Psilocybin and SSRI Interaction Evidence

No study we read says whether a person can safely take psilocybin with an SSRI (selective serotonin reuptake inhibitor) antidepressant. None gives a time to stop an SSRI before psilocybin. In the controlled study, escitalopram left psilocybin's positive mood effects intact, while in a survey the estimated probability of weaker-than-expected effects was 0.47 for SSRIs.

If you take an antidepressant, any change to it is the prescriber's decision. Do not stop or adjust it on your own.

Psilocybin and SSRI Combination Evidence

Psilocybin itself is investigational and is not approved by the FDA for any use.

In a 2022 crossover study in healthy subjects, Becker and colleagues report that escitalopram pretreatment "had no relevant effect on positive mood effects of psilocybin." The same pretreatment reduced bad drug effects, anxiety, adverse cardiovascular effects and other adverse effects compared with placebo pretreatment.

A 2023 survey by Gukasyan and colleagues found a different pattern in people who used psilocybin mushrooms while taking an antidepressant. The authors conclude that SSRIs and SNRIs (serotonin-norepinephrine reuptake inhibitors) "appear to weaken psilocybin drug effects," and that the dampening "may last as long as 3 months following antidepressant discontinuation."

Psychedelic trials usually require participants to stop SSRIs and SNRIs before enrolling, according to a 2024 paper by Erritzoe and colleagues. How far ahead of enrollment those trials require people to stop is not on our record. No source we read gives a stopping time for anyone outside a trial.

None of these sources tells a specific person to continue or stop an antidepressant, and that question belongs with your prescriber. For other drug combinations, read our psychedelic medication safety guide. For MDMA, read our guide to MDMA and SSRIs.

Escitalopram Pretreatment Study Results

In a randomized, double-blind, placebo-controlled crossover study published in Clinical Pharmacology and Therapeutics in 2022, escitalopram pretreatment had no relevant effect on psilocybin's positive mood effects in healthy subjects. Each participant had two psilocybin test sessions, held at least 16 days apart.

Before one session, participants took escitalopram daily for 14 days, including the day of psilocybin. Before the other session, they took placebo for 14 days. The order of the two pretreatments was random and counterbalanced.

Escitalopram did not alter the pharmacokinetics of psilocin, the psychoactive form of the drug in the body. The half-life of free psilocin was 1.8 hours, with a range of 1.1 to 2.2 hours.

Escitalopram also did not alter expression of the HTR2A and SCL6A4 genes measured before psilocybin. It did not alter QTc intervals or circulating BDNF (brain-derived neurotrophic factor) before or after psilocybin.

The authors write: "Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin." The participants were healthy and took escitalopram for 14 days, so the study does not describe patients or people who take an SSRI every day for months or years. One author reports consulting for Mind Medicine, Inc.; the other authors declare no competing interests.

Survey of SSRI and SNRI Users Who Took Mushrooms

A 2023 online retrospective survey in the Journal of Psychopharmacology linked SSRIs and SNRIs to weaker-than-expected psilocybin mushroom effects more often than bupropion. Respondents had used psilocybin mushrooms while taking an antidepressant, within 2 years of stopping one, or both. Respondents who took mushrooms with an antidepressant rated the strength of effects against their expectation, using either their own dose from before the antidepressant or the same dose taken with people not on one. Respondents who took mushrooms after stopping reported whether effects were weakened.

Across 611 reports of taking mushrooms with an antidepressant, the probability of weaker-than-expected effects was 0.47 (95% confidence interval 0.41 to 0.54) for SSRIs and 0.55 (0.44 to 0.67) for SNRIs. For bupropion, which the authors describe as a non-serotonergic antidepressant, it was 0.29 (0.2 to 0.39).

The survey also looked at 1,542 reports from people who had stopped an SSRI or SNRI. The probability of reduced effects did not differ statistically from the earliest timepoint, within 1 week of stopping, until the 3 to 6 month timepoint. The abstract reports a probability of 0.3 (95% confidence interval 0.20 to 0.46, p = 0.001) for this result and does not give the probability at each timepoint.

Fluoxetine has an especially long half-life, and removing responses involving it did not significantly alter this result. The authors' background section says: "Limited data suggest that psilocybin's effects may be diminished by serotonergic antidepressants acutely and even after a medication washout period."

The findings rest on self-report and recall, with each respondent judging effects against personal expectations.

The two studies on our record differ in design. Becker and colleagues gave psilocybin to healthy subjects in a lab after 14 days of escitalopram, while Gukasyan and colleagues collected recalled reports from people who used psilocybin mushrooms with an antidepressant or within 2 years of stopping one.

Antidepressant Discontinuation and Psilocybin Trials

Psychedelic trials usually require participants to stop SSRIs and SNRIs before enrolling, according to the 2024 paper by Erritzoe and colleagues in the Journal of Psychopharmacology. The paper gives the reason as "the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy."

The paper reports a post hoc exploratory analysis of one trial. That trial compared psilocybin plus about 20 hours of psychological support with a 6-week daily course of escitalopram plus matched support.

In the psilocybin group, patients who had stopped an SSRI or SNRI before entry had a reduced treatment effect on all outcome measures, compared with patients who were unmedicated at entry. No effects of stopping on measures of the acute psychedelic experience were found.

The authors write that "we cannot infer such causation" and that the analyses are "hypothesis generating, and not confirmatory." They conclude that "a controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required." Results from that kind of trial would change what we can report about stopping an antidepressant before psilocybin.

How long trials require people to stop, and how trial teams manage that change, is not on our record. We do not publish a stopping schedule, and any plan to change an antidepressant has to come from a prescriber.

To look up a specific study, use our clinical trial finder or read our psilocybin clinical trials guide. Our guides to psilocybin and antidepressants and psilocybin for depression cover the depression research separately.

Serotonin Syndrome and Questions for a Prescriber

Serotonin syndrome is "a potentially life-threatening reaction to certain medicines," according to MedlinePlus, and it most often occurs when two or more medicines or drugs that affect serotonin are taken together. MedlinePlus lists SSRIs, SSNRIs (selective serotonin-norepinephrine reuptake inhibitors), monoamine oxidase inhibitors (MAOIs), triptans and street drugs including ecstasy and LSD among the drugs associated with it.

MedlinePlus does not name psilocybin in the version we read. It names LSD, a different psychedelic. A rate of serotonin syndrome for psilocybin taken with an SSRI is not on our record.

According to MedlinePlus, symptoms occur within minutes to hours and can include agitation or restlessness, fast heartbeat, high blood pressure, increased body temperature and hallucinations. It also lists abnormal eye movements, diarrhea, loss of coordination, nausea and vomiting, overactive reflexes, and rapid changes in blood pressure. MedlinePlus says to contact your provider right away if you have symptoms and that its information must not be used during a medical emergency. In an emergency, call your local emergency number. For mental health support lines, see our crisis resources page.

These questions are for the person who prescribes your antidepressant. Ask whether your medicine is an SSRI, an SNRI or bupropion, because the 2023 survey reported each one separately. Ask whether any other medicine you take affects serotonin.

Ask which serotonin syndrome symptoms to watch for, and who to call if they appear. Ask what to do about any symptom that appears, such as trouble sleeping. If you are considering a clinical trial, ask what the 2024 finding of a reduced treatment effect in people who had stopped SSRIs or SNRIs means for your situation.

Bring a written list of every medicine you take to that appointment. See also our medication safety checker.

Psilocybin Legal and Approval Status

Psilocybin is a Schedule I controlled substance under federal law, listed with code 7437 in 21 CFR 1308.11 (Title 21 of the Code of Federal Regulations). Psilocyn is listed separately under code 7438.

Psilocybin is not FDA-approved as a medicine for any use and is investigational in clinical trials. Oregon and Colorado run state-regulated adult access programs, covered in our guides to psilocybin in Oregon and psilocybin in Colorado. Those state programs are not FDA approval, and they do not change the federal Schedule I listing.

For federal status, read our guide to whether psilocybin is legal in the US, and for other states, use our legal status by state tool.

Before any decision about psilocybin and SSRI medication, take the questions above and the MedlinePlus serotonin syndrome page to the prescriber who manages your antidepressant.