BACKGROUND: Early life stress (ELS) increases the risk of substance use disorder (SUD) in adulthood. The pathway from ELS to SUD is hypothesized to be influenced by sex. We examine the impact of ELS on adolescent first substance use, a common precursor to adult SUDs, and test for sex differences in the relationship between ELS and risk of first use of alcohol, nicotine, and marijuana. METHODS: Individuals from the Adolescent Brain Cognitive Development study (ABCD
N = 8608 US children aged 9-10 at baseline) were assessed for multiple measures of ELS (Environmental, Family, Trauma), covariates (race/ethnicity, age in months at baseline, pubertal development score), and first substance use. Cox proportional hazards regression was performed for total population and stratified by sex, generating adjusted hazard ratios (aHRs) of first substance use. RESULTS: One unit increase in ELS Total scores significantly increased aHRs of first use of all substances. Dimensional ELS analysis revealed associations with risk that differed across sex, type of ELS, and substance. Females with higher ELS Environmental scores display a significant increase in risk of first use across all substances, while males with higher ELS Trauma scores showed a significant increase in risk of first nicotine and marijuana use. CONCLUSIONS: Findings highlight sex differences in the association of ELS Environmental and Trauma scores with the risk of first substance use, while illustrating the consistency of the association of ELS Family scores with risk. Existing family-based prevention and intervention strategies should consider addressing sex differences in adolescent substance use risk and protection.