PROJECT SUMMARY/ABSTRACT Adolescence is a time of increased risk for alcohol use and depression. The co-occurrence of depression and alcohol use disorder (AUD) is one of the most prevalent and disabling psychiatric combinations in youth. The high prevalence makes this comorbidity a treatment norm and adolescents who struggle with this comorbidity exhibit poor treatment outcomes. As such, this population has considerable needs that are currently unmet by available treatments. One potential way to improve alcohol treatment for adolescents who have co-occurring depression is to augment the best available psychosocial interventions with pharmacotherapy designed to simultaneously treat both conditions. Currently there are four FDA approved medications for the treatment of AUD in adults. However, no medication is indicated for AUD in adolescents and controlled clinical trials with teenagers are noticeably absent for the literature. Improving treatment options for youth will require closing this important gap in medication development research. This two-year preparatory project (R21) will support the collection of pilot data for an integrative therapy that combines a promising novel medication, shown to reduce depressive symptoms, namely anhedonia, and alcohol craving in adults, with a gold standard psychosocial intervention for treating AUD among adolescents. Specifically, we will use rigorous protocol that embeds human lab and ecological momentary methods in the context of randomized placebo-controlled trial to examine if our candidate pharmacotherapy, acetyl-L-carnitine, enhances the effects of psychosocial treatment for AUD in adolescents with comorbid depression. Our specific aims are to: a) evaluate the feasibility, acceptability, and tolerability of acetyl-L-carnitine in adolescents with comorbid depression and AUD; b) test whether acetyl-L- carnitine decreases alcohol craving in the human laboratory and real-world setting and blunts the reinforcing effects of alcohol while drinking in daily life; c) test whether acetyl-L-carnitine reduces depressed mood, depression symptoms, and anhedonia; and d) test whether acetyl-L-carnitine decreases alcohol use in this population. Our aims address national priorities to gather safety and efficacy data on medications for treating AUD in youth. Findings from this exploratory study will contribute to personalized medicine for AUD by establishing evidence for targeting endophenotypes endemic to co-occurring depression and AUD. The proposed R21 will also provide critical pilot data for a future large-scale clinical trial of acetyl-L-carnitine in this population. This award is consistent with NIH's goal to address the nation's clinical research needs.