Abstract
Concurrent use of heroin and cocaine (known as the "speedball") prevails among substance use disorder populations, especially in opioid-dependent individuals, with severe consequences and a high fatality rate. Little is known about the patterns and correlations of the concurrent use of heroin and cocaine. It is vital to investigate such a polydrug use in both humans and animals to uncover concomitant toxicity and the cause of fatal overdose (death). In this study, we aimed to shed some light on the role of cocaine in the etiology of heroin-related deaths in the context of molecular pharmacokinetics (PK). For the purpose, a high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of heroin, cocaine, and their metabolites in whole blood was developed and fully validated in accordance with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Then, this method was used to analyze heroin, cocaine, and their metabolites in blood from the rats intraperitoneally administered non-lethal 10 mg/kg heroin or 20 mg/kg cocaine alone, or their combination that is lethal with a proximal mortality of 33 %. The obtained results from the rats that experienced the lethal toxicity revealed that the concurrent use of heroin and cocaine significantly increased the risk of fatality from overdose. Heroin significantly slowed down the elimination of cocaine and its main metabolites in blood, while cocaine significantly enhanced heroin metabolism from 6-monoacetylmorphine (6-MAM) to morphine. Similar elimination half-lives for other heroin metabolites were observed. These findings are reported for the first time in this study, facilitating our understanding of the polysubstance metabolism and severe consequences produced by the polydrug use.