- MAOIs (phenelzine, tranylcypromine, isocarboxazid, selegiline at higher doses, moclobemide) block monoamine oxidase, raising synaptic serotonin globally.
- LSD activates 5-HT2A receptors. With elevated synaptic serotonin and a 5-HT2A agonist on board, the combination can drive serotonin syndrome.
- Required washout: 2 weeks for most MAOIs, 5+ weeks for fluoxetine before starting MAOI (different direction but illustrates the drug-class washout principle).
- Ayahuasca contains MAO-inhibitor harmala alkaloids (harmine, harmaline). Combining ayahuasca with an SSRI or LSD is the same class of risk.
- This combination has documented serotonin syndrome cases including hospitalizations.
Why people ask this question
MAOIs are uncommon but still prescribed for treatment-resistant depression, atypical depression, social anxiety, Parkinson’s disease (selegiline at low dose for PD has different MAO selectivity), and rare conditions. They have a notorious reputation for food and drug interactions, and serotonergic combinations are the most dangerous category.
LSD users on an MAOI are usually either patients on a “last-resort” antidepressant or recreational users unaware of an interaction. Both groups need this page.
Mechanism of harm
Serotonin syndrome is a clinical emergency caused by excess serotonergic activity, specifically:
- MAOIs block monoamine oxidase A and/or B, the enzymes that break down serotonin (and norepinephrine, dopamine). Synaptic serotonin rises chronically across all serotonergic neurons.
- LSD is a 5-HT2A partial agonist. On its own it activates 5-HT2A receptors. On a brain with already-elevated synaptic serotonin, the combined activation drives signaling beyond physiological range.
- Result: serotonin syndrome triad — mental status changes (agitation, confusion), autonomic instability (tachycardia, hyperthermia, sweating), neuromuscular hyperactivity (clonus, hyperreflexia, tremor).
Severity ranges from mild (resolves with discontinuation) to severe (hyperthermia above 40°C, rhabdomyolysis, seizures, death). Mortality rate is low but real, particularly in hyperthermic cases.
What the case data shows
The Halman et al. 2024 systematic review identified MAOI + classical psychedelic case reports across decades of literature:
- Multiple case reports of full serotonin syndrome requiring hospitalization following MAOI + LSD or psilocybin.
- Several reports of hyperthermia and rhabdomyolysis, the most dangerous serotonin-syndrome trajectory.
- Sarparast et al. (2022) review identified MAOI as the highest-concern interaction class for psychedelic-medication interactions.
- Ayahuasca-related cases: combining ayahuasca (which contains MAO-inhibitor harmala alkaloids) with SSRIs or other serotonergic drugs has produced serotonin syndrome in published case reports.
MAOI washout windows
Switching off an MAOI takes time. Tissue MAO regeneration is the rate-limiting step:
| MAOI | Type | Washout before psychedelic |
|---|---|---|
| Phenelzine (Nardil) | Irreversible, non-selective | 2 weeks minimum, 4 weeks safer |
| Tranylcypromine (Parnate) | Irreversible, non-selective | 2 weeks minimum |
| Isocarboxazid (Marplan) | Irreversible, non-selective | 2 weeks minimum |
| Selegiline (Eldepryl, Emsam patch) | Selective MAO-B at low dose; non-selective at higher | 2 weeks if non-selective dosing |
| Moclobemide (Manerix) | Reversible MAO-A (RIMA) | ~3 days due to reversibility |
| Ayahuasca harmala alkaloids | Reversible MAO-A | 24-48 hours typically clear, but residual considered |
Irreversible MAOIs require new MAO enzyme synthesis, which takes ~2 weeks. Reversible MAOIs (moclobemide, ayahuasca’s harmala) clear faster.
Serotonin syndrome, in plain terms
Three clusters of signs, increasing in severity:
Tremor, sweating, tachycardia, anxiety, dilated pupils
Common. Resolves with discontinuation. Hydrate, monitor temperature.
Clonus, hyperreflexia, agitation, fever <38.5°C, hypertension
Needs medical attention. Cyproheptadine (5-HT2A antagonist) may help. ER evaluation.
Hyperthermia >40°C, sustained clonus, rhabdomyolysis, seizures
Life-threatening. ICU. Aggressive cooling, sedation, intubation if needed.
Onset within hours of co-administration
Most cases peak within 6 hours. Resolution after discontinuation typically 24-72 hours.
Alternatives
- Wait through the washout. 2 weeks for most irreversible MAOIs, longer is safer. The strongest single thing you can do.
- Switch off MAOI to a different antidepressant first. Cross-tapers between MAOIs and other antidepressants are themselves dangerous; this requires psychiatric supervision.
- Ketamine therapy (NMDA antagonist) is generally compatible with MAOIs at low doses. Used in some TRD patients on MAOIs. Talk to prescriber.
- If the MAOI is selegiline for Parkinson’s at low (selective MAO-B) dose: the interaction is less clear but still risky. Consult neurology.
If during or after a session you observe:
Body temperature above 38.5°C / 101°F · Sustained tachycardia above 130 · Tremor or clonus that won’t stop · Severe agitation, confusion · Sweating, dilated pupils, dry mouth simultaneously · Loss of consciousness · Seizure
Call 911 or your local emergency line. State “possible serotonin syndrome from MAOI plus psychedelic.” Bring all medication bottles. Do not give the patient more antiserotonergic substances at home; cyproheptadine is given in hospital under supervision.
