Signal detection and characterisation of a novel drug–drug interaction between methadone and a synthetic cannabinoid receptor agonist

BACKGROUND AND PURPOSE: Little is known about how synthetic cannabinoid receptor agonist (SCRA) co-use with other psychoactive substances may exacerbate risk of death. This study aimed to characterise the polypharmacy of deaths where SCRAs were detected at post-mortem, investigate the cardiotoxicity of SCRAs and probe their inhibition of human ether-a-go-go-related gene (hERG) channel function. EXPERIMENTAL APPROACH: Deaths with detections of SCRA(s) were analysed from the National Programme on Substance Use Mortality. Isolated hearts from guinea pigs were perfused with modified Krebs solution. Methadone and the SCRA 5F-ADB (5F-MDMB-PINACA) were applied singly and in combination, with electrocardiogram recording. Software tools and patch-clamp electrophysiology were employed to investigate 5F-ADB-hERG channel interaction. KEY RESULTS: In deaths with SCRA detections, pharmacoepidemiological analyses showed that methadone was the most commonly co-detected medication with long QT liability. Sub-analysis of SCRA-methadone deaths revealed a significantly lower median blood concentration of methadone proved fatal, compared to deaths solely attributed to methadone. In perfused guinea pig hearts, sole application of methadone, but not 5F-ADB, prolonged the QTc interval, compared to baseline. Co-application significantly increased the QTc interval. The in silico and in vitro analyses showed 5F-ADB to be a low affinity hERG channel inhibitor. CONCLUSIONS AND IMPLICATIONS: The reduction in the toxicity threshold of methadone and the facilitation of its QT prolongation by the SCRA 5F-ADB suggests the former may result from pro-arrhythmia. Use of QT-prolonging medications by people who use SCRAs may result in a drug-drug interaction that increases the risk of pro-arrhythmic death.