Psilocybin helped male mice unlearn oxycodone-associated reward faster, acting through 5-HT2A receptors on frontal-cortex pyramidal neurons. Males and females showed distinct gene-expression changes in the frontal cortex and nucleus accumbens, especially in learning, excitability, and opioid-signaling pathways. Structural plasticity also diverged: males showed reduced NAc spine density after psilocybin, while females showed increased spines and displayed place-preference under a modified protocol. Overall, the results point to psilocybin’s potential for reducing drug-seeking through sex-specific 5-HT2A-mediated mechanisms.