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Clinical Research

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

Abstract

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.

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Fig. 1: Peripheral CB1 blockers induce hypophagia by likely acting at the level of the vagus nerve.
Fig. 2: The prolonged use of peripheral CB1 blockers may lead to brain leakage in obese patients having alterations in the blood-brain barrier.

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Acknowledgements

CQ is supported by INSERM, the French Society of Diabetes (SFD), the French Society of Endocrinology (SFE), the French Society of Nutrition (SFN). DC is supported by INSERM, Nouvelle Aquitaine Region, Labex BRAIN ANR-10-LABX-43, ANR-10-EQX-008-1 OPTOPATH, ANR-17-CE14-0007 BABrain, and ANR-18-CE14-0029 Mitobesity.

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Quarta, C., Cota, D. Anti-obesity therapy with peripheral CB1 blockers: from promise to safe(?) practice. Int J Obes 44, 2179–2193 (2020). https://doi.org/10.1038/s41366-020-0577-8

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