Modulation of postictal hypoxia: Sex- and route-specific effects of acute and chronic cannabidiol and Delta9-tetrahydrocannabinol

-tetrahydrocannabinol (THC), the primary phytocannabinoids from cannabis, have been shown to exhibit vasoactive and antioxidant properties that may mitigate the local oxygen deficiency observed after seizures. Here, we focus on the effects of CBD and THC on seizure-induced hypoxia. Adult Long-Evans rats of both sexes were assigned to drug-specific cohorts and the effects on local hippocampal oxygen were measured before and after seizure elicitation following either vaporized or oral administration of the two phytocannabinoids. Acute effects were assessed following a single administration of each drug, whereas chronic effects were evaluated over 28 days of daily treatment. In naïve rats, acute vaporized CBD significantly attenuated postictal hypoxia in both sexes, whereas acute oral THC attenuated postictal hypoxia in male rats. With chronic daily administration, phytocannabinoids produced time-dependent adaptations. Chronic vaporized CBD in females and chronic oral THC in males maintained attenuating effects on postictal hypoxia but exhibited partial tolerance, characterized by diminished effects on postictal oxygen decline in both sexes, recovery of postictal oxygen in females, and severity of hypoxia in males. These results demonstrate that acutely and chronically administered phytocannabinoids attenuate postictal hypoxia in a route-, sex-, and time-dependent manner. Together, these findings provide evidence that vaporized CBD and oral THC hold potential to treat the postictal hypoxia-induced comorbidities associated with seizures, potentially increasing the overall quality of life of people with epilepsy.