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

Background: Opioid use disorder (OUD) remains a critical global health challenge, with highly potent synthetic opioids like fentanyl contributing to overdose deaths. The available treatments have limitations. The endocannabinoid system has emerged steadily as a therapeutic target for the opioid crisis due to its modulatory effects on opioid reward and withdrawal and its involvement in regulating inflammation. These studies investigate the potential of cannabidiol (CBD) and its synthetic derivative (L-1β IN-1) in mitigating fentanyl effects. Methods: C57BL/6 male mice were used in several behavioral assays: two-bottle choice (TBC) to measure fentanyl reward/seeking behaviors, hot plate to assess antinociception, and marble burying to evaluate compulsive/adverse effects. Additionally, a neurometabolic study was conducted to evaluate the impact of chronic high doses of fentanyl alone and in combination with CBD or L-1β-IN-1 on brain metabolic signatures. Results: The mice consistently preferred to drink fentanyl, and i.p. injections of 10 mg/kg CBD or 5–25 mg/kg of L-1β-IN-1 decreased the fentanyl preference scores to values below 0.5. The antinociceptive effects of pretreatment groups showed a trend of enhanced analgesic effects in the hot plate assay. However, they showed no significant changes in the marble-burying assay, suggesting that pretreatment with these compounds lacks acute stereotypic effects. The Fentanyl metabolomics revealed robust metabolic activation with fentanyl alone, while CBD or L-1β-IN-1 showed different profiles in modulating these fentanyl-induced metabolic signatures. Conclusions: These studies provide evidence about the in vivo behavioral and neurometabolic profiles of fentanyl after pretreatment with CBD and synthetic CBD, presenting them as possible pharmacological tools for OUD research.