Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action

The hallucinogen psilocybin induces a psychosis-like state in healthy people that resembles early schizophrenia. In human volunteers, these effects were blocked in a dose-dependent manner by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. This provides the first human evidence that psilocybin-induced psychosis results from serotonin-2A receptor activation, independent of dopamine stimulation. The findings suggest that serotonin-2A overactivity may play a role in schizophrenia and that blocking this receptor may contribute to antipsychotic benefits.

Study at a glance

Abstract

Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.