St. John's Wort for Depression: It Beats Placebo in Pooled Trials, but Its Drug Interactions Are Serious
Reviews find St. John's wort works about as well as antidepressants for mild to moderate depression, though two large US trials found no benefit in moderately severe cases. It can weaken birth control, blood thinners, transplant and HIV drugs, and can be dangerous with antidepressants.
By Kymata Health Editorial Published Last checked
What this article covers
1 evidence profileKey takeaways
From 9 sources- A 2016 review of 18 placebo-controlled trials with 2,922 people found more responders on St. John's wort than placebo (RR 1.53) and similar results to antidepressants (RR 1.01), with fewer side effects2.
- The Cochrane review found smaller effects in larger trials (RR 1.28) than smaller ones (RR 1.87), and more favourable results from German-speaking countries1.
- Two large US trials in moderately severe major depression found no benefit over placebo; one was funded by Pfizer and the National Institute of Mental Health, the other sponsored by the institute345.
- NCCIH says St. John's wort can interact in dangerous, sometimes life-threatening ways with many medicines, including birth control pills, warfarin, cyclosporine and some HIV and cancer drugs7.
- Combining it with antidepressants or other serotonin-affecting drugs may cause serious serotonin-related side effects7. FDA labeling for the SSRI sertraline lists St John's wort among the drugs that raise the risk of serotonin syndrome, a potentially life-threatening condition9.
The evidence, graded
Pulled from the trial tables in our evidence profiles. Grades follow our evidence-grading policy.
Graded findings
2 rows- BGrade BMajor depression (response)Improved Larger placebo-controlled trials: response rate ratio 1.28 (95% CI 1.10–1.49); versus SSRIs, response was similar (RR 1.00). Results from German-speaking countries were more favourable.St. John's wort · Systematic review · n=5,489 · 2008 · PMID 18843608
- BGrade BMild to moderate depressionImproved More responders than placebo (RR 1.53, moderate-quality evidence, high heterogeneity); similar effectiveness to antidepressants with fewer adverse events.St. John's wort · Systematic review · n=2,922 · 2016 · PMID 27589952
Where these trials agree: St. John's wort and depression, counted row by row in the Consensus finder.
The short answer
NCCIH says St. John's wort appears more effective than placebo and as effective as standard antidepressants for mild or moderate depression, but it is uncertain whether that holds for severe depression or beyond 12 weeks7. Its bigger practical problem is that it weakens many crucial medicines7.
Depression can be serious; NCCIH advises anyone who may have it to see a health care provider rather than self-manage with an herb7.
What the reviews found
The 2008 Cochrane review included 29 trials with 5,489 people with major depression1. Against placebo, larger trials gave a response rate ratio of 1.28 (95% CI 1.10 to 1.49) and smaller trials 1.871. Against older antidepressants and SSRIs, response was similar, and fewer people dropped out because of side effects than with older antidepressants or SSRIs1. The authors warned that the link between country of origin, trial size and effect size complicates interpretation1.
A 2016 review from the RAND Corporation, funded by the US Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, looked at 35 studies with 6,993 people26. St. John's wort produced more responders than placebo (RR 1.53, 95% CI 1.19 to 1.97), but with high heterogeneity (I² 79%), and the authors said a lack of research in severe depression lowers confidence2.
The two big US trials that missed their main goals
In a trial at 11 US academic centres, 200 adults with major depression took 900 to 1,200 mg a day of extract or placebo for 8 weeks3. Depression scores did not differ, though remission was more common on the herb (14.3% vs 4.9%) and headache was more frequent (41% vs 25%)3. The trial was funded by Pfizer, which makes the antidepressant sertraline, and by the National Institute of Mental Health48.
In the NIMH-sponsored Hypericum Depression Trial, 340 adults took St. John's wort (900 to 1,500 mg a day), sertraline or placebo for 8 weeks5. Full response occurred in 23.9% on the herb, 24.8% on sertraline and 31.9% on placebo5. Because sertraline also failed to beat placebo on the main outcomes, the authors said low trial sensitivity may explain part of the result5. The extract and its placebo were supplied by its maker, Lichtwer Pharma, and sertraline by Pfizer8.
Industry ties on both sides
Three Cochrane review authors disclosed links to Schwabe, a St. John's wort manufacturer: one had received a research grant on hypericum in the past and speaking fees from Schwabe, and two had travel expenses reimbursed by it1. The 2016 review authors declared no competing interests26.
Funding does not decide whether a result is right, but it is worth knowing that both the favourable review and the negative trials had commercial links148.
Who should be careful
For most adults who take no medicine, NCCIH says St. John's wort appears safe for up to 12 weeks; side effects can include diarrhea, dizziness, trouble sleeping, restlessness and skin tingling7. Large oral doses may cause severe skin reactions after sun exposure7. The interaction list is the main concern:
- Birth control pills: St. John's wort can weaken them7.
- Antidepressants and other serotonin-affecting drugs: it can weaken some (amitriptyline, bupropion) and, combined with serotonergic drugs, may cause serious serotonin-related side effects7; the FDA label for sertraline names St John's wort among serotonergic drugs that increase the risk of serotonin syndrome9.
- Warfarin: it can weaken the blood-thinning effect7.
- Transplant patients: it can weaken cyclosporine, the drug that stops the body rejecting a transplanted organ7.
- Seizure, heart, HIV and cancer drugs and some statins: NCCIH lists phenytoin, carbamazepine, digoxin, ivabradine, indinavir, nevirapine, irinotecan, imatinib, docetaxel and simvastatin7.
- Pregnancy and breastfeeding: it may be unsafe in pregnancy because of a possible risk of birth defects, and breastfed infants have had colic, drowsiness and lethargy7.
- Anyone on any prescription medicine: NCCIH advises talking with your health care provider first7.
Quick answers
Common questions
4 answersHow long does St. John's wort take to work?
Can I take St. John's wort with an SSRI?
Does St. John's wort stop birth control from working?
NCCIH lists birth control pills among the medicines St. John's wort can weaken7.
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References
9 sources. Numbers in the text link here.
Sources cited in this article
9 sources- 1St John's wort for major depressionCochrane Database Syst Rev, 2008 · PMID 18843608
- 2A systematic review of St. John's wort for major depressive disorderSyst Rev, 2016 · PMID 27589952
- 3Effectiveness of St John's wort in major depression: a randomized controlled trialJAMA, 2001 · PMID 11308434
- 4St John's wort was not better than placebo for reducing depression scores (summary noting sources of funding: Pfizer Inc and National Institute of Mental Health)Evidence-Based Mental Health (BMJ), 2002
- 5Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trialJAMA, 2002 · PMID 11939866
- 6A systematic review of St. John's wort for major depressive disorder (full text: funding and competing-interests statements)PubMed Central (PMC5010734), 2016
- 7St. John's Wort: Usefulness and Safety (last updated May 2025)National Center for Complementary and Integrative Health (NCCIH), 2025
- 8Effect of Hypericum perforatum (St John's Wort) in Major Depressive Disorder (full text: study medications supplied by Lichtwer Pharma and Pfizer)JAMA, 2002
- 9ZOLOFT (sertraline hydrochloride) prescribing information, section 5.2 Serotonin Syndrome (revised 2023)US Food and Drug Administration (Drugs@FDA), 2023
St. John's wort and other dietary supplements are not intended to diagnose, treat, cure or prevent any disease, and these statements have not been evaluated by the FDA. Talk to your clinician or pharmacist before starting a supplement, especially if you take prescription medicines. This page has no product or affiliate links.