The resurgence of interest in psychedelics as psychiatric treatments highlights a need to understand potential sex differences in response. Human studies show efficacy across diagnoses and cognition, but sex-specific effects remain unclear. Animal studies often use one sex or fail to analyze sex differences, hindering translation. Estrogen interacts with the serotonin system, central to psychedelic action, by influencing serotonin synthesis, release, and receptor sensitivity. This interaction may alter psychedelic efficacy in females across menstrual cycles and developmental stages. Investigating estrogen-serotonin interactions could improve therapeutic outcomes, especially for conditions with sex-specific prevalence.
A single dose of psilocybin (1.5 mg/kg) in C57BL/6 J mice produces sex-specific effects on social behavior and dopamine signaling. In females, psilocybin acutely increased huddling and induced hypothermia, and post-acutely enhanced novelty-seeking and grooming, with no comparable effects in males. By 24 hours, males showed reduced grooming and rearing but increased sociability toward a cage-mate, accompanied by blunted novelty-evoked nucleus accumbens dopamine responses lasting up to 7 days. At 7 days, females shifted social preference toward familiarity, associated with prolonged dopamine release during familiar interactions, while males increased grooming. Both 5-HT1A and 5-HT2A receptors contributed to these sex-specific behavioral effects.