Alternative pharmacotherapy approaches may arise from improved understanding of the neuropharmacology of cannabis use disorders, including the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence [55]. These findings suggest that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters anandamide and 2-arachidonoylglycerol (2-AG) might alleviate cannabis withdrawal and dependence. One such agent, the FAAH inhibitor URB597, selectively increased anandamide levels in the brain of rodents and primates. Preclinical studies showed that URB597 produced analgesic, anxiolytic-like, and antidepressant-like effects in rodents, which were not accompanied by overt signs of abuse liability. This evidence suggests that FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal [55].
