The Effect of N‐Acetylcysteine ( NAC ) on Neurometabolites and Cognitive Function in Adults With Alcohol Use Disorder: A Preliminary Randomized Controlled Trial

Background and Aims Preclinical studies have demonstrated that N‐acetylcysteine stabilizes levels of glutamate and glutathione and reduces alcohol‐seeking behaviors, indicating it as a potential pharmacotherapy for the management of alcohol use disorder. In this preliminary study, we examined brain metabolite levels and cognitive functioning in individuals with alcohol use disorder enrolled in a randomized controlled trial of N‐acetylcysteine versus placebo. Methods In this preliminary trial, 23 participants (average age = 49; 70% male) with moderate to severe alcohol use disorder (DSM‐5) were randomized to receive 2400 mg/day of N‐acetylcysteine ( N = 9) or placebo ( N = 14). At baseline and follow‐up ( M = 19 days; SD = 3.73 days post‐baseline), participants underwent proton magnetic resonance spectroscopy ( 1 H‐MRS) to assess levels of glutamate (Glu), glutathione (GSH) and total N‐acetylaspartate (tNAA) in the anterior cingulate cortex (ACC) and completed the Stroop Color and Word Test (SCWT; a measure of distractor interference and cognitive control) and the Trail Making Test (TMT; a measure of set shifting ability). Results There were no significant differences between the N‐acetylcysteine or placebo groups in neurometabolite concentrations (GSH/Cr: p = 0.75, CI; −0.12–0.09, tNAAG/Cr: p = 0.797, CI; −0.10–0.13, Glu/Cr: p = 0.60, CI; −0.19–0.32), or cognitive scores (Stroop: p = 0.57, CI; −306.93–172.78, TMT: p = 0.166, CI; −6.62–36.77). Conclusion These preliminary findings indicate that N‐acetylcysteine may not alter brain neurometabolite levels within the ACC or show improvements in certain domains of cognitive functioning measured by the SCWT and TMT, specifically resistance to distractor interference and set‐shifting ability respectively, in individuals with alcohol use disorder. Trial Registration ClinicalTrials.gov identifier: NCT03879759