Targeting Endocannabinoid Signaling: FAAH and MAG Lipase Inhibitors

Inspired by the medicinal properties of the plant Cannabis sativa and its principal component (-)-trans-Δ⁹-tetrahydrocannabinol (THC), researchers have developed a variety of compounds to modulate the endocannabinoid system in the human brain. Inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are the enzymes responsible for the inactivation of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, respectively, may exert therapeutic effects without inducing the adverse side effects associated with direct cannabinoid CB₁ receptor stimulation by THC. Here we review the FAAH and MAGL inhibitors that have reached clinical trials, discuss potential caveats, and provide an outlook on where the field is headed. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.