For the 20 million American adults suffering depression, findings that a St. John's Wort extract improves mood as much as popular anti-depressant drugs represents exciting news.

Hyperforin is one of their main chemical components of St. John's wort and is found in the blood stream for several hours after a St. John's wort supplement is ingested. Hyperforin is a natural prenylated phloroglucinol and has been identified as the major molecule responsible for the antidepressant effects of this herb. A number of studies have hinted that hyperforin has other effects in the body. Hyperforin may have antibacterial capacity and inhibitory effects on inflammatory mediators. Hyperforin also induces apoptosis of various cancer cells from solid tumors and hematological malignancies. Hyperforin may also inhibit the capacity of migration and invasion of different tumor cells, as well as exhibiting antiangiogenic effects. There's much we still need to learn about the benefits and side effects of hyperforin.

Content in the herb
Biochemical Systematics and Ecology, May-June 2008
Pseudohypericin and hyperforin in two Turkish Hypericum species: Variation among plant parts and phenological stages Faculty of Agriculture, Ondokuz Mayıs University, Samsun, Turkey, Institute of Botany, Lithuania
The genus Hypericum has received considerable interest from scientists, as it contains the variety of structurally diverse natural products which possess a wide array of biological properties, mainly hypericins and hyperforin. In the present study, variations of pseudohypericin and hyperforin were investigated in two Turkish species of Hypericum, namely Hypericum perfoliatum and Hypericum origanifolium. Wild growing plants were harvested at vegetative, floral budding, flowering, fresh fruiting and mature fruiting stages, and dissected into stem, leaf and reproductive tissues and assayed for chemical contents by high performance liquid chromatography method. Content of pseudohypericin and hyperforin in samples of the whole plant increased during the course of ontogenesis in both species. The highest levels of the chemicals were reached at full flowering (2.6 mg/g dry weight (DW) pseudohypericin and 1.8 mg/g DW hyperforin for H. perfoliatum; 0.9 mg/g DW pseudohypericin and 1.6 mg/g DW hyperforin for H. origanifolium). Among different reproductive parts, full opened flowers produced the highest amount of pseudohypericin and hyperforin in H. origanifolium. Similarly, the highest pseudohypericin accumulation was observed in full opened flowers in H. perfoliatum (7 mg/g DW) while floral buds of this species produced the highest amount of hyperforin (7 mg/g DW). Keywords: HPLC; Hyperforin; Hypericum origanifolium; Hypericum perfoliatum; Ontogenetic and morphogenetic variation; Pseudohypericin

Hyperforin research in JAMA
An article presented in a medical journal in 2005 reported significant differences 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. 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.
     What would account for these differences, and why did the reviewers of the JAMA article not point out this major discrepancy? Vitiello suggests 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 research study is cross-arm contamination.” 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 at the National Institutes of Health. Davidson and his colleagues found no statistically significant difference between either St. John's wort or sertraline 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 hyperforin in St. John’s wort or sertraline than from a sugar pill. 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 sertraline. 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.

Hyperforin plasma level as a marker of treatment adherence in the National Institutes of Health Hypericum Depression Trial. J Clin Psyhopharm 2005.

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, 2002.

Hyperforin plasma level as a marker of treatment adherence in the National Institutes of Health Hypericum Depression Trial.
J Clin Psychopharmacol. 2005. National Institute of Mental Health, Bethesda, MD
A previously reported clinical trial of Hypericum perforatum in depression did not demonstrate efficacy. We assessed treatment adherence by measuring plasma hyperforin and evaluated the possible impact of adherence on study results. Outpatients with major depression (N = 340) were randomized to an 8-week trial of H. perforatum (900-1500 mg/d), sertraline (50-100 mg/d) as active comparator, or placebo. Plasma was available from 292 patients (86% of randomized). Samples from the placebo and H. perforatum groups were assayed for hyperforin, and samples from the sertraline group for sertraline/N-desmethyl-sertraline. Of the 104 patients randomized to placebo, 18 (17%) had detectable plasma hyperforin. Of the 97 patients randomized to H. perforatum, 17 (17%) had no detectable plasma hyperforin. All the assayed sertraline patients (N = 91) had plasma sertraline/N-desmethyl-sertraline. The clinical trial conclusions remained unchanged when only patients with plasma assay consistent with random assignment were included in the analyses. One of every 6 patients assigned to placebo had plasma hyperforin, and 1 of every 6 patients assigned to H. perforatum had no detectable plasma hyperforin. The finding underscores the difficulty of enforcing treatment adherence in clinical trials of preparations that are readily available in the community.

According to a randomized, double-blind, reference-controlled clinical study published in the prestigious British Medical Journal, the proprietary St. John's Wort extract WS(R) 5570 is at least as effective in treating depression and better tolerated by patients than the widely prescribed anti-depressant paroxetine.
     In the study, 251 patients with moderate to severe forms of depression were divided into two groups: one receiving 900 mg/day of St. John's wort WS 5570, and the other 20 mg/day of paroxetine, for six weeks. Any patients not responding after two weeks had their dose doubled at that time. St. John's wort produced a significantly better improvement in patients as measured by internationally accepted diagnostics such as the Hamilton Depression Rating Scale (HAMD). In fact, WS(R) 5570 delivered a three point greater decrease in the average HAMD total score versus baseline than did paroxetine. This clinically relevant superiority was further supported by a responder rate of 70% versus 60% and a remission rate of 50% versus 35% for WS 5570 and paroxetine respectively. In addition, all secondary efficacy measures, as well as a lower rate of adverse events, favoured WS(R) 5570. Results are consistent with an earlier double-blind, randomized, placebo-controlled study of 375 depressed patients published in the American Journal of Psychiatry, in which the same St. John's Wort extract WS 5570 was clearly superior to placebo.(2) In the U.S., an identical strength version of WS 5570 is sold as a natural dietary supplement for promoting a positive mood, rather than a drug for the treatment of depression. This extract (WS 5572) contains the same patented, standardized and stabilized hyperforin content as WS(R) 5570, and is marketed as Perika St. John's Wort by Nature's Way Products, Inc., Springville, Utah. WS 5570 and WS 5572 are patented extracts developed and produced by Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany. They are uniquely standardized to hyperforin, the key constituent within St. John's Wort responsible for its mood balancing effect. The patent also ensures long-term stability of the hyperforin content.
     Most other St. John's Wort products are standardized to a different constituent known as hypericin, and some may contain a non-stabilized amount of hyperforin. Consequently, the results of these two clinical studies cannot be extrapolated to other St. John's Wort products that do not contain the same standardized and stabilized potency of hyperforin as WS(R) 5570 and WS 5572.
     Dr. Sahelian comments: Practically speaking, I don't think it makes too much difference which substance -- hyperforin or hypericin -- St. John's wort is standardized to.