Fig. 3
Proposed mechanism(s) of action of cannabidiol on the ECS in FXS. Treatment of FXS with cannabidiol is proposed to lead to (1) cannabidiol’s acting as a negative allosteric modulator (NAM) at the CB1 receptors, resulting in (2) reduction of β-arrestin recruitment, along with prevention of internalization and desensitization of CB1 receptors in the presence of ectopic/abnormal 2-AG, which leads to (3) restoration of retrograde inhibitory signaling and (4) reduction in glutamate release and activation of mGluR5 receptors and (5) restoration of GABAergic function. 2-AG, 2-arachidonoylglycerol; β-arr, β-arrestin; CB1, cannabinoid type 1 receptor; CBD, cannabidiol; DAG, diacylglycerol; DAGL, diacylglycerol lipase; DGKκ, diacylglycerol kinase-κ; ECS, endocannabinoid system; FMRP, FMR1 protein; FXS, fragile X syndrome; G, G proteins; GABA, γ-aminobutyric acid; mGluR5, group I metabotropic glutamate receptor 5; PA, phosphatidic acid; PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase C