Supplement evidence
St John’s Wort
The depression trials, and the interaction list that makes it dangerous with other drugs.
What Its Legal Status Actually Means
Read this before anything below it. Legal to sell is not the same fact as reviewed, verified, or approved.
In the United States St. John's wort is sold as a dietary supplement under DSHEA, which means it reaches the shelf without FDA review of efficacy, safety, or potency and the FDA can act only after a problem emerges. It has never been FDA-approved to treat depression or anything else. The FDA issued a Public Health Advisory on 10 February 2000 warning that St. John's wort substantially lowered blood levels of the HIV drug indinavir through CYP3A4 induction and that the same mechanism would affect many other medicines. In Germany and several other European countries, by contrast, standardised hypericum extracts are licensed medicines that doctors prescribe for depression, which is why most of the trial evidence comes from German-speaking countries. Because US products are supplements rather than drugs, hypericin and hyperforin content varies widely between brands and batches — and hyperforin content is what drives the drug interactions, so two bottles labelled identically can behave very differently.
Quoted whole from the 2026-08-18 study harvest. Not summarized, not shortened.
What the Research Shows
5 records from the 2026-08-18 harvest, each checked against PubMed and Europe PMC on that date. How a study was designed, how many people were in it, and who paid for it are printed above what it found, because those three facts decide how much the finding is worth.
Study 1 · 2008
- Meta-analysis of randomized trials
- 5,489 participants
- Top-tier journal
- Funding not established
- Preregistered
- Declared conflicts of interest
strong76/100Well-supported by good-quality research.
Read this first: All three review authors disclosed financial relationships with Schwabe, a hypericum manufacturer: one had received a research grant and conference speaking fees, and all three had accepted travel reimbursement. The review itself flags that country of origin and trial size both predicted the result, which the authors say "complicates the interpretation" — plain language for probable bias in the underlying literature. The review is from 2008 and has not been updated.
Pooling 29 randomised double-blind trials in 5,489 patients with major depression, hypericum extracts beat placebo on response rate — but the size of the advantage depended on the trial: in the nine larger trials the response rate ratio was 1.28 (95% CI 1.10-1.49) versus 1.87 (95% CI 1.22-2.87) in the nine smaller ones, a classic sign that small trials inflate the effect. Against standard antidepressants it was equivalent (RR 1.00, 95% CI 0.90-1.11 versus SSRIs, 12 trials) and fewer people dropped out for side effects (OR 0.53 versus SSRIs). Trials from German-speaking countries reported systematically more favourable results.
Linde K, Berner MM, Kriston L. (2008). St John's wort for major depression. Cochrane Database of Systematic Reviews. PMID 18843608.
How this record was checked
PubMed record 18843608 fetched via NCBI efetch 2026-08-18; title, authors, journal, year, DOI (CD000448.pub3), the 29 trials / 5,489 patients count, and every effect estimate quoted above confirmed from the abstract, along with the verbatim conflict-of-interest statement naming Schwabe. Europe PMC core record checked 2026-08-18: no grant list; the Cochrane full text is not deposited (PMC7032678 returns abstract only via NCBI efetch and 404 on Europe PMC fullTextXML), so the Sources of Support section could not be read and funding is recorded UNKNOWN. Preregistered recorded true because Cochrane reviews are preceded by a published protocol and this version is an update of CD000448.pub2.
Study 2 · 2016
- Systematic review of randomized trials
- 6,993 participants
- Reputable journal
- Independently funded
- Preregistered
- Declared conflicts of interest
gold standard94/100Top of the evidence hierarchy, independently funded.
Read this first: The review's own evidence tables record that a substantial share of the included trials were industry-funded, had a manufacturer author, or were supplied with the product by the manufacturer, and that funding was simply unreported for several others. The authors also note that adverse events were poorly reported in the source trials and that none of the studies was designed to detect rare harms — including the drug interactions that are St. John's wort's main danger.
A RAND Corporation review of 35 trials in 6,993 patients found St. John's wort produced more treatment responders than placebo (RR 1.53, 95% CI 1.19-1.97, from 18 RCTs in 2,922 people) and worked about as well as antidepressants in mild and moderate depression (RR 1.01, 95% CI 0.90-1.14) with fewer adverse events (OR 0.67, 95% CI 0.56-0.81). Every one of those conclusions was graded only moderate quality because heterogeneity was severe (I-squared 79-89%), and there is essentially no research in severe depression.
How this record was checked
PubMed record 27589952 fetched via NCBI efetch 2026-08-18; title, all seven authors, journal, year, DOI, the 35 studies / 6,993 patients count, every effect estimate quoted above, and the PROSPERO registration CRD42015016406 confirmed from the abstract. Europe PMC core record and full text (PMC5010734) fetched 2026-08-18: the Funding section reads "The research was funded by the Department of Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury (DCoE). The funder had no role in the collection, analysis, and interpretation of the data" — hence funding INDEPENDENT — and the Competing Interests section reads "The authors declare that they have no competing interests."
Study 3 · 2017
- Meta-analysis of randomized trials
- 3,808 participants
- Reputable journal
- Funding not established
strong73/100Well-supported by good-quality research.
Read this first: The abstract reports p<0.001 alongside pooled risk ratios whose 95% confidence intervals comfortably include 1.0, which is internally inconsistent; read the confidence intervals, which show equivalence rather than superiority. This meta-analysis also inherits the industry funding and country-of-origin biases present in the underlying trial literature, and it did not assess drug interactions at all.
Pooling 27 trials that compared St. John's wort head-to-head with SSRIs in 3,808 patients, response rates were statistically indistinguishable (RR 0.983, 95% CI 0.924-1.042) as were remission rates (RR 1.013, 95% CI 0.892-1.134), and fewer people stopped St. John's wort than stopped the SSRI (OR 0.587, 95% CI 0.478-0.697). Every included trial ran only 4 to 12 weeks, and the authors state it is unclear whether St. John's wort helps people with severe depression or high suicide risk.
How this record was checked
PubMed record 28064110 fetched via NCBI efetch 2026-08-18; title, authors, journal, year, DOI, the 27 trials / 3,808 patients count, and every effect estimate quoted above confirmed from the abstract. Europe PMC core record checked 2026-08-18: no grant list and no PMC full text available, so the funding statement could not be read and funding is recorded UNKNOWN.
Study 4 · 2016
- Systematic review of observational studies
- Reputable journal
- Independently funded
- Declared conflicts of interest
strong73/100Well-supported by good-quality research.
Read this first: Only four eligible studies existed, none of them powered to measure pregnancy rates, so the evidence establishes a mechanism and a warning signal rather than a quantified failure rate. Different St. John's wort products produced different degrees of interaction, which means a negative result for one brand does not clear the others.
A CDC and FDA systematic review found only four studies comparing combined oral contraceptives alone with the same pills taken alongside St. John's wort, but three of the four showed breakthrough bleeding, three showed reduced hormone exposure on pharmacokinetic measures, and one showed increased follicular growth and probable ovulation — meaning the pill may stop working. The one product that showed no significant pharmacokinetic difference was a low-hypericin preparation.
How this record was checked
PubMed record 27444983 fetched via NCBI efetch 2026-08-18; title, authors, journal, year, DOI, and the finding that 4 of 48 identified articles met inclusion criteria confirmed from the abstract; the record carries the statement "Conflicts of interest: none." Europe PMC core record fetched 2026-08-18 lists grant agency "Intramural CDC HHS" (grant CC999999), hence funding INDEPENDENT. Participant totals are not stated in the abstract, so sampleSize is left null rather than guessed.
Study 5 · 2020
- Narrative review
- Reputable journal
- Funding not established
- Declared conflicts of interest
contested32/100Weak or heavily disputed. Treat as a question, not an answer.
Read this first: Three of the four authors are employees of Max Zeller Söhne AG, a manufacturer of a St. John's wort herbal medicinal product, and this is a narrative review rather than a systematic one — so it sits at the bottom of the evidence rubric and its framing should be read with the authors' commercial interest in mind. Note the direction of that interest: authors paid by an SJW manufacturer nonetheless document the interactions, which makes the interaction findings harder, not softer.
Twenty years after St. John's wort caused acute graft rejection in two heart transplant patients on cyclosporine, this review confirms the mechanism: St. John's wort activates the pregnane-X receptor, inducing CYP3A4 and P-glycoprotein, and so lowers blood levels of cyclosporine, tacrolimus, digoxin, indinavir, warfarin, alprazolam, simvastatin, and oral contraceptives. The degree of CYP3A4 induction correlates significantly with how much hyperforin the particular preparation contains, which is why interaction risk differs between products bearing the same name.
How this record was checked
PubMed record 31742659 fetched via NCBI efetch 2026-08-18; title, authors, journal, year, and DOI confirmed. Europe PMC full text (PMC7056460) fetched 2026-08-18: the only declaration present is the conflict-of-interest statement "S.N., J.D., and V.B. are employees of a manufacturer of an SJW herbal medicinal product. H.M. has no conflict of interest to declare"; no funding statement exists in the article, so funding is recorded UNKNOWN and independent is recorded false on the strength of the employment disclosure.
The Risks
Nobody checks this purchase the way a prescription is checked. No prescriber reviews it against the rest of what you take, no pharmacist screens the interaction, and no regulator confirms the dose in the capsule before it is sold. That is why this section sits here at full length rather than as a footnote.
What the paragraph below covers:
- Serotonin syndrome
- Psychosis and mania
- Drug interactions
- Fertility and pregnancy
- What is actually in the product
- Skin reactions
St. John's wort is one of the most dangerous interacting substances sold over the counter, and its reputation as a gentle herbal alternative is the problem. It is a potent activator of the pregnane-X receptor and therefore induces CYP3A4 and P-glycoprotein, which lowers blood levels of a long list of drugs: cyclosporine and tacrolimus (two heart transplant patients rejected their grafts in 2000), HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, warfarin, digoxin, simvastatin, alprazolam, some chemotherapy agents, anticonvulsants, and oral contraceptives — where the documented consequences are breakthrough bleeding, follicular growth and probable ovulation, i.e. unintended pregnancy. Taken with an SSRI, SNRI, triptan, tramadol, or MAOI it can add serotonergic load and precipitate serotonin syndrome, so it is not something to layer on top of an antidepressant, and stopping it abruptly while on an interacting drug can swing that drug's level the other way into toxicity. It also causes photosensitivity, can precipitate mania in people with bipolar disorder, and — because the trials that support it ran only four to twelve weeks in mild to moderate depression — there is no evidence for its use in severe depression, in people with high suicide risk, or over the long term. Because content is unregulated, the strength of both the antidepressant effect and the interaction risk varies by product.
What Is Not Known
The boundaries of the section above, in the harvest’s own words. What it excluded, why, and where it looked and found nothing. An absence of evidence is not evidence of absence, and it is not evidence of benefit either.
What Was Left Out, and Why
Quoted from the harvest, where these notes sat above the study list rather than after it. Where a note says “below” it means the studies in the section above.
- Ng 2017 (PMID 28064110) is included, but note that its abstract reports p<0.001 for pooled risk ratios whose confidence intervals cross 1.0 (response RR 0.983, 95% CI 0.924-1.042); that is an internal reporting inconsistency and the finding text below reports the intervals, not the p-values.
- Individual efficacy RCTs (Hypericum Depression Trial Study Group 2002, Szegedi 2005, Fava 2005 and others) excluded in favour of the pooled analyses below, which subsume them; the Apaydin evidence tables record that many of those trials were industry-funded or had industry authors.
- Single case reports of serotonin syndrome, transplant rejection, and contraceptive failure excluded in favour of the interaction reviews below.
- No verifiable PubMed-indexed record was found for a regulatory action document (FDA Public Health Advisory of 10 February 2000 on St. John's wort and indinavir) that could be confirmed end-to-end under this batch's verification protocol, so it is described in regulatory_status rather than entered as a study.
The Retraction Check
PubMed efetch records for all five PMIDs fetched 2026-08-18 and inspected for "Retraction in", "Erratum", "Expression of concern", and "Withdrawn" flags; none present. Europe PMC correction lists checked; none present.
Questions for a Prescriber or Pharmacist
This page does not tell anyone to take St John’s Wort or to avoid it. It is not able to: it does not know what else you take, what you have tried, or what you are treating. These are the questions each study above raises, written to be asked out loud.
- The Cochrane evidence for St. John's wort is for mild-to-moderate major depression over a few weeks — does my depression fit that, and does St. John's wort interact with anything else I'm taking?
- This review found St. John's wort works about as well as an antidepressant for mild to moderate depression but wasn't tested in severe depression — where does mine sit, and what would you recommend given that?
- All the head-to-head studies of St. John's wort against SSRIs lasted twelve weeks or less — if I need treatment for longer than that, what do we actually know?
- I take hormonal birth control — does St. John's wort make it less reliable for me, and if so what backup contraception should I be using?
- Can you check every one of my prescriptions against St. John's wort — including anything I take for transplant, HIV, blood thinning, heart rhythm, or seizures — before I start or stop it?
And the one to ask at the counter, whatever the answers above turn out to be: given everything I am already taking, what would you want to know about St John’s Wort before I put it in the same body?
Where This Page Comes From
Transcribed from the study-harvest-2026-08-18 record for st-johns-wort, built into this page by scripts/supplement-ingest.mjs on 2026-09-07. Nothing here is fetched at page load, and nothing here was written by a model without a citation behind it.
| Source file | study-harvest/2026-08-18/st-johns-wort.yaml |
|---|---|
| Source repo | REPTechnologies/avalo-backend |
| SHA-256 | 1a415c0ca6f5e35dbf5b1cbcd5bd6bb6b28ba375366a8f9453242d8bdf035897 |
| Also searched as | Hypericum perforatum, SJW, hypericum, Klamath weed, Tipton's weed, LI 160, WS 5570, STW3-VI, Ze 117 |
The Other Substances
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Do any supplements actually work? asks the question across all of them. The full library has the medication records, the funding investigations, and the glossary.