Clinical Trial for Alcohol Use Disorder and Post Traumatic Stress Disorder (PTSD)

The primary objective of the proposed Phase II study is to evaluate the effects of
N-acetylcysteine (NAC), in reducing (1) Alcohol Use Disorder (AUD) severity and (2) Post
Traumatic Stress Disorder (PTSD) symptomatology among individuals (N=200) with current AUD
and PTSD. We will also use functional magnetic resonance imaging (fMRI) and proton magnetic
resonance spectroscopy (MRS) to investigate the neural circuitry and neurochemistry
underlying comorbid AUD/PTSD and prognostic indicators of positive treatment response.
Secondary objectives are to evaluate the effects of NAC on impairment in associated areas of
functioning (e.g., depression, anxiety, sleep, risky behaviors). In order to accomplish this
we will (1) employ an intent-to-treat, double-blind, placebo-controlled randomized controlled
trial that will consist of 12 weeks of treatment with NAC (2400 mg per day) or placebo
medication; (2) examine standardized, repeated dependent measures of clinical outcomes at
baseline, week 6, week 12, and 3-, 6-, and 12-month follow-up; and (3) employ advanced
neuroimaging methodologies, a laboratory cue paradigm, and collect biologic measures of
alcohol consumption. All participants will also undergo weekly individual cognitive behavior
therapy sessions (CBT).The following specific aims are proposed:

Specific Aim 1: To determine the efficacy of N-acetylcysteine (NAC), as compared to placebo,
in reducing alcohol use severity (i.e., total standard drinks, percent days drinking,
abstinence rates) and craving.

Specific Aim 2: To determine the efficacy of N-acetylcysteine (NAC), as compared to placebo,
in reducing self-report and clinician-rated PTSD symptomatology.

Specific Aim 3: To use multimodal neuroimaging techniques to investigate the pathophysiology
underlying AUD and comorbid PTSD, and prognostic indicators of treatment outcome.

The proposed study will answer critical questions regarding the potential of NAC as an
effective pharmacotherapy for AUD and comorbid PTSD, and elucidate possible mechanisms
underlying improved outcomes. This study has the particular advantage of building directly on
positive preliminary findings by (1) further testing NAC in the treatment of individuals with
co-occurring AUD/PTSD using a double-blind, placebo-controlled randomized design; (2)
measuring functioning in related areas, such as depression and risky behaviors; (3) employing
innovative measurements including neuroimaging and laboratory cue paradigms; and (4)
employing a multidisciplinary team of experts who have successfully collaborated in the past
and are uniquely qualified to implement this type of investigation. This project is directly
responsive to the mission of the National Institute of Alcohol and Alcoholism (NIAAA) and the
new AUD/PTSD initiative in that it seeks to evaluate a promising therapeutic agent for the
treatment of AUD/PTSD and identify neurobiological mechanisms common to AUD/PTSD as potential
treatment targets. The findings from this study have the potential to significantly improve
the standard of patient care, advance the comorbidity science in this area, and decrease
public health expenditures associated with AUD and comorbid PTSD.

Inclusion Criteria:

1. Male or female; any race or ethnicity; age 18 to 70 years old.

2. Subjects must be able to comprehend English.

3. Meet DSM-5 criteria for current alcohol use disorder (AUD).

4. 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 (panic disorder, agoraphobia, social phobia,
generalized anxiety disorder, or obsessive compulsive 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
AUD and PTSD (Brady et al., 2000; Kessler et al., 2005). Subjects may meet DSM-5
criteria for another substance use disorder as long as AUD is the primary substance of
choice.

5. 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.

6. Must consent to random assignment to N-acetylcysteine (NAC) or placebo.

7. Must consent to complete all treatment and follow-up visits.

8. Must live within 50 miles (one hour) of MUSC in Charleston, SC or be willing to travel
to MUSC for visits.

Exclusion Criteria:

1. Subjects meeting DSM-5 criteria for a history of or current psychotic or bipolar
affective disorders, as the study protocol may be therapeutically insufficient.

2. Subjects with a current eating disorder (bulimia, anorexia nervosa) or with
dissociative identity disorder, as they are likely to require specific time-intensive
psychotherapy.

3. 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.

4. Individuals considered an immediate suicide risk or who are likely to require
hospitalization during the course of the study for suicidality.

Women who are pregnant, nursing or not practicing an effective form of birth control.

5. Evidence of liver failure; alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) levels greater than 3 times the upper limit of normal; asthma
or any clinically significant medical condition that in the opinion of the
investigator would adversely affect safety or study participation.

6. 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.

7. History of childhood or adult seizures of any cause.