Primary Prevention of Drug Overdoses in Rural Low-Resource and Tribal Communities: A Cluster Randomized Trial.

To determine the Connect intervention's effectiveness in reducing substance use among rural and tribal adolescents in northeastern Oklahoma. We conducted a 2-arm cluster randomized trial from 2021 to 2024, with 10 high schools per condition. At baseline, 919 students were enrolled (mean age = 15 years), and the majority were American Indian or White. Alcohol-use days during the past 30 days was reduced by 18% per survey wave in the intervention compared with the control condition (rate ratio [RR] = 0.82; 95% confidence interval [CI] = 0.72, 0.93; t = -3.02;  = .003), binge drinking was reduced by 26% (RR = 0.74; 95% CI = 0.64, 0.86; t = -3.90;  < .001), cannabis use was reduced by 11% (RR = 0.89; 95% CI = 0.80, 1.00; t = -2.03;  = .04), and prescription opioid misuse was reduced by 40% (RR = 0.60; 95% CI = 0.43, 0.85; t = -2.86;  = .004). Model-predicted means revealed the control condition followed the expected developmental trajectory of increased substance use and the intervention condition showed a flat or decreasing use pattern. The Connect intervention prevented the typical escalation of substance use during adolescence. ClinicalTrials.gov NCT04839978. Registered on April 9, 2021. Version 10, April 30, 2025. (. 2025;115(9):1508-1517. https://doi.org/10.2105/AJPH.2025.308205).