BACKGROUND: Using substances before the age of 15 is a key antecedent of substance use treatment later in life. Since the turn of the 21st century, adolescents' lives have changed considerably, presenting new risk and protective factors. Identifying factors and contexts associated with use of specific substances among contemporary adolescents is therefore a key public health priority.

METHODS: We investigated vaping, smoking, alcohol consumption, and illicit drug use, in 30,920 adolescents aged 12-15 attending 100 schools and living across 1539 neighbourhoods in the south of England. Cross-classified multi-level models were used to evaluate the relative importance of school and neighbourhood contexts, before investigating putative determinants of substance use.

RESULTS: A school-only context yielded the best model fit and explained the most variance across substances (ICC range 5.8% to 8.5%). Several patterns pertaining to inequalities in substance use emerged (e.g., age positively associated with greater odds of any substance use, particularly illicit drugs), although the magnitude and direction of associations varied by substance and subgroup. Findings allude to coping-related motives (e.g., concomitant internalising symptoms) as potential risk factors for vaping, smoking, and alcohol consumption. Strong parental and teacher relationships and school-based factors (e.g., happiness with attainment) were protective against all substances.

CONCLUSION: Differences between schools matter more than differences between neighbourhoods for adolescent substance use. Our results reveal both substance-general and substance-specific putative determinants, highlighting the need for tailored approaches that target shared and unique drivers of use. Such strategies should also account for sociodemographic differences.