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

Authors

Kirsten L Rock, Louise M Hesketh, Hongwei Cheng, Shuoqi Chen, Simon Hudson, Graeme Henderson, Jules C Hancox, Michael J Shattock, Michael J Curtis, Caroline S Copeland

Published in

British journal of pharmacology. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

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.
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.
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.
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.

PMID:
42601331
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.