Pemoline was chosen as the study medication because of its similar efficacy but lower abuse liability than the Schedule II psychostimulants. This 12 week randomized, placebo-controlled trial, conducted between 1996 and 2000, was designed to evaluate the efficacy and tolerability of pemoline for attention-deficit/hyperactive disorder (ADHD) in out-of-treatment adolescents with comorbid conduct disorder (CD) and substance use disorders (SUD). Subjects were 13- to 19-year-olds (58 males, 11 females) recruited either from the community or from a pool of adolescents that had formerly been in substance treatment. The results showed that pemoline had greater efficacy than placebo for ADHD. There was also greater reduction in ADHD severity on the parent-rated scale in pemoline-treated study completers compared to placebo-treated completers. Substance use did not decline in either group, and there was no difference between groups in substance use or CD symptoms. Pemoline was well tolerated, demonstrating a good safety profile and no elevation in liver enzyme levels. There is a critical need for more clinical trials in youths with SUD to expand knowledge of the safety and efficacy of a broader range of medications for comorbidity. Future research should also evaluate the separate and combined effects of pharmacotherapies and psychosocial interventions in dually diagnosed adolescents to enhance progress in developing integrated treatment guidelines. 1 figure, 3 tables, 27 references