St John’s wort is an inducer, not an inhibitor — and that is the dangerous direction

Most famous food/herb interactions are inhibition (grapefruit, piperine). St John's wort (Hypericum perforatum) is the opposite: it is an inducer, and induction fails drugs silently. The mechanism Hyperforin is a potent agonist of the pregnane X receptor (PXR), which upregulates CYP3A4 and the P-glycoprotein efflux transporter. Over 1-2 weeks of dosing the body makes MORE of these, so CYP3A4 substrates are cleared FASTER and their blood levels FALL. Why induction is the scary direction An inhibitor makes a drug too strong — you notice side-effects. An inducer makes a drug too weak — nothing happens, and the failure is invisible until the protected-against event occurs. Documented consequences: - Loss of efficacy of oral contraceptives (breakthrough bleeding, unplanned pregnancy). - Transplant rejection from subtherapeutic ciclosporin/tacrolimus. - Reduced levels of some antiretrovirals, warfarin, digoxin, and certain anticoagulants and anticonvulsants. The timing trap Both onset and offset are slow (days to weeks), because they depend on protein turnover. Stopping St John's wort does not instantly restore the drug level — and a dose set while induced can then become too high once the enzyme normalises. St John's wort is ALSO serotonergic, so on top of the induction it carries serotonin-syndrome risk with SSRIs, SNRIs and MAOIs. Two independent reasons to treat it as a real drug. Induction vs inhibition, laid out: https://wiki.soapbox.community/wiki/Cytochrome_P450_System_Inhibition_and_Induction Sources: FDA; Markowitz JS et al., JAMA 2003 (CYP3A4 induction); Henderson L et al., Br J Clin Pharmacol 2002.