Methadone use is contraindicated in people who use SCRAs

Background:

Deaths following the use of synthetic cannabinoid receptor agonists (SCRAs) have risen sharply in the past 10 years, although the mechanism as to their toxicity remains elusive. In addition, SCRAs are frequently used with other psychoactive substances, which can increase toxicity. We aimed to investigate the poly-pharmacology of SCRA-related deaths using a post-mortem database and performed complementary ex vivo pharmacology experiments.

Methods:

NPSAD case analysis – Cases with post-mortem detections of SCRA(s) and/or methadone detected by toxicological testing of blood samples were extracted from the National Programme on Substance Abuse Deaths (NPSAD).

Ex vivo pharmacology experiments – Guinea pig hearts were perfused (Langendorff mode) in standard Krebs solution at constant pressure. The ECG was recorded, and the beat-to-beat ventricular cycle length variability was quantified. Clinically relevant concentrations of methadone and the SCRA 5F-ADB were applied alone and in combination.

Results:

NPSAD case analysis – In SCRA-related deaths, polydrug use was evident in 94.5% of cases (n=240/254). Of these deaths, 92.9% (n=223/240) had licensed pharmaceutical medications that possess long QT liability and/or non-medicinal substances which negatively impact upon cardiac function. In only 5.5% of cases was a SCRA alone detected at post-mortem (n=14/254). Methadone was the most commonly co-detected pharmaceutical medication (n=68). A sub-analysis of deaths with methadone-SCRA co-administration revealed a significantly lower median methadone concentration in comparison to deaths solely attributed to methadone (methadone & SCRA: 0.47mg/L; methadone alone: 0.66mg/L; Student’s t-test p<0.05).

Ex vivo pharmacology experiments – 10µM methadone prolonged the QTc interval by 13.8msec(±3.1msec) compared to baseline QTc interval. Co-application of 5F-ADB further increased the QTc interval, in a dose-dependent manner (0.3-30nM), by a maximum of 60.9msec(±7.4msec). Application of 5F-ADB alone had no effect on the QTc interval.

Conclusions:

The SCRA 5F-ADB significantly reduces the toxicity threshold of methadone, likely via QT prolongation. SCRA-related fatality may therefore be linked to co-administration with compounds that induce long QT syndrome. The prescribing of licensed medications in people who use SCRAs needs careful consideration to select compounds with no or low long QT liability. For example, it is likely safer for people who use SCRAs and are receiving opioid agonist therapy to be prescribed buprenorphine rather than methadone, as long QT risk with buprenorphine is considerably lower.