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Sex-specific role of the 5-HT2A receptor in psilocybin-induced extinction of opioid reward

Summary

Researchers discovered that a single dose of psilocybin can reduce opioid addiction-related behaviors in male mice by activating serotonin receptors in specific brain circuits, but this effect does not work the same way in females. The study reveals that psilocybin changes how the brain processes opioid rewards and withdrawal symptoms, suggesting psychedelics could become a new treatment approach for opioid addiction. However, important sex differences in how the brain responds mean treatments may need to be tailored differently for men and women.

Background

Opioid use disorder (OUD) affects millions of individuals with limited treatment options. Emerging evidence suggests classical psychedelics may offer therapeutic potential by alleviating altered reward processing and dependence, though the underlying mechanisms remain unclear.

Objective

To investigate the mechanisms by which psilocybin (PSI) reduces opioid-seeking behavior and withdrawal symptoms, with particular focus on the 5-HT2A receptor and sex-specific differences in neural circuits governing reward pathways.

Results

PSI reduced oxycodone-induced CPP and withdrawal symptoms in male mice via 5-HT2A receptor activation in frontal cortex pyramidal neurons projecting to the nucleus accumbens, effects absent in female mice. PSI modulated epigenomic regulation and induced sex-specific dendritic plasticity, with females showing fewer enhancer region changes than males.

Conclusion

A single psilocybin dose produces sex-specific therapeutic effects on opioid reward through 5-HT2A receptor signaling in frontal cortex-to-nucleus accumbens circuits, with epigenetic and synaptic plasticity contributing to therapeutic potential while highlighting important sex differences in treatment response.
  • Published in:Nature Communications,
  • Study Type:Preclinical Research Study,
  • Source: PMID: 41266307, DOI: 10.1038/s41467-025-64887-w
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