NEUROINFLAMMATION, EXCITOTOXICITY AND OXIDATIVE STRESS ARE THE KEY MEDIATORS OF NEURODEGENERATION. ON THE OTHER HAND, THE END OCannabinoid (ECB) system IS CONSIDERED AS A REGULATOR OF MANY NEURONAL MECHANISMS THAT ARE RELEVANT TO NEURODEGENERATIVE DISORDERS. THE EXPRESSION LEVEL OF Cannabinoid RECEPTORS IN NEURONS AND GLIAL CELLS MAY CHANGE IN A NEUROLOGICAL DISEASE AND CHRONIC ALTERATIONS IN ECB SIGNALLING ARE OFTEN ACCOMPANIED WITH CHRONIC ACTIVATION OF THE IMMUNE system AND A NUMBER OF IMMUNE CELLS. ACTIVATION OF CB1 AND CB2 RECEPTORS ARE KNOWN TO BE INVOLVED IN THE REGULATION OF CALCIUM HOMEOSTASIS, MITOCHONDRIAL FUNCTION, AND NEUROTROPHIC PROCESS, WHILE OTHER RECEPTORS GATED BY CannabinoidS SUCH AS PPARG, ARE GAINING INTEREST IN THEIR ANTI-INFLAMMATORY PROPERTIES. BASED ON THESE MECHANISMS, DURING THE LAST TWO DECADES, PHARMACOLOGICAL MANIPULATION OF THE ENDOGENOUS Cannabinoid system, AS WELL AS APPLICATION OF PHYTOCannabinoidS AND SYNTHETIC CannabinoidS HAVE BEEN INVESTIGATED TO FIND NEW THERAPIES FOR NEURODEGENERATIVE CONDITIONS AND TARGETING THE Cannabinoid system HAS EMERGED AS A POTENTIAL THERAPEUTIC APPROACH TO TREAT MANY NEURODEGENERATIVE DISEASES SUCH AS MULTIPLE SCLEROSIS (MS), PARKINSON’S DISEASE (PD), AND ALZHEIMER’S DISEASE (AD). MOST OF THE SUPPORTING EVIDENCE HAS BEEN OBTAINED BY USING CELLULAR AND ANIMAL MODELS. META-ANALYSIS OF CLINICAL TRIAL REPORTS REVEALED THAT MOST BENEFICIAL EFFECTS OF CannabinoidS HAVE BEEN SHOWN IN THE TREATMENT OF MS. IN FACT, THERE IS MODERATE-QUALITY EVIDENCE FOR BENEFICIAL EFFECTS OF CannabinoidS IN RELIEVING SPASTICITY, NEUROPATHIC PAIN OR PAINFUL SPASMS, AND URINARY DYSFUNCTION IN MS PATIENTS. ORAL ADMINISTRATION OF Cannabinoid COMPOUNDS IS PROBABLY INEFFECTIVE FOR TREATING LEVODOPA INDUCED DYSKINESIA IN PATIENTS WITH PD. MOREOVER, ORAL CannabinoidS ARE OF UNKNOWN EFFICACY IN NON–CHOREA-RELATED SYMPTOMS OF HUNTINGTON DISEASE, TOURETTE SYNDROME, CERVICAL DYSTONIA, AND EPILEPSY. IT SHOULD BE NOTED THAT THE RISKS AND BENEFITS OF MEDICAL CannabinoidS SHOULD BE WEIGHED CAREFULLY. RISK OF SERIOUS ADVERSE PSYCHOPATHOLOGIC EFFECTS WAS NEARLY 1% AND CONSISTED OF ADDICTION, WITHDRAWAL SYNDROME, IMPAIRED MOTOR COORDINATION, SCHIZOPHRENIA, MOOD DISORDERS, AND PROGRESSION TO USE OF OTHER DRUGS. DESPITE THE FACTS MENTIONED ABOVE, THERE IS STILL TREND USING Cannabinoid COMPOUNDS WITH NO PSYCHOACTIVE ADVERSE EFFECTS SUCH AS CANNABIDIOL OR USING SELECTIVE ACTIVATOR OF CB2 RECEPTORS. AUGMENTATION OF ECB system IN THE CNS BY INHIBITING RELEVANT ENZYMES OR TRANSPORTERS IS ANOTHER THERAPEUTIC STRATEGY THAT WOULD BE EFFECTIVE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES WITH LESS ADVERSE EFFECTS.