Identification of the Synthetic Cannabinoid 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide (CUMYL-4CN-BINACA) in Plant Material and Quantification in Post-Mortem Blood Samples

153

Drug misuse in prisons contributes to increased disruption and violence and negatively impacts prisoner safety, rehabilitation, and recovery. Synthetic cannabinoid receptor agonists (SCRAs), colloquially known as “spice”, are infused into papers and are of particular concern in a prison setting where they are commonly vaped. Methods for the qualitative and quantitative analysis of SCRA infused papers, including impurity profiling, were developed using gas chromatography–mass spectrometry (GC–MS) with qualitative confirmation by ultra high pressure liquid chromatography with photodiode array and quadrupole time of flight mass spectrometry detection (UPLC‐PDA‐QToF‐MS) and applied to 354 individual seized paper samples originating from 168 seizures from three Scottish prisons. Of these samples, 41% (146 samples from 101 seizures) contained at least one SCRA and multiple SCRAs were detected on 23% of these papers. Concentrations ranged from < 0.05–1.17 mg/cm2 paper, representing the first reported quantitative data for SCRA infused papers. An evolution in the SCRAs detected was demonstrated; 5F‐MDMB‐PINACA (5F‐ADB) predominated until late 2018, after which time 5F‐MDMB‐PICA and 4F‐MDMB‐BINACA became increasingly more prevalent, followed by the arrival of MDMB‐4en‐PINACA in June 2019. Concentration mapping data from two seized paper samples demonstrated that SCRA concentrations across larger papers were highly variable (0.47–2.38 mg/cm2 paper) making consistent dosing by users, and representative sampling by laboratory analysts, difficult. Near real‐time qualitative and quantitative information on SCRAs circulating in prisons acts as an early warning system for SCRAs emerging on the wider illicit market, inform the methods used to detect them and limit supply, and provide information to support harm reduction measures.

Section: Resultsmentioning

confidence: 99%

Detection and quantitation of synthetic cannabinoid receptor agonists in infused papers from prisons in a constantly evolving illicit market

Norman

Walker

McKirdy

et al. 2020

153

“…To interpret post‐mortem blood concentrations, it is sometimes useful to compare with those from the living or from post‐mortem cases not related to intoxication. To date, there are blood concentration values available from 2 papers: In blood samples from drug abuse suspects (it is assumed that these are ante‐mortem samples) 0.1 to 36.14 ng/mL CUMYL‐4CN‐BINACA was found ; in 11 post‐mortem samples, in which the only drug detected was CUMYL‐4CN‐BINACA, a range of 0.4 to 34.3 ng/mL was determined . For 5 of the fatal cases, cause of death was ruled “CUMYL‐4CN‐BINACA intoxication” and in these cases specifically the concentration range was 0.4 to 11.9 ng/mL.…”

Section: Discussionmentioning

confidence: 99%

“…To date, there are blood concentration values available from 2 papers: In blood samples from drug abuse suspects (it is assumed that these are ante-mortem samples) 0.1 to 36.14 ng/mL CUMYL-4CN-BINACA was found 7; in 11 post-mortem samples, in which the only drug detected was CUMYL-4CN-BINACA, a range of 0.4 to 34.3 ng/mL was determined. 13 For 5 of the fatal cases, cause of death was ruled "CUMYL-4CN-BINACA intoxication" and in these cases specifically the concentration range was 0.4 to 11.9 ng/mL. These values suggest that there is an overlap of concentration ranges found in living people and in dead people.…”

Section: Autopsy Casesmentioning

confidence: 92%

Metabolism study for CUMYL‐4CN‐BINACA in human hepatocytes and authentic urine specimens: Free cyanide is formed during the main metabolic pathway

Åstrand

Vikingsson

Lindstedt

et al. 2018

To further elucidate the metabolism of CUMYL-4CN-BINACA, a new synthetic cannabinoid with a cyano group, and to evaluate biomarkers, we incubated the substance in human hepatocytes and analysed 9 authentic urine specimens. We also quantified CUMYL-4CN-BINACA and cyanide in blood and provide comprehensive data on the 7 autopsy cases, 5 of them determined CUMYL-4CN-BINACA intoxications. For metabolite elucidation, CUMYL-4CN-BINACA was incubated with pooled human hepatocytes for up to 5 hours, urine samples were analysed with and without enzymatic hydrolysis. Data was acquired in data-dependent mode by ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) with an Agilent 6550 QTOF. For quantitative analysis of CUMYL-4CN-BINACA, blood samples were precipitated and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cyanide was determined by gas chromatography-headspace-nitrogen phosphorus detection (GC-headspace-NPD). CUMYL-4CN-BINACA was metabolised via CYP450-mediated hydroxylation at 4-butyl position generating a cyanohydrin (M12), which releases free cyanide to form an aldehyde intermediate and eventually generates 4-hydroxybutyl CUMYL-BINACA (M11) and CUMYL-BINACA butanoic acid (M10). Other minor metabolites were produced by hydroxylation, dihydroxylation, N-dealkylation, and dihydrodiol formation; glucuronidation was observed. One urine sample showed high intensities of M10 and a wide variety of metabolites; the other samples contained fewer metabolites in low abundance and 1 sample showed no metabolites. CUMYL-4CN-BINACA blood concentrations ranged from 0.1 to 8.3 ng/g showing an overlap between fatal and non-fatal concentrations. One blood sample contained 0.36 μg/g cyanide. Release of free cyanide during metabolism is worrying as it might induce liver toxicity. As suggested earlier, CUMYL-BINACA butanoic acid is the most abundant biomarker in urine, but monitoring of additional metabolites or, even better, analysis for the parent in blood is recommended.

“…It continues to be a challenge for laboratories to develop methods which can detect the wide range of existing and new SCs in a broad range of biological matrices . Many laboratories analyze urine as a sample of choice, which necessitates metabolic studies to determine the major SC metabolites, as the parent compounds are often not detected in urine.…”

Section: Introductionmentioning

confidence: 99%

“…6 It continues to be a challenge for laboratories to develop methods which can detect the wide range of existing and new SCs in a broad range of biological matrices. [8][9][10] Many laboratories analyze urine as a sample of choice, 8,9 which necessitates metabolic studies to determine the major SC metabolites, [11][12][13][14] as the parent compounds are often not detected in urine. The analysis of SCs is further complicated by the fact that some are known to be unstable during storage, 15 and to be thermally labile.…”

Section: Introductionmentioning

confidence: 99%

Identification of a thermal degradation product of CUMYL‐PEGACLONE and its detection in biological samples

Nash

Glowacki

Gerostamoulos

et al. 2019

The structural diversity of synthetic cannabinoids makes it a challenging task to have a comprehensive screening method for this class of drugs. The difficulty is increased by the fact that some synthetic cannabinoids undergo thermal decomposition during common routes of administration, such as smoking or vaping. CUMYL‐PEGACLONE is a relatively new synthetic cannabinoid which has a structural variant from most other synthetic cannabinoids: a γ‐carbolinone core. To investigate its thermal stability, CUMYL‐PEGACLONE was heated in an oven at temperatures ranging from 200 to 350oC, and a major thermal degradation product, N‐pentyl‐γ‐carbolinone, was subsequently identified. Unlike some other synthetic cannabinoids, the thermal degradation product of CUMYL‐PEGACLONE is not one of its known metabolites, nor were any known metabolites detected during the thermal stability experiments. The degradation product was formed in significant amounts at temperatures above 250°C, and has been detected (along with CUMYL‐PEGACLONE) in case samples, including post‐mortem blood and urine, and residue found at a scene.