The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine.
Molecular psychiatry – July 07, 2025
Source: PubMed
Summary
Remarkably, rapid-acting compounds can relieve severe depressive disorder symptoms in mere hours. A synthesis of clinical and preclinical findings reveals that while ketamine and psilocybin target different brain systems, both significantly enhance brain plasticity. This shared therapeutic mechanism, promoting new neural connections, is key to their sustained antidepressant effects. Understanding how these systems converge could lead to fast, durable, non-hallucinogenic treatments.
Abstract
Major depressive disorder is a debilitating condition, with many patients unresponsive to conventional monoaminergic antidepressants. Rapid-acting antidepressants such as ketamine and psilocybin offer promising alternatives, relieving symptoms within hours. Ketamine, an NMDA receptor antagonist, and psilocybin, a serotonergic psychedelic primarily targeting 5-HT2A receptors, both enhance synaptic plasticity in mood-regulating circuits through distinct mechanisms. This review synthesizes recent clinical and preclinical findings on ketamine and psilocybin, emphasizing their molecular targets, circuit-level effects, and converging downstream pathways. A key shared mechanism involves BDNF-TrkB signaling, which promotes spinogenesis and synaptogenesis critical for sustained antidepressant efficacy. We also discuss 5-HT2A receptor biased agonism as a potential strategy to dissociate psilocybin's therapeutic effects from its hallucinogenic actions. By comparing their mechanistic profiles, we identify both overlapping and distinct features that may inform the development of next-generation rapid-acting antidepressants. Understanding how serotonergic, glutamatergic, and neurotrophic systems converge may guide the development of fast-acting, durable, and non-hallucinogenic antidepressants.