Sex differences in the vulnerability to substance use, development of substance use disorders, and treatment outcomes, along with the biological response to drugs are evident from both preclinical and clinical studies116–118. Our findings suggest sex-specific alterations in the transcriptional response to opioids across striatal cell types. Based on the transcriptional patterns, we found a more pronounced inflammatory response associated with striatal microglia in females compared to males with OUD, suggesting microglia in the human brain also exhibit sex-specific responses to stress and substances119,120. In addition, we identified the upregulation of FKBP5 as a potential female-specific factor in several glial subtypes in OUD. FKBP5 acts as a co-chaperone of the glucocorticoid receptor activated in response to stress, with major implications in the pathology of several psychiatric disorders and the impact of stress on substance withdrawal, craving, and relapse121,122. Further, the transcriptional alterations within microglia, oligodendrocytes, and astrocytes in female individuals with OUD were significantly enriched for FKBP5 target genes identified in rodents administered opioids. Genes related to synaptic functions were also enriched in astrocytes of females, while enrichment was mostly in
