St. John's Wort
Hypericum perforatum
A flowering herb with real antidepressant activity for mild-to-moderate depression — and serious, sometimes life-threatening drug interactions.
Moderate evidence
🌙Sleep & Mood
Evidence tier
Moderate
Research weight
Citations
16 verified / 16
Classification
Sleep & Mood
❝
What the evidence says. Graded moderate: multiple RCTs and a Cochrane review show genuine antidepressant effect in mild-to-moderate depression, comparable to SSRIs — but trials are heterogeneous, mostly non-US, thin for severe depression, and products vary widely; the tier reflects that real-but-uneven evidence, not the (serious) interaction risk. (Moderate evidence: Several controlled trials; effects real but modest or context-dependent.)
⚠
Health warning. St. John's Wort is a potent CYP3A4/P-glycoprotein inducer that can cause contraceptive failure, transplant rejection, antiretroviral or anticoagulant failure, and serotonin syndrome when combined with antidepressants — never combine it with prescription medications without medical supervision.
What is St. John's Wort?
St. John's Wort (Hypericum perforatum) is a sleep and mood supplement used for reduces symptoms of mild-to-moderate depression, with efficacy broadly comparable to standard ssris in several meta-analyses. NutriDex grades the human evidence as Moderate. St. John's Wort (Hypericum perforatum) is a flowering herb whose standardized extracts have demonstrated genuine antidepressant activity for mild-to-moderate depression, performing similarly to placebo-superior SSRIs across multiple randomized trials and meta-analyses, often with fewer side effects and lower dropout rates. Its principal active constituents are hyperforin and hypericin, with hyperforin thought to be the main contributor to both efficacy and its pharmacokinetic dangers. The central concern is that hyperforin is a potent inducer of CYP3A4 and P-glycoprotein via activation of the pregnane X receptor, which accelerates clearance of many co-administered drugs. This has produced documented contraceptive failure and breakthrough bleeding, reduced plasma levels of warfarin, cyclosporine and other immunosuppressants, antiretrovirals, digoxin, and chemotherapy agents, plus serotonin syndrome when combined with SSRIs, SNRIs, or other serotonergic drugs. Evidence quality for efficacy is moderate (heterogeneous trials, mostly outside the US, limited data in severe depression), and product standardization varies widely between brands. It should be regarded as an active pharmacological agent rather than a benign supplement.
Purported Benefits
✓Reduces symptoms of mild-to-moderate depression, with efficacy broadly comparable to standard SSRIs in several meta-analyses
✓Generally better short-term tolerability and lower treatment-discontinuation rates than conventional antidepressants in head-to-head trials
✓May modestly improve mood-related sleep disturbance and somatic complaints that accompany depressive disorders (secondary, less well-established)
Evidence by outcome
The same supplement can be well-proven for one use and unproven for another — here is the human evidence graded outcome by outcome.
| Outcome | Evidence | Effect | Studies |
|---|---|---|---|
| Reduced mild-to-moderate depression symptomsCochrane and multiple meta-analyses show efficacy comparable to SSRIs, but trials are short, heterogeneous and unproven in severe depression. | Moderate | ↑ benefit · moderate | 5 |
| Better tolerability / fewer dropouts vs SSRIsHead-to-head meta-analyses show significantly lower discontinuation and adverse-event rates than antidepressants. | Moderate | ↑ benefit · moderate | 3 |
| Reduced somatic / somatoform complaintsOne RCT (n=173) in somatoform disorders showed superiority over placebo; secondary, less-established use. | Preliminary | ↑ benefit · moderate | 1 |
| Reduced menopausal hot flashesSingle RCT (n=100) reduced hot-flash frequency and severity; isolated finding not addressed by other entry evidence. | Preliminary | ↑ benefit · moderate | 1 |
| Drug interactions via CYP3A4/P-gp inductionWell-documented PXR-mediated induction causes contraceptive failure, transplant rejection, and serotonin syndrome with SSRIs. | Strong | ⚠ risk · large | 4 |
Dosing & Compounds
Typical Dose
Standardized extract (e.g., 0.3% hypericin / ~3-5% hyperforin) 300 mg three times daily (900-1,800 mg/day total) is the most-studied regimen for depression; antidepressant effects build over 4-6 weeks. Lower-hyperforin formulations (<1 mg hyperforin/day) reduce — but do not eliminate — interaction risk.
Active Compounds
Safety & Cautions
DANGER: This is a pharmacologically active herb, not a benign supplement. As a potent inducer of CYP3A4 and P-glycoprotein, it can dangerously lower blood levels and efficacy of many drugs — combined oral and other hormonal contraceptives (risk of unintended pregnancy and breakthrough bleeding), warfarin and other anticoagulants, immunosuppressants such as cyclosporine and tacrolimus (risk of organ-transplant rejection), antiretrovirals (e.g., indinavir and other HIV drugs), many chemotherapy agents (e.g., irinotecan, imatinib), digoxin, some statins, certain anticonvulsants, and direct-acting antivirals. Combining it with SSRIs, SNRIs, MAOIs, triptans, tramadol, or other serotonergic agents can precipitate serotonin syndrome (agitation, hyperthermia, rapid heart rate, muscle rigidity — a medical emergency). It can also cause photosensitivity (sunburn-like skin reactions), and discontinuation can cause rebound rises in previously suppressed drug levels. AVOID in pregnancy and breastfeeding, in anyone taking the medications above, in people with bipolar disorder (mania/hypomania risk) or scheduled for surgery (stop at least 5 days before, ideally 1-2 weeks, due to anesthesia and bleeding interactions). Always disclose use to physicians and pharmacists, and never self-combine with antidepressants. Product potency varies widely, so interaction risk cannot be reliably predicted from the label alone. Educational only — always check with your doctor or pharmacist before combining St. John's Wort with any medicine.
St. John's Wort drug interactions
Known or theoretical interactions between St. John's Wort and common medications — educational, not exhaustive. Always check with your doctor or pharmacist before combining St. John's Wort with any medicine.
Avoid
Warfarin
St. John's Wort lowers warfarin levels, weakening anticoagulation and raising clot risk.
Potent CYP3A4/CYP2C9 induction speeds warfarin metabolism, reducing its blood-thinning effect. NIH NCCIH — St. John's Wort
Avoid
SSRIs / SNRIs (sertraline, fluoxetine, venlafaxine)
Can cause serotonin syndrome: agitation, tremor, fever, rapid heartbeat; can be life-threatening.
St John's Wort has serotonergic activity that adds to SSRI/SNRI reuptake inhibition, raising CNS serotonin. NCCIH — St. John's Wort
Avoid
MAOIs (phenelzine, tranylcypromine)
High risk of serotonin syndrome and hypertensive reactions; do not combine.
MAOIs block serotonin breakdown while St John's Wort raises serotonergic tone — dangerous excess. NCCIH — St. John's Wort
Avoid
Triptans & tramadol
Adding these serotonergic drugs raises the risk of serotonin syndrome.
Triptans and tramadol increase serotonin signaling, compounding St John's Wort's serotonergic effect. NCCIH — St. John's Wort
Avoid
Birth-control pills
Lowers contraceptive hormone levels — breakthrough bleeding and unintended pregnancy.
Strong CYP3A4 / P-glycoprotein induction accelerates metabolism of contraceptive steroids. NCCIH — St. John's Wort
Avoid
Cyclosporine / tacrolimus
Drops drug levels below therapeutic range — documented transplant rejection.
CYP3A4 / P-gp induction sharply increases clearance of cyclosporine and tacrolimus. NCCIH — St. John's Wort
Avoid
HIV antiretrovirals
Lowers antiretroviral levels, risking loss of viral suppression; FDA advises against combining.
Induces CYP3A4/P-gp, markedly increasing clearance of protease inhibitors and NNRTIs. NCCIH — St. John's Wort
Avoid
Digoxin
Lowers digoxin blood levels, reducing heart-rate/rhythm control.
Induces intestinal P-glycoprotein, increasing digoxin efflux and clearance. NCCIH — St. John's Wort
Avoid
Some chemotherapy (irinotecan, imatinib)
Lowers chemo drug levels, potentially reducing anticancer efficacy.
CYP3A4 induction accelerates metabolism of CYP3A4-dependent chemotherapeutics. NCCIH — St. John's Wort
Caution
Many CYP3A4 drugs (statins, CCBs, etc.)
Can reduce blood levels and effectiveness of a wide range of CYP3A4-metabolized medicines.
Hyperforin is a potent CYP3A4 inducer, increasing metabolism of many co-administered drugs. NCCIH — St. John's Wort
Key Studies ★ 16 studies
Meta-analysis of RCTs
14 RCTs, 2,270 patients
✓ PubMed
In a 2023 meta-analysis of 14 randomized trials, St. John's wort extract reduced depressive symptoms more than SSRIs (pooled OR 2.44, 95% CI 1.33-4.45) with fewer reported side effects, though heterogeneity was high (I-squared = 77%).
Systematic review
Pharmaceuticals (Basel) 2024
✓ Full text
Documentary analysis of 60 publications (16 RCTs) reported St. John's Wort extract Ze 117 caused adverse effects in 19% of patients versus 32% for sertraline, supporting comparable efficacy with a better tolerability profile in mild-to-moderate depression.
Meta-analysis
Apaydin 2016 (RAND/Systematic Reviews)
✓ PubMed
35 studies / 6,993 patients with major depressive disorder. SJW yielded more treatment responders than placebo (RR 1.53, 95% CI 1.19-1.97; SMD 0.49, 95% CI 0.23-0.74) and no significant difference vs antidepressants in mild-moderate MDD (RR 1.01, 95% CI 0.90-1.14). Fewer adverse events than antidepressants (OR 0.67, 95% CI 0.56-0.81). Heterogeneity high; lack of data in severe depression (moderate-quality GRADE).
Meta-analysis
Ng 2017 (J Affect Disord)
✓ PubMed
27 RCTs / 3,808 patients comparing SJW directly with SSRIs. Comparable response (pooled RR 0.983, 95% CI 0.924-1.042) and remission (RR 1.013, 95% CI 0.892-1.134), with significantly lower discontinuation/dropout (OR 0.587, 95% CI 0.478-0.697). Concludes comparable efficacy and better tolerability vs SSRIs for mild-to-moderate depression; trials only 4-12 weeks, severe depression unproven.
Cochrane systematic review
29 trials, 5,489 patients
✓ PubMed
The Cochrane review found Hypericum extracts superior to placebo and similarly effective to standard antidepressants in major depression, with fewer dropouts due to adverse events than older antidepressants.
RCT
RCT, 173 patients (ITT)
✓ PubMed
In a randomized, double-blind, placebo-controlled trial in somatoform disorders, St. John's wort extract LI 160 (600 mg/day for 6 weeks) produced 45.4% responders versus 20.9% on placebo (p=0.0006), with statistically significant superiority across all six primary outcome measures.
RCT
RCT, 100 women
✓ PubMed
In a randomized, double-blind, placebo-controlled trial, St. John's wort over 8 weeks significantly reduced both the frequency (p<0.001) and severity (p<0.001) of hot flashes in peri- and postmenopausal women compared with placebo.
RCT
van Gurp 2002
✓ PubMed
Double-blind 12-week primary-care RCT, 87 patients with major depression, SJW (900-1800 mg/d) vs sertraline (50-100 mg/d). No significant difference in Hamilton-D or Beck Depression Inventory change between groups at 12 weeks; significantly fewer side effects with SJW at weeks 2 and 4.
Review
European Psychiatry 2025
✓ Full text
Review found St. John's Wort induces CYP3A4/CYP2C19, raising serotonin syndrome risk when combined with SSRIs (notably citalopram, escitalopram, sertraline) and recommends screening patients on SSRIs for SJW use.
Review
Nicolussi 2020 (Br J Pharmacol)
✓ PubMed
Authoritative mechanistic review of SJW drug interactions. SJW is a potent pregnane-X-receptor activator, inducing CYP3A4 and P-glycoprotein; degree of CYP3A4 induction correlates with hyperforin content. Reduces bioavailability/efficacy of cyclosporine, tacrolimus, digoxin, indinavir, warfarin, alprazolam, simvastatin, and oral contraceptives; low-hyperforin (<1 mg/day) preparations carry lower interaction risk.
toxicology database
NIH LiverTox monograph
✓ Full text
The NIH LiverTox database assigns St. John's wort a likelihood score of E (unlikely cause of clinically apparent liver injury), finding no convincing case reports or enzyme elevations from the herb itself, but cautioning it can raise or lower drug-induced liver injury risk from co-administered medications via CYP3A4/2C9 and P-glycoprotein induction.
Pharmacology review
Review of marketed products
✓ PubMed
A pharmacological review concluded that drug-interaction risk is hyperforin-dose-dependent, with products delivering less than 1 mg hyperforin per day far less likely to cause major CYP3A4/P-glycoprotein interactions (but not interaction-free).
Clinical review
Narrative review
✓ Full text
A clinical review of St. John's wort pharmacokinetics and interactions documents potent PXR-mediated induction of CYP3A4 and P-glycoprotein and resulting failure of cyclosporine, indinavir, warfarin, digoxin, and other narrow-therapeutic-index drugs.
case report
Case report, 2 patients
✓ PubMed
A report in The Lancet described two heart transplant recipients who developed acute graft rejection after self-medicating with St. John's wort, driven by a metabolic interaction that lowered cyclosporine levels into the subtherapeutic range.
Clinical pharmacokinetic study
12 healthy women
✓ PubMed
In a controlled study, St. John's wort shortened ethinyl estradiol half-life (23.4 to 12.2 hours) and increased norethindrone clearance, with breakthrough bleeding in 7 of 12 women (vs 2 of 12 at baseline), indicating reduced oral-contraceptive reliability.
authoritative body
NIH/NCCIH evidence summary
✓ Source
The U.S. NIH National Center for Complementary and Integrative Health warns that combining St. John's wort with antidepressants can precipitate potentially life-threatening serotonin syndrome, and notes the FDA has not approved it for depression because efficacy evidence remains inconclusive.