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

Pharmacological blockers of the cannabinoid receptor type-1 (CB1) were shown in both research and clinical settings to deliver highly efficient anti-obesity results. However, the first generation of these drugs, such as Rimonabant, which targeted both the brain and peripheral tissues, caused serious psychiatric side effects. As a result, their clinical use was revoked by authorities shortly after they became available.

To overcome such adverse effects, new CB1 blockers targeting only cells outside of the nervous system have been developed over the past 10 years. Several of these second-generation peripheral CB1 inhibitors have been tested in mice, where they demonstrated multiple advantages including reducing food intake – particularly fat-rich food, augmenting energy expenditure, elevating breakdown of dietary fat, and improving glucose metabolism. Through this interacting net of mechanism, these peripheral CB1 inhibitors retained or even outperformed the anti-obesity efficiency of first generation drugs. In addition, they also showed potential for treatment of the long-term negative consequences of obesity and diabetes on liver functions, blood lipid levels, and kidney injury.

However, research warned that the second-generation peripheral CB1 blockers may pose threats to other organ systems, including the gastrointestinal tract, the heart, and the endocrine system which regulates hormones. Their use in treating obesity and diabetes, therefore, requires further investigation and careful considerations.


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