Effects of a single dose of psilocybin on behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig

A single dose of psilocybin given to awake female pigs caused behavioral changes—headshakes, scratching, and rubbing—lasting about 20 minutes. The dose produced a 67% occupancy of cerebral 5-HT2A receptors and plasma psilocin levels comparable to those in humans during an intense psychedelic experience. One day after injection, 19 genes in the prefrontal cortex were differentially expressed; after one week, only 3 genes were. Gene set enrichment analysis showed multiple immunological pathways were regulated one week after exposure. The authors suggest that any effects on gene expression are very modest, providing a framework for future research into the lasting molecular mechanisms of a single psilocybin dose.

Study at a glance

Abstract

Psilocybin has in some studies shown promise as treatment of major depressive disorder and psilocybin therapy was in 2019 twice designated as breakthrough therapy by the U.S. Food and Drug Administration (FDA). A very particular feature is that ingestion of just a single dose of psilocybin is associated with lasting changes in personality and mood. The underlying molecular mechanism behind its effect is, however, unknown. In a translational pig model, we here present the effects of a single dose of psilocybin on pig behaviour, receptor occupancy and gene expression in the brain. An acute i.v. injection of 0.08 mg/kg psilocybin to awake female pigs induced characteristic behavioural changes in terms of headshakes, scratching and rubbing, lasting around 20 min. A similar dose was associated with a cerebral 5-HT2A receptor occupancy of 67%, as determined by positron emission tomography, and plasma psilocin levels were comparable to what in humans is associated with an intense psychedelic experience. We found that 19 genes were differentially expressed in prefrontal cortex one day after psilocybin injection, and 3 genes after 1 week. Gene Set Enrichment Analysis demonstrated that multiple immunological pathways were regulated 1 week after psilocybin exposure. This provides a framework for future investigations of the lasting molecular mechanisms induced by a single dose of psilocybin. In the light of an ongoing debate as to whether psilocybin is a safe treatment for depression and other mental illnesses, it is reassuring that our data suggest that any effects on gene expression are very modest.