Taken together, these prior studies raise the possibility that inhibiting FAAH to selectively boost endogenously recruited anandamide in corticolimbic circuits could drive long-term reductions in fear following extinction. Furthermore, such effects would be predicted to occur in the absence of concomitant alterations in cannabinoid-mediated central nervous system and peripheral functions produced by nonspecifically augmenting anandamide and 2-arachidonoylglycerol levels, or by indiscriminate CB1R activation. This functional selectivity is of critical relevance to the side-effect burden and potential clinical utility of FAAH inhibitors for anxiety disorders. In fact, even prototypical FAAH inhibitors (for example, URB597) can produce unwanted peripheral effects, including hyperglycemia and insulin resistance.19 This study therefore employed a novel compound, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride), that is a highly potent and selective FAAH inhibitor,20 but devoid of undesirable hepatic effects.19
