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 via PubMed
Summary
AI-generated from the abstractA single dose of the psychedelic psilocybin reduces conditioned behavior and withdrawal caused by the opioid oxycodone in male mice but not in females. This sex-specific effect is mediated by the 5-HT2A receptor in frontal cortex pyramidal neurons that project to the nucleus accumbens. Psilocybin also alters epigenomic regulation after repeated oxycodone exposure and induces sex-specific structural plasticity in the nucleus accumbens independently of the 5-HT2A receptor. Female frontal cortex and nucleus accumbens show fewer changes at gene enhancer regions in response to psilocybin, repeated oxycodone, or their combination compared to males, with the frontal cortex displaying more pronounced sex differences at the epigenomic level.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male and female mice |
| Interventions | Psilocybin Oxycodone |
| Topics | Addiction Neuroplasticity Psilocybin |
| Keywords | Psychedelic Hallucinogen Opioid dependence Opioid addiction |
| Citations | 9 |
| Key finding | 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.