Probing the antidepressant potential of psilocybin: integrating insight from human research and animal models towards an understanding of neural circuit mechanisms.

Psilocybin, a serotonergic psychedelic, shows promise as a rapid and lasting antidepressant in human clinical research, but its acute mechanisms leading to enduring cognitive and behavioral changes remain poorly understood. Human neuroimaging reveals both immediate and sustained changes in functional connectivity within key cortical brain networks. Preclinical evidence emphasizes psilocybin-induced neuroplasticity and alterations in the prefrontal cortex (PFC). This review examines how acute modulation of PFC circuits may drive long-term structural and functional changes underlying antidepressant effects, highlighting the need for preclinical circuit and behavioral approaches to clarify how psilocybin affects cognitive and affective neural circuits and support its development as a depression treatment.

Study at a glance

Abstract

Interest in the therapeutic potential of serotonergic psychedelic compounds including psilocybin has surged in recent years. While human clinical research suggests psilocybin holds promise as a rapid and long-lasting antidepressant, little is known about how its acute mechanisms of action mediate enduring alterations in cognition and behavior. Human neuroimaging studies point to both acute and sustained modulation of functional connectivity in key cortically dependent brain networks. Emerging evidence in preclinical models highlights the importance of psilocybin-induced neuroplasticity and alterations in the prefrontal cortex (PFC). Overviewing research in both humans and preclinical models suggests avenues to increase crosstalk between fields. We review how acute modulation of PFC circuits may contribute to long-term structural and functional alterations to mediate antidepressant effects. We highlight the potential for preclinical circuit and behavioral neuroscience approaches to provide basic mechanistic insight into how psilocybin modulates cognitive and affective neural circuits to support further development of psilocybin as a promising new treatment for depression.