In this commentary, the authors review the history of the discovery of the endocannabinoid system, the development of CB1 antagonists and the experience of Rimonabant and its suspension following psychiatric adverse effects. Dysregulation of endocannabinoid activity is a key contributor to the development of intra-abdominal adiposity and of subsequent lipotoxicity, insulin resistance, accumulation of ectopic fat and atherogenic inflammation. Clinical data indicate that high-risk patients with abdominal obesity and no evidence of past or present depression represented was the subgroup most likely to benefit from CB1 antagonists, instead of patients with global obesity. The authors propose that any type of intervention that targets endocanabinoids will clearly need to be weighed against the adverse effects that might derive from potential interference with the normal physiological role of endocannabinoids, particularly in the brain. It is concluded that the criteria currently used by regulatory authorities to evaluate and approve anti-obesity drugs should be re-examined to target the right drug for the right patient, the endocannabinoids being an interesting avenue to treat intra-abdominal adiposity and its atherogenic metabolic consequences.
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