Safe Use7 min read

Psilocybin and Medications: Interactions to Know and Questions to Ask Your Doctor

If you take any prescription medication, or even some over-the-counter ones and supplements, this guide is for you. Psilocybin works mainly through the brain's serotonin system, so anything else that acts on serotonin, or on seizure risk, heart rhythm or how the body processes drugs, can change how psilocybin affects you. Some combinations simply make mushrooms weaker. Others can be genuinely dangerous. Here's a clear, cautious overview, with the important reminder that this is general education, not medical advice.

How psilocybin works, briefly

When you take psilocybin, your body converts it into psilocin. Psilocin acts on serotonin receptors, especially the 5-HT2A receptor, which is responsible for most of the psychedelic effects. Psilocin is then broken down, partly by the enzyme monoamine oxidase (MAO) and partly by other pathways. Medications that change serotonin levels, block or alter these receptors, inhibit MAO, or lower the seizure threshold can all interact.

The most serious: lithium

Lithium is used mainly for bipolar disorder. It's the interaction we're most concerned about. A 2021 analysis of online experience reports by researchers including Johns Hopkins scientists found that 47 per cent of 62 reports involving lithium combined with a classic psychedelic described seizures, and a further 18 per cent described bad trips. About 39 per cent of the lithium reports involved medical attention. By contrast, no seizures were reported with lamotrigine, another mood stabilizer.

These are self-reported cases, not a controlled trial, but the signal is strong enough that the advice is simple: do not combine lithium with psilocybin. And because bipolar disorder itself is a reason most clinical trials exclude people, people with bipolar disorder should avoid psilocybin unless a specialist has advised otherwise.

MAOIs

Monoamine oxidase inhibitors include some older antidepressants, such as phenelzine and tranylcypromine, and moclobemide, as well as some other medications, like the antibiotic linezolid. Because MAO helps break down psilocin, an MAOI can make the effects of psilocybin stronger, longer and less predictable. MAOIs also carry their own risks of dangerous reactions with many other substances. Don't combine them with psilocybin. The same caution applies to traditional preparations containing harmala alkaloids, such as ayahuasca and Syrian rue.

SSRIs and SNRIs

These are the most commonly prescribed antidepressants, including sertraline, escitalopram, fluoxetine, citalopram, paroxetine, venlafaxine and duloxetine. Their main interaction with psilocybin is usually blunting: they often make the experience noticeably weaker.

A 2023 Johns Hopkins online survey of people who had taken psilocybin mushrooms while on, or after stopping, antidepressants found that SSRIs and SNRIs were associated with weaker-than-expected effects, and that this dampening might last as long as three months after stopping the antidepressant. Bupropion, which doesn't act mainly on serotonin, showed much less of this effect.

There's also a theoretical risk of serotonin toxicity when combining serotonergic drugs, though a 2022 review in Psychopharmacology concluded that combining serotonergic medications with psychedelics like psilocybin appears to be low risk as long as no MAOI is involved. Combinations that include an MAOI are where serious serotonin toxicity becomes a real concern. The more practical risks are people taking much larger amounts to "break through" the blunting, or stopping their antidepressants abruptly. Both can backfire.

Never stop or reduce an antidepressant to make room for mushrooms. Stopping suddenly can cause discontinuation symptoms and, more importantly, relapse of the condition it's treating. Any change should be planned with your prescriber.

Tramadol

Tramadol is a painkiller that also increases serotonin and is known to lower the seizure threshold. Combining it with serotonergic substances adds risk on both fronts. Avoid psilocybin if you take tramadol, and talk to your doctor about other medications with similar properties.

Antipsychotics

Many antipsychotic medications block the 5-HT2A receptor, which can significantly reduce or even cancel the effects of psilocybin. More importantly, people taking antipsychotics often have conditions like schizophrenia or bipolar disorder, for which psilocybin may pose a risk of triggering psychosis or mania. Avoid psilocybin unless a specialist has advised otherwise.

Tricyclic antidepressants and other psychiatric medications

Tricyclic antidepressants, other mood stabilizers, ADHD stimulants and benzodiazepines can all change how psilocybin feels, sometimes unpredictably. Benzodiazepines are sometimes used by medical professionals to calm acute anxiety, but don't self-medicate with them during a trip. Discuss any psychiatric medication with your doctor before considering psilocybin.

Heart medications and heart conditions

Psilocybin raises heart rate and blood pressure modestly. For healthy people that's usually not a concern, but if you have a heart condition, high blood pressure or take heart medication, talk to a doctor first. Clinical trials usually exclude people with significant heart disease.

Supplements and other substances

St. John's wort: Affects serotonin and interacts with many drugs. Avoid combining.
5-HTP and tryptophan supplements: Increase serotonin. Avoid combining.
Dextromethorphan (in some cough syrups): Serotonergic. Avoid combining.
Alcohol: Makes judgment worse, increases nausea and makes effects less predictable. Skip it.
Cannabis: Can dramatically intensify a psilocybin experience and increase anxiety, especially for people who don't use it often.
Stimulants like amphetamines or cocaine: Increase strain on the heart and anxiety. Don't combine.
Other psychedelics: Combining makes effects much harder to predict.

MDMA and other serotonergic recreational drugs

Some people combine psilocybin with MDMA or other recreational drugs. MDMA releases large amounts of serotonin and puts its own strain on the heart and body temperature. Combining it with psilocybin makes the experience far less predictable and adds risk, especially for anyone also taking prescription medications that affect serotonin. We strongly advise against mixing.

Tell your sitter what you take

Whoever is with you should know about every medication and supplement you take, and how much you've had of everything on the day. If you ever need medical help, that information lets paramedics act quickly and safely.

Who should avoid psilocybin entirely

Even without medication, psilocybin isn't for everyone. Avoid it if you:

Have a personal or family history of psychosis, schizophrenia or bipolar disorder.
Have significant heart disease or uncontrolled high blood pressure.
Are pregnant or breastfeeding.
Have a history of seizures.
Are under 19.

How clinical trials handle medications

Clinical trials give a good sense of how seriously researchers take these interactions. Most psilocybin trials exclude people taking lithium, antipsychotics and many other psychiatric medications. In many depression trials, participants on serotonergic antidepressants have had to taper off them, under close medical supervision, before receiving psilocybin. This is done carefully, over weeks, with a clinician watching for withdrawal symptoms and relapse. It's not something to try on your own.

Quick reference

A simplified summary of the combinations covered above. It isn't exhaustive, and your doctor or pharmacist is the right person to ask about your specific situation.

Do not combine: lithium, MAOIs (including harmala-containing brews), tramadol.
Avoid unless a specialist advises: antipsychotics, other mood stabilizers, seizure medications.
Talk to your doctor first: SSRIs, SNRIs, tricyclics, ADHD stimulants, heart and blood pressure medications, any psychiatric medication.
Avoid combining: St. John's wort, 5-HTP, dextromethorphan, alcohol, cannabis, stimulants and other psychedelics.

If you're not sure whether a medication or supplement belongs on this list, assume it might, and ask.

What about microdosing?

Smaller doses don't remove interaction risks. The lithium seizure reports, for example, aren't limited to large doses, and regular microdosing means repeated exposure. Antidepressants may blunt microdose effects too. Treat microdosing with the same care as a full dose when it comes to medications.

How to bring it up with your doctor

Many people worry about being judged. Health professionals are there to keep you safe, and what you discuss is confidential. Be honest. Questions you might ask:

"Could any of my medications interact with psilocybin?"
"Are there medications I take that could make psilocybin dangerous, or that it could make dangerous?"
"If I ever wanted to explore psilocybin, what would you want me to know?"
"Are there clinical trials or legal access options I could look into?"

A pharmacist is also a great, accessible resource for interaction questions.

What's normal, and what isn't

On psilocybin, it's normal to experience yawning, nausea, chills, a modestly faster heart rate, visual changes, emotional waves and time distortion. What isn't normal, and especially worth watching for if someone takes other medications: seizures, muscle rigidity or twitching, very high temperature, heavy sweating with confusion, chest pain or trouble breathing. Call 911 if you see any of these.

When in doubt, sit it out

If you're not sure, skip it. A missed experience costs you nothing; a bad interaction can cost a great deal. There will always be another day once you have clear answers. Read more in our safety guide and What Are Magic Mushrooms?, and our microdosing guide if you're considering small doses. You must be 19 or older to shop with us, and psilocybin is a controlled substance in Canada.

Sources

This guide is general information, not medical or legal advice. If you have health questions, talk to a health professional.