Endocannabinoids are synthesized and released ‘on-demand’ on the basis of physiological need.8 Augmenting released endocannabinoids can be achieved pharmacologically by blocking their reuptake from the extracellular space9 or interfering with their catabolic degradation by inhibiting the activity of endocannabinoid-degrading enzymes. The endocannabinoids anandamide and 2-arachidonoylglycerol are predominantly degraded by the respective catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and produce distinct behavioral effects.10,11 However, chronic inhibition of MAGL causes physical dependence, impaired endocannabinoid-mediated synaptic plasticity and CB1R desensitization, potentially limiting its therapeutic potential.12 These effects do not appear to be produced by chronic inhibition of FAAH.12
