Psychedelic drugs are being investigated as a new class of rapid-acting antidepressants, but their mechanisms remain unclear—specifically whether antidepressant and psychedelic effects arise from related or independent processes. This review examines behavioral methods used in animal studies to measure both the psychedelic and antidepressant effects of these drugs. It highlights conceptual and methodological challenges, stresses the importance of using doses comparable to those in human clinical use, and calls for attention to potential sex differences in preclinical research. Understanding these mechanisms could help identify new drug targets and improve treatments.
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.