Attention deficit hyperactivity disorder (ADHD) is one of the most common co-occurring psychiatric disorders (30-50%) in adolescents with substance use disorders (SUD). Yet, little is known about the safety and efficacy of medications for ADHD in adolescents with SUD, since such youths have been excluded from most medication trials. Clinicians are therefore understandably reluctant to treat ADHD in substance abusing adolescents, often first referring such youths to substance treatment. Untreated ADHD is associated with poorer substance treatment outcomes. We address this research gap by proposing a randomized controlled trial of bupropion vs placebo in 130 adolescents (13-19 years) with Diagnostic and Statistical Manual (DSM IV) ADHD, nicotine dependence and cannabis use disorder (not excluding other SUD). Participants in both bupropion and placebo treatment groups will receive weekly individual manualized-standardized cognitive behavioral therapy (CBT) targeting SUD (at no cost to them) throughout the 16 weeks of the medication trial. Bupropion also is effective in treating nicotine dependence in adults; the majority of adolescents with marijuana and other drug abuse also smoke tobacco. More recent research in adults indicates that bupropion may reduce craving and use of other substances of abuse (e.g. methamphetamine, cocaine). It's possible impact on cannabis use disorder (the addiction for which most teens are referred to treatment) has not yet been evaluated. However since all drugs of abuse have a final common pathway leading to addiction via action in the so called brain reward system (ventral tegmental area (VTA), accumbens) -an important secondary aim is to evaluate bupropion's potential impact on craving and use of marijuana (MJ) in addition to its known similar action on nicotine.

Research has shown that bupropion is a safe and effective treatment for both ADHD and nicotine dependence in individuals without SUD, and newer research provides empirical support for its unique pharmacotherapeutic properties and potential for treating other addictive disorders (e.g., methamphetamine dependence, pathological gambling). No controlled studies have yet evaluated bupropion's safety and efficacy for ADHD and SUD (including nicotine and cannabis) in adolescents. The lack of research on the safety and efficacy of medications in adolescents with SUD and psychiatric comorbidities contributes to a serious lack of integrated treatment for commonly co-occurring mental health and substance problems in community-based adolescent drug treatment programs. This then contributes to poorer treatment outcomes and prognosis for the large number of comorbid youths with substance abuse and mental health problems that significantly impact public health. The specific aims of the proposed study will address this research gap by conducting a 16-week randomized controlled trial of bupropion vs. placebo to evaluate the safety and efficacy of this low abuse potential medication on ADHD, nicotine dependence, and cannabis use disorders (not excluding other SUD) in 130 adolescents (13-19) receiving concurrent outpatient substance treatment (CBT). The study design and analytic approach will enable assessment of the complex inter-relationship between change in ADHD, depression/dysphoria (and other psychiatric symptoms) and change in nicotine, cannabis and other substance use within and between treatment groups. Thus, the study addresses important research gaps in at least two priority areas of the National Institute on Drug Abuse/ National Institutes of Health(NIDA/NIH) research agenda: 1) research on effective treatments for adolescents with addiction and psychiatric comorbidity, and 2) medications development research for nicotine and cannabis use disorders in adolescents.

Inclusion Criteria:

• Between the ages of 13 and 19, with a parent or legal guardian available to complete parental assessments for minors;
• Meet DSM-IV diagnostic criteria for ADHD on the K-SADS-PL;
• Schedule for Affective Disorders and Schizophrenia score ≥ 22 on the DSM-IV ADHD symptom checklist;
• Meet DSM-IV criteria for nicotine dependence (and/or cut off score of >3 on modified Fagerstrom);
• Meet DSM-IV criteria for cannabis abuse or dependence on the Kiddie-Sads-Present and Lifetime (K-SADS-PL);
• Have used marijuana at least 5 of the past 30 days;
• Have used nicotine at least 15 days out of the past 30 days;
• Be medically healthy;
• If female, subjects must use an effective birth control method if sexually active.

Exclusion Criteria:

• Current or past psychosis;
• Bipolar I or II disorder;
• A first-degree relative with bipolar I disorder;
• A lifetime history of seizure disorder;
• Any other chronic or serious medical illnesses;
• A lifetime history of eating disorder;
• Current pregnancy;
• Previous clinically significant adverse reaction to bupropion;
• The need to take other psychotropic medications at the time of study entry. Patients may have had previous psychotherapy or pharmacotherapy for ADHD or other co-morbidity but cannot have been on psychotropic medication for at least one month prior to study entry;
• Active participation in substance abuse treatment or mental health treatment (including outpatient, day-treatment, residential, or inpatient) within 28 days prior to signing consent;
• Non-English speaking (due to the difficulty in translating the additional materials given to the subjects);
• Cognitively impaired or of low intelligence;
• Breastfeeding;
• Current use of other psychotropic medications including nicotine replacement therapy;
• Current opiate dependence.

Actual study enrollment N=105 was less than targeted enrollment N=130. Thus, negative results should be interpreted with caution because the study was likely underpowered.