Disclosed are compositions for affecting weight loss comprising a first compound and a second compound, where the first compound is a metabolite of naltrexone, such as 6-.beta.-naltrexol or a prodrug of a naltrexone metabolite, and the second compound causes increased agonism of a melanocortin 3 receptor (MC3-R) and/or a melanocortin 4 receptor (MC4-R), and/or increases the concentration of .alpha.-MSH in the central nervous system. Also disclosed are methods of affecting weight loss, increasing energy expenditure, increasing satiety in an individual, or suppressing the appetite of an individual, comprising identifying an individual in need thereof and treating that individual to antagonize opioid receptor activity with a metabolite of naltrexone, such as 6-.beta.-naltrexol or a prodrug of a naltrexone metabolite, and treating that individual to enhance .alpha.-MSH activity, e.g., by administration of a second compound causes increased agonism of MC3-R and/or MC4-R, and/or increases the concentration of .alpha.-MSH in the central nervous system.