Soon after the discovery of cannabis by western societies, its psychotropic effects overshadowed its medical benefits. How-ever, investigation into the molecular action of the main constituents of cannabis has led to the discovery of an intercellularsignalling system, called the endocannabinoid system (ECS). The ECS comprises a set of molecular components, including en-zymes, signalling lipids and G-protein coupled receptors, which has an outstanding role in modulating eating behaviour andenergy homeostasis. Interestingly, evidence has shown that the ECS is present at the central and peripheral nervous system,modulating the function of the hypothalamus, the brain reward system and the brainstem, and coordinating the crosstalk be-tween these brain structures and peripheral organs. Indeed, the ECS is present and functional in metabolically relevant periph-eral tissues, directly modulating their physiology. In the context of a global obesity pandemic, these discoveries are highlysuggestive in order to design novel pharmaceutical tools to fight obesity and related morbidities. In fact, a cannabinoid-based first generation of drugs was developed and marketed. Their failure, due to central side-effects, is leading to a secondgeneration of these drugs unable to cross the blood–brain barrier, as well as other ECS-focused strategies that are still in thepipeline. In the next few years we will hopefully know whether such an important player in energy homeostasis can be suc-cessfully targeted without significantly affecting other vital processes related to mood and sense of well-being.
