Sex-Moderated and Sex-Specific Effects of Adverse Childhood Experiences on Neural Alcohol Cue Reactivity and Daily Craving in Individuals With Alcohol Use Disorder.
OBJECTIVE Adverse childhood experiences (ACEs) play a pivotal role in alcohol use disorder (AUD), and evidence suggests that this role differs by sex. Neural alcohol cue reactivity may represent one pathway linking ACEs to alcohol craving and use. The authors examined whether cue reactivity is differentially associated with the relationship between ACEs and alcohol-related outcomes in males and females with AUD. METHODS Functional MRI data were analyzed from 231 non-treatment-seeking individuals (40.7% female; mean age=39.1 years, SD=13.5) with mainly mild to moderate AUD (mean number of DSM-5 criteria, 3.92, SD=1.6) from a 12-month prospective multicenter study. ACEs were assessed via Childhood Trauma Screener score. Participants completed a functional MRI alcohol cue reactivity task, followed by ecological momentary assessment of daily craving and consumption. Linear regression, general linear models, and sex-moderated mediation examined associations among ACEs, brain activation, and alcohol outcomes. Sensitivity analyses controlled for age, AUD severity, baseline consumption, tobacco use, Brief Symptom Inventory score, and progesterone-to-estradiol ratio. RESULTS Higher Childhood Trauma Screener scores were associated with significantly greater left superior frontal gyrus/anterior cingulate cortex (SFG/ACC) activation during alcohol-related cues than during neutral cues in females compared with males. This activation significantly predicted prospective daily craving only in females. Sex-moderated mediation showed opposing indirect effects of ACEs on craving via SFG/ACC activation (ab=path a × path b; females: ab=0.008, 95% CI=0.001, 0.022; males: ab=-0.013, 95% CI=-0.034, -0.002). Sensitivity analyses supported robust SFG/ACC activation and directional consistency after adjustment for covariates. CONCLUSIONS Sex-specific prefrontal cue reactivity patterns suggest differential neural pathways linking ACEs to craving vulnerability in early AUD, particularly in females. The findings support sex-sensitive, trauma-informed intervention strategies.