Rationale <p>Though half of people with posttraumatic stress disorder (PTSD) develop alcohol use disorder (AUD), co-occurring PTSD and AUD (PTSD + AUD) is associated with more severe clinical outcomes relative to either alone and little remains known about the pathophysiology of PTSD + AUD. PTSD and AUD have each been associated with marked dysfunction in brain glutamate and GABA systems, making these systems promising targets for pharmacological intervention, including N-acetylcysteine (NAC), which restores extracellular glutamate concentrations via GLT-1 and System Xc-.</p> Objectives and Methods <p>Based on promising results from our pilot study of NAC, we recently completed a 12-week, randomized, double-blind, placebo-controlled clinical trial of NAC for PTSD + AUD. As part of this trial, we acquired proton MR spectroscopy (¹H-MRS) data at pretreatment and ~ 8-weeks posttreatment in a subsample of (<i>n</i> = 44) participants to evaluate whether NAC significantly affects frontal glutamate levels (i.e., represented by Glx, glutamate + glutamine), with exploratory evaluation of GABA and glutathione levels, and whether NAC-related changes in neurometabolite levels correspond to decreased drinking and/or PTSD symptoms, in people with PTSD + AUD.</p> Results <p>We found that NAC was associated with significantly higher frontal Glx (<i>t</i> = 2.45, <i>p</i> = 0.017), and significantly lower GABA (<i>t</i> = -2.82, <i>p</i> = 0.007) but equivalent glutathione (<i>t</i> = -1.00, <i>p</i> = 0.321), levels relative to placebo. Finally, lower NAC-related GABA, but not Glx or glutathione, levels were significantly associated with decreased drinks per drinking day (<i>t</i> = 2.57, <i>p</i> = 0.014), but not percent drinking days or PTSD symptoms (<i>p</i>s &gt; 0.10).</p> Conclusions <p>Though preliminary, these findings are consistent with the mechanistic hypothesis that NAC reduces drinking quantity through its effects on excitatory and inhibitory neurotransmission in people with PTSD + AUD.</p>