Endocannabinoid system enzymes (ECS enzymes)

The endocannabinoid system (ECS) enzymes are a group of metabolic proteins responsible for the synthesis and degradation of endogenous cannabinoids, primarily anandamide (AEA) and 2-arachidonoylglycerol (2-AG) (Int. J. Mol. Sci., 2018; Wikipedia). Key enzymes include fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which degrade AEA and 2-AG respectively, as well as biosynthetic enzymes like N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL) (NIH, 2020). These enzymes maintain endocannabinoid tone, which regulates a wide array of physiological processes including pain sensation, mood, appetite, and immune response (Healthline, 2021; Medical News Today, 2021). Dysregulation of these enzymes is implicated in various pathologies, such as chronic pain, neurodegenerative diseases, and psychiatric disorders (Frontiers in Psychiatry, 2018; BMS, 2025). Pharmacological targeting of ECS enzymes, particularly through inhibition of FAAH and MAGL, offers a therapeutic strategy to enhance endocannabinoid signaling indirectly (Annual Review of Pharmacology and Toxicology, 2021). This approach potentially avoids the adverse psychotropic effects associated with direct cannabinoid receptor agonists like THC (NIH, 2022). However, drug development in this area has faced challenges, including off-target toxicity and the need for precise modulation to avoid receptor desensitization (Annual Review of Pharmacology and Toxicology, 2021). Notable examples of drugs in development include FAAH inhibitors like PF-04457845 and MAGL inhibitors like ABX-1431 (NIH, 2022).

Other names

Endocannabinoid metabolic enzymesEndocannabinoid biosynthetic and degradative enzymesEndocannabinoidome enzymes

Modulation of endocannabinoid tone through the inhibition of biosynthetic or degradative enzymes. Inhibition of degradative enzymes like FAAH and MAGL increases levels of anandamide and 2-arachidonoylglycerol, respectively, leading to indirect activation of cannabinoid receptors. Conversely, inhibition of biosynthetic enzymes like DAGL reduces endocannabinoid levels.