FAAH belongs to the amidase signature (AS) superfamily and is expressed widely across the central nervous system, liver, small intestine, and reproductive organs. Its principal substrate is anandamide (N-arachidonoylethanolamine), one of the two best-characterised endogenous cannabinoids. Following cellular uptake of anandamide, FAAH catalyses hydrolysis of the amide bond, yielding arachidonic acid and ethanolamine. This catabolic step effectively terminates anandamide's signalling activity at CB1 and CB2 receptors, as well as at TRPV1 and certain nuclear receptors.
The enzyme's catalytic mechanism centres on an unusual Ser-Ser-Lys triad , distinct from the canonical Ser-His-Asp triad of most serine hydrolases , which confers substrate selectivity across a range of fatty acid amides beyond anandamide, including oleamide and palmitoylethanolamide (PEA). FAAH activity is highest in brain regions with dense CB1 receptor expression, including the hippocampus, cerebral cortex, and cerebellum, a co-localisation consistent with its role in spatially restricting endocannabinoid tone.
Pharmacological inhibition of FAAH has been studied extensively in preclinical models as a strategy for elevating endogenous anandamide levels without directly activating cannabinoid receptors. Selective FAAH inhibitors have been developed and, in some instances, progressed to early-phase human trials. Researchers have noted that this indirect approach produces a biochemically distinct profile from exogenous cannabinoid administration, though the clinical relevance of this distinction in humans remains under active investigation and no FAAH inhibitor is currently approved by the Therapeutic Goods Administration (TGA) for any indication in Australia.
A loss-of-function single nucleotide polymorphism in the human FAAH gene (C385A; Pro129Thr) has been associated in genetic studies with altered pain sensitivity, stress reactivity, and elevated peripheral anandamide. The hypothesis that reduced FAAH activity contributes to a "Clinical Endocannabinoid Deficiency" syndrome has been proposed in the literature, but this remains an unconfirmed hypothesis; causality has not been established and the concept is not recognised as a clinical diagnosis by any regulatory or medical authority.
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