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Background: School-based programs are the most convenient interventions to tackle substance use among youth. "Unplugged" is a Social Influence universal school curriculum developed and tested in the "EU-Dap" project. In 2015, Nigeria implemented a large-scale project to promote healthy lifestyles in schools, families and communities. Within the project, the effectiveness of "Unplugged" was evaluated through a cluster randomized controlled trial.Methods: The program was adapted to the Nigerian context, assembling suggestions from monitoring forms and interviews, and performing fidelity checks on content and method. Thirty-two secondary schools were extracted from a list provided by the Federal Ministry of Education, and randomly allocated to intervention and control arms. A self-completed anonymous questionnaire was used for baseline and follow-up surveys. The analysis sample finally included 2685 pupils (mean age 14.2 years). Multilevel models were run to estimate program effects on prevalence of self-reported cigarettes, alcohol, and marijuana use. Mediation analysis was performed to identify possible mediators of program effect on alcohol use.Results: Unplugged significantly reduced the prevalence of recent alcohol use in intervention vs control pupils. The effect on prevalence of cigarette and marijuana use was not statistically significant. The program prevented progress and encouraged regress across stages of intensity of alcohol use. Negative beliefs, risk perceptions, and class climate mediated the effect of Unplugged on alcohol use.Conclusions: Unplugged was effective in preventing alcohol use improving beliefs, class climate and risk perceptions among Nigerian students. The implementation of the program at a larger scale in the country should be supported. [ABSTRACT FROM AUTHOR]