St. John's Wort

The flowering top is gathered while the flowers are open, around midsummer. The link with St John’s Day (24 June) gives the plant its name in most European languages.

Internally it is a nervine, given for nervous exhaustion, low mood, anxiety and disturbed sleep, and for the shooting pain of neuralgia and sciatica. Externally it is a vulnerary, applied to wounds, burns, bruises and injured nerves.

Internal preparations are an infusion of the dried herb or an alcoholic tincture. For the skin, the fresh flowering tops are macerated in oil until the oil turns deep red.

The EU herbal monograph records long-standing use of the herb for temporary mental exhaustion, for nervous restlessness with difficulty falling asleep, for mild digestive discomfort, and on the skin for minor inflammations such as sunburn and as an aid to healing minor wounds ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}.

Modern practice has rebuilt the internal use around standardised extracts, which are the preparations the clinical trials tested.

The 2008 Cochrane review pooled 29 randomised, double-blind trials in 5,489 patients with major depression. Hypericum extracts were superior to placebo and similarly effective to standard antidepressants, with fewer patients dropping out because of adverse effects ^{1Reference 1Linde et al. · 2008Meta-analysisSt John’s wort for major depression — systematic review, meta-analysisView study →}.

Later meta-analyses agree. A 2017 analysis of 27 trials (3,808 patients) found response and remission rates comparable to SSRIs with a significantly lower dropout rate ^{2Reference 2Ng et al. · 2017Meta-analysisClinical use of Hypericum perforatum (St John’s wort) in depression: A meta-analysisView study →}, and a 2023 analysis of 14 trials against SSRIs reached a similar conclusion ^{3Reference 3Zhao et al. · 2023Meta-analysisThe efficacy and safety of StView study →}.

In a 375-patient placebo-controlled trial in mild to moderate major depression, WS 5570 at 300 mg three times daily reduced Hamilton scores more than placebo, with more responders and remissions ^{5Reference 5Lecrubier et al. · 2002RCTEfficacy of StView study →}. A 2025 meta-analysis of milder depression found no difference in response between St. John’s wort and fluoxetine across two trials ^{4Reference 4Urata et al. · 2025Meta-analysisEfficacy of Pharmacological Interventions in Milder Depression: A Systematic Review and Meta-AnalysisView study →}.

⚠ Two large US trials in more severe major depression (HAM-D ≥20) found no separation from placebo. One used LI 160 at 900–1500 mg a day in 340 patients, and the other tested 900–1200 mg a day in 200 patients ^{6,7Reference 6Hypericum Depression Trial Study Group · 2002RCTEffect of Hypericum perforatum (St John’s wort) in major depressive disorder: a randomised controlled trialView study →Reference 7Shelton et al. · 2001RCTEffectiveness of St John’s wort in major depression: a randomised controlled trialView study →}.

Gap: trials are dominated by proprietary German extracts and last 4–12 weeks, and the benefit has not been shown in severe depression ^{1,2Reference 1Linde et al. · 2008Meta-analysisSt John’s wort for major depression — systematic review, meta-analysisView study →Reference 2Ng et al. · 2017Meta-analysisClinical use of Hypericum perforatum (St John’s wort) in depression: A meta-analysisView study →}.

Two placebo-controlled trials used the extract LI 160 in people with somatoform disorders, bodily symptoms without an organic cause.

A 2004 randomised, double-blind study in 184 outpatients without major depression gave 300 mg twice daily for six weeks. The extract was superior to placebo on all six outcome measures, and 45.4% responded against 20.9% on placebo ^{8Reference 8Müller et al. · 2004RCTTreatment of somatoform disorders with StView study →}.

An earlier multicentre trial in 151 outpatients (600 mg/day, six weeks) found a greater fall in somatic anxiety than placebo, and the effect held with or without mild depressive symptoms ^{9Reference 9Volz et al. · 2002RCTSt John’s wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trialView study →}.

Gap: both trials lasted six weeks and used the same extract, so long-term data and other extracts are missing.

A 2014 meta-analysis found Hypericum preparations, alone or combined with other herbs, superior to placebo for menopausal complaints, with an adverse-event rate similar to placebo ^{10Reference 10Liu et al. · 2014Meta-analysisHypericum perforatum L. preparations for menopause: a meta-analysis of efficacy and safetyView study →}.

Several of the pooled trials combined St. John’s wort with Vitex agnus-castus. In a double-blind pilot of the herb alone (900 mg three times daily) in 47 perimenopausal women, the fall in hot-flush score was not significant, but quality of life and sleep improved more than on placebo ^{11Reference 11Al-Akoum et al. · 2009RCTEffects of Hypericum perforatum (StView study →}.

Gap: the best evidence bundles St. John’s wort with other herbs, and its effect on hot flushes alone is unconfirmed in adequately powered trials.

A randomised, double-blind, placebo-controlled crossover trial in 36 women with mild PMS gave 900 mg a day of a standardised extract. Physical and behavioural symptoms improved significantly more than on placebo, but mood and pain symptoms did not ^{12Reference 12Canning et al. · 2010RCTThe efficacy of Hypericum perforatum (St John’s wort) for the treatment of premenstrual syndrome: a randomised, double-blind, placebo-controlled trialView study →}.

A second trial from Iran was published in 2011 as a short communication ^{13Reference 13Ghazanfarpour et al. · 2011RCTHypericum perforatum for the treatment of premenstrual syndrome — randomised controlled trialView study →}.

Gap: small samples, few trials and inconsistent effects across symptom groups; no large confirmatory trial.

A randomised, double-blind trial in 144 women after caesarean section applied Hypericum ointment three times a day for 16 days. Wound healing on day 10 and scarring on day 40 were better than with placebo ointment or no treatment, and pain and itching were lower ^{14Reference 14Samadi et al. · 2010RCTThe effect of Hypericum perforatum on the wound healing and scar of caesarean — randomised, double-blind trialView study →}.

A 2025 trial of St. John’s wort oil on stage 1–2 pressure injuries in 48 nursing-home residents found no difference from saline at any weekly time point ^{15Reference 15Yıldırım et al. · 2025RCTThe Effects of StView study →}.

Gap: few trials, different wound types and formulations, and one clear null; topical results say nothing about oral use.

This work uses the isolated pigment hypericin as a photosensitiser activated by light, which is photodynamic therapy. In cell studies, light-activated hypericin inhibits the growth of many tumour cell types, including bladder, colon, breast, melanoma and glioma ^{16Reference 16Dong et al. · 2021ReviewHypericin-mediated photodynamic therapy for the treatment of cancer: a reviewView study →}.

Hypericin also binds the envelope of SARS-CoV-2 and reduces its infectivity in cell culture, with a smaller effect in the dark ^{17Reference 17Delcanale et al. · 2022In vitroThe Interaction of Hypericin with SARS-CoV-2 Reveals a Multimodal Antiviral Activity — in vitroView study →}. Earlier work showed it inactivates several enveloped viruses, an effect strengthened by light ^{18Reference 18Hudson et al. · 1991In vitroAntiviral activities of hypericin — in vitroView study →}.

Gap: in vitro and photodynamic only. Swallowing the herb delivers neither the concentrations nor the targeted light these effects need, and there are no clinical trials of the herb for cancer or viral infection.

A 2016 meta-analysis of 13 rodent studies found a large positive effect of Hypericum perforatum on memory tasks, both in healthy animals and in stressed ones ^{19Reference 19Ben-Eliezer et al. · 2016Meta-analysisHypericum perforatum as a cognitive enhancer in rodents: A meta-analysis (animal model)View study →}.

In a single-dose, randomised, double-blind, placebo-controlled trial in 82 healthy students, 250 mg improved digit span, while 500 mg worsened it ^{20Reference 20Yechiam et al. · 2019RCTThe acute effect of Hypericum perforatum on short-term memory in healthy adults — randomised, double-blind, placebo-controlled trialView study →}.

Gap: the positive evidence is mostly in rodents; the one controlled human test was acute, small and mixed, and there are no chronic-dosing human trials.

An open-label trial in 12 patients (450 mg of an extract with 0.3% hypericin twice daily for 12 weeks) reported improvement on the Yale-Brown Obsessive Compulsive Scale ^{22Reference 22Taylor et al. · 2000An open-label trial of StView study →}.

A 12-week double-blind trial then randomised 60 patients to LI 160 (600–1800 mg a day) or placebo, and found no significant difference; 17.9% and 16.7% were much improved ^{21Reference 21Kobak et al. · 2005RCTSt John’s wort versus placebo in obsessive-compulsive disorder: results from a double-blind study (RCT)View study →}.

Gap: the single controlled trial was null; the positive data are uncontrolled.

How the interactions work. Hyperforin activates the pregnane X receptor, which raises the activity of CYP3A4, CYP2B6, CYP2C9, CYP2C19 and P-glycoprotein. Drugs handled by these pathways are cleared faster, and their blood levels fall ^{25,33Reference 25Nicolussi et al. · 2020ReviewClinical relevance of StView study →Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}. The effect grows with the dose: in 11 healthy volunteers, 300, 900 and 1800 mg a day raised midazolam clearance about 2-, 3.9- and 5.6-fold ^{27Reference 27Hohmann et al. · 2024Dose-dependent induction of CYP3A activity by StView study →}. The strength of induction tracks the product’s hyperforin content ^{25Reference 25Nicolussi et al. · 2020ReviewClinical relevance of StView study →}.

Drugs not to combine with it. The EU monograph contraindicates coumarin-type anticoagulants such as warfarin; the immunosuppressants ciclosporin, tacrolimus (systemic), sirolimus and everolimus; fosamprenavir, indinavir and other HIV protease inhibitors; nucleoside reverse transcriptase inhibitors; and irinotecan, imatinib and other cancer drugs handled by these enzymes or by P-glycoprotein ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}. In 2000, the ciclosporin interaction caused acute rejection in two heart-transplant patients ^{25Reference 25Nicolussi et al. · 2020ReviewClinical relevance of StView study →}.

Drugs that need care. Blood levels may fall for amitriptyline, fexofenadine, alprazolam, diazepam, midazolam, methadone, simvastatin, digoxin and finasteride ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}.

Hormonal contraceptives. Lower hormone levels can cause intermenstrual bleeding and reduce protection against pregnancy, and women using hormonal contraception should use an additional method ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}. A systematic review found breakthrough bleeding in three of four studies and signs of ovulation in one ^{26Reference 26Berry-Bibee et al. · 2016Systematic reviewCo-administration of StView study →}.

Serotonergic drugs. Combined with SSRIs such as sertraline or paroxetine, with buspirone, or with other serotonergic drugs, it may add to serotonergic effects. Serotonin syndrome, with sweating, fast heart rate, agitation, tremor or muscle jerks, has occurred very rarely ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}. Triptans, tramadol and MAOIs are among the other serotonergic drugs.

Before surgery. Possible interactions with anaesthetic drugs should be checked before elective surgery, and the herb stopped if needed. Raised enzyme activity returns to normal within about a week of stopping ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}.

Sun sensitivity. Intense UV exposure should be avoided during use. Fair-skinned people may notice tingling, burning or stronger sunburn-like reactions in strong sun. At 1800 mg of extract a day for 15 days, skin sensitivity to UVA increased; no phototoxicity has been reported at recommended doses ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}.

Other effects. Nausea, abdominal pain, diarrhoea, allergic skin reactions, tiredness and restlessness may occur. Seizures and confusion were reported after an overdose of up to 4.5 g of dry extract a day for two weeks plus 15 g at once ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}.

Low-hyperforin products. Preparations supplying no more than 1 mg of hyperforin a day, used for up to two weeks, have not shown clinically relevant interactions ^{33Reference 33Committee on Herbal Medicinal Products ( · 2022ReviewEuropean Union herbal monograph on Hypericum perforatum L., herba — final, revision 1 (EMA/HMPC/7695/2021) — regulatory monographView study →}.