Supplements Face JAMA's Fire

September 16, 2003

4 Min Read
Supplements Face <I>JAMA</I>'s Fire

CHARLESTON, S.C.--Direct evidence that St. John's wort interferes with drug metabolism was published in the Sept. 17 issue of The Journal of the American Medical Association (JAMA) (290, 11:1500-4, 2003) ( An open-label crossover trial led by John S. Markowitz, PharmD, of the University of South Carolina, further elucidated the herb's effects on the cytochrome P450 (CYP) enzymes, which are extensively involved in drug metabolism.

To determine the herb's actions on the CYP 3A4 enzyme and the drug efflux transporter P-glycoprotein (CYP 2D6)--which, together, are involved in the metabolism of approximately 70 percent of prescription and over-the-counter medications--researchers enrolled 12 healthy, nonsmokers who were not taking dietary supplements. Subjects were given drugs at baseline (30 mg of dextromethorphan, a cough suppressant, and 2 mg of alprazolam, an anti-anxiety medication) and blood tests were taken to establish baseline enzyme activity. After a minimum seven-day washout period, all subjects were instructed to take 300 mg of Kira St. John's wort (marketed in the United States by Lichtwer Pharma, Eatontown, N.J.) three times daily. After two weeks of herbal therapy, subjects were given the drugs again, and blood tests were taken.

Blood test comparisons showed alprazolam was eliminated from plasma twice as quickly during St. John's wort treatment than at baseline. After 36 hours, only seven of 12 participants had measurable alprazolam concentrations compared to all 12 participants at baseline. At 48 hours, none of the participants exhibited measurable alprazolam concentrations compared to 11 of 12 volunteers at baseline. Researchers concluded this increased clearance was likely due to CYP 3A4 induction, although the herb did not appear to affect CYP 2D6 activity.

"These results indicate that long-term administration of St. John's wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP 3A4 substrates, which represent at least half of all marketed medications," the authors concluded. "These findings underscore the potential problems associated with the widespread practice of using herbal products concomitantly with conventional medications."

Catherine D. DeAngelis, M.D., MPH, JAMA editor, and Phil B. Fontanarosa, M.D., JAMA corresponding author, commented on these conclusions in an accompanying editorial in which they suggested dietary supplements should be regulated as drugs (290, 11:1519-20, 2003). "The study by Markowitz et al adds to the growing literature on the biological actions and adverse effects of other dietary supplements such as ephedra, yohimbine and saw palmetto," they wrote. "We recognize that insufficient funding and resources are a great part of the problem," they continued. "However, having two mechanisms, one to handle dietary supplements and another to handle drugs (as many if not most dietary supplements are or claim to be), is not a cost-effective answer. . The U.S. public deserves to have the funding and resources allocated for their protection."

Another study published in the Sept. 17 issue of JAMA (290, 11:1505-9, 2003) reported disease claims made by dietary supplement makers are commonplace on the Internet. Charles A. Morris, M.D., and Jerry Avorn, M.D., both affiliated with Harvard Medical School in Boston, conducted an Internet study of the eight most popular dietary supplements to review marketing claims. They used five Internet search engines and entered the names of the eight most widely used herbal products: Ginkgo biloba, St. John's wort, echinacea, ginseng, garlic, saw palmetto, kava and valerian. They identified 522 sites, 443 of which were included for analysis.

The reviewers looked at Internet marketing claims and independently categorized them as "disease" or "non-disease," according to FDA criteria. Of the 443 sites, 76 percent were retail sites either selling product or directly linked to a vendor. Of the 338 retail sites identified, 81 percent made one or more health claims, with 55 percent of these claiming to treat, prevent, diagnose or cure specific diseases. More than half (52 percent) of the retail sites failed to include the mandated federal disclaimer for dietary supplement sales. And, only 12 percent of the 443 sites provided referenced materials without a link to a distributor or vendor.

In conclusion, the reviewers stated, "Consumers may be misled by vendors' claims that herbal products can treat, prevent, diagnose or cure specific diseases, despite regulations prohibiting such statements."

In a comment on this study, DeAngelis and Fontanarosa stated that despite advisory activity by the Federal Trade Commission (FTC), the current regulatory system for dietary supplement marketing is ineffective. They stated, "The study by Morris and Avorn provides evidence for the easily accessible and widespread potentially misleading claims made by vendors of herbal products on the Internet."

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