Scand J Gastroenterol 17:517-520,1982 Schalin-Karrila M, Mattila L, Jansen CT, et al: Evening primrose oil in the treatment of atopic eczema: effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. Br J Dermatol 11711-19,1987 Shader RI, Greenblatt DJ: Phenelzine and the dream machine-ramblings and reflections. J Clin Psychopharmacol5:65,1985 Sheehan MP, Atherton DJ: A controlled trial of traditional Chinese medicine plants in widespread, non-exudative atopic eczema. Br J Dermatol 126:179-184,1992 Sheehan MP, Rustin MHA, Atherton DJ: Efficacy of traditional Chinese herbal treatment in adult atopic dermatitis. Lancet 340:13-17, 1992 Sikora R, Sohn M, Deutz F-J, et al: Ginkgo biloba extract in the therapy of erectile dysfunction. J Urol 141:188A, 1989 Silagy CA, Neil HAW: A meta-analysis of the effect of garlic on blood pressure. J Hypertens 12463468, 1994 Sobota AE: Inhibition of bacterial adherence by cranberry juice: Potential use for the treatment of urinary tract infections. J Urol 131:1013-1016,1984 Sotaniemi EA, Haapakoski E, Rautio A: Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care 18(10):1373-75, 1995 Stewart JJ, Wood MJ, Wood CD, et al: Effects of ginger on motion sickness susceptibility and gastric function. Pharmacology 42:111-120, 1991 Sy ND, Hoan DB, Dung NP, et al: Treatment of malaria in Vietnam with oral artemisinin. Am J Trop Med Hyg 48(3):398402,1993 Syed TA, Ahmad SA, Holt AH, et al: Management of psoriasis with aloe Vera extract in a hydrophilic cream: A placebo-controlled, double-blind study. Trop Med Int Health 1(4):505-509, 1996 Tsukada K, Tokunaga K, Iwama T, et al: Cranberry juice and its impact on peri-stoma1 skin conditions for urostomy patients. Ostomy/Wound Mgmt 40(9):60-67,1994 Vorberg G, Scneider B: Therapy with garlic: Results of a placebo-controlled, doubleblind study. Br J Clin Pract 7-11, 1990 Warshafsky S, Kamer RS, Sivak SL: Effect of garlic on total serum cholesterol: A metaanalysis. Ann Intern Med 119:599-605, 1993 Watson CPN, Evan RJ: The postmastectomy pain syndrome and topical capsaicin: A randomized trial. Pain 51:372-379, 1992 Westendorf J: Pyrrolizidine alkaloids-Symphytum species. In De Smet vol I:219-22. Woolf GM, Petrovic LM, Rojter SE, et al: Acute hepatitis associated with the Chinese herbal product Jin Bu Huan. Ann Intern Med 121:729-735,1994 Wright S, Burton JL: Oral evening-primrose-seed oil improves atopic eczema. Lancet 1120-1122,1982 Zycyznski HM, Culbertson S,Gruss J, et al: Substance P and the pathophysiology of vulvar vestibulitis. J SOCGynecol Invest 4(1):107A, 1997
Address reprint requests to Adriane Fugh-Berman, MD National Women’s Health Network 514 10th St. #400 Washington DC 20004
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+ .20
CLINICAL TRIALS OF HERBS Adriane Fugh-Berman, MD
The use of plants as medicine predates even the existence of humans: great apes consumed specific medicinal plants when they are In Eisenberg's 1990 study, herbal medicine was found to be used by 3% of the U.S. population in 1990.19This widely invoked survey almost certainly underestimated the actual prevalence of use, as it was limited to Englishspeaking participants with telephones. There is certainly higher utilization of herbs by immigrants from Asian, African, Caribbean, and Central and South American cultures. About one quarter of our pharmaceuticals originally were derived from plantsF4and only a tiny fraction of plants have been screened for medicinal compounds. Plant-derived products used regularly by primary care physicians include oral contraceptives (the progestin component is derived from Diascorea villosa, the Mexican yam); digoxin from foxglove (Digitalis lanata); cephalosporins, derived from a marine fungus (Cepkalosporium acremonium); cromolyn sodium, a khellin derivative from the Ayurvedic herb A m m i uisnaga; and the statins, which are derived from the fungus Aspergillus terreus. Recently there has been renewed interest from both large and small pharmaceutical companies in searching for novel molecules from plants. In 1991Merck contracted with Costa Rica's Instituto Nacional de Biodiversidad for a supply of biological samples. Since then, Bristol MeyersSquibb, Smith-Kline, Glaxo, and Pfizer have negotiated arrangements in various countries, including China, Surinam, Peru, Argentina, Mexico, Chile, Nigeria, and Cameroon.' While the larger companies usually depend on high-throughput random screening programs, a few companies rely on an ethnobotanical approach. Shaman Pharmaceuticals, a small company founded in 1990, typifies this more directed, low-tech approach, in which close relationships are established with local herbalists and only plant species historically used medicinally are tested. From the National Women's Health Network, Washington, DC PRIMARY CARE
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Although the extraction of discrete active compounds from plants is a laudable goal, it is often an elusive one. Many herbs lose their activity when purified. This may be because the wrong compound was identified (each species contains hundreds or even thousands of ingredients), but it is more likely that an unknown number of compounds may be acting synergistically. There is growing openness within both the research and regulatory communities to clinical testing of whole herbs or even herb mixtures and a growing number of clinical trials of herbs. A sampling of clinical trials of interest to primary care practitioners follows.
PAIN Mastalgia
Evening primrose oil, high in the essential fatty acids linoleic and gamma-linolenic acid, may be effective for mastalgia. A Welsh series of 414 patients with either cyclic or noncyclic mastalgiaZ5found that evening primrose oil, in a dose of 3g daily (containing 240 mg of gamma-linolenic acid), equalled bromocriptine in effectiveness. Neither treatment was as effective as danazol. The evening primrose oil group experienced fewer side effects than did other groups; 30% of the danazol group and 35% of the bromocriptine group reported significant adverse events, compared with 4% of those taking evening primrose oil.
Migraines
Several trials indicate that feverfew (Tanaceturn partheniurn) may be effective in migraine prophylaxis. A small study tested feverfew withdrawal in regular users. Seventeen patients who ate fever few leaves daily to prevent migraine were randomized to either dried feverfew leaves or placebo.38Those who received placebo had a significant increase in the frequency and severity of headache, nausea, and vomiting; those in the feverfew group showed no change in the incidence of their migraines. In a larger, cross-over study:2 72 migraine patients were given either one capsule of dried feverfew or placebo daily for 4 months, then received the other therapy for 4 more months. Patients receiving feverfew had fewer migraines, less severe attacks, and less emesis, although the duration of migraines that did occur remained the same. Feverfew can cause aphthous ulcers, oral edema, or loss of taste.4 Taking the herb in capsules reduces but does not eliminate these effects.
Arthritis
One double blind controlled study of 21 patients57found that capsaicin cream applied topically reduced tenderness and pain of osteoar-
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thritis patients by 40% but had no effect on patients with rheumatoid arthritis. Evening primrose oil may help rheumatoid arthritis patients to reduce their use of painkillers; one study6 found that 60% of rheumatoid arthritis patients were able to reduce or stop their painkillers. A study of 37 patients with rheumatoid arthritis" compared gammalinoleic acid (a fatty acid found in evening primrose, black currant seed, and borage seed oil) with cottonseed oil and found that in patients who completed 24 weeks of treatment, GLA improved pain, ability to perform tasks, and global assessment by physician. Another study that used an olive oil placebo found evening primrose oil equivalent to the placebo and neither very effe~tive.'~
Fibromyalgia
Of 45 patients treated with topical capsaicin or placebo for fibromyalgia,56those receiving capsaicin reported less tenderness at their trigger points. A significant increase in grip strength also was noted.
Vulvar Vestibulitis
Topical capsaicin (.025%)also has been tested in a vehicle-controlled trial of 14 subjects with vulvar vestibulitiss7;the nine subjects who had completed the study at the time of its presentation experienced a 77% reduction of pain.
Neuropathy
Topical capsaicin may be useful for diabetic neuropathy; one study of 252 patients with diabetic neuropathy15 found that 69.5% of patients treated with the capsaicin cream reported pain improvement to their physicians compared with 53.4% of those on placebo. Intensity of pain also was lessened in the capsaicin group. A controlled trial of 32 elderly patients with postherpetic neuralgia7 found that almost 80% of the capsaicin-treated patients experienced some relief from their pain after 6 weeks. A small, controlled study of 23 patientss3found that capsaicin cream is helpful in postmastectomy pain syndrome. Five of 13patients receiving the capsaicin cream reported good to excellent results compared with one out of ten patients in the placebo group. Capsaicin cream can cause a brief local burning or stinging sensation: this effect usually disappears after a few doses. Patients should be counseled to wash their hands after applying the cream and to avoid touching their eyes.
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CARDIOVASCULAR DISEASE
Hypercholesterolemia Garlic (Allium safivum) may have beneficial cardiovascular effects. Alliums (which also include onions) lower blood lipid levels, and may have anticoagulant and antioxidant effects as well. A placebo-controlled trial'" with 88 participants found that garlic decreased total cholesterol in both healthy volunteers and patients with coronary heart disease. After taking garlic for 6 to 8 months, total cholesterol fell 20% in the healthy volunteers and 18% in those diagnosed with cardiovascular disease; triglycerides and low-density lipoprotein also fell while high-density lipoprotein rose. Another double blind study of 40 patients with hypercholesterolemias' found that after 4 months, the group taking garlic had a 21% reduction in total cholesterol, compared with a 3% reduction in the control group. Triglycerides also decreased 24% in the garlic-treated group, compared with a 5% reduction in the control group. A more recent doubleblind, placebo-controlled found a more modest effect: garlic tablets reduced LDL cholesterol 11%and total cholesterol about 6%; cholesterol levels went down 1%in the placebo group. A meta-analysiss2of five trials that examined the effect of garlic on cholesterol found that the equivalent of one half to one clove of garlic lowered cholesterol about 9% in the groups of patients studied. The rise in blood lipid levels that occurs within a few hours of consuming fat is reduced by garlic or onion." Two studies found that alliums inhibit platelet aggregation in human b l o ~ d ~ another , ~ * ; laboratory study found allicin, one of the components in garlic, had the same effect. Garlic also appears to have some antioxidant qualities.26 Amla, an ayurvedic herb, is used to treat hypercholesterolemia. In an 50g of raw uncontrolled study with a number of methodologic Amla (Emblica oficinalis), also called Indian gooseberry, was found to lower cholesterol in 35 men (some of whom were hypercholesterolemic and some of whom had normal cholesterol levels). After a month, there was significant reduction in total cholesterol as well as LDL cholesterol.
Hypertension Garlic may have an effect on mild hypertension, but studies have been mixed. In one double blind trial of 47 patients with mild hypertension,2diastolic blood pressure was reduced from 102 to 89 mm Hg after 12 weeks in the garlic group; no significant changes occurred in the placebo group. Decreased cholesterol and triglycerides also were noted in the garlic-treated group. An analysis of eight trials with a total of 415 subjects found the general quality of trials poor; only three of the trials were limited to hyper-
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tensive patients. Four of the seven placebo-controlledtrials found an effect on diastolic blood pressure.74
Intermittent Claudication
Of 15 controlled trials on intermittent claudication, only two were deemed to be of acceptable Both of these trials showed a benefit, as did all of the poorer quality trials.
ENDOCRINE EFFECTS Hyperprolactinemia
Chaste-tree berry (Vitex agnus castus) may have profound hormonal effects. In a double blind placebo-controlled trial of 52 women with luteal phase defect due to latent hyperprolactinemia, one 20-mg capsule of Vitex daily reduced prolactin levels, normalized the length of luteal phases, and normalized luteal phase progesterone levels.60A case of ovarian hyperstimulation apparently due to ingestion of Vitex has been reported (REF TK).
Diabetes
A double blind, placebo-controlled study of 36 newly diagnosed NIDDM patients76compared two doses of standardized ginseng with placebo and found that ginseng reduced fasting blood glucose and (in the 200 mg but not 100 mg group) reduced HbAlc. Mood, psychomotor performance, and physical activity also improved in patients receiving ginseng.
PSYCHIATRIC CONDITIONS Depression
The herb St. John’s wort (Hypericum perforaturn) is an effective treatment for mild to moderate depression. A meta-analysis of 23 randomized controlled trials with a total of 1757 outpatients found that St. John’s wort was almost three times more effective than placebo and comparable when tested against standard antidepressant^.^^ St. John’s wort also may cause photosensitivity. St. John’s wort has mild MA0 inhibition effects, but its antidepressant effects are not exclusively due to this mechanism. Still, patients using St. John’s wort probably should observe MA01 precautions.
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Dementidcerebral Insufficiency
Ginkgo bilboa is very promising for the treatment of dementia. A placebo-controlled double blind study of a standardized ginkgo extract (EGb761)in 216 patients with Alzheimer’s or multi-infarct dernentia4Oadministered 240 mg of the extract daily for 24 weeks after a 4-week placebo run-in. Patients who received ginkgo did better on tests of attention, memory, and psychopathologic assessment. Another placebo-controlled trial of 40 Alzheimer’s patients32given 80 mg of ginkgo extract three times daily found that patients given ginkgo improved in tests on memory, attention, psychopathologic disorder, and functional dynamics over those given placebo. A third trial of 31 patients67with mild to moderate memory impairment found a benefit of a standardized extract on cognitive function at 24 weeks. The dose in this trial was 40 mg three times daily. About 40 studies have been done on the use of ginkgo for the illdefined diagnosis of cerebral insufficiency; a m e t a - a n a l y ~ i sfound ~ ~ , ~ that ~ in seven of the eight best placebo-controlled trials, ginkgo was more effective than placebo for a variety of patient complaints, including memory and concentration problems, headaches, depression, and dizziness. UROLOGIC CONDITIONS Sexual Dysfunction
Ginkgo may help sexual dysfunction. An open trial of ginkgo was conducted in 37 male and female patients with serotonin reuptake inhibitor associated sexual problems, including erectile difficulty, delayed ejaculation, anorgasmia, and decreased libido.’*All patients had previously attempted to address sexual difficulties through the use of cyproheptadine, yohimbine, amantadine, buspirone, or dosage adjustment. After 4 weeks of taking 60 mg of ginkgo biloba extract three or four times a day, 86% reported significant improvement. In another uncontrolled trial of 60 men with unsuccessfully treated impotence secondary to arterial flow problems,73ginkgo extract improved blood flow within 8 weeks. After 6 months half of the men had regained potency. Benign Prostatic Hypertrophy
A double blind studyI6of saw palmetto (Serenoa repens) extract in 110 patients in France found that flow rate improved by 50%, and the number of nighttime bathroom trips also decreased significantly. In an uncontrolled trial of saw palmetto in 305 men with mild to moderate symptoms of BPH,12 improvements in International Prostate Symptom Scores, quality of life scores, urinary flow rates, and residual urinary volume were seen after 45 days of treatment. PSA levels were not
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affected. Prostatic volume (measured by transrectal echography) decreased by a mean of 9% at 45 days. At 3 months, 88% of patients considered the therapy effective; and equal percentage of physicians agreed. The herb was administered in a dose of 160 mg twice daily for 3 months. Five percent of patients experienced side effects; more than half of these were gastrointestinal. Other effects reported included dizziness, dry mouth, tachycardia, angina, and testicular pain.
IMMUNE EFFECTShNFECTIOUSDISEASE
Echinacea (Echinacea augustifoh or E. purpurea) appears to enhance both cellular and humoral immunity. It is popular in Europe, especially in Germany, where more than 300 preparations of Echinacea are available. A review of 26 controlled clinical trials58(18 randomized, 11 double blind) of pure or mixed Echinacea preparations found positive results claimed for 30 of the 34 treated groups. Nineteen trials studied whether the preparation prevented or cured infections (most commonly upper respiratory infections), four trials the reduction of side effects of cancer therapies, and three looked at the effect of echinacea on immune measures. Authors of the review, however, note that although the evidence points to a positive effect of Echinacea on the immune system, most of the trials were of poor methodologic quality and do not provide enough information to make clear recommendations on how much of which preparation to use and under what circumstances it should be used.
Bronchiolitis
An herbal mixture was effective in the treatment of acute bronchiolitis in children with respiratory syncytial virus. In a single-blind 96 children were randomized to antibiotics, herbs, or a combination of both; those receiving the herbs, with or without antibiotics, had earlier resolution of fever, cough, and wheezing.
Malaria
Long an herbal remedy for parasites, including those that cause malaria, wormwood (Arternisia annua), also called quinghao, is staging a comeback, perhaps owing to the emergence of drug-resistant types of malaria. Several studies show its e f f e c t i v e n e ~ s .One ~~,~ study ~ of artemisinin in 638 malaria patients in Vietnam7*showed a dramatic success rate; parasites in the blood decreased more than 98% within 24 hours and were cleared by 48 hours. Recurrence of symptoms was high with short-term artemisinin, but the herbal extract works faster than known drugs. The ideal treatment for malaria probably is a combination of wormwood and a pharmaceutical agent. No acute toxicity was apparent.
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UTI
Cranberry juice acidifies the urine but also decreases bacterial adhere n ~ eIn. ~ one ~ study? 153elderly women drank 300 mL a day of cranberry juice or a placebo juice matched for taste, appearance, and vitamin C content. Those who drank the placebo drink had more than twice the incidence of bacteriuria and pyuria as those who drank the cranberry juice. The effect of a number of fruit juices on the adhesive ability of E. coli has been tested; only Vaccinia species (which includes both cranberry and blueberry) were benefi~ial.~~ HEPATIC DISEASE
Milk thistle, (Silybum marianum) appears to protect the liver. Intravenous preparations of milk thistle are used in Germany to treat Amanita mushroom ("Deadly Angel") poisoning. Although clinical studies on this herb are problematic, results are intriguing enough that more research should be done on milk thistle, especially given the dearth of effective treatments for liver disease. In a double blind study of patients admitted to a Finnish military hospital for hepatitis,68the 47 patients who received silymarin had a greater decrease in liver enzymes than 50 controls. Some patients had preand post- liver biopsies: treated patients showed more histologic improvement than did controls. No distinction was made among various causes of increased liver enzymes. A better study compared silymarin to placebo in 170 patients with cirrhosis.22Patients in the treated group were less likely to die; the treatment appeared to be more effective in those with alcohol-induced cirrhosis or less severe forms of cirrhosis. DERMATOLOGIC CONDITIONS Psoriasis
A double blind, placebo-controlled trial of topical aloe Vera extract in 60 patients with mild to moderate chronic psoriasis ~ u l g a r i found s ~ ~ that after 4 weeks, 83.3% of aloe-treated patients were cured, versus 6.6% of the placebo treated group. The preparation used was aloe Vera extract 0.5% in hydrophilic cream, applied three times daily without occlusion for 5 days a week for a maximum of 4 weeks. Eczema
Chinese herbs, traditionally used in often complex mixtures, have been shown to be effective in both children and adults with atopic eczema. In a double-blind crossover study, 40 adults with long-standing, refrac-
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(Reglan), ginger equalled metoclopramide in preventing postoperative nausea and vomiting. A small trial of 11 patients who regularly experienced nausea after taking 8-MOP prior to photopheresis found that ginger reduced nausea scores by two thirds (several patients complained of a feeling of heartburn).59 Ginger also has been shown to be superior to dimenhydrinate (Dramamine) for preventing laboratory-induced motion sickness. In one study, 36 undergraduates ingested capsules of dimenhydrinate, powdered ginger, or a placebo herb, and then were blindfolded and placed in a tilted rotating chair for whichever of the following came first: 6 minutes; emesis; three triplings in the magnitude of nausea; or pleas for freedom. None of the subjects in the placebo and dimenhydrinate groups could stay in the chair for 6 minutes, but half of those in the ginger group did.61Another laboratory study of eight volunteers found ginger more effective than placebo in controlling induced dizziness.30 The effect of ginger in real-life, roiling seas is less clear. A placebocontrolled trial of 80 naval cadets in heavy seas found that ginger reduced the number of vomiting episodes and cold sweats but did not significantly reduce nausea or dizziness. A recent study of 28 volunteers compared ginger with scopolamine or placebo and found ginger ineffecti~e.~~ Hot Flashes
Evening primrose oil, a good source of gamma linolenic acid, has been evaluated in a double blind controlled trial of 56 women and found to be no more effective than placebo for hot flashes.I7 Symptomatic HIV Infection
A 12-week, placebo-controlled trial of a Chinese herb mixture in 30 symptomatic HIV infection found no significant differences between the two groups in terms of symptoms, perceived health, or life satisfa~ti0n.l~ Insomnia
In one trial, a preparation containing VaZerian officinalis with other ingredients was compared with an extract containing only ~ a l e r i a nboth ~~: were tested against placebo. Both valerian preparations had a significant positive effect on sleep latency and subjective quality of sleep. patients received two pills In a study of 27 patients with and took one pill on the first night and the other on the second night. Both pills contained hops (Flores kumuli) and, apparently, lemon balm (Melissa officinalis, misnamed in the text), but one pill contained only 4 mg of valerian while the other contained a full dose of 400 mg of valerian. (Both hops and lemon balm are mild sedatives; valerian is considered
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tory atopic dermatitis were randomized to receive a Chinese herbal mixture or an inactivated herb placebo, and then were crossed over to the other group. Itching, erythema, and surface damage improved significantly during the time patients were on active treatment.72Forty-seven children in a similar trial responded ~ i m i l a r l y . ~ ~ Fatty acids were used in the 1930s and 1940s for eczema, but are not generally used today. Several studies of evening primrose oil, which contains the omega-6 fatty acid gamma-linolenicacid, indicate a possible benefit for eczema. In one study of 99 patients with atopic adults taking 8 to 12 capsules a day and children taking four capsules a day of evening primrose oil experienced improvement in itch, scaling, general severity, and physician assessment of the condition. Lower doses improved only itching, and adults responded better than children. Another study of 17 children and 15 adults with found that evening primrose oil was more effective than placebo by both physician and patient assessment. A third also found a beneficial effect on eczema. Peristomal Skin Integrity A small study of 13 urostomy patients found that daily ingestion of 160 to 320 g of cranberry juice resulted in improvement in five of the six patients who started the study with peristomal skin conditions, even though urine did not become more acidic.80 RESPIRATORY DISEASE Fifteen patients with severe respiratory illness requiring home oxygen treatment were given a standardized ginseng extract in a dose of 200 mg, twice daily.31After three months PFTs, ABGs, and walking distance increased dramatically. FVC increased from 32.1% to 72.8%; FEVl increased from 34.75% to 47.3%; PEFR increased 37.5% to 47.2%; Pao2from 47.0 torr to 69.3 torr. Six-minute walking distances increased from 600 meters to 1123 meters. MISCELLANEOUS SYMPTOMS Emesis Ginger (Zingiber officinale) may be a useful therapy for nausea and emesis of assorted causes. In a double blind crossover trial of 30 women with morning sickness, each woman received ginger capsules or placebo for four days.23After a two-day washout period, she was crossed over to the other group for four days. Seventy percent of the women preferred the ginger, which reduced both emesis and the degree of nausea. Ginger also is helpful in postoperative nausea and vomiting. In a double blind study8 that compared ginger, placebo, and metoclopramide
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much stronger). Twenty-one of 27 patients rated the full-dose valerian preparation as better; two subjects rated the preparations as equally good, and four preferred the control preparation. The difference was statistically significant.
ADVERSE EFFECTS OF HERBS
Most plant-related poisonings are due to accidental consumption of toxic ornamental plants, not herbs.55Mistaking poisonous plants for beneficial herbs has resulted in deaths (poison hemlock, for instance, has a superficial resemblance to parsley), but even correctly identified herbs may have both mild and severe side effects.34Herbs also can interact with drugs, and caution should be used when combining herbal and pharmaceutical treatments. The most dangerous medicinal herbs are those that contain pyrrolizidine alkaloids. Comfrey (Symphytum officinale), coltsfoot (Petasites hybridus), and members of the Heliotropiurn, Senecio, and Crotalaria species, among others, contain pyrrolizidine alkaloids, which have been associated with hepatitis, hepatic failure, hepatic veno-occlusive disease, and possibly cirrhosis. External use of coltsfoot or comfrey (commonly used as a compress for injuries) probably is not a problem; in rats, percutaneous absorption of alcohol-extracted comfrey is only 2% to 5% that of oral ab~orption~~). Senecio and Crotolaria species often are used in herbal teas in Africa, Jamaica, and South and Central America. Liver toxicity also has been as~~,~~ (Teucrium chasociated with chaparral (Larrea d i u u r i ~ a t a )germander47 maedrys), and a Chinese herbal product called Jin Bu H ~ a n . * ~ Licorice (Glycyrrhiza glabra) an important herb in Chinese medicine, affects the metabolism of cortisol, apparently by inhibiting the 11B-hydroxysteroid dehydrogenase system;*lthis can result in a pseudoprimary aldosteronism with edema, hypertension, and hypokalemia,2°J and there is one case of nonfatal cardiac a r r e ~ t . ~ It bears noting that all of the reported cases of licorice-induced problems were from licorice-containing candies, gum, laxatives, or chewing tobacco: not from the medicinal use of licorice. Most "licorice" candies manufactured in the United States are actually flavored with anise; imported candies usually contain real licorice. However, licorice tinctures and extracts, capsules, lozenges, etc., are available in the United States, so it is useful to know about possible side effects. In terms of drug interaction, hypokalemia due to licorice may be potentiated by the use of diuretics, and it would be expected that side effects of systemic steroids and licorice might be additive. Ginseng can cause estrogenic effects, although the plant does not actually contain phytoestrogens. Several cases of postmenopausal uterine bleeding after ingesting ginseng have been reported;28,66 another case occurred after use of a face cream that contained ginseng.33Mastalgia has also been rep0rted.~6,6~ Ginseng may cause hypertension in some individ-
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uals, and there are two cases of possible interactions between ginseng and phenel~ine.”,~~ Ephedra (Ephedra sinicu), also called ma huang, is an herb used most often for asthma (one component, ephedrine, is the primary ingredient of OTC asthma drugs, and another component, pseudoephedrine, is commonly used in OTC decongestant products). All of these may cause tachycardia, anxiety, hypertension, and arrhythmias. Ephedra should not be combined with theophylline; thyroid hormone, tricyclic antidepressants, methylphenidate, or any other drugs that can cause tachycardia or hypertension. Effects of herbal medications (or pharmaceutical medications, for that matter) vary according to age, weight, genetics, sex, and biochemical individuality. At the same time, just because a plant contains a toxin does not mean that the herb is toxic. Cabbage, for instance, contains a substance that can cause goiter, but unless one is subsisting on Cole slaw and sauerkraut, no harm results. Poison is always a question of dose. CONCLUSION
Primary care practitioners should be aware of the literature on phytotherapies because these preparations are in wide use and may interact with conventional medications. There may be a place for the use of herbal medications in primary care, especially in light of clinical studies indicating efficacy in alleviating symptoms and enhancing function in patients with chronic diseases. There is also intriguing evidence for therapeutic efficacy in several conditions (including neuropathy, dementia, and sexual dysfunction) for which conventional treatments are inadequate. More research needs to be done on phytotherapies as both alternatives and adjuncts to conventional treatment.
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