An exploration of the relationships between the effects of psilocybin on behavior, 5-HT 2A receptor occupancy, and neuroplastic effects in mice
Journal of Psychopharmacology January 6, 2026 Connor J. Maltby, Adam K. Klein, Enya Paschen et al. 3 citations
Psilocybin produces rapid and sustained antidepressant effects in major depressive disorder, but the underlying neurobiological mechanisms are unclear. In mice, psilocybin caused dose-dependent occupancy of the 5-HT₂A receptor in the prefrontal cortex, with an inverted-U dose-response for head twitch behavior peaking between 44% and 62% receptor occupancy. A 1.5 mg/kg dose increased time spent in open areas of the elevated zero maze, indicating reduced anxiety, while 3 mg/kg reduced immobility in the forced swim test, suggesting antidepressant-like effects. Both doses shifted α-tubulin post-translational modifications toward more dynamic microtubules and selectively increased synaptic protein expression in the prefrontal cortex, but not the amygdala. These findings indicate that psilocybin's therapeutic effects may involve dose- and region-specific enhancement of neuronal plasticity, with distinct signatures for anxiolytic-like and antidepressant-like properties.