St. John’s wort is an extract of the flowering plant Hypericum perforatum. It has a long history in traditional medicine and today is sold mainly for low mood and depression. In the US it is marketed as a dietary supplement, so the FDA has not approved it for any use (NCCIH).
Two facts matter most. First, a Cochrane review of 29 randomized trials found it worked better than placebo for major depression and about as well as standard antidepressants, but two large US trials found no benefit. Second, it is one of the best-documented herbal causes of drug interactions. It switches on the liver and gut machinery that clears many drugs, mainly the enzyme CYP3A4 and the drug pump P-glycoprotein. This has led to transplant rejection, breakthrough bleeding and signs of ovulation on the pill, and weaker anticoagulation. Taken with serotonergic antidepressants, it has also been linked to serotonin syndrome.
This page summarizes what clinical trials, pharmacology studies and the NIH report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Type | Herbal extract of the aerial parts of Hypericum perforatum |
| Key constituents | Hyperforin, hypericin, pseudohypericin |
| US status | Dietary supplement; not FDA-approved for any indication |
| Route | Oral (tablets, capsules, tinctures) |
| Doses used in major trials | 900 mg/day extract (300 mg three times daily), up to 1,200–1,500 mg/day |
| Half-life | No single value: hypericin ≈43 h, pseudohypericin ≈25 h, hyperforin ≈9 h |
| Main interaction mechanism | Activates the pregnane X receptor (PXR), inducing CYP3A4 and P-glycoprotein |
| Offset of induction | CYP3A activity back to baseline about 1 week after stopping |
What it is
St. John’s wort is a plant with yellow flowers. It has been used in Greek, Islamic and Chinese medicine for depression, stomach ulcers, colds and wound healing. The name refers to John the Baptist, because the plant blooms around his feast day in late June (NCCIH).
Extracts contain many compounds. Three are the best studied:
| Constituent | Role in research |
|---|---|
| Hyperforin | Proposed antidepressant constituent; main driver of drug interactions |
| Hypericin | Naphthodianthrone used as the usual standardization marker; causes light sensitivity in animals and cell culture |
| Pseudohypericin | Naphthodianthrone counted with hypericin as “total hypericins” on labels |
How the extract affects mood is not settled. In mouse brain nerve endings, hyperforin reduced the reuptake of serotonin by a different route from SSRIs (selective serotonin reuptake inhibitors). It raised sodium levels inside the cell instead of blocking the serotonin transporter directly (Singer et al., J Pharmacol Exp Ther 1999). This is laboratory animal data, and it has not been shown to explain effects in people.
How it works in the body
Absorption and half-life
The constituents have very different kinetics, so the extract has no single half-life. Key human data:
| Constituent | Study | Peak | Elimination half-life |
|---|---|---|---|
| Hypericin | 13 healthy volunteers, extract LI 160 (Kerb et al., 1996) | Lag time 1.9 h before absorption | 43.1 h (median) |
| Pseudohypericin | Same study | Lag time 0.4 h | 24.8 h (median) |
| Hyperforin | Healthy volunteers, 300 mg extract containing 14.8 mg hyperforin (Biber et al., 1998) | ≈150 ng/mL at 3.5 h | 9 h |
Kerb’s study estimated that only about 14% of hypericin and 21% of pseudohypericin reached the bloodstream. With three daily doses, steady-state levels were reached after about 7 days for hypericin and 4 days for pseudohypericin. Hyperforin did not accumulate with repeated dosing.
Enzyme and transporter induction
The interaction problem has a clear molecular cause. Hyperforin binds and activates the pregnane X receptor (PXR), a nuclear receptor that switches on the CYP3A4 gene, with a binding constant of 27 nM (Moore et al., PNAS 2000). In human liver cells in culture, both the extract and pure hyperforin strongly increased CYP3A4. The authors noted that CYP3A4 handles the oxidative metabolism of over 50% of all drugs.
Human studies confirm the effect:
| Study | Design | Finding after 14 days of St. John’s wort |
|---|---|---|
| Dürr et al., Clin Pharmacol Ther 2000 | 8 healthy men; duodenal tissue and breath test | Gut P-glycoprotein up 1.4-fold, gut CYP3A4 up 1.5-fold, liver CYP3A4 activity up 1.4-fold; digoxin exposure down 18% |
| Markowitz et al., JAMA 2003 | 12 healthy adults; 300 mg three times daily | Alprazolam (a CYP3A4 probe) exposure halved; half-life fell from 12.4 h to 6.0 h. No significant change in CYP2D6 |
| Imai et al., Br J Clin Pharmacol 2008 | 12 healthy men; midazolam probe | Midazolam oral clearance rose from 65.3 to 86.8 L/h, then returned to baseline 7 days after stopping (estimated recovery half-life 46.2 h) |
P-glycoprotein is a pump in the gut wall that pushes drugs back out before they are absorbed. Inducing it lowers the absorption of drugs such as digoxin and ciclosporin. Inducing CYP3A4 speeds the breakdown of many more.
The size of the effect depends on the product. Interactions track the daily dose of hyperforin. A review of interaction studies found that products giving under 1 mg of hyperforin per day were less likely to cause major interactions with CYP3A4 or P-glycoprotein substrates, though the risk could not be excluded (Chrubasik-Hausmann et al., J Pharm Pharmacol 2019). Most products are not labeled with their hyperforin content.
Regulatory status
In the US, oral St. John’s wort products are generally sold as dietary supplements. The FDA does not approve supplements before sale; manufacturers are responsible for their safety and labeling (NCCIH). No St. John’s wort product is an FDA-approved treatment for depression.
What the research shows
Depression: the Cochrane review
The main Cochrane review included 29 randomized, double-blind trials with 5,489 patients with major depression (Linde et al., Cochrane 2008). The main outcome was the response rate ratio (RR), the relative chance of responding to treatment:
| Comparison | Trials | Result |
|---|---|---|
| vs placebo, larger trials | 9 | RR 1.28 (95% CI 1.10–1.49) |
| vs placebo, smaller trials | 9 | RR 1.87 (95% CI 1.22–2.87) |
| vs tricyclic or tetracyclic antidepressants | 5 | RR 1.02 (95% CI 0.90–1.15) |
| vs SSRIs | 12 | RR 1.00 (95% CI 0.90–1.11) |
| Dropouts due to side effects vs older antidepressants | — | OR 0.24 (95% CI 0.13–0.46) |
| Dropouts due to side effects vs SSRIs | — | OR 0.53 (95% CI 0.34–0.83) |
The authors concluded that the extracts tested were better than placebo, about as effective as standard antidepressants and better tolerated. They also flagged two problems that complicate the picture:
- Placebo-controlled results varied widely between trials.
- Trials from German-speaking countries gave more favorable results than trials from elsewhere. Smaller, less precise trials also showed larger effects.
A later RAND systematic review of 35 trials (6,993 patients) reached a similar conclusion for mild to moderate depression. It found more responders than with placebo (RR 1.53, 95% CI 1.19–1.97; 18 trials), no difference from antidepressants (RR 1.01, 95% CI 0.90–1.14; 17 trials) and fewer adverse events than antidepressants (OR 0.67, 95% CI 0.56–0.81) (Apaydin et al., Syst Rev 2016). It rated the evidence as moderate quality and noted a lack of research in severe depression.
The large US trials
Two large US multicenter trials in more severe major depression (baseline Hamilton depression score, HAM-D, of 20 or more) were negative:
| Trial | n | Arms | Main result |
|---|---|---|---|
| Shelton et al., JAMA 2001 | 200 | Extract 900 mg/day (raised to 1,200 mg/day if needed) vs placebo, 8 weeks | No significant difference on HAM-D or response. Remission 14.3% vs 4.9% (p = 0.02), but rates were low |
| Hypericum Depression Trial Study Group, JAMA 2002 | 340 | LI-160 extract 900–1,500 mg/day vs sertraline 50–100 mg/day vs placebo, 8 weeks | Neither active drug beat placebo. Full response: 23.9% extract, 24.8% sertraline, 31.9% placebo |
In the 2002 trial, sertraline also failed on the primary outcomes, which suggests the trial may have had low sensitivity. The authors still noted the “complete absence of trends” favoring the extract.
Other uses
The NIH’s complementary health center reports that small numbers of studies suggest possible benefit for menopausal hot flashes and somatic symptom disorder. Evidence for ADHD, irritable bowel syndrome, obsessive-compulsive disorder, premenstrual syndrome, smoking cessation and wound healing has not clearly shown benefit (NCCIH). There are no controlled human data on muscle, strength, recovery or hormone outcomes.
Drug interactions
Interactions are the main safety issue. NCCIH lists drugs whose effects St. John’s wort can weaken, including birth control pills, ciclosporin, warfarin, digoxin, some HIV drugs (indinavir, nevirapine), some anti-seizure drugs, some cancer drugs and simvastatin (NCCIH). The best-studied cases follow.
Ciclosporin and transplant rejection
The first major warning came in 2000, when two heart transplant patients had acute rejection due to a metabolic interaction between St. John’s wort and ciclosporin (Ruschitzka et al., Lancet 2000). Later studies in kidney transplant patients measured the size of the effect:
| Study | Design | Effect on ciclosporin |
|---|---|---|
| Bauer et al., Br J Clin Pharmacol 2003 | 11 patients, extract 600 mg/day for 14 days | Dose-corrected exposure (AUC) down 46%, peak down 42%, trough down 41%. Median dose had to rise from 2.7 to 4.2 mg/kg/day; first adjustment needed after 3 days |
| Mai et al., Clin Pharmacol Ther 2004 | 10 patients, crossover, 900 mg/day high- vs low-hyperforin extract | High-hyperforin: AUC down 52%, trough down 55%, dose up 65%. Low-hyperforin: no significant change |
The Mai trial is the clearest human evidence that hyperforin content drives the interaction.
Oral contraceptives
Three controlled studies in healthy women found that St. John’s wort speeds the breakdown of contraceptive hormones and increases breakthrough bleeding:
| Study | Pill | St. John’s wort dose | Key findings |
|---|---|---|---|
| Hall et al., Clin Pharmacol Ther 2003 | Ethinyl estradiol + norethindrone; 12 women | 300 mg three times daily | Ethinyl estradiol half-life 23.4 → 12.2 h; norethindrone clearance up. Breakthrough bleeding 7 of 12 vs 2 of 12 |
| Pfrunder et al., Br J Clin Pharmacol 2003 | 0.02 mg ethinyl estradiol + desogestrel; 18 women, randomized | 300 mg twice or three times daily | 3-ketodesogestrel exposure down ≈42–44%. Intracyclic bleeding 77–88% vs 35%. No evidence of ovulation |
| Murphy et al., Contraception 2005 | Low-dose pill (Loestrin 1/20); 16 women | 300 mg three times daily | Hormone exposure down 13–15%; more breakthrough bleeding, follicle growth and probable ovulation |
Hall’s group advised that women on the pill be told to expect breakthrough bleeding and to consider a barrier method while using St. John’s wort. Pfrunder’s group noted that bleeding problems and lower progestin levels could together raise the risk of unintended pregnancy.
Warfarin
In a randomized crossover study, 12 healthy men took a single 25 mg dose of warfarin alone or after 14 days of St. John’s wort (Jiang et al., Br J Clin Pharmacol 2004):
| Measure | Ratio with St. John’s wort vs warfarin alone (90% CI) |
|---|---|
| S-warfarin clearance | 1.29 (1.16–1.46) |
| R-warfarin clearance | 1.23 (1.11–1.37) |
| INR over time (AUC) | 0.79 (0.70–0.95) |
INR (international normalized ratio) measures how long blood takes to clot. Faster clearance of both warfarin forms led to a weaker anticoagulant effect. The same induction works in reverse on stopping: Imai’s data show CYP3A activity takes about a week to return to baseline, so levels of affected drugs would be expected to rise over that period.
SSRIs and serotonin syndrome
This interaction is pharmacodynamic rather than metabolic: two products that raise serotonin activity are combined. Serotonin syndrome is a potentially dangerous state of excess serotonin activity in the nervous system. A case series described five older patients who developed clinically diagnosed serotonin syndrome after combining prescription antidepressants with St. John’s wort (Lantz et al., J Geriatr Psychiatry Neurol 1999). NCCIH states that combining it with certain antidepressants or other serotonergic drugs may increase serotonin-related side effects, which can be serious (NCCIH).
Side effects and risks
Common side effects
For adults not taking other medicines, NCCIH describes St. John’s wort as appearing safe for up to 12 weeks, with some studies suggesting safety for a year or more. Reported side effects include diarrhea, dizziness, trouble sleeping, restlessness and skin tingling (NCCIH). In the Shelton trial, headache was the only side effect more common than with placebo (41% vs 25%).
Sensitivity to light
Hypericin causes light-related skin damage in animals and cell culture. In humans, the effect at studied doses was small. In 50 volunteers given 1,800 mg/day for 15 days, sensitivity to UV-A light increased modestly; the authors calculated that it could be offset by cutting sun exposure time by 21% (Brockmöller et al., Pharmacopsychiatry 1997). The study could not exclude reactions at higher doses. NCCIH notes that large oral doses or use on the skin might cause severe skin reactions after sun exposure.
Pregnancy and breastfeeding
NCCIH states it may be unsafe during pregnancy because it may increase the risk of birth defects. Breastfed infants of mothers taking it have shown colic, drowsiness and lethargy (NCCIH).
Who is most at risk
Based on the interaction evidence above, the highest-risk groups are people taking:
- immunosuppressants after an organ transplant;
- hormonal contraceptives;
- warfarin or other drugs with a narrow therapeutic range;
- SSRIs or other serotonergic drugs;
- HIV, anti-seizure or cancer drugs listed by NCCIH.
Quality and contamination
Because St. John’s wort is sold as a supplement, content varies between products. A Canadian study tested 54 products bought in Canada and the US with a specific chromatography method (Draves and Walker, Can J Clin Pharmacol 2003). Results:
- capsules contained 0% to 108.62% of their labeled hypericin content;
- tablets contained 31.34% to 80.18%;
- only two products were within 10% of their label claim;
- on average, labels overstated hypericin content by a factor of almost two.
Labels usually report hypericin, while interaction risk tracks hyperforin, which is often not stated.
Key takeaways
- Mixed evidence in depression. A Cochrane review of 29 trials found benefit over placebo and parity with antidepressants, but the two large US trials in more severe depression were negative.
- A strong enzyme inducer. Hyperforin activates PXR, raising CYP3A4 and P-glycoprotein; alprazolam exposure halved after 14 days in healthy adults.
- Interactions with real consequences. Documented effects include transplant rejection with ciclosporin, lower contraceptive hormone levels with breakthrough bleeding, and a weaker warfarin effect.
- Serotonin risk with antidepressants. Combining it with SSRIs or other serotonergic drugs has been linked to serotonin syndrome.
- Effects outlast the last dose. CYP3A activity took about a week to return to baseline after stopping.
- Products vary. Hyperforin content drives interaction risk, and label claims for hypericin were often inaccurate in independent testing.
Sources
- National Center for Complementary and Integrative Health. St. John’s Wort: Usefulness and Safety. NCCIH.
- Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448. PubMed.
- Apaydin EA, Maher AR, Shanman R, et al. A systematic review of St. John’s wort for major depressive disorder. Syst Rev. 2016;5(1):148. PubMed.
- Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John’s wort in major depression: a randomized controlled trial. JAMA. 2001;285(15):1978–1986. PubMed.
- Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287(14):1807–1814. PubMed.
- Singer A, Wonnemann M, Müller WE. Hyperforin, a major antidepressant constituent of St. John’s Wort, inhibits serotonin uptake by elevating free intracellular Na+1. J Pharmacol Exp Ther. 1999;290(3):1363–1368. PubMed.
- Kerb R, Brockmöller J, Staffeldt B, et al. Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemother. 1996;40(9):2087–2093. PubMed.
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- Ruschitzka F, Meier PJ, Turina M, et al. Acute heart transplant rejection due to Saint John’s wort. Lancet. 2000;355(9203):548–549. PubMed.
- Bauer S, Störmer E, Johne A, et al. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John’s wort in renal transplant patients. Br J Clin Pharmacol. 2003;55(2):203–211. PubMed.
- Mai I, Bauer S, Perloff ES, et al. Hyperforin content determines the magnitude of the St John’s wort-cyclosporine drug interaction. Clin Pharmacol Ther. 2004;76(4):330–340. PubMed.
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- Pfrunder A, Schiesser M, Gerber S, et al. Interaction of St John’s wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br J Clin Pharmacol. 2003;56(6):683–690. PubMed.
- 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;71(6):402–408. PubMed.
- 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. Br J Clin Pharmacol. 2004;57(5):592–599. PubMed.
- Lantz MS, Buchalter E, Giambanco V. St. John’s wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol. 1999;12(1):7–10. PubMed.
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