Psilocybin and tricyclic antidepressants
CautionAntidepressant, tricyclic · also: amitriptyline, nortriptyline, imipramine, clomipramine, doxepin
Psilocybin and tricyclic antidepressants: caution, the only human data (with LSD) suggest stronger rather than weaker effects, and tricyclics carry their own heart and seizure risks.
Reports of intensified effects. Additive cardiovascular strain, psilocybin already produces a modest rise in heart rate and blood pressure.
Claims re-checked against the cited sources:
Why it happens
Unlike SSRIs, chronic tricyclic use was linked to stronger LSD effects in a very small study, possibly through changes in serotonin or dopamine receptor sensitivity. Tricyclics also have anticholinergic effects and can cause arrhythmias and slowed cardiac conduction, especially at high doses. Clomipramine inhibits serotonin reuptake and has a notable seizure risk of its own.
What is known
Potentiation of LSD by tricyclics was described by Bonson and Murphy in the 1990s; psilocybin is assumed to behave similarly on mechanism. Direct data is thin.
- 1996
- People on chronic tricyclics (3 weeks or longer) reported increased physical, hallucinatory and psychological responses to LSD in a retrospective questionnaire study of ten people in total. Bonson & Murphy, 'Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, MAOIs or lithium', Behav Brain Res
- 2024
- A 2024 systematic review notes the tricyclic findings come from a single study with a very small number of participants; no psilocybin-tricyclic study was found. Halman et al., 'Drug-drug interactions involving classic psychedelics: a systematic review', J Psychopharmacol
- 2026
- The amitriptyline label warns that tricyclics, particularly at high doses, can cause arrhythmias, sinus tachycardia and prolonged conduction time, and advises caution with seizure history. Amitriptyline hydrochloride tablets US prescribing information, DailyMed (label version Oct 2026)
- 2024
- The clomipramine label identifies seizure as its most significant risk (cumulative 1.45% at one year at doses up to 300 mg/day) and attributes its effect to serotonin reuptake inhibition. ANAFRANIL (clomipramine) US prescribing information, DailyMed (label version Dec 2024)
- 2024
- In healthy volunteers, psilocybin raised autonomic measures only moderately; heart rate over 100 occurred in 7% of administrations. Straumann et al., 'Safety pharmacology of acute psilocybin administration in healthy participants', Neurosci Appl (pooled analysis, 85 participants)
Safety guidance
- Expect more effect than you planned for, not less; start low.
- If you have any heart condition, the added cardiovascular load is the part to take seriously.
- Clomipramine users should be more careful because of its seizure risk.
- Do not stop or reduce a tricyclic on your own; talk to your prescriber.
When to seek help
Call emergency services for chest pain, fainting, a racing or irregular heartbeat that does not settle, or any seizure. Emergency red flags.
Common questions
Will a tricyclic block my trip like an SSRI?
Probably not. The only data, from LSD users, point to stronger effects, though the study was tiny.
Is a low dose of amitriptyline for pain or sleep a concern?
The heart risks in the label are greatest at high doses; low doses are less concerning, but the interaction has not been studied.
Should I stop my tricyclic first?
No. Any change should go through your prescriber.
Sources
How we research this: sources, evidence grading, review and updates.