The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine.

Ketamine and psilocybin both provide rapid relief from major depressive disorder by enhancing synaptic plasticity in mood-regulating circuits, but through distinct initial mechanisms: ketamine blocks NMDA receptors while psilocybin primarily activates 5-HT2A receptors. A shared downstream pathway involves BDNF-TrkB signaling, which promotes spinogenesis and synaptogenesis critical for sustained antidepressant effects. The review also discusses 5-HT2A receptor biased agonism as a potential strategy to separate therapeutic benefits from hallucinogenic effects. Understanding how serotonergic, glutamatergic, and neurotrophic systems converge may guide development of fast-acting, durable, and non-hallucinogenic antidepressants.

Study at a glance

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.