A three-drug polysubstance use model of ethanol, nicotine, and cocaine co-use in female and male cynomolgus monkeys.

BACKGROUND: Polysubstance use is common in cocaine use disorder (CUD), yet most preclinical models still study cocaine in isolation. A recent Pharmacological Reviews article (Rough and Nader, 2026) from our group identified a major preclinical gap: despite epidemiologic evidence that most people who use cocaine also co-use alcohol and nicotine, no preclinical studies have modeled this three-drug combination. In prior studies from our laboratory, adding nicotine to cocaine under a choice procedure increased cocaine's reinforcing potency and strength, whereas oral ethanol self-administration prior to cocaine self-administration under a choice procedure increased cocaine's reinforcing strength without altering potency. METHODS: Building on these findings, we developed a three-drug model in which oral ethanol or vehicle was available simultaneously while monkeys (N = 6; 4 females, 2 males) chose between food pellets and intravenous cocaine or cocaine + nicotine. RESULTS: Nicotine increased cocaine choice under both ethanol and vehicle conditions. While ethanol did not alter the reinforcing potency of cocaine alone, it increased the potency of cocaine + nicotine relative to vehicle. CONCLUSION: Together, these findings indicate that ethanol potentiated the reinforcing effects of cocaine + nicotine. Future studies should incorporate polysubstance use into preclinical models to model the human condition and to evaluate interventions for CUD.