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Key takeaways
Strongest evidence: mild-to-moderate depression — a Cochrane review of 29 trials (5,489 patients) found St John's Wort more effective than placebo and comparable to standard antidepressants for mild-to-moderate depression, with fewer side effects than SSRIs.
Not effective for severe depression, bipolar depression, or as an alternative to prescribed SSRIs for confirmed major depressive disorder — evidence base is weak or negative for these.
Dangerous interactions are the main concern: St John's Wort strongly induces CYP3A4 and P-glycoprotein, reducing effectiveness of oral contraceptives, warfarin, cyclosporine, HIV antiretrovirals, immunosuppressants, some cancer drugs (imatinib, irinotecan), and digoxin.
Serotonin syndrome risk when combined with SSRIs, SNRIs, MAOIs, tramadol, triptans, and other serotonergic drugs — can be life-threatening; do not combine.
Standard dose: 300 mg 3× daily of a standardized extract (typically 0.3% hypericin or 3–6% hyperforin) for at least 4–6 weeks to see effect.
St John’s wort (
Hypericum perforatum ) has the best evidence for
short-term mild-to-moderate depression , but it is not a casual “mood herb” because it can dangerously reduce the effect of many medicines and can combine with antidepressants to raise serotonin to life-threatening levels (
NCCIH ,
Cochrane Review ). The biggest safety issue is that many preparations, especially higher-hyperforin extracts, induce CYP3A4 and P-glycoprotein, which can lower blood levels of oral contraceptives, immunosuppressants, HIV medicines, anticoagulants, digoxin, some cancer drugs, and other narrow-therapeutic-index medicines (
NCCIH Herb–Drug Interactions ,
British Journal of Pharmacology review ). If you take prescription medication, are pregnant, have bipolar disorder, or are being treated for depression, St John’s wort should be treated as a medicine-level decision, not a self-experiment (
EMA herbal monograph ,
NCCIH ).
SAFETY WARNING: St John’s wort has serious interaction risks
Do not combine St John’s wort with SSRIs, SNRIs, MAOIs, tricyclic antidepressants, triptans, tramadol, linezolid, or other serotonergic medicines unless a qualified clinician explicitly supervises the combination, because NCCIH warns that combining St John’s wort with certain antidepressants can cause a potentially life-threatening serotonin increase (NCCIH ). Do not use St John’s wort with oral contraceptives, warfarin, cyclosporine, tacrolimus, HIV antiretrovirals, digoxin, anticonvulsants, many statins, calcium channel blockers, irinotecan, imatinib, or other CYP3A4/P-glycoprotein substrates without prescriber approval, because documented interactions can cause contraceptive failure, transplant rejection, HIV treatment failure, loss of anticoagulation, or reduced cancer-drug exposure (NCCIH Herb–Drug Interactions , Mills et al., BMJ , EMA herbal monograph ). Stop reading and contact emergency care if agitation, fever, diarrhea, tremor, fast heartbeat, high blood pressure, hallucinations, confusion, or muscle rigidity occur after combining St John’s wort with serotonergic medicines, because these are serotonin-syndrome warning signs described by NCCIH (NCCIH ).
Evidence summary
Claim Evidence Source Funding / conflict trace Strength
St John’s wort can improve mild-to-moderate depression symptoms. Systematic review of 35 RCTs and 6,993 patients found more responders than placebo, but with substantial heterogeneity. Apaydin et al., Systematic Reviews United States; funded by the Department of Defense Centers of Excellence; authors declared no competing interests; funder reported no role in analysis or publication. Moderate Evidence for severe depression is not strong enough for self-treatment. The same review found lack of research on severe depression lowered evidence quality, and the large NIH-supported U.S. JAMA trial did not show benefit in moderately severe major depression. Apaydin et al. ; Hypericum Depression Trial Study Group, JAMA Apaydin: public funding; JAMA: U.S. academic/community trial, Hypericum supplied by Lichtwer Pharma and sertraline supplied by Pfizer according to the trial record. Mixed / caution Drug-interaction risk is high and clinically important. NCCIH states St John’s wort is a potent inducer of cytochrome P450 enzymes and intestinal P-glycoprotein; 22 pharmacokinetic trials in a BMJ review mostly showed decreased drug bioavailability. NCCIH Herb–Drug Interactions ; Mills et al., BMJ NCCIH: U.S. federal public-health source; Mills: Canada/UK/US authorship, funded by Ontario HIV Treatment Network, no competing interests declared. High Oral contraceptive exposure can fall and breakthrough bleeding can increase. Systematic review found increased breakthrough bleeding and possible ovulation signals; a clinical trial reported 77% and 88% intracyclic bleeding during St John’s wort cycles versus 35% on oral contraceptive alone. Berry-Bibee et al., Contraception ; Pfrunder et al., British Journal of Clinical Pharmacology Systematic review: U.S. CDC-affiliated authors, public-health context; Pfrunder trial: Switzerland, partly supported by Senglett Foundation for Young Pharmacists. Moderate to high safety concern Product composition varies materially. EMA assessment lists multiple constituents, and a 2020 review reports hyperforin in commercial products varying from less than 0.5 mg per unit to 13 mg per unit in one German analysis. EMA assessment report ; Nicolussi et al., British Journal of Pharmacology EMA: European regulator; Nicolussi review: Switzerland, three authors employed by an SJW herbal-product manufacturer, so interaction-minimizing claims are downgraded. High for variability; cautious for low-hyperforin claims Topical use for minor wounds is traditional and supported by limited clinical evidence. EMA recognizes traditional topical use for minor inflammation and minor wounds; one Iranian episiotomy trial found lower pain, redness, edema, and ecchymosis but no significant discharge or dehiscence difference. EMA herbal monograph ; Samadi et al., J Matern Fetal Neonatal Med EMA: European regulator; episiotomy trial: Iran, funding not clear from PubMed record. Limited / low-to-moderate
St John’s Wort Interaction Risk Matrix
Red = avoid unless prescriber explicitly manages the interaction.Mechanisms: serotonin excess, CYP3A4 induction, P-gp induction.
SSRIs / SNRIs / MAOIsSerotonin syndrome
Transplant medicinesRejection risk
HIV antiretroviralsTreatment failure
Oral contraceptivesReduced efficacy / pregnancy risk
Warfarin / anticoagulantsLower anticoagulant effect
Digoxin / heart drugsLower drug levels
ChemotherapyIrinotecan, imatinib exposure ↓
AnticonvulsantsSeizure-control risk
Statins / CCBs / thyroid medsMonitor or avoid
Clinical rule:
If the medicine prevents pregnancy, transplant rejection, blood clots, seizures,HIV progression, arrhythmia, or cancer progression, do not add St John’s wort casually.
Text version of this infographic
Medication group Risk color Main mechanism Why it matters SSRIs, SNRIs, MAOIs, tricyclics, triptans, tramadol, linezolid Red / avoid Serotonergic effect plus serotonergic drugs Serotonin syndrome can be life-threatening. Cyclosporine, tacrolimus, sirolimus, everolimus Red / avoid CYP3A4 and P-glycoprotein induction Drug levels can fall and transplant rejection may occur. HIV antiretrovirals, especially protease inhibitors and non-nucleoside reverse-transcriptase inhibitors Red / avoid CYP3A4 and P-glycoprotein induction Antiviral exposure can fall and treatment failure or resistance is possible. Oral contraceptives and other hormonal contraception Red / avoid or use reliable nonhormonal backup after clinician advice CYP induction and lower hormone exposure Breakthrough bleeding, ovulation signals, and unplanned pregnancy risk. Warfarin and anticoagulants Orange to red / avoid unless prescriber monitors CYP induction and altered anticoagulant exposure INR or anticoagulant effect may fall. Digoxin, chemotherapy, anticonvulsants, statins, calcium channel blockers, thyroid medication Orange / prescriber review required Reduced exposure or reduced clinical effect, depending on drug Loss of disease control can be clinically serious.
What it is
St John’s wort is the common name for Hypericum perforatum L., a yellow-flowering plant native to Europe and introduced to many other regions; the leaves and flowering tops are used in extracts, tinctures, teas, and oils (LiverTox , EMA assessment report ). EMA’s herbal inventory lists Hyperici herba as a finalized European herbal assessment with therapeutic areas that include mood disorders, mental stress, gastrointestinal disorders, skin disorders, and minor wounds (EMA product page ).
The active compounds — what actually does the work
The main compound families are naphthodianthrones such as hypericin and pseudohypericin, phloroglucinol derivatives such as hyperforin and adhyperforin, flavonoids such as hyperoside, rutin, isoquercitrin, quercitrin, quercetin, biflavones, procyanidins, tannins, trace xanthones, and volatile-oil components (EMA assessment report , LiverTox ). EMA states that dried Hyperici herba contains not less than 0.08% total hypericins expressed as hypericin, while the broader constituent profile varies by raw material, age, extraction solvent, and processing (EMA assessment report ). Hyperforin is especially important for drug interactions because it activates the pregnane X receptor pathway that upregulates CYP3A4 and P-glycoprotein, while hypericin is historically used for standardization and is linked to photosensitivity at high exposures (British Journal of Pharmacology review , P-glycoprotein clinical study ).
Form What it is Typical standardization / variability Best-supported use Main downside Verdict
Standardized dry extract tablets / capsules Concentrated extract of flowering tops, commonly used in depression trials. Many trials used extracts standardized around 0.3% hypericin; some extracts also report hyperforin, commonly 1–4% in the RAND review, while commercial hyperforin content has varied widely (Apaydin et al. , British Journal of Pharmacology review ). Mild-to-moderate depression under clinician supervision. Highest concern for clinically meaningful interactions when hyperforin is not low. Most evidence, highest safety burden. Low-hyperforin standardized extract Extract quantified to keep hyperforin low. A conflicted 2020 review argues that up to 1 mg/day hyperforin is not expected to produce clinically relevant pharmacokinetic interactions, but three authors were employees of an SJW product manufacturer, so this claim needs independent verification before it is used as a safety guarantee (British Journal of Pharmacology review ). Potentially safer option only when a clinician chooses SJW and verifies the product. Low-hyperforin status is often not clear on consumer labels. Promising but not a free pass. Whole herb / dried flowering tops / tea Comminuted dried herb prepared as infusion. EMA lists herbal tea using 1.5–2 g in 150 ml boiling water, 2–3 times daily, but whole-herb chemistry can vary by plant source and processing (EMA herbal monograph ). Traditional use; less clinical depression evidence than standardized extracts. Dose and active-compound exposure are less predictable. Not ideal for therapeutic claims. Tinctures Alcohol-water extracts, often drops. EMA lists tincture ratios such as 1:5 in ethanol 50–70% v/v and 1:10 in ethanol 45–50% v/v among traditional preparations (EMA assessment report ). Traditional use when dosing is product-specific. Alcohol content, variable dosing, and interaction risk remain. Use only with label clarity and clinician review. Oils / infused oils Vegetable-oil macerates or liquid extracts used topically. EMA lists liquid extracts in vegetable oil or maize oil for traditional topical use (EMA assessment report ). Traditional use for minor inflammation and minor wounds. Should not be used on deep, infected, severe, or non-healing wounds; photosensitivity and product contamination are practical concerns. Topical-only, limited evidence. Combination formulas St John’s wort combined with black cohosh, valerian, or other botanicals. Clinical interpretation is difficult because the St John’s wort contribution cannot be isolated when multiple herbs are used (Black cohosh + St John’s wort trial ). Specific formula-specific use, not ingredient-level proof. More interaction uncertainty and harder attribution of side effects. Generally avoid for clean safety assessment.
Which St John’s Wort Form Is Most Predictable?
More clinical dataLess predictable
Standardized extractEvidence strongest; interaction risk high
Low-hyperforin extractMay reduce induction; verify label
TinctureDose varies by product
Whole herb / teaLess standardized exposure
OilTopical use only; limited data
Buying rule:
Choose products that state extract ratio, plant part,
hypericin, hyperforin, batch testing, and contraindications.
Avoid any product that claims “no interactions” without specifying hyperforin content and documented safety testing.
Text version of this infographic
Standardized extracts have the most clinical trial data but also the greatest need for interaction screening. Low-hyperforin extracts may reduce CYP3A4/P-glycoprotein induction only if the product clearly states low hyperforin and the claim is independently verified. Tinctures and whole-herb teas are less standardized and should not be assumed safer. Oils are primarily topical and should not be taken internally unless a qualified clinician has prescribed a regulated product. Quality products should state extract ratio, plant part, hypericin content, hyperforin content, batch testing, and contraindications.
How it works: mechanism of action
What the body does with it
The antidepressant mechanism is not fully settled, but pharmacology reviews and LiverTox identify hypericin, pseudohypericin, and hyperforin as likely active candidates, with effects across serotonergic, noradrenergic, dopaminergic, GABA, glutamate, inflammatory, and neuroendocrine pathways proposed in the literature (LiverTox , Hypericum traditional uses review ). The safety mechanism is clearer than the antidepressant mechanism: hyperforin activates pregnane X receptor, which increases expression of CYP3A4 and P-glycoprotein, leading to faster metabolism or efflux of susceptible medicines and lower systemic exposure (British Journal of Pharmacology review , P-glycoprotein clinical study ).
Different extracts can behave differently because hyperforin, hypericin, and flavonoid concentrations vary widely by extraction method and product, and a German analysis cited in the 2020 pharmacology review found hyperforin from less than 0.5 mg per unit to 13 mg per unit while hypericin varied from 0.1% to 0.3% (British Journal of Pharmacology review ). The Cochrane review also warns that hypericum preparations can differ considerably because composition depends on raw material, extraction process, and solvent, which means a trial-tested extract is not automatically interchangeable with a marketplace capsule or tea (Cochrane Review ).
How St John’s Wort Lowers Drug Levels
Hyperforinvaries by product
PXRnuclear receptor
CYP3A4 ↑
P-glycoprotein ↑
Less medicine reaches or stays in the bloodstreamOral contraceptives, cyclosporine, tacrolimus, antiretrovirals,warfarin, digoxin, statins, chemotherapy, and others may fail.
Text version of this infographic
Some St John’s wort products contain meaningful hyperforin. Hyperforin activates pregnane X receptor, abbreviated PXR. PXR activation increases CYP3A4 enzyme expression and P-glycoprotein transporter activity. CYP3A4 induction increases metabolism of susceptible medicines, while P-glycoprotein induction pumps some medicines back into the gut or out of tissues. The result can be lower medicine exposure and treatment failure for oral contraceptives, cyclosporine, tacrolimus, antiretrovirals, warfarin, digoxin, statins, chemotherapy medicines, and other substrates.
What works & what doesn’t
Claimed benefit Verdict Evidence Key caveat
Mild-to-moderate depression WORKS, with limits Systematic review found SJW monotherapy superior to placebo and not significantly different from antidepressant medication in mild and moderate depression (Apaydin et al. ). Product variability, heterogeneity, and interaction risks mean it is not a first-line self-treatment. Severe depression MIXED / NOT FOR SELF-TREATMENT Evidence is limited, and a U.S. randomized trial in moderately severe major depression failed to support efficacy versus placebo (JAMA trial ). Severe depression requires clinician-led care because suicide risk and undertreatment risk are serious. Anxiety / social anxiety DOESN’T A 40-person social phobia pilot RCT found no significant benefit over placebo on the Liebowitz Social Anxiety Scale (Kobak et al. ). Depression improvements may secondarily reduce anxious distress, but that is not proof for anxiety disorders. Obsessive-compulsive disorder DOESN’T A 60-person 12-week double-blind OCD trial found Y-BOCS change was not significantly different with St John’s wort versus placebo (Kobak et al. ). Do not replace evidence-based OCD treatments such as ERP-focused CBT and SSRIs. Seasonal affective disorder INSUFFICIENT EVIDENCE Searchable clinical evidence is dominated by light therapy and depression studies rather than strong SJW-specific SAD trials (Cochrane light-therapy SAD review ). Phototherapy has a clearer evidence base for SAD than St John’s wort. Wound healing, topical MIXED / LIMITED EMA recognizes traditional topical use for minor wounds, and an episiotomy trial reported improvements in pain and inflammatory signs but not discharge or dehiscence (EMA herbal monograph , Samadi et al. ). Do not apply to serious, infected, deep, surgical, diabetic, or non-healing wounds without medical care. Menopausal symptoms MIXED / INSUFFICIENT A pilot trial in 47 perimenopausal women showed nonsignificant hot-flash changes favoring St John’s wort and some quality-of-life signals (Menopause trial ). Combination trials with black cohosh cannot prove St John’s wort alone works. ADHD DOESN’T A JAMA randomized trial in children and adolescents found 8 weeks of Hypericum perforatum did not improve ADHD symptoms versus placebo (Weber et al., JAMA ). Do not use it instead of evidence-based ADHD care. Somatoform disorders INSUFFICIENT EVIDENCE Accessible evidence is not strong enough to support a verdict beyond exploratory or secondary claims in broader reviews (Hypericum review ). Any use is especially risky if the person takes multiple medicines.
Evidence Strength by Claim
Higher bar = stronger evidence for benefit; red labels mean evidence does not justify self-treatment.
Depressionmild/moderate
Severe depression
Topical wounds
Menopause
OCD / ADHD / anxiety
Best signalMixedLimitedPilot onlyNegative / insufficient
Text version of this infographic
The strongest evidence signal is for mild-to-moderate depression. Severe depression has mixed evidence and should not be self-treated. Topical wound use has traditional support and limited clinical evidence. Menopausal symptoms have pilot-level evidence and cannot be treated as proven. OCD, ADHD, and social anxiety have negative or insufficient trial evidence.
Benefits by claim
Mild-to-moderate depression — Grade B, clinician-supervised only
The best-supported benefit is short-term symptom improvement in mild-to-moderate depression, with the 2016 RAND-linked systematic review finding more responders than placebo and no significant difference from antidepressants in mild and moderate depression (Apaydin et al. ). The Cochrane review found hypericum extracts superior to placebo and similarly effective as standard antidepressants in major depression trials, but it also emphasized that country of origin and study precision complicated interpretation and that German-speaking-country trials tended to be more favorable (Cochrane Review ). This evidence grade is not “green light for self-treatment” because depression can become severe and because St John’s wort can interact with many medications (NCCIH ).
Severe or moderately severe depression — Grade C / mixed
A German manufacturer-funded trial reported WS 5570 was at least as effective as paroxetine and better tolerated in moderate-to-severe depression, but the authors disclosed funding and employment or consultancy relationships with Dr Willmar Schwabe Pharmaceuticals, the manufacturer of WS 5570 (Szegedi et al., BMJ ). A large U.S. JAMA trial in 340 adults with major depression did not find St John’s wort significantly better than placebo on the primary outcomes and concluded the study failed to support efficacy in moderately severe major depression (Hypericum Depression Trial Study Group, JAMA ). The practical verdict is that severe depression, suicidal thoughts, bipolar depression, psychosis, postpartum depression, or depression with functional impairment needs clinician-led care, not unsupervised St John’s wort (NCCIH ).
Topical wound support — Grade C
EMA’s monograph includes traditional topical use for symptomatic treatment of minor inflammations and minor wounds, which supports traditional external use rather than strong modern proof (EMA herbal monograph ). A clinical trial in 140 primiparous women reported that Hypericum perforatum ointment reduced perineal pain, redness, edema, and ecchymosis after episiotomy compared with controls, but discharge and dehiscence did not significantly differ (Samadi et al. ). This does not justify applying St John’s wort oil to deep, infected, diabetic, surgical, or non-healing wounds without medical care.
Risks & all side effects
St John’s wort side effects are often described as uncommon or mild in depression RCTs, but RCTs were not designed to detect rare serious events, and interaction harms are the dominant safety issue (Apaydin et al. , NCCIH ). NCCIH lists upset stomach, dry mouth, headache, fatigue, dizziness, confusion, sexual dysfunction, and sensitivity to sunlight as side effects, and it notes that St John’s wort may worsen anxiety in some people because it can act as a stimulant (NCCIH ). LiverTox lists gastrointestinal upset, dizziness, confusion, fatigue, anxiety, and photosensitivity, and it emphasizes major interactions through CYP3A4, CYP2C9, and P-glycoprotein rather than convincing clinically apparent acute liver injury from St John’s wort alone (LiverTox ).
Side effect Frequency / dose relationship What to do Source
Photosensitivity / sun sensitivity Uncommon at usual doses but more plausible at higher exposures; a pharmacology review cites volunteer photosensitization at 2–4 g/day commercial preparation equivalent to about 5–10 mg hypericin. Avoid intense UV exposure, tanning beds, and photosensitizing drugs; stop and seek care for severe rash or burns. British Journal of Pharmacology review ; EMA monograph Gastrointestinal upset Usually mild; a European drug-monitoring study cited in the pharmacology review reported gastrointestinal irritation at 0.6%. Take only with clinician-approved dosing; stop if persistent or severe. British Journal of Pharmacology review Fatigue Reported in NCCIH and drug-monitoring data; one cited monitoring study reported fatigue at 0.4%. Avoid driving if sedated or dizzy. NCCIH ; British Journal of Pharmacology review Restlessness / anxiety stimulation Restlessness was reported at 0.3% in a cited monitoring study, and NCCIH notes it may worsen anxiety in some people. Stop and discuss with a clinician if agitation, insomnia, panic, or restlessness emerges. British Journal of Pharmacology review ; NCCIH Headache Usually minor and uncommon in general summaries. Stop if severe, new, or associated with blood pressure, fever, confusion, or serotonin-syndrome symptoms. NCCIH Dry mouth Usually minor and uncommon in general summaries. Review other anticholinergic or antidepressant medicines because combined effects may worsen dryness. NCCIH Sexual dysfunction Listed by NCCIH; exact frequency varies by product and trial reporting. Discuss with a clinician; do not add serotonergic drugs to “balance” mood effects. NCCIH Dizziness / confusion Listed by NCCIH and LiverTox. Stop and seek medical advice, especially in older adults or with CNS-active medicines. NCCIH ; LiverTox Induced mania or worsening psychosis Rare but serious; NCCIH notes case reports of dangerous worsening of psychotic symptoms in people with bipolar disorder or schizophrenia. Avoid in bipolar disorder, mania history, psychosis, or schizophrenia unless a psychiatrist specifically supervises it. NCCIH Serotonin syndrome Rare but potentially life-threatening, especially with SSRIs, SNRIs, MAOIs, TCAs, triptans, tramadol, linezolid, lithium, MDMA, or other serotonergic agents. Do not combine; emergency care for agitation, diarrhea, fever, fast heartbeat, high blood pressure, hallucinations, tremor, or rigidity. NCCIH
Serotonin Syndrome Warning
Risk rises when St John’s wort is combined with serotonergic medicines.
Agitation
Diarrhea
Fever
Tremor
Fast heartbeat
High BP
Confusion
Hallucinations
Action:
Stop the combination and seek urgent medical care if symptoms appear.
Text version of this infographic
Serotonin syndrome warning signs include agitation, diarrhea, fever, tremor, fast heartbeat, high blood pressure, confusion, and hallucinations. The clinical action is to stop the combination and seek urgent medical care if these symptoms appear after combining St John’s wort with serotonergic medicines.
All interactions
St John’s wort is one of the highest-risk botanical supplements for drug interactions because it induces CYP3A4 and P-glycoprotein and because it has serotonergic pharmacodynamic activity (NCCIH Herb–Drug Interactions , Mills et al., BMJ ). The interaction can persist after stopping because CYP3A recovery is not immediate; a clinical study found apparent oral midazolam clearance returned to control around 7 days after cessation in healthy volunteers, so prescribers often need a washout plan rather than same-day switching (Imai et al. ).
Interacts with Type Severity Mechanism Clinical action
SSRIs such as sertraline, fluoxetine, paroxetine, citalopram, escitalopram Pharmacodynamic SERIOUS / avoid Additive serotonergic effects can raise serotonin to potentially life-threatening levels. Do not combine unless a psychiatrist explicitly supervises; urgent care for serotonin-syndrome symptoms (NCCIH ). SNRIs such as venlafaxine, desvenlafaxine, duloxetine Pharmacodynamic SERIOUS / avoid Additive serotonin and norepinephrine effects can precipitate serotonin toxicity. Avoid; use clinician-directed taper and washout plan (NCCIH ). MAOIs such as phenelzine, tranylcypromine, isocarboxazid, selegiline Pharmacodynamic SERIOUS / avoid MAO inhibition plus serotonergic herb effect can dangerously increase serotonin and blood pressure. Contraindicated in practice unless specialist-managed; do not self-combine (NCCIH ). Tricyclic antidepressants such as amitriptyline, nortriptyline, clomipramine, imipramine PK + PD SERIOUS / avoid Possible serotonin toxicity plus reduced antidepressant levels through enzyme induction; amitriptyline interaction is cited in clinical-interaction literature. Avoid or specialist-supervise with therapeutic monitoring where applicable (Mills et al., BMJ ). Oral contraceptives and hormonal contraception Pharmacokinetic SERIOUS CYP3A4/CYP2C9 induction can lower hormone exposure; clinical studies show breakthrough bleeding and possible ovulation signals. Avoid; use nonhormonal backup and speak with a prescriber before starting or stopping (Berry-Bibee et al. , Pfrunder et al. ). Warfarin and coumarin anticoagulants Pharmacokinetic SERIOUS Enzyme induction can reduce anticoagulant effect; EMA contraindicates concomitant use with coumarin-type anticoagulants for higher-hyperforin preparations. Avoid unless prescriber chooses and monitors INR closely; do not start or stop suddenly (EMA monograph , LiverTox ). DOACs and antiplatelets such as apixaban, rivaroxaban, dabigatran, clopidogrel Likely pharmacokinetic / pharmacodynamic HIGH Many are P-gp and/or CYP3A substrates, so induction can reduce exposure; platelet/bleeding risk context complicates management. Avoid unless anticoagulation specialist approves; monitor clinically because routine levels may not be available (LiverTox ). Digoxin Pharmacokinetic SERIOUS P-glycoprotein induction can reduce digoxin exposure; NCCIH lists documented clinically significant interaction. Avoid or monitor digoxin levels and symptoms under prescriber care (NCCIH Herb–Drug Interactions , P-gp study ). Cyclosporine Pharmacokinetic CRITICAL / avoid CYP3A4 and P-gp induction can lower levels and has been linked to transplant rejection. Contraindicated unless transplant team explicitly directs; never self-use after transplant (NCCIH , cyclosporine study ). Tacrolimus, sirolimus, everolimus, and other immunosuppressants Pharmacokinetic CRITICAL / avoid EMA lists systemic tacrolimus, sirolimus, everolimus, and cyclosporine among contraindicated combinations for relevant preparations. Do not combine; consult transplant specialist before any botanical supplement (EMA monograph ). Antiretrovirals including indinavir, other protease inhibitors, NNRTIs, and NRTIs Pharmacokinetic CRITICAL / avoid CYP3A4/P-gp induction can reduce antiretroviral concentrations, risking treatment failure and resistance. Contraindicated unless HIV specialist explicitly directs; NCCIH lists indinavir and HIV medicines (NCCIH , EMA monograph ). Theophylline Pharmacokinetic HIGH Enzyme induction may reduce exposure to narrow-therapeutic-index respiratory medicine. Avoid unsupervised use; monitor levels and symptoms if a prescriber permits (Mills et al., BMJ ). Anticonvulsants such as carbamazepine, phenytoin, phenobarbital, valproate, lamotrigine Pharmacokinetic / CNS SERIOUS Enzyme and transporter effects can alter antiseizure medicine exposure, and uncontrolled seizures are high-risk. Avoid unless neurologist approves; monitor seizure frequency and drug levels where available (Apaydin et al. ). Triptans such as sumatriptan, rizatriptan, zolmitriptan Pharmacodynamic SERIOUS / avoid Additive serotonergic effect can contribute to serotonin syndrome risk. Avoid without prescriber guidance; urgent care for serotonin symptoms (NCCIH ). Statins, especially simvastatin and atorvastatin Pharmacokinetic HIGH CYP3A4 induction can reduce statin exposure; a clinical study found LDL and total cholesterol increased during simvastatin plus St John’s wort. Avoid with simvastatin; if already exposed, check lipids and discuss alternatives such as non-CYP3A statins with prescriber (simvastatin study ). Calcium channel blockers such as nifedipine, amlodipine, verapamil, diltiazem Pharmacokinetic HIGH Many are CYP3A4 substrates, so induction can reduce blood-pressure or antianginal effect. Avoid unsupervised use; monitor blood pressure, angina, edema, and heart rate under clinician care (NCCIH Herb–Drug Interactions ). Chemotherapy and targeted cancer medicines including irinotecan and imatinib Pharmacokinetic CRITICAL / avoid EMA lists irinotecan, imatinib, and other cytostatic agents metabolized by CYP3A4, CYP2B6, CYP2C9, CYP2C19, or transported by P-gp as contraindicated combinations for relevant preparations. Do not combine; oncology team must review every supplement (EMA monograph , NCCIH ). Thyroid medication such as levothyroxine Possible clinical interaction MODERATE / monitor Evidence is less direct than for CYP3A4/P-gp substrates, but thyroid control is sensitive to absorption, metabolism, adherence, and supplement timing. Do not start without the prescriber who manages thyroid labs; check TSH/free T4 after changes and separate dosing from supplements. Photosensitizing drugs such as tetracyclines, fluoroquinolones, thiazides, retinoids, amiodarone, phenothiazines Pharmacodynamic HIGH St John’s wort can increase sunlight sensitivity, and combining with photosensitizing drugs may increase skin reaction risk. Avoid intense UV exposure; use protective clothing and SPF; stop and seek care for severe rash or burns (EMA monograph , NCCIH ). Benzodiazepines, sedatives, oxycodone, and other CYP3A substrates Pharmacokinetic HIGH NCCIH lists benzodiazepines and oxycodone among documented or clinically important interaction concerns, mainly through reduced drug exposure. Prescriber review required; monitor sedation, withdrawal symptoms, pain control, and therapeutic failure (NCCIH , NCCIH Herb–Drug Interactions ).
Clinical action rule: St John’s wort should be entered into the medication list like a prescription drug. The safest default is avoid when the other medicine prevents pregnancy, organ rejection, HIV progression, blood clots, seizures, arrhythmia, cancer progression, severe depression, or hospitalization.
Who should avoid it: contraindications
Avoid St John’s wort if you take any prescription medication unless the prescribing clinician has checked the interaction, because NCCIH states that it weakens many prescription medicines and has documented clinically significant interactions with cyclosporine, indinavir, oral contraceptives, warfarin, digoxin, and other medicines (NCCIH Herb–Drug Interactions ). Avoid it during pregnancy and lactation because EMA states safety during pregnancy and breast-feeding has not been established and use is not recommended (EMA monograph ). Avoid it in children and adolescents unless a qualified clinician is involved, because EMA states there are insufficient data and use under 18 is not recommended for listed uses (EMA monograph ). Avoid it in bipolar disorder, mania history, psychosis, or schizophrenia because NCCIH notes case reports of dangerous worsening of psychotic symptoms in people with bipolar disorder or schizophrenia (NCCIH ). Avoid it before surgery unless the surgical team approves, because interactions with anesthetics, analgesics, anticoagulants, and perioperative medicines can create avoidable risk.
Dosage & how to take
Most depression trials used standardized extracts rather than loose herb, commonly 300 mg three times daily or 600–1,200 mg/day depending on extract, while specific studies used STEI 300 at 350 mg three times daily or WS 5570 at 600–1,200 mg/day (Philipp et al., BMJ , Kasper et al. ). EMA lists tea as 1.5–2 g comminuted herb in 150 ml boiling water 2–3 times daily, and the EMA herbal monograph on Hypericum perforatum . These numbers are not a recommendation for self-treatment because the same dose in two products can contain very different hyperforin and hypericin levels (British Journal of Pharmacology review ).
If a clinician decides St John’s wort is appropriate: choose a product that identifies Hypericum perforatum L., plant part, extract ratio, solvent, hypericin percentage, hyperforin amount per daily dose, batch testing, country of manufacture, contraindications, and interaction warnings. Do not start, stop, or switch brands while taking interacting medicines without clinician guidance, because induction and de-induction can change drug levels over days (Imai et al. ).
Independent evidence, funding & conflict review
The European evidence base is historically stronger because St John’s wort extracts have been used and prescribed more often in German-speaking countries, but that same history creates an evidence-risk problem: many positive trials studied branded extracts, were conducted in German-speaking settings, or were funded by manufacturers. The Cochrane review explicitly found that trials from German-speaking countries reported more favorable findings and that country of origin and precision complicated interpretation (Cochrane Review ). The U.S. caution is driven by a different regulatory environment and large publicly visible negative or mixed trials, including the JAMA Hypericum Depression Trial and NCCIH’s safety-focused consumer guidance (JAMA trial , NCCIH ).
Source Country / institution Evidence type Funding / conflicts Independence rating Credibility rank How used in this article
Apaydin et al., 2016 systematic review United States; RAND-linked authors and Systematic Reviews journal. Systematic review, 35 studies, 6,993 patients. Funded by Department of Defense Centers of Excellence; authors declared no competing interests; funder reported no role. Independent Very strong for evidence synthesis; limited by underlying trials. Primary efficacy grade for mild-to-moderate depression. Linde et al., Cochrane Review Germany-affiliated authors; Cochrane. Systematic review, 29 trials, 5,489 patients. Cochrane methodology; review notes manufacturer contacts; funding disclosures not as complete in PMC extract as modern standards. Probably independent Strong. Used for depression benefit and Germany-country-effect caution. Hypericum Depression Trial Study Group, JAMA 2002 United States, 12 academic/community psychiatric clinics. 340-person RCT versus placebo and sertraline. Hypericum supplied by Lichtwer Pharma and sertraline by Pfizer according to trial record; public/academic context but product supply creates disclosed industry involvement. Probably independent with material product-supply context. Strong for U.S. moderately severe depression caution. Used to avoid overclaiming severe-depression benefit. Szegedi et al., BMJ 2005 WS 5570 trial Germany. Moderate-to-severe depression RCT versus paroxetine. Funded by Dr Willmar Schwabe Pharmaceuticals; employees and consultants disclosed. Conflicted Moderate; useful but downgraded. Included as context, not decisive proof. Kasper et al., WS 5570 placebo trial Austria/Germany. Placebo-controlled RCT. Funded by Dr Willmar Schwabe Pharmaceuticals; employees, consultants, and medical-writing support disclosed. Conflicted Moderate; useful but downgraded. Included for dose context and conflict transparency. Mills et al., BMJ interaction review Canada/UK/US authorship. Systematic review of 22 pharmacokinetic trials. Funded by Ontario HIV Treatment Network; no competing interests declared. Independent Very strong for interaction risk. Primary interaction evidence source. Nicolussi et al., 2020 interaction review Switzerland. Pharmacology review. Three authors were employees of a manufacturer of an SJW herbal medicinal product. Conflicted Moderate; mechanistic details useful, low-hyperforin safety claims downgraded. Used for product-variability and mechanism, with conflict warning. NCCIH consumer monograph United States federal public-health agency. Authoritative consumer safety summary. Publicly funded; no product sales incentive; publication reviewed by named experts. Independent Very strong for safety communication. Primary safety warning source. EMA/HMPC monograph European Union regulator. Regulatory herbal monograph. Public regulator; monograph process included consultation. Independent regulator Very strong for EU indications, preparations, contraindications. Used for forms, contraindications, pregnancy/lactation, and topical traditional use.
Text version of this infographic
Independent reviews such as Cochrane, RAND-linked systematic reviews, and BMJ interaction reviews receive higher weight. Manufacturer-funded trials from Schwabe and Steiner are useful but downgraded because the sponsor benefits from positive findings. A 2020 low-hyperforin interaction review is useful for mechanism and product variability but its low-interaction conclusion is downgraded because three authors worked for an SJW herbal-product manufacturer. The editorial bottom line is that European positive evidence matters, but interaction safety gets the highest weight.
For deeper, evidence-graded context on the conditions St John's wort is most often used for, see Pure City Research's condition guides:
Frequently Asked Questions
Is St John’s wort safe to take with antidepressants?
No, not without specialist supervision. NCCIH warns that combining St John’s wort with certain antidepressants can cause a potentially life-threatening serotonin increase, so SSRIs, SNRIs, MAOIs, tricyclics, and other serotonergic drugs should generally be treated as avoid combinations (NCCIH ).
Does St John’s wort really work for depression?
It has moderate evidence for mild-to-moderate depression, but results vary by study setting, extract, and severity. A 2016 systematic review found St John’s wort superior to placebo and not significantly different from antidepressant medication in mild and moderate depression, while severe-depression evidence remains weaker (Apaydin et al. ).
Can St John’s wort make birth control fail?
Yes, it can reduce hormonal contraceptive exposure and has been associated with breakthrough bleeding and concern for reduced contraceptive efficacy. A systematic review found increased breakthrough bleeding and possible ovulation signals when combined oral contraceptives were co-administered with St John’s wort (Berry-Bibee et al. ).
How long do St John’s wort interactions last after stopping?
Interaction intensity may decline over days rather than immediately. A CYP3A recovery study found midazolam oral clearance returned to control around 7 days after St John’s wort cessation, so medication changes should be planned with a prescriber rather than handled as a same-day switch (Imai et al. ).
Is topical St John’s wort oil safer than capsules?
Topical oil avoids much of the systemic CYP3A4/P-gp induction concern if it is not swallowed, but it is not risk-free. EMA supports traditional topical use for minor inflammation and minor wounds, but serious, infected, deep, diabetic, surgical, or non-healing wounds require medical care (EMA herbal monograph ).
What is the difference between hypericin and hyperforin?
Hypericin is a naphthodianthrone often used for standardization and associated with photosensitivity at higher exposure, while hyperforin is a phloroglucinol derivative strongly tied to PXR activation and CYP3A4/P-glycoprotein induction. EMA lists both as important constituents, and pharmacology reviews emphasize hyperforin as a key interaction driver (EMA assessment report , British Journal of Pharmacology review ).
Is St John’s wort legal or allowed
Yes. In most countries St John’s wort is legal and available over the counter as a herbal supplement — for example as a dietary supplement in the United States and over the counter across much of Europe, where in Germany standardised extracts are also licensed as a medicine for mild depression. It is not a controlled substance. Because it interacts with many prescription drugs, however, regulation varies by country (Ireland, for instance, reclassified it as prescription-only), and health agencies widely advise checking with a pharmacist or doctor before use.
Who should never self-start St John’s wort?
People taking prescription medicines, oral contraceptives, anticoagulants, transplant drugs, HIV medicines, cancer medicines, antidepressants, triptans, anticonvulsants, digoxin, or multiple chronic medicines should not self-start it. Pregnant or lactating people, children and adolescents, people with bipolar disorder, mania, psychosis, schizophrenia, severe depression, or suicidal thoughts should avoid unsupervised use (NCCIH , EMA herbal monograph ).
Sources
NCCIH — St. John’s Wort and Depression: In Depth NCCIH — Herb–Drug Interactions EMA — Hyperici herba product page EMA/HMPC — European Union herbal monograph on Hypericum perforatum L., herba EMA/HMPC — Final assessment report on Hypericum perforatum L., herba Apaydin EA et al. A systematic review of St. John’s wort for major depressive disorder. Systematic Reviews . 2016 Linde K et al. St John’s wort for major depression. Cochrane Database of Systematic Reviews . 2008 Hypericum Depression Trial Study Group. Effect of Hypericum perforatum in major depressive disorder. JAMA . 2002 Mills E et al. Interaction of St John’s wort with conventional drugs: systematic review of clinical trials. BMJ . 2004 Nicolussi S et al. Clinical relevance of St. John’s wort drug interactions revisited. British Journal of Pharmacology . 2020 Berry-Bibee EN et al. Co-administration of St. John’s wort and hormonal contraceptives: a systematic review. Contraception . 2016 Pfrunder A et al. Interaction of St John’s wort with low-dose oral contraceptive therapy. British Journal of Clinical Pharmacology . 2003 LiverTox — St. John’s Wort Kobak KA et al. St John’s wort versus placebo in obsessive-compulsive disorder. International Clinical Psychopharmacology . 2005 Kobak KA et al. St. John’s wort versus placebo in social phobia. Journal of Clinical Psychopharmacology . 2005 Weber W et al. Hypericum perforatum for ADHD in children and adolescents. JAMA . 2008 Samadi N et al. Achillea millefolium and Hypericum perforatum ointments on episiotomy wound healing. Journal of Maternal-Fetal & Neonatal Medicine . 2018 Effects of Hypericum perforatum on hot flashes and quality of life in perimenopausal women. Menopause . 2009 Imai H et al. Recovery time-course of CYP3A after induction by St John’s wort. British Journal of Clinical Pharmacology . 2008 Hennessy M et al. St John’s wort increases expression of P-glycoprotein. British Journal of Clinical Pharmacology . 2002 Eggertsen R et al. Effects of St John’s wort and simvastatin treatment. Scandinavian Journal of Primary Health Care . 2007 Kasper S et al. WS 5570 compared to placebo in major depression. BMC Medicine . 2006 Szegedi A et al. WS 5570 versus paroxetine in moderate to severe depression. BMJ . 2005 Philipp M et al. Hypericum extract versus imipramine or placebo. BMJ . 1999 Clauson KA et al. Clinically relevant safety issues associated with St. John’s wort product labels. BMC Complementary and Alternative Medicine . 2008 Greenblatt DJ et al. Saint John’s wort: in vitro P-glycoprotein induction. British Journal of Pharmacology . 2001 Wenk M et al. Effect of St John’s wort on CYP activities in healthy males and females. British Journal of Clinical Pharmacology . 2004
Medical disclosure: This is educational content, not medical advice. St John’s wort has clinically serious interaction risks; consult a qualified healthcare professional before using it, especially if you take any medication or have depression symptoms.
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