Long-term effects of stimulant medications on the brain: possible relevance to the treatment of attention deficit hyperactivity disorder

In spite of extensive data supporting the short-term efficacy and safety of stimulant medications in the treatment of children with attention deficit hyperactivity disorder (ADHD), only limited information is available on the long-term effects of these drugs. On one hand, it is unclear whether treatment of ADHD with amphetamine-like stimulant medications for extended periods of time during child development can carry negative consequences, as manifested by an increase in use of illicit drugs, higher incidence of mania, psychosis, or other manifestations of psychopathology. On the other hand, it is not known whether the beneficial effects of stimulants extend beyond acute symptomatic relief and affect important outcome variables, such as later psychopathology, educational achievement, antisocial behavior, and social or occupational status. Data from naturalistic follow-up of clinical samples are limited by lack of appropriate controls and self-selection biases that are difficult to determine and control. These studies have reached conflicting conclusions, although most of them found no lasting negative effects of chronic stimulant treatment. Studies in animals, mainly in rodents, indicate that repeated exposure to stimulants leads to behavioral sensitization to the psychomotor effects of these medications. Extrapolation of these data to therapeutic use in humans is difficult given interspecies differences and the relatively high doses and parenteral route of administration usually employed in animals. This report is based on the proceedings of a workshop organized by the National Institute of Mental Health in December 1999 to discuss possible research approaches to studying the long-term effects of stimulants in children with ADHD. Both clinical and basic neuroscience data are reviewed, and opportunities for future research are highlighted.