Serotonergic Medicines and Substance-Specific Evidence

Urgent help first

Serotonin syndrome is a potentially life-threatening reaction that most often occurs when two or more medicines or drugs that affect serotonin are taken together. [1] Symptoms occur within minutes to hours and can include agitation, abnormal eye movements, diarrhea, fast heartbeat, high blood pressure, hallucinations, increased body temperature, loss of coordination and overactive reflexes. [1] In the US call 911 for an emergency; US Poison Help is 1-800-222-1222. MedlinePlus advises not to stop a medicine without first talking to a provider. [1] This page is education only and never tells anyone to start, stop or change a medicine.

Why one chart does not work

"Serotonergic" covers very different drugs. NIDA says classic psychedelics such as psilocybin and LSD mainly interact with serotonin 5-HT2A receptors. [2] MDMA works differently: a human study concluded its psychological effects involve serotonin release through the serotonin uptake site. [3] Antidepressants are another class again. A 2022 review concluded that risks differ: serotonergic drugs without MAOIs are low risk with psychedelics without MAOIs, while some combinations carry significant risk of serotonin toxicity and others are likely benign. [4] NIDA adds that reported cases of psychedelic drug interactions are exceedingly rare and that some researchers suspect interactions with serotonin-raising prescription medicines. [2]

That is why this page goes substance by substance. Evidence labels used: promising but limited, mixed, insufficient evidence, evidence of harm. See how we label evidence.

Substance by substance

The psilocybin result is the most important for readers who assume a combination is dangerous: in this one small study, the SSRI did not increase risks, but the authors said longer antidepressant pretreatment and studies in patients with psychiatric disorders are needed. [5] The study cannot say what happens with other antidepressants, other doses, long-term use or people with depression.

What systematic reviews say about the whole evidence base

A 2022 systematic review included 40 publications: 26 randomized studies in healthy adults, 3 epidemiologic studies and 11 case reports. MDMA was covered by 24 and psilocybin by 5. [6] Participants in the trials were young healthy adults given a psychiatric medicine once or, rarely, for up to 14 days, so the findings are limited when extrapolating to real-world settings where medicines are taken daily for months or years. [6] In a survey in the review, people who took ecstasy together with antidepressants still experienced euphoria but reported higher rates of adverse effects, and the survey did not separate antidepressant classes and included MAOIs. [6]

For ayahuasca, which contains an MAO inhibitor, see MAO-inhibiting preparations and interactions.

Trial exclusion is not interaction evidence

Researchers often exclude people on certain medicines, or manage medicines in a controlled way, for safety and clean results. For example, in a US trial of single-dose psilocybin for major depression, participants taking psychotropic medicines were eligible following medication taper. [8] NIDA notes that modern psychedelic studies exclude people with psychosis or bipolar disorder, and sometimes other mental illnesses, as a precaution. [2]

An exclusion or a taper step in a protocol shows that researchers wanted a controlled setting. It does not measure how a given combination behaves, and it is not advice for anyone outside the study. Only a prescriber who knows the person can decide about medicines.

Other medicines and groups

• MAOI antidepressants: the label for one MAOI says it should not be used together with serotonin-acting agents because serious, sometimes fatal reactions have been reported. [9]
• Cough and cold ingredients and pain medicines: MedlinePlus says MAOIs can cause serotonin syndrome with medicines including meperidine, fentanyl and dextromethorphan. [1]
• Other classes (mirtazapine, trazodone, lithium, buspirone, atypical antipsychotics): the 2022 review lists these as classes that modulate serotonin and may raise the risk of toxidromes such as serotonin syndrome. [6] Proper evidence not found for quantified risk estimates for each pairing with psilocybin or LSD. For lithium see lithium-related concerns.

What the evidence cannot say

• Whether results in healthy volunteers apply to people with depression, anxiety or PTSD.
• What happens after months of antidepressant treatment, since the longest exposure in the controlled studies was short.
• Whether any particular product sold outside medicine contains what its label claims. See contamination and adulteration.

For related pages see psychedelic drug interactions and toxicology, interactions by drug class and talking with a health professional.