In a mouse model of chronic unpredictable mild stress, two doses of psilocybin (1 mg/kg, given 7 days apart) reversed stress-induced anhedonia and behavioral despair, but not apathy-related behavior. Psilocybin also produced an anxiolytic-like effect. However, it did not reverse stress-induced physiological signs of a hyperactive HPA axis or restore decreased brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Psilocybin increased expression and function of serotonin-2A receptors in the cortex of both control and stressed mice, and selectively increased glucocorticoid receptor expression in the cortex of stressed mice. These findings suggest psilocybin can rescue certain depressive and anxiety-like behaviors without normalizing all stress-related physiological or neuroplasticity impairments.
The intensity of acute psychedelic effects from psilocybin is inversely related to cortical serotonin levels. In mice, the head-twitch response—a behavioral measure of psychedelic-like effects—was lower in animals lacking the serotonin 2A receptor and was dose-dependently reduced by the antidepressant citalopram, which increases synaptic serotonin. Conversely, depleting serotonin with p-chlorophenylalanine potentiated the response. A serotonin 1A receptor agonist also decreased the response, indicating functional interaction between receptor types. These findings suggest that prior antidepressant treatment may influence individual variability in acute responses to psilocybin, with implications for optimizing psychedelic-based therapies.