Inhibition of cortico-amygdala projections underlies affective bias modification by psilocybin
bioRxiv (Cold Spring Harbor Laboratory) March 4, 2026 Matthew D. B. Claydon, Justyna K. Hinchcliffe, Julia M. Bartlett et al.
Psilocybin, the active compound in magic mushrooms, produces rapid and lasting antidepressant effects in people with major depressive disorder, but the underlying brain mechanisms are not fully understood. In rats, psilocin (the active metabolite of psilocybin) alters negative affective biases—a key feature of depression—by acting on a specific circuit in the medial prefrontal cortex. It suppresses excitatory signals to cortico-amygdala projection neurons while enhancing excitatory transmission to other targets, effects dependent on 5HT1A and 5HT2A receptors. These changes persist for at least 24 hours and shift from suppressed excitation to enhanced inhibition in those same cells. Chemogenetically inhibiting these neurons reproduced psilocybin's effects on affective biases and reward memories, identifying this circuit as a key substrate for its antidepressant actions.