Sex-specific role of the 5-HT2A receptor in psilocybin-induced extinction of opioid reward.
Alaina M Jaster, Thomas M Hadlock, Belle Buzzi, Jessica L Maltman, Gabriella M Silva, Somdatta Saha, Eda Koseli, Abby M Pondelick, Nikita Thakur, Xin Zhang, Gaoshan Li, Sandra Ledesma-Corvi, Karah N Moore, Hannah R Peterson, Barbara Fujita, Alexia L Zylko, Melissa R Lewis, Justin L. Poklis, Matthew S Halquist, Jennifer T Wolstenholme, Dana E Selley, Peter J Hamilton, Chang Lu, M Imad Damaj, Javier González-Maeso
Nature Communications November 20, 2025 DOI: 10.1038/s41467-025-64887-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male and female mice |
| Interventions | Psilocybin Oxycodone |
| Topics | Addiction Neuroplasticity Psilocybin Serotonin |
| Keywords | Psychedelic Hallucinogen Opioid dependence Opioid addiction Drug dependence Substance abuse Addiction treatment Sex differences Gender differences Sex-specific effects Male vs female Biological sex Brain mechanisms Neurobiology Neuropharmacology Reward pathways Brain circuits Gene expression |
| Citations | 9 |
| Key findings | Psilocybin reduces oxycodone-conditioned behavior and withdrawal in male mice but not in females, an effect mediated by 5-HT2A receptors in frontal cortex pyramidal neurons projecting to the nucleus accumbens. |
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.