Impact of Cannabidiol and Its Synthetic Derivative on Fentanyl Consumption and Fentanyl-Induced Neurometabolic Alterations in Mice.

AlKhelb D.; Alahmadi J.; Alqarni M.; Ahamad S.; Alameen A.; Altuwaijri A.; AlSharari S.; Alasmari F. · Molecules (Basel, Switzerland) · 2026

**Background & Methods** This preclinical study investigated cannabidiol (CBD) and a synthetic CBD derivative (L-1β-IN-1) as potential therapeutics for opioid use disorder in C57BL/6 male mice. Researchers employed multiple behavioral assays (two-bottle choice preference testing, hot plate analgesia assessment, and marble-burying compulsivity evaluation) alongside neurometabolic profiling to evaluate the compounds' effects on fentanyl consumption, reward-seeking, pain processing, and brain metabolic signatures. **Key Findings** • CBD (10 mg/kg) and L-1β-IN-1 (5-25 mg/kg) significantly reduced fentanyl preference scores to below 0.5, demonstrating decreased fentanyl reward-seeking behavior compared to vehicle controls. • Pretreatment with CBD or L-1β-IN-1 showed trends toward enhanced analgesic effects in hot plate testing; however, no significant effects were observed in marble-burying assays, indicating absence of acute stereotypic/compulsive behavioral changes. • Fentanyl monotherapy produced robust metabolic activation in brain tissue, while co-administration with CBD or L-1β-IN-1 produced distinct metabolic profiles that modulated fentanyl-induced neurometabolic alterations. **Dosage & Administration** CBD: 10 mg/kg intraperitoneal injection. L-1β-IN-1: 5-25 mg/kg intraperitoneal injection. Specific treatment duration and dosing schedules not detailed in abstract. **Safety & Adverse Effects** No adverse effects or safety concerns were specifically reported in the study abstract. The marble-burying assay indicated no acute stereotypic adverse effects with pretreatment compounds. **Evidence Quality** This is a preclinical animal study with significant translational limitations. Findings are restricted to mouse models and cannot be directly extrapolated to human populations. The study lacks information regarding sample sizes, statistical power, or detailed methodology. As a basic research investigation, evidence quality is considered preliminary; human clinical trials would be necessary to establish safety, efficacy, and optimal dosing for opioid use disorder treatment. The neurometabolic findings require further mechanistic characterization to clarify therapeutic pathways. Results suggest CBD and its synthetic derivatives warrant further investigation as adjunctive OUD therapies, but clinical applicability remains unestablished.

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