Atypical cannabinoid compounds O-1602 and O-1918 are ligands for the putative cannabinoid receptors G protein-coupled receptor 55 and G protein-coupled receptor 18. The role of O-1602 and O-1918 in attenuating obesity and obesity-related pathologies is unknown. Therefore, we aimed to determine the role that either compound had on body weight and body composition, renal and hepatic function in diet-induced obesity. Male Sprague Dawley rats were fed a high fat diet (40% digestible energy from lipids) or a standard chow diet for 10 weeks. In a separate cohort, male Sprague Dawley rats were fed a high-fat diet for 9 weeks and then injected daily with 5mg/kg O-1602, 1mg/kg O-1918 or vehicle (0.9% saline/ 0.75% Tween 80) for a further 6 weeks. Our data demonstrated that high fat feeding up-regulates whole kidney G protein-receptor 55 expression. In diet-induced obesity, we also demonstrated O-1602 reduces bodyweight, body fat and improves albuminuria. Despite this, treatment with O-1602 resulted in gross morphological changes in the liver and kidney. Treatment with O-1918 improved albuminuria but did not alter bodyweight or fat composition. In addition, treatment with O-1918 also up-regulated circulating pro-inflammatory cytokines including IL-1α, IL-2, IL-17α, IL-18 and RANTES as well as plasma AST. Thus O-1602 and O-1918 appear not to be suitable treatments for obesity and related co-morbidities, due to their effects on organ morphology and pro-inflammatory signalling in obesity.