Evidence Level
St. John's Wort has one of the strongest evidence bases of any herbal medicine. The Cochrane Collaboration's landmark review (Linde et al., 2008) analyzed 29 RCTs with 5,489 patients and concluded that St. John's Wort extracts are superior to placebo and comparable to standard antidepressants for mild-to-moderate major depression, with significantly fewer side effects. Gastpar et al. (2006) directly compared 900mg/day St. John's Wort to 20mg citalopram in a double-blind RCT, finding equivalent efficacy with better tolerability. Mechanistically, hyperforin is the primary active compound, inhibiting reuptake of five neurotransmitters (serotonin, norepinephrine, dopamine, GABA, glutamate) through TRPC6 channel activation — a unique mechanism not shared by any pharmaceutical antidepressant. However, St. John's Wort is also one of the most potent known inducers of CYP3A4 and P-glycoprotein, the drug-metabolizing systems responsible for clearing approximately 50% of all prescription medications. This creates an extensive and dangerous interaction profile. Moore et al. (2000) documented the scope of these interactions in The Lancet, and subsequent case reports have confirmed life-threatening consequences including organ transplant rejection, HIV treatment failure, and unplanned pregnancies. The German Commission E and the European Medicines Agency both approve St. John's Wort for mild-to-moderate depression, but require drug interaction screening.