1. Antidepressant action—The hypericin fraction was initially reported to have MAO-A and -B inhibitor properties. Later studies found that the concentration required for this inhibition was higher than that achieved with recommended dosages. In vitro studies using the commercially formulated hydroalcoholic extract have shown inhibition of nerve terminal reuptake of serotonin, norepinephrine, and dopamine. While the hypericin constituent did not show reuptake inhibition for any of these systems, the hyperforin constituent did. Chronic administration of the commercial extract has also been reported to significantly down-regulate the expression of cortical β adrenoceptors and up-regulate the expression of serotonin receptors (5-HT2) in a rodent model.
Other effects observed in vitro include sigma receptor binding using the hypericin fraction and GABA receptor binding using the commercial extract. Interleukin-6 production is also reduced in the presence of the extract.
a.
Clinical trials for depression—The most recent systematic review and meta-analysis involved 29 randomized, double-blind, controlled trials (18 compared St. John’s wort with placebo, 5 with tricyclic antidepressants, and 12 with selective serotonin reuptake inhibitors [SSRIs]). Only studies meeting defined classification criteria for major depression were included. St. John’s wort was reported to be more efficacious than placebo and equivalent to prescription reference treatments including the SSRIs for mild to moderate major depressive disorder but with fewer side effects. Most trials used 900 mg/d of St. John’s wort for 4–12 weeks. Depression severity was mild to moderate in 19 trials, moderate to severe in 9 trials, and not stated in 1 trial. In a longer but uncontrolled trial, the use of the herb for up to 52 weeks was reported to reduce depression scores in patients with mild to moderate major depression. These data and the mechanism of action data reported above suggest a potential role for St. John’s wort in relieving symptoms of mild to moderate major depression. Due to the short study duration of these clinical trials, efficacy beyond 12 weeks still requires further study.
b.
Other mood-related conditions—St. John’s wort has been studied for several other indications related to mood, including premenstrual dysphoric disorder, climacteric complaints, somatoform disorders, and anxiety. For most of these indications, studies are too few in number to draw any firm conclusions regarding efficacy. Evidence for climacteric complaints was the subject of a recent meta-analysis. Six trials were included where two used mono-preparations of St. John’s wort and four used combinations of St. John’s wort and black cohosh, Cimicifuga racemose (note black cohosh warning in Table 64-1). St. John’s wort significantly reduced hot flashes (severity, duration, and frequency) compared to placebo when used for up to 16 weeks. Heterogeneity in these trials limits drawing firm conclusions on efficacy for this indication.
2. Antiviral and anticarcinogenic effects—The hypericin constituent of St. John’s wort is photolabile and can be activated by exposure to certain wavelengths of visible or ultraviolet A light.
Parenteral formulations of hypericin (photoactivated just before administration) have been used investigationally to treat HIV infection (given intravenously) and basal and squamous cell carcinoma (given by intralesional injection). In vitro, photoactivated hypericin inhibits a variety of enveloped and nonenveloped viruses as well as the growth of some neoplastic cells. Inhibition of protein kinase C and inhibition of singlet oxygen radical generation have been proposed as possible mechanisms. The latter could inhibit cell growth or cause cell apoptosis. These studies were carried out using the isolated hypericin constituent of St. John’s wort; the usual hydroalcoholic extract of St. John’s wort has not been studied for these indications and should not be recommended for patients with viral illness or cancer.