Can I take psilocybin while using an antidepressant?

In our recent large-scale study of psilocybin we, 4.6% of users reported using psilocybin while on an antidepressant. Notably, in our study, individuals who reported taking an antidepressant with psilocybin exhibited weaker acute subjective effects, including lowered scores of mystical experiences and challenging experiences.

While there is still limited empirical evidence available on the interactions between common serotonin reuptake inhibitors (SSRIs) and psilocybin, there is some evidence to suggest that chronic administration of serotonergic antidepressants reduces the subjective effects of classic psychedelics, such as LSD (Bonson et al., 1996). In a summary of results from online survey and online interviews, Bonson noted that individuals taking serotonin-selective antidepressants had a decrease or abolishment of their response to psychedelics. In another study examining the effect of buspirone, a common anxiolytic (anti-anxiety) medication acting as a serotonin receptor agonist, buspirone reduced psilocybin-induced visual perceptual changes (Sarparast et al., 2022). Anecdotal user reports from Erowid, a non-profit educational organization that provides information about psychoactive plants and chemicals, frequently report a reduction or absence of effects of psychedelics while using common SSRIs.

One of the primary concerns in combining psychedelics with psychiatric medications is the risk of serotonin toxicity or serotonin syndrome, a rare but a potentially life-threatening condition precipitated by the use of serotonergic drugs (Simon and Keenaghan, 2022). Regarding safety, in a recent talk held by Dr. Erica Zelfand, data of over 400 participants and found that there is not enough evidence to suggest toxic interaction between antidepressants (SSRI or otherwise) and psilocybin or LSD. Toxicity is extremely rare when mixing antidepressants with these two classical psychedelics.

More recently, in a study on the effects of psilocybin, individuals using escitalopram (i.e., Lexapro), a common selective SSRI, showed no relevant effects on the positive mood effects of psilocybin, but escitalopram significantly reduced negative effects of psilocybin, including anxiety and adverse cardiovascular effects (Becker et al., 2021). For the study, participants either received 10mg of escitalopram daily for seven days followed by 20mg daily for the next seven days, including the day of psilocybin administration, or 14 days of placebo pre-treatment before psilocybin administration. The researchers found that pre-treatment with escitalopram did not alter the pharmacokinetics of psilocin — the active compound that the prodrug psilocybin is converted into in humans by the process of dephosphorylation. These results suggest that escitalopram and psilocybin can be safely administered together.

In summary, although more research is needed, current evidence-based research suggests that the likelihood of toxicity in interactions between SSRIs and psilocybin is low, but SSRIs may reduce the subjective effects of psilocybin.

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