The sensitization hypothesis posits a neuroadaptation model in which exposure to stimulants results in dopamine system alterations that, in turn, increase sensitivity to the reinforcing effects of the previously experienced drug. This study examines whether stimulant treatment in childhood confers increased risk for substance use and abuse in later life, as the model predicts. Children, ages 7-12 years, with developmental reading disorders but no other psychiatric diagnoses were randomly assigned to methylphenidate treatment (n = 43) or matching placebo (n = 66) for 12-18 weeks. At 16-year follow-up (mean age 26 years), 94% of probands and 129 normal comparisons were evaluated by trained clinicians who were blind to group and treatment status. There were no significant differences between groups on the prevalence of substance use disorder (abuse or dependence) for any of the seven drug categories studied. There were no significant group differences among substance abusers regarding age at onset, duration, or number of episodes of substance abuse and dependence. Significantly more normals (60%) than treated (46%) and untreated probands (41%) ever used stimulants in adolescence or adulthood. Findings from this randomized trial contradict the notion that stimulant treatment in childhood leads to substance use or abuse in later life. The sensitization hypothesis is not supported.