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Herbalists, Scientists and Trade Organizations Criticize JAMA Report Of NIH Study of St. John's Wort

St. John's Wort Study Misinterpreted
Austin TX, 9 April 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). 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 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 US, 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.

Study design

The study conducted from December 1998 to June 2000 included 340 moderate to severely depressed patients who were randomly assigned to three groups. Over an eight-week period, one group received a dose between 9001500 milligrams of a leading brand of St. John's wort extract, one group took the antidepressant drug sertraline (50100 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.

Study sensitivity and accuracy

According to Jerry Cott, PhD, 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.

Cott added that "this study does not invalidate the use of St. John's wort 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."

Study fails to show effectiveness — rather than shows ineffectiveness

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.

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."

Difficulties facing trials of antidepressants

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 antidepressant, 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.

Study conclusions based on "secondary measures" are challenged

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. However, we know that this is not the case; looking at the body of published research as a whole, both sertraline and St. John's wort are effective."

History of studies on St. John's wort

"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 to 10 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.

Blumenthal 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 antidepressants."

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 its publication on 10 April, so it is not possible to adequately evaluate all the details.

Study funding and background

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 US. 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.

Other study of St. John's wort and major depression

Last April, another US-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 US as Kira® by Lichtwer Pharma USA).

About St. John's wort and other research

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.


American Botanical Council (ABC).end-of-story

NIH Study On Depression Called Misleading
Washington DC, 9 April 2002

The Council for Responsible Nutrition (CRN) and expert scientists today questioned the value of a study of St. John's wort on moderate to severe depression to be published in the April 10 issue of the Journal of the American Medical Association (JAMA), calling it "misdirected and inconsequential."

St. John's wort, the most commonly used antidepressant in Germany and one of the top five selling botanicals in the United States, is recommended and proven beneficial only for mild to moderate depression, based on more than 30 published clinical studies and several meta-analyses and systematic reviews. This new, multi-million dollar, NIH-sponsored study was targeted at moderate to severe depression, a use not recommended or supported for St. John's wort.

NIH trial found no difference among St. John's wort, Zoloft®, and placebo for severely depressed patients

This NIH-sponsored clinical trial compared St. John's wort (an herbal extract), sertraline (better known as Zoloft®, a prescription antidepressant, used as a positive control), and placebo (dummy treatment, used as negative control) for the treatment of moderate to severe depression. The detailed results of this new study indicate that the patient group was, in general, non-responsive to any treatment offered. According to the studies' authors (Davidson et al.), "On the two primary outcome measures, neither sertraline nor H. perforatum [St. John's wort] was significantly different from placebo."

Scientists affirm value of St. John's wort for mild to moderate depression

According to John Cardellina, PhD, vice president, botanical science and regulatory affairs, CRN, "This new report dismisses the scientific fact that St. John's wort has been proven safe and beneficial for the treatment of mild to moderate depression, stress and anxiety, according to a substantial body of evidence in the medical literature based on more than 30 controlled clinical studies and three meta-analyses or systematic reviews."

Norman E. Rosenthal, MD, clinical professor of psychiatry at Georgetown University and author of The Emotional Revolution, said, "The findings of this study are of limited value, because St. John's wort is not generally used for moderate to severely depressed people. Instead, extensive research has demonstrated the herb's efficacy for mild to moderate depression. It would be a shame if we discarded St. John's wort as a treatment for mildly to moderately depressed persons on the basis of these findings."

Scientist questions study's focus on severe depression

"It is difficult to understand why NIH chose to study this type of patient population," said Jerry Cott, PhD, psychopharmacologist and former chief of the Psychopharmacology Research Program at the National Institute of Mental Health (NIMH), NIH. "It appears that they enrolled a population of patients who were too depressed to respond to either sertraline or hypericum. If they had designed the study to focus on mild to moderate depression, then we likely would have seen a very different result with both standard antidepressant and St. John's wort. The lack of response in the standard treatment (positive control) group prevents any valid conclusions from this study regarding the effectiveness of St. John's wort."


Council for Responsible Nutrition (CRN), via PR Newswire.end-of-story

New St. John's Wort Study Misleads Public
Silver Spring MD, 9 April 2002

A study on the popular herbal remedy St. John's wort published in the April 10 edition of the Journal of the American Medical Association (JAMA) concluded that neither St. John's wort nor the widely prescribed antidepressant Zoloft® are more effective overall than placebo in treating severe forms of depression. The American Herbal Products Association (AHPA) and the National Nutritional Foods Association (NNFA) are critical of the study saying that it ignores the traditional use of St. John's wort and recent modern clinical trials that have demonstrated conclusively that St. John's wort is effective in the treatment of "mild to moderate" depression.

"This is a quintessential case of the Emperor's New Clothes," said Steven Dentali, PhD, vice president for scientific and technical affairs for AHPA. "It is inexplicable that JAMA has created such fanfare over the fact that St. John's wort is not shown to be effective for a condition that it was never intended to treat. The real story here is that if this study is believable it showed that a blockbuster drug, with sales of over $2 billion and prescribed to millions of Americans for severe forms of depression, may be no more effective than placebo."

St. John's wort is one of the top five selling herbal products in the United States and is the number one antidepressant used in Germany for the treatment of mild to moderate depression. The new multi-million-dollar National Institutes of Health study was conducted on 340 patients diagnosed as having major depression. The study broke patients into three groups: assigning one group to take a leading brand of St. John's wort, another group to take the anti-depressant pharmaceutical Zoloft® and the third group a placebo (sugar pill). The researchers reported that neither St. John's wort nor Zoloft® were significantly different from placebo.

"This research in no way invalidates the scores of clinical studies and analyses that have clearly demonstrated that St. John's wort is effective for mild to moderate depression," said Phil Harvey, PhD, director of science and quality assurance for NNFA. "In fact, contemporary researchers have found evidence that St. John's wort extracts are `therapeutically equivalent to' and `at least as effective as' some commonly prescribed antidepressant drugs. Researchers also note that people have better tolerance for the herb."

Relevant facts

According to Web MD, in the US, approximately 10% of people suffer from major depression at any one time, and 20-25% suffer a major depressive episode at some point during their lifetimes.

According to Nutrition Business Journal, St. John's wort sales in 2000 were $180 million.

According to Med Ad News, Zoloft® is the third best-selling selective serotonin reuptake inhibitor and the leading antidepressant in terms of share of new prescriptions. According to IMS Health Inc., 2000 Zoloft® sales reached $2.14 billion.


American Herbal Products Association (AHPA).end-of-story



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