Some of the more commonly studied polydrug combinations include administration of cocaine with other drugs (Francesco et al., 2003; Leri et al., 2003b; Substance Abuse and Mental Health Services Administration, 2016). However, in contrast to human reports (Heil et al., 2001; Williamson et al., 2006; Staiger et al., 2013; Preston et al., 2016; Lorvick et al., 2018; Kariisa et al., 2019), an increase in addiction-like severity has not been observed in preclinical studies, suggesting a need for models with greater translational relevance that can capture the enhanced severity seen in human polysubstance users. Specifically, animal studies of sequential cocaine and alcohol or cocaine and heroin use have not found differences in drug intake or reinstatement of drug-seeking as a function of single versus polydrug use (Pattison et al., 2014; Fredriksson et al., 2017; Crummy et al., 2020; Stennett et al., 2020). These effects were observed despite variance in the use of contingent and non-contingent drug administration, drug doses, and species, including rats (Crummy et al., 2020; Stennett et al., 2020) and rhesus monkeys (Aspen and Winger, 1997). Consistent with this work, intermittent alcohol exposure has not been shown to affect cocaine self-administration (Aspen and Winger, 1997; Fredriksson et al., 2017) or the reinforcing properties of cocaine measured via demand curves in rhesus monkeys (Winger et al., 2007). In addition, intermittent alcohol exposure has not been shown to affect progressive ratio tests of motivation for cocaine (Mateos-García et al., 2015), or the long-term reconsolidation of preference for cocaine in drug-paired contexts (Zhu et al., 2020) in rats. In contrast, adolescent alcohol exposure has been shown to have long-lasting effects on cocaine self-administration and reward, suggesting that this population is particularly susceptible to the effects of polysubstance use. For example, adolescent alcohol exposure increases motivation for cocaine (Mateos-García et al., 2015), enhances the development of a cocaine CPP in both mice (Molet et al., 2013) and rats (Hutchison and Riley, 2012; Mateos-García et al., 2015), and weakens cocaine-induced taste aversion (Busse et al., 2005). In addition, simultaneous heroin and psychostimulant administration increases the motivation to self-administer cocaine (Ward et al., 2006) and methamphetamine (Ranaldi and Wise, 2000), and both simultaneous and sequential administration of morphine and methamphetamine have been shown to be rewarding, as measured by the development of a CPP (Briggs et al., 2018). Pretreatment with an opioid also enhances methamphetamine-induced psychomotor sensitization (Liang et al., 2006). These findings suggest that opioids can enhance the rewarding and motivational properties of psychostimulants, particularly when administered simultaneously.

Polydrug studies with cocaine and nicotine have largely reported additive and/or synergistic effects of the two drugs. In particular, co-administration of cocaine and nicotine increases drug intake in rhesus monkeys (Mello et al., 2014) and rats (Bechtholt and Mark, 2002), enhances locomotor sensitization and the development of a CPP in mice (Levine et al., 2011), and induces a cross-sensitized drug-craving (Reid et al., 1998; Weinberger and Sofuoglu, 2009; Cortright et al., 2012). Additionally, chronic nicotine pretreatment facilitates the acquisition of cocaine self-administration (Horger et al., 1992; Bechtholt and Mark, 2002; Linker et al., 2020), increases motivation under a progressive ratio schedule, impairs extinction learning, and enhances drug-primed reinstatement for amphetamine following amphetamine self-administration (Cortright et al., 2012). Conversely, prior nicotine treatment history reduces demand elasticity for cocaine (Schwartz et al., 2018). Notably, the effects of nicotine and psychostimulant polydrug use are largely dose-dependent as pretreatment with a smaller dose of nicotine [0.3 mg/kg, subcutaneous (sc)] increases motivation to take cocaine under a progressive ratio schedule in rats, whereas a larger dose of nicotine (0.6 mg/kg, sc) has the opposite effect (Bechtholt and Mark, 2002). Additionally, simultaneous administration of methamphetamine [2.0 mg/kg, intraperitoneal (ip)] and nicotine (1.0 mg/kg ip) induces a conditioned place aversion in mice, while sequential administration of the same dose induces a CPP (Briggs et al., 2018). Together, these studies demonstrate that the effects of nicotine on psychostimulant motivation, intake, and reward are heavily impacted by the parameters surrounding nicotine delivery (e.g. dose, route, pattern, etc.), which should be carefully considered when comparing study results and developing preclinical polydrug paradigms. Notably, adolescent exposure to nicotine has no effect on the subsequent development of a cocaine CPP, cocaine-induced taste aversion, cocaine self-administration, extinction, or reinstatement of cocaine-seeking in adulthood (Pomfrey et al., 2015), although it has been shown to enhance cocaine self-administration in adolescent rats (Linker et al., 2020). These data suggest that, unlike alcohol, early exposure to nicotine does not lead to increases in addiction-like behavior to cocaine in animals.

In humans, simultaneous cocaine and cannabis use produces feelings of “stimulated” and “high” that last longer than either drug alone (Foltin et al., 1993), and cue-induced drug-craving in individuals who co-use cocaine and cannabis lasts longer than for those who only use cocaine (Giasson-Gariépy et al., 2017). In contrast, THC reduces the motivation to self-administer cocaine in rodents (Panlilio et al., 2007). Although this suggests a differential regulation of cocaine’s effects in humans and rodents, further work is necessary to ensure that animal models of increased addiction severity cannot, in fact, be developed. Notably, however, neither cocaine and cannabis nor cocaine and alcohol co-administration in humans produces subjective effects that are different from cocaine, cannabis, or alcohol alone (Foltin et al., 1993). Similarly, THC pretreatment in rodents has no effect on psychostimulant reward or self-administration, nor does it potentiate the development of a CPP to amphetamine (Panlilio et al., 2007; Cortright et al., 2011; Keeley et al., 2018), indicating a unique effect of cocaine and cannabis on drug-craving. Interestingly, CBD has no effect on cocaine self-administration, motivation, or cue-induced reinstatement of cocaine-seeking (Mahmud et al., 2017), suggesting the effects of cannabis on cocaine craving are likely due to THC, rather than CBD. However, CBD treatment has been found to reduce motivation to self-administer methamphetamine on a progressive ratio schedule and to reduce methamphetamine-primed reinstatement of drug-seeking (Hay et al., 2018). The additive effects of cannabinoid and psychostimulant polydrug use appear to be dependent on both the amount of drug consumed and the age range during use. For example, acute THC weakens psychomotor sensitization, but repeated THC administration promotes tolerance to the acute effects, increasing amphetamine-induced stereotypy and locomotor activity (Gorriti et al., 1999; Cortright et al., 2011). Additionally, adolescent THC exposure accelerates acquisition of cocaine self-administration and increases intake of low doses of cocaine (Friedman et al., 2019), indicating long-lasting changes in reward circuitry following adolescent THC use, similar to alcohol.