Hypericum perforatum L. · herb
Evidence tier: strong
A traditional mood support herb backed by extensive modern evidence. Effective for mild to moderate depression and seasonal low mood.
Two mechanisms, and the dangerous one is not the therapeutic one. For mood, hypericin and hyperforin are thought to inhibit the reuptake of serotonin, dopamine and noradrenaline, broadly the same target family as conventional antidepressants. For interactions, hyperforin is a potent activator of the pregnane X receptor, which switches on CYP3A4, CYP2B6, CYP2C9, CYP2C19 and the P-glycoprotein efflux pump. That is an INDUCER, not an inhibitor: it accelerates the clearance of other drugs and drives their blood levels down. The EMA notes that preparations delivering under 1 mg of hyperforin per day escape the interaction warnings, which is the clearest possible statement that hyperforin is the culprit.
Strong, and it is one of the very few in this catalogue that genuinely earns the word. The Cochrane review of St John's wort for major depression pooled 29 trials in 5,489 patients and concluded that the extracts tested were superior to placebo, similarly effective as standard antidepressants, and had fewer side effects than standard antidepressants. NCCIH agrees in its own words: St John's wort appears to be more effective than a placebo and as effective as standard antidepressant medications for mild or moderate depression. Europe's regulator goes furthest of all: the EMA HMPC monograph grants Hypericum perforatum WELL ESTABLISHED USE, an evidence based status, for the treatment of mild to moderate depressive episodes. That is a higher regulatory tier than turmeric, chamomile or valerian ever reach. The honest caveats belong here too. Cochrane found marked heterogeneity, smaller trials reporting much larger effects than large ones (RR 1.87 versus 1.28), results considerably more favourable in German speaking countries where the authors could not rule out that some smaller studies were flawed and reported overoptimistic results, and enormous variability between the products actually sold. The largest US trial, the NIH funded Hypericum Depression Trial Study Group (JAMA 2002, 340 patients, hypericum versus sertraline versus placebo), failed to support efficacy in moderately severe major depression, and neither the herb nor sertraline beat placebo. NCCIH is explicit that effectiveness for severe depression, and beyond 12 weeks, is not known. So: strong for MILD TO MODERATE depression, unproven for severe. And the second half of the verdict is not about efficacy at all. St John's wort is the most dangerous interaction herb in common use. It induces CYP3A4, CYP2B6, CYP2C9, CYP2C19 and P-glycoprotein, meaning it makes other drugs stop working. The EMA CONTRAINDICATES it with coumarin type anticoagulants, ciclosporin, everolimus, sirolimus, tacrolimus, indinavir and other protease inhibitors, nucleoside reverse transcriptase inhibitors, irinotecan, imatinib and other cytostatics. Documented consequences are not theoretical: the UK MHRA received 19 reports of suspected contraceptive interaction between 2000 and 2014, of which 15 were unintended pregnancies; transplant patients on ciclosporin have gone subtherapeutic and rejected their organs; HIV therapy has failed. Combined with SSRIs it can cause serotonin syndrome. Notably, and against expectation, the herb is NOT itself a liver toxin: NIH LiverTox assigns it likelihood score E, an unlikely cause of clinically apparent liver injury, with no convincing case reports, while warning that it can raise the hepatotoxicity of OTHER drugs by altering their metabolism.
EMA well established use, adults: dry extract single dose 300 to 600 mg, one to three times daily, daily dose 600 to 1800 mg. Not recommended under 18. The onset of the effect can be expected within 4 weeks (EMA section 4.2). Traditional use preparations for temporary mental exhaustion are dosed far lower, 180 to 360 mg daily.
300 mg standardised extract (0.3% hypericin) three times daily. Allow 4 to 6 weeks for full benefit.
Onset: ~28 days
CRITICAL drug interactions via CYP3A4 induction, reduces efficacy of contraceptives, SSRIs, warfarin, immunosuppressants, antiretrovirals. Always screen medications first.
Pregnancy: avoid
Breastfeeding: caution
Active compounds: hypericin, pseudohypericin, hyperforin, flavonoids
Remedies using St Johns Wort · Browse by body system · Check it against what you take
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.