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Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation. The Fmr1 knockout model recapitulates the main traits of the disease. Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5)^, and mammalian target of rapamycin (mTOR) signaling^,, seem crucial in the pathology of this disease. The endocannabinoid system (ECS) is a key modulator of synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility, all of which are affected in FXS. The cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are activated by phospholipid-derived endocannabinoids, and CB1R-driven long-term regulation of synaptic strength, as a consequence of mGluR5 …