Many people who are curious about psilocybin already take medication for depression or anxiety. That makes one question especially important: how do psilocybin and antidepressants interact? This harm reduction guide explains what research shows about psilocybin and SSRIs, older antidepressants and lithium, and why medication changes should never happen without a doctor.
This article is for general information only. It is not medical advice. Never stop, reduce or change any medication on your own. Stopping antidepressants suddenly can cause withdrawal symptoms and a return of depression.
Why Psilocybin and Antidepressants Can Interact
Psilocybin turns into psilocin in the body, and psilocin acts mainly on the serotonin 2A receptor [1]. Most common antidepressants also affect the serotonin system, although in different ways. Because both act on serotonin, each can change how the other works. Our guide to psilocybin and the brain explains this receptor in more detail.
SSRIs: Weaker Effects, but Not Always
Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, citalopram and escitalopram, are the most widely prescribed antidepressants in Europe. For many years, people reported that SSRIs made psychedelic experiences weaker. An older study of LSD users supported this: people who took SSRIs long term described much weaker LSD effects [2]. However, that study looked at LSD, not psilocybin.
More recent research has looked at psilocybin and SSRIs directly. In a 2021 study at University Hospital Basel, healthy volunteers took escitalopram or a placebo for two weeks before a dose of psilocybin [3]. Surprisingly, escitalopram did not clearly reduce the positive effects. Instead, it reduced anxiety, unpleasant effects and the rise in blood pressure. Still, the volunteers took the SSRI for only two weeks, so the results may differ for people who have taken it for months or years.
In addition, a small open-label study in 2023 gave psilocybin to 19 people with treatment-resistant depression who continued their SSRI [4]. Psilocybin was generally well tolerated, and many participants improved. However, without a control group, this study cannot show how well the combination works.
Psilocybin With Older Antidepressants and MAOIs
Older types of antidepressants may interact differently. In another LSD study, people taking tricyclic antidepressants reported stronger effects, whereas people taking monoamine oxidase inhibitors (MAOIs) reported weaker ones [5]. Again, these findings concern LSD, so they can only hint at what happens with psilocybin.
MAOIs deserve special caution. They block an enzyme that breaks down psilocin and other substances, which can make effects stronger, longer and harder to predict. Moreover, combining MAOIs with other serotonergic substances can be dangerous.
Lithium: A Serious Seizure Risk
Lithium is used mainly for bipolar disorder. In 2021, researchers analyzed online reports from people who combined lithium with classic psychedelics such as psilocybin or LSD [6]. A large share of these reports described seizures, while reports involving lamotrigine, another mood stabilizer, did not show the same pattern. Although online reports have limits, the warning is serious. Psilocybin and lithium should never be combined.
Serotonin Syndrome and Other Concerns
Serotonin syndrome happens when too much serotonin activity builds up in the body. Symptoms include agitation, fever, sweating, muscle twitching and a fast heartbeat. With psilocybin and antidepressants such as SSRIs, the risk appears to be low, but it rises with MAOIs and with combinations of several serotonergic substances. Severe symptoms are a medical emergency, so call 112 in Europe.
Some other medications also affect psilocybin. For example, certain antipsychotics can block its effects. Our article on psilocybin and the heart covers interactions with blood pressure medication.
Stopping Antidepressants for Psilocybin Is Risky
Some people consider stopping their antidepressant so that psilocybin works more strongly. This can be harmful. Stopping suddenly can cause dizziness, irritability and flu-like symptoms, and depression or anxiety may return. In clinical trials, any medication change happens slowly under medical supervision, often with extra support. To learn how these trials work, read our guide to psilocybin therapy.
Frequently Asked Questions
Can you take psilocybin while on SSRIs?
Early studies suggest the combination is usually not dangerous for healthy people, but the effects may be weaker or different. Always talk to a doctor before combining any substances.
Does microdosing psilocybin interact with antidepressants?
The same interactions may apply, even at low doses. In addition, regular microdosing adds long-term questions that research has not answered. See our microdosing guide for more.
Is psilocybin safe with lithium?
No. Reports link the combination to seizures, so it should be avoided.
Conclusion: Psilocybin and Antidepressants Need Care
Psilocybin and antidepressants can interact in different ways. SSRIs may weaken or change the experience, MAOIs can make it stronger and less predictable, and lithium is linked to seizures. Research is growing, but most studies are small. If you take any medication, speak to a doctor first and never change your treatment alone. For an overview of other risks, read our guide to psilocybin effects and safety.
Sources
- Nichols DE. Psychedelics. Pharmacological Reviews. 2016. doi:10.1124/pr.115.011478
- Bonson KR, et al. Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans. Neuropsychopharmacology. 1996. doi:10.1016/0893-133X(95)00145-4
- 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. Clinical Pharmacology & Therapeutics. 2021. doi:10.1002/cpt.2487
- Goodwin GM, et al. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacology. 2023. doi:10.1038/s41386-023-01648-7
- Bonson KR, Murphy DL. Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium. Behavioural Brain Research. 1995. doi:10.1016/0166-4328(96)00102-7
- 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. doi:10.1055/a-1524-2794
