Herb ·Moderate evidence ·Reviewed May 2026
Widely used herbal antidepressant with one of the most dangerous supplement-drug interaction profiles. Potent CYP3A4 and P-glycoprotein inducer, reduces effectiveness of many critical medications.
The bottom line
Evidence rating moderate. Most-documented uses: mild-to-moderate depression, mood support, anxiety reduction. 16 sources indexed (2000–2024), with 68 interaction records on file.
Core mechanism
Hyperforin inhibits reuptake of serotonin, norepinephrine, dopamine, GABA, and glutamate via modulation of sodium-dependent transporters. Hypericin contributes photosensitizing activity. Hyperforin is a potent inducer of CYP3A4, CYP2C9, CYP1A2, and P-glycoprotein via PXR activation.9,13
Take with meals to reduce GI upset. Effects take 4-6 weeks to manifest.
Dosing protocol
Critical: potent CYP3A4 inducer. Screens drug list before use. Reduces oral contraceptive, warfarin, cyclosporine, antiretroviral levels.
Ranked by evidence and value.
Real-world pricing across three quality tiers. Assumes Standardized St. John's Wort Extract.
Assumes 300 mg 3 times daily. Vendor basis: NOW/iHerb, Vitacost, Life Extension, and Amazon marketplace; standardized hypericin/hyperforin extracts set mid and premium tiers. Updated 2026-05-28.
How much you'd eat to match a supplemental dose.
St. John's wort is a medicinal herb extract and has major drug-interaction concerns; it is not a culinary food.
Dose: 300 mg extract three times daily
Timing: With meals
Clinical dose evidence: PMID 28064110. Major CYP3A4 and serotonergic interaction risk; medication review is essential.
What to test, the optimal window inside the conventional range, and how long a response takes.
Hypericum perforatum (300 mg three times daily, standardized to 0.3 percent hypericin or 3 to 5 percent hyperforin) has efficacy comparable to SSRIs in mild-to-moderate depression in meta-analyses.1,5
Critical: St. John's wort is a potent CYP3A4 inducer and reduces levels of oral contraceptives, warfarin, cyclosporine, antiretrovirals, tacrolimus, and many other drugs. Screen drug list before recommending. No reliable blood biomarker for the supplement itself.
Where this appears in the symptom-to-supplement map, ranked by relevance.
It appears to modulate serotonin, dopamine, and norepinephrine signaling and has shown benefit for mild to moderate depression in trials.
Major caution: it induces liver enzymes and can dangerously reduce levels of many drugs including antidepressants, oral contraceptives, and warfarin.
Can support mild depressive symptoms in some people, but drug interactions are extensive and serious.5,7
Avoid if you take antidepressants, oral contraceptives, anticoagulants, or many prescriptions.
Evidence-based stacks that include it, with the exact dose and timing each one uses.
St. John's Wort inhibits reuptake of serotonin, dopamine, and norepinephrine and has trial support for mild to moderate low mood. It is also a potent inducer of CYP3A4 and P-glycoprotein, so it carries major drug interaction risk and is included only as a flagged, optional, supervised adjunct.1,2
St. John's wort induced CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole in a pharmacogenetic interaction study (PMID 15001970).
Recommendation: Avoid St. John's wort with prescription drugs unless a clinician has reviewed interaction and pharmacogenomic risk.
St. John's Wort inhibits serotonin reuptake while 5-HTP floods serotonin synthesis. Combined use risks serotonin syndrome: a potentially fatal condition.
Recommendation: Do NOT combine. Both increase serotonergic activity through different mechanisms.
St. John's Wort inhibits serotonin reuptake while L-Tryptophan increases serotonin synthesis. Risk of serotonin syndrome.
Recommendation: Do NOT combine without medical supervision.
Rhodiola and St. John's Wort both have CNS-active and possible serotonergic effects. Human interaction evidence is limited, but combining them can make mood, sleep, blood pressure, and serotonergic side effects harder to predict.
Recommendation: Avoid using Rhodiola and St. John's Wort together as a self-directed mood stack, especially with antidepressants or other serotonergic medications.
Both herbs carry independent hepatic safety signals, so combining them can complicate monitoring and attribution if liver enzymes rise or symptoms of liver injury appear.
Recommendation: Avoid routine co-use. If both are taken, watch for signs of liver injury (fatigue, dark urine, jaundice, right upper quadrant pain) and consider baseline and periodic liver function tests.
St. John's Wort both adds to serotonergic load and induces drug-metabolizing enzymes, so combined with MDMA it can raise serotonin syndrome risk while also unpredictably altering MDMA blood levels.
Recommendation: Do not combine. Seek medical advice, and watch for signs of serotonin excess such as agitation, sweating, tremor, and rapid heartbeat.
St. John's Wort has serotonergic and weak monoamine-oxidase-modulating activity, so combining it with the serotonergic psychedelic psilocybin raises the theoretical risk of excessive serotonergic effects and unpredictable response.
Recommendation: Do not combine without medical guidance. Anyone using St. John's Wort should seek medical advice before considering psilocybin.
St. John's Wort is a potent inducer of CYP3A4, CYP2C9, and P-glycoprotein, which dramatically accelerates warfarin metabolism and reduces its plasma levels. This can cause a clinically significant drop in INR, leading to loss of anticoagulant protection and potential thromboembolic events including stroke.
Recommendation: Do not take St. John's Wort with warfarin. This is a well-established dangerous interaction. If you are currently taking both, consult your prescriber immediately, do not abruptly stop St. John's Wort as INR may rebound sharply.
St. John's Wort potently induces CYP3A4 and P-glycoprotein, both of which are major pathways for apixaban metabolism and transport. This induction can reduce apixaban plasma levels by 50% or more, potentially rendering the anticoagulant ineffective and increasing the risk of thromboembolic events.
Recommendation: Avoid combining St. John's Wort with apixaban. The FDA and EMA both list strong CYP3A4 inducers as contraindicated with DOACs. Discuss alternative mood support options with your prescriber.
St. John's Wort potently induces CYP3A4 and P-glycoprotein, the primary metabolic pathways for rivaroxaban. This can substantially reduce rivaroxaban plasma concentrations, compromising anticoagulant efficacy and increasing thromboembolic risk.
Recommendation: Avoid combining St. John's Wort with rivaroxaban. Strong CYP3A4 inducers are listed as a contraindication in rivaroxaban prescribing information. Seek alternative supplements for mood support.
St. John's Wort is a potent CYP3A4 inducer that significantly increases atorvastatin metabolism, reducing its plasma levels and cholesterol-lowering efficacy. Studies have shown up to 50% reduction in statin AUC with concurrent St. John's Wort use.
Recommendation: Avoid combining St. John's Wort with atorvastatin. If mood support is needed, discuss alternative options with your prescriber that do not induce CYP3A4.
St. John's Wort induces CYP3A4 and P-glycoprotein, which can reduce rosuvastatin levels. While rosuvastatin is less dependent on CYP3A4 than other statins, P-glycoprotein induction can still significantly reduce its bioavailability, potentially compromising cholesterol management.
Recommendation: Avoid combining St. John's Wort with rosuvastatin. P-glycoprotein induction may reduce rosuvastatin absorption even though it is not primarily CYP3A4-metabolized.
St. John's Wort dramatically reduces simvastatin levels through potent CYP3A4 induction. Simvastatin is highly dependent on CYP3A4 for metabolism, making this one of the most clinically significant statin-herb interactions. Simvastatin AUC may be reduced by over 50%.
Recommendation: Do not combine St. John's Wort with simvastatin. This interaction can render simvastatin ineffective for cholesterol management. Discuss alternative mood support with your prescriber.
Numbered references. Citations throughout the page link here.
Meta-analysis of 27 trials (3,808 patients) found St. John's wort had comparable response and remission rates to SSRIs with significantly lower discontinuation/dropout rate.
Berry-Bibee EN, Kim MJ, Tepper NK et al.. Co-administration of St. John's wort and hormonal contraceptives: a systematic review. Contraception. 2016
Cochrane review of 29 trials found hypericum extracts tested in trials were (a) superior to placebo for major depression and (b) similarly effective as standard antidepressants with fewer side effects.
Gaster B, Holroyd J. St John's wort for depression: a systematic review. Archives of internal medicine. 2000
Landmark study demonstrating SJW induces intestinal P-glycoprotein/MDR1 and both intestinal and hepatic CYP3A4, establishing the dual mechanism for dangerous drug interactions.
Hypericum perforatum (St. John's wort) was identified as one of the most well-supported phytochemical treatments for depression, with consistent evidence from multiple clinical trials.
Nobakht SZ, Akaberi M, Mohammadpour AH et al.. Hypericum perforatum: Traditional uses, clinical trials, and drug interactions. Iranian journal of basic medical sciences. 2022
Updated review confirming significant herb-drug interactions associated with hyperforin content, with low-hyperforin preparations showing reduced but not eliminated interaction risk.
St. John's wort had the strongest evidence base among complementary therapies for depression, with multiple systematic reviews supporting its efficacy comparable to standard antidepressants.
Systematic review of 35 studies (6,993 patients) found SJW associated with more treatment responders than placebo, with moderate quality of evidence.
Schulz V. Safety of St. John's Wort extract compared to synthetic antidepressants. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2006
Madabushi R, Frank B, Drewelow B et al.. Hyperforin in St. John's wort drug interactions. European journal of clinical pharmacology. 2006
Comprehensive review documenting SJW's induction of CYP3A4, CYP2C9, CYP1A2, and P-glycoprotein via PXR activation, substantially decreasing blood levels of cyclosporine, indinavir, digoxin, warfarin, and oral contraceptives.
Detailed pharmacokinetic analysis showing SJW reduces plasma concentrations of oral contraceptives, HIV antiretrovirals, immunosuppressants, and cancer drugs to potentially subtherapeutic levels.
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