Influence of n-acetylcysteine maintenance on the pharmacodynamic effects of oral ethanol

Abstract

Rationale Glutamate systems play an important role in the abuse related effects of alcohol. n-Acetylcysteine, a drug that promotes glutamate homeostasis, attenuates a range of alcohol effects in preclinical models. Objectives This human laboratory study determined the influence of n -acetylcysteine maintenance on alcohol self-administration using a model predictive of treatment effectiveness, along with the subjective, performance and physiological effects of alcohol. We hypothesized that n -acetylcysteine would attenuate alcohol self-administration, as well as positive subjective effects of alcohol. Methods Nine subjects with alcohol use disorder completed this within-subjects study. Subjects were maintained on placebo, 1.2 and 2.4 g n -acetylcysteine in random order on an outpatient basis. After five days of maintenance on the target dose, subjects completed overnight inpatient experimental sessions in which the pharmacodynamic effects of alcohol were determined. Results Alcohol produced prototypic effects (e.g., increased breath alcohol concentration, increased ratings of Feel Drink). n-Acetylcysteine did not alter the effects of alcohol. Conclusions These results indicate that although n -acetylcysteine can safely be combined with alcohol, it does not attenuate the abuse related effects of alcohol and is unlikely to be an effective standalone alcohol use disorder treatment. However, considering study limitations, future work is needed to further understand whether and how n -acetylcysteine might be used as a treatment for alcohol use disorder (e.g., in combination with a behavioral treatment or another pharmacological agent).

Baclofen and naltrexone, but not N-acetylcysteine, affect voluntary alcohol drinking in rats regardless of individual levels of alcohol intake

“…The cysteine precursor N -acetylcysteine did not affect alcohol intake and preference in the current study. This is in contrast to reports that show reduced alcohol self-administration upon treatment with N -acetylcysteine in rats ( Quintanilla et al ., 2016 ; Lebourgeois et al, 2018 , 2019 ) and reduced alcohol-related behaviours in clinical samples (Back et al ., 2016; Squeglia et al ., 2018), although negative findings of N -acetylcysteine on alcohol use in humans have also been reported ( Stoops et al ., 2020 ). The discrepancy between our findings and other (pre)clinical reports may be related to methodological differences, in particular voluntary home-cage consumption versus operant-self-administration.…”

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

“…Alcohol use has been shown to alter the glutamate system. Chronic and binge drinking inhibit glutamate levels and transmission through blockade of NMDA receptors, subsequently leading to elevated glutamate levels during alcohol withdrawal [212][213][214]. N-Acetylcysteine (NAC) is a cysteine prodrug that works to restore glutamatergic tone in reward circuitry by improving the expression and function of the cysteine-glutamate exchanger and normalizing glial glutamate transporters [215,216].…”

“…A secondary analysis of a 12-week, multisite RCT of NAC to treat cannabis use disorder in 277 participants found that NAC increased odds of between-visit abstinence, and reduced alcohol consumption (i.e., drinks per week and drinking days per week) by 30% [ 223 ]. However, a recent 5-day human laboratory study ( N = 9) found that NAC did not attenuate alcohol self-administration [ 212 ]. Additional clinical trials will also examine the effectiveness of NAC in adolescent and adult samples of AUD ([ 224 ], NCT03707951).…”

“…Orally-administered NAC appears to be well tolerated, with the most common adverse effects being nausea and diarrhea [ 212 , 222 ]. Of note, NAC is currently being tested in adolescent AUD, a unique prospect as no other AUD pharmacotherapies are yet approved for adolescents [ 225 ].…”

Logical fallacies and misinterpretations that hinder progress in translational addiction neuroscience

“…One recent example of this failure of translation involves NAC. There is a large literature of positive reports regarding the ability of NAC to decrease reinstatement of drug “seeking” in rodent models (e.g., Moussawi et al, 2009; Reichel et al, 2011; Reissner et al, 2015; Zhou & Kalivas, 2008), yet the clinical efficacy of NAC to reduce drug use or measures of “craving” in human subjects is mixed at best (LaRowe et al, 2013; McClure et al, 2021; Stoops et al, 2020). Another recent example of this translation failure is the 5‐HT2C agonist lorcaserin.…”