An article that was quietly presented in a medical journal last summer reported significant disparities in hyperforin plasma levels in many of the participants in a study on St. John’s wort (Hypericum perforatum) and major depression that had been published in the Journal of the American Medical Association (JAMA) over 3 years earlier. Hyperforin is a constituent in St. John’s wort that is found in the blood stream for several hours after the consumption of the herb.

The authors of the more recent study (Vitiello et al., 2005) evaluated the residual plasma of 86 percent of the participants in the JAMA published article (Davidson, et al., 2002). Davidson had reported the results of a three-arm double-blind, randomized and placebo-controlled study that evaluated the benefits in major depression of both a St. John’s wort extract and of the commonly prescribed drug sertraline (Zoloft®). But Vitiello found plasma hyperforin in 18 of 104 subjects (17%) who had been assigned the placebo, and conversely, no hyperforin in 17 of 97 subjects (18%) who were supposed to have used St. John’s wort in the Davidson study. In contrast, all of the 91 plasma analyses for subjects assigned sertraline found the drug present, as expected.

Vitiello suggested that the observed discrepancies may have resulted on the one hand from undeclared use of St. John’s wort by the control group, or on the other by individual differences in elimination times by those who were assigned St. John’s wort. He also noted that “the most damaging threat to the integrity of a trial is cross-arm contamination,” though opined that such a mix-up was “unlikely.” In addition, he suggested that mislabeling of the plasma samples could not be ruled out.

The 2002 Davidson study was funded by the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH). Davidson and his colleagues found no statistically significant difference between either the herb or the drug and the placebo for any of the primary outcome measures. In other words, the severely depressed subjects of the study received no greater relief in these primary measures from either St. John’s wort or sertraline than from a sugar pill. Sertraline, but not St. John’s wort, was observed to work better than placebo on one secondary measure.

The media that followed the publication of the Davidson article, however, focused almost entirely on St. John’s wort, with little mention of the lack of efficacy observed for the pharmaceutical drug. Also, most of the media attention to this study ignored numerous other studies that have found the herb to be beneficial for the treatment of mild to moderate depression. Another criticism that was not widely reported was that the study design was insufficiently sensitive to actually observe any benefits, either from the herb or the drug.

In trying to make the best of the new data, Vitiello attempted to recalculate the results of the Davidson study using only those subjects for which the analytical results matched their assigned study medication. The reevaluated results were nearly the same as the original conclusions: none of the primary measures for the treatment of severe depression showed any significant difference between either St. John’s wort or sertraline and placebo.

“What Vitiello did not attempt was to put all of the subjects with hyperforin in their system into one group, and all of those without it in another,” commented Michael McGuffin, AHPA president. “While I might be curious to see how that comes out, the information has become pretty scrambled, and the Davidson study is now burdened with one additional criticism.”

Vitiello, B. et al. Hyperforin plasma level as a marker of treatment adherence in the National Institutes of Health Hypericum Depression Trial. J Clin Psyhopharm 25(3):243-249, June 2005.

Davidson, JRT, et al. (Hypericum Depression Trial Study Group). An extract of Hypericum perforatum (St. John’s Wort) in major depressive disorder: a randomized, double-blind trial with placebo and active control. JAMA 287(14):1807–1814. April 10, 2002.