Perhaps the most striking examples of the importance of the ECS in weight gain and glucose metabolism are demon- strated in experiments using CB-1 knock-out mice. These genetically engineered mice with absent CB-1 represent an experimental model of signiﬁcantly decreased ECS activa- tion. CB-1 knockout mice are leaner than wild type mice and consume less food (Cota et al 2003). When treated with the CB-1 antagonist rimonabant, wild type mice decrease food intake to the level of CB-1 knockout mice (Di Marzo et al 2001). Ravinet Trillou studied the differences in CB-1 knockout mice and wild type mice when both were given a choice of a very palatable high fat diet or standard diet (Ravinet Trillou et al 2004). Wild type mice fed the high fat diet exhibited a marked increase in weight compared with those fed the standard diet. However, in the CB-1 knockout mouse the difference in weight gain between high fat diet and standard diet was signiﬁcantly attenuated (Table 1). Over the course of the study the hyperphagia in wild type mice dimin- ished but the weight gain over controls continued. The CB-1 knockout mice also chose the high fat diet, but they did not eat excessively and remained lean. Additionally, compared with those fed a standard diet, wild type mice fed a high fat diet demonstrated a signiﬁcantly increased glucose response to exogenous insulin injection (increased insulin resistance), while once again this effect was markedly attenuated in the CB-1 knockout mouse. Multiple studies also indicate that the ECS is overactive in overweight and obese humans. Engeli et al demonstrated that obese women have elevated circulating levels of the endocannabinoids and reduced activity of the inactivating enzyme FAAH. These levels were not reversed with a 5% weight loss (Engeli et al 2005). Sipe et al showed that over- weight and obese individuals have an approximately two-fold increased frequency of an abnormal FAAH gene, resulting in decreased activity of this endocannabinoid-inactivating enzyme and presumably higher levels of ECS activation (Sipe et al 2005). Table 1 Body weight of wild type mice (+/+) and CB1 knockout mice (-/-) fed a standard diet (SD) or a free choice of SD and high fat diet (SD/HFD) for 12 weeks Group Body weight (g) SD-/- 31.8 ± 1.2 SD/HFD-/- 34.3 ± 2.4 SD+/+ 41.1 ± 1.6 SD/HFD+/+ 48.6 ± 1.6 Adapted from Ravinet Trillou et al (2004). Results reported as mean + standard error measure. p < 0.05 for SD-/- vs SD+/+; p < 0.05 for SD/HFD+/+ vs SD+/+. Vascular Health and Risk Management 2007:3(2) Rimonabant and cardiometabolic risk Thus, multiple lines of evidence in both human and animal models suggest that over-activity of the ECS is intimately involved in management of weight, energy, and metabolism. As such, interruption of ECS over-activity may provide an attractive therapeutic target for management of the increased cardiometabolic risk associated with overweight and obesity. Rimonabant, a selective CB-1 antagonist Rimonabant, an orally available selective CB-1 antagonist, has shown promise in both animals and humans in the treat- ment of cardiometabolic risk, especially in patients who are overweight, obese, or have T2DM. It represents the ﬁrst agent affecting the ECS to undergo extensive clinical development. Rimonabant has been approved for weight loss in overweight and obese persons in Europe, but at the time of this publica- tion has not been approved in the US. Pharmacology and pharmacokinetics of rimonabant In healthy human subjects, rimonabant shows linear pharma- cokinetics in doses up to 20 mg, which is the maximum dose used in large-scale clinical trials (Turpault et al 2006). Median time to maximal plasma concentration in the obese patient is 2 hours. The half-life of rimonabant is 6–9 days in non-obese subjects; in obese subjects the half-life is approximately 16 days due to a larger area of distribution. Likewise, the time required to reach steady state is also increased in obese sub- jects (25.5 days) versus the non-obese (12.7 days). Gender does not affect pharmacokinetics. In vitro, rimonabant is metabolized in part by hepatic CYP3A enzyme pathways, leading to the potential for drug interactions with common CYP3A inhibitors such as ketokonazole, itraconazole, rito- navir, and clarithromycin, and inducers such as rifampin, phenytoin, phenobarbital, and carbamezapine (Gadde and Allison 2006). Further studies are needed to determine the clinical signiﬁcance of these potential interactions. Animal data with rimonabant Ravinet Trillou et al demonstrated that mice with diet induced obesity treated with 5 weeks of rimonabant were 20% lighter than those receiving placebo (Ravinet Trillou et al 2003). In addition, the weight loss in response to a 24-hour fast was greater in animals treated with rimonabant, suggesting that metabolic effects other than simple reduction of caloric intake contributed to the weight loss. The rimonabant treated mice also demonstrated a 50% decrease in plasma 183