Emerging mechanisms of psilocybin-induced neuroplasticity

Psilocybin, a serotonergic psychedelic, shows rapid and lasting therapeutic effects for depression and other hard-to-treat neuropsychiatric conditions, likely due to its ability to enhance neuronal plasticity. While these effects are often attributed to activation of the serotonin 2A (5-HT2A) receptor, emerging evidence indicates a more complex pharmacological profile involving multiple serotonin receptor subtypes and non-serotonergic targets like TrkB. This review integrates current findings on the molecular interactome of psilocin, the active metabolite of psilocybin, focusing on receptor selectivity, biased agonism, and intracellular receptor localization. These insights provide a refined framework for understanding psilocybin's enduring effects and guiding the development of next-generation neuroplastogens with improved specificity and safety.

Study at a glance

Abstract

Psilocybin, a serotonergic psychedelic, is gaining attention for its rapid and sustained therapeutic effects in depression and other hard-to-treat neuropsychiatric conditions, potentially through its capacity to enhance neuronal plasticity. While its neuroplastic and therapeutic effects are commonly attributed to serotonin 2A (5-HT 2A ) receptor activation, emerging evidence reveals a more nuanced pharmacological profile involving multiple serotonin receptor subtypes and nonserotonergic targets such as TrkB. This review integrates current findings on the molecular interactome of psilocin (psilocybin active metabolite), emphasizing receptor selectivity, biased agonism, and intracellular receptor localization. Together, these insights offer a refined framework for understanding psilocybin's enduring effects and guiding the development of next-generation neuroplastogens with improved specificity and safety.