Austin, TX. (April 9, 2002).

The American public may be receiving misleading information about the effectiveness of the popular herbal dietary supplement St. John’s wort, says the nonprofit American Botanical Council. ABC and some of its scientific advisors noted that a new clinical study being released to the media is being misinterpreted.

The long-awaited government-sponsored study on the effectiveness of the popular herb is being published this Wednesday, April 10 in the Journal of the American Medical Association. The study, conducted by researchers at Duke University and 11 other medical centers in the U.S., concludes that neither St. John’s wort nor the drug sertraline showed any measurable benefit in patients with more severe forms of depression. Although the study was conducted in patients with moderate to severe depression, the herb has been tested and used mainly in patients with less severe forms of depression.

The study conducted from December 1998 to June 2000 included 340 moderate to severely depressed patients that were randomly assigned to three groups. Over an eight-week period, one group received a dose between 900-1500 milligrams of a leading brand of St. John’s wort extract, one group took the antidepressant drug sertraline (50-100 mg), popularly know by its trade name Zoloft , and the third group took a placebo, a sugar or dummy pill. Patients who responded to treatment continued to receive their assigned treatment for an additional 18 weeks. Curiously, fewer of the patients in both the herb and the drug groups responded to the treatments than did those in the placebo group.

According to Jerry Cott, Ph.D., former Chief of the Psychopharmacology Research Program, at the National Institute of Mental Health, the NIH designed this trial to include a standard anti-depression drug (sertraline) as “an active comparator” to document the sensitivity of the trial, that is, the ability of this trial to detect an actual treatment effect. “The fact that the sertraline was not effective in the primary measures of depression demonstrates (according to the NIH’s own design protocol) that this trial lacked assay sensitivity and should not be considered a successful study.” Dr. Cott was involved in the original design of the trial when he worked for the NIMH.

He added that “this study does not invalidate the use of SJW in clinical depression. There are still many well-controlled trials supporting the use of St. John’s wort in mild to moderate depression, and additional studies with more appropriate patient populations are in progress.”

In Dr. Cott’s estimation, this study could be considered “neutral”, one that simply fails to show effectiveness of either treatment rather than proving the test drug doesn’t work. “This result is not uncommon in pharmaceutical industry-sponsored studies, though normally they are not published. The study simply lacked the sensitivity to detect a difference.” Dr. Cott is an expert on the effects of herbs and conventional drugs on mental disorders, including depression. He also formerly worked at the Food and Drug Administration where he evaluated clinical studies on new antidepressant drugs. (More information available at jerrycott.com.)

Dr. Steven Bratman, a physician-author in Fort Collins, Colorado agrees “The conclusion of the study is taken too far. Both treatments have been found effective in the majority of clinical trials. This study, while not supporting the use of St. John’s wort, doesn't discredit it either.”

Dr. Bratman, co-author of the Natural Pharmacy: Clinical Evaluation of Medicinal Herbs, explained the intricacies of the interpretation of clinical studies of this type. “In many studies of antidepressants, perhaps as many as one-third, the tested drug doesn't do any better than placebo. The cause is probably a combination of the high placebo effect often seen in studies testing antidepressants and the relative coarseness and subjectivity of the type of rating scales that must be used to evaluate severity of depression.” Dr. Bratman explained that these rating scales are by their very nature less precise than biomedical tests, such as those that measure cholesterol levels. “In consequence, it is quite easy for a truly effective anti-depressant, such as sertraline, to fail to prove efficacy in a given double-blind, placebo-controlled trial. The problem is not the treatment itself, but in the difficulties of studying such treatments.”

Because this study included sertraline, a drug that previously has been shown effective, the inescapable conclusion is that details of the patient group and the methods by which the ratings were determined were such that this study could not discern the effectiveness of a known effective treatment. This also applies to St. John’s wort (which has also been shown effective in many studies) as it does to sertraline.

Bratman took issue with the authors of the study when they used a secondary outcome measure to conclude that sertraline was more effective than placebo and therefore better than St. John’s wort. According to the standard rules of interpreting clinical studies, one should take only the primary outcome measures as meaningful, he explained. On those measures, neither sertraline nor St. John’s wort was effective. Digging into secondary measures is widely accepted as being inappropriate, he added.

Thus, when the authors conclude that St. John’s wort is ineffective for moderate depression and shouldn't be used, noted Bratman, “it would be equally valid to say that sertraline is ineffective for moderate depression, and shouldn't be used,” he added. "However, we know that this is not the case; looking at the body of published research as whole, both sertraline and St. John's wort are effective."

“Herbs should be tested according to a reasonable expectation of their previously documented benefits,” said Mark Blumenthal, founder and executive director of the nonprofit American Botanical Council. He referred to10 previous studies on St. John’s wort extract where the herb preparation was compared directly with pharmaceutical antidepressants for treatment of mild to moderate depression. These studies indicated a comparable efficacy with St. John’s wort and the conventional drugs.

He also noted, “In Germany many physicians use St. John’s wort as a first-line remedy for mild to moderate depression; if it doesn’t work, then they can always put the patient on more powerful, pharmaceutical anti-depressants.”

Blumenthal added, “It is important for the NIH to continue conducting clinical trials on many popular herbal dietary supplements. This adds to the growing body of scientific information on their safety and efficacy. This process is a constructive contribution to the maturation of the herbal movement. At the same time, however, it is equally important that the results of these studies are accurately interpreted and communicated to the public. Unfortunately, it appears that some aspects of this first NIH-funded study are not being properly characterized.” He also noted that the full text of the study is not available prior to this Wednesday, so it is not possible to adequately evaluate all the details.

The study was funded with $4 million from the National Institutes of Health’s National

Center for Complementary and Alternative Medicine. It was the first clinical trial established by the NIH to test the efficacy of herbal remedies. St. John’s wort was chosen because at the time the study was designed and funded in 1996, St. John’s wort had begun to significantly increase in popularity in the U.S. This new awareness was based on media reports of a meta-analysis (statistical review of clinical trials) of 23 European clinical trials that showed that St. John’s wort was safe and effective in treating mild to moderate forms of depression.

Last April, another U.S.-based multi-center clinical trial on St. John’s wort also failed to show any activity for the herb, again in more severely depressed patients. The placebo-controlled study was criticized for targeting patients that were too chronically and severely depressed and thus not consistent with the profile of patients normally included in clinical trials. It was also criticized for not including an active control, like the drug sertraline (Zoloft , produced by Pfizer, the funder of the study), to determine the level of response by the patients. Both trials used the leading German St. John’s wort extract (known in Germany as Jarsin 300, made by Lichwter Pharma of Berlin, and sold in the U.S. as Kira by Lichtwer Pharma USA).

St. John’s wort, also known by its scientific name Hypericum perforatum, is a traditional European herb that has drawn significant attention for its ability to help elevate mood in mild or moderately depressed people. At least 22 controlled clinical trials have been published in European medical journals suggesting that St. John’s wort extract is a safe and effective remedy for mild to moderate depression. An estimated 131 million doses of St. John’s wort were prescribed by psychiatrists in Germany in 1999, according to German sources.

The American Botanical Council is the nation's leading non-profit organization addressing research and educational issues regarding herbs and medicinal plants. The 13-year-old organization occupies a 2.5 acre site in Austin, Texas where it publishes HerbalGram, a peer-reviewed journal on herbal medicine, and will publish a forthcoming book and continuing education course for healthcare professionals, The ABC Clinical Guide to Herbs, containing an extensive monograph on the safety and efficacy of St. John’s wort. Information contact: ABC at P.O. Box 144345, Austin, TX 78714-4345, ph: 512-926-4900, fax: 512-926-2345. Website: www.herbalgram.org.

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