PROJECT SUMMARY/ABSTRACT Alcohol use is prevalent and problematic among youth, who are more likely than adults to initiate alcohol use, develop alcohol use disorder (AUD), and suffer lasting adverse alcohol-related consequences. Despite the clear need for youth-targeted AUD treatments, established psychosocial and behavioral interventions offer limited efficacy, with very few youth achieving sustained alcohol abstinence or reduction. Pharmacotherapies play a key role in bolstering substance use disorder treatment outcomes in adults, but to date, no medications for AUD in youth have merited FDA approval. The development of safe and effective adjunctive medications to treat adolescent AUD is needed to improve treatment outcomes and to potentially reduce the long-term consequences of adolescent use. Cannabidiol (CBD), one of the main phytocannabinoids in the Cannabis sativa plant, is a potentially promising candidate pharmacotherapy for youth AUD. It is particularly appealing as a youth treatment option since it is non-intoxicating, appears generally well-tolerated, and demonstrates no signal of abuse liability. CBD has many potential targets within the central nervous system that may mitigate the symptoms of AUD via modulation of the glutamatergic, GABAergic, dopaminergic, opioidergic, and endocannabinoid pathways. Preclinical work has shown that CBD affects an array of drinking behaviors (e.g., reduces ethanol seeking and intake; mitigates symptoms of withdrawal, relapse, anxiety, and impulsivity), and recent clinical work has indicated CBD's potential to reduce alcohol intake within adults who endorse alcohol and cannabis co-use. Establishing the acute neurometabolic, neurobehavioral, and psychophysiological effects of CBD in youth with AUD will be a critical first step in the pharmacotherapy development pipeline before initiating larger scale trials. The goal of this application is to test CBD as a potentially effective candidate medication for youth AUD by leveraging developmentally informed neuroimaging methods (magnetic resonance spectroscopy and functional MRI) and lab-based alcohol cue reactivity procedures. To accomplish this goal, this study will use a randomized, double-blind, within-subjects crossover design. In counterbalanced order, 35 youth (ages 14-24) who meet criteria for AUD will receive 600 mg of CBD or placebo with a standardized meal (to modulate CBD absorption rates) three hours before a neuroimaging and behavioral assessment paradigm, separated by a 13-day washout period. This proposal is consistent with the trans-NIH initiative to identify neurally-informed novel substance use treatments for youth. Findings will bridge a critical translational gap (“the valley of death”) in pharmacotherapy development for youth AUD, advancing methodology for rigorous neural-behavioral early efficacy testing of CBD. Effects established through this study could pave the way to a larger-scale clinical trial and, ultimately, improved long-term...