Anti-obesity therapy with peripheral CB1 blockers: from promise to safe(?) practice

Pharmacological blockers of the cannabinoid receptor type-1 (CB1) have been
considered for a long time as the holy grail of obesity pharmacotherapy. These
agents were hastily released in the clinical setting, due to their clear-cut
therapeutic efficacy. However, the first generation of these drugs, which were
able to target both the brain and peripheral tissues, had serious
neuropsychiatric effects, leading authorities to ban their clinical use. New
peripherally restricted CB1 blockers, characterized by low brain penetrance, have
been developed over the past 10 years. In preclinical studies, these molecules
seem to overcome the neuropsychiatric negative effects previously observed with
brain-penetrant CB1 inhibitors, while retaining or even outperforming their
efficacy. The mechanisms of action of these peripherally restricted compounds are
only beginning to emerge, and a balanced discussion of the risk/benefits ratio
associated to their possible clinical use is urgently needed, in order to avoid
repeating past mistakes. Here, we will critically discuss the advantages and the
possible hidden threats associated with the use of peripheral CB1 blockers for
the pharmacotherapy of obesity and its associated metabolic complications. We
will address whether this novel pharmacological approach might ‘compete’ with
current pharmacotherapies for obesity and diabetes, while also conceptualizing
future CB1-based pharmacological trends that may significantly lower the
risk/benefits ratio associated with the use of these drugs.

Auteurs Bordeaux Neurocampus