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

The takeaway

FAAH, the main enzyme that breaks down endocannabinoids, modulates mood, pain, reward, appetite, and inflammation, but clinical trials of FAAH inhibitors have produced less striking results than animal models predicted.

Pharmacologists, drug developers, neuroscientists, pain researchers.

FAAH inhibitor clinical trials have produced less striking results than animal models predicted

What the researchers found

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.

Why it matters

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 numbers in context

FAAH discovered in 1996. Involved in mood, pain, reward, appetite, and inflammation. Genetic variants linked to substance use disorders, obesity, eating disorders. Clinical trial results less striking than animal predictions.

How the study worked

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

What this study cannot tell us

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.

How to read the evidence

Comprehensive narrative review integrating genetic, neuroimaging, and clinical trial evidence.

When this study was published

Published in 2023.

The bigger picture

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.

Questions still open

Can patient selection based on FAAH genetic variants improve clinical trial outcomes?
Would combining FAAH inhibition with other endocannabinoid-modulating approaches be more effective?

Common questions

What is FAAH and why does it matter?

FAAH is the main enzyme that breaks down endocannabinoids in the body. It influences mood, pain, appetite, and inflammation, making it a promising but so far disappointing drug target.

Why havent FAAH-targeting drugs worked well?

Clinical trials have produced modest results compared to impressive animal studies. The reasons may include species differences, dosing challenges, and the complexity of modulating a system that affects multiple pathways.

Read the original research

Fatty Acid Amide Hydrolase: An Integrative Clinical Perspective.

Cannabis and cannabinoid research, 8(1), 56-76

View on PubMed ↗Publisher’s paper ↗

Citation

Santoso, Anugrah D; De Ridder, Dirk. (2023). Fatty Acid Amide Hydrolase: An Integrative Clinical Perspective.. Cannabis and cannabinoid research, 8(1), 56-76. https://doi.org/10.1089/can.2021.0237