Antinociceptive interaction of Δ9-tetrahydrocannabinol and cannabidiol in a humanized mouse model of sickle cell disease.

Mabou Tagne A.; Ajeigbe O.; Avalos H.; Galvani F.; Al Masri S.; Mireles C.; Gupta K.; Piomelli D. · The Journal of pharmacology and experimental therapeutics · 2026

**Background & Methods** This preclinical study investigated the pharmacological interaction between Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) in HbSS-BERK mice, a humanized model of sickle cell disease (SCD). Researchers employed fixed-ratio isobolographic analyses to assess acute coadministration effects and examined sustained efficacy through 14 days of repeated treatment, with molecular analysis of spinal cord tissue and plasma biomarkers. **Key Findings** • Δ9-THC and CBD demonstrated dose-dependent antinociceptive effects when coadministered acutely. Isobolographic analysis revealed an additive (rather than synergistic) interaction, with experimentally determined median effective doses comparable to theoretical additive values, though differences were not statistically significant. • Repeated coadministration over 14 days maintained antinociceptive efficacy without tolerance development and reduced SCD-evoked anxiety-like behavior in tested cohorts. However, the combination did not improve recognition-memory deficits observed in the disease model. • Molecular analysis demonstrated that combined treatment produced superior anti-inflammatory effects compared to monotherapy: CBD alone reduced malondialdehyde (oxidative stress marker) and IL-1β transcription; Δ9-THC reduced malondialdehyde and increased IL-10 (anti-inflammatory cytokine); combined treatment simultaneously suppressed oxidative stress, reduced pro-inflammatory IL-1β signaling, and enhanced anti-inflammatory IL-10 expression. **Dosage & Administration** Not reported. The abstract does not specify doses, routes of administration, or treatment schedules beyond the 14-day repeated administration protocol. **Safety & Adverse Effects** Not reported. The study did not describe adverse effects or safety outcomes associated with acute or repeated cannabinoid coadministration in this model. **Evidence Quality** This is a preclinical study using a humanized mouse model, representing early-stage evidence with significant limitations for human translation. The additive (not synergistic) interaction observed reduces the pharmacological rationale for fixed-ratio combination formulations. The study's relevance to human SCD pain management is limited by species differences, controlled dosing conditions, and the absence of cognitive or motor outcome measures beyond memory recognition. No tolerance development was observed over 14 days, which is promising but does not address longer-term effects or potential cannabinoid-specific adverse events in human patients. Further human clinical trials are needed to establish safety, efficacy, dosing, and optimal THC:CBD ratios.

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