Following injury, the endocannabinoid system is activated in the brain suggesting a strategic role in the self-repair mechanisms. Indeed endocannabinoid system manipulation ameliorates traumatic brain injury (TBI) symptoms. Cannabidiol (CBD), together with △9-tetrahydrocannabinol (THC), is the main phytocannabinoid extracted from the plant Cannabis sativa, and it plays anti-inflammatory, antioxidant, neuroprotective, anticonvulsant, hypnotic, and antiemetic effects and has proven to be useful in neuropsychiatric, neurodegenerative, post-traumatic stress, and ischemic disorders. Unlike THC, CBD is not psychoactive and enhances the beneficial and reduces the side effects of THC. CBD has negligible action on cannabinoid receptors and modulates the endocannabinoid system throughout the inhibition of endocannabinoid degradation and reuptake. It also stimulates serotonin 1A (5-HT1A), adenosine 2A (A2A), transient receptor potential vanilloid subtype 1 (TRPV1), and nuclear peroxisome proliferator-activated receptor γ (PPARγ). We collect in this chapter all the preclinical and clinical evidence on the beneficial effects of CBD in the TBI considering it important for two main reasons: the lack of effective therapy for the TBI and the good tolerability of the CBD
