Neuroscience-informed Treatment Development for Adolescent Alcohol Use Disorders

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PROJECT SUMMARY/ABSTRACT Relevance: Adolescent alcohol use is problematic and has long-term negative cognitive and social consequences. Decreasing substance use at this early stage could have significant long-term benefits to psychosocial outcomes and deter progression to habitual use; however, efforts to prevent or decrease alcohol use during adolescence have only been modestly effective, and pharmacotherapy research focused on adolescent alcohol use has been sparse. Evaluation of alternative and more efficacious treatments for adolescent alcohol users is warranted. Description: N-acetylcysteine (NAC) is an over-the-counter antioxidant supplement with glutamatergic properties that has shown promise in treating marijuana dependence in adolescents. Preclinical findings suggest NAC works through restoring glutamate homeostasis disrupted by addiction, a finding replicated across multiple substances of abuse. No published clinical trials to date have examined the efficacy of NAC on alcohol use. This is surprising, given previous promising NAC findings in marijuana-dependent adolescents and the safety, tolerability, and affordability of this over-the-counter supplement. This K23 application proposes to examine the effects of NAC on alcohol cue reactivity, adolescent glutamatergic systems, and drinking behaviors in a randomized, double-blind, placebo-controlled within-subjects crossover study. In counterbalanced order, 40 participants will receive a 10-day course of NAC 1200 mg twice daily and a subsequent 10-day course of matched placebo twice daily, separated by washout period. Human laboratory and imaging procedures will be conducted at baseline and after each course of medication treatment to clarify NAC's effect on glutamatergic systems and alcohol cue reactivity. Functional magnetic resonance imaging (fMRI) will examine alcohol reactivity and magnetic resonance spectroscopy will examine glutamate levels in the anterior cingulate after NAC versus placebo over the same interval. Aims: This proposal provides optimal training for the applicant to gain expertise in substance use disorder clinical trials research, evidence based treatments for adolescent substance users, and magnetic resonance spectroscopy methods and analysis needed to conduct independent, patient-oriented, developmental research on neural mechanisms associated with adolescent substance use and treatment. Findings from this study will help establish if NAC could be a promising treatment for adolescent substance users, an area of research that is consistent with trans-NIH initiative to identify and generate novel substance use treatments for adolescents (see PA-15-036 and PA-15-256).