St. John's Wort
Commonly used for
Focus
Read the interactions list before starting -- this is one of the most clinically significant sources of supplement-drug interactions, affecting many common prescription medications.
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The cheapest product is usually low quality, but more expensive doesn’t always mean better.
What is it? / Overview
Standardized Hypericum perforatum extracts have substantial randomized-controlled-trial evidence for mild-to-moderate major depression, with systematic reviews finding efficacy comparable to conventional antidepressants in some populations and fewer reported adverse effects. Hyperforin activates the pregnane X receptor (PXR), inducing CYP3A4 and other drug-metabolizing enzymes as well as P-glycoprotein -- this is why the interaction profile extends well beyond a single enzyme pathway.
How is it used? / Administration
Form: Standardized Hypericum perforatum extract; potency varies by product (commonly standardized to ~0.3% hypericin, with hyperforin content varying meaningfully by manufacturer)
Typical dose studied: Product/extract dependent -- many of the classic clinical trials used a standardized extract at 300 mg three times daily (~900 mg/day total)
Timing: With meals to reduce GI upset
Different products vary meaningfully in hypericin/hyperforin content and pharmacokinetics -- low-hyperforin preparations may carry less enzyme-inducing (drug interaction) potential, but this isn't consistent across all products, so don't assume any given bottle is 'safer' without checking.
How well does it work? / Evidence
✓ Well-established
Who should avoid it?
Avoid with: Bipolar disorder / bipolar-spectrum illness (antidepressant-like effect can trigger mania or hypomania); Pregnancy or breastfeeding (insufficient safety evidence -- avoid unless medically advised); Scheduled surgery (enzyme-inducing effects create uncertainty around anesthesia and perioperative medications -- stop only under medical guidance)
Interacts with: Antidepressants -- SSRIs, SNRIs, MAOIs (serotonin syndrome risk, a pharmacodynamic concern separate from enzyme induction); Hormonal contraceptives (reduced effectiveness); Anticoagulants, e.g. warfarin (reduced effectiveness); Transplant/immunosuppressant medications, e.g. cyclosporine, tacrolimus (reduced drug levels -- can risk organ rejection); HIV antiretroviral therapy (reduced drug levels); Anticonvulsants; Digoxin; Statins
Already taking it? This has some of the most clinically important supplement-drug interactions that exist -- never start or continue this alongside any prescription medication without your prescriber's or pharmacist's explicit sign-off.
Research & references
Linde K, et al. St John's wort for major depression. Cochrane Database of Systematic Reviews. Apaydin EA, et al. A systematic review of St. John's wort for major depressive disorder. Systematic Reviews.
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