St John’s WortHypericum perforatum · 4 claims

A Cochrane review of 29 trials covering 5,489 patients found St John’s Wort more effective than placebo and comparable to standard antidepressants for mild-to-moderate depression, with fewer side effects than SSRIs.

Its own adverse event profile is genuinely mild: gastrointestinal irritation 0.6%, allergic reactions 0.5%, fatigue 0.4%, restlessness 0.3% — an incidence roughly ten times lower than synthetic antidepressants.

A more sceptical review characterises the efficacy as slight at best. Both readings can be true: a real effect, modest in size, in a condition with a large placebo response.

• MetaLinde K, Berner MM, Kriston L. St John’s wort for major depression, as cited in Nicolussi et al. Cochrane Database Syst Rev 2008;CD000448 · 29 trials, 5,489 patients
• RevSt John’s wort and depression: slight efficacy at best, many drug interactions PMID 15499702

There is insufficient evidence to determine efficacy in more severe depression. The Cochrane finding applies to mild-to-moderate presentations and does not extend upward.

Separately, use has been associated with the induction of mania or hypomania in people with bipolar disorder. That is a meaningful signal for anyone self-treating low mood without a diagnosis.

• RevPrescrire review: insufficient evidence in more severe depression PMID 15499702
• RevClinically relevant safety issues associated with St John’s wort product labels Induction of mania or hypomania in bipolar disorder

Hyperforin activates the pregnane X receptor, which induces CYP3A4 and P-glycoprotein. The result is that susceptible drugs are metabolised and cleared faster, so less medicine reaches or stays in the bloodstream.

Human studies and case reports document reduced blood concentrations of cyclosporine, tacrolimus, warfarin, digoxin, indinavir, nevirapine, simvastatin, methadone, midazolam, amitriptyline, theophylline, phenprocoumon and fexofenadine. It reduced the active metabolite of irinotecan in cancer patients. It did not alter carbamazepine, dextromethorphan, mycophenolic acid or pravastatin.

These are not theoretical. In 2000 a St John’s Wort–cyclosporine interaction caused acute rejection in two heart transplant patients. There are published cases of breakthrough bleeding and unintended pregnancies in women taking oral contraceptives. Combined with SSRIs, SNRIs, MAOIs, tramadol or triptans it carries serotonin syndrome risk.

• RevNicolussi S, Drewe J, Butterweck V, Meyer zu Schwabedissen HE. Clinical relevance of St John’s wort drug interactions revisited Br J Pharmacol 2020;177(6) · doi 10.1111/bph.14936
• PKZhou S, Chan E, et al. Pharmacokinetic interactions of drugs with St John’s wort Systematic identification of affected and unaffected drugs

Cochrane warns that hypericum preparations can differ considerably, because composition depends on the raw material, the extraction process and the solvent used. A trial-tested extract is not automatically interchangeable with a capsule or tea bought off a shelf.

For most supplements that is a quality annoyance. Here it is a safety problem, because the degree of CYP3A4 induction correlates significantly with hyperforin content — which varies between products and is not on the label. Two products at the same milligram dose can carry materially different interaction risk.

• RevNicolussi S, et al. CYP3A4 induction correlates with hyperforin content Br J Pharmacol 2020;177(6)