FAAH

FAAH is a serine hydrolase, identified and cloned by Cravatt et al. (1996, Nature 384:83), that hydrolyzes anandamide and other fatty acid amides (PEA, OEA) to their corresponding free fatty acids and ethanolamine. FAAH is a major brake on endocannabinoid tone at the AEA arm of the system. Pharmacological FAAH inhibitors (URB597, PF-04457845) elevate AEA and produce anxiolytic, analgesic, and antidepressant-like effects in rodents. Human clinical translation has been mixed: PF-04457845 showed modest analgesic signals but failed as an osteoarthritis therapeutic. The BIA 10-2474 phase-1 disaster (France, 2016) in which one volunteer died and several sustained brain injury was traced to off-target activity, not to on-target FAAH inhibition per se (Kerbrat et al., 2016, New England Journal of Medicine 375:1717), but the event reshaped the regulatory approach to FAAH drug development. → See also: Anandamide, MAGL, Endocannabinoid.