Sex-specific neural activation to stress and alcohol cues in high-risk drinkers: links between orbitofrontal...

High-risk drinking is known to disrupt stress and reward pathways including orbitofrontal cortex (OFC) circuits, which may increase cue-induced craving and alcohol use disorder (AUD) risk. Although high-risk drinking is more prevalent in men, it is increasing rapidly among women. It remains unclear whether sex differences in reactivity to stress and alcohol cues contribute to these trends. One hundred eighteen adults (56 high-risk drinkers, 62 low-risk drinkers; 52.5% female) completed an fMRI cue provocation task involving alcohol, stress, and neutral cues in a randomized block design with repeated craving assessments. Linear mixed-effects models tested Group (high-risk, low-risk)-by-Sex-by-Condition (Alcohol, Stress, Neutral) effects on craving and brain activation. High-risk drinkers of both sexes reported greater alcohol cue-induced craving (p < 0.001); however, only high-risk women reported increased craving during stress cues (p = 0.020). Whole-brain voxel-based analyses (p < 0.001, cluster corrected at α < 0.05) revealed alcohol cue-related hyperactivation in OFC circuits in high-risk women, but blunted activation in high-risk men. OFC activation correlated positively with craving in women, but negatively in men. During stress cues, high-risk women exhibited increased OFC and hippocampal activation, whereas high-risk men showed heightened amygdala and reduced striatal activity. Decreased stress-related salience network and striatal activity in women but increased activity in men was associated with prospective drinking frequency. These results demonstrate that risky-drinking men and women showed distinct subjective craving and OFC circuit responses to alcohol and stress cues. These sex-specific OFC circuit-related neural patterns may reflect differential risk pathways for AUD and underscore the need for sex-informed prevention and intervention strategies.