ABSTRACT/PROJECT SUMMARY Cannabis is the most commonly used addictive substance among U.S. adolescents after alcohol. Adolescence may be a unique developmental window during which cannabis exerts its most profound impact on cognition, due to ongoing maturation in brain regions critical to attention and executive functioning (AEF), cognitive capacities centrally involved in academic success and social functioning. Yet, highly contradictory findings exist on the degree to which cannabis-associated cognitive deficits persist even in the early days of abstinence, and whether individual-level factors, importantly Attention Deficit/Hyperactivity Disorder (ADHD), moderate these effects. Addressing this knowledge has a large potential for broad impact, including informing physician advice to adolescents and their parents, and local, statewide, and national policymaking. This 5-year mentored patient-oriented research career development award will test the hypotheses that (1) AEF improves slowly across 4 weeks of abstinence, but that (2) genetic risk for ADHD may blunt the rate of AEF change. We propose to recruit adolescents with and without regular cannabis use from Boston-area public high schools. Eligible cannabis users will be randomized to either a contingency management intervention which will incentivize 4 weeks of cannabis abstinence, or non-contingent monitoring with no abstinence requirement. All participants (including non-users) will complete cognitive assessments, toxicology testing, self-report questionnaires and semi-structured mood and substance use interviews at 7 time points during the 4 week study as well as 1 30-day follow-up visit. Abstinence will be indexed by decreasing levels of cannabis metabolites in urine. Analyses will examine the (1) differences in AEF after 4 weeks among abstinent cannabis users, non-abstinent users, and non-users; (2) longitudinal, within-subject change in AEF among abstinent cannabis users; and (3) association between ADHD polygenic risk and cannabis use, baseline AEF, and AEF recovery. Each scientific aim corresponds to specific training goals, mapping onto competency in 3 areas: (1) clinical trial design and implementation, (2) longitudinal analysis, and (3) psychiatric genetics, as well as training in the responsible conduct of research and career development. Training goals will be implemented with the expert guidance of Dr. A. Eden Evins (primary mentor), Dr. Jordan Smoller (co-mentor), and the advisory team consisting of Drs. David Schoenfeld, Alysa Doyle, and Robin Mermelstein. This study, coupled with completion of the training goals, will effectively propel me towards my long-term goal of an independent career as a translational clinical scientist aiming to understand the cognitive risk factors and mechanisms of adolescent cannabis use, and how these and other factors (e.g., genetics, environment, psychopathology) affect treatment engagement, response and functional outcomes. This will lay the foundation for several future high-impact studies focused on prevention and intervention of early problem substance use in youth.

PROJECT NARRATIVE Cannabis exposure during adolescence is associated with deficits in higher-order cognitive capacities; however, it is not known for how long these deficits persist after last use, and whether adolescents with greater genetic risk for Attention Deficit/Hyperactivity Disorder experience more lasting cognitive compromise. The current study will combine behavioral, cognitive, and genetic measures with a prospective design of change in attention and executive function during 30 days of cannabis abstinence. The resulting data may enable the definition of the course of cognitive recovery during the early days of cannabis abstinence, and the stratification of adolescents based on genetic profiles for ADHD for risk of poor cognitive outcomes secondary to cannabis exposure.