The complex regional pain syndrome (CRPS) is a disabling neuropathic pain condition that may develop following injuries of the extremities. The pathogenesis of this syndrome is not clear; however, it includes complex interactions between the nervous and the immune system resulting in chronic inflammation, pain and trophic changes. This interaction may be mediated by chronic stress which is thought to activate the endogenous cannabinoid (endocannabinoid) system (ECS). We conducted an open, prospective, comparative clinical study to determine plasma level of the endocannabinoid anandamide by high-performance liquid chromatography and a tandem mass spectrometry system in 10 patients with CRPS type I versus 10 age- and sex-matched healthy controls. As compared to healthy controls, CRPS patients showed significantly higher plasma concentrations of anandamide. These results indicate that the peripheral ECS is activated in CRPS. Further studies are warranted to evaluate the role of the ECS in the limitation of inflammation and pain. Copyright (C) 2009 S. Karger AG, Basel