St. John's Wort Set for U.S. Clinical Trials

After years of clinical studies in Germany, St. John's wort (Hypericum perforatum) is poised to undergo scientific scrutiny in the United States as a treatment for depression. Never clinically tested in this country, the yellow-blossomed, roadside weed, native to much of America's Northwest and to many other parts of the world, is now the focus of four such trials. Perhaps foremost among them is a $4.3 million study funded by the Office of Alternative Medicine (OAM) in the National Institutes of Health. Enrollment of 336 patients will begin in the spring at 12 centers nationwide. Cosponsored by the National Institute of Mental Health and the Office of Dietary Supplements, the trial arises from growing consumer interest in alternative medicine and a boost in OAM's 1999 budget to $50 million, 2.5 times its 1998 allocation.1 Also, recruitment of 200 subjects is under way in a 10-site, placebo-controlled trial headed by Richard Shelton, an associate professor of psychiatry at Vanderbilt University School of Medicine. Funding is via an unrestricted grant from pharmaceutical company Pfizer Inc. of New York, which manufactures Zoloft, the active control in the NIH study. However, Shelton says the Vanderbilt trial will not have an active control arm. Another trial is being conducted by Harvard Medical School. Biotechnology company PharmaPrint of Irvine, Calif., intends to mount a fourth study later this year. St. John's wort has been used medicinally for millennia, to treat kidney and lung ailments, insomnia and depression, and externally for wounds.2 The plant has been involved in more than 20 clinical trials in Germany, where one extract of it is the country's best-selling antidepressant.3 Most of those trials showed evidence of safety and efficacy in cases of mild to moderate depression.4 "I do find it curious that in the United States we tend to not believe something if studies were done outside this country," says Alan L. Miller, a naturopath with Thorne Research, a private company in Sandpoint, Idaho, that develops and markets St. John's wort and other nutritional supplements to pharmacies and clinics. But he adds, "It's always nice to see how plant medicines work compared to other drugs out there." Murali Doraiswamy, director of clinical trials in the psychiatry department at Duke University Medical Center, which is conducting the NIH-sponsored trial, says previous studies "have not been long-term, [have] not been dosed in a fashion we consider to be optimal, and [have not used] the instruments we use for measuring outcome." He says the German trials did not compare Hypericum with serotonin-specific reuptake inhibitors (SSRIs) such as Prozac or Zoloft, which have been slower to gain market share in Germany than in America. Moreover, diagnosis of the German patients as mildly to moderately depressed was based mostly on the International Classification of Diseases. It is less specific in detailing symptoms than the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) used in America, notes Benedetto Vietiello, NIH's project officer for the Hypericum study. He adds that the Hamilton Rating Scale for Depression, one of several interview-based techniques employed in both countries to assess symptoms, was used less rigorously in Germany. This resulted in recruitment of subjects who had, for example, adjustment disorder with depression, a condition different from major depression. The NIH trial will be double blinded, and patients diagnosed as moderately depressed will be randomized into three groups that receive Zoloft, a placebo, or IL-160, the most-studied extract of Hypericum. IL-160 is standardized on 0.3 percent content of the active ingredient, hypericin. However, Hypericum may have up to 10 active constituents, and Doraiswamy says there is limited evidence that at least one of them, hyperforin (related to hop bitters), could be more active than hypericin. The dosage for those who receive IL-160 will begin at 900 milligrams daily, but could double by the end of the trial's eight-week "active" phase. Those who receive Zoloft will start with 50 mg daily, which could rise to 150 mg. There is some evidence that Hypericum in higher doses will be more effective in treating moderate or severe depression, and the trial will help to clarify that question. Patients classified as responders in any of the three arms will be followed up for an additional four months, to see if initial efficacy is maintained, and to monitor long-term tolerability. Zoloft has a relatively benign side-effect profile for an SSRI, and has generally good drug-to-drug interactions, which makes it popular among primary care physicians who may treat people with multiple ailments. Hypericum is extremely well tolerated at the 900 mg dosage, according to results of about 1,000 patients thus treated in Germany, says Vietiello. Of course, clinical trials won't answer how Hypericum works. "There's a lot of preclinical work that hasn't been done yet," remarks Robert B. Raffa, an associate professor of pharmacology at Temple University, and senior author of a recent review on the plant's neuropharmacology.5 Raffa and his student team were the first to have the botanical extensively screened for receptor binding. These tests showed that the highest levels of inhibition were at muscarinic cholingeric receptors (mAChR) and sigma receptors. The level of mAChR binding might help to estimate clinically relevant concentrations of Hypericum extract, but the most intriguing finding was the sigma receptor affinity. Once thought to be an opioid receptor, sigma now is most closely associated with the antipsychotic drug haloperidol, although the receptor's function is not completely defined, Raffa says. More preclinical work should be done on Hypericum and the sigma receptor, he thinks. The compound should be administered chronically to rats, and biochemical changes monitored. Receptor screens of Hypericum's other active constituents also remain to be performed. Raffa's review concluded that there are three major possibilities for the compound's mechanism of action: It is similar to that of synthetic antidepressants; it is due to some unknown mechanism; or, the most likely possibility, there is a combination of mechanisms too weak individually to yield therapeutic effects. "The interesting part of this is the broader question of whether CNS (central nervous system) drugs might be more beneficial when they have multiple mechanisms of action," he comments. Multiple actions could share the common therapeutic end point of antidepression, but could have different adverse effects that might not be additive, thus avoiding the more severe side effects that can accompany a single-action compound, he explains. Doraiswamy says studies of Hypericum's interaction with SSRIs would be among work to follow the current clinical trials. He doesn't know whether the botanical might eventually be labeled with indications or sold by prescription. But he does predict, "What we'll see is a greater interest in putting herbal products through scientific tests. And, hopefully, some of these products will turn out to be effective." Steve Bunk is a contributing editor for The Scientist . P. Smaglik, "NIH, NSF post biggest gains in FY 1999 budget," The Scientist, 12[22]:1, Nov. 9, 1998. J.M. Cott, A. Fugh-Berman, "Is St. John's wort (Hypericum perforatum) an effective antidepressant?" The Journal of Nervous and Mental Disease, 186:500-1, August 1998. H.P. Volz, "Controlled clinical trials of hypericum extracts in depressed patients-an overview," Pharmacopsychiatry, 30 Suppl. 2:72-6, 1997. K. Linde et al., "St. John's wort for depression-an overview and meta-analysis of randomized clinical trials," British Medical Journal, 313:53-8, 1996. D.A. Bennett Jr. et al., "Neuropharmacology of St. John's wort (Hypericum)," The Annals of Pharmacotherapy, 32:1201-7, Nov. 1998.

St. John's Wort Set for U.S. Clinical Trials

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