Synthetic Cannabinoid and Methadone Co-administration in Prolonging the QTc Interval

Synthetic cannabinoid receptor agonists (SCRAs) are frequently used with other psychoactive substances. We aimed to investigate the poly-pharmacology of SCRA-related deaths and mechanism of SCRA toxicity. NPSAD analysis - Cases with post-mortem detections of SCRA(s) and/or methadone were extracted from the National Programme on Substance Abuse Deaths (NPSAD). In vitro pharmacology - Guinea pig hearts were perfused in standard Krebs solution at constant pressure. The ECG was recorded, with the beat-to-beat ventricular cycle length variability quantified. Methadone and the SCRA 5F-ADB were applied alone and in combination. NPSAD analysis - In SCRA-related deaths, methadone was the most commonly co-detected pharmaceutical medication (n=68/254 cases). The median methadone concentration in methadone-only deaths (0.66mg/L) was significantly higher than in deaths attributable to methadone-SCRA co-administration (0.47mg/L; p<0.05). In vitro pharmacology - Low dose (10µM) methadone elongated the QTc interval (13.8msec±2.6). Co-application of 5F-ADB further increased the QTc interval, in a dose-dependent manner (0.3-30nM), by a maximum of 60.9msec±7.4. 5F-ADB alone had no effect. The SCRA 5F-ADB significantly reduces the toxicity threshold of methadone, likely via QT elongation. SCRA-related fatality may therefore be linked to co-administration with compounds that induce long QT syndrome. Careful consideration is needed when prescribing medications to people who use SCRAs.