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, Wiktor Bilecki, Krystyna Gołembiowska
Progress in neuro-psychopharmacology & biological psychiatry June 20, 2026 Peer reviewed DOI: 10.1016/j.pnpbp.2026.111710 via PubMed
Summary
Psilocybin, administered in two doses to stressed rats, reversed anhedonia and produced antidepressant-like effects. It increased hippocampal neurogenesis by raising the number of BrdU-positive, DCX-positive, and Ki-67-positive cells. Additionally, psilocybin appeared to normalize stress-induced reductions in brain-derived neurotrophic factor (BDNF) levels and hypothalamic-pituitary-adrenal (HPA) axis activity. These results highlight the potential of psilocybin to promote neuroplasticity linked to its therapeutic effects.
Study at a glance
| Population | stressed rats |
|---|---|
| Key finding | Psilocybin reversed anhedonia and produced antidepressant-like effects while inducing hippocampal neurogenesis in stressed rats. |
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.