Targeting cannabinoid receptors for obesity faces safety hurdles

Obesity is a chronic metabolic disease associated with insulin resistance, cardiometabolic complications, and increased mortality. Limitations of existing therapies have driven interests in alternative biological targets, including the endocannabinoid system and the cannabinoid-1 receptor (CB1R) signaling pathway. This review examines the rationale for targeting peripheral CB1R signaling and summarizes preclinical and clinical evidence supporting peripherally restricted CB1R antagonists and inverse agonists for obesity and related metabolic disorders. The metabolic effects of CB1R blockade in peripheral tissues are discussed, as well as distinctions between central and peripheral CB1R inhibition. The article also reviews the current development landscape of CB1R-targeted compounds, including agents evaluated in early-phase clinical trials. Literature was identified through PubMed, Embase, and Scopus, supplemented by ClinicalTrials.gov. Peripherally restricted CB1R antagonists aim to deliver the metabolic benefits of CB1R blockade while avoiding the toxicity that ended development of centrally acting agents such as rimonabant. Recent phase 2 data with monlunabant demonstrated dose-dependent psychiatric adverse events and high discontinuation rates. Nimacimab, an antibody-based approach, has shown only marginal efficacy. The future of this drug class will therefore likely depend on rigorous long-term safety evaluation, biased CB1R pharmacology, and multitarget strategies including combinations with incretin-based therapies.