Two primary active constituents: hyperforin (non-selective monoamine reuptake inhibition via sodium-conductive pathway — distinct from classical SERT binding) + hypericin (mild MAO inhibition at high concentrations; photosensitiser). Antidepressant effect is hyperforin-mediated. Critical: hyperforin is a potent PXR activator → strongly induces CYP3A4, CYP2C9, P-glycoprotein → dramatically increases clearance of many co-administered drugs. One of the most clinically dangerous herbal supplements for drug interactions.
Half-Life (t½)
PO: 9h
Dosing Guidelines
PO: Typical 400 mg (Range: 300–600 mg)
Target Organ Systems
nervous
digestive
Interactions
Cyclosporine (contraindicated): CYP3A4 + P-gp induction by hyperforin. Mai 2004 (n=10 renal transplant, crossover): cyclosporine AUC ↓52% after 2 weeks SJW → ke ratio ≈ 2.08. Acute transplant rejection documented; combination is contraindicated in transplant patients.
Tacrolimus (contraindicated): CYP3A4 + P-gp induction. Hebert 2004 (n=10 healthy, 18 d SJW 300 mg TID): tacrolimus AUC 306.9 → 198.7 µg·h/L (ratio 0.647) → ke ratio ≈ 1.55. Sub-therapeutic levels → rejection risk; contraindicated in transplant.
Warfarin (major): CYP2C9 + CYP3A4 induction. Jiang 2004 (n=12, 14 d SJW): S-warfarin apparent CL ratio 1.29 (90% CI 1.16–1.46). Monitor INR; expect modest reduction in effect.
Hormonal contraceptives (major): CYP3A4 induction reduces ethinylestradiol exposure. Murphy 2005 (n=16, 2 cycles SJW 300 mg TID): EE AUC ↓~14% → ke ratio ≈ 1.16. Kinetic effect is small; the clinical contraceptive failure is driven more by progestin trough loss + breakthrough ovulation than AUC alone — backup contraception still required.
Digoxin (caution): P-gp induction (digoxin is primarily P-gp substrate, not CYP3A4). Johne 1999 (PMID:10546917) verbatim: "10 days of treatment with hypericum extract resulted in a decrease of digoxin AUC(0-24) by 25% (day 15, 17.2+/-4.0 microg x h/L and 12.9+/-2.3 microg x h/L; P = .0035)". Single-blind placebo-controlled parallel, n=13 SJW (LI160 900 mg/d × 10d) vs n=12 placebo. AUC ratio 12.9/17.2 = 0.75 → induction_factor 1/0.75 = 1.33.
Methadone (caution): CYP3A4 induction. Eich-Höchli 2003 (PMID:12649774) verbatim: trough methadone after SJW gave "median decrease to 47% of the original concentration (range: 19% - 60%)". n=4 OPEN CASE SERIES (not crossover), SJW 900 mg/d × ~31d. Trough → AUC proxy ratio 0.47 → induction_factor 2.13. Provenance is case-series — lower confidence than controlled crossover; flagged here so the registry maintainer can re-cite when a primary RCT publishes.
Midazolam (caution): CYP3A4 induction. Hall 2003 (PMID:14663455) verbatim: "The oral clearance of midazolam was significantly increased (109.2 +/- 47.9 L/h to 166.7 +/- 81.3 L/h, P =.007)" by SJW. 12 healthy premenopausal women, controlled crossover-within-cycle design, SJW 300 mg tid × 14d. Oral CL ratio 109.2/166.7 = 0.655; AUC_oral_ratio = 0.655 → induction_factor 1/0.655 = 1.53.
Simvastatin (warn): CYP3A4 induction. Sugimoto 2001 (PMID:11753267) verbatim: simvastatin acid "area under the plasma concentration-time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P <.05) by St John\u2019s Wort". n=8 simvastatin arm, double-blind crossover, SJW 300 mg tid × 14d. Active-metabolite AUC ratio 0.48 → induction_factor 1/0.48 = 2.08. Statin efficacy loss.