By Shankar Vedantam

According to the first large study to evaluate it in the United States, St. John's wort, the popular herbal remedy, is useless for alleviating severe depression.

The study, which tested the herb for eight weeks among 200 patients whose depression made it hard for them to get out of bed in the morning or look after their children, found the supplement was no better than a placebo.

The research casts doubt on the effectiveness of St. John's wort, which has been marketed as a safe and effective alternative to prescription antidepressants. About 30 previous studies found the herbal supplement effective for depression, mostly in mild to moderate cases.

Richard Shelton, the lead author of the new research, said the fact that none of the previous studies had produced negative findings suggested that the work may have been poorly designed or suffered from the bias of scientists eager to prove a pet hypothesis.

Far from settling what has long been a matter of dispute, the new study is likely to spur greater controversy between practitioners of mainstream and alternative medicine.

As more Americans try alternative remedies, scientists are struggling to evaluate natural and herbal cures with the rigor and rules of conventional medicine. This controversy is part of that endeavor.

Supporters of herbal medicines pointed out that Shelton's study examined only patients with serious depression -- it did not address the effectiveness of the herb against milder depression. Shelton agreed.

One of the authors of a study that last year found St. John's wort useful suggested that far from proving the herb useless, an unintentional bias against it may have tipped the new study against the supplement.

"You have a host of literature on the other side that you cannot dismiss," said Ronald Brenner, chairman of psychiatry at St. John's Episcopal Hospital in New York City and professor of clinical psychiatry at State University of New York downstate in Brooklyn, who found St. John's wort useful in treating mild to moderate depression. "There is no study that is unflawed. If there are flaws in the other studies, there are flaws here, too."

Brenner's study, which was one of just a few studies of St. John's wort conducted in the United States, lasted six weeks and tested the herb among 30 patients. He found it was as effective as the conventional antidepressant Zoloft. Shelton's study tested St. John's wort against placebo pills.

Brenner and other St. John's wort supporters said that in most depression studies, 30 percent to 40 percent of patients report getting better while taking inert pills. There was a lower response rate in Shelton's study, which could mean that researchers subtly communicated to patients that neither the herb nor the placebo would work, or that the particular group of patients studied would not have responded to any treatment, they said.

"It's possible that everyone happened to be people who wouldn't have responded to any treatment," Shelton said. But "that's unlikely."

In interviews, Shelton and Brenner agreed that one potential problem with both of their studies was that neither had three groups of patients -- one taking St. John's wort, one taking a standard antidepressant and one on a placebo.

Both said they would regard as definitive a study that is nearing completion. Jointly sponsored by the National Institute of Mental Health and the National Center for Complementary and Alternative Medicine, it will be the largest and most comprehensive study of St. John's wort. The study will evaluate the herbal supplement in treating major depression.

The latest study was supported by a grant from the pharmaceutical company Pfizer Inc., which makes Zoloft as well as St. John's wort extract.

It is not clear how the scientific tussle will affect consumption of St. John's wort. Sales of the herb are on the decline -- down from $310 million in 1998 to $195 million last year, according to Grant Ferrier, editor of the Nutrition Business Journal in San Diego.

Mark Blumenthal, founder of the American Botanical Council, a nonprofit group that aims to educate people about medicinal herbs, speculated that the reduced sales were caused by recent reports of problems with herbal supplements and findings that St. John's wort could interfere with AIDS medicines, cardiac drugs and oral contraceptives.

Washington Post April 18, 2001; Page A02

Journal of the American Medical Association 2001; 285: 1976-1986