The endocannabinoid system is an endogenous signaling system which acts in the regulation of energetic homeostasis and of the lipid and carbohydrate metabolism and in many another mechanism. CB1 receptor, one of the receptors involved in the endocannabinoid system, belongs to a superfamily of G-protein activated receptors, was shown to be an effective target to develop drugs with a therapeutic action on obesity rationally. Rimonabant is the first antagonist of this receptor drawn up to treat obesity. Furthermore, several other cannabinoid-1 receptor blockers have been planned to deal with this and other conditions such as schizophrenia, type II diabetes, alcoholism, smoking and Alzheimer’s disease. However, many studies have been demonstrating the most frequent spontaneous reports of depression and fatal and non-fatal behavior. Despite some beneficial properties of CB1 receptors antagonist, also some disadvantages may be considered and the scientific community still needs to have caution.