Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone

Abstract

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone's effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934.

Fig. 1. Peripheral COMT activity.

a Effect of COMT rs4680 genotype on COMT activity in red blood cells at baseline. b Effects of medication group and COMT rs4680 genotype on COMT activity on day 7 of medication ingestion. Figures are mean normetanephrine concentrations normalized to hemoglobin, ± standard errors from the linear mixed model. **p < 0.01.

Fig. 2. Drinking during the medication period.

a Effects of medication group and COMT rs4680 genotype on drinks per day. b Effects of medication group and COMT rs4680 genotype on drinks per drinking day. Figures are means ± standard errors from the general linear model, controlling for age, AUDIT score, baseline drinking, and whether the participant completed the study before or during the COVID-19 pandemic. **p < 0.01.

Fig. 3. Alcohol craving and self-administration in the bar lab.

Effects of medication group and COMT rs4680 genotype on (a) peak alcohol craving (Alcohol Urge Questionnaire [AUQ] score) in the bar lab following consumption of a priming drink; and (b) the number of drinks (out of 8 possible) that participants chose to self-administer in the bar lab. Figures are means ± standard errors from the general linear model, controlling for age and AUDIT score. *p < 0.05.

Fig. 4. Alcohol cue-elicited brain activation and association with drinking.

a Inset: Right inferior frontal gyrus (rIFG) region of interest. Main figure: Effect of medication group on alcohol cue-elicited rIFG activation. Figures are means ± standard errors from the linear mixed model, controlling for scanner. b Association between cue-elicited rIFG activation and drinks per drinking day during the first 6 days of the medication period. *p < 0.05.