Acamprosate and naltrexone have each demonstrated safety and efficacy for alcohol dependence in placebo-controlled clinical trials. There is scientific and clinical interest in evaluating these drugs in combination, given their high tolerability, moderate effect sizes, different pharmacological profiles and potentially different effects on drinking outcomes. Thus, this is the first human pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Twenty-four normal, healthy adult volunteers participated in a double-blind, multiple dose, within subjects, randomized, 3-way crossover drug interaction study of the standard therapeutic dose of acamprosate (2 g/d) and the standard therapeutic dose of naltrexone (50 mg/d), given alone and in combination, with seven days per treatment condition and seven days washout between treatments. Blood samples were collected on a standardized schedule for pharmacokinetic analysis of naltrexone, 6-beta-naltrexol, and acamprosate. A computerized assessment system evaluated potential drug effects on cognitive functioning. Coadministration of acamprosate with naltrexone significantly increased the rate and extent of absorption of acamprosate, as indicated by an average 33% increase in acamprosate maximum plasma concentration, 33% reduction in time to maximum plasma concentration, and 25% increase in area under the plasma concentration-time curve. Acamprosate did not affect the pharmacokinetic parameters of naltrexone or 6-beta-naltrexol. A complete absence of negative interactions on measures of safety and cognitive function supports the absence of a contraindication to co-administration of acamprosate and naltrexone in clinical practice.