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There are several interrelated knowledge gaps in the literature on skills-building interventions for middle schoolers designed to prevent initiation of substance use, all of which concern the limited study of the adolescent pathways of those intervention effects on distal young adult outcomes. Among the most important yet understudied pathways of influence on long-term effects are positive youth relationship outcomes of middle-school interventions. Other influential pathways for long-term effects are reductions in adolescent substance misuse, particularly marijuana use, considering the long-term consequences of early marijuana initiation. To address these knowledge gaps, data from a randomized controlled trial were used to test a longitudinal, developmental model positing pathways of intervention effects on age 21 illicit drug use and positive relationship affect, via earlier effects on adolescent relationships and marijuana use. Sixth-graders and their families enrolled in 22 Iowa schools were randomly assigned to the Iowa Strengthening Families Program or a control group (N = 446). The average age of students at baseline was 11.3 years (10-13 year age range); 48% were male and 98% were Caucasian, reflective of the demographics in the participating rural Midwest communities. Measures included middle-school relationships (parents, peers, school), high school marijuana use, plus age 21 illicit drug use and relationship affect (parents, work, school), 10 years past intervention implementation. As expected, intervention effects on young adult variables were indirect, through effects on adolescent outcomes, with higher-risk participants showing greater intervention impact. The findings suggest preventive interventions with young adolescents have potential to demonstrate effects into young adulthood. [ABSTRACT FROM AUTHOR]