Endocannabinoids, cannabinoids and the regulation of anxiety.

Cannabis has been used for hundreds of years, with its ability to dampen feelings of anxiety often reported as a primary reason for use. Only recently has the specific role cannabinoids play in anxiety been thoroughly investigated. Here we discuss the body of evidence describing how endocannabinoids and exogenous cannabinoids are capable of regulating the generation and termination of anxiety states. Disruption of the endogenous cannabinoid (eCB) system following genetic manipulation, pharmacological intervention or stress exposure reliably leads to the generation of an anxiety state. On the other hand, upregulation of eCB signaling is capable of alleviating anxiety-like behaviors in multiple paradigms. When considering exogenous cannabinoid administration, cannabinoid receptor 1 (CB1) agonists have a biphasic, dose-dependent effect on anxiety such that low doses are anxiolytic while high doses are anxiogenic, a phenomenon that is evident in both rodent models and humans. Translational studies investigating a loss of function mutation in the gene for fatty acid amide hydrolase, the enzyme responsible for metabolizing AEA, have also shown that AEA signaling regulates anxiety in humans. Taken together, evidence reviewed here has outlined a convincing argument for cannabinoids being powerful regulators of both the manifestation and amelioration of anxiety symptoms, and highlights the therapeutic potential of targeting the eCB system for the development of novel classes of anxiolytics. This article is part of the special issue on 'Cannabinoids'.