We applied mouse microglial cells in culture activated by lipopolysaccharide (LPS, 10 ng/ml) to study the anti-inflammatory possible of cannabidiol (CBD), the significant nonpsychoactive element of cannabis. Beneath LPS stimulation, CBD (1-10 μM) potently inhibited the release of prototypical proinflammatory cytokines (TNF-α and IL-1β) and that of glutamate, a noncytokine mediator of inflammation. The effects of CBD have been predominantly receptor-independent and only marginally blunted by blockade of CB2 receptors. We established that CBD inhibited a mechanism involving, sequentially, NADPH oxidase-mediated ROS production and NF-κB-dependent signaling events. In line with these observations, active concentrations of CBD demonstrated an intrinsic absolutely free-radical scavenging capacity in the cell-absolutely free DPPH assay. Of interest, CBD also prevented the rise in glucose uptake observed in microglial cells challenged with LPS, as did the inhibitor of NADPH oxidase apocynin and the inhibitor of IκB kinase-two, TPCA-1. This indicated that the capacity of CBD to avoid glucose uptake also contributed to its anti-inflammatory activity. Supporting this view, the glycolytic inhibitor two-deoxy-d-glucose (two-DG) mimicked the antioxidant/immunosuppressive effects of CBD. Interestingly, CBD and two-DG, as effectively as apocynin and TPCA-1 brought on a reduction in glucose-derived NADPH, a cofactor essential for NADPH oxidase activation and ROS generation. These distinctive observations recommend that CBD exerts its anti-inflammatory effects towards microglia by means of an intrinsic antioxidant impact, which is amplified by means of inhibition of glucose-dependent NADPH synthesis. These outcomes also additional confirm that CBD might have therapeutic utility in circumstances exactly where neuroinflammatory processes are prominent.