Serotonergic antidepressant use is associated with weaker psilocybin effects

Background: Psilocybin is being studied for depression, but little is known about how it interacts with common antidepressants. Limited data suggests that psilocybin’s effects may be diminished by serotonergic antidepressants acutely and even after a medication washout period.Aims: To learn the extent to which serotonergic antidepressants may diminish psilocybin’s effects both concurrently and after discontinuation of antidepressants.

Methods: Online survey of individuals with use of psilocybin 1) with an antidepressant and/or 2) within two years of discontinuing an antidepressant. Participants who took psilocybin with an antidepressant and either took the same dose of psilocybin pre-antidepressant or took the same dose with other people not on antidepressant reported the strength of psilocybin’s effect relative to their expectation. Participants who took psilocybin following discontinuation of a serotonergic antidepressant also reported the presence of weakened effects.

Results: In reports (n=595) of taking psilocybin with an antidepressant, probabilities [95% CI] of weaker than expected psilocybin effects were 0.48 [0.41-0.54] (SSRIs), 0.56 [0.44-0.67] (SNRIs) and 0.29 [0.2-0.39] (bupropion). Following serotonergic antidepressant discontinuation (n=1,542 reports), the odds of reduced psilocybin effects were not significantly different from the earliest post-discontinuation timepoint (within 1 week) until 3-6 months OR = 0.42, 95% [0.25-0.72] p = 0.001.Conclusions: Serotonergic antidepressants appear to weaken psilocybin’s effects relative to a non-serotonergic antidepressant. This dampening effect on psilocybin effects may last as long as 3 months following antidepressant discontinuation.