Psilocybin Interactions: Lithium, SSRIs, MAOIs and 23 More

The short answer

Lithium is the clearest red flag: in 62 online reports of lithium taken with a classic psychedelic such as LSD or psilocybin, 47% described seizures and 39% involved medical attention.¹ SSRIs and SNRIs mostly weaken the experience,² MAOIs and stimulants add blood pressure and serotonin risks,³ and stopping an antidepressant brings discontinuation symptoms in about 31% of people.⁴ If you take a prescription medicine, ask your prescriber or pharmacist, and never stop it on your own.

The evidence is thin. A 2024 systematic review found 52 interaction studies across all classic psychedelics, only 10 of them on psilocybin.⁵ Much of the rest comes from LSD studies, surveys, case reports and pharmacology, and each card says which.

How to use the checker and read its labels

Search by generic name, the one printed under the brand on a pharmacy label ("sertraline", not the brand), or tap a filter. With JavaScript off, all 26 cards are listed, most serious first. Each card carries one of three flags:

Serious reaction reported or likely (8 of 26): seizures, a blood pressure emergency, serotonin toxicity or a similar danger.
Blunts or changes the effect (8 of 26): psilocybin feels weaker or different.
Unclear or little evidence (10 of 26): no human data, or too little to say. Unclear doesn't mean safe.

What the evidence labels mean
Evidence label	What it is	How much weight it carries
Controlled study	Psilocybin compared with and without the other drug, under supervision	The strongest type, but the psilocybin studies of this kind each enrolled fewer than 30 people, mostly healthy volunteers
Observational or survey	Self-reports online or in surveys, or poison center records	A real-world signal, but self-selected
Case reports	One or a few patients described by their doctors	Shows something can happen, not how often
Pharmacological theory	Reasoning from receptors, enzymes and drug labels	A reason for caution, not proof of harm or safety

The interaction checker: 26 medicine and drug classes

A summary of published evidence, not medical advice. It describes what researchers found, never how to combine anything.

LithiumSerious reaction reported or likelylithium carbonate, lithium citrate

In 62 online reports of lithium taken with a classic psychedelic (such as LSD or psilocybin), 47% described seizures and 39% involved medical attention, while none of 34 lamotrigine reports described seizures (Nayak 2021). A 2024 case report described three seizures after LSD in a teenager recently started on low-dose lithium, and a 2024 scoping review concluded lithium could increase seizure risk with psychedelics. Older LSD reports (n = 3) described stronger and faster effects on chronic lithium.

Evidence: observational or survey (online experience reports) plus case reports.

What this means: This is the strongest warning among the medicines in this checker: seizures. If you take lithium, talk to your prescriber or pharmacist before any decision involving psilocybin. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Nayak et al. 2021; Edwards et al. 2024; Soto-Angona et al. 2024; Bonson and Murphy 1996; Johnson, Richards, Griffiths 2008. Human hallucinogen research: guidelines for...; Lithium carbonate prescribing information (serotonin syndrome warning).
Stopping prescribed medication (antidepressant discontinuation)Serious reaction reported or likelyany antidepressant, benzodiazepines, lamotrigine and other anticonvulsants, beta-blockers, clonidine

A 2024 meta-analysis (79 studies, 21,002 patients) found discontinuation symptoms in 31% after stopping antidepressants vs 17% after placebo, with severe symptoms in 2.8% vs 0.6%; a 2025 reanalysis of 5 systematically measured studies estimated 55% (95% CI 31-81%). Labels warn that abrupt stopping can cause seizures (lamotrigine, benzodiazepines), angina or heart attack (beta-blockers) and rebound high blood pressure (clonidine). Trials tapered antidepressants under weekly supervision with suicidality checks, and post hoc analyses disagree on whether stopping helps psilocybin work (Erritzoe 2024 vs Marwood 2024).

Evidence: controlled study (meta-analysis of trials) plus drug labels.

What this means: Stopping a prescribed medicine is itself a medical decision with real risks. Any change belongs with your prescriber or pharmacist; never stop abruptly.

Sources: Henssler et al. 2024; Moncrieff et al. 2025; Erritzoe et al. 2024; Marwood et al. 2024; Zoloft (sertraline) prescribing information: discontinuation syndrome; Lamictal XR (lamotrigine) prescribing information: withdrawal seizures; Xanax (alprazolam) prescribing information: dependence and withdrawal reactions; Toprol-XL (metoprolol) prescribing information: abrupt cessation; Catapres-TTS (clonidine) prescribing information: withdrawal; COMPASS COMP001 protocol v4.0 (NCT03775200).
MAOIs (monoamine oxidase inhibitors, prescription)Serious reaction reported or likelyphenelzine, tranylcypromine, isocarboxazid, selegiline, rasagiline, moclobemide, linezolid

A 2025 case report described a hypertensive emergency with ST-elevation about half an hour after psilocybin mushrooms in a man taking tranylcypromine plus extended-release amphetamine; the authors suspect phenylethylamine in the mushrooms. A 2026 review lists hypertensive urgency or emergency with MAOIs plus psilocybin mushrooms among reported events. Serotonin toxicity reviews place the main risk on combinations involving MAOIs. In older LSD reports, phenelzine nearly abolished LSD effects (n = 2). MAO-A breaks down part of the psilocin, but glucuronidation is likely the main route.

Evidence: case reports plus pharmacological theory.

What this means: MAOIs have many dangerous interactions, and a published case links an MAOI plus a stimulant plus psilocybin mushrooms with a hypertensive emergency. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Barnett et al. 2025; Rached et al. 2026; Malcolm and Thomas 2022; Bonson and Murphy 1996; Thomann et al. 2024; Sacher et al. 2011; Nardil (phenelzine) prescribing information; Parnate (tranylcypromine) prescribing information; Emsam (selegiline transdermal) prescribing information.
Harmala alkaloids and ayahuasca (beta-carboline MAO-A inhibitors)Serious reaction reported or likelyharmine, harmaline, tetrahydroharmine, Syrian rue (Peganum harmala), ayahuasca vine (Banisteriopsis caapi)

Beta-carbolines inhibit MAO-A and are what make DMT in ayahuasca orally active. Case reports describe serotonin-toxicity-like reactions when ayahuasca or harmala extracts met fluoxetine, and severe reactions and a death with harmala alkaloids plus 5-MeO-DMT. No human study or case report of psilocybin combined with harmala alkaloids was found. Psilocybe mushrooms themselves contain small amounts of beta-carbolines such as harmane and harmine (Blei 2020).

Evidence: case reports (with other tryptamines) plus pharmacological theory.

What this means: Harmala products add MAO inhibition, and serious reactions have been reported when they meet antidepressants or other tryptamines. If you take prescribed medicines, talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Halman et al. 2024; Blei et al. 2020; Malcolm and Thomas 2022; Rached et al. 2026.
Tricyclic antidepressants (TCAs)Serious reaction reported or likelyamitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin

In 1996 retrospective reports, people on chronic imipramine (n = 2), desipramine (n = 2) or clomipramine (n = 1) described earlier onset and stronger LSD effects; no psilocybin-specific data were found. Hopkins safety guidelines treat chronic TCAs as potentiating hallucinogen effects and a safety concern. TCAs carry their own seizure and heart-rhythm risks: the clomipramine label calls seizure its most significant risk.

Evidence: case reports (LSD) plus pharmacological theory.

What this means: Unlike SSRIs, TCAs may intensify psychedelic effects, and they affect seizure threshold and heart rhythm. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Bonson and Murphy 1996; Halman et al. 2024; Johnson, Richards, Griffiths 2008. Human hallucinogen research: guidelines for...; Anafranil (clomipramine) prescribing information: seizures; Henssler et al. 2024.
Tramadol and other seizure-threshold-lowering drugsSerious reaction reported or likelytramadol, bupropion, clomipramine and other TCAs, lithium

No study or case of psilocybin plus tramadol was found. Tramadol's label warns of potentially life-threatening serotonin syndrome with serotonergic drugs and of seizure risk that rises with SSRIs, SNRIs, TCAs, MAOIs, neuroleptics and other drugs that lower seizure threshold. A 2024 scoping review concluded that psychedelics may not raise seizure risk in healthy people taking no other drugs, but that other substances such as lithium or kambo could.

Evidence: pharmacological theory.

What this means: The concern is stacking several drugs that lower the seizure threshold or raise serotonin. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Tramadol ER prescribing information: serotonin syndrome, seizure risk; Soto-Angona et al. 2024; Rached et al. 2026; Wellbutrin XL (bupropion) prescribing information: seizure risk, hypertension.
Stimulants and ADHD medicationsSerious reaction reported or likelyamphetamine salts, lisdexamfetamine, methylphenidate, dexmethylphenidate, atomoxetine

Psilocybin raises blood pressure in trials, and stimulant labels warn of raised blood pressure and heart rate and risks in heart disease. A 2025 case report described a hypertensive emergency when psilocybin mushrooms were taken with extended-release amphetamine and the MAOI tranylcypromine. No controlled study of psilocybin with a stimulant was found. Usona's trial required stopping prescribed stimulants 2 weeks before baseline, and COMP001 excluded methylphenidate.

Evidence: case reports plus pharmacological theory.

What this means: Both raise blood pressure and heart rate, and the risk is highest with an MAOI also involved. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Barnett et al. 2025; Adderall XR prescribing information: blood pressure and heart rate; Usona PSIL201 protocol v10.0 (NCT03866174), exclusion criteria; COMPASS COMP001 protocol v4.0 (NCT03775200).
Mushroom products with unlisted or unknown ingredientsSerious reaction reported or likelymushroom chocolates, gummies, syrups, products sold as legal or microdose supplements

US poison centers reported a 2024 surge in exposures to products marketed as psychedelic mushrooms; some recalled products contained O-acetylpsilocin, psilocin, kavalactones, pregabalin and muscimol. From 2010 to 2024 there were 1,195 processed mushroom product exposures, 21.6% in children under 13. In 2023 to 2024 edible data, polysubstance exposure (aOR 2.58), confusion and CNS depression were linked to hospital admission. Alkaloid content of non-standardized products can vary by more than tenfold.

Evidence: observational or survey (poison-center data).

What this means: When contents are unknown, interactions with your medicines cannot be predicted. If you take prescribed medicines, talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Beuhler et al. 2025; Jorgenson et al. 2026; Szarpak et al. 2026.
SSRIs (selective serotonin reuptake inhibitors)Blunts or changes the effectsertraline, escitalopram, citalopram, fluoxetine, paroxetine, fluvoxamine, vilazodone, vortioxetine

In an online survey, weaker-than-expected mushroom effects were reported with SSRIs in 47% of cases (95% CI 41-54%; n = 611 reports across antidepressants), and reduced effects persisted at about 30% for up to 3 to 6 months after stopping (Gukasyan 2023). In a controlled crossover study of 23 healthy people, 14 days of escitalopram did not reduce positive effects but reduced anxiety, bad drug effects and blood pressure rises (Becker 2022). In 19 patients kept on SSRIs, 2 had severe blood pressure rises treated with clonidine and none had serious adverse events (Goodwin 2023). Reviews rate serotonin toxicity risk as low when no MAOI is involved (Malcolm and Thomas 2022).

Evidence: controlled study (small) plus observational or survey.

What this means: SSRIs often weaken the experience, and this can persist for months after stopping. Talk to your prescriber or pharmacist; do not stop an SSRI to make room for psilocybin. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Gukasyan et al. 2023; Becker et al. 2022; Goodwin et al. 2023; Bonson et al. 1996; Malcolm and Thomas 2022; Do et al. 2024; Prozac (fluoxetine) prescribing information: elimination half-life.
SNRIs (serotonin-norepinephrine reuptake inhibitors)Blunts or changes the effectvenlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran

Weaker-than-expected effects were reported with SNRIs in 55% of survey cases (95% CI 44-67%) (Gukasyan 2023). No controlled study of psilocybin with an SNRI was found; one case report describes psilocybin-assisted therapy given with duloxetine plus vortioxetine without cardiovascular concerns. Venlafaxine and desvenlafaxine are among the antidepressants most associated with frequent and severe discontinuation symptoms (Henssler 2024).

Evidence: observational or survey.

What this means: Likely to weaken effects, and these medicines are among the hardest to stop. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Gukasyan et al. 2023; Do et al. 2024; Henssler et al. 2024; Malcolm and Thomas 2022.
TrazodoneBlunts or changes the effecttrazodone

Trazodone blocks 5-HT2A receptors (the main psilocybin target) and inhibits serotonin reuptake. One 1996 case reported reduced LSD effects on trazodone; no psilocybin data were found. Its label warns of serotonin syndrome and QT prolongation. Usona's phase 2 trial required stopping trazodone used for sleep 2 weeks before baseline.

Evidence: case reports (LSD) plus pharmacological theory.

What this means: Expected to weaken effects. Talk to your prescriber or pharmacist before changing any sleep or antidepressant medicine. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Halman et al. 2024; Bonson et al. 1996; Trazodone prescribing information: serotonin syndrome, QT; Usona PSIL201 protocol v10.0 (NCT03866174), exclusion criteria.
MirtazapineBlunts or changes the effectmirtazapine, mianserin

Mirtazapine blocks 5-HT2A receptors, and a 2024 systematic review lists it among medicines expected to diminish psychedelic effects. No human psilocybin data were found. Its label lists serotonin syndrome and QT prolongation risks.

Evidence: pharmacological theory.

What this means: Likely to dampen effects; no safety data for the combination. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Halman et al. 2024; Remeron (mirtazapine) prescribing information.
BuspironeBlunts or changes the effectbuspirone

In a double-blind within-subject study (n = 19 healthy), buspirone significantly reduced psilocybin-induced visual effects (Visionary Restructuralization, p < 0.001), with a trend reduction in oceanic boundlessness (p = 0.062). Its label contraindicates use with MAOIs because of serotonin syndrome and raised blood pressure.

Evidence: controlled study.

What this means: Shown to reduce visual effects in a controlled study. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Pokorny et al. 2016; Halman et al. 2024; Buspirone prescribing information: MAOI contraindication.
Antipsychotics and 5-HT2A blockersBlunts or changes the effectrisperidone, olanzapine, quetiapine, aripiprazole, haloperidol, chlorpromazine, ketanserin (research only)

In controlled studies in healthy volunteers, risperidone and the research drug ketanserin blocked psilocybin's effects in a dose-dependent way, while haloperidol increased anxiety and psychosis-like effects without reducing visual effects (Vollenweider 1998). Chlorpromazine reduced visual distortion in a 1967 study (n = 8). Hopkins guidelines advise against haloperidol as rescue medication. People prescribed antipsychotics usually have conditions (psychosis, bipolar disorder) that trials exclude.

Evidence: controlled study.

What this means: Most antipsychotics blunt psilocybin, and the conditions they treat are the main reason trials exclude people. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Vollenweider et al. 1998; Halman et al. 2024; Johnson, Richards, Griffiths 2008. Human hallucinogen research: guidelines for...; Imperial psilocybin vs escitalopram protocol v7 (NCT03429075); COMPASS COMP001 protocol v4.0 (NCT03775200).
BenzodiazepinesBlunts or changes the effectlorazepam, diazepam, alprazolam, clonazepam, midazolam

Clinical guidelines and trial protocols name benzodiazepines as the rescue medication of choice when severe anxiety does not respond to reassurance, and a 2026 emergency case report describes their use with supportive care. Some trials allowed stable prescribed benzodiazepines. In a small controlled study (n = 8), midazolam allowed a conscious psychedelic experience while partly impairing memory of it. Benzodiazepine labels warn that abrupt discontinuation can cause withdrawal reactions including seizures.

Evidence: controlled study (small) plus clinical guidance and case reports.

What this means: These are what clinicians use to calm severe reactions in emergencies; that is a medical decision, not self-treatment. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Johnson, Richards, Griffiths 2008. Human hallucinogen research: guidelines for...; COMPASS COMP001 protocol v4.0 (NCT03775200); Usona PSIL201 protocol v10.0 (NCT03866174), exclusion criteria; Nicholas et al. 2024; Udoro et al. 2026; Xanax (alprazolam) prescribing information: dependence and withdrawal reactions.
CannabisBlunts or changes the effectcannabis, THC products

In a prospective online survey (n = 321), cannabis used together with a psychedelic was associated with more intense experiences in a dose-related way, and with a curved (quadratic) relationship to challenging-experience scores. A global survey of emergency treatment after mushroom use found mixing substances among the most reported reasons for incidents. Usona's trial required participants to abstain from cannabis.

Evidence: observational or survey.

What this means: Cannabis may intensify the experience, including difficult parts. If you take prescribed medicines, talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Kuc et al. 2022; Kopra et al. 2022; Usona PSIL201 protocol v10.0 (NCT03866174), exclusion criteria.
BupropionUnclear or little evidencebupropion

In the 2023 survey, weaker-than-expected effects were reported less often with bupropion (29%; 95% CI 20-39%) than with SSRIs (47%) or SNRIs (55%). Bupropion's label warns of dose-related seizure risk and raised blood pressure. No case of seizure from psilocybin plus bupropion was found; in one LSD case, seizures appeared only after lithium was added to fluoxetine plus bupropion.

Evidence: observational or survey plus pharmacological theory.

What this means: Less dampening than SSRIs in one survey, but bupropion lowers the seizure threshold and can raise blood pressure on its own. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Gukasyan et al. 2023; Wellbutrin XL (bupropion) prescribing information: seizure risk, hypertension; Edwards et al. 2024.
Blood pressure and heart medicationsUnclear or little evidencelisinopril, losartan, amlodipine, metoprolol, clonidine, hydrochlorothiazide

No interaction study between psilocybin and blood pressure medicines was found. The main issue is the underlying condition: psilocybin raised systolic pressure above 160 mmHg in 34% of high-dose trial sessions, and trials exclude uncontrolled hypertension and many heart conditions. Clonidine was used to treat severe blood pressure rises in one psilocybin trial. Labels warn that stopping beta-blockers abruptly can trigger angina or heart attack and stopping clonidine abruptly can cause a rapid rise in blood pressure.

Evidence: pharmacological theory.

What this means: Needing these medicines means the heart and blood vessels need protecting from extra strain, which psilocybin adds. Talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Goodwin et al. 2023; Griffiths et al. 2016; Toprol-XL (metoprolol) prescribing information: abrupt cessation; Catapres-TTS (clonidine) prescribing information: withdrawal; Halman et al. 2024.
LamotrigineUnclear or little evidencelamotrigine

None of 34 online reports of lamotrigine taken with a classic psychedelic described seizures, and 65% were judged not to change the experience (Nayak 2021). This is a small, self-selected sample, not proof of safety. The lamotrigine label warns against abrupt discontinuation because of withdrawal seizures.

Evidence: observational or survey.

What this means: No seizure signal in one small report set. Talk to your prescriber or pharmacist; never stop lamotrigine abruptly because of withdrawal seizure risk.

Sources: Nayak et al. 2021; Lamictal XR (lamotrigine) prescribing information: withdrawal seizures.
Other anticonvulsants and mood stabilizersUnclear or little evidencevalproate (divalproex), carbamazepine, oxcarbazepine, phenytoin, topiramate, gabapentin, pregabalin

No human data on psilocybin with these drugs were found. Usona's phase 2 protocol excluded people who could not stop UGT enzyme modulators such as valproate, because glucuronidation is a major route for clearing psilocin; valproate is known to slow glucuronidation of some drugs (its label reports lamotrigine half-life rising from 26 to 70 hours). Imperial's protocol listed mood stabilisers as possibly attenuating psilocybin. Epilepsy itself is excluded in every major trial.

Evidence: pharmacological theory.

What this means: No direct data, and the conditions these medicines treat are trial exclusions. Talk to your prescriber or pharmacist; never stop an anticonvulsant abruptly because of withdrawal seizure risk.

Sources: Usona PSIL201 protocol v10.0 (NCT03866174), exclusion criteria; Manevski et al. 2010; Depakote (divalproex) prescribing information: drug interactions; Imperial psilocybin vs escitalopram protocol v7 (NCT03429075).
AlcoholUnclear or little evidencebeer, wine, spirits

In a small study (n = 15), psilocybin blunted how intoxicated alcohol felt, while psilocybin effects were unchanged for 80% of participants. A Dutch risk review flagged combined use with alcohol as a concern. Multiple-drug toxicity accounted for 20% of psilocybin-related deaths in Australian coronial data, and polysubstance exposure was linked to hospital admission in US poison-center data on mushroom edibles (aOR 2.58).

Evidence: observational or survey.

What this means: Alcohol may feel weaker than it is, and mixing is linked to worse outcomes in poison-center data. If you take prescribed medicines, talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Barrett et al. 2000; Halman et al. 2024; van Amsterdam et al. 2011. Harm potential of magic mushroom use: a review....; Darke et al. 2024; Jorgenson et al. 2026.
St John's wortUnclear or little evidenceSt John's wort (Hypericum perforatum)

No psilocybin-specific data were found. St John's wort is serotonergic (the lithium label lists it as raising serotonin syndrome risk) but is not a meaningful brain MAO-A inhibitor on PET (under 5% occupancy vs 74% for moclobemide). NCCIH warns it weakens many medicines and can cause serious serotonin-related effects with some antidepressants.

Evidence: pharmacological theory.

What this means: It interacts with many prescription drugs. Tell your prescriber or pharmacist about any supplement. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Sacher et al. 2011; NCCIH: St. John's Wort (last updated May 2025); Lithium carbonate prescribing information (serotonin syndrome warning).
MDMAUnclear or little evidenceMDMA, ecstasy, molly

A prospective convenience sample (27 co-users among 698 people) linked low-amount MDMA co-use with less intense challenging experiences; it was small and non-experimental. In a controlled LSD study, adding MDMA made LSD effects last about 1.5 hours longer, attributed to CYP2D6 inhibition, which matters less for psilocin. MDMA has its own serious risks, including deaths when combined with MAOIs, and chronic heavy use is linked to heart valve disease.

Evidence: observational or survey.

What this means: No controlled safety data exist for this combination, and MDMA's own risks multiply with MAOIs. If you take prescribed medicines, talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Zeifman et al. 2023; Halman et al. 2024; Rached et al. 2026; Tagen et al. 2023; Thomann et al. 2024.
Ketamine and esketamineUnclear or little evidenceketamine, esketamine

No human data on psilocybin combined with ketamine or esketamine were found. COMP001 excluded people who had received ketamine for their current depressive episode. Any added cardiovascular effect is theoretical and unconfirmed.

Evidence: pharmacological theory.

What this means: No data. If you receive ketamine or esketamine treatment, talk to the prescriber running it before any decision involving psilocybin. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: COMPASS COMP001 protocol v4.0 (NCT03775200).
Other psychedelicsUnclear or little evidenceLSD, DMT, mescaline, 5-MeO-DMT, 2C-B, Amanita muscaria products

Combining psychedelics has no controlled safety data. In US poison-center data for 2024, psilocybin mushrooms appeared in two deaths, both with LSD ranked as the main substance. Reoccurring drug-like experiences were reported by 14.3% of healthy volunteers given both LSD and psilocybin vs 8.3% for psilocybin alone. Serious reactions and a death have been reported with 5-MeO-DMT combined with MAO-inhibiting harmala alkaloids.

Evidence: observational or survey plus case reports.

What this means: Combinations are unstudied and appear in poison-center and coroner records. If you take prescribed medicines, talk to your prescriber or pharmacist. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Beuhler et al. 2025; Darke et al. 2024; Muller et al. 2022; Halman et al. 2024.
Drugs affecting psilocin metabolism (UGT, MAO-A, CYP2D6, CYP3A4)Unclear or little evidencevalproate (UGT inhibition), strong MAO-A inhibitors, strong CYP2D6 inhibitors (for example fluoxetine), strong CYP3A4 inhibitors (for example ketoconazole)

Psilocybin is converted to psilocin, which is cleared by glucuronidation and by an oxidative pathway that starts with MAO-A; studies differ on which handles more. For glucuronidation, UGT1A10 (mostly in the gut) has the highest activity and UGT1A9 is likely the main liver enzyme. Of eight CYP enzymes only CYP2D6 and CYP3A4 metabolized psilocin in vitro; CYP2D6 genotype did not change psilocin blood levels in people. Free psilocin's half-life is about 1.4 to 1.8 hours, and escitalopram did not change its pharmacokinetics. Whether any specific drug raises psilocin exposure in people is unconfirmed.

Evidence: pharmacological theory (in vitro and human pharmacokinetic data).

What this means: Metabolic interactions are possible in theory but unmeasured. A pharmacist can check whether any medicine you take affects these enzymes. Do not stop or change a prescribed medicine on your own: stopping some medicines abruptly can cause withdrawal effects or relapse.

Sources: Manevski et al. 2010; Thomann et al. 2024; Dinis-Oliveira 2017; Holze et al. 2023; Becker et al. 2022; Usona PSIL201 protocol v10.0 (NCT03866174), exclusion criteria.

Download this data. Psilocybin medication and substance interaction evidence summary, 26 rows, updated October 26, 2026. Free to reuse under CC BY 4.0 with a link to this page.

Shrooms and lithium: the clearest warning

The signal comes from online experience reports on Erowid, Shroomery and Reddit. Of 62 reports of lithium with a classic psychedelic such as LSD or psilocybin, 47% described seizures and 39% involved medical attention; of 34 lamotrigine reports, none described seizures.¹ The reports are self-selected, so 47% isn't a risk rate, but the authors concluded that psychedelic use "may pose a significant seizure risk for patients on lithium."¹ A 2024 scoping review agreed that substances such as lithium could raise seizure risk with psychedelics.⁶ If you're prescribed lithium, talk to your prescriber or pharmacist, and don't stop or change it on your own.

Shrooms and SSRIs or SNRIs: mostly weaker effects

In an online survey (611 reports of mushrooms taken with an antidepressant), effects were weaker than expected in 47% of SSRI reports (95% CI 41 to 54%), 55% of SNRI reports (44 to 67%) and 29% of bupropion reports. After people stopped an SSRI or SNRI, reduced effects were still reported about 30% of the time for up to 3 to 6 months (1,542 reports).²

In the only randomized controlled study of psilocybin with an SSRI we found, 23 healthy volunteers had psilocybin twice, once after 14 days of escitalopram and once after placebo. Escitalopram didn't reduce positive mood or the overall alteration of consciousness, but it reduced anxiety and psilocybin's blood pressure rise, and it didn't change psilocin levels.⁷ In an open-label study of 19 patients who stayed on an SSRI, 2 had severe blood pressure rises treated with clonidine.⁸

On serotonin syndrome, a 2022 review found that true serotonin toxicity typically involves an overdose or an MAOI, and rated combinations without an MAOI as low risk.⁹ We found no confirmed published case from psilocybin plus an SSRI. Low risk isn't no risk.

MAOIs and harmala products: blood pressure and serotonin

A 2026 review of 219 publications lists hypertensive urgency or emergency among the events reported with MAOIs plus psilocybin mushrooms.¹⁰ In one case, a 42-year-old taking the MAOI tranylcypromine and extended-release amphetamine developed severe high blood pressure, chest pain and ECG changes about half an hour after eating psilocybin mushrooms and was treated for a heart attack; catheterization found no significant abnormality. The authors suspect phenylethylamine in the mushrooms reacted with both drugs.³

Serotonin toxicity reviews place the main risk on combinations that include an MAOI.⁹ Old LSD reports suggest MAOIs blunt rather than strengthen effects (phenelzine nearly abolished them in 2 patients),⁵ and a metabolism study judged that glucuronidation, not MAO-A, likely remains the main route for clearing psilocin, making MAO inhibition "potentially less important."¹¹ The concern is blood pressure and serotonin toxicity, not strength.

Harmala alkaloids (harmine and harmaline, in Syrian rue and the ayahuasca vine) are also MAO-A inhibitors. Case reports describe serotonin-toxicity-like reactions when they met fluoxetine, and severe reactions and a death with 5-MeO-DMT.⁵ We found no study or case of psilocybin with harmala alkaloids. Never stop an MAOI abruptly; talk to your prescriber or pharmacist.

Why stopping a medicine isn't the safe option

Stopping a prescribed medicine to "make room" for psilocybin is a medical event of its own. A 2024 meta-analysis of 79 studies (21,002 patients) found discontinuation symptoms in 31% of people after stopping an antidepressant, against 17% after stopping a placebo, and severe symptoms in 2.8% against 0.6%.⁴ A 2025 reanalysis of 5 studies that measured withdrawal systematically put the figure at 55% (95% CI 31 to 81%).¹² The estimates are disputed; both agree the symptoms are real.

The sertraline label lists nausea, dizziness, electric-shock sensations, anxiety, confusion and seizures among reactions seen "particularly after abrupt discontinuation".¹³ Labels for lamotrigine, benzodiazepines, beta-blockers and clonidine carry similar warnings (see the stopping medication card). When trials took people off antidepressants, COMP001 held weekly clinic visits for at least 3 weeks, with suicide-risk checks at each contact.¹⁴ And the blunting can outlast stopping by months anyway.² Our page on who clinical trials exclude covers how trials handled medicines.

How the body clears psilocin

Psilocybin is converted to psilocin, the compound that acts on the brain (see psilocybin vs psilocin). Psilocin is cleared by two major routes, and studies differ on which handles more. One is glucuronidation: the enzyme UGT1A10, mostly in the gut, has the highest activity, and UGT1A9 is likely the main contributor once psilocin is absorbed.¹⁵ The other starts with MAO-A, which a 2024 study calls a key enzyme in psilocin's major oxidative pathway, though it expects glucuronidation to dominate. Of eight CYP enzymes tested, only CYP2D6 and CYP3A4 broke psilocin down in lab tests; CYP2D6 genotype didn't change blood levels in people.¹¹ Free psilocin's half-life is about 1.4 to 1.8 hours, effects lasted 5.5 to 6.4 hours on average in one trial, and body weight didn't change how it was handled¹⁶ (more in does body weight matter).

Whether any medicine raises psilocin levels in people hasn't been measured; in the one controlled study that checked, escitalopram didn't.⁷ Usona's phase 2 trial still excluded people who couldn't stop drugs that affect glucuronidation, such as valproate.¹⁷ A pharmacist can check your medicines against these enzymes.

What dosage calculators leave out

Of the 36 online magic mushroom dosage calculators we checked in October 2026, 8 name lithium, 8 name SSRIs or antidepressants and 13 name MAOIs. Only 6 name all three, and 22 of the 35 readable pages name none. Four ask about medicines as an input, all about MAOIs or antidepressants; none asks about lithium. The records are in our calculator audit. Your medicines belong in a conversation with a prescriber or pharmacist, not in a form.

Questions people ask

Is it dangerous to mix shrooms and lithium?

It's the strongest warning in the research: seizures in 47% of 62 online reports of lithium with a classic psychedelic, and medical attention in 39%. The reports are self-selected, so that isn't a precise risk. Talk to your prescriber or pharmacist, and don't stop lithium on your own.

Do SSRIs stop shrooms from working?

Often they weaken the effect. In one survey, 47% of SSRI reports and 55% of SNRI reports described weaker-than-expected effects, and about 30% still did up to 3 to 6 months after stopping.

Should I stop my antidepressant first?

Not on your own. In a meta-analysis of 79 studies, 31% of people had discontinuation symptoms after stopping an antidepressant, against 17% after a placebo. Any change belongs with your prescriber.

What are the warning signs of serotonin syndrome?

A 2022 review lists muscle jerking, muscle rigidity, a high fever, agitation or a comatose state, extreme or swinging heart rate and blood pressure, and seizures as signs that need immediate medical attention. Call 911 if you see them.

Why does this page use LSD studies?

Because there's so little on psilocybin: only 10 of 52 interaction studies across classic psychedelics involved it. LSD findings are a clue, not psilocybin data, and the cards say when a finding comes from LSD.

Sources

Nayak SM, et al. Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports. Pharmacopsychiatry, 2021. PMID 34348413.
Gukasyan N, et al. Attenuation of psilocybin mushroom effects during and after SSRI/SNRI antidepressant use. J Psychopharmacol, 2023. PMID 37291890.
Barnett BS, et al. Hypertensive emergency secondary to combining psilocybin mushrooms, extended release dextroamphetamine-amphetamine, and tranylcypromine. J Psychoactive Drugs, 2025. PMID 38903003.
Henssler J, et al. Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. Lancet Psychiatry, 2024. PMID 38851198.
Halman A, et al. Drug-drug interactions involving classic psychedelics: a systematic review. J Psychopharmacol, 2024. PMID 37982394.
Soto-Angona O, et al. Do classic psychedelics increase the risk of seizures? A scoping review. Eur Neuropsychopharmacol, 2024. PMID 38917636.
Becker AM, et al. Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clin Pharmacol Ther, 2022. PMID 34743319.
Goodwin GM, et al. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacology, 2023. PMID 37443386.
Malcolm B, Thomas K. Serotonin toxicity of serotonergic psychedelics. Psychopharmacology (Berl), 2022. PMID 34251464.
Rached G, et al. Safety and efficacy of monoamine oxidase inhibitors in patients who use psychoactive substances. CNS Drugs, 2026. PMID 41546846.
Thomann J, et al. In vitro and in vivo metabolism of psilocybin's active metabolite psilocin. Front Pharmacol, 2024. PMID 38741590.
Moncrieff J, et al. Evidence on antidepressant withdrawal: an appraisal and reanalysis of a recent systematic review. Psychol Med, 2025. PMID 40692314.
Sertraline prescribing information (discontinuation of treatment). DailyMed, US National Library of Medicine.
COMP001 clinical trial protocol, version 4.0. COMPASS Pathways, July 22, 2019, posted on ClinicalTrials.gov (NCT03775200).
Manevski N, et al. Glucuronidation of psilocin and 4-hydroxyindole by the human UDP-glucuronosyltransferases. Drug Metab Dispos, 2010. PMID 20007669.
Holze F, et al. Pharmacokinetics and pharmacodynamics of oral psilocybin administration in healthy participants. Clin Pharmacol Ther, 2023. PMID 36507738.
PSIL201 clinical trial protocol, version 10.0. Usona Institute, March 5, 2021, posted on ClinicalTrials.gov (NCT03866174).

Psilocybin drug interactions: lithium, SSRIs, MAOIs and 23 more