Psilocybin restores behavioral and neuroplastic deficits induced by chronic stress in rats
This is a preclinical rat study published in Progress in Neuro-Psychopharmacology & Biological Psychiatry in 2026.
The researchers used adult male Wistar-Han rats and induced a chronic-stress state using chronic unpredictable mild stress (CUMS) for three weeks. This model produces behavioural changes including anhedonia (reduced interest in normally rewarding stimuli), anxiety-like behaviour and depressive-like behaviour.
They then gave the stressed rats:
Psilocybin: 0.6 mg/kg subcutaneously
Two doses, seven days apart
They assessed several domains rather than simply looking at one behavioural test:
Key Findings
1. Psilocybin reversed stress-induced anhedonia
Three weeks of chronic stress significantly reduced the rats' preference for sucrose, indicating an anhedonia-like state.
Psilocybin significantly increased sucrose preference after both doses, suggesting reversal of this stress-induced reward deficit.
2. It produced antidepressant-like effects
Psilocybin improved performance in the forced swim test, which the authors interpret as an antidepressant-like effect.
Again, this should be described as "antidepressant-like", not "treated depression", because this was an animal behavioural model rather than human depression.
3. It reduced anxiety-like behaviour
Psilocybin also produced anxiolytic-like effects across several behavioural paradigms:
Light/dark box
Elevated plus maze
Open field
The authors therefore reported improvements across multiple measures of anxiety-like behaviour in the stressed animals.
4. Neurogenesis increased
The researchers found evidence that psilocybin increased/restored markers of hippocampal neurogenesis in the chronically stressed rats.
That is a particularly interesting mechanistic finding because chronic stress is associated with reduced hippocampal neurogenesis.
The researchers also found that psilocybin increased BDNF expression in the hippocampus and frontal cortex.
5. Psilocybin affected the stress-response system
Psilocybin suppressed the stress-induced elevation in corticosterone and the authors report that it modulated HPA-axis activity.
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.
Bysiek A, Szpręgiel I, Wojtas A, Maćkowiak M, Wawrzczak-Bargieła A, Leśkiewicz M, et al. Psilocybin restores behavioral and neuroplastic deficits induced by chronic stress in rats. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2026;147:111710. doi:10.1016/j.pnpbp.2026.111710. Read Paper
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