Sex-specific role of the 5-HT2A receptor in psilocybin-induced extinction of opioid reward.
Nature communications – November 20, 2025
Source: PubMed
Summary
A single dose of psilocybin effectively reduces opioid-seeking behavior and withdrawal symptoms in male mice, but surprisingly, not in females. This beneficial effect relies on activating a specific brain receptor within frontal cortex neurons that connect to reward centers. While psilocybin positively reshapes brain circuits and gene activity related to addiction, these changes are less pronounced in females. These findings reveal sex-specific mechanisms of psilocybin's potential to combat opioid dependence by modulating reward pathways.
Abstract
Emerging evidence suggests that classical psychedelics may offer therapeutic potential for opioid use disorder (OUD) by alleviating key hallmarks such as altered reward processing and dependence. However, the mechanisms behind these effects remain unclear. Our data demonstrate that a single administration of the psychedelic psilocybin (PSI) reduces conditioned behavior and withdrawal induced by the opioid oxycodone (OXY) in male mice but not in females, and this effect is mediated via the 5-HT2A receptor (5-HT2AR). We show that the sex-specific attenuation of OXY preference is driven by 5-HT2AR activation in frontal cortex pyramidal neurons projecting to the nucleus accumbens (NAc). Additionally, PSI modulates epigenomic regulation following repeated OXY exposure and induces sex-specific NAc dendritic structural plasticity independently of 5-HT2AR. Notably, female frontal cortex and NAc show fewer changes at gene enhancer regions in response to PSI, repeated OXY, or combined PSI-OXY treatment compared to males, with the frontal cortex exhibiting more pronounced sex differences than the NAc at the epigenomic level. Together, these results provide new insights into the neural and epigenetic mechanisms of psychedelic-induced plasticity in OUD, while also highlighting sex differences in PSI's modulation of reward pathways and its therapeutic potential.