The catechol-O-methyltransferase inhibitor tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder

Abstract

Rationale: Individuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD.

Objectives: To determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks.

Methods: We used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100 mg TID for 5 days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD.

Results: Tolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo.

Conclusions: These data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.

Trial registration: ClinicalTrials.gov Identifier: NCT02740582.

Keywords: AUD; Alcohol use disorder; COMT; Decision-making; Impulsivity; Tolcapone.

Figures

Figure 1.. Overview of Study Design.

Subjects participated in a total of seven visits; Screening, Drug Dispensing x 2, Compliance x 2, and Laboratory Session x 2. Upon completion of the first randomized double blind drug cycle and a washout, subjects were crossed over to complete the second drug cycle.

Figure 2.. Alcohol Consumption.

There was a significant decrease in weekend alcohol consumption following tolcapone administration. Means and SEM depicted for tolcapone and placebo drinking. (A), 13.35 ± 0.92 drinks on placebo vs. 11.78 ± 0.95 drinks on tolcapone, Cohen’s d = −.225, t(54) = 2.05, p = 0.045, n = 55.

Figure 3.. Impulsive Choice.

There was a significant positive correlation between the tolcapone effect on weekend drinking and the tolcapone effect on delay discounting (A), r(45) = 0.40, p = 0.0053, as well as an overall effect of genotype on change in ICR following tolcapone (B), Means and SEM depicted for each genotype, F(2,44) = 3.35, p = 0.044, n = 13 Met/Met, 21 Met/Val, 13 Val/Val, respectively.