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St. John's Wort (Hypericum perforatum)

Hypericum perforatum
Evidence Level
Strong
3 Clinical Trials
3 Documented Benefits
4/5 Evidence Score

St. John's Wort (Hypericum perforatum) is a flowering plant whose standardized extracts contain hypericin and hyperforin. It has been tested for mood support in many placebo-controlled trials, mostly in adults diagnosed with mild to moderate depression, where systematic reviews found that more people responded to the extract than to placebo; a large US trial in more severe depression found no benefit. Evidence for anxiety is weak, and menopause findings rest on one small trial and pooled data that include herb combinations. It is not a substitute for medical treatment. It also interacts with more medicines than most popular herbs: it speeds the breakdown or removal of many drugs, including birth control pills, warfarin, cyclosporine, digoxin and some HIV and cancer drugs, so check with a doctor or pharmacist before using it.

Studied Dose Many trials used 300 mg of extract three times daily (900 mg/day); the large US trial allowed 900 to 1,500 mg/day for 8 weeks. In a systematic review, trial follow-up ranged from 4 to 12 weeks (median 6).
Active Compound Hypericin (a naphthodianthrone) and hyperforin (a phloroglucinol). In one systematic review, 8 of 35 trials used an extract standardized to 0.3% hypericin and 1 to 4% hyperforin; LI 160 is the extract used in the large US trial.

Benefits

Mood and emotional wellbeing support

In placebo-controlled trials of standardized extracts in adults diagnosed with major depression, mostly of mild to moderate severity, more people responded to St. John's Wort than to placebo, according to a Cochrane review of 29 trials and a separate systematic review of 35 studies. A large US trial in more severe depression found no benefit over placebo. It is not a substitute for medical treatment.

Supported by Trial 1

Anxiety symptoms

A review of herbal research on mood and anxiety disorders concluded that current evidence supports St. John's Wort only for depression, not for anxiety disorders. In a 12-week placebo-controlled pilot in 40 people with social anxiety disorder, it did no better than placebo. None of the research cited here tested everyday stress.

Supported by Trial 1, Trial 3

Menopausal symptoms and quality of life

In a 12-week randomized pilot in 47 perimenopausal women with daily hot flashes, St. John's Wort did not significantly reduce hot flashes versus placebo but improved menopause-specific quality of life and reduced sleep problems. A meta-analysis pooling the herb alone or with other herbs reported fewer menopausal symptoms than placebo. Evidence is limited: one small trial, and pooled data that mix in herb combinations.

Supported by Trial 3, Trial 1

Mechanism of action

1

Neurotransmitter reuptake inhibition (hyperforin)

Hyperforin inhibits neuronal reuptake of several neurotransmitters, including serotonin and norepinephrine. Cell studies suggest it acts indirectly: it activates the TRPC6 ion channel, and the resulting breakdown of sodium gradients may explain the reduced reuptake. How much this explains effects in people has not been established.

2

CYP3A4 and P-glycoprotein induction

Hyperforin binds the pregnane X receptor, which switches on the drug-metabolizing enzyme CYP3A4, and St. John's Wort extract also appears to induce the P-glycoprotein drug transporter. Together these lower blood levels of many medicines, and hyperforin is suspected of driving most reported interactions.

Clinical trials

1
Cochrane review of 29 double-blind St. John's Wort trials
PubMed

Systematic review and meta-analysis of 29 randomized double-blind trials: 18 comparisons with placebo and 17 with standard antidepressants (Linde et al. 2008, Cochrane Database Syst Rev).

5,489 patients diagnosed with major depression. St. John's Wort is not a substitute for medical treatment.

Placebo-controlled results varied widely. More people responded to hypericum extract than to placebo: response rate ratio 1.28 (95% CI 1.10 to 1.49) in nine larger trials and 1.87 (1.22 to 2.87) in nine smaller trials. In trials with tricyclic, tetracyclic or SSRI comparators, response rates did not differ statistically and fewer participants dropped out for side effects; these are research comparisons, not a basis for replacing prescribed medication. Trials from German-speaking countries reported more favorable results.

2
Winter mood: uncontrolled postal survey of St. John's Wort users
PubMed

Postal survey of volunteers with no placebo or light-only group and no randomization reported; symptoms rated before and after 8 weeks of a hypericum extract (Kira) taken alone or with light therapy (Wheatley 1999, Curr Med Res Opin).

301 volunteers from the SAD Association: 168 took hypericum alone and 133 took hypericum plus light therapy.

On an 11-item rating scale (maximum 44), mean scores fell from 21.3 to 13 with hypericum alone and from 20.6 to 11.8 with hypericum plus light (within-group changes, both p < 0.001). The two groups did not differ except for greater sleep improvement with added light (p < 0.01). With no control group, the survey cannot show that St. John's Wort caused the improvement; a later review rated this evidence as weak and preliminary.

3
Menopausal quality of life: 12-week randomized pilot trial
PubMed

Double-blind, randomized, placebo-controlled pilot trial of an ethanolic St. John's Wort extract taken three times daily for 12 weeks (Al-Akoum et al. 2009, Menopause).

47 symptomatic perimenopausal women aged 40 to 65 with at least three hot flashes a day.

Daily hot flash frequency fell by 2.3 with St. John's Wort and 1.0 with placebo, a difference that was not statistically significant (P = 0.11). After 3 months the St. John's Wort group reported better menopause-specific quality of life (P = 0.01) and fewer sleep problems (P = 0.05) than placebo. The authors call for a larger trial to confirm these results.

Side effects and drug interactions

Common Potential side effects

Photosensitivity (increased sensitivity to sunlight) has been reported; use sun protection
In trials, overall side effects were similar to placebo, though nervous-system complaints were somewhat more common than on placebo
Rare reports of mania and hypertensive crisis
Not studied enough in severe depression: anyone with severe or worsening depression or thoughts of self-harm needs professional care

Important Drug interactions

Serious drug interactions: St. John's Wort speeds the breakdown and removal of many medicines (through CYP3A4 and P-glycoprotein), lowering their blood levels. Check with a doctor or pharmacist before combining it with any prescription drug.
Oral contraceptives: unwanted pregnancies have been reported in women taking St. John's Wort with birth control pills; avoid the combination
HIV antiretrovirals (for example indinavir, nevirapine): blood levels are reduced, risking loss of effect
Cyclosporine (transplant anti-rejection drug): blood levels fall; acute heart transplant rejection has been reported in two patients
Warfarin: in healthy volunteers St. John's Wort increased warfarin clearance and reduced its anticoagulant effect, which can raise clotting risk
Digoxin: 10 days of St. John's Wort extract lowered digoxin blood levels by about 25% in healthy volunteers
Some cancer drugs (for example irinotecan, imatinib): blood levels are reduced
Antidepressants and other serotonergic drugs: serotonin syndrome has been reported with serotonin reuptake inhibitors; do not combine with, add to, or replace any prescribed antidepressant without medical supervision
Anticonvulsants: named in clinical guidance among drugs with potentially serious interactions

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Frequently asked questions about St. John's Wort (Hypericum perforatum)

What is St. John's wort used for?

St. John's wort is mainly studied for mood support; most trials enrolled adults with mild to moderate depression. It is not a substitute for medical care, and anyone with depression should work with a clinician. It is thought to act on serotonin and other neurotransmitters.

How much St. John's wort should I take?

Many trials used 300 mg of extract three times daily (900 mg total). Some extracts are standardized to 0.3% hypericin and 1 to 4% hyperforin, but products vary, so check the label and talk to a healthcare provider first.

What medications interact with St. John's wort?

St. John's wort speeds up the breakdown of many drugs, reducing their effectiveness. It interacts with antidepressants, birth control pills, blood thinners such as warfarin, transplant drugs such as cyclosporine, digoxin, some HIV and cancer drugs, among others. Never combine it with prescription drugs without your doctor's guidance.

How long does St. John's wort take to work?

Most trials followed people for 4 to 12 weeks, so any mood effect was judged over weeks, not days. Because of its many serious drug interactions and the importance of proper mood care, talk to a healthcare provider before starting it.

What is St. John's Wort?

St. John's Wort (Hypericum perforatum) is a flowering plant whose standardized extracts contain hypericin and hyperforin. It has been tested for mood support in many placebo-controlled trials, mostly in adults diagnosed with mild to moderate depression, where systematic reviews found that more people responded to the e…

Is St. John's Wort safe, and does it have side effects?

Side effects and cautions reported for St. John's Wort include: Photosensitivity (increased sensitivity to sunlight) has been reported; use sun protection In trials, overall side effects were similar to placebo, though nervous-system complaints were somewhat more common than on placebo It may also interact with some medications. St. John's Wort is not right for everyone, so check with a healthcare provider first if you are pregnant or breastfeeding, have a medical condition, or take prescription medication.

Does St. John's Wort interact with any medications?

Possible interactions include: Serious drug interactions: St. John's Wort speeds the breakdown and removal of many medicines (through CYP3A4 and P-glycoprotein), lowering their blood levels. Check with a doctor or pharmacist before combining it with any prescription drug. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for St. John's Wort?

NutraSmarts rates the evidence for St. John's Wort as Strong (4 out of 5). It is backed by 3 study summaries and 14 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(14 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev. 2008;2008(4):CD000448. doi: 10.1002/14651858.CD000448.pub3.PubMedUsed to support: Cochrane review of 29 randomized double-blind trials (5,489 patients with major depression; 18 placebo and 17 standard-antidepressant comparisons). Versus placebo, response rate ratio 1.28 (95% CI 1.10 to 1.49) in nine larger and 1.87 (1.22 to 2.87) in nine smaller trials, with marked heterogeneity. Comparator trials showed no statistical difference in response and fewer dropouts for adverse effects (research comparisons only). Trials from German-speaking countries were more favorable to hypericum. Authors disclosed past grant, speaker fees or travel reimbursement from an extract manufacturer (Schwabe).
  2. Hypericum Depression Trial Study Group, Davidson JR, Gadde KM, Fairbank JA, Krishnan KRR, Califf RM, Binanay C, Parker CB, Pugh N, Hartwell TD, Vitiello B, Ritz L, Severe J, Cole JO, de Battista C, Doraiswamy PM, Feighner JP, Keck P, Kelsey J, Lin KM, Londborg PD, Nemeroff CB, Schatzberg AF, Sheehan DV, Srivastava RK, Taylor L, Trivedi MH, Weisler RH. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287(14):1807-14. doi: 10.1001/jama.287.14.1807.PubMedUsed to support: Double-blind RCT at 12 US clinics in 340 adult outpatients with major depression (HAM-D at least 20): LI-160 extract 900 to 1,500 mg/day vs placebo vs sertraline (active comparator) for 8 weeks. On both primary outcomes (HAM-D change, full response) neither St John's wort nor sertraline differed from placebo (full response 23.9% vs 31.9% placebo); the authors note possible low assay sensitivity. Does not support efficacy in moderately severe major depression.
  3. Borrelli F, Izzo AA. Herb-drug interactions with St John's wort (Hypericum perforatum): an update on clinical observations. AAPS J. 2009;11(4):710-27. doi: 10.1208/s12248-009-9146-8.PubMedUsed to support: Review of clinical herb-drug interaction reports. Well-documented interactions: reduced cyclosporin levels, serotonin syndrome or lethargy with serotonin reuptake inhibitors, unwanted pregnancies with oral contraceptives, and reduced levels of antiretrovirals (indinavir, nevirapine) and anticancer drugs (irinotecan, imatinib), mainly via cytochrome P450 and P-glycoprotein; hyperforin is strongly suspected of causing most of them.
  4. Apaydin EA, Maher AR, Shanman R, Booth MS, Miles JN, Sorbero ME, Hempel S. A systematic review of St. John's wort for major depressive disorder. Syst Rev. 2016;5(1):148. doi: 10.1186/s13643-016-0325-2.PubMedUsed to support: RAND systematic review of 35 RCTs (6,993 adults with major depressive disorder). Versus placebo: more treatment responders (RR 1.53, 18 RCTs, moderate quality, high heterogeneity). Versus antidepressants in mild and moderate depression: no significant difference in response (RR 1.01, 17 RCTs) and fewer adverse events (OR 0.67); research comparisons only. Limits: heterogeneity, 4 to 12 week follow-up, almost no data in severe depression, poor adverse event reporting. Background notes photosensitivity, rare mania and hypertensive crisis, and guidance warning of interactions with oral contraceptives, anticoagulants and anticonvulsants.
  5. Wheatley D. Hypericum in seasonal affective disorder (SAD). Curr Med Res Opin. 1999;15(1):33-7. doi: 10.1185/03007999909115171.PubMedUsed to support: Uncontrolled postal survey: 301 SAD Association volunteers rated symptoms before and after 8 weeks of hypericum extract (Kira) alone (n = 168) or with light therapy (n = 133). Both groups improved within group (p < 0.001); no between-group differences except better sleep with added light (p < 0.01). No placebo or light-only arm and no randomization reported.
  6. Sarris J, Kavanagh DJ. Kava and St. John's Wort: current evidence for use in mood and anxiety disorders. J Altern Complement Med. 2009;15(8):827-36. doi: 10.1089/acm.2009.0066.PubMedUsed to support: Systematic review: evidence supports St John's wort for mild-moderate depression and kava for generalized anxiety; only weak preliminary evidence for St John's wort in seasonal affective disorder; current evidence does not support St John's wort for anxiety disorders.
  7. Kobak KA, Taylor LV, Warner G, Futterer R. St. John's wort versus placebo in social phobia: results from a placebo-controlled pilot study. J Clin Psychopharmacol. 2005;25(1):51-8. doi: 10.1097/01.jcp.0000150227.61501.00.PubMedUsed to support: Randomized placebo-controlled pilot: 40 participants with generalized social anxiety disorder (comorbid depression excluded), St John's wort 600 to 1,800 mg/day vs placebo for 12 weeks. No significant difference in mean change on the Liebowitz Social Anxiety Scale (11.4 with St John's wort vs 13.2 with placebo, P = 0.27); fails to support efficacy in social phobia.
  8. Liu YR, Jiang YL, Huang RQ, Yang JY, Xiao BK, Dong JX. Hypericum perforatum L. preparations for menopause: a meta-analysis of efficacy and safety. Climacteric. 2014;17(4):325-35. doi: 10.3109/13697137.2013.861814.PubMedUsed to support: Meta-analysis of placebo-controlled trials in menopausal women: St John's wort alone or combined with other herbs was superior to placebo for menopausal symptoms (SMD -1.08, 95% CI -1.38 to -0.77); adverse events 17.4% vs 15.4% on placebo (RR 1.16, not significant). Pooled trials include herb combinations.
  9. Al-Akoum M, Maunsell E, Verreault R, Provencher L, Otis H, Dodin S. Effects of Hypericum perforatum (St. John's wort) on hot flashes and quality of life in perimenopausal women: a randomized pilot trial. Menopause. 2009;16(2):307-14. doi: 10.1097/gme.0b013e31818572a0.PubMedUsed to support: Double-blind randomized placebo-controlled pilot in 47 symptomatic perimenopausal women for 12 weeks. Hot flash frequency and score: non-significant differences favoring St John's wort (P = 0.11 and 0.10). Menopause-specific quality of life (P = 0.01) and sleep problems (P = 0.05) significantly better than placebo; authors call for a larger trial.
  10. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA. St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A. 2000;97(13):7500-2. doi: 10.1073/pnas.130155097.PubMedUsed to support: Laboratory study: hyperforin is a potent ligand of the pregnane X receptor (Ki 27 nM), and hypericum extract or hyperforin markedly induced CYP3A4 expression in primary human hepatocytes, explaining interactions with oral contraceptives, cyclosporin and indinavir.
  11. Leuner K, Kazanski V, Müller M, Essin K, Henke B, Gollasch M, Harteneck C, Müller WE. Hyperforin--a key constituent of St. John's wort specifically activates TRPC6 channels. FASEB J. 2007;21(14):4101-11. doi: 10.1096/fj.07-8110com.PubMedUsed to support: Cell study: hyperforin specifically activates TRPC6 channels, causing sodium and calcium entry; the resulting breakdown of sodium gradients may explain its indirect inhibition of neuronal serotonin and norepinephrine uptake.
  12. Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther. 1999;66(4):338-45. doi: 10.1053/cp.1999.v66.a101944.PubMedUsed to support: Single-blind placebo-controlled study in healthy volunteers on digoxin: 10 days of LI160 900 mg/day reduced digoxin AUC by 25% and trough and peak levels by 33% and 26% versus placebo; P-glycoprotein induction proposed.
  13. Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2004;57(5):592-9. doi: 10.1111/j.1365-2125.2003.02051.x.PubMedUsed to support: Open-label randomized crossover in 12 healthy men: St John's wort raised apparent clearance of S- and R-warfarin (ratios 1.29 and 1.23) and reduced the INR area under the curve (ratio 0.79), a significant reduction in warfarin's effect.
  14. Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G. Acute heart transplant rejection due to Saint John's wort. Lancet. 2000;355(9203):548-9. doi: 10.1016/S0140-6736(99)05467-7.PubMedUsed to support: Case report: acute rejection in two heart transplant patients caused by a metabolic interaction between St John's wort and cyclosporin.