Clinical and preclinical evidence of psilocybin as antidepressant. A narrative review

Psilocybin, along with its active metabolite psilocin, shows promise as a treatment for neuropsychiatric disorders. Clinical trials report that psilocybin produces a large, rapid, and lasting improvement in symptoms of depression and anxiety, with a favorable safety profile of low toxicity and good tolerance. Preclinical studies in naïve animals and animal models of disease have yielded somewhat discrepant results in standard tests for depression- and anxiety-like behavior, but overall suggest positive outcomes. This review provides an overview of clinical trials of psilocybin-assisted psychotherapy and surveys up-to-date preclinical research, including rodent models used to study the neurobiological and behavioral actions of psilocybin and its primary molecular target, the serotonin 2A receptor.

Study at a glance

Abstract

In the rapidly growing field of psychedelic research, psilocybin (and active metabolite psilocin) has been proposed as a promising candidate in the search for novel treatments for neuropsychiatric disorders. Clinical trials have revealed that psilocybin has a large, rapid, and persistent effect in the improvement of symptoms of depression and anxiety. The safety profile is considered favourable, with low toxicity and good tolerance. Several preclinical studies have also been carried out to determine the long-term mechanism of action of this drug. In this sense, preclinical studies in naïve animals as well as in animal models of disease have shown somewhat discrepant results in conventional tests for assessment of depression- and anxiety-like phenotype in response to psilocybin, but overall suggest positive outcomes. Additionally, several valuable assays in rodent models have been developed over the years to elucidate the neurochemical correlates of serotonin 2A receptor (5HT2AR) activation in the brain, primary molecular target of psilocin. This review aims to provide a general overview of the current and most recent literature in the therapeutic potential of psilocybin through a description of clinical trials of psilocybin-assisted psychotherapy, and to showcase the scene in the up-to-date preclinical research. A detailed description of preclinical rodent models and experimental approaches that have been used to study the neurobiological and behavioural actions of psilocybin is provided, and potential therapeutic mechanisms of action are discussed.