Childhood Maltreatment and Risk for Illicit Substance Use: Evidence for Mid-Adolescence as a Sensitive Exposure Period.

Background: Childhood maltreatment is a well-established risk factor for substance misuse. However, it remains unclear whether risk for specific illicit substances is driven primarily by the cumulative burden of adverse experiences or by exposures during specific sensitive developmental periods. Methods: We administered the Maltreatment and Abuse Chronology of Exposure (MACE) scale to 2,013 medically healthy young adults (693M/1320F, ages 18-25) to assess severity of exposure to ten maltreatment types across each year of childhood. Lifetime non-medical use of opioids, stimulants, cocaine, sedatives, hallucinogens, and polysubstance involvement was determined using the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). We employed an integrative analytical approach, combining machine learning (random forests) with modern causal inference (Targeted Maximum Likelihood Estimation) and survival modeling. Findings: Although maltreatment multiplicity (number of types) was associated with substance use in initial models, it was not a significant predictor in analyses that included specific type-time exposures. Machine learning and causal inference instead identified peer emotional abuse at age 15 in males and childhood sexual abuse at age 15 in females as potent risk factors for multiple outcomes, including opioid, stimulant, and polysubstance use. These specific exposures increased absolute risk by 20-35% (Risk Ratios: 2- to 4-fold), with associations robust to unmeasured confounding (E-values: 4-10). The apparent population-level dose-response relationship for multiplicity is therefore likely explained by the higher concentration of these critical type-time exposures among individuals with high maltreatment multiplicity. Interpretation: Our findings challenge the cumulative burden model, providing robust evidence for mid-adolescence as a sensitive period during which specific maltreatment exposures, peer victimization in males and sexual abuse in females, causally shape trajectories of illicit substance misuse. Prevention strategies targeting these adversities and clinical screening during this developmental window may be crucial for reducing the population burden of substance use disorders. Funding: National Institute on Drug Abuse USA (RO1 DA-017846), National Institute of Mental Health USA (RO1 MH-091391), the ANS Foundation, the Trauma Research Foundation, and Bessel van der Kolk.