Chronic psilocybin (1 mg/kg, daily for 5 weeks) boosted sociability and reduced startle response in male wild-type mice, but not in an OCD-model strain. It also slowed gut transit and shifted the microbiome, reducing Lactobacillus and Alistipes species, suggesting links between serotonin signaling, gut function, and social behavior. Importantly, these changes were sex- and genotype-specific, highlighting that psilocybin’s gut–brain effects may depend strongly on baseline biology.