Cannabinoid receptor 1 (CB1R), a G protein-coupled receptor, plays a critical role in regulating appetite and exhibits increased expression in peripheral insulin-target tissues during obesity. This suggests its potential involvement in obesity-induced pro-inflammatory responses. Selective targeting of peripheral CB1R could offer a novel therapeutic approach to break the link between insulin resistance and metabolic inflammation. However, The widespread distribution of CB1R, including the central nervous system (CNS), presents a challenge. CNS-directed CB1R blockade can lead to severe psychological effects like depression and suicidality. This study investigates the development of peripherally-restricted, high-affinity single-domain antibodies (sdAbs) targeting CB1R for selective appetite modulation. We employed an APG-solubilized, recombinant CB1R for rabbit immunization. Antigen-specific sdAbs were subsequently isolated from the immunoglobulin heavy chain variable region. Biopanning of the resulting phage display library was conducted to identify sdAbs with high binding affinity for CB1R. Our findings demonstrate the development of CB1R-specific sdAbs, potentially offering a novel and targeted strategy for obesity management with minimized CNS exposure and reduced risk of associated psychiatric side effects