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The endocannabinoid system is found throughout the CNS and the body where it impacts many important physiological processes. Expectations were high that targeting cannabinoid receptors would prove therapeutically beneficial; pharmaceutical companies quickly seized on the appetitive and metabolic effects of cannabinoids to develop a drug for the treatment of weight loss. Alas, the experience with first-in-class cannabinoid type-1 receptor (CB1R) antagonist rimonabant is a now-classic cautionary tale of the perils of drug development and the outcome of rimonabant’s fall from grace dealt a blow to those pursuing therapies involving CB1R antagonists. And this most commercially compelling application of rimonabant has now been partially eclipsed by drugs with different mechanisms of action and greater effect. Still, blocking CB1 receptors causes intriguing metabolic effects, some of which appear to occur outside the CNS. Moreover, recent years have seen a startling change in the legal status of cannabis, accompanied by a popular embrace of ‘all things cannabis’. These changes combined with new pharmacological strategies and diligent medicinal chemistry may yet see the field to some measure of fulfillment of its early promise. Here, we review the story of rimonabant and some of the therapeutic niches and strategies that still hold promise after the fall.

The endocannabinoid system is found throughout the CNS and the body where it impacts many important physiological processes. Expectations were high that targeting cannabinoid receptors would prove therapeutically beneficial; pharmaceutical companies quickly seized on the appetitive and metabolic effects of cannabinoids to develop a drug for the treatment of weight loss. Alas, the experience with first-in-class cannabinoid type-1 receptor (CB1R) antagonist rimonabant is a now-classic cautionary tale of the perils of drug development and the outcome of rimonabant's fall from grace dealt a blow to those pursuing therapies involving CB1R antagonists. And this most commercially compelling application of rimonabant has now been partially eclipsed by drugs with different mechanisms of action and greater effect. Still, blocking CB1 receptors causes intriguing metabolic effects, some of which appear to occur outside the CNS. Moreover, recent years have seen a startling change in the legal status of cannabis, accompanied by a popular embrace of 'all things cannabis'. These changes combined with new pharmacological strategies and diligent medicinal chemistry may yet see the field to some measure of fulfillment of its early promise. Here, we review the story of rimonabant and some of the therapeutic niches and strategies that still hold promise after the fall. [ABSTRACT FROM AUTHOR]

Abstract Metabolic syndrome (MetS), an epidemic defined as a group of interconnected physiological, biochemistry, clinical, and metabolic factors, directly increases the risk of cardiovascular disease, atherosclerosis, type 2 diabetes, and death. MetS therapy includes diet, physical exercise, and a poly-pharmacological intervention. Cannabis is mainly recognized for its recreational uses and has several medical applications for neurological diseases, due to its hypnotic, anxiolytic, antinociceptive, anti-inflammatory, and anticonvulsant activities. Although several clinical observations in Cannabis smokers suggest metabolic effects, its utility in metabolic disorders is unclear. This review aims to determine under what conditions Cannabis might be useful in the treatment of MetS. Cannabis contains 120 phytocannabinoids, of which Δ9-THC mediates its psychoactive effects. Cannabinoids exert biological effects through interactions with the endocannabinoid system, which modulates several physiologic and metabolic pathways through cannabinoid receptors (CB1/CB2). Signaling through both receptors inhibits neurotransmitter release. In general, endocannabinoid system stimulation in Cannabis smokers and Δ9-THC signaling through CB1 have been implicated in MetS development, obesity, and type 2 diabetes. In contrast, CB1 antagonists and non-psychotropic phytocannabinoids like cannabidiol reduce these effects through interactions with both cannabinoid and non-cannabinoid receptors. These pharmacological approaches represent a source of new therapeutic agents for MetS. However, more studies are necessary to support the therapeutic potential of Cannabis and cannabinoids in metabolic abnormalities.

The prevalence of obesity continues to increase and represents one of the principal causes of cardiovascular morbidity and mortality. After the discovery of a specific receptor of the psychoactive principle of marijuana, the cannabinoid receptors and their endogenous ligands, several studies have demonstrated the role of this system in the control of food intake and energy balance and its overactivity in obesity. Recent studies with the CB1 receptor antagonist rimonabant have demonstrated favorable effects such as a reduction in body weight and waist circumference and an improvement in metabolic factors (cholesterol, triglycerides, glycemia etc). Therefore, the antagonism of the endocannabinoid (EC) system, if recent data can be confirmed, could be a new treatment target for high risk overweight or obese patients. Obesity is a growing problem that has epidemic proportions worldwide and is associated with an increased risk of premature death (1-3). Individuals with a central deposition of fats have elevated cardiovascular morbidity and mortality (including stroke, heart failure and myocardial infarction) and, because of a growing prevalence not only in adults but also in adolescents, it was reclassified in AHA guidelines as a "major modifiable risk factor" for coronary heart disease (4, 5). Although first choice therapy in obesity is based on correcting lifestyle (diet and physical activity) in patients with abdominal obesity and high cardiovascular risk and diabetes, often it is necessary to use drugs which reduce the risks. The EC system represents a new target for weight control and the improvement of lipid and glycemic metabolism (6, 7).