Chronic Δ9-Tetrahydrocannabinol Vapor Self-Administration Modulates Gut Microbiota and the Immune and Endocannabinoid Systems in Female Sprague- Dawley Rats.

Rosado-Franco J.; Ellison A.; Weerts E.; Moore C.; Williams D. · bioRxiv : the preprint server for biology · 2026

**Background & Methods** This preclinical study investigated systemic effects of chronic THC exposure in adult female Sprague-Dawley rats (N=5-6 per group) using a passive vapor exposure followed by nine months of intermittent self-administered vaporized THC or vehicle control. Researchers analyzed gene expression in 14 brain regions and 9 peripheral organs, along with plasma biomarkers, immune function, and gut microbiota composition. **Key Findings** • Chronic THC vapor exposure selectively modulated endocannabinoid system gene expression in the brain (primarily dorsal striatum and hippocampus) while peripheral organ expression remained unchanged, despite widespread distribution of cannabinoid receptors throughout the body. • Brain-specific immune gene modulation occurred with altered expression of il-1β, il-6, ccl2, and mx1; however, peripheral organs showed no changes in these immune-related genes, suggesting CNS-selective immune effects. • Systemic effects were observed at the periphery, including elevated plasma IL-17A concentrations, gut microbiota dysbiosis, and significant alterations in circulating metabolites (amino acids, fatty acids, aminosugars, and nucleic acids), indicating whole-body metabolic consequences despite localized endocannabinoid and immune gene modulation. **Dosage & Administration** Not reported. Study utilized self-administered vaporized THC without specification of dose or concentration parameters. **Safety & Adverse Effects** Not reported. Study focused on molecular and physiological endpoints rather than clinical adverse effects or behavioral safety outcomes. **Evidence Quality** This preclinical animal study has significant limitations including small sample size (5-6 animals per group), single species/sex evaluation (female rats only), and lack of generalizability to human cannabis use patterns. As a preprint, findings lack peer review. The nine-month exposure duration in rodents provides some chronic exposure modeling but does not fully parallel human adolescent or adult consumption patterns. The disconnect between brain-selective endocannabinoid/immune gene changes and systemic metabolic/microbiota changes requires mechanistic clarification. Findings represent exploratory evidence suggesting THC's complex body-wide effects warrant further investigation in larger studies with dose-response characterization and mechanistic pathway elucidation.

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