A Double-Blind Randomized Controlled Trial of N-Acetylcysteine in Cannabis-Dependent Adolescents

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
American Journal of Psychiatry (Impact Factor: 12.3). 06/2012; 169(8):805-12. DOI: 10.1176/appi.ajp.2012.12010055
Source: PubMed


Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy.
In an 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group.
Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events.
This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.

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    • "Disulfiram (DSF; PubChem CID: 3117), originally identified as a treatment for alcohol addiction [1], has now been found to also have potential for the treatment of several other substance use disorders. These include addiction to cocaine [2] [3], nicotine [4], marijuana [5] and the behavioral addiction pathological gambling [6] [7]. The pharmacological basis for DSF's use in alcohol addiction is its ability to inhibit liver mitochondrial aldehyde dehydrogenase (ALDH 2 ) [1]. "
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    ABSTRACT: Disulfiram (DSF), a treatment for alcohol use disorders, has shown some clinical effectiveness in treating addiction to cocaine, nicotine, and pathological gambling. The mechanism of action of DSF for treating these addictions is unclear but it is unlikely to involve the inhibition of liver aldehyde dehydrogenase (ALDH2). DSF is a pro-drug and forms a number of metabolites, one of which is N-acetyl-S-(N,N-diethylcarbamoyl) cysteine (DETC-NAC). Here we describe a LCMS/MS method on a QQQ type instrument to quantify DETC-NAC in plasma and intracellular fluid from mammalian brain. An internal standard, the N,N-di-isopropylcarbamoyl homolog (MIM: 291>128) is easily separable from DETC-NAC (MIM: 263>100) on C18 RP media with a methanol gradient. The method's linear range is 0.5-500nM from plasma and dialysate salt solution with all precisions better than 10% RSD. DETC-NAC and internal standards were recovered at better than 95% from all matrices, perchloric acid precipitation (plasma) or formic acid addition (salt) and is stable in plasma or salt at low pH for up to 24h. Stability is observed through three freeze-thaw cycles per day for 7 days. No HPLC peak area matrix effect was greater than 10%. A human plasma sample from a prior analysis for S-(N,N-diethylcarbamoyl) glutathione (CARB) was found to have DETC NAC as well. In other human plasma samples from 62.5mg/d and 250mg/d dosing, CARB concentration peaks at 0.3 and 4nM at 3h followed by DETC-NAC peaks of 11 and 70nM 2h later. Employing microdialysis sampling, DETC-NAC levels in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and plasma of rats treated with DSF reached 1.1, 2.5 and 80nM at 6h. The correlation between the appearance and long duration of DETC-NAC concentration in rat brain and the persistence of DSF-induced changes in neurotransmitters observed by Faiman et al. (Neuropharmacology, 2013, 75C, 95-105) is discussed. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jan 2015 · Journal of Pharmaceutical and Biomedical Analysis
    • "Chronic NAC reverses chronic cocaine-induced glutamate dysregulation, including normalizing drug-dependent decreases in extracellular glutamate levels, and protein expression levels of xCT (the catalytic subunit of the cystine-glutamate exchanger) and GLT-1 (a high affinity astroglial glutamate transporter) (Baker et al. 2003; Knackstedt, Melendez & Kalivas 2010). Extensive pre-clinical data supports the therapeutic potential for NAC in addiction and other psychiatric conditions (Dean, Giorlando & Berk 2011; Olive et al. 2012), and clinical data provides promising findings for treating cocaine and marijuana addiction (Kalivas & Volkow 2011; Schmaal et al. 2012; Gray et al. 2012). Hence, understanding the mechanism of action of NAC may aid in discovering therapeutic targets for treating addiction. "
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    ABSTRACT: Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.
    No preview · Article · Feb 2014 · Addiction Biology
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    • "Importantly, NAC was well tolerated, as has been the case in children with autism (Hardan et al. 2012), in adolescents with cannabis dependence (Gray et al. 2012), in adults with trichotillomania (Grant et al. 2009), and when used adjunctively with SSRIs, in adults with SSRI-resistant anxiety disorders (Lafleur et al. 2006). Additional, prospective trials are urgently needed to assess the potential role of glutamate modulators, such as NAC, in youth with anxiety disorders, including those who have had partial responses to ''first-line'' psychopharmacologic and psychotherapeutic interventions. "

    Full-text · Article · Dec 2012 · Journal of child and adolescent psychopharmacology
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