Background: ABT-436, a potent and selective arginine vasopressin (AVP) type 1B receptor (V 1B ) antagonist, has previously demonstrated basal hypothalamic-pituitary-adrenal (HPA) axis attenuation in man. A V 1B antagonist is hypothesized as an alcohol-dependent treatment based on the role of the V 1B receptor in stress regulation and the finding that stress is a trigger for relapse in alcoholics. A V 1B antagonist has shown favorable effects in rat models of alcohol dependence. A single-dose clinical study was conducted to assess the potential for pharmacokinetic or pharmacodynamic interaction between ABT-436 and alcohol.Methods: Twenty moderate alcohol drinkers each received the 4 possible combinations of a single 1,000 mg ABT-436 dose (or matching placebo) and a single 0.5 g/kg alcohol dose (or placebo for alcohol) in a double-blind, randomized, 4-period crossover study. Plasma ABT-436 and blood alcohol levels were measured to assess pharmacokinetic interactions. A computerized cognitive test battery (CDR System), Bond-Lader Visual Analog Scales scales, and a postural stability test were used to measure the effects of alcohol and the potential interaction with ABT-436. The pharmacologic effect of ABT-436 was assessed by measuring serum cortisol.Results: Neither ABT-436 nor alcohol affected the blood levels of the other. Alcohol reduced performance on 2 of 5 CDR System composite variables (power of attention, p = 0.002; quality of secondary episodic memory, p < 0.001), and decreased postural stability (p = 0.043). ABT-436 did not exacerbate those deleterious effects. ABT-436 reduced serum cortisol (p < 0.001), and alcohol did not significantly diminish this expected effect on the HPA axis.Conclusions: No pharmacokinetic or pharmacodynamic interaction between ABT-436 and alcohol was observed.