Psilocybin restores behavioral and neuroplastic deficits induced by chronic stress in rats.

Agnieszka Bysiek, Izabela Szpręgiel, Adam Wojtas, Marzena Maćkowiak, Agnieszka Wawrzczak-Bargieła, Monika Leśkiewicz, Ewa Trojan, Katarzyna Kamińska, Weronika Kumorek, W Bilecki, Krystyna Gołembiowska

Prog Neuropsychopharmacol Biol Psychiatry

Jun 19, 2026

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Abstract

Psychedelics have emerged as a promising novel therapeutic approach for major depressive disorder (MDD). Altered activity and structural atrophy of the prefrontal cortex, hippocampus, and limbic structures are associated with depressive disorders. Psilocybin may reverse the loss of synaptic connections and restore the function of these brain regions. In this study, we investigated the effects of psilocybin on rat behavior, hippocampal neurogenesis, expression level of brain-derived neurotrophic factor (BDNF) and hypothalamic-pituitary-adrenal (HPA) axis activity. Psilocybin administered in two doses (0.6 mg/kg, s.c., 7 days apart) reversed anhedonia in stressed rats, produced antidepressant-like effects in the forced swim test (FST), and exerted anxiolytic activity in the light/dark box (LDB), elevated plus maze (EPM), and open field (OF) tests in stressed animals. Psilocybin induced hippocampal neurogenesis as evidenced by increasing the number of BrdU-positive cells (an exogenous marker of cell proliferation and survival), DCX-positive cells (a marker of immature neurons), and Ki-67-positive cells (an endogenous marker of cell proliferation) in stressed animals. Stress-induced reductions in BDNF expression levels appeared to be associated with normalization of HPA axis activity. These findings underscore the role of psilocybin-induced neuroplasticity in the antidepressant and anxiolytic mechanisms of psychedelics.