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

This paper (1998) was one of the first to identify psilocybin/psilocin as working on the serotonin (5-HT2A) receptor and not only on the dopaminergic system. The direct comparisons as mentioned in the article are nowadays a bit more nuanced.

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.”

Authors: Franz X. Vollenweider, Margreet F. I. Vollenweider-Scherpenhuyzen, Andreas Bäbler, Helen Vogel & Daniel Hell

Notes

This study used ketanserin, risperidone, and haloperidol pretreatments to identify which system was (then not) activated by psilocybin.

Ketanserin is a selective antagonist of the 5-HT2A receptor. It is (now) commonly used on studying the serotonin system.

Haloperidol is an antagonist for the dopamine D2 receptor. It is sometimes used as an anti-psychotic.

Risperidone is a mixed 5-HT2A and D2 antagonist. It is an atypical antipsychotic.

“[P]retreatment with the 5-HT₂ antagonist ketanserin dose-dependently blocked psilocybin-induced psychosis, as revealed by two-way ANOVAs and significant drug x pretreatment interactions (OSE (F(2,8) = 12.2, p < 0.004); VUS (F(2,8) = 26.3, p < 0.0003); AIA (F(2,8) = 21.7, p < 0.0006)). Specifically, 20 mg ketanserin reduced the psilocybin-induced [Altered States of Consciousness] APZ-OAV scores by about 50-70%, while 40 mg ketanserin completely prevented the development of psilocybin effects in four of five subjects (98-100%).”

“Similarly, 0.5 mg of the mixed 5-HT_2/D2 antagonist risperidone attenuated the effects of psilocybin on all three APZ-OAV scales (69-78%), while 1 mg risperidone effectively blocked the development of psilocybin-induced psychosis (98-99%). Two-way ANOVAs yielded again significant drug x pretreatment interactions (OSE (F(2,8) = 7.4, p < 0.02); VUS (F(2,8) = 8.2, p < 0.01); AIA (F(2,8) = 8.5, p < 0.01))”

The pretreatment with haloperidol resulted in smaller reductions of psilocybin effects, except for a larger effect on ego dissolution (AIA).

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

The dopamine hypothesis of schizophrenia suggests that a dysbalance of dopamine and serotonin is critical for the pathophysiology and treatment of schizophrenia. However, increasing evidence suggests that the serotonin system may also be involved.

Psilocybin, an indoleamine hallucinogen, is similar in some respects to the first manifestation of schizophrenic decompensation. It causes ego- and thought disorders, affective changes, loosened associations, and perceptual alterations.

Psilocybin and LSD share similarities in chemical structure and psychological effects with serotonin and phenalkylamine hallucinogens, such as 2,5-dimethoxy-4-iodoamphetamine. Both bind to 5-HT2 receptors and have similar neurochemical actions in animals. Although data from animal studies suggest a contribution of the 5-HT2 receptor system in hallucinogenic drug action, it remains unclear whether psilocybin and LSD mediate their psychological effects in humans via 5-HT2 receptor stimulation alone or subsequent activation of the dopamine systems, or both.