Over the past two decades, St. John's wort has been studied in thousands of patients for the treatment of mild to moderate depression. Most preparations are standardized to hypericin or hyperforin. The precise mechanisms of action are not known but are postulated to include selective inhibition of serotonin, -aminobutyrate, norepinephrine, and dopamine reuptake in the central nervous system.
Most of the 60-plus randomized controlled clinical trials, systematic reviews, and meta-analyses have shown that St. John's wort is more effective than placebo and as effective as tricyclic antidepressants for the treatment of mild to moderate depression. Several recent placebo-controlled studies lasting 4–12 weeks have also shown that it has efficacy similar to the selective serotonin reuptake inhibitors (SSRIs) sertraline, fluoxetine, and paroxetine. Pooled analyses of six recent, large trials restricted to patients with major depression, however, showed only minimal effects of St. John's wort compared with placebo. A 4-year NIH study of 300 patients with mild symptoms of depression began in 2003. Patients are being randomized to St. John's wort, placebo, or citalopram for 12 weeks.
St. John's wort is generally well tolerated. Side effects are not common and include mild headache, photosensitivity, gastrointestinal upset, and restlessness. Data from 35 double-blind randomized trials show that drop out and adverse event rates in patients receiving Hypericum extracts were similar to placebo, lower than with older antidepressants, and slightly lower than with SSRIs. Patients are advised to avoid taking St. John's wort in addition to prescription antidepressants, as there have been case reports of the serotonin syndrome. St. John's wort also induces the cytochrome P450 system (isozyme CYP3A4), which may lower the blood levels of other drugs that are metabolized by this system (eg, ethinyl estradiol, warfarin, cyclosporine, statins, and indinavir). At least 50% of all medications currently on the market are at least partially metabolized by this isozyme. Several cases of cardiac and renal organ rejection have been reported in patients whose previously stable level of cyclosporine was lowered after initiation of St. John's wort. Of further concern is that this herb-drug interaction may persist even after St. John's wort is discontinued. A 40% decrease in serum levels of the chemotherapeutic agent irinotecan noted in five patients taking concurrent St. John's wort persisted for 3 weeks after St. John's wort was discontinued.
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