Psilocybin and MAOIs (irreversible)
DangerousAntidepressant, monoamine oxidase inhibitor · also: phenelzine, nardil, tranylcypromine, parnate, isocarboxazid
Psilocybin and irreversible MAOIs (phenelzine, tranylcypromine and similar): dangerous, mainly because of the risk of a blood-pressure emergency and because the effect on the trip cannot be predicted.
Unpredictable. User reports describe stronger and longer effects than expected, and a published case describes a hypertensive emergency after psilocybin mushrooms in a man taking tranylcypromine together with an amphetamine. Because the size of any effect is not predictable, a dose someone has taken safely before can behave very differently.
Claims re-checked against the cited sources:
Why it happens
Psilocin is cleared mainly by glucuronidation and by conversion to 4-HIAA. In lab studies MAO-A, CYP2D6 and CYP3A4 all contribute, but MAO-A alone produced only small amounts of 4-HIAA, so how much an MAOI changes psilocin levels in people is unknown. The better-documented hazard is blood pressure: irreversible MAOIs can cause hypertensive crisis with certain foods and drugs, and mushrooms contain other amines besides psilocybin.
What is known
MAO-A's role in psilocin metabolism is established in laboratory work. What happens in humans comes from case reports and self-reports rather than controlled study, and an older survey of LSD users on MAOIs reported weaker rather than stronger effects, which is precisely the problem: nobody can tell you in advance what the combination will do to you.
- 2024
- A 42-year-old man on tranylcypromine and extended-release dextroamphetamine-amphetamine took 1 g of Psilocybe cubensis and about half an hour later developed severe hypertension with chest pain, palpitations and headache, was treated in hospital and discharged the next day without lasting harm. The authors suspected phenylethylamine in the mushrooms interacting with both drugs. Barnett et al., 'Hypertensive emergency secondary to combining psilocybin mushrooms, extended release dextroamphetamine-amphetamine, and tranylcypromine', J Psychoactive Drugs (online 2024, issue 2025)
- 2024
- In lab work, MAO-A, CYP2D6 and CYP3A4 were all involved in psilocin metabolism, but MAO-A converted psilocin into only minimal amounts of 4-HIAA. Thomann et al., 'In vitro and in vivo metabolism of psilocybin's active metabolite psilocin', Front Pharmacol
- 1996
- In a small retrospective questionnaire study, people on chronic MAOIs reported weaker, not stronger, responses to LSD. Bonson & Murphy, 'Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, MAOIs or lithium', Behav Brain Res
- 2025
- The tranylcypromine label warns of hypertensive crisis with certain drugs and tyramine-rich food, contraindicates amphetamines, and states MAO inhibition may persist up to 10 days after stopping. PARNATE (tranylcypromine) US prescribing information, DailyMed (label version Jul 2025)
- 2024
- A 2024 systematic review found no controlled human study of psilocybin with an MAOI; human psilocybin interaction data covered buspirone, antipsychotics, escitalopram, alcohol, ketanserin and ergotamine. Halman et al., 'Drug-drug interactions involving classic psychedelics: a systematic review', J Psychopharmacol
Safety guidance
- Treat this as a firm no unless you are working with a prescriber who knows both drugs.
- Stopping recently does not clear it: MAO inhibition can last days after the last dose (up to 10 days per the tranylcypromine label).
- Do not stop an MAOI on your own; abrupt stopping can cause withdrawal effects including delirium, so any change goes through your prescriber.
- Stimulants on top of an MAOI add to the blood-pressure risk; the one published emergency involved all three.
When to seek help
Call emergency services for a sudden severe headache, chest pain, pounding heartbeat, stiff neck, vomiting or confusion. These can signal a hypertensive crisis, which needs treatment within minutes to hours. Emergency red flags.
Common questions
Will an MAOI make the trip stronger?
Nobody can say. MAO-A plays only a small role in breaking down psilocin in lab studies, and an older survey found MAOIs weakened LSD. The unpredictability is the problem.
How long after my last MAOI dose does the risk last?
MAO inhibition can persist after stopping; the tranylcypromine label says up to 10 days. Ask your prescriber about your specific drug, and do not stop it to make a trip possible.
Why is blood pressure the main worry?
Irreversible MAOIs make the body very sensitive to some amines. The one published case involving mushrooms was a hypertensive emergency, possibly from phenylethylamine in the mushrooms plus an amphetamine.
Sources
- [1]Thomann et al., 'In vitro and in vivo metabolism of psilocybin's active metabolite psilocin' (2024)
- [2]Barnett et al., 'Hypertensive emergency secondary to combining psilocybin mushrooms, extended release dextroamphetamine-amphetamine, and tranylcypromine' (2024)
- [3]Bonson & Murphy, 'Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, MAOIs or lithium' (1996)
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