Toxicity of heroin laced with synthetic opioid β-U10 and etizolam

Abstract

Illicit heroin can be substituted or adulterated with New Psychoactive Substances (NPS) including highly potent fentanyl-type substances or other opioid-like compounds to counteract low-purity supply. The addition of unknown NPS to the heroin supply poses an additional risk of overdose and death. In 2020, the Emerging Drug Network of Australia VIC (EDNAV) study was funded to monitor drug related harm in individuals attending emergency departments (ED) at major hospitals within Victoria. In September 2020, a previously unreported NPS, β-U10 (2-napthyl-U-47700), was detected in discarded drug paraphernalia samples collected during a pilot study of an early warning system for illicit drug use in Melbourne, Australia. Subsequently, blood samples of EDNAV project individuals with positive heroin detections were analysed for β-U10, in addition to NPS and traditional illicit drugs. After liquid-liquid extraction, blood samples underwent extensive toxicological analysis via targeted liquid-chromatography tandem mass spectrometry (LC-MS/MS) and untargeted screening via high-resolution quadrupole time-of-flight mass spectrometry (LC-QTOF). Confirmation of β-U10 concentrations were measured via LC-MS/MS using certified reference material. In total, seven cases were found to contain synthetic opioid β-U10. Six samples were collected in October 2020, with the remaining case detected more than a year later in December 2021. Measured β-U10 concentrations ranged from 0.01 to 22 ng/mL (median 3 ng/mL). All cases also contained methylamphetamine and etizolam. Morphine was detected in all cases along with 6-acetylmorphine in three of these cases. Other drugs included diphenhydramine, diazepam, doxylamine, gamma-hydroxybutyrate, MDMA, methadone, and mitragynine. The average age was 37 and ranged from 20 to 52 years of age. All individuals presented to ED with varying levels of sedation (Glascow Coma Scale 3–14, median 9) and recovered with supportive care (median stay 6.8 hours). Two cases showed a positive response to naloxone. The Poisons Severity Score for one case was 3, with 4 cases assessed as level 2. The pharmacological activity of β-U10 is largely unknown. β-U10 was first published by the Upjohn Company in the 1970's and is a structural analogue of the widely reported NPS U-47700, which has approximately seven times greater affinity to the μ-opioid receptor than morphine (Cheney. Journal of Medicinal Chemistry 1985;28:1853–1864). U-47700 has been utilised recreationally for its sedative properties in addition to positive effect on mood. The co-ingestion of other sedatives and respiratory depressants, including opioids and the NPS benzodiazepine etizolam in each of these reported cases precludes definitive conclusions regarding the clinical effect of β-U10. Additional studies that examined heroin supply at the time found the addition of β-U10 was associated with a decrease in heroin purity. The detection of β-U10 in one case 12 months following the previous detection may indicate the drug re-supply of the adulterated mixture in Australia. The detection of β-U10 has also informed toxicological investigations into heroin-related deaths that occurred during the same time-period. The consumption of adulterated illicit substances by unsuspecting individuals with unknown compounds such as β-U10, particularly in conjunction with other opioids and CNS depressants such as etizolam, is an alarming trend and poses a significant public health risk.