BackgroundANS‐6637, an orally bioavailable selective and reversible aldehyde dehydrogenase‐2 (ALDH2) inhibitor, is under development for drug and alcohol use disorders. During the elimination of alcohol, ALDH2 metabolizes acetaldehyde to acetate; inhibiting this enzyme can lead to aversive reactions due to the accumulation of acetaldehyde. Thus, understanding the safety and tolerability of ANS‐6637 in combination with alcohol is essential.Trial Design and MethodsForty eight healthy males participated in a randomized, double‐blind, placebo‐controlled, single‐ascending dose cohort study of oral ANS‐6637. Eligible participants were randomized to ANS‐6637 (n = 36) or placebo (n = 12) in a 3:1 fashion in each of 6 dose cohorts (8 per cohort; ANS‐6637 dose levels were 25, 50, 100, 200, 400, and 600 mg). Two hours after receiving study drug, participants drank up to 5 standard drinks, 1 every 30 minutes. Safety assessments, pharmacodynamic measures, and pharmacokinetic blood samples were obtained.ResultsFlushing was the most common adverse event (AE) associated with ANS‐6637 (24 of 36 participants) compared with placebo (3 of 12). Statistically significant, but modest, increases in heart rate (HR) occurred (+10.5 bpm after 2 drinks; +16.9 to + 20.5 bpm after 3rd through 5th drink). No participant met HR or systolic blood pressure criteria for stopping ethanol administration. There were no clinically significant QTc interval prolongations. Individuals receiving ANS‐6637 reported lower ratings of liking, alcohol effects, and feeling drunk.ConclusionsA single oral dose of ANS‐6637 with up to 5 standards drinks over 2.5 hours was generally well tolerated in healthy males. The most common pharmacological response was flushing and an increase in HR, which are known effects of acetaldehyde accumulation and consistent with inhibition of ALDH2 with oral ANS‐6637 in combination with alcohol. The results of this alcohol interaction study support further testing of ANS‐6637 in individuals who consume alcohol heavily.