A randomized trial of the effects of COMT inhibition on subjective response to alcohol: Moderation by baseline COMT activity and mediation of alcohol self‐administration

Background Poor inhibitory control and enhanced subjective response to alcohol are interrelated risk factors for alcohol use disorder (AUD) that share underlying neural substrates, including dopamine signaling in the right prefrontal cortex, a potential target for pharmacological intervention. Cortical dopamine inactivation is primarily regulated by catechol‐O‐methyltransferase (COMT), an enzyme with large variation in activity as a function of the COMT rs4680 (val158met) single nucleotide polymorphism. In a previous randomized, placebo‐controlled trial of the COMT inhibitor tolcapone (200 mg TID) in non‐treatment‐seeking participants with AUD, we found that tolcapone, relative to placebo, reduced alcohol self‐administration only among rs4680 val‐allele homozygotes, whose COMT activity is higher than in met‐allele carriers. Methods We conducted secondary analyses of the effects of tolcapone and baseline COMT activity, as indexed by both rs4680 genotype and an enzymatic activity assay, on the subjective response to alcohol in a bar‐laboratory paradigm among 60 participants in the previous trial. Results Tolcapone did not affect alcohol‐induced stimulation or sedation more than placebo. However, baseline COMT activity moderated the effects of the drug on both outcomes, such that tolcapone‐treated participants with higher baseline COMT activity had less stimulation (p = 0.008) and sedation (p = 0.053) than participants with lower baseline COMT activity and those treated with placebo. Additionally, alcohol‐induced stimulation significantly mediated the interacting effects of baseline COMT activity and tolcapone on bar‐laboratory self‐administration. Conclusions Tolcapone may reduce subjective response to alcohol more effectively among individuals with preexisting high COMT activity an effect that could account for the drug's reduction of alcohol consumption among these individuals. Using a human laboratory paradigm, we tested the effects of the catechol‐O‐methyltransferase (COMT) inhibitor tolcapone, which selectively potentiates evoked cortical dopamine release, on subjective response to alcohol among non‐treatment‐seeking individuals with alcohol use disorder (AUD). Tolcapone, relative to placebo, reduced alcohol‐induced stimulation and sedation more among individuals with higher baseline COMT activity, and stimulation mediated the interacting effects of baseline COMT activity and tolcapone on alcohol self‐administration, suggesting COMT inhibition may be a