Changes in drug availability, price, law enforcement activities and pressures form social networks and drug markets can force people who use drugs to change their polysubstance use patterns. An agent-based model was developed to simulate such changes. We considered six drugs: heroin, methamphetamine, crack cocaine, powdered cocaine, marijuana, and “other” which is a proxy for new drugs such as fentanyl, xylazine, or any other substance with known properties. “Other” could also serve as a proxy for alternative non-drug reinforcements, e.g. recreational activities, that could be potentially introduced. The model was calibrated to represent qualitative changes in drug use (methamphetamine and heroin co-use patterns) in rural Ohio. Ethnographic data was used to estimate the relative role of these factors in the choices of drug combinations. Scenarios dealt with law enforcement actions on methamphetamine, heroin, and both: heroin and methamphetamine. The model replicated historic (baseline) patterns of use and changes from methamphetamine to heroin to both in rural Ohio. Analysis of the scenarios illustrated the adaptive nature of individual choices leading to short- and long-term changes depending on the length and the strength of the interventions. The role of “other” reinforcer depends on its properties and the length and strength of the interventions. It is possible to temporarily switch to the “other” reinforcer, but the sustainability depends on its properties and correlation with other drugs. We identified gaps in knowledge and data that could be filled with ethnographic research.