NutriStack
Amitriptyline and St. John's Wort, a caution.
St. John's Wort can substantially lower amitriptyline and nortriptyline exposure, which may cause loss of antidepressant, migraine, sleep, or neuropathic pain control. In a clinical study, comedication reduced amitriptyline and nortriptyline AUC, and stopping St. John's Wort can then let TCA levels rise again. St. John's Wort also adds serotonergic activity, so the risk is both reduced efficacy and unpredictable toxicity during starts and stops.
One pair, every claim cited. The two substances, the type, the mechanism, the recommendation, and the primary literature.
Same shape as the other 1,729 pairs in the public database.
From the interaction database
What the row says.
Every entry follows the same shape: what is happening, the mechanism, the recommendation, and the primary literature.
At a glance
- Substances
- Amitriptyline and St. John's Wort
- Pair type
- Caution
- Evidence (highest tier)
- Strong
- Source citations
- 3 sources
- Stack Score effect
- −5 to your Stack Score (per scored caution row).
- Scope
- Supplement × Prescription
- Last verified
- May 30, 2026
Caution · Strong evidence
Caution
What is happening. St. John's Wort can substantially lower amitriptyline and nortriptyline exposure, which may cause loss of antidepressant, migraine, sleep, or neuropathic pain control. In a clinical study, comedication reduced amitriptyline and nortriptyline AUC, and stopping St. John's Wort can then let TCA levels rise again. St. John's Wort also adds serotonergic activity, so the risk is both reduced efficacy and unpredictable toxicity during starts and stops.
Mechanism. St. John's Wort induces CYP3A4 and P-glycoprotein through hyperforin-mediated pregnane X receptor activation. Amitriptyline is metabolized through CYP2C19, CYP2D6, and CYP3A pathways, and the active metabolite nortriptyline is also affected by the interaction.
Recommendation. Avoid St. John's Wort while taking amitriptyline. If the combination is already in use, do not start or stop St. John's Wort abruptly without a medication plan; your prescriber may need symptom checks, TCA blood levels, or dose adjustment. Watch for relapse when St. John's Wort starts and for TCA side effects when it stops.
Sources (3)
- Johne A, Schmider J, Brockmoller J, Stadelmann AM, Stormer E, Bauer S, et al. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort (Hypericum perforatum). J Clin Psychopharmacol. 2002;22(1):46-54. PMID 11799342
- Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John's wort. J Psychopharmacol. 2004;18(2):262-276. PMID 15260917
- Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69(13):1777-1798. PMID 19719333
Stack Score
How this pair moves the number.
Effect on the composite score
If both Amitriptyline and St. John's Wort are in the same stack, this pair applies −5 to your Stack Score (per scored caution row).
The full algorithm, the clamping rules, and four worked stacks are documented at /methodology/stack-score.
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