Delta-8-tetrahydrocannabinol ameliorates murine autoimmune hepatitis and is associated with epigenetic modulation of immune responses.

Hamida H.; Kakar K.; Palrasu M.; Marudamuthu A.; Yang X.; Halder U.; Wilson K.; Nagarkatti P.; Nagarkatti M. · International immunopharmacology · 2026

**Background & Methods** This preclinical study investigated delta-8-tetrahydrocannabinol (Δ8-THC) effects in concanavalin A (ConA)-induced autoimmune hepatitis using female C57BL/6 mice. Researchers employed miRNA sequencing, flow cytometric analysis, qRT-PCR, Western blot, and functional assays including miRNA transfection and CD4+ T-cell differentiation studies to elucidate molecular and epigenetic mechanisms of action. **Key Findings** • Δ8-THC markedly suppressed ConA-induced autoimmune hepatitis by restoring hepatic immune homeostasis, specifically reducing inflammatory monocytes, neutrophils, and natural killer cells while preserving tolerogenic Kupffer cells and expanding regulatory T cells (Tregs). • Treatment preserved expression of hepatoprotective microRNAs (miR-100-5p and miR-199a-3p) that were downregulated following ConA exposure, with mTOR identified as a direct target of these miRNAs in T cells and macrophages. • Functional validation demonstrated that miR-100-5p/miR-199a-3p-mediated mTOR suppression promotes Treg differentiation while limiting pro-inflammatory Th1 and Th17 polarization, establishing a mechanistic pathway for Δ8-THC's immunoregulatory effects. **Dosage & Administration** Δ8-THC was administered at 20 mg/kg via intraperitoneal injection; ConA was administered at 12.5 mg/kg intravenously. Clinical dosing in humans not evaluated in this study. **Safety & Adverse Effects** Not reported. This preclinical murine study did not assess adverse effects or safety parameters in the experimental protocol. **Evidence Quality** This is a basic science study with significant limitations regarding clinical applicability. Evidence is restricted to a single murine autoimmune hepatitis model using inbred female mice, limiting generalizability to human autoimmune hepatitis and mixed-sex populations. The ConA-induced model, while established, may not fully recapitulate human disease pathophysiology. No human clinical trials, dose-ranging studies, or safety assessments were conducted. The mechanistic findings are robust at the molecular level but require validation in additional animal models and eventual human studies before clinical translation. Publication as a 2026 review article suggests synthesis of existing literature, though the abstract presents original experimental data. Long-term efficacy, optimal dosing, and comparative effectiveness versus standard immunosuppressive therapies remain unexplored.

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