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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-.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objectives and Methods<\/jats:title>\n            <jats: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\u2009+\u2009AUD. As part of this trial, we acquired proton MR spectroscopy (<jats:sup>1<\/jats:sup>H-MRS) data at pretreatment and\u2009~\u20098-weeks posttreatment in a subsample of (<jats:italic>n<\/jats:italic>\u2009=\u200944) participants to evaluate whether NAC significantly affects frontal glutamate levels (i.e., represented by Glx, glutamate\u2009+\u2009glutamine), 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\u2009+\u2009AUD.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We found that NAC was associated with significantly higher frontal Glx (<jats:italic>t<\/jats:italic>\u2009=\u20092.45, <jats:italic>p<\/jats:italic>\u2009=\u20090.017), and significantly lower GABA (<jats:italic>t<\/jats:italic>\u2009=\u2009-2.82, <jats:italic>p<\/jats:italic>\u2009=\u20090.007) but equivalent glutathione (<jats:italic>t<\/jats:italic>\u2009=\u2009-1.00, <jats:italic>p<\/jats:italic>\u2009=\u20090.321), levels relative to placebo. Finally, lower NAC-related GABA, but not Glx or glutathione, levels were significantly associated with decreased drinks per drinking day (<jats:italic>t<\/jats:italic>\u2009=\u20092.57, <jats:italic>p<\/jats:italic>\u2009=\u20090.014), but not percent drinking days or PTSD symptoms (<jats:italic>p<\/jats:italic>s\u2009&gt;\u20090.10).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats: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\u2009+\u2009AUD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00213-025-06932-6","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T05:48:13Z","timestamp":1760334493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of N-acetylcysteine treatment on frontal glutamate and GABA levels and associations with drinking quantity in people with co-occurring posttraumatic stress disorder and alcohol use disorder"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8877-7871","authenticated-orcid":false,"given":"James J.","family":"Prisciandaro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amber M.","family":"Jarnecke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane E.","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin M.","family":"Gray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth J.","family":"Santa Ana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudie E.","family":"Back","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"6932_CR1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.neulet.2016.11.064","volume":"649","author":"LA Averill","year":"2017","unstructured":"Averill LA, Purohit P, Averill CL, Boesl MA, Krystal JH, Abdallah CG (2017) Glutamate dysregulation and glutamatergic therapeutics for PTSD: evidence from human studies. 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Dr. Gray has provided consultation to Achieve Life Sciences and Indivior and has received research support from Aelis Farma.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}