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The literature supports various pathophysiologies in individuals affected with autism spectrum disorder (ASD), including cerebral hypoperfusion, inflammation, mitochondrial dysfunction and
oxidative stress. It has been hypothesized that children affected with ASD might benefit from Hyperbaric oxygen treatment (HBOT) owing to the increase in cerebral perfusion occurring during treatment. Various hyperbaric centers have utilized HBOT to treat individuals with autism spectrum disorders (ASD). The cell-danger response and endocannabinoid signaling pathways have been described as possible key elements in the pathophysiology of microglia driven neuroinflammation, with resulting behavioral problems associated with ASD. With the growing body of evidence in the literature that describes beneficial phytocannabinoid effects in patients affected with ASD, we highlight the principle mechanisms of a novel concept, e.g. phytocannabinoid-hyperbaric-oxygen synergy and its role in paving the way for faster and lasting clinical benefits.