Toward modulation of the endocannabinoid system for treatment of gastrointestinal disease: FAAHster but not “higher”

Cannabis has been used to treat various afflictions throughout the centuries, including nausea, vomiting, and pain. It has also been used recreationally for its psychotropic properties, which can include a pleasurable ‘high’ feeling and a decrease in anxiety and tension; however, other may experience dysphoria. Changes in cognition and psychomotor performance are also well‐known with cannabis use. In recent years, our understanding of the endocannabinoid system (ECS) has progressed dramatically; the objective of identifying agents which may allow modulation of the ECS without significant psychotropic side effects may be possible. Inhibition of fatty acid amide hydrolase (FAAH), an important enzyme for the degradation of anandamide and other endogenous cannabinoids, is a promising target to achieve this goal. In this issue of Neurogastroenterology and Motility, Fichna and colleagues report on a novel selective FAAH inhibitor, PF‐3845, with potent antinociceptive and antidiarrheal effects in a mouse model. In this context, we briefly review the components of the ECS, discuss pharmacologic targets for indirect cannabinoid receptor stimulation, and describe recent research with cannabinoids for gut disorders.