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N-acetylcysteine does not alter neurometabolite levels in non-treatment seeking adolescents who use alcohol heavily: A preliminary randomized clinical trial

Neuropsychopharmacology volume 48, pages 1184–1193 (2023)Cite this article

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Abstract

Current treatments for adolescent alcohol use disorder (AUD) are mainly psychosocial and limited in their efficacy. As such, pharmacotherapies are being investigated as potential adjunctive treatments to bolster treatment outcomes. N-acetylcysteine is a promising candidate pharmacotherapy for adolescent AUD because of its tolerability and demonstrated ability to modulate glutamatergic, GABAergic, and glutathione systems. The primary objective of this double-blind, placebo-controlled, within-subjects crossover preliminary investigation was to measure potential changes within glutamate + glutamine (Glx), GABA, and glutathione levels in the dorsal anterior cingulate cortex (dACC) using proton magnetic resonance spectroscopy during 10-days of N-acetylcysteine (1200 mg twice daily) compared to 10-days of placebo in non-treatment seeking adolescents who use alcohol heavily (N = 31; 55% female). Medication adherence was confirmed via video. Effects on alcohol use were measured using Timeline Follow-Back as an exploratory aim. Linear mixed effects models controlling for baseline metabolite levels, brain tissue composition, alcohol use, cannabis use, and medication adherence found no significant differences in Glx, GABA, or glutathione levels in the dACC after N-acetylcysteine compared to placebo. There were also no measurable effects on alcohol use; however, this finding was underpowered. Findings were consistent in the subsample of participants who met criteria for AUD (n = 19). The preliminary null findings in brain metabolite levels may be due to the young age of participants, relatively low severity of alcohol use, and non-treatment seeking status of the population investigated. Future studies can use these findings to conduct larger, well-powered studies within adolescents with AUD.

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Fig. 1: Experimental design of the clinical trial.
Fig. 2: Differences between N-acetylcysteine vs. placebo in primary and secondary metabolite levels in the dorsal anterior cingulate cortex of adolescents who drink heavily (raw data).

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Funding

This work was supported by the National Institute of Alcohol and Alcoholism (NIAAA-K23-AA025399). AEK is supported by F32-AA029930-01A1, BDB is supported by T32DA007288, RG is supported by T32AA007474.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA

    Anna E. Kirkland, ReJoyce Green, James J. Prisciandaro, Kathleen T. Brady, Rachel L. Tomko, Kevin M. Gray & Lindsay M. Squeglia

  2. Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA

    Brittney D. Browning

  3. College of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Helen Liu

  4. Department of Psychological Sciences, University of Missouri-Columbia, Columbia, MO, USA

    Anna M. Maralit

  5. Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA

    Pamela L. Ferguson

  6. Department of Radiology, University of California San Francisco, San Francisco, CA, USA

    Dieter J. Meyerhoff

  7. Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA

    Robert Miranda Jr.

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  1. Anna E. Kirkland
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Contributions

All authors made significant contributions to this work. The project was conceived by LMS, KMG and RLT. LMS received funding for this project. DJM, JJP, RM, KTB and KMG were mentors for LMS K23. AMM, HL, BDB and AEK acquired data. AEK, PLF, and RG analyzed the data. The manuscript was written by AEK, BDB, RG, PLF, LMS and revised by all authors. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Anna E. Kirkland.

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Competing interests

KMG has provided consultation to Jazz Pharmaceuticals and has received research funding from Aelis Farma. RLT has received funding from the American Society of Addiction Medicine. The authors declare no other competing interests.

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Kirkland, A.E., Browning, B.D., Green, R. et al. N-acetylcysteine does not alter neurometabolite levels in non-treatment seeking adolescents who use alcohol heavily: A preliminary randomized clinical trial. Neuropsychopharmacol. 48, 1184–1193 (2023). https://doi.org/10.1038/s41386-023-01553-z

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