Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor

Psilocybin and its metabolite psilocin produce psychedelic effects by activating the 5-HT2A receptor. While proposed as a treatment for depression and anxiety, psilocybin can also induce acute anxiety. In mice, psilocybin increased anxiety in behavioral tests. Blocking the 5-HT2A receptor reduced the head twitch response (a proxy for psychedelic effects) but did not prevent the anxiety-related behavior. Phosphopeptide analysis of the amygdala revealed signal transduction pathways both dependent and independent of the 5-HT2A receptor. Presynaptic proteins were specifically involved in psilocybin-induced acute anxiety. These findings suggest that anxiety and psychedelic effects involve separable mechanisms, informing clinical use.

Study at a glance

Abstract

Psilocybin, and its metabolite psilocin, induces psychedelic effects through activation of the 5-HT2A receptor. Psilocybin has been proposed as a treatment for depression and anxiety but sometimes induces anxiety in humans. An understanding of mechanisms underlying the anxiety response will help to better develop therapeutic prospects of psychedelics. In the current study, psilocybin induced an acute increase in anxiety in behavioral paradigms in mice. Importantly, pharmacological blocking of the 5-HT2A receptor attenuates psilocybin-induced head twitch response, a behavioral proxy for the psychedelic response, but does not rescue psilocybin's effect on anxiety-related behavior. Phosphopeptide analysis in the amygdala uncovered signal transduction pathways that are dependent or independent of the 5-HT2A receptor. Furthermore, presynaptic proteins are specifically involved in psilocybin-induced acute anxiety. These insights into how psilocybin may induce short-term anxiety are important for understanding how psilocybin may best be used in the clinical framework.