As a result of sustained operations in Afghanistan and Iraq, there are an increasing number of U.S. military Veterans with substance use disorders and comorbid posttraumatic stress disorder (PTSD). If left untreated, individuals with substance use disorders and PTSD are at increased risk for developing other mental health problems (e.g., depression, anxiety), suicidal ideation and attempts, medical problems, reduced resiliency and military readiness, vocational problems, and family/social impairment. This study will determine the benefits of N-acetylcysteine (NAC) in treating alcohol use disorder and comorbid post-traumatic stress disorder (PTSD) among military Veterans.

As a result of sustained operations in Afghanistan and Iraq, there are an increasing number of U.S. military Veterans with substance use disorders and comorbid posttraumatic stress disorder (PTSD). While mental health services are in place for U.S. service members, substantial gaps in the treatment of co-occurring substance use disorders and PTSD exist and there is little scientific evidence available to guide the provision of care. Treatment for comorbid substance use disorders and PTSD, especially pharmacologic treatment, is largely ineffective and short-lived. While there have been numerous studies focused largely on dopaminergic mechanisms of reward, they have not led to the development of adequate treatments for comorbid substance use disorders and PTSD. Animal models demonstrate that (a) acute stress and chronic use of addictive substances reduce the capacity of glia to remove the neurotransmitter glutamate, and (b) this impairment as well as relapse can be prevented or reversed by N-acetylcysteine (NAC). Further, human studies indicate that NAC is associated with reduced craving and substance use. Based on this, the investigators conducted a Proof of Principle (PoP) study which was the first to examine the use of NAC for the treatment of PTSD, with or without comorbid addiction. In this randomized, controlled double-blind pilot study the investigators showed that Veterans with substance use disorders (81.5% alcohol use disorder) and PTSD who were treated with 2400mg NAC for 8 weeks demonstrated significant reduction in PTSD severity and craving. Moreover, reductions in PTSD and substance-related symptomatology were sustained at 1-month follow-up. However, to extend and confirm its clinical utility in the military/Veteran context, it is important to know whether NAC reduces severity of alcohol use disorder (AUD), the most common addiction among Veterans and military service members, and the mechanisms underlying therapeutic response. Based on promising data from the PoP project, the proposed Extend-and-Confirm (EC) study will determine the efficacy of NAC in reducing AUD and comorbid PTSD in Veterans (N=90). Further, new aims include the application of functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1H-MRS) to investigate the pathophysiology of AUD/PTSD, as well as prognostic indicators of treatment outcome. These aims extend the Future Plans proposed in the original PoP study and provide an opportunity for collaboration among clinical and preclinical investigators at the Ralph H. Johnson Veterans Affairs (VA) Medical Center and the Medical University of South Carolina (MUSC) to solve this critical health problem in the military context. In the proposed EC study, the investigators will (1) employ a randomized, double-blind, between-groups experimental design that will consist of 8 weeks of treatment with NAC (2400mg) or placebo medication, and follow-up assessment at 1-, 3-, and 6-months post treatment; (2) use standardized, repeated dependent measures to rigorously assess AUD severity and PTSD symptomatology during treatment and follow-up; (3) collect biologic measures of alcohol use; (4) measure impairment in associated areas of functioning (e.g., depression, sleep, suicidality, risky sexual behaviors, family/social functioning); and (5) employ advanced neuroimaging techniques before and after treatment among a subset of enrolled subjects. This proposal is directly responsive to the missions of the Institute for Translational Neuroscience (ITN), and the US Army/Department of Defense (DoD) in that it seeks to accelerate the development of new, medication-based treatments to mitigate the impact of AUD and comorbid psychological conditions, such as PTSD, in the military/Veteran context. The findings of this study will provide critically needed empirical evidence to help inform practice guidelines and better serve the needs of U.S. service members, Veterans and their families.

Inclusion Criteria:

• Male or female, any race or ethnicity, age 18 to 75 years old.
• U.S. military Veteran, including National Guard and Reservists.
• Able to comprehend English.
• Meet Diagnostic and Statistical Manual (DSM-5) criteria for current alcohol use disorder (AUD) and/or substance use disorder (SUD).
• Meet DSM-5 criteria for current PTSD or subthreshold PTSD. Subjects may also meet criteria for a mood disorder (except bipolar affective disorder, see Exclusion Criteria) or other anxiety disorders (e.g., panic disorder, agoraphobia, social phobia, generalized anxiety disorder). The inclusion of subjects with affective and other anxiety disorders is essential because of the marked frequency of the co-existence of mood and other anxiety disorders among patients with PTSD (Brady et al., 2000; Kessler et al., 2005).
• Subjects taking psychotropic medications will be required to be maintained on a stable dose for at least four weeks before treatment initiation. This is because initiation or change of medications during the course of the trial may interfere with interpretation of results.
• Must consent to random assignment to N-acetylcysteine (NAC) or placebo.
• Must consent to complete all treatment and follow-up visits.

Exclusion Criteria:

• Subjects meeting DSM-5 criteria for a history of or current psychotic or bipolar affective disorders, as the study protocol may be therapeutically insufficient.
• Subjects with a current eating disorder (bulimia, anorexia nervosa) or with dissociative identity disorder, as they are likely to require specific time-intensive psychotherapy.
• Subjects experiencing significant withdrawal symptoms, as evidence by a score of 10 or above on the Clinical Institute Withdrawal Assessment of Alcohol (CIWA).These subjects will be referred for clinical detoxification and may be re-assessed for study eligibility after medically supervised detoxification has been completed.
• Individuals considered an immediate suicide risk based on the Columbia Suicide Severity Rating Scale (C-SSRS) or who are likely to require hospitalization during the course of the study.
• Women who are pregnant, nursing or not practicing an effective form of birth control.
• Asthma or any clinically significant medical condition that in the opinion of the investigators would adversely affect safety or study participation.
• Use of carbamazepine, phenytoin, nitrous oxide, methotrexate, 6 azauridine triacetate, or nitroglycerin within the last 14 days or any other medication felt to have a hazardous interaction if taken with NAC.
• History of childhood or adult seizures of any cause.
• MRI exclusions: Claustrophobia; tattoos above the shoulders; permanent eyeliner or permanent artificial eyebrows; cardiac pacemaker; metal fragments in eye, skin, or body, including shrapnel; heart valve replacement; brain clips; venous umbrella; being a sheet-metal worker or welder; lifetime history of aneurysm surgery; intracranial bypass, renal, or aortic clips; prosthetic devices such as middle ear, eye, joint, or penile implants; joint replacements; non-removable hearing aid, neurostimulator, or insulin pump; shunts/stents; metal mesh/coil implants; metal plate/pin/screws/wires; or any other metal implants. Note that individuals who meet inclusion/exclusion criteria for the medication component of the study but not the MRI portion (e.g., excluded due to metal implants) will still be eligible to enroll in and complete the medication/treatment phase.
• Subjects on maintenance anxiolytic, antidepressant, or mood stabilizing medications which have been initiated during the past four weeks. If it is determined, based on clinical criteria, that a subject needs to be started on maintenance medications for anxiety, mood or psychotic symptoms during the course of the study, they will be discontinued from the treatment trial.

Approximately 8-9 months.