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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'. human studies evidence suggest that cannabidiol (CBD), a non-psychotomimetic substance found in the Cannabis sativa plant, could be a relatively safe and effective treatment to regulate abnormally persistent and disturbing memories associated with anxiety, stress, and drug use disorders. cannabinoids can interact with a non-canonical signaling network by modulating ionotropic cannabinoid receptors (TRP channels) and other GPCRs (GPR55, PPARα) [164]. Through this modulation of synaptic efficacy they have an important role in many brain processes including memory, anxiety and movement [165,166]. The CB1 receptor is the most abundant G-protein-coupled receptor in mammalian brain. Animal and human studies published over the past decades suggest that cannabidiol (CBD) can be a relatively safe and effective treatment for several mental health conditions such as epilepsy, schizophrenia, anxiety, and affective disorders (for a review, see Crippa et al., 2018; Elsaid et al., 2019; Friedman et al., 2019; Luján and Valverde, 2020; Bitencourt et al., 2021; Britch et al., 2021; Franco et al., 2021; Petrie et al., 2021) . Growing evidence indicates that CBD may also potentially regulate abnormal emotional memories associated with posttraumatic stress and drug use disorders.