Do the therapeutic effects of psilocybin involve actions in the gut?

Psilocybin, a psychedelic compound being tested as a treatment for mental health conditions, strongly activates serotonin receptors found not only in the brain but also in the gastrointestinal tract. Despite evidence that gut-brain signaling is disrupted in conditions where psilocybin is used, no research has examined whether its effects on the gut contribute to mental health improvements. This opinion piece argues that psilocybin's peripheral actions in the gut may play a role in its rapid and lasting therapeutic effects, and that understanding all sites of action could guide more targeted drug development.

Study at a glance

Abstract

The psychedelic compound psilocybin has recently emerged as a therapeutic intervention for various mental health conditions. Psilocybin is a potent agonist of serotonin (5-HT) receptors (5-HTRs), which are expressed in the brain and throughout peripheral tissues, with particularly high expression in the gastrointestinal (GI) tract. However, no studies have investigated the possibility that peripheral actions of psilocybin may contribute to improvements in mental health outcomes. This is despite strong evidence for disturbed gut-brain signalling in conditions in which psilocybin is being tested clinically. In this Opinion, we highlight the likely actions of psychedelics in the gut and provide initial support for the premise that peripheral actions may be involved in rapid and long-term therapeutic effects. A greater understanding of all sites and modes of action will guide more targeted approaches to drug development.