BackgroundSubstance use disorders are associated with severe negative social and health-related outcomes. Evidence has accumulated that chronic substance use is associated with alterations in social interaction behavior, which likely contributes to the vicious cycle of substance use disorder. However, little is known about whether these social problems originate from contextual factors only or also from the substance use itself—in other words, if they are predisposed or substance induced. MethodsWe studied the causation behind behavioral alterations of substance users over a 9-year period (ages 11–20) in an urban age cohort (n = 1002) with a high prevalence of substance use at age 20. We identified common substance use patterns using toxicological hair analysis, examined behavioral alterations with incentivized games, and used teacher assessments across different ages to determine the causes and effects that underlie substance use–related impairments in social interaction. ResultsWe found that opioid and stimulant users showed reduced prosocial behavior compared with nonusers, particularly in interpersonal trust and perspective taking (e.g., they were approximately 50% less likely to trust others). Our longitudinal analyses suggest a causal relationship between the nonmedical use of prescription opioids and impaired social behavior, whereas impairments among stimulant users seem to be partially predisposed. Moreover, women tend to be more severely affected by opioid use than men. However, no behavioral alterations were found among young adult cannabis or ecstasy users. ConclusionsHighly addictive substances such as opioids can impair users’ social behavior by undermining fundamental human interaction, thereby fueling a vicious cycle of substance use and social isolation.