This progress report on the anorectic effect of serotoninergic indirect antagonists compares the action of D-fenfluramine, fluoxetine and sertraline and their N-dealkylated metabolites. Brain levels of drugs and their metabolites were measured after equi-active anorectic doses. Fluoxetine and sertraline inhibit 5-HT uptake in vitro with a potency which is at least one order of magnitude higher than for D-fenfluramine while all three drugs release 5-HT from synaptosomes and the active concentrations are closer to the brain concentrations reached after anorectic doses. However, a number of differences have been observed between D-fenfluramine and fluoxetine regarding the mechanisms of 5-HT release. Furthermore fluoxetine affected storage of 5-HT in vesicles much more than D-fenfluramine did. The anorectic effect induced by fluoxetine was not antagonized by antiserotoninergic drugs. No evidence of an involvement of CCK in the anorectic effect of D-fenfluramine was found when food intake was determined in rats previously submitted to food deprivation.