ImportanceScreening and brief intervention (SBI) programs in schools have the potential to provide substance use prevention messages to large numbers of adolescents. This study evaluated the association between exposure to a school-based SBI program and reductions in substance use among youths after enactment of a law that required Massachusetts schools to provide SBI to all students.ObjectiveTo estimate the association between exposure to a school-based SBI program and changes in substance use among youths.Design, Setting, and ParticipantsIn this mixed-method quality improvement study using an effectiveness-implementation hybrid design, stakeholder interviews were conducted to describe the operations, timing, and impressions of SBI implementation at 14 intervention schools in Massachusetts. Repeated cross-sectional surveys of youths in intervention and comparison groups were administered between December 19, 2017, and May 22, 2019, to assess substance use and associated measures of perceived risk, knowledge, and adult support before and approximately 3 months after SBI implementation among exposed groups. A difference-in-differences framework was used to estimate substance use outcomes associated with SBI exposure among students in middle school (grades 7 and 8) and high school (grades 9 and 10) using adjusted overlap-weighted generalized models to account for covariate imbalance between exposed and unexposed school grades. In addition, 14 school staff members were interviewed about implementation.ExposuresExposure vs nonexposure to a school-based SBI program.Main Outcomes and MeasuresFrequency of alcohol, cannabis, and e-cigarette use (measured in days) and any binge drinking in the past 3 months.ResultsBetween December 2017 and May 2019, 8771 survey responses were collected from 4587 students in grades 7 through 10 who were attending one of 23 participating school districts. The median (IQR) age was 13 (13-14) years (range, 12-17 years); 2226 students self-identified as female (48.5%), 2206 (48.1%) as male, and 155 (3.4%) as transgender or preferred not to answer. Overall, 163 students (3.6%) identified their race as Asian, 146 (3.2%) as Black or African American, 2952 (64.4%) as White, and 910 (19.8%) as mixed or other race (including American Indian or Alaska Native and Native Hawaiian or Pacific Islander); 416 students (9.1%) preferred not to answer or were missing data on race. A total of 625 students (13.6%) identified their ethnicity as Hispanic and 3962 (86.4%) as non-Hispanic. Cannabis use increased over time in both the SBI group (middle school: marginal estimated probability, 0.73 [95% CI, 0.21-2.51] at baseline vs 2.01 [95% CI, 0.60-6.70] at follow-up; high school: marginal estimated probability, 2.86 [95% CI, 0.56-14.56] at baseline vs 3.10 [95% CI, 0.57-16.96] at follow-up) and the control group (middle school: marginal estimated probability, 0.24 [95% CI, 0.05-1.03] at baseline vs 3.38 [95% CI, 0.81-14.18] at follow-up; high school: marginal estimated probability, 1.30 [95% CI, 0.27-6.29] at baseline vs 1.72 [95% CI, 0.34-8.66] at follow-up). e-cigarette use also increased over time in both the SBI group (middle school: marginal estimated probability, 0.81 [95% CI, 0.22-3.01] at baseline vs 1.94 [95% CI, 0.53-7.02] at follow-up; high school: marginal estimated probability, 3.82 [95% CI, 0.72-20.42] at baseline vs 3.51 [95% CI, 0.55-22.59] at follow-up) and the control group (middle school: marginal estimated probability, 0.51 [95% CI, 0.12-2.30] at baseline vs 3.40 [95% CI, 0.72-16.08] at follow-up; high school: marginal estimated probability, 2.29 [95% CI, 0.41-12.65] at baseline vs 3.53 [95% CI, 0.62-20.16] at follow-up). Exposure to SBI was associated with a significantly smaller increase in the rate of cannabis use among middle school students (adjusted rate ratio [aRR], 0.19; 95% CI, 0.04-0.86) and significantly smaller increases in the rates of cannabis and e-cigarette use among all female students (cannabis use: aRR, 0.17 [95% CI, 0.03-0.96]; e-cigarette use: aRR, 0.16 [95% CI, 0.03-0.82]) compared with nonexposure. No other significant differences were observed among students in grades 7 and 8, and no differences were found in any comparison between groups in grades 9 and 10.Conclusions and RelevanceIn this quality improvement study, exposure to a school-based SBI program was associated with a significantly smaller increase in the rate of cannabis use among middle school students and significantly smaller increases in the rates of cannabis and e-cigarette use among all female students. These findings suggest that implementation of SBI programs in schools may help to reduce substance use among middle school and female students, and further study of these programs is warranted.