Molecular psychiatryJul 7, 2025

Psilocybin's possible medical uses beyond psychedelic effects through shared actions with ketamine

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 1, 2026

Abstract

Rapid-acting antidepressants like ketamine and psilocybin may relieve symptoms of major depressive disorder within hours.

Ketamine and psilocybin act through different mechanisms but both enhance synaptic plasticity in mood-regulating circuits.
A shared mechanism between the two substances involves BDNF-TrkB signaling, which is important for creating and strengthening synapses.
Psilocybin's therapeutic effects may be separated from its hallucinogenic properties through biased agonism at 5-HT receptors.
Comparing the mechanisms of ketamine and psilocybin reveals both overlapping and unique characteristics that could aid in developing new antidepressants.
Understanding the interaction between serotonergic, glutamatergic, and neurotrophic systems may help create fast-acting antidepressants that are durable and non-hallucinogenic.

Simplified

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-HTreceptors, 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-HTreceptor 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. 2A2A

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Psilocybin's possible medical uses beyond psychedelic effects through shared actions with ketamine

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