Impact of Δ9-tetrahydrocannabinol and oxycodone coadministration on measures of antinociception, dependence, circadian activity, and reward in mice.

Slivicki R.; Wang J.; Kucz K.; Hines J.; Tran Nhat V.; Kravitz A.; Creed M.; Gereau R. · The Journal of pharmacology and experimental therapeutics · 2026

**Background & Methods** This preclinical study examined the combined effects of Δ9-tetrahydrocannabinol (Δ9-THC) and oxycodone in male and female mice using behavioral assays and neurobiological recordings. Investigators evaluated antinociception (pain relief), physical dependence, circadian activity alterations, and reward-related behaviors following acute and repeated coadministration over 5 days. **Key Findings** • Δ9-THC potentiated oxycodone-induced antinociception in a dose-dependent manner and delayed the development of antinociceptive tolerance compared to oxycodone alone; oxycodone demonstrated lower potency in female mice. • Repeated oxycodone treatment produced physical dependence and circadian rhythm disruptions, neither of which was exacerbated by concurrent Δ9-THC administration—suggesting the cannabinoid did not worsen these specific adverse effects. • Combination treatment produced conditioned place preference (indicating rewarding properties) at doses that were ineffective when either drug was administered alone; fiber photometry recordings demonstrated that Δ9-THC potentiated nucleus accumbens dopamine release in response to subeffective oxycodone doses, providing a neurobiological mechanism for enhanced reward. **Dosage & Administration** Not reported. The abstract does not specify particular doses, routes of administration, or dosing schedules beyond "twice daily for 5 days" for tolerance development studies. **Safety & Adverse Effects** Oxycodone alone produced physical dependence and circadian activity alterations. Coadministration with Δ9-THC did not exacerbate these effects. However, the combination enhanced rewarding properties and increased abuse liability at therapeutic doses. No other specific adverse effects were detailed in the abstract. **Evidence Quality** This is a preclinical animal study with significant translational limitations. Findings are restricted to mouse models and may not directly extrapolate to human pharmacology or clinical outcomes. The study design does not assess human-relevant endpoints such as addiction severity, long-term opioid use patterns, or comprehensive safety profiles. Sex differences were noted but not comprehensively analyzed. The primary strength is controlled laboratory conditions allowing mechanistic investigation of dopamine signaling. The primary weakness is the inability to determine clinical relevance or predict human abuse liability, tolerance development, and dependence risk with certainty.

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