Endocannabinoid system in the regulation of appetite with pharmaceutical applications

Abstract

The endocannabinoid system (ECS) is a molecular network that consists of two cannabinoid receptors (CB1 and CB2) along with their endogenous ligands, anandamide and 2-arachidonoyl glycerol. The ECS is expressed throughout the central nervous system as well as some peripheral organs and tissues. In the brain, it regulates various neural processes related to mood, memory, cognition, and behavior by mediating synaptic signaling between neurons. The discovery of the ECS was preceded by the isolation of tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, in the 1960s. THC has also been identified as the chemical that causes hyperphagia, as in excessive appetite and hedonic eating, upon cannabis consumption.

Similarly to plant-derived cannabinoid agonists, endocannabinoids are known to stimulate appetite and feeding behavior, as they are secreted by homeostatic brain circuits as well as the gastrointestinal tract in response to hunger and food deprivation. Correspondingly, dysregulation of the ECS has been observed in altered states of energy metabolism, such as diet-induced obesity and eating disorders. Cannabinoid agonists also have antiemetic properties, as they prevent nausea and vomiting. On these grounds, THC and its analogues can be used as antiemetics and appetite stimulants in disorders that manifest as nausea, vomiting, and loss of appetite. Cannabinoid receptor blockers in turn are being studied as appetite suppressants for obesity, although the first-in-class CB1 receptor inverse agonist, rimonabant, had to be withdrawn from the market due to psychiatric side effects. Bearing in mind the past challenges, further research is needed to develop effective yet safe ECS-targeting pharmaceuticals for these purposes.