Preclinical studies offer strong support for a major role of FAAH, via effects on BLA AEA–CB1R signaling, in modulating stress-induced anxiety and fear extinction. Moreover, recent clinical reports have demonstrated decreased peripheral levels of AEA and increases in brain CB1R-binding in patients with anxiety disorders, such as post-traumatic stress disorder [107]. Taken together, these findings encourage the development of novel anxiolytics based around restoring deficient AEA levels by pharmacologically inhibiting FAAH. Encouragingly, preliminary clinical trials with selective FAAH inhibitors, including PF04457845 and URB597, are either underway (www.clinicaltrials.gov/ct2/show/NCT01665573) or being planned. The `on-demand' nature of ECB release makes it a particularly attractive target for drug development because FAAH inhibitors would selectively augment CB1R signaling in neural circuits where AEA was recruited [52]. This refined mechanism of action would avoid the widespread activity of THC or CB1R agonism and, as a result, is expected to produce fewer clinically unwanted side effects and be less liable to CB1R downregulation after repeated dosing. Although this prediction awaits thorough clinical investigation, and some important questions also remain to be addressed (Box 4), the field is at an exciting juncture and has genuine promise for advancing our understanding and treatment of anxiety disorders.
