A three-drug polysubstance use model of ethanol, nicotine, and cocaine co-use in female and male cynomolgus monkeys.
TL;DR
It is indicated that ethanol potentiated the reinforcing effects of cocaine + nicotine, and future studies should incorporate polysubstance use into preclinical models to model the human condition and to evaluate interventions for CUD.
Abstract
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.