Modulation of Postictal Hypoxia: Sex- and Route-Specific Effects of Acute and Chronic Cannabidiol and Delta9-tetrahydrocannabinol.

Rha S.; Gom R.; Bascope V.; Fick L.; Imoukhuede A.; Hume C.; Lightfoot S.; Hill M.; Teskey G. · Neuropharmacology · 2026

**Background & Methods** This study investigated the effects of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) on postictal hypoxia in adult Long-Evans rats of both sexes. Researchers measured local hippocampal oxygen levels before and after seizure induction following either vaporized or oral administration of phytocannabinoids, evaluating both acute (single dose) and chronic (28-day daily treatment) effects. **Key Findings** • Acute vaporized CBD significantly attenuated postictal hypoxia in both male and female rats, while acute oral THC demonstrated attenuation only in males, indicating route- and sex-specific effects. • Chronic daily administration produced time-dependent adaptations with partial tolerance development: chronic vaporized CBD maintained protective effects in females with diminished postictial oxygen decline, while chronic oral THC maintained effects in males but showed reduced severity of hypoxia. • The phytocannabinoids demonstrated vasoactive and antioxidant properties that mitigated seizure-induced local oxygen deficiency through sex-dependent and administration route-dependent mechanisms. **Dosage & Administration** Not reported. The abstract does not specify the doses of CBD or THC administered via vaporized or oral routes. **Safety & Adverse Effects** Not reported. The abstract does not provide information regarding adverse effects or safety outcomes associated with acute or chronic CBD and THC administration. **Evidence Quality** This is a preclinical animal study with significant limitations regarding clinical applicability. The use of rodent models limits direct translation to human epilepsy populations. The study's primary strength is its systematic evaluation of sex differences and route-specific effects across acute and chronic timeframes. However, the lack of reported dosing information and absence of safety data limit comprehensive assessment. The demonstrated tolerance development with chronic administration raises questions about long-term therapeutic efficacy in clinical settings. While findings suggest potential for CBD and THC in managing postictal hypoxia-related comorbidities, substantial additional research—including dose-response studies, mechanistic investigations, and human clinical trials—would be necessary before clinical implementation. The sex-dependent and route-dependent effects highlight the importance of considering these variables in future therapeutic development.

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