The proposed study has the broad goal of elucidating the mechanisms underlying the therapeutic action of amphetamine in Attention Deficit- Hyperactivity Disorder (ADHD). The form of amphetamine that is currently used to treat ADHD (d-amphetamine or Dexedrine) has both central and peripheral action. A form of amphetamine that has only peripheral direct action (4-OH amphetamine) has been shown to affect learning in animals. We plan to investigate whether experimental laboratory measures or clinical symptoms are affected by 4-OH amphetamine through a peripheral mechanism that subsequently modulates CNS activity. Several hypotheses that have theoretical and clinical significance will be tested. First, a subset of ADHD symptoms is predicted to respond to 4-OH amphetamine. Second, this peripherally acting stimulant is hypothesized to show fewer or milder side effects that stimulants with central action. Third, dose-response curves for the different stimulants are expected to show the phenomenon of """"""""cognitive toxicity"""""""" (deterioration of improvement in effortful learning) .
The specific aims of the study are (a) to compare the safety and side effects of 4-OH amphetamine to those of the form of amphetamine in clinical use (d-amphetamine), and (b) to compare dose-response curves for d-, and 4-OHG amphetamine on paired-associate learning, effortful memory scanning, disruptive social behavior, response to behavioral contingencies, motor activity, and side effects in children with ADHD who have been diagnosed as having ADHD.
The first aim will be achieved by a medically supervised open trial of single administrations of three doses (.15, .3, and .5 mg/kg) of 4-OH and d-amphetamine.
The second aim will be achieved using a within-subjects crossover experimental design in which each child will be assessed after receiving each of four doses (0, .15, .3, and .5 mg/kg) of d, dl, and 4-OH amphetamine for one-week durations. Data from this 3 x 4 (drug x dose) factorial design will be evaluated using analysis of variance and trend analysis.
