The endocannabinoid system has emerged as an important regulator of stress and emotional processing, but a potentially intractable target for neuropsychiatric medications due to widespread effects on a variety of behaviors. Our mouse data suggest that, by preventing FAAH-mediated degradation, augmenting anandamide in the basolateral amygdala may boost on-demand recruitment of endocannabinoids to facilitate the extinction of traumatic fear memories. Further we report an association between a putative loss-of-function human FAAH gene variant, an amygdala fear-plasticity endophenotype, and reduced trait stress reactivity. The collective results of our study support the endocannabinoid system and FAAH as a key signaling mechanism regulating fear plasticity that is conserved across mouse and man. More generally, our approach illustrates the broad potential of focused translational research bridging animal models and human studies. Further work will be needed to test the possibility of targeting of endocannabinoids, via FAAH inhibition, as a novel approach to treating fear-related disorders.
