BACKGROUND AND PURPOSEWhile cannabinoids have been proposed as a potential treatment for neuropathic pain, they have limitations. Cannabinoid receptor agonists have good efficacy in animal models of neuropathic pain; they have a poor therapeutic window. Conversely, selective fatty acid amide hydrolase (FAAH) inhibitors that enhance the endocannabinoid system have a better therapeutic window, but lesser efficacy. We examined whether JZL195, a dual inhibitor of FAAH and monacylglycerol lipase (MAGL), could overcome these limitations. EXPERIMENTAL APPROACHC57BL/6 mice underwent the chronic constriction injury (CCI) model of neuropathic pain. Mechanical and cold allodynia, plus cannabinoid side effects, were assessed in response to systemic drug application. KEY RESULTSJZL195 and the cannabinoid receptor agonist WIN55212 produced dose-dependent reductions in CCI-induced mechanical and cold allodynia, plus side effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED 50 at least four times less than that at which it produced side effects. By contrast, WIN55212 reduced allodynia and produce side effects with similar ED50s. The maximal anti-allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195-induced anti-allodynia was maintained during repeated treatment. CONCLUSIONS AND IMPLICATIONSThese findings suggest that JZL195 has greater anti-allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. Thus, dual FAAH/MAGL inhibition may have greater potential in alleviating neuropathic pain, compared with selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists.