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Cannabis is the most commonly abused illicit drug and accounts for the greatest number of adolescent substance abuse treatment admissions. Despite urgent need for effective interventions, the best available psychosocial treatment options yield only modest effects. Topiramate showed promise as an adjunctive pharmacotherapy to a psychosocial intervention for cannabis misuse among adolescents and young adults in a recent clinical trial, but it was not well tolerated. This study investigated associations between clinical characteristics and side effects and dropout among adolescents and young adults randomized to topiramate.This study involved secondary data analysis of a randomized placebo-controlled trial of topiramate for treating cannabis misuse (ages, 15–24 years; 50% female). We explored the interaction effects of baseline characteristics and medication condition (topiramate vs placebo) on treatment dropout. We also explored the relationship between side effects and dropout.Higher cannabis problems were significantly associated with reduced hazard of dropout in the topiramate group (P = 0.048) and were nonsignificantly associated with increased hazard of dropout in the placebo group (P = 0.062). Results also showed that memory difficulties were an overwhelming predictor of dropout in the topiramate condition; 42% of participants who dropped out experienced memory difficulties, whereas none of those who remained in the study experienced these effects.By identifying who may most benefit from and tolerate this medication, treatment for substance use disorders can become more individualized and positive outcomes may be enhanced.