Emerging mechanisms of psilocybin-induced neuroplasticity

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. Introducing psilocybin: clinical relevance and signaling pathways underlying neuroplasticitySerotonergic psychedelics (see Glossary), particularly psilocybinthe compound found in 'magic mushrooms'are receiving increasing attention for their emerging therapeutic potential in the treatment of different neuropsychiatric disorders 1.Psilocybin currently leads clinical investigations among serotonergic psychedelics because of its favorable safety profile, good tolerability, and low risk of abuse.It is a prodrug that, once administered, is rapidly dephosphorylated by alkaline phosphatase into its active metabolite, psilocin 2 (Figure 1).Accordingly, throughout this review, we refer to psilocin when discussing mechanism of action and to psilocybin when referencing the administered prodrug.Psilocybin has shown fast-acting antidepressant effects, particularly in major depressive disorder (MDD) and treatment-resistant depression (TRD) 345678, earning the 'breakthrough therapy' designation by the FDA in 2019 and 2018 for these indications, respectively.Recent trials have also assessed its efficacy in treating alcohol use disorder (AUD) 9,10, obsessive-compulsive disorder (OCD) 11, Parkinson's disease 12,13, fibromyalgia 14, and anorexia nervosa 15, with preliminary findings suggesting broad clinical promise in traditionally difficult-to-manage conditions.The growing clinical relevance of psilocybin underscores the importance of elucidating psilocin mechanisms of action.A striking feature of psilocybin pharmacology is its ability to produce rapid and enduring improvements in mood, cognition, and adaptive behavior within 24 h of a single dose, with effects persisting for several weeks or months 4,6,7,10.This therapeutic profile contrasts markedly with conventional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), which require weeks to take effect and fail to produce meaningful benefits in a substantial proportion of patients 5,16.