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      The effect of N-acetylcysteine on brain glutamate and gamma-aminobutyric acid concentrations and on smoking cessation: A randomized, double-blind, placebo-controlled trial

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          Abstract

          Using data form a 14-day double-blind trial with 48 smokers randomized to either N-acetylcysteine (2400 mg) or placebo, we tested the effect of N-acetylcysteine on glutamate and gamma-aminobutyric acid concentrations in the dorsal anterior cingulate cortex and on smoking cessation. Smoking related behaviors and neurotransmitter concentrations in the dorsal anterior cingulate cortex were assessed before and after treatment. Forty-seven non-smoking males served as baseline controls. Smokers showed higher baseline glutamate but similar gamma-aminobutyric acid concentrations than non-smokers. There were no treatment effects on dorsal anterior cingulate cortex neurotransmitter concentrations, smoking cessation, craving, or withdrawal symptoms. These results confirm glutamate disbalance in smokers, but not efficacy of N-acetylcysteine.

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          Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review.

          John Slattery, Nihit Kumar, Leanna Delhey … (2015)
          N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.
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            N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study.

            Lianne Schmaal, Wim Brink, Dick J. Veltman … (2012)
            Treatment with N-acetylcysteine (NAC) normalizes glutamate (Glu) homeostasis and prevents relapse in drug-dependent animals. However, the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated. Proton magnetic resonance spectroscopy ((1)H MRS) was used to investigate Glu changes in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC in cocaine-dependent patients and normal controls. In an open-label, randomized, crossover study, 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions: one group receiving no compound and the other following a single administration of 2400 mg NAC. The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity. In the medication-free condition, Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls. After administration of NAC, Glu levels were reduced in the cocaine-dependent group, whereas NAC had no effect in healthy controls. Higher baseline Glu levels were associated with higher impulsivity, and both were predictive of greater NAC-induced Glu reduction. The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients. These findings may have important implications for treatment, because abnormal Glu levels are related to relapse, and treatment with NAC prevented relapse in animal studies. Furthermore, clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients, and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities.
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              Potential role of N-acetylcysteine in the management of substance use disorders.

              Zoë E. McClure, R. Malcolm, William Gray … (2014)
              There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Psychopharmacol
                Journal ID (iso-abbrev): J. Psychopharmacol. (Oxford)
                Journal ID (publisher-id): JOP
                Journal ID (hwp): spjop
                Title: Journal of Psychopharmacology (Oxford, England)
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 0269-8811
                ISSN (Electronic): 1461-7285
                Publication date (Electronic): 19 September 2017
                Publication date (Print): October 2017
                Volume: 31
                Issue: 10
                Pages: 1377-1379
                Affiliations
                [1 ]Addiction, Development, and Psychopathology (ADAPT) Laboratory, University of Amsterdam, Amsterdam, the Netherlands
                [2 ]Amsterdam Institute for Addiction Research, University of Amsterdam, Amsterdam, the Netherlands
                [3 ]Arkin Mental Health, Amsterdam, the Netherlands
                [4 ]Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, Australia
                [5 ]Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia
                [6 ]Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
                Author notes
                [*]Mieke HJ Schulte, Department of Psychology, University of Amsterdam, Nieuwe Achtergracht 129B, 1018WS, Amsterdam, the Netherlands. Email: miekehjschulte@ 123456gmail.com
                Article
                Publisher ID: 10.1177_0269881117730660
                DOI: 10.1177/0269881117730660
                PMC ID: 5639948
                PubMed ID: 28922968
                SO-VID: 671ecf3e-e5a9-44e8-bc41-37a94f17b76d
                Copyright © © The Author(s) 2017
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

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                Categories
                Subject: Null Results in Brief

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: proton magnetic resonance spectroscopy,gamma-aminobutyric acid,glutamate,n-acetylcysteine,smoking cessation,tobacco dependence
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: proton magnetic resonance spectroscopy, gamma-aminobutyric acid, glutamate, n-acetylcysteine, smoking cessation, tobacco dependence

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