This page shows what was measured, who it was measured in, and what that does not settle.
What St John's wort does in the body
Mild to moderate depression — with serious interactions
St John's wort contains hyperforin, hypericin and several flavonoids. Hyperforin inhibits the reuptake of serotonin, noradrenaline and dopamine, which is a plausible antidepressant mechanism. Hyperforin also binds a receptor in the liver called PXR, which switches on the body's main drug-clearing enzyme, CYP3A4, and the transport pump P-glycoprotein. That second effect is the reason a plant sold beside vitamins can cause a transplanted heart to be rejected.
What happened in people
Response rate ratio 1.28 (95% CI 1.10 to 1.49) against placebo across nine larger trials
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The recorded finding that sits closest to something a person would notice. Written into the record, not signed off, and it carries no population or interval.
No recorded sentence describes the change this makes in a way that stands on its own. The page opens with what it is taken for instead, and the recorded explanation follows below.
Shown as the opening line on this page.
A limit recorded against this substance. Not signed off as a reviewed claim.
The four opening statements run to 94 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Randomisation
Randomisation means chance decides who gets which treatment.
A picture of it, and where the picture fails
It is like a coin toss deciding the groups.
Where that stops being true. A coin toss is fair once. Fairness here comes from doing it for everyone.
What people get wrong. It is thought to make groups identical. It makes them similar on average, including on things nobody measured.
Allocation of participants to arms by a chance process, so that unmeasured factors are balanced in expectation.
Confidence interval
A confidence interval is the range the true answer is likely to sit in.
A picture of it, and where the picture fails
It is like a weather forecast giving a range rather than one number.
Where that stops being true. A forecast range covers tomorrow. This one covers what the study could resolve.
What people get wrong. The middle number is read as the answer. A range crossing zero means no change is still possible.
An interval estimate that would contain the true parameter in a stated proportion of repeated studies.
Receptor
A receptor is a part of a cell that a signal fits into.
A picture of it, and where the picture fails
A receptor is like a lock waiting for one key.
Where that stops being true. A lock either opens or does not. A receptor can be half-triggered, or worn out.
What people get wrong. Fitting a receptor is read as causing a benefit. It causes a step, and nothing more.
A protein that binds a specific ligand and converts that binding into a cellular response.
Pathway
A pathway is a chain of steps inside a cell, each one setting off the next.
A picture of it, and where the picture fails
A pathway is like a row of dominoes.
Where that stops being true. Dominoes fall one way. Pathways loop back and can switch themselves off.
What people get wrong. Changing one step is read as changing the outcome. Other steps often absorb it.
An ordered series of molecular interactions producing a defined cellular change.
What happened in people◇Read from sources, not yet reviewed
What was measured, goal by goal
One row for each goal a registered study measured something for. One column for each kind of thing that could be measured.
Registered studies list 6 outcome measures that RNAWiki could read. A registered study says what someone planned to measure. It does not say what they found. 0 of the matched studies tested this substance, and 0 posted a result.
There is no single score. A strong test result and a weak life result are different facts.
Goals down the side, kinds of measurement across the top. Each cell says what kind of thing was registered, not what was found.
Goal
Life outcome
What a body can do
How a person feels
A test result
A step in the body
Harms
How long
Who was studied
Mood
∅Nothing in the sources checkedNo registered study lists a life outcome for this goal.
∅Nothing in the sources checkedNo registered study lists a performance measure for this goal.
…Waiting for a reviewer1 registered symptom measure.
∅Nothing in the sources checkedNo registered study lists a test result for this goal.
∅Nothing in the sources checkedNo registered study lists a body-step measure for this goal.
—Not recordedHarms were not a registered measure for this goal.
—Not recordedNo finished study window is recorded.
…Waiting for a reviewerWho was studied is listed further down the page.
Which registered measures put each goal on this table
Mood
hamilton depression scale 17
Sorted by fixed word lists, version v1. A name the rules do not recognise stays unsorted rather than moving to the nearest column.
What each mark on this table means
∅ Nothing in the sources checked
No registered study lists a life outcome for this goal.
… Waiting for a reviewer
1 registered symptom measure.
— Not recorded
Harms were not a registered measure for this goal.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
Response rate on depression scales versus placebo and versus standard antidepressants
RR 1.28 (95% CI 1.10 to 1.49) versus placebo in larger trials; RR 1.00 (0.90 to 1.11) versus SSRIs
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Marked heterogeneity in the placebo comparisons, with smaller trials showing far larger effects, and an association between country of origin and effect size that the authors said complicates interpretation.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet or capsule of standardised Hypericum perforatum extract
Interval reported. 95% CI 1
Written into the record, not signed off as a reviewed claim.
Change in HAM-D total score from baseline to eight weeks, and full response rate
✗ The study did not show it
Who was studied
Hypericum Depression Trial Study Group 2002 (hypericum, sertraline, placebo)
How many people
340
Study design
Randomised, double-blind, placebo-controlled with active comparator
Compared against
A dummy treatment
Kind of result
A number that stands in for health
What was found
P = 0.59 for hypericum versus placebo; P = 0.18 for sertraline versus placebo
Repeated elsewhere
Replicated
What this does not prove. A study that did not show an effect does not show that no effect exists anywhere.
The limits of this study, and where it came from
Main limit. The active comparator also failed, which raises assay sensitivity as an explanation. The authors noted that the complete absence of any trend toward efficacy for hypericum is nevertheless noteworthy.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet or capsule of standardised Hypericum perforatum extract
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
Rate of change on the Hamilton Depression Rating Scale over eight weeks
✗ The study did not show it
Who was studied
Shelton 2001 (hypericum versus placebo, major depression, 11 US centres)
How many people
200
Study design
Randomised, double-blind, placebo-controlled
Compared against
A dummy treatment
Kind of result
A number that stands in for health
What was found
P = 0.16 for treatment effect on HAM-D
Repeated elsewhere
Replicated
What this does not prove. A study that did not show an effect does not show that no effect exists anywhere.
The limits of this study, and where it came from
Main limit. Remission was significantly more frequent on hypericum (14.3% versus 4.9%, P = 0.02) but at very low absolute rates. Headache was more common on hypericum, 41% versus 25%.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet or capsule of standardised Hypericum perforatum extract
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
RNAWiki holds 3 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What happened in people◇Read from sources, not yet reviewed
How close this is to real life
The top step is something a person would feel or care about. The bottom is a guess from software. Filled steps are where evidence exists for this substance.
□Living longer, or avoiding a major eventNo evidence recorded. Death, a heart attack, a stroke, a hospital stay.No registered study measures this.
□What a body can do day to dayNo evidence recorded. Walking, dressing, breathing, recovering.No registered study measures this.
□Measured performanceNo evidence recorded. How much was lifted, how far was run, how fast.No registered study measures this.
■Symptoms and quality of lifeEvidence recorded. Pain, tiredness, mood, sleep, as the person rated it.1 registered measure of this kind.
□A number that stands in for healthNo evidence recorded. Cholesterol, blood sugar, bone density. A stand-in, not the thing itself.No registered study measures this.
■A step measured inside a personEvidence recorded. Something measured in human tissue or human cells.A human record sits on the stored organism ladder.
■AnimalsEvidence recorded. Mice, rats, dogs. Useful for ideas, not proof about people.Stored records in C. elegans (roundworm), Mouse, Rat. A result in animals says what to test next. It does not say what happens in people.
□Cells in a dishNo evidence recorded. Cells or chemistry on a bench, far from a whole body.No cell or bench record is stored.
□A guess from softwareNo evidence recorded. Nobody measured it. RNAWiki never publishes one as a finding.RNAWiki stores no prediction for this record. Software can suggest a link. RNAWiki does not publish one as a finding.
Higher on these steps means closer to something a person would feel. It does not mean better done.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Start
St John's wort
What a person takes: Oral tablet or capsule of standardised Hypericum perforatum extract.
The measurement behind this step
Sold as a dietary supplement in the United States and licensed as a prescription antidepressant for mild to moderate depression in Germany. Extracts differ substantially in hyperforin content depending on solvent, and low-hyperforin preparations exist specifically to reduce interaction risk. Trial evidence attaches to named extracts, not to the plant generically.
Getting in
A multi-component extract, with hyperforin doing most of the work
The extract contains several active families, and one of them is responsible for both the benefit and the danger.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Hyperforin is a prenylated phloroglucinol; hypericin is a naphthodianthrone; the extract also contains flavonoids including rutin and quercetin. Hyperforin content varies with solvent and degrades on air exposure, which is why the licensed European extracts are individually named and specified.
It gets into the bloodstream well enough to act on the brain — and on the liver, which is where the trouble starts.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Hyperforin is absorbed with a plasma half-life of around nine hours and reaches concentrations consistent with its in vitro reuptake inhibition. The same systemic exposure delivers it to hepatocytes and enterocytes, where the induction occurs.
At the synapse it blocks reuptake of three transmitters at once
It keeps serotonin, noradrenaline and dopamine in the synapse for longer, which is broadly what antidepressants do.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Hyperforin inhibits synaptosomal reuptake of serotonin, noradrenaline and dopamine, and also GABA and glutamate, apparently by dissipating the sodium gradient the transporters depend on rather than by binding them directly. That non-selective mechanism differs from every prescription antidepressant class.
At the liver it switches on the main drug-clearing enzyme
In the liver, the same compound activates a genetic switch that ramps up the machinery for destroying medicines.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Hyperforin is a potent pregnane X receptor agonist. Activated PXR transcriptionally induces CYP3A4 and the efflux transporter P-glycoprotein in liver and intestine, increasing both first-pass metabolism and systemic clearance of their substrates.
Depression improves; co-administered drugs stop working
The mood effect is real. So is the failure of whatever else the person is taking.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Response rate ratio 1.28 against placebo in larger trials and 1.00 against SSRIs. In parallel: ciclosporin loss causing transplant rejection, an 81% fall in indinavir exposure, and contraceptive steroid clearance sufficient to cause breakthrough bleeding.
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 5 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What it would be like to take◇Read from sources, not yet reviewed
Felt, measured, or meaningful
Three different things that get called the same word. Registered studies measured all three, and mixing them is how a blood test becomes a health claim.
Felt
Things a person could notice without a test.
hamilton depression scale 17
Measured
Things only a test, a scale or a device shows.
No registered study measured anything of this kind.
Meaningful
Things that change how a life goes, not only a number.
No registered study measured anything of this kind.
A registered study says what someone planned to measure. It does not say what they found. A number moving is not the same as a life going better. The two are shown apart here.
Felt, but not shown to help. A person notices a change. No study showed it leads anywhere good.
Measured, but not felt. A number moves. The person notices nothing. Both can be true.
Measured, but not shown to matter. A number moves in the good direction. Nobody showed that lives went better.
Matters, but takes years. The result that counts may take longer than anyone would keep watching.
Names that fit none of the three (5)
adhd iv rating scale
progesterone levels above 3 0 / at time 1 and time 2
frequency of raynaud s phenomenon attacks
duration of rp attacks
severity of rp attacks
These are harms, study-process measures, or names the rules did not recognise. They are shown rather than dropped.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Adults with mild to moderate depressive symptoms, very often self-medicating and very often without telling a doctor — which is exactly the circumstance in which the interaction risk becomes dangerous.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
Where the result stopped carrying
Shelton 2001 in 200 US outpatients with major depression: no significant treatment effect on any primary or secondary scale
The Hypericum Depression Trial Study Group in 340 patients: neither hypericum nor sertraline separated from placebo
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied for a different goal
The studies measured something else entirely.
On this record: Some registered studies measured things that match no goal on this page.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
The product may not be what it says
Contents of a sold product are not always what the label states.
On this record: This is sold as a supplement, so no agency checked what is in a given tub before it was sold.
Other reasons RNAWiki checked and found nothing for (9)
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Varies by country
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Oral tablet or capsule of standardised Hypericum perforatum extract
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
Not usually supervised: sold as a supplement or food ingredient where recorded. That is a legal category, not a safety judgement.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
The identity record classes it as a supplement ingredient; no medicines register records an approval.
No source is stored against this line.
What is in the pack
Sold as a dietary supplement in the United States and licensed as a prescription antidepressant for mild to moderate depression in Germany. Extracts differ substantially in hyperforin content depending on solvent, and low-hyperforin preparations exist specifically to reduce interaction risk. Trial evidence attaches to named extracts, not to the plant generically.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold and what that means for what is in the pack.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
Direct adverse effects are mild and fewer than with standard antidepressants; headache was the only event more frequent than placebo in Shelton 2001, at 41% versus 25%. Photosensitivity is associated with hypericin. The dominant risk is pharmacokinetic: CYP3A4 and P-glycoprotein induction reduces exposure to ciclosporin, tacrolimus, oral contraceptives, warfarin, protease inhibitors, some anticonvulsants, statins and many oncology drugs. Combining it with an SSRI risks serotonin syndrome.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
These are reports people sent to a regulator. They do not show the medicine caused the reaction.
Nobody counted how many people took the medicine and reported nothing.
The same event can be reported more than once, and many reports are incomplete.
News coverage, lawsuits and new warnings change how often people report.
A count is not a rate and not a risk.
St John's wort appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 84 reaction mentions were counted. One report can name several reactions.
open-targets-adr · recorded 2026-06-24 · a recorded source, not a stored snapshot
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Oral tablet or capsule of standardised Hypericum perforatum extract
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
Extracts differ substantially in hyperforin content depending on solvent, and low-hyperforin preparations exist specifically to reduce interaction risk. Trial evidence attaches to named extracts, not to the plant generically.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on which forms are sold and how they compare.
No source is stored against this line.
What is recorded as being sold
24 products list this as an active ingredient in the United States drug directory. 2 of them contain it and nothing else.
FDA National Drug Code directory · 48951-1195 · read 2026-08-29
They are sold as globule, liquid, ointment, salve and solution/ drops, taken oral and topical.
FDA National Drug Code directory · 48951-1195 · read 2026-08-29
24 published labels name it as an active ingredient. 2 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · e3f39461-e27d-419a-8271-eb96457be189 · read 2026-08-29
Those labels are classed as human otc drug.
US prescribing information · e3f39461-e27d-419a-8271-eb96457be189 · read 2026-08-29
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
Watching one thing carefully can tell you whether it moved. It cannot tell you what moved it.
This is sold without a prescription, so a person can sensibly watch one thing and see whether it moves.
Pick one goal. One goal only. Two at once cannot be told apart afterwards.
Pick one thing to watch. No registered study lists a measure RNAWiki could read for this.
Measure before you start. Take the same measurement several times first. One reading is not a starting point.
Know the swing. Write down how much it moves on its own across a normal week.
Change one thing. Change nothing else at the same time, including training and sleep.
Give it the study length. No finished study window is recorded, so no length is suggested here.
Track whether you took it. Missed days are the most common reason a home test shows nothing.
Read the trend. Look at the line across weeks. A single reading tells you almost nothing.
What not to measure
Anything that swings more day to day than the change you are looking for.
A wearable estimate of sleep stages, which is an estimate and not a measurement.
Weight on one morning, which mostly records water.
A feeling you did not write down before starting, such as: hamilton depression scale 17.
When to stop
Stop if something new and unpleasant starts, and ask a pharmacist or doctor.
Stop if you cannot keep everything else steady, because the result will not mean anything.
Stop at the end of the window you set, and read the trend then.
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki does not work out an amount for anyone.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That efficacy in mild to moderate depression extends to severe major depression — two large US trials found nothing there
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That a botanical sold beside vitamins carries a supplement-level interaction risk
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the pooled effect applies uniformly, when effect size tracked country of origin and trial precision
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
How fast does the body clear it?
The sources RNAWiki checked hold nothing for this field.
Why it matters. Without this, nothing on this page can say how long anything lasts.
What would answer it
A stored source that records it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of St John's wort are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
Cochrane 2008: superior to placebo and equivalent to standard antidepressants
In plain words
Twenty-nine randomised trials in nearly 5,500 patients found St John's wort better than placebo and about as good as prescription antidepressants, with fewer side effects.
What was measured
Response rate ratio against placebo and against standard antidepressants
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Linde et al. included 29 randomised double-blind trials comprising 5,489 patients, with 18 placebo comparisons and 17 comparisons against synthetic antidepressants. Placebo-controlled results were markedly heterogeneous: in nine larger trials the combined response rate ratio was 1.28 (95% CI 1.10 to 1.49), and in nine smaller trials 1.87 (95% CI 1.22 to 2.87). Comparisons against standard antidepressants were statistically homogeneous, with response rate ratios of 1.02 (95% CI 0.90 to 1.15) against tricyclics and tetracyclics across five trials and 1.00 (95% CI 0.90 to 1.11) against SSRIs across 12 trials. Fewer patients dropped out for adverse effects on hypericum. The authors flagged that country of origin and trial precision were associated with effect size, which complicates interpretation.
Written into the record, not signed off as a reviewed claim
Two US trials in more severe depression found nothing — and neither did sertraline
In plain words
In two large American trials in properly diagnosed major depression, St John's wort did not beat placebo. In one of them, the antidepressant used as a comparator did not either.
What was measured
Change in Hamilton Depression Rating Scale over eight weeks
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
Shelton et al. randomised 200 outpatients with major depression and a baseline HAM-D of at least 20 across 11 US academic centres to hypericum extract or placebo for eight weeks, and found no significant treatment effect on HAM-D, HAM-A, CGI-S or CGI-I. The Hypericum Depression Trial Study Group then randomised 340 outpatients across 12 centres to hypericum, placebo or sertraline as an active comparator for eight weeks: neither hypericum nor sertraline separated from placebo on the two primary outcomes. HAM-D change was -9.20 for placebo, -8.68 for hypericum (P = 0.59) and -10.53 for sertraline (P = 0.18). Full response occurred in 31.9% on placebo, 23.9% on hypericum and 24.8% on sertraline. The authors noted the failure of the active comparator raises the question of assay sensitivity, while adding that the complete absence of any trend toward efficacy for hypericum is noteworthy.
Written into the record, not signed off as a reviewed claim
Acute heart transplant rejection caused by St John's wort
In plain words
Two heart transplant patients began rejecting their transplants after starting St John's wort, because it stripped out the drug protecting the graft.
What was measured
Ciclosporin trough concentration and endomyocardial biopsy rejection grade
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Ruschitzka et al. reported acute heart transplant rejection in two patients who had started St John's wort while on stable ciclosporin. Ciclosporin trough concentrations fell to subtherapeutic levels through CYP3A4 and P-glycoprotein induction, rejection followed, and levels and graft function recovered on stopping the herb and increasing the dose. This is the case report that converted a theoretical interaction into a clinical one, and it is why the plant is contraindicated in transplant medicine.
Written into the record, not signed off as a reviewed claim
CYP3A4 induction measured directly: 1.4-fold clearance, 2.5-fold bioavailability loss
In plain words
Fourteen days of St John's wort measurably sped up the body's main drug-clearing enzyme and more than halved how much of an oral test drug got into the blood.
What was measured
Systemic clearance and oral bioavailability of CYP3A4 probe substrates
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Markowitz et al. gave healthy volunteers St John's wort for 14 days and measured the pharmacokinetics of intravenous and oral alprazolam and midazolam as CYP3A4 probes. Systemic clearance increased and oral bioavailability fell substantially, consistent with induction of intestinal and hepatic CYP3A4. CYP3A4 is responsible for the metabolism of roughly half of all marketed drugs, so this is not one interaction but a class of them.
Written into the record, not signed off as a reviewed claim
Oral contraceptive failure and HIV treatment failure, both documented
In plain words
The same enzyme induction breaks hormonal contraception and strips out HIV drugs.
What was measured
Contraceptive steroid clearance and breakthrough bleeding; indinavir area under the concentration-time curve
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Hall et al. studied the interaction between St John's wort and a low-dose oral contraceptive in healthy women and found increased contraceptive steroid clearance with breakthrough bleeding, a recognised marker of reduced contraceptive reliability. Piscitelli et al. separately measured an 81% reduction in indinavir area under the curve in healthy volunteers, an exposure loss large enough to permit viral rebound and resistance. These are not incidental findings: they are the two interactions most likely to be encountered by someone who buys the product without telling anyone.
Written into the record, not signed off as a reviewed claim
Effect size tracked country of origin, which the Cochrane authors flagged themselves
In plain words
The trials showing the biggest benefits were disproportionately from one part of the world, and the reviewers said so.
What was measured
That the pooled response rate ratio applies uniformly across populations and severities
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Linde et al. reported marked heterogeneity among placebo-controlled trials, with smaller trials showing response rate ratios nearly twice those of larger ones (1.87 versus 1.28), and stated that the association of country of origin and precision with effect size complicates interpretation. German-speaking countries, where hypericum is a licensed prescription medicine, contributed a large share of the positive trials, while the two large US trials found nothing. That geographic pattern is the honest reason the pooled estimate sits where it does rather than higher.
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What is not here
4 questions this page could not answer
These sections were prepared and left out because there was nothing to put in them. They are listed rather than hidden, so the gaps in this record are visible.
How long anything takes — found nothing in the sources checked.
What it may clash with — found nothing in the sources checked.
Other ways to the same goal — found nothing in the sources checked.
What changed on this page — found nothing in the sources checked.
The record as stored
The full record, for auditing
Everything above is built from what is below. This layer keeps the technical vocabulary, record identifiers and every stored row, so a reader who wants to check the page can.
The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
Twenty-nine randomised trials in 5,489 patients show hypericum extracts superior to placebo and similarly effective to standard antidepressants with fewer side effects — while the same plant induces CYP3A4 strongly enough to have caused acute heart transplant rejection, and failed twice in severe major depression in US trials where sertraline also failed.
Recorded evidence blocks (11)
Q1
What did St John's wort's largest trial (118 people) and its longest (4.2 years) measure?
118 people in St John's wort's largest registered study, 4.2 years in its longest registered window, measuring Area Under the Concentration Versus Time Curve for 0 to 24 Hours After Drug Administration, Done Between Days 9 and 12 of the Menstrual Cycle at Time 1 (Before) and Time 2 (During Treatment With St.… ClinicalTrials.gov · 2026-09-01
6 phase2, 4 phase1, 4 phase3, 3 phase4, 1 na, 1 na or unstated; NCT00048815; 2007-04; no ageing endpoint recorded. Last human test completed 2018, NCT03482817.
Interpretation These counts include studies where St John's wort was a comparison treatment, a background treatment or an exposure in an observational study, and the longest window may be a planned end date. Trial roles have not yet been classified for this record.
Show the evidence
phase2
6
phase1
4
phase3
4
phase4
3
na
1
na or unstated
1
1 more recorded row
Last recorded human testNCT03482817
2018-06-23
recorded 2026-09-01 · last checked 2026-09-04
Q2
From C. elegans to human: where has St John's wort shown lifespan?
Area Under the Concentration Versus Time Curve for 0 to 24 Hours After Drug Administration, Done Between Days 9 and 12 of the Menstrual Cycle at Time 1… — the recorded outcome words.
Show the evidence
C. elegans
lifespan
mouse
lifespan
rat
lifespan
humanNCT00131885
biomarker; Area Under the Concentration Versus Time Curve for 0 to 24 Hours After Drug Administration, Done Between Days 9 and 12 of the Menstrual Cycle at Time 1 (Before) and Time 2 (During Treatment With St. John's Wort or Placebo); 19
3 recorded entries; human; also "St. John's Wort-900 mg/day", "St. John's Wort-1800mg/day"
Show the evidence
human
NCT00066859
St. John's Wort 600 mg
NCT00405912
St. John's Wort-900 mg/day
NCT00405912
St. John's Wort-1800mg/day
recorded 2026-09-01 · last checked 2026-09-04
Q5
More St John's wort was worse in human: at what point?
U-shaped in human: "The observations made using different doses indicate that these learning-facilitating and/or memory-consolidating effects by the agents follow inverse U-shaped dose-response curves in dose ranges lower than (for hyperforin) or equal to (for Hypericum extract) their effective dose in the behavioral despair test for…" Europe PMC · dose-response search · 2006-07-01
4 recorded sentences naming St John's wort; U-shaped, biphasic, dose-response
Show the evidence
U-shaped
PMID 11518079
"The observations made using different doses indicate that these learning-facilitating and/or memory-consolidating effects by the agents follow inverse U-shaped dose-response curves in dose ranges lower than (for hyperforin) or equal to (for Hypericum extract) their effective dose in the behavioral despair test for antidepressants."
PMID 10625112
"In the case of the hypericum extracts the dose-response relationship was inverted U-shaped with a MED value of 20 mg/kg and a maximal effect of 41% and 32% immobility reduction, for Ze 117 and LI 160, respectively."
biphasicPMID 16903853
"A biphasic effect, serotonergic stimulation of activity at low concentrations that is overridden by GABAergic inhibition at higher concentrations, is apparent with Hypericum alone and the triple combination of the extracts."
dose-responsePMID 23196026
"The data point to a dose-response relationship between the antidepressant efficacy of Hypericum extract and its hyperforin content."
recorded 2006-07-01 · last checked 2026-09-04
Q6
Could one person measure St John's wort's effect on adhd iv rating scale?
Adhd iv rating scale: measured in St John's wort's trials.
Interpretation adhd iv rating scale is the recorded endpoint.
Show the evidence
biomarkers
adhd iv rating scale; 2026-09-01
progesterone levels above 3 0 / at time 1 and time 2; 2026-09-01
frequency of raynaud s phenomenon attacks; 2026-09-01
duration of rp attacks; 2026-09-01
severity of rp attacks; 2026-09-01
hamilton depression scale 17; 2026-09-01
human trials at or under30
8
Not recorded for this substance
a recorded half-life
smallest human trial
2; NCT00066859; PHASE3; the smallest recorded human enrolment at or below 30; the registry states no direction of its result; COMPLETED
Q7
Which of adhd iv rating scale, duration of rp attacks and frequency of raynaud s phenomenon attacks did St John's wort's trials measure?
adhd iv rating scale, duration of rp attacks and frequency of raynaud s phenomenon attacks lead 6 outcome terms across St John's wort's trials. ClinicalTrials.gov · 2026-09-01
duration of rp attacks, severity of rp attacks and hamilton depression scale 17 follow.
Show the evidence
adhd iv rating scale
1
progesterone levels above 3 0 / at time 1 and time 2
1
frequency of raynaud s phenomenon attacks
1
duration of rp attacks
1
severity of rp attacks
1
hamilton depression scale 17
1
recorded 2026-09-01 · last checked 2026-09-04
Q8
Which 10 trials of St John's wort posted no result?
Posted no result
10 of 10 completed trials
Registrations
NCT00006395, NCT00035438, NCT00035412, NCT00027014, NCT00066859 and NCT00100295, and 4 more
Completion dates
oldest 2001-04; newest 2014-12
Show the evidence
Trial
NCT00006395
2001-04
NCT00035438
2003-09
NCT00035412
2004-08
NCT00027014
2005-05
NCT00066859
2005-11-01
NCT00100295
2006-11
4 further recorded trials
NCT05477472
2007-01
NCT00351117
2008-08
NCT01726764
2014-05
NCT01921881
2014-12
Q9
At the median, St John's wort's trials enrolled 38 people — anything larger?
Median enrolment
38
Largest enrolment
118
Registered trials counted
18
Q10
What do 84 spontaneous reports say about St John's wort — and not say?
These are reports people sent to a regulator. They do not show the medicine caused the reaction. Nobody counted how many people took the medicine and reported nothing. The same event can be reported more than once, and many reports are incomplete. News coverage, lawsuits and new warnings change how often people report. A count is not a rate and not a risk.
St John's wort appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 84 reaction mentions were counted: anxiety 12; sleep disorder 11; cognitive disorder 10; arthralgia 9. open-targets-adr · CHEMBL2108102 · 2026-06-24
Show the evidence
anxiety
12
sleep disorder
11
cognitive disorder
10
arthralgia
9
depressed mood
9
drug interaction
7
4 more recorded rows
panic attack
7
suicidal ideation
7
attention deficit/hyperactivity disorder
6
generalised anxiety disorder
6
recorded 2026-06-24 · last checked 2026-09-04
Q11
Was St John's wort studied with exercise?
exercise is named in St John's wort's label sentences: "The CAM therapies selected for this review (ie, S-adenosylmethionine, omega-3 fatty acids, St John's wort, bright light therapy, acupuncture, and exercise) were based on their prevalence of use and the availability of randomized, placebo-controlled data." openfda-label+europepmc · 2010-06-01
1 recorded statement; exercise
Show the evidence
exercise
The CAM therapies selected for this review (ie, S-adenosylmethionine, omega-3 fatty acids, St John's wort, bright light therapy, acupuncture, and exercise) were based on their prevalence of use and the availability of randomized, placebo-controlled data.
recorded 2010-06-01 · last checked 2026-09-04
Where it is registeredIdentifiers, relations and other names
Chase-devil whole, Common st johnswort flowering top, Common st. john's wort herb, Common st johnswort whole, Common st. john's wort whole, Eola-weed whole, Goat-weed whole, Guanyejinsitao, Hyperici herba, Hyperici perforati herba, Hypericum, Hypericum perforatum
Development code
ZE-117
Trade name
Hypericum 3x, Bm Hypericum, Sold as standardised Hypericum perforatum extracts including LI-160, WS 5570 and Ze 117
Sources (9)
Sources
ClinicalTrials.govclinicaltrials.gov ·
ClinicalTrials.govClinicalTrials.gov API v2 snapshot 2026-09-01T09:00:05 ·
ChEMBL ATC CC BY-SA · ClinicalTrials.gov — US Government work · Europe PMC — metadata only, under the recorded legal gate · Open Targets 26.06 — CC0 · derived from this page's own recorded fields; no external licence · mixed register set; per-register licences in docs/specs/corpus-20k-sources.md · openFDA / DailyMed — US Government work
✗ required summary fields resolved: 5 required field(s) not terminal: Why people use it, Best-supported result, Most important common problem, Biggest unanswered question, Human evidence
✓ public claims reviewed: 0 reviewed claim(s); drafts are never rendered
✓ source coverage passed: 9 source rows
✓ no critical contamination: no quarantine open
✓ canonical metadata passed: slug and display name present
✓ no raw internal fields: enforced by the copy-contract test over the rendered page
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