N-acetylcysteine for the treatment of comorbid alcohol use disorder and posttraumatic stress disorder: Design and methodology of a randomized clinical trial.

Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are two prevalent psychiatric conditions in the U.S. The co-occurrence of AUD and PTSD is also common, and associated with a more severe clinical presentation and worse treatment outcomes across the biopsychosocial spectrum (e.g., social and vocational functioning, physical health) as compared to either disorder alone. Despite the high co-occurrence and negative outcomes, research on effective medications for AUD/PTSD is sparse and there is little empirical evidence to guide treatment decisions. The study described in this paper addresses this knowledge gap by testing the efficacy of N -acetylcysteine (NAC) in reducing alcohol use and PTSD symptoms. Animal studies and prior clinical research suggest a role for NAC in the treatment of substance use disorders and PTSD via glutamate modulation. NAC is a cysteine pro-drug that stimulates the cystine-glutamate exchanger, normalizes glial glutamate transporters, and restores glutamatergic tone on presynaptic receptors in reward regions of the brain. Moreover, NAC is available over-the-counter, has a long-established safety record, and does not require titration to achieve the target dose. This paper describes the rationale, study design, and methodology of a 12-week, randomized, double-blind, placebo-controlled trial of NAC (2400 mg/day) among adults with co-occurring AUD and PTSD. Functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1H-MRS) are utilized to investigate the neural circuitry and neurochemistry underlying comorbid AUD/PTSD and identify predictors of treatment outcome. This study is designed to determine the efficacy of NAC in the treatment of co-occurring AUD/PTSD and provide new information regarding mechanisms of action implicated in co-occurring AUD/PTSD. • Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur. • Medications that normalize glutamatergic dysregulation, such as NAC, are potential pharmacotherapies for AUD/PTSD treatment. • This paper describes the rationale, study design and methods of a randomized controlled trial of NAC for AUD/PTSD treatment. • FMRI and 1H-MRS are utilized to elucidate behavioral and neurobiological mechanisms underlying comorbid AUD/PTSD. [ABSTRACT FROM AUTHOR]