NAC for Treating Comorbid PTSD and SUD

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.