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Psilocybin mitigates chronic behavioral and neurobiological alterations in a rat model of recurrent intimate partner violence-related brain injury

Molecular Psychiatry volume 31, pages 1857–1870 (2026)Cite this article

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Abstract

Intimate partner violence (IPV) poses a significant medical concern, predominantly affecting females. IPV-related brain injuries (IPV-BI), such as mild traumatic brain injury (mTBI) and non-fatal strangulation (NFS), sustained during physical attacks are common and often repetitive. Chronic neurobehavioral sequalae from IPV-BI are associated with neuroinflammation and impaired neuroplasticity, and effective treatment options are scarce, particularly in the context of IPV. However, psilocybin, a 5-HT2A receptor agonist with therapeutic potential in psychiatric disorders that share overlapping pathophysiology as BI, is a promising candidate. This study evaluated psilocybin’s effects on behavior, cognition, and neurobiology in a novel rat model of recurrent IPV-BI. Female rats underwent daily mTBI (lateral impact) followed by NFS (90 s) for five days, followed by 16 weeks of recovery. Rats then received a single intraperitoneal injection of psilocybin (1 mg/kg) or saline, with behavioral testing 24 h later. To investigate whether psilocybin’s effects were 5-HT2A receptor dependent, additional rats received pre-treatment with selective 5-HT2A receptor antagonist M100907 (1.5 mg/kg) one hour before psilocybin administration. Psilocybin recovered mTBI+NFS-induced abnormalities in the elevated plus-maze, increased sucrose preference when administered without M100907, and improved reversal learning in the water maze and spatial memory in the Y-maze. In the dorsal hippocampus, mTBI+NFS rats treated with saline, but not those treated with psilocybin, exhibited an increased number of microglial cells in the molecular layer and fewer reelin-positive cells in the subgranular zone. These findings suggest psilocybin’s antidepressant, pro-cognitive, anti-inflammatory, and neuroplasticity-enhancing effects hold promise for improving chronic IPV-BI outcomes and highlight the critical role of 5-HT2A receptors in mediating psilocybin’s therapeutic benefits.

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Fig. 1: Experimental design and confirmation of injury.
Fig. 2: The effect of mTBI + NFS, M100907, and psilocybin on chronic behaviour.
Fig. 3: The effect of mTBI + NFS, M100907, and psilocybin on neurobiology.

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Data availability

Data will be made available upon request to the corresponding author.

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Acknowledgements

The authors thank the USONA Institute Investigational Drug Supply Program for providing the psilocybin used.

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Authors and Affiliations

  1. Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, VIC, Australia

    Josh Allen, Mujun Sun, Tamara L. Baker, Stuart J. McDonald & Sandy R. Shultz

  2. Centre for Trauma and Mental Health Research, Vancouver Island University, Nanaimo, B.C., Canada

    Josh Allen & Sandy R. Shultz

  3. Division of Medical Sciences, University of Victoria, Victoria, B.C., Canada

    Josh Allen, Brian R. Christie & Sandy R. Shultz

  4. Psychedelic-Assisted Therapy Post-Graduate Program, Health Sciences and Human Services, Vancouver Island University, Nanaimo, BC, Canada

    Shannon Dames & Pamela Kryskow

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Contributions

JA, SD, PK, BRC, SM, and SS conceptualised and designed the study. JA, MS, and TB conducted the experiments and collected the data. JA, BRC, SM, and SS analysed the data. JA and SS drafted the manuscript. All authors provided feedback and approved the final manscript.

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Correspondence to Sandy R. Shultz.

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Allen, J., Sun, M., Baker, T.L. et al. Psilocybin mitigates chronic behavioral and neurobiological alterations in a rat model of recurrent intimate partner violence-related brain injury. Mol Psychiatry 31, 1857–1870 (2026). https://doi.org/10.1038/s41380-025-03329-x

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