A Randomized Controlled Trial of N-Acetylcysteine for Alcohol Use Disorder and Comorbid PTSD

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ABSTRACT Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are chronic and debilitating psychiatric conditions which frequently co-occur. If left untreated, individuals with AUD and co-occurring PTSD are at increased risk for developing other mental health problems (e.g., depression, anxiety), suicidal ideation and attempts, medical problems, family/relationship impairment, and employment problems. Despite the frequent co-occurrence and deleterious consequences associated with comorbid AUD/PTSD, there is little scientific evidence available to guide the provision of care. The proposed study directly addresses this critical knowledge gap by testing the efficacy of N-acetylcysteine (NAC) as compared to placebo in reducing AUD and PTSD severity. NAC represents a promising and novel candidate pharmacotherapy for individuals with AUD and comorbid PTSD. Accumulating preclinical and preliminary clinical research suggests a role for NAC in the treatment of substance use disorders and PTSD via glutamate modulation. Data from a randomized, double-blind pilot study recently completed by the investigative team in Veterans with substance use disorders (primarily alcohol) and PTSD provides encouraging support for the therapeutic potential of NAC in the treatment of AUD and PTSD. Moreover, NAC is an inexpensive, over-the-counter agent with a favorable tolerability profile, all of which confer ease of transferability from the research setting to clinical practice. In this Stage II study, we will (1) employ a two-arm randomized, double-blind, between-groups experimental design that will consist of 12 weeks of treatment with NAC or placebo medication; (2) use standardized, repeated dependent measures to rigorously assess AUD severity and PTSD symptomatology at 6 time points (baseline, week 6, week 12, and 3-, 6-, and 12-month follow-up); (3) measure impairment in associated mental and behavioral health problems (e.g., depression, sleep, suicidality, risky sexual behaviors, family/social functioning); and (4) use functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (MRS) to investigate the underlying pathophysiology of comorbid AUD/PTSD and prognostic indicators of treatment outcome. To achieve these aims, we have assembled a multidisciplinary team of investigators with nationally-recognized expertise in AUD and comorbid PTSD, clinical trials, human laboratory paradigms, and neuroimaging who have successfully collaborated in the past and are uniquely qualified to implement this type of investigation. The proposed project is directly responsive to the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the new AUD/PTSD initiative to accelerate research on the development of effective pharmacologic treatments for this common and highly disabling comorbidity. The findings from this study will provide critically needed empirical evidence to help inform clinical practice guidelines and accelerate research on the treatment of AUD and comorbid PTSD.