The conformational preferences of cocaine and ecgonine methyl ester were determined through ab initio and density functional theory calculations. They share the same preferred orientation of the acetate group with a hydrogen bond between the amine and carbonyl groups, and s-cis conformation for the methoxyl group. The benzoyloxy group of cocaine defines a specific accessible conformational region. In solution the most stable conformers are stabilized by internal hydrogen bonds in contrast to the lesser stables, which are stabilized by solute/solvent interactions. Overall, these conformational features explain why ecgonine methyl ester is the principal metabolite of cocaine in a human environment. (c) 2008 Elsevier B. V. All rights reserved.