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

Abstract

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 longestablished 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 (1 H-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 *

Altered cytoskeletal arrangement in induced pluripotent stem cells and motor neurons from patients with riboflavin transporter deficiency

“…Importantly, the proposed combined treatment of the two compounds appears consistently efficacious, irrespective of the severity of disease, suggesting this therapeutic approach to rescue at least in part RTD-associated cell damage. Translational studies hold considerable promise in this respect, as both RF and NAC are easily retrieved, have long-established safety records and do not require titration to achieve the target dose ( Back et al, 2020 ).…”

Mitochondrial Abnormalities in Induced Pluripotent Stem Cells-Derived Motor Neurons from Patients with Riboflavin Transporter Deficiency

“…This result is consistent with work in progress at our laboratories showing that such combined treatment results in increased neurite length in RTD MNs [ 25 ], possibly by the restoration of ROS-sensitive microtubule dynamics [ 26 , 27 ]. Studies on different pathological conditions have associated the efficacy of NAC with its action in cystine-glutamate exchange, glial glutamate transporters normalization, and in restoring glutamatergic tone on presynaptic receptors in reward regions of the brain [ 28 , 29 ]. Importantly, NAC has a long-established safety record and does not require titration to achieve the target dose [ 28 ]; thus, proposing this compound for future therapeutic studies aimed at improving clinical outcomes of RTD patients.…”

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

“…Interestingly, the antioxidant N-acetylcysteine (NAC) was recently shown to inhibit conditioned stress-induced cocaine and alcohol seeking when administered during or immediately following restraint stress (Garcia-Keller et al, 2020), which raises the question as to whether suppression of oxidative stress and inflammation via NAC treatment is therapeutic in this context. Importantly, NAC is currently being investigated clinically for its use in treating comorbid AUDs and PTSD (Back et al, 2020). Drugs with immunomodulatory activity, such as monoclonal antibodies, glucocorticoids, and cannabinoids, are also being investigated for their use in the treatment of PTSD (Hori and Kim, 2019).…”