This is an academic paper that examines polysubstance use disorders, the need for treatment systems to account for their high prevalence, and the high risks of developing more than one substance use disorder. For example, the increased risk of developing heroin dependence is twofold for alcohol misusers, threefold for cannabis users, 15-fold for cocaine users, and 40-fold for prescription misusers. Behavioral and neural circuitry in the context of co-use of substance is explored.