FAAH and anandamide: is 2-AG really the odd one out?

Fatty acid amide hydrolase (FAAH) is a hydrolytic enzyme that recognizes as substrates and inactivates the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG). Following the observation that endocannabinoids produced by tissues during pathological conditions often have protective roles, FAAH inhibitors have been proposed as therapeutic drugs. Yet it has been suggested that FAAH functions in vivo only as an anandamide-degrading enzyme because its pharmacological and genetic inactivation is usually accompanied by elevation of anandamide, but not 2-AG, levels. We believe, however, that this concept needs to be revisited in light of reports that, under certain experimental conditions, FAAH inhibitors also elevate 2-AG tissue levels in vivo and, more recently, that FAAH inactivation in the striatum instead reduces 2-AG concentrations through upregulation of anandamide levels, activation of transient receptor potential vanilloid 1 receptors and inhibition of 2-AG biosynthesis.