Amitriptyline and St John's Wort: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
St John's Wort
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
These two can pull in opposite directions, and neither is good. St. John's Wort speeds up the enzymes in your liver that break down amitriptyline (Elavil). That means your body clears the amitriptyline faster, so it can become less effective at treating your mood, pain, or sleep.
At the same time, St. John's Wort also raises serotonin, and so does amitriptyline. Together they can, in rare cases, push serotonin too high, causing symptoms like agitation, a racing heart, sweating, shivering, muscle twitching, or fever. This is manageable. Please don't start or stop anything on your own. Talk with your pharmacist or doctor so they can adjust your care and watch for any warning signs.
Direction: St. John's Wort (hyperforin) induces CYP enzymes, lowering amitriptyline and nortriptyline AUC (reduced antidepressant efficacy). Concurrently, additive serotonergic activity (SJW's serotonin reuptake inhibition and mild MAO activity plus a TCA) creates a theoretical risk of serotonin syndrome.
- Mechanism: enzyme induction (PK) plus additive serotonergic effect (PD)
- Onset: delayed; Evidence: established for AUC reduction, theoretical for serotonin syndrome (extrapolated from SSRI/MAOI + TCA reports)
- Management: avoid or use SJW products delivering not more than 1 mg hyperforin/day; monitor antidepressant response and for serotonin toxicity (hypertension, hyperthermia, myoclonus, mental status changes). Amitriptyline dose may need individualization.
What happens
Decreased effectiveness of amitriptyline and possible increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
Interaction Deep Dive
When amitriptyline is given together with St. John's Wort, the AUC of amitriptyline is reduced 4, as is the AUC of its metabolite nortriptyline 5. From a theoretical standpoint, because St. John's Wort is believed to block serotonin reuptake and may possess weak monoamine oxidase inhibitory activity 67, combining it with a tricyclic antidepressant like amitriptyline could give rise to serotonin syndrome. Support for this theoretical serotonin syndrome risk also comes from case reports describing serotonin syndrome after selective serotonin reuptake inhibitors were used alongside tricyclic antidepressants 8, and after monoamine oxidase inhibitors were used together with tricyclic antidepressants 213. Even St. John's Wort products with a low hyperforin content do not eliminate the possibility of interactions; nonetheless, choosing products that deliver a daily hyperforin dose no greater than 1 mg may reduce the likelihood of interactions 4.
Why it happens (mechanism)
Induction of metabolizing enzymes; additive serotonergic effect
How to manage this interaction
The good news: your care team can manage this. Keep taking your amitriptyline exactly as prescribed and do not stop it suddenly on your own.
- Tell your pharmacist or prescriber that you are taking (or thinking about taking) St. John's Wort, including the brand and hyperforin content if you can find it.
- Products delivering no more than 1 mg of hyperforin per day may lower the risk, but the interaction can't be fully ruled out even then.
- Your amitriptyline dose may need to be adjusted and individualized, and your team may monitor your response more closely.
- Seek prompt care for agitation, fever, sweating, fast heartbeat, muscle twitching, or confusion.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
a) In a systematic review of studies examining pharmacokinetic interactions involving St John's Wort, one study (n=12) found that taking it together with amitriptyline led to a 22% reduction in amitriptyline AUC when using products containing hyperforin 7.5 mg/day 4.
b) An open-label study of twelve depressed patients evaluated how St. John's Wort affects the steady-state pharmacokinetics of amitriptyline, a tricyclic antidepressant. St. John's Wort (900 mg/day) was given alongside amitriptyline (75 mg twice daily) for at least fourteen days. A significant 21.7% reduction in the AUC of amitriptyline and a significant 41.6% reduction in the AUC of nortriptyline, the metabolite of amitriptyline, were observed. This interaction may be caused by St. John's Wort inducing drug metabolizing enzymes or drug transporters 5.
Common questions
Can I take Amitriptyline and St John's Wort together?
St. John's Wort can make amitriptyline less effective and, less commonly, raise the risk of serotonin syndrome, so let your pharmacist or doctor know before combining them and keep taking your medicine as prescribed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and St John's Wort interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Amitriptyline and St John's Wort interaction managed?
The good news: your care team can manage this. Keep taking your amitriptyline exactly as prescribed and do not stop it suddenly on your own. Tell your pharmacist or prescriber that you are taking (or thinking about taking) St. John's Wort, including the brand and hyperforin content if you can find it. Products delivering no more than 1 mg of hyperforin per day may lower the risk, but the interacti… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Amitriptyline or St John's Wort need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (8)
- Spigset O, Mjorndal T, & Lovheim O: Serotonin syndrome caused by a moclobemide-clomipramine interaction. Br Med J 1993; 306:248. PubMed
- Brodribb TR, Downey M, & Gilbar PJ: Efficacy and adverse effects of moclobemide (letter). Lancet 1994; 343:475. DOI
- Tackley RM & Tregaskis B: Fatal disseminated intravascular coagulation following a monoamine oxidase inhibitor/tricyclic interaction. Anaesthesia 1987; 42(7):760-763. PubMed
- Chrubasik-Hausmann S, Vlachojannis J, & McLachlan AJ: Understanding drug interactions with St John's wort (Hypericum perforatum L.): impact of hyperforin content. J Pharm Pharmacol 2019; 71(1):129-138.
- Roots I, Johne A, Schmider J, et al: Interaction of a herbal extract from St. John's Wort with amitriptyline and its metabolites (abstract). Clin Pharmacol Ther 2000; 67(2):159.
- Singer A, Wonnemann M, & Muller WE: Hyperforin, a major antidepressant constituent of St. John's Wort, inhibits serotonin uptake by elevating free intracellular Na+. J Pharmacol Exp Ther 1999; 290(3):1361-1368.
- Thiede HM & Walper A: Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatry Neurol 1994; 7 (Suppl 1):S54-S56. DOI
- Alderman CP & Lee PC: Comment: serotonin syndrome associated with combined sertraline-amitriptyline treatment (letter). Ann Pharmacother 1996; 30(12):1499-1500. PubMed
Keep reading about Amitriptyline
Keep reading about St John's Wort
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