What does the research show about st. john's wort?

St. John's Wort

In a Cochrane review, extracts outperformed placebo in major depression and matched standard antidepressants, with fewer dropouts. A large US trial found no difference from placebo. The herb speeds the breakdown of many drugs. Trials and case reports show lower levels of contraceptives, cyclosporine, indinavir and warfarin, and transplant rejection.

Add to Bio HackChecked 2026-11-09

Status: Dietary supplement in the US. Not approved by the FDA as a drug for any use.
Also called: Hypericum perforatum, hypericum, hypericin, hyperforin, LI 160, Ze 117, WS 5570, Johanniskraut
Taken for: depression, low mood, anxiety, premenstrual symptoms, menopause symptoms, sleep

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help2

StrongShown to match standard antidepressants for response in adults with mild to moderate or major depression, with fewer dropouts than on SSRIs, over 4 to 12 weeks.
ModerateShown to lower PMS anxiety, depression, mood and behavioral symptoms modestly against placebo. One small trial found physical and behavioral gains but no mood change.

Reported risks6

ModerateShown to lower birth control pill levels and raise breakthrough bleeding in healthy women, with signs of probable ovulation in one study. Pregnancies were not measured.How often is not known
ModerateShown to cut cyclosporine levels about half in kidney transplant patients with a high-hyperforin extract. Two heart transplant patients had acute rejection from the interaction.How often is not known
ModerateShown to lower levels of the HIV drug indinavir about 57% in healthy volunteers. Reports show lower levels or effect of warfarin, cyclosporine, digoxin and birth control pills.How often is not known
LimitedOne small study found 14 days of St. John's wort sped warfarin clearance and lowered its blood-thinning effect in healthy men.How often is not known
LimitedCase reports: five older patients combining prescription antidepressants with St. John's wort were diagnosed with serotonin syndrome.How often is not known
LimitedCase reports: a young man with no psychiatric history developed mania and psychosis after months at standard doses, improving within a week on medication after stopping.How often is not known

What people take it for, and what was found

Shown to help2

Strong

Compared with standard antidepressants

Shown to match standard antidepressants for response in adults with mild to moderate or major depression, with fewer dropouts than on SSRIs, over 4 to 12 weeks.

The numbers and sources

Effect: Response matched tricyclic and tetracyclic drugs (RR 1.02, 95% CI 0.90 to 1.15, 5 trials) and SSRIs (RR 1.00, 95% CI 0.90 to 1.11, 12 trials) [1]. A 2017 meta-analysis of 27 trials (3,808 patients) against SSRIs found similar response (RR 0.983) and remission (RR 1.013) and fewer dropouts (OR 0.587, 95% CI 0.478 to 0.697) [3].
Population: Adults with mild to moderate or major depression [1][3].
Sources: [1], [3]
Caveats: Trials ran 4 to 12 weeks, so long-term effects are not known. Benefit in severe depression or high suicide risk is unclear [3]. The 2017 search included Chinese databases [3].

Moderate

Premenstrual symptoms

Shown to lower PMS anxiety, depression, mood and behavioral symptoms modestly against placebo. One small trial found physical and behavioral gains but no mood change.

The numbers and sources

Effect: Across 9 RCTs, St. John's wort lowered PMS anxiety (SMD -0.21, 95% CI -0.37 to -0.05), depression (SMD -0.45, 95% CI -0.74 to -0.17), mood disturbance (SMD -0.36, 95% CI -0.66 to -0.06) and behavioral symptoms (SMD -0.43, 95% CI -0.68 to -0.19) against placebo [4]. In a crossover trial of 36 women with mild PMS, 900 mg a day for two cycles improved physical and behavioral symptoms more than placebo. Mood and pain symptoms, anxiety, depression, hormones and cytokines did not differ [5].
Population: 1,020 participants in 9 RCTs published from 2000 to 2023 [4]. 36 women aged 18 to 45 [5].
Sources: [4], [5]
Caveats: One meta-analysis, which searched Iranian regional databases alongside international ones. The authors note a lack of high-quality evidence for some outcomes [4]. The single crossover trial found no mood difference, unlike the pooled result [5].

Mixed results1

Moderate

Major depression against placebo

Mixed results: a review of 29 trials found more responses than placebo in major depression, while a US trial found no difference, with sertraline also no different.

The numbers and sources

Effect: In 29 trials (5,489 patients), response rates against placebo had a rate ratio of 1.28 (95% CI 1.10 to 1.49) in 9 larger trials and 1.87 (95% CI 1.22 to 2.87) in 9 smaller ones [1]. In a 2002 US trial of 340 outpatients with a Hamilton score of at least 20, the 8-week drop in score was 8.68 points on St. John's wort and 9.20 on placebo, and full response was 23.9% against 31.9%. Sertraline did not differ from placebo on these measures either [2].
Population: Adults with major depression [1][2].
Sources: [1], [2]
Caveats: Placebo-controlled results were markedly heterogeneous, and trials from German-speaking countries reported more favorable results [1]. The US trial was funded by the NIMH, and its authors raise low assay sensitivity [2].

Doses studied

The US depression trial gave 900 to 1,500 mg a day for 8 weeks [2]. The PMS trial gave 900 mg a day standardized to 0.18% hypericin and 3.38% hyperforin [5]. The contraceptive studies gave 300 mg three times a day [6][7], and the cyclosporine study 900 mg a day [8].

Risks

Reported risks6

ModerateStudied in womenHow often is not known

Lower contraceptive levels, breakthrough bleeding and ovulation

Shown to lower birth control pill levels and raise breakthrough bleeding in healthy women, with signs of probable ovulation in one study. Pregnancies were not measured.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: In 12 women on a combined pill, 300 mg three times a day raised norethindrone clearance from 8.2 to 9.5 L/h and halved ethinyl estradiol half-life, from 23.4 to 12.2 hours. Breakthrough bleeding rose from 2 of 12 women to 7 of 12 [6]. In 16 women on a low-dose pill, contraceptive exposure fell 13% to 15%, with more breakthrough bleeding and evidence of follicle growth and probable ovulation [7].
Population: 28 healthy premenopausal women in two studies [6][7].
Sources: [6], [7]
Caveats: Small pharmacokinetic studies. Neither measured pregnancies.

ModerateHow often is not known

Cyclosporine and transplant rejection

Shown to cut cyclosporine levels about half in kidney transplant patients with a high-hyperforin extract. Two heart transplant patients had acute rejection from the interaction.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: Two heart transplant patients had acute rejection from an interaction between St. John's wort and cyclosporine [9]. In 10 kidney transplant patients, a high-hyperforin extract at 900 mg a day for 14 days cut cyclosporine exposure by 52% and trough levels by 55%, and cyclosporine doses had to rise 65%. A low-hyperforin extract had no significant effect [8].
Population: 2 heart transplant patients [9]. 10 kidney transplant patients in a randomized crossover [8].
Sources: [9], [8]
Caveats: The size of the interaction varied with hyperforin content [8].

ModerateHow often is not known

Lower levels of HIV drugs and other medicines

Shown to lower levels of the HIV drug indinavir about 57% in healthy volunteers. Reports show lower levels or effect of warfarin, cyclosporine, digoxin and birth control pills.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: In healthy volunteers, St. John's wort cut exposure to the HIV protease inhibitor indinavir by a mean 57% and its trough level by 81% [10]. A systematic review of literature and European regulator reports found clinically significant interactions with warfarin, phenprocoumon, cyclosporine, HIV protease inhibitors, theophylline, digoxin and oral contraceptives, each lowering the drug's level or effect. Sweden and the UK sent warnings to health professionals and patients [11].
Population: Healthy volunteers [10]. Published reports and spontaneous reports to European regulators [11].
Sources: [10], [11]
Caveats: The review notes the degree of enzyme induction varies with product content [11].

LimitedStudied in menHow often is not known

Warfarin

One small study found 14 days of St. John's wort sped warfarin clearance and lowered its blood-thinning effect in healthy men.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: In 12 healthy men, 14 days of St. John's wort raised the clearance of S-warfarin by 29% and R-warfarin by 23%, and lowered the INR effect (AUC ratio 0.79, 90% CI 0.70 to 0.95) [12].
Population: 12 healthy men given one 25 mg warfarin dose [12].
Sources: [12]
Caveats: A single warfarin dose in healthy volunteers, not patients on long-term therapy.

LimitedHow often is not known

Serotonin syndrome with antidepressants

Case reports: five older patients combining prescription antidepressants with St. John's wort were diagnosed with serotonin syndrome.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: Five elderly patients who combined prescription antidepressants with St. John's wort were diagnosed with central serotonergic syndrome [13]. The interaction review also identified possible interactions with SSRIs and triptans, with a higher risk of adverse reactions [11].
Population: Case series [13]. Regulator and published reports [11].
Sources: [13], [11]
Caveats: Case reports cannot give a rate.

LimitedHow often is not known

Mania and psychosis

Case reports: a young man with no psychiatric history developed mania and psychosis after months at standard doses, improving within a week on medication after stopping.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: A man in his early twenties with no notable psychiatric history developed acute mania and psychosis, with grandiose and persecutory delusions, after several months of St. John's wort at standard doses. Tests and brain imaging were normal. He improved within a week on aripiprazole, and St. John's wort was stopped [14]. The authors note that earlier reported cases typically involved high doses, psychotropic drugs or a psychiatric history [14].
Population: One case report [14].
Sources: [14]
Caveats: A single case. The link is described as possible, and the episode followed a COVID-19 infection [14].

Possible, not studied in people1

UntestedHow often is not known

Glucuronidation (UGT) inhibition in lab studies

Lab studies only: hyperforin and hypericin blocked 11 drug-clearing enzymes. Modeled gut risk fell sharply once poor dissolution was included.

No study in people. This rests on lab studies.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: In vitro, hyperforin and hypericin inhibited 11 UGT enzymes, which clear many drugs. Hyperforin was the most potent (UGT1A1 Ki 1.46 μM). A model using FDA thresholds first flagged a high gut interaction risk (R1,gut 69.49 against a threshold of 11), which fell to about 2.0 to 2.9 once hyperforin's poor dissolution was included [15].
Population: In vitro, recombinant human enzymes and computer modeling [15].
Sources: [15]
Caveats: No people were studied. The authors describe the interaction as potential, with a size that depends on the product [15].

Claims tested and not found

That St. John's wort relieves moderately severe major depression. In 340 US outpatients, change in Hamilton score and full response did not differ from placebo over 8 weeks [2].

Sources

Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database of Systematic Reviews. 2008. https://doi.org/10.1002/14651858.CD000448.pub3
Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John's Wort) in Major Depressive Disorder: A Randomized Controlled Trial. JAMA. 2002. https://doi.org/10.1001/jama.287.14.1807
Ng QX, Venkatanarayanan N, Ho CYX. Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis. Journal of Affective Disorders. 2017. https://doi.org/10.1016/j.jad.2016.12.048
Bozorgian L, Ghanbari S, Mottaghipisheh J, et al. The efficacy of Hypericum perforatum L. for the treatment of premenstrual syndrome: A systematic review and meta-analysis. Avicenna Journal of Phytomedicine. 2026. https://pubmed.ncbi.nlm.nih.gov/42920783/
Canning S, Waterman M, Orsi N, et al. The Efficacy of Hypericum perforatum (St John's Wort) for the Treatment of Premenstrual Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. CNS Drugs. 2010. https://doi.org/10.2165/11530120-000000000-00000
Hall SD, Wang Z, Huang SM, et al. The interaction between St John's wort and an oral contraceptive. Clinical Pharmacology & Therapeutics. 2003. https://doi.org/10.1016/j.clpt.2003.08.009
Murphy PA, Kern SE, Stanczyk FZ, et al. Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception. 2005. https://doi.org/10.1016/j.contraception.2004.11.004
Mai I, Bauer S, Perloff ES, et al. Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction. Clinical Pharmacology & Therapeutics. 2004. https://doi.org/10.1016/j.clpt.2004.07.004
Ruschitzka F, Meier PJ, Turina M, et al. Acute heart transplant rejection due to Saint John's wort. The Lancet. 2000. https://doi.org/10.1016/S0140-6736(99)05467-7
Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St John's wort. The Lancet. 2000. https://doi.org/10.1016/S0140-6736(99)05712-8
Henderson L, Yue QY, Bergquist C, et al. St John's wort (Hypericum perforatum): drug interactions and clinical outcomes. British Journal of Clinical Pharmacology. 2002. https://doi.org/10.1046/j.1365-2125.2002.01683.x
Jiang X, Williams KM, Liauw WS, et al. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. British Journal of Clinical Pharmacology. 2004. https://doi.org/10.1111/j.1365-2125.2003.02051.x
Lantz MS, Buchalter E, Giambanco V. St. John's Wort and Antidepressant Drug Interactions in the Elderly. Journal of Geriatric Psychiatry and Neurology. 1999. https://doi.org/10.1177/089198879901200103
Yoshioka D, Yamanashi T, Iwata M. Acute mania and psychosis potentially triggered by St John's wort. Psychiatry and Clinical Neurosciences Reports. 2026. https://doi.org/10.1002/pcn5.70292
Chen J, Zhang Y, Zhao X, et al. Hypericin and hyperforin from St. John's Wort are potent intestinal UGT inhibitors with distinct binding modes: mechanistic and quantitative prediction of clinical drug-drug interaction risk. Frontiers in Pharmacology. 2026. https://doi.org/10.3389/fphar.2026.1899795

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