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Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. The initial injury is followed by a series of secondary processes that can further harm the injured brain and worsen the outcome. The endocannabinoid system (ECS) consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g., Cannabinoid receptor type 1 and Cannabinoid receptor type 2), as well as transporters, and enzymes. Dexanabinol (HU-211) is a synthetic cannabinoid with cerebroprotective effects devoid of cannabimimetic effects, which exhibits the pharmacological properties of N-Methyl-D-aspartate receptor antagonist. The increase in the brain levels of endocannabinoids in the pathogenic events of brain injury suggests that this system plays a role in compensatory repair mechanisms. In recent year, the therapeutic effects of cannabinoid manipulative drugs have been numerously studied through the manipulation of the ECS in TBI. Therefore, the literature review was performed to assess the therapeutic effects of ECS manipulation, cannabinoid-derived drugs, and HU-211 in traumatic brain injury pathology. The ECS possesses promising effects in the treatment of diverse TBI pathologies through releasing endogenous ligands and changes in cannabinoid receptors activity or both. Preclinical studies suggest that the ECS has many targets for therapeutic agents that might help decrease TBI pathologic effects and should be considered for developing novel drugs. Furthermore, more clinical trials with larger populations and more extended follow-up periods should be performed for a better understanding of the effects of ECS manipulative drugs.

Effects of endocannabinoid system, synthetic and nonsynthetic cannabinoid drugs on traumatic brain injury outcome: a narrative review