St. John's Wort
Herb ·Exploratory record · not publication-reviewed ·Updated July 13, 2026
Widely used herbal antidepressant with one of the most dangerous supplement-drug interaction profiles. Potent CYP3A4 and P-glycoprotein inducer, reduces effectiveness of many critical medications.
Exploratory record, not a reviewed medical publication.
See the editorial and medical-review policies for the publication gate.
This generated database record has not completed a claim-level review by a qualified human medical reviewer. Bibliography links and evidence labels are not approval. The page remains available for reference and is excluded from search indexing.
What the research says.
A quick, data-only summary. The full evidence, dosing, and sources are below.
St. John's Wort is a herb most often used for mild-to-moderate depression, mood support, anxiety reduction. NutriStack rates the overall evidence as moderate. A typical adult dose is 300 mg 3x daily (standardized to 0.3% hypericin), commonly taken as standardized extract (0.3% hypericin, 1-5% hyperforin). This profile indexes 16 sources.
The bottom line
Evidence rating moderate. Most-documented uses: mild-to-moderate depression, mood support, anxiety reduction. 16 sources indexed (2000–2024), with 0 interaction records on file.
How it works, mechanistically.
Core mechanism
Hyperforin inhibits reuptake of serotonin, norepinephrine, dopamine, GABA, and glutamate via modulation of sodium-dependent transporters. Hypericin contributes photosensitizing activity. Hyperforin is a potent inducer of CYP3A4, CYP2C9, CYP1A2, and P-glycoprotein via PXR activation.9,13
Dosing & protocol.
Take with meals to reduce GI upset. Effects take 4-6 weeks to manifest.
What it actually costs.
Real-world pricing across three quality tiers. Assumes Standardized St. John's Wort Extract.
Assumes 300 mg 3 times daily. Vendor basis: NOW/iHerb, Vitacost, Life Extension, and Amazon marketplace; standardized hypericin/hyperforin extracts set mid and premium tiers. Updated 2026-05-28.
The same dose, as food.
How much you'd eat to match a supplemental dose.
St. John's wort is a medicinal herb extract and has major drug-interaction concerns; it is not a culinary food.
Full safety detail.
Side effects
- Photosensitivity (avoid prolonged sun exposure)
- GI upset
- Dizziness
- Dry mouth
- Anxiety/restlessness
Contraindications
- SSRIs/SNRIs (serotonin syndrome risk, DANGEROUS)1,16
- Oral contraceptives (reduces effectiveness, breakthrough bleeding and unplanned pregnancies reported)14,15
- HIV antiretrovirals (can reduce to subtherapeutic levels, treatment failure risk)15
- Immunosuppressants including cyclosporine and tacrolimus (organ rejection risk)15,14
- Warfarin and other anticoagulants (reduced anticoagulation)14
- Cancer chemotherapy drugs (reduced efficacy)15,10
- Digoxin (reduced levels)14
- Statins metabolized by CYP3A4 (reduced efficacy)10,16
- Benzodiazepines (reduced levels)
- Pregnancy/breastfeeding
- Bipolar disorder (may trigger mania)11
- Planned surgery (photosensitivity risk with anesthesia)
Sources, by evidence tier.
Numbered references. Citations throughout the page link here.
Meta-analyses & systematic reviews
4- 1Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysisPMIDNg QX et al. · J Affect Disord · 2017
Meta-analysis of 27 trials (3,808 patients) found St. John's wort had comparable response and remission rates to SSRIs with significantly lower discontinuation/dropout rate.
- 2Co-administration of St. John's wort and hormonal contraceptives: a systematic reviewPMIDBerry-Bibee EN, Kim MJ, Tepper NK et al. · Contraception · 2016
Berry-Bibee EN, Kim MJ, Tepper NK et al.. Co-administration of St. John's wort and hormonal contraceptives: a systematic review. Contraception. 2016
- 3St John's wort for major depressionPMIDLinde K et al. · Cochrane Database Syst Rev · 2008
Cochrane review of 29 trials found hypericum extracts tested in trials were (a) superior to placebo for major depression and (b) similarly effective as standard antidepressants with fewer side effects.
- 4St John's wort for depression: a systematic reviewPMIDGaster B, Holroyd J · Archives of internal medicine · 2000
Gaster B, Holroyd J. St John's wort for depression: a systematic review. Archives of internal medicine. 2000
Randomized controlled trials
2- 5Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression: a randomized double-blind trialSource linkedPMIDFava M, Alpert J, Nierenberg AA et al. · J Clin Psychopharmacol · 2005
- 6St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4PMIDDurr D et al. · Clin Pharmacol Ther · 2000
Landmark study demonstrating SJW induces intestinal P-glycoprotein/MDR1 and both intestinal and hepatic CYP3A4, establishing the dual mechanism for dangerous drug interactions.
Reviews & position papers
9- 7Phytochemicals in the treatment of patients with depression: a systemic reviewPMIDPicheta N, Piekarz J, Daniłowska K et al. · Frontiers in Psychiatry · 2024
Hypericum perforatum (St. John's wort) was identified as one of the most well-supported phytochemical treatments for depression, with consistent evidence from multiple clinical trials.
- 8Hypericum perforatum: Traditional uses, clinical trials, and drug interactionsPMIDNobakht SZ, Akaberi M, Mohammadpour AH et al. · Iranian journal of basic medical sciences · 2022
Nobakht SZ, Akaberi M, Mohammadpour AH et al.. Hypericum perforatum: Traditional uses, clinical trials, and drug interactions. Iranian journal of basic medical sciences. 2022
- 9Clinical relevance of St. John's wort drug interactions revisitedPMIDNicolussi S, Drewe J, Butterweck V et al. · British journal of pharmacology · 2020
Updated review confirming significant herb-drug interactions associated with hyperforin content, with low-hyperforin preparations showing reduced but not eliminated interaction risk.
- 10Complementary therapies for clinical depression: an overview of systematic reviewsPMIDHaller H, Anheyer D, Cramer H, Dobos G · BMJ Open · 2019
St. John's wort had the strongest evidence base among complementary therapies for depression, with multiple systematic reviews supporting its efficacy comparable to standard antidepressants.
- 11A systematic review of St. John's wort for major depressive disorderPMIDApaydin EA et al. · Syst Rev · 2016
Systematic review of 35 studies (6,993 patients) found SJW associated with more treatment responders than placebo, with moderate quality of evidence.
- 12Safety of St. John's Wort extract compared to synthetic antidepressantsPMIDSchulz V · Phytomedicine : international journal of phytotherapy and phytopharmacology · 2006
Schulz V. Safety of St. John's Wort extract compared to synthetic antidepressants. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2006
- 13Hyperforin in St. John's wort drug interactionsPMIDMadabushi R, Frank B, Drewelow B et al. · European journal of clinical pharmacology · 2006
Madabushi R, Frank B, Drewelow B et al.. Hyperforin in St. John's wort drug interactions. European journal of clinical pharmacology. 2006
- 14Drug interactions with St John's wort: mechanisms and clinical implicationsPMIDZhou SF et al. · Drug Saf · 2004
Comprehensive review documenting SJW's induction of CYP3A4, CYP2C9, CYP1A2, and P-glycoprotein via PXR activation, substantially decreasing blood levels of cyclosporine, indinavir, digoxin, warfarin, and oral contraceptives.
- 15Pharmacokinetic interactions of drugs with St John's wortPMIDZhou SF et al. · J Psychopharmacol · 2004
Detailed pharmacokinetic analysis showing SJW reduces plasma concentrations of oral contraceptives, HIV antiretrovirals, immunosuppressants, and cancer drugs to potentially subtherapeutic levels.
Reference material
1Common questions.
Quick answers about St. John's Wort, drawn from the data on this page.
What is St. John's Wort?
Widely used herbal antidepressant with one of the most dangerous supplement-drug interaction profiles. Potent CYP3A4 and P-glycoprotein inducer, reduces effectiveness of many critical medications.
What is St. John's Wort used for?
Commonly cited benefits of St. John's Wort include: Mild-to-moderate depression; Mood support; Anxiety reduction. NutriStack rates the overall evidence as moderate.
What is a typical dose of St. John's Wort?
A typical adult dose of St. John's Wort is 300 mg 3x daily (standardized to 0.3% hypericin). The commonly recommended form is Standardized extract (0.3% hypericin, 1-5% hyperforin). These are general ranges, not personalized advice; confirm the right dose with a clinician.
What are the side effects of St. John's Wort?
Reported side effects include photosensitivity (avoid prolonged sun exposure), gi upset, dizziness, dry mouth, anxiety/restlessness. This is educational information; check with a healthcare professional before use.
How strong is the evidence for St. John's Wort?
NutriStack rates this as Moderate, meaning several aligned RCTs or one large RCT plus supporting reviews. Full tier criteria are at https://nutristackapp.com/methodology/evidence-tiers.
Use this with your stack
St. John's Wort in NutriStack.
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