Herbal Medicine:

In the United States, herbal medicine has grown faster than any other type of complementary or alternative medicine (CAM).^1,2 An estimated 60 million Americans use herbal and other dietary supplements; they spend more than $5 billion on herbal supplements³ and $10 billion on nonherbal supplements annually.⁴

Most physicians are not opposed to their patients' use of supplements and other types of CAM.⁵ However, as many as 70% of patients do not tell their physicians they are taking herbs or other supplements.⁴ Thus, it is often necessary to ask about supplement use. Pose the question in a neutral manner: for example, "Patients with your condition often use herbs or other supplements. Have you taken or considered taking such products for your chief complaint or for other reasons?"

Effective communication with patients who use CAM-as well as optimal care-is based on these key elements:

• Information that is scientific and, if possible, evidence-based.
• Recognition of the legal ramifications of the use of CAM therapies (Box I).
• Lack of condescension.

My aim here is to help you apply the methods of evidence-based medicine to evaluate CAM therapies. I examine the most recent data on the pharmacodynamics, efficacy, and safety of 5 commonly used herbs: echinacea, St John's wort, ginkgo biloba, saw palmetto, and black cohosh.

WHERE TO FIND RELIABLE INFORMATION

It is becoming easier to stay abreast of the latest scientific evidence about herbs. However, a discerning and critical approach to all information about herbal products remains necessary.

Books and journals. Several publications on herbs for the physician audience have recently appeared⁶; however, few are evidence-based and/or clinically oriented.

The Internet. The Internet is a rich source of information; however, keep in mind that it is also a vehicle for spreading myths, hoaxes, and rumors. Several of the more reliable Web sites are listed in Table 1. In addition, although it is far from exhaustive (because of the limitations of voluntary reporting), the FDA's MedWatch Web site is an important source of information about safety issues, such as herb-drug interactions. The address is www.fda.gov/medwatch.

A multimodal approach. Consult more than one source to ensure that your information about the herbs your patients use is as broad and reliable as possible. If you rely only on the published results of clinical trials and guidelines from major medical organizations, you will find too little information available. If you rely only on the FDA MedWatch program, you may be misled by the small numbers of adverse events reported. And if you use only resources tied to the supplement industry-as many Web sites are-you will find numerous unsubstantiated claims.

Patient education. Guide patients to reliable sources of information about herbs. A recent review by Ernst⁶ of books on herbs for a lay audience found them "more of a risk to the health of the reader than a helpful source of knowledge." Although it is not exhaustive, the FDA's article, "Tips for the Savvy Supplement User," can be printed out from their Web site and made available to all patients who inquire about the use of herbal products. The address is (www.cfsan.fda.gov/~dms/dssavvy.html)

EFFICACY: ASSESSING THE EVIDENCE

Both herbs and standard pharmaceuticals are best evaluated by double-blind, randomized, controlled trials.⁷ Thus, in theory, there should be no difference in the research meth- ods applied to botanicals and pharmaceuticals to assess their efficacy. Although trials of herbal products have become more common and more peer-reviewed journals are publishing evidence-based reviews of herbs, several obstacles have hindered close scrutiny of many herbal products.

First, the manufacturers of herbal products have little incentive to fund rigorous studies, since the law permits them to sell their products without doing so (Box II).⁸ Consequently, very few herbs have been evaluated rigorously in randomized controlled trials.

Second, systematic reviews and meta-analyses of these trials usually reveal multiple inadequacies. These include:

Reported effects that are limited and/or require confirmation by larger trials.³

No consideration of long-term effects. Because most clinical trials of herbal products have been short-term and because the adverse effects of many such products develop only after a certain period⁹ or occur infrequently, such trials reveal little about the products' safety profiles.

Comparison of the herb with placebo rather than with the standard of care, or if the herb is compared with the standard of care, failure to consistently use the correct dosages. Rigorous investigations-those in which herb, placebo, and conventional therapy are studied (to assess the sensitivity of the participants to placebo)-are rare.

Unreliable results-even in well-done clinical trials-because of the lack of standardized manufacturing procedures in the herbal supplement industry (see Box II). The multitude of formulations of a given herb that are available, or batch-to-batch inconsistency of any given formulation, can cause a product to vary from one trial to the next, or even within the same trial.

Publication bias (the more frequent reporting of positive results than of negative results), which leads to an overestimation of the treatment effect of many products.^10,11

With these limitations in mind, I summarize the recent evidence on 5 widely used herbs (Table 2).

ECHINACEA

Commercially available herbal medications are produced from 3 species of the herb: Echinacea augustifolia,Echinacea pallida, and Echinacea purpurea.⁶

Pharmacodynamics. Depending on the part of the plant used in its manufacture, an echinacea product may contain 6 or more distinct chemical constituents with pharmacologic activity.¹² The types of activity include stimulation of the immune system; local anesthesia; and anti-inflammatory, hormonal, antiviral, and free radical-scavenging properties. The nonspecific immunostimulatory activity includes wound healing.¹² The specific immunostimulatory effects of echinacea are anti-infective and probably result from activation of phagocytosis, release of tumor necrosis factor, and production of macrophage interleukin-1 and interferon beta-2.¹² Echinacea is not thought to be directly bactericidal or bacteriostatic.¹³

Evidence of efficacy. A systematic review of 26 clinical trials examined the effect of echinacea on immunomodulation.¹⁴ Of these 26 trials, 18 were randomized and 11 were double-blind. Thirty of the 34 outcomes in the treatment groups were identified as "superior to controls" by the authors of the original studies. However, the review found that only 22 of the 34 outcomes were "reasonably demonstrated."

In another review of the results of 5 randomized studies of the immunomodulatory activity of different preparations of echinacea, 2 of the 5 studies demonstrated statistically significant evidence of immunomodulatory activity in the treatment groups (significant changes in phagocytic activity).¹⁵ The 3 other studies were unable to be compared because of differences in evaluation methods.

Most double-blind, randomized, controlled trials of echinacea have evaluated its effectiveness in the prevention and treatment of upper respira-tory tract infections (URTIs). In one such trial, no prophylactic effect of echinacea could be demonstrated, although more patients in the group that received echinacea believed they had benefited from the treatment.¹⁶

In other randomized trials of echinacea, researchers found that echinacea did not significantly decrease the incidence, duration, or severity of respiratory tract infections compared with placebo.¹⁷ Other double-blind, randomized, controlled trials have found significant diminution in severity and duration of symptoms-especially at higher doses-in patients with colds or flu-like symptoms.¹⁸

More recently, a Cochrane review of 16 randomized clinical trials of echinacea for treatment of URTIs was done.¹⁹ The authors concluded that the evidence was insufficient to recommend a specific echinacea product for treatment of URTIs. They also noted that, although publication bias may have distorted the results, echinacea might be efficacious. The trial data, however, are weak and inconclusive.

Caveats. The safety and tolerability data suggest that echinacea is a relatively benign substance.²⁰ Adverse effects are rare.²¹

Echinacea products should not be combined with immunosuppressants because of the possibility of pharmacodynamic drug interactions. Echinacea is therefore contraindicated in patients with multiple sclerosis, autoimmune disorders, AIDS, or tuberculosis.²² Because of insufficient safety data, echinacea products are best avoided during pregnancy and lactation, although one study found no evidence of adverse pregnancy outcomes after echinacea consumption.²³ Most researchers also recommend that echinacea not be used for longer than 8 weeks²⁴ because no long-term data are available.

Recommended dosages and formulations. Because a variety of dosages and formulations have been used in clinical trials, the most effective dosage and formulation are not known. The most commonly used preparations in the United States are liquid extract of E purpurea root and echinacea tea. Typical dosing for the extract (for treatment of a URTI) is 3 mL every 3 to 4 hours for the first day or two, then 3 times daily for the subsequent week. Suggested dosing for the tea formulation is 6 to 8 oz 4 times daily for the first 2 days, titrated down to once or twice daily on days 3 through 7.²⁵

ST JOHN'S WORT

This herb, derived from the plant Hypericum perforatum, has been used since ancient times to treat mental disorders, nerve pain, wounds, burns, and insect bites. It has also been used as an antiviral/antibacterial agent. Most recently, it has received widespread attention because of its purported effectiveness as an antidepressant.

Pharmacodynamics. The mechanism of action of St John's wort has not been completely delineated. St John's wort contains at least 10 components that may contribute to its pharmacologic effects.²⁶ Multiple mechanisms of action have been proposed; the most likely is selective inhibition of serotonin, dopamine, and norepinephrine reuptake in the CNS.

Evidence of efficacy. Based on several systematic reviews of St John's wort from the early to mid 1990s,^27,28 the Agency for Healthcare Policy and Research noted that St John's wort was more effective than placebo for the short-term (6- to 12-week) treatment of mild depressive disorders in patients who did not have suicidal tendencies.²⁹ Since that time, other systematic reviews have tended to confirm this statement.^30-33 St John's wort has also been shown to be equivalent to some older medications (for example, imipramine) for the treatment of mild depression.³⁴

Trials that used the herb, a placebo, and a prescription medication, however, have raised many questions.^34,35 In these studies, patients with major depression showed a high rate of response to placebo. These results raised concerns about the generalizability of findings in trials of St John's wort in patients with mild depressive disorders to other populations with depression. Moreover, in a study by Shelton and colleagues³⁶ of the effectiveness of St John's wort in major depression, remission rates were significantly higher in the patients who received St John's wort than in those who received placebo-although the rates were still very low overall.

Trials that compared St John's wort with selective serotonin reuptake inhibitors (SSRIs) but did not use a placebo have all suffered from methodologic errors.^37-41 The effectiveness of the herb compared with that of SSRIs is not known.

Thus, the evidence at this time suggests that St John's wort should not be substituted for conventional antidepressants in patients with moderate or severe depression; however, it may be adequate for short-term treatment of mild depression.

Caveats. The most commonly noted adverse effects associated with St John's wort are photosensitivity, followed by fatigue and GI upset. It is probably relatively benign when used alone; there were only 32 reported adverse effects among 3.8 million patients who used the extract LI 160 between 1991 and 1996.⁴² St John's wort is generally associated with a lower frequency of side effects than low-dose tricyclic antidepressants.

Herb-drug interactions, however, are numerous.⁴³ St John's wort lowers blood concentrations of cyclosporine, amitriptyline, digoxin, indinavir, warfarin, and theophylline. When used in conjunction with oral contraceptives, it has caused intermenstrual bleeding; with loperamide, it has caused delirium; and with nefazodone, it has caused mild serotonin syndrome.

St John's wort has been associated with other herb-drug interactions. Little in vitro or in vivo data on the interaction of St John's wort-or other herbs-and drugs is available; moreover, current in vitro methods for screening conventional medications may have limited application to herbal agents, which usually have numerous constituents whose pharmacokinetics are unknown. However, available data from clinical studies and case reports suggest that St John's wort likely induces cytochrome P-450 (CYP) 3A4 (although it is unlikely to inhibit CYP3A4 or CYP2B6). Thus, any medication that may undergo significant CYP3A4 induction should not be used-or should be used with extreme caution-in patients who are taking St John's wort. Examples of such drugs include tacrolimus, nevirapine, pravastatin, and cyclosporine.

Because several cases of serotonin syndrome have been reported in elderly patients who used hypericum extracts and SSRIs concomitantly, it is also recommended that the combination of St John's wort and an SSRI be avoided.⁴⁴ When switching a patient's medication from an SSRI to St John's wort, use a washout similar to that recommended when switching from one SSRI to another.⁴⁵

Dosing. The effective dose is thought to be 300 mg tid.

GINKGO BILOBA

Ginkgo biloba has been used for over 5000 years in traditional Chinese medicine for various purposes, including treatment of asthma, poor digestion, vascular problems, and dementia. It is one of the most commonly used and most studied herbal products in the world. Published animal studies and clinical trials of ginkgo biloba now number over 400.

Pharmacodynamics. The major active ingredients of ginkgo biloba are flavonoids and terpenoids (ginkgolides and bilobalide). The free-radical scavenging and antioxidant properties of the flavonoids are thought to act synergistically with several organic acids to scavenge free radicals and there- by protect vascular walls and nerve cells.⁴⁶ There is some evidence that ginkgolides are platelet-activating factor antagonists,⁴⁷ but whether they have this property in vivo is unknown.

Evidence of efficacy. The most studied uses of gingko biloba are in the treatment of cognitive deficits, including Alzheimer disease and multi-infarct dementia, and in peripheral vascular disease.

Dementia. Both a systematic review⁴⁸ and a meta-analysis⁶ of the effects of ginkgo biloba on dementia demonstrated overall positive results. The scores of patients who received gingko were 3% higher on the Alzheimer's Disease Assessment Scale Cognitive (ADAS-COG) subscale than the scores of patients who received placebo. These results suggest that the effect of ginkgo on dementia is clinically relevant.⁶

One of the best studies of ginkgo focused on its effect on patients with Alzheimer-type dementia. This large multicenter, randomized, placebo-controlled trial involved 2020 patients.⁴⁹ The investigators found that the patients who received ginkgo biloba showed an average improvement in their ADAS-COG subscale score of 1.4 points (P = .04) and an improvement of 0.14 points in their instrument score on a rated geriatric evaluation by relatives (P = .004). A 4-point improvement on the ADAS-COG subscale is equivalent to a 6-month delay in disease progression. However, the study authors also concluded that it is unclear how long the effects of ginkgo persist. There was no significant difference in the adverse effects experienced by the gingko group and the placebo group.

In adults with healthy cognitive functioning, Solomon⁵⁰ found that ginkgo provides no measurable benefit in memory or related cognitive function.

Peripheral vascular disease. In most of the trials for this indication, gingko biloba produced a greater improvement in pain-free walking distance than placebo.^51-59 A meta-analysis of trials of ginkgo biloba for the treatment of intermittent claudication found that the patients who received ginkgo biloba extract had a significantly greater increase in pain-free walking distance than those who received placebo.⁶⁰ However, ginkgo is less effective than regular walking.⁶¹

Caveats. Ginkgo biloba is generally safe and has no significant adverse effects in healthy patients. However, it can cause GI upset or headache.

Gingko has been associated with 2 cases of subarachnoid hemorrhage and 1 case of hyphema; use it with caution in patients who are also receiving NSAIDs, heparin, or vitamin K antagonists.^62,63 Gingko has also been reported to have raised blood pressure when used with a thiazide diuretic and to have resulted in coma when used with trazadone.⁴³

Dosages and formulations. Many of the trials mentioned above used the extract EGb761 in a dosage of 40 mg, 3 times a day, or a dosage of 80 mg twice daily; duration of treatment in studies has generally ranged from 2 to 6 weeks. This particular extract is standardized to contain 24% flavonoid glycosides and 6% terpenoids. However, other studies have used different regimens; Oken and colleagues'⁶⁴ review of studies of the effect of ginkgo biloba on cognitive function in Alzheimer disease, for example, included trials in which regimens that consisted of 120 to 240 mg of ginkgo biloba extract daily were used for up to 6 months.

SAW PALMETTO

Saw palmetto is used principally to treat benign prostatic hyperplasia.

Pharmacodynamics. Saw palmetto has been shown in vivo to lower dihydrotestosterone levels and raise testosterone levels,⁶⁵ to have antiestrogenic activity,⁶⁶ and to reduce cell proliferation⁶⁷ in prostatic tissue of patients with benign prostatic hyperplasia. The liposterolic (fat-soluble) extract of saw palmetto provides fatty acids, sterols, and esters and is believed to reduce the amount of dihydrotestosterone (an active form of testosterone) locally in the prostate. The specific mechanisms of action appear to be inhibition of the binding of dihydrotestosterone to cytosolic androgen receptors in prostate cells, and α₁-adrenergic blocking.

Evidence of efficacy. A recent systematic review of 16 randomized trials showed saw palmetto to be superior to placebo at reducing nocturia and at increasing peak urinary flow.⁶⁸ The review authors suggested that saw palmetto is similar in effectiveness to finasteride. A 6-month randomized controlled trial corroborated these results, and the investigators concluded that saw palmetto is "a safe and highly desirable option for men with moderately symptomatic benign prostatic hyperplasia."⁶⁹

Caveats. In placebo-controlled trials, side effects have been few and similar to placebo. No herb-drug interactions have been documented.

Dosing. The dosage in most trials has been 320 mg/d or 160 mg bid of a liposterolic extract.⁷⁰

BLACK COHOSH

Black cohosh is indigenous to the eastern United States and Canada and has long been used to treat general malaise, malaria, rheumatism, and menstrual irregularities, and to relieve the pain of childbirth. Its primary use today is in the treatment of menopausal symptoms. Because recent clinical studies have shown that estrogen replacement therapy has significant adverse effects, black cohosh is likely to become more widely used.

Pharmacodynamics. The active component of black cohosh is not known. The possibility that the herb has estrogenic activity has been studied, but the evidence is contradictory.⁷¹

Evidence of efficacy. Three of 4 studies of black cohosh found the herb to be beneficial for treating hot flashes.⁷² However, there are several problems with these trials:

There was a lack of rigor in study design (some were not placebo-controlled, and one used diazepam as a treatment control).

The trials were of short duration (less than 6 months).

Although almost all standardized trials used a standardized extract (Remifemin), the formulations and dosages of this product differed depending on when the trial was conducted.

Caveats. The American College of Obstetrics and Gynecology has stated that black cohosh might be helpful in the short-term treatment of the vasomotor symptoms of menopause⁷³; however, this guarded endorsement is based only on consensus and expert opinion.

Dosages and formulations. Almost all the clinical studies of black cohosh have used Remifemin. The optimal dose of black cohosh is not known. Most sources recommend 40 mg/d.

References:

REFERENCES:1. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-1575.
2. Ernst E, White A. The BBC survey of complementary medicine use in the UK. Complement Ther Med. 2000;8:32-36.
3. De Smet P. Herbal remedies. N Engl J Med. 2002; 347:2046-2056.
4. Bonakdar RA. Herb-drug interactions: what physicians need to know. Patient Care. January 2003. Available at: www.patientcareonline.com. Accessed March 1, 2003.
5. Crock RD, Jarjoura D, Polen A, Rutecki GW. Confronting the communication gap between conventional and alternative medicine: a survey of physicians' attitudes. Altern Ther Health Med. 1999;5:61-66.
6. Ernst E. The risk-benefit profile of commonly used herbal therapies: ginkgo, St John's wort, ginseng, echinacea, saw palmetto, and kava. Ann Intern Med. 2002;136:42-53.
7. Barrett B, Kiefer D, Rabago D. Assessing the risks and benefits of herbal medicine: an overview of scientific evidence. Altern Ther Health Med. 1999; 5:40-49.
8. Correspondence. Alternative medicine: the case of herbal remedies. N Engl J Med. 1999;340:564-566.
9. Blumenthal M. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, Tex: American Botanical Council; 1998.
10. Ernst E, Pittler MH. Alternative therapy bias. Nature. 1997;385:480.
11. Pittler MH, Abbot NC, Harkness EF, Ernst E. Location bias in controlled clinical trials of complimentary/alternative therapies. J Clin Epidemiol. 2000;53:485-489.
12. Gunning K. Echinacea in the treatment and prevention of upper respiratory tract infections. Best Practice. 1999;171:198-200.
13. Tyler V, Robbers JE. Tyler's Herbs of Choice: The Therapeutic Use of Phytomedicinals. New York: The Haworth Herbal Press; 2000.
14. Melchart D, Linde K, Worku F, et al. Immunomodulation with echinacea: a systematic review of controlled clinical trials. Phytomedicine. 1994;1:245.
15. Melchart D, Linde K, Worku F, et al. Results of five randomized studies on immunomodulatory activity of preparations of echinacea. J Altern Complement Med. 1995;1:145.
16. Melchart D, Walther E, Linde K, et al. Echinacea root extracts for the prevention of upper respiratory tract infections: a double-blind, placebo-controlled randomized trial. Arch Fam Med. 1998;7:541-545.
17. Grimm W, Muller HH. A randomized controlled trial of the effect of fluid extract of echinacea purpurea on the incidence and severity of colds and respiratory infections. Am J Med. 1999;106:138-143.
18. Hoheisel O, Sandberg M, Bertram S, et al. Echinagard treatment shortens the course of the common cold: a double-blind, placebo-controlled clinical trial. Eur J Clin Res. 1997;9:261-268.
19. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2000;CD000530.
20. Giles JT, Palat CT 3rd, Chien SH, et al. Evaluation of echinacea for treatment of the common cold. Pharmacotherapy. 2000;20:690-697.
21. Mullins RJ. Echinacea associated anaphylaxis. Med J Aust. 1998;168:170-171.
22. Miller L. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998;158:2200-2211.
23. Gallo M, Sarkar M, Au W, et al. Pregnancy outcome following the gestational exposure to echinacea: a prospective controlled study. Arch Intern Med. 2000;160:3141-3143.
24. Newall CA, Anderson LA, Philipson JD. Herbal Medicine: A Guide for Healthcare Professionals. London: The Pharmaceutical Press; 1996.
25. Kligler B. Echinacea. Am Fam Physician. 2003; 67:77-80, 83.
26. Bennett DA, Phun L, Polk JF, et al. Neuropharmacology of St John's wort (hypericum). Ann Pharmacother. 1998;32:1201.
27. Linde K, Ramirez G, Mulrow CD, et al. St John's wort for depression: an overview and meta-analysis of randomized clinical trials. BMJ. 1993; 313:253-258.
28. Ernst E. St John's wort, an antidepressant? A systematic, criteria-based review. Phytomedicine. 1995;2:67.29. Treatment of depression-newer pharmacotherapies. Summary, evidence report/technology assessment no. 7. Rockville, Md: Agency for Health Care Policy and Research; 1999. AHCPR publication 99-E014. Available at: http://www.ahcpr.gov/clinic/ epcsums/deprsumm.htm. Accessed August 25, 2003.
30. Gaster B, Holroyd J. St John's wort for depression: a systematic review. Arch Intern Med. 2000;160: 152-156.
31. Williams JW. A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med. 2000;132: 743-756.
32. Linde K, Mulrow CD. St John's wort for depression. Cochrane Database Syst Rev. 2000;2:CD000448.
33. Whiskey E, Werneke U, Taylor D. A systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review. Int Clin Psychopharmacol. 2001;16:239-252.
34. Phillip M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: a randomized multicentre study of treatment for eight weeks. BMJ. 1999;319: 1534-1538.
35. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287:1807-1814.
36. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John's wort in major depression: a randomized controlled trial. JAMA. 2001;285:1978-1986.
37. Harrer G. Comparison of equivalence between St John's wort extract LoHyp-57 and fluoxetine. Arzneimittel-Forschung. 1999;49:289-296.
38. Schrader E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized controlled study in mild-moderate depression. Int Clin Psychopharmacol. 2000;15:61-68.
39. Brenner R, Azbel V, Madhusoodanan S, Pawlowska M. Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther. 2000;22:411-419.
40. Behnke K, Jensen GS, Graubaum HJ, Gruenwald J. Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression. Adv Ther. 2000;19:43-52.
41. van Gurp G, Meterissian GB, Haiek LN, et al. St John's wort or sertraline? Randomized controlled trial in primary care. Can Fam Physician. 2002;48: 905-912.
42. Hippius H. St John's wort (hypericum perforatum): an herbal antidepressant. Curr Med Res Opin. 1998;14:171.
43. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs; a systematic review. Drugs. 2001;61(15):2163-2175.
44. Lantz MS, Buchalter E, Giambanco V. St John's wort and antidepressant drug interactions in the elderly. J Geritr Psychiatry Neurol. 1999;12:7.
45. Brinker F. Herb Contraindications and Drug Interactions. 2nd ed. Sandy, Ore: Eclectic Medical Publications; 1998.
46. Sastre J, Millán A, García de la Asunción J, et al. A ginkgo biloba extract (Egb 761) prevents mitochondrial aging by protecting against oxidative stress. Free Radic Bio Med. 1998;24:298-304.
47. Braquat P, Hosford D. Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents. J Ethnopharmacol. 1991;32: 135-139.
48. Ernst E, Pittler MH.Ginkgo biloba for dementia: a systematic review of double-blind placebo-controlled trials. Clin Drug Investigation. 1999;17:301-318.
49. Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double blind, randomized trial of an extract of ginkgo biloba for dementia. JAMA. 1997; 278:1327-1332.
50. Solomon PQ, Adams F, Silver A, et al. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002;288:835-840.
51. Bauer U. 6-Month double-blind randomised clinical trial of Ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneimittelforschung. 1984;34:716-720.
52. Blume J, Kieser M, Holscher U. Placebo-controlled double-blind study of the effectiveness of ginkgo biloba special extract EGb 761 in trained patients with intermittent claudication. Vasa. 1996;25: 265.
53. Ginkgo biloba extract (Egb 761). In: DeFeudis FV, ed. Pharmacological Activities and Clinical Applications. Paris: Elsevier; 1991.
54. Rokan (ginkgo biloba). In: Funfgeld EW, ed. Recent Results in Pharmacology and Clinic. Berlin: Springer-Verlag; 1988.
55. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet. 1992;340:1136.
56. Thomson GJ, Vohra RK, Carr NJ, et al. A clinical trial of ginkgo biloba extract in patients with intermittent claudication. Int Angiol. 1990;9:75.
57. Saudreau FD, Serise JM, Pillet J, et al. Efficacy of an extract of ginkgo biloba in the treatment of chronic obliterative arteriopathies of the lower limbs of stage III of Fontaine's classification. J Mal Vasc. 1989;14:1477.
58. Rudofsky G. Effect of ginkgo biloba extract in arterial occlusive disease. Randomized placebo controlled crossover study. Fortschr Med. 1987;105(20): 397-401.
59. Bauer U. Ginkgo biloba extract in the treatment of arteriopathy of the lower extremities. A 65 week trial. Presse Med. 1986;15:1546.
60. Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med. 2000;108: 276.
61. Leng GC, Fowler B, Ernst E. Exercise for intermittent claudication. Cochrane Database Syst Rev. 2000;CD000990.
62. Rowin J, Lewis SI. Spontaneous bilateral subdural hematomas associated with chronic ginkgo biloba ingestion. Neurology. 1996;46:1775.
63. Vale S. Subarachnoid haemorrhage associated with ginkgo biloba. Lancet. 1998;352:36.
64. Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol. 1998;55:1409-1415.
65. Di Silverio F, Monti S, Sciarra A, et al. Effects of long term treatment with Serenoarepens (Permixon) on the concentrations and regional distributions of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate. 1998;37:77-83.
66. Di Silverio F, D'Eramo G, Lubrano C, et al. Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hyperplasia. Eur Urol. 1992;21:309-314.
67. Vacherot F, Azzouz M, Gil-Diez-De-Medina S, et al. Induction of apoptosis and inhibition of cell proliferation by the lipido-sterolic extract of Serenoa repens (LSESr, Permixon) in benign prostatic hyperplasia. Prostate. 2000;45:259-266.
68. Wilt T, Ishani A, Stark G, et al. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2000;CD001423.
69. Marks LS, Partin AW, Epstein JI, et al. Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia. J Urol. 2000; 163:1451-1456.
70. Saw palmetto. Rockville, Md: Pharmacopeal Convention; 2002. Available at: http://www.usp.org. Accessed July 21, 2003.
71. Questions and answers about black cohash and the symptoms of menopause. Available at: http:// ods.od.nih.gov/factsheets/blackcohash pf.html. Accessed March 1, 2003.
72. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med. 2002;137:805-813.
73. ACOG Practice Bulletin: use of botanicals for management of menopausal symptoms. Available at: http://www.acog.org/from_home/publications/ misc/pb028.htm. Accessed March 1, 2003.
74. Wilt TJ, Ishani A, Stark G, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia. A systematic review. JAMA. 1998;280:1604-1609.
75. Cohen JD, Eisenberg DM. Potential malpractice liability associated with complementary and integrative medical therapies. Ann Intern Med. 2002;136: 596-603.
76. Au AM, Ko R, Boo FO, et al. Screening methods for drugs and heavy metals in Chinese patent medicines. Bull Environ Contam Toxicol. 2000;65:112-119.
77. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Int Med. 2002;252:107-113.
78. Marcus D, Grollman A. Botanical medicines: the need for new regulations. N Engl J Med. 2002; 347:2073-2076.
79. Winslow LC, Kroll DJ. Herbs as medicines. Arch Intern Med. 1998;158:2192-2199.