National Drug Abuse Treatment Clinical Trials Network National Drug Abuse Treatment Clinical Trials Network New Findings from a Randomized Controlled Trial Osmotic- Release Methylphenidate (OROS-MPH) for ADHD in Adolescents with Substance Use Disorders in Adolescents with Substance Use Disorders AACAP Annual Meeting New York City, October 26-31, 2010 New Findings from a Randomized Controlled Trial Osmotic- Release Methylphenidate (OROS-MPH) for ADHD in Adolescents with Substance Use Disorders in Adolescents with Substance Use Disorders AACAP Annual Meeting New York City, October 26-31, 2010 NATIONAL INSTITUTE ON DRUG ABUSE NID A A

Overview of Main Study Findings

Aims AIM 1: To evaluate the efficacy of OROS-MPH vs. placebo in adolescents with ADHD and SUD concurrent CBT AIM 1: To evaluate the efficacy of OROS-MPH vs. placebo in adolescents with ADHD and SUD concurrent CBT AIM 2: Impact of OROS- MPH + CBT vs placebo + CBT on substance treatment outcomes AIM 2: Impact of OROS- MPH + CBT vs placebo + CBT on substance treatment outcomes AIM 3: Safety, tolerability, abuse AIM 3: Safety, tolerability, abuse 3Background ADHD 3-5x more common in adolescents with SUD (30-50%) Associated with poorer treatment outcomes Little known about safety / efficacy in adolescents with ADHD and SUD

Study Design 16-week RCT 16-week RCT OROS-MPH+ CBT* vs placebo + CBT N=303 adolescents w/ ADHD, SUD Interventions Interventions – OROS-MPH 72mg daily dose – CBT: weekly, individual, manual-standardized outpatient substance tx across participating sites Sample Size, Power, Analytic Approach Intent-to-treat (ITT) Intent-to-treat (ITT) Power Power N=300; >.80 power OROS-MPH vs placebo on ADHD.80 power to detect mediated effect size = > 0.4 OROS-MPH vs placebo on substance outcomes 4

5 Study Flow Diagram 76% research visit attendance 68% CBT sessions attended (mean = 10.4) 79% research visit attendance 72% CBT sessions attended (mean=11.1) Medication compliance = 80% Tolerability: 96% achieved 72 mg daily dose; 86% sustained

Demographics Race 60% Caucasian 22% African American 18% other Ethnicity 15% Hispanic

Baseline Clinical Characteristics 7 Substance Diagnoses & Past 28 day use Abuse diagnoses0.9 (1.1)0.8 (1.0) Dependence diagnoses1.2 (0.9)1.1 (0.9) Abuse + Dependence dx2.1 (1.2)1.9 (1.3) Days of past 28 day drug use 14.0 (9.6)15.1 (9.4) ADHD OROS-MPH + CBT N=151 PLACEBO + CBT N=152 DSM IV ADHD symptom checklist score (adolescent) 38.2 (9.0)39.3 (8.7) Current/past methamphetamine ab/dep and current opiate dependence excluded

Significant Differences in Adverse Events By Treatment Group Adverse EffectOROS-MPH PlaceboP-value Statistical Significance Excoriation14/151 (9.3%) > 4/152 (2.6%)0.016 Abdominal Discomfort8/151 (5.3%) > 2/152 (1.3%)0.016 Nervousness12/151 (7.9%) > 3/152 (2.0%)0.018 Heart Rate Increased8/151 (5.3%) > 1/152 (0.7%)0.019 Heart rate = > 10019/149 (12.8%) > 8/148 (5.4%)0.028 Palpitations (males only)5/122 (4.1%) > 0/117 (0.9%)0.024 Statistical Trend Migraine Headaches4/151 (2.6% ) > 0/152 (0.0%)0.06 Anorexia6/151 (4.0%) > 1/152 (0.7%)0.067 Mood Altered4/151 (2.6%) > 0/152 (0.0%)0.06 Road Traffic Accidents4/151 (2.6%) > 0/152 (0.0%)0.06 Limb Injury 1/151 (0.7%) < 7/152 (4.6%) Systolic BP = > 14027/149 (18.1%) > 16/148 (14.5%)0.073 OROS-MPH + CBT > study related AEs/subject compared to placebo + CBT (2.4 v 1.6; p=0.022) SAEs OROS-MPH = 1 study related SAE/4 total Placebo = 3 study related SAEs/7 total

Clinician-Administered, Adolescent ADHD RS by Treatment Group 9 Clinically and statistically significant reduction in ADHD symptoms in both groups (OROS + CBT 46%; placebo + CBT 45%; p< ) No difference between groups Estimated decrease from baseline to study end for the OROS-MPH + CBT group was (95% CI, -17.1, -21.2; p < 0.001) and for the placebo + CBT group was (95% CI -19.1,- 23.2, p < Clinically and statistically significant reduction in ADHD symptoms in both treatment groups (50%)..but no difference between groups on the primary ADHD outcome measure

Past 28 Day Substance Use The trajectories of past 28 day drug use based on adolescent self-reports did not differ between treatment groups (Chi-square = 3.04, 3 df, p = ; Proc Glimmix ). Clinically and statistically significant reduction in past 28 day drug use in both groups, but no difference between groups Placebo= days; 33% p< OROS MPH= -6.1 days; 43%; p< NS Similar to reduction in days of drug use other evidence based substance treatments

Limitations Hawthorne Effect? Hawthorne Effect? Heavy reliance on adolescent self- reports Heavy reliance on adolescent self- reports Steps taken to address limitations Careful attention to adolescent psycho- education Careful attention to adolescent psycho- education ADHD symptoms Clinical severity ratings Inclusion criteria ADHD RS = > 22 adolescent (without parent) Inclusion criteria ADHD RS = > 22 adolescent (without parent) 11 STUDY LIMITATIONS RESULTS MUST BE INTERPRETED WITH CAUTION

12 Summary of Main Study Findings 1. OROS – MPH safe, well-tolerated 2. Treatment compliance, completion = > than reported for youths with less severe psychopatholgy and SUD 3. Substance outcomes as good or better than in youth with less severe psychopathology 4. Reduction in ADHD symptoms => than reported for psychostimulant treatment of ADHD in youth without SUD 5. Similar reduction of ADHD symptoms in placebo + CBT suggests contribution of CBT to both SUD and ADHD outcomes

Emerging Research Supports the Efficacy of CBT for ADHD Adults Safren et al, 2005, 2010: 56% treatment responders medication + CBT vs 13% treatment responders medication alone Safren et al, 2005, 2010: 56% treatment responders medication + CBT vs 13% treatment responders medication alone Solanto et al, 2010: Meta-cognitive therapy effective for adults with ADHD Amer J Psychiatry, March, 2010 Solanto et al, 2010: Meta-cognitive therapy effective for adults with ADHD Amer J Psychiatry, March, 2010

Interpretation of Results in the Context of Previous Research Results are inconsistent With most controlled trials of psychostimulant vs placebo (alone) for ADHD With most controlled trials of psychostimulant vs placebo (alone) for ADHD Results are consistent With 3 controlled psychostimulant trials in adults concurrently receiving weekly individual CBT for SUD (Levin et al 2006; 2007; Schubiner et al 2004) With 3 controlled psychostimulant trials in adults concurrently receiving weekly individual CBT for SUD (Levin et al 2006; 2007; Schubiner et al 2004) () 14

Interpretation of Results in the Context of Previous Research Results are inconsistent With most controlled trials of psychostimulant vs placebo (alone) for ADHD With most controlled trials of psychostimulant vs placebo (alone) for ADHD Results are consistent With 3 controlled psychostimulant trials in adults concurrently receiving weekly individual CBT for SUD (Levin et al 2006; 2007; Schubiner et al 2004) With 3 controlled psychostimulant trials in adults concurrently receiving weekly individual CBT for SUD (Levin et al 2006; 2007; Schubiner et al 2004) () 15 ? Medication compliance ? validity of adolescent self report ? contribution of CBT Whereas, 2 controlled trials in adolescents (pemoline) and adults (atomoxetine): Active medication > efficacy than placebo in the absence of concurrent behavioral treatment for SUD ( Riggs et al 2004; Wilens et al 2008) Psychostimulant treatment 20-50% continue to have functional impairment; no long term benefit (Molina et al 2009; Safren et al., 2005; Advokat, 2009)

16 NEW FINDINGS Secondary Outcomes Post-Hoc Analyses

ARCQ P<0.023P< P<0.02 P< Secondary ADHD Outcome Measures ARCQ

Clinician-Rated ADHD Treatment Responders (CGI-I) ITT Sample

Responders v Non responders 19 ADHD RESPONDERS (N=55) (CGI-I; regardless of medication group assignment) 2X > NEGATIVE UDS Responders (N=55) = 6.2 Non-responders (n=172) = 3.1 p< MORE DAYS OF ABSTINENCE Responders, median = 94 days Non-responders, median = 77 days p<0.001

Depression as Predictor of Outcomes? MDD > Non-MDD Baseline Baseline –days/28 day substance use baseline –> cannabis days of use/28 days baseline End of Treatment End of Treatment DEPRESSED subjects continue to use > days/28 throughout tx No Difference –nicotine severity –trajectories of change or magnitude of reduction in days of substance use –tx adherence/completio n 20 MDD is frequently comorbid with substance use disorders (SUD) and with ADHD and SUD. IMPACT OF MDD on substance treatment outcomes unknown MDD (N=38) vs Non- MDD (N=265 )

21 Trajectories of Change in Marijuana and Cigarette Smoking BACKGROUND Cigarette smoking is common in adolescents with ADHD and SUD However, little is known about the relationship between nicotine and cannabis use trajectories in the context of treatment for both ADHD and SUD Kevin M. Gray, M.D. 1, Paula D. Riggs, M.D. 2, Sung-Joon Min, Ph.D. 2, Susan K. Mikulich, Ph.D. 2, Dipankar Bandyopadhyay, Ph.D. 1, Theresa Winhusen, Ph.D. 3

Adolescents with SUD have Higher rates of smoking; more negative health consequences and greater risk for progression to more serious nicotine dependence compared to adolescent smokers without other SUD (Meyers and Prochaska, 2008) Higher rates of smoking; more negative health consequences and greater risk for progression to more serious nicotine dependence compared to adolescent smokers without other SUD (Meyers and Prochaska, 2008) As many as 80% of report current tobacco use; many daily smokers; 50-60% nicotine dependent. As many as 80% of report current tobacco use; many daily smokers; 50-60% nicotine dependent. S moking cessation interventions during SUD treatment was associated with higher rates of abstinence from alcohol and other drugs 12-months following SUD treatment (meta-analysis Prochaska et al., 2004). S moking cessation interventions during SUD treatment was associated with higher rates of abstinence from alcohol and other drugs 12-months following SUD treatment (meta-analysis Prochaska et al., 2004). Advances in Research Support Treatment for Smoking Cessation/Nicotine Dependence During SUD Treatment

Priming The use of one substance may act as a cue to prime the use of the second substance (e.g. smoking/drinking) The use of one substance may act as a cue to prime the use of the second substance (e.g. smoking/drinking) Priming may be an even more important factor in adolescents Priming may be an even more important factor in adolescents - MJ/cigarettes - common route administration –Marijuana is the most commonly used illicit drug used in adolescents and 5.9 times more likely to be current, heavier smokers/>nicotine dependent compared to marijuana non-users ( Agrawal and Lynskey 2009; Okoli et al 2008). –Despite the strong relationship between marijuana and cigarette smoking, little is known about the relationship between changes in cigarette smoking in adolescents attempting to reduce their marijuana use and vice versa. Treatment for MJ without smoking cessation may inadvertently contribute to more severe nicotine dependence Adolescents may have more difficulty achieving abstinence from marijuana if they continue to smoke cigarettes due to priming effects (cue-reactivity)

24 Trajectories of Change in Marijuana and Cigarette Smoking METHODS Participants completed nicotine and cannabis use self-report at baseline and throughout treatment. Analyses were performed to explore the relationships between nicotine use, cannabis use, and other factors, such as medication treatment assignment Regular cannabis and cigarette smokers defined as using > 14 days baseline Substance tx responders => 50% decline in days of non- tobacco substance use

Trajectories of Change in Marijuana and Cigarette Smoking Trajectories of Change in Marijuana and Cigarette Smoking Baseline Baseline cigarette smoking was positively correlated with cannabis use Baseline cigarette smoking was positively correlated with cannabis use p < 0.05 Results SUD treatment responders reduced cigarette use SUD treatment responders reduced cigarette use from 6.7 to 4.7 days/week p = from 10.8 to 6.2 cigarettes per day p = Conclusions Significant reduction in cannabis use during substance treatment associated with modest reduction, not increased, cigarette smoking