St. John’s Wort (Hypericumperforatum)

ST. JOHN’S WORT (HYPERICUMPERFORATUM)

Chemistry

St. John’s wort, also known as hypericum, contains a variety of constituents that might contribute to its claimed pharmacologic activity in the treatment of depression. Hypericin, a marker of standardization for currently marketed products, was thought to be the primary antidepressant constituent. Recent attention has focused on hyperforin, but a combination of several compounds is probably involved. Commercial formulations are usually pre-pared by soaking the dried chopped flowers in methanol to create a hydroalcoholic extract that is then dried.

Pharmacologic Effects

A. 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 adrenocep-tors 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.

Clinical trials for depression—The most recent systematicreview and meta-analysis involved 29 randomized, double-blind, controlled trials (18 compared St. John’s wort to placebo, 5 to tricyclic antidepressants, and 12 to 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 tomoderate depression 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 one trial. These data support a role for St. John’s wort in relieving symptoms of major depression.

St. John’s wort has been studied for several other indications related to mood, including premenstrual dysphoric disorder, cli-macteric complaints, somatoform disorders, and anxiety. These studies are too few in number, however, to draw any firm conclu-sions regarding efficacy.

B. 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 ultra-violet 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, photoacti-vated hypericin inhibits a variety of enveloped and non-enveloped viruses as well as the growth of cells in some neoplastic tissues. 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 rec-ommended for patients with viral illness or cancer.

Adverse Effects

Photosensitization is related to the hypericin and pseudohypericin constituents in St. John’s wort. Consumers should be instructed to wear sunscreen and eye protection while using this product when exposed to the sun. Hypomania, mania, and autonomic arousal have also been reported in patients using St. John’s wort.

Drug Interactions & Precautions

Inhibition of reuptake of various amine transmitters has been high-lighted as a potential mechanism of action for St. John’s wort. Drugs with similar mechanisms (ie, antidepressants, stimulants) should be used cautiously or avoided in patients using St. John’s wort due to the risk of serotonin syndrome. This herb may induce hepatic CYP enzymes (3A4, 2C9, 1A2) and the P-glycoprotein drug transporter. This has led to case reports of sub-therapeutic levels of numerous drugs, including digoxin, birth control drugs (and subsequent pregnancy), cyclosporine, HIV pro-tease and nonnucleoside reverse transcriptase inhibitors, warfarin, irinotecan, theophylline, and anticonvulsants.

Dosage

The most common commercial formulation of St. John’s wort is the dried hydroalcoholic extract. Products should be standardized to 2–5% hyperforin, although most still bear the older standardizedmarker of 0.3% hypericin. The recommended dosing for mild to moderate depression is 900 mg of the dried extract per day in three divided doses. Onset of effect may take 2–4 weeks. Long-term benefits beyond 12 weeks have not been sufficiently studied.