Cannabinoids for clinicians: the rise and fall of the cannabinoid antagonists

The endocannabinoid system has emerged as a significant player in the control of energy balance and metabolism, through its direct central and peripheral effects, as well as via its interaction with other appetite-regulating pathways. There is mounting evidence that the endocannabinoid system is overactive in obesity and were it possible to safely dampen-down the elevated endocannabinoid tone, lipid and carbohydrate profiles could be improved and weight loss induced. The series of randomised clinical trials showed reproducible beneficial effects on weight, HbA1c and lipid parameters, in addition to other cardiovascular risk factors. However, to date, clinical developments have been halted because of psychiatric side effects. Although recent evidence has highlighted the importance of an appetite-independent, peripheral mode of action, it is still unclear whether selectively blocking the peripheral system could potentially solve the problem of the central side effects, which thus far has led to the demise of the cannabinoid antagonists as useful pharmaceuticals. In this concise review, we summarise the data on the metabolic effects of the cannabinoid pathway and its antagonists.