Background: One in four adolescents worldwide experiences significant loneliness, and about half of U.S. adults experience loneliness with highest rates among young adults. This calls for research and intervention on root causes and downstream effects. This study assesses the effect of substance use and mental health distress in 12th grade on loneliness in young adulthood in rural reservation-based communities.

Methods: Data were drawn from a cluster-randomized substance use prevention trial following n=484 high school seniors (Spring 2024) into young adulthood (Fall 2024). To examine the effect of past 30-day alcohol use, binge drinking, cannabis use, vaping, prescription opioid misuse, and past 2-week anxiety and depressive symptoms on subsequent loneliness, we implemented independence estimating equations (IEEs) for the participant-average effects with an independence working correlation structure. Poisson regression was used. In all models, interaction between the trial’s study condition and exposure was not statistically significant and was re-estimated without the interaction term. Covariates included age, gender, race, food insecurity, normative estimates of peer substance use, and study condition.

Results: Mean age was 18 years, and 55% self-identified as female. Alcohol use (RR: 1.23, 95% CI [1.07, 1.42]), binge drinking (RR: 1.22, 95% CI [1.02, 1.46]), cannabis use (RR: 1.21, 95% CI [1.03, 1.43]), vaping cannabis (RR: 1.23, 95% CI [1.01, 1.50]), vaping nicotine (RR: 1.12, 95% CI [1.12, 1.38]), anxiety symptoms (RR: 1.03, 95% CI [1.02, 1.04]), and depressive symptoms (RR: 1.04, 95% CI 1.03, 1.05]) in 12th grade significantly predicted subsequent loneliness post high school.

Conclusions: Substance misuse and mental health distress predict loneliness into young adulthood among rural reservation-based communities. Interventions should target these risk factors before and during high school senior year to prevent downstream loneliness.