A Clinical Review of FAAH, the Enzyme That Breaks Down Endocannabinoids, Found Broad Therapeutic Potential But Disappointing Drug Trials

FAAH is highly expressed in both the central nervous system and peripheral tissues. It modulates mood/emotional response, reward systems, pain perception, energy metabolism, appetite, and inflammation. Genetic variants may be associated with substance use disorders, obesity, and eating disorders. Clinical trials of FAAH inhibitors have shown some potential but results are less impressive than animal models suggested. Neuroimaging can now evaluate FAAH in brain tissue.

Comprehensive multidisciplinary review of FAAH-related clinical and experimental evidence, covering biological plausibility, genetic studies, neuroimaging, and clinical trials.

FAAH inhibition was seen as a way to get the benefits of the endocannabinoid system without the side effects of cannabis. Understanding why clinical results have been disappointing helps calibrate expectations and identify which patients might benefit most.

The gap between impressive animal results and modest human trials is a recurring theme in cannabinoid drug development. This may reflect species differences in endocannabinoid system distribution (as shown by other studies), dosing challenges, or the fact that modulating a single enzyme affects multiple pathways simultaneously.

Narrative review without systematic methodology. Clinical trial data are still limited. FAAH inhibitor safety concerns after the 2016 BIA 10-2474 trial (though that was likely due to off-target effects). Translation from animal models remains challenging.