Toxic by design? Formation of thermal degradants and cyanide from carboxamide-type synthetic cannabinoids CUMYL-PICA, 5F-CUMYL-PICA, AMB-FUBINACA, MDMB-FUBINACA, NNEI, and MN-18 during exposure to high temperatures

Kevin, Richard C.; Kovach, Alexander L.; Lefever, Timothy W.; Gamage, Thomas F.; Wiley, Jenny L.; McGregor, Iain S.; Thomas, Brian F.

doi:10.1007/s11419-018-0430-0

Cited by 31 publications

(39 citation statements)

References 37 publications

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“…In some cases, the metabolite exhibits toxicity not observed with the parent (Couceiro et al, 2016). Further, toxicity may not even involve cannabinoid receptor mechanisms, as metabolism of CUMYL-4CN-BINACA has been reported to liberate cyanide (Åstrand et al, 2018;Kevin et al, 2018). Thus synthetic cannabinoids could produce toxicity by a multitude of ways.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Gamage

Farquhar

McKinnie

et al. 2018

J Pharmacol Exp Ther

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Synthetic cannabinoids (SCs) are novel psychoactive substances that are easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity and seizures. Although the structural bases of these compounds are scaffolds with known affinity and efficacy at the human cannabinoid type-1 receptor (hCB 1 ), upon ingestion or inhalation they can be metabolized to multiple chemical entities of unknown pharmacological activity. A large proportion of these metabolites are hydroxylated on the pentyl chain, a key substituent that determines receptor affinity and selectivity. Thus, the pharmacology of SC metabolites may be an important component in understanding the in vivo effects of SCs. We examined nine SCs (AB-PINACA, 5F-AB-PINACA, ADB/MDMB-PINACA, 5F-ADB, 5F-CUMYL-PINACA, AMB-PINACA, 5F-AMB, APINACA, and 5F-APINACA) and their hydroxypentyl (either 4-OH or 5-OH) metabolites in [ 3 H]CP55,940 receptor binding and the [ 35 S] GTPgS functional assay to determine the extent to which these metabolites retain activity at cannabinoid receptors. All of the SCs tested exhibited high affinity (,10 nM) and efficacy for hCB 1 and hCB 2 . The majority of the hydroxypentyl metabolites retained full efficacy at hCB 1 and hCB 2 , albeit with reduced affinity and potency, and exhibited greater binding selectivity for hCB 2 . These data suggest that phase I metabolites may be contributing to the in vivo pharmacology and toxicology of abused SCs. Considering this and previous reports demonstrating that metabolites retain efficacy at the hCB 1 receptor, the full pharmacokinetic profiles of the parent compounds and their metabolites need to be considered in terms of the pharmacological effects and time course associated with these drugs.

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Section: Discussionmentioning

confidence: 99%

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Gamage

Farquhar

McKinnie

et al. 2018

J Pharmacol Exp Ther

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“…The authors also acknowledged the problem of maintaining a stable temperature. 12 Kevin et al 13 recently by-passed the issue of uctuating temperature by conducting a temperature controlled study on six carboxamide type SC at 200, 400, 600, and 800 C using a pyro-probe coupled to a GC-MS, thus creating temperature-controlled pyrolysis conditions where the degradants were analysed at each temperature. 13 A focus on the simulation of smoking is the aim of this paper rather than pyrolysis at high temperatures coupled to anaerobic conditions.…”

Section: Introductionmentioning

confidence: 99%

“…12 Kevin et al 13 recently by-passed the issue of uctuating temperature by conducting a temperature controlled study on six carboxamide type SC at 200, 400, 600, and 800 C using a pyro-probe coupled to a GC-MS, thus creating temperature-controlled pyrolysis conditions where the degradants were analysed at each temperature. 13 A focus on the simulation of smoking is the aim of this paper rather than pyrolysis at high temperatures coupled to anaerobic conditions. Work on the combustion and degradation products is an area that requires further investigation due to the generation of potentially harmful products with possible alteration in the target receptor or the affinity for that receptor of any new compounds.…”

Section: Introductionmentioning

confidence: 99%

Analysis of synthetic cannabinoid agonists and their degradation products after combustion in a smoking simulator

et al. 2019

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Synthetic cannabinoids are a major class of NPS with a high impact on analytical, forensic and toxicological fields. The main route of administration of synthetic cannabinoids is through inhalation, delivered by smoking a conventional or electronic cigarette, pyrolysis possibly altering the nature of these compounds and resulting in unknown combustion products with unknown biological activity/toxicology.In this study, a twin-trap smoking inhalation model that simulates human inhalation has been developed.The smoking simulator allows the efficient trapping of the combustion products. Analysis using UHPLC-TOF-ESI-MS and GC-MS allowed the detection of all six synthetic cannabinoids tested in the smoking simulator. A novel combustion product of MDMB-CHMICA was identified, a dihydro-1H-pyridoindoledione with its structure and mechanism of formation proposed. This study of SC combustion products provides markers which may be useful for drug analysts and toxicologists in examining samples obtained from suspected SC users/abusers.

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“…The unchanged naphthoylindole SCs JWH‐018 and JWH‐073 have also been reported to be detected at lower positivity rates and concentrations relative to their metabolites in blood due to their lipophilicity and short half‐lives . Taking into account that SCs in New Zealand are typically distributed on plant material for smoking, the pyrolytic process can also lead to the formation of thermal degradation artefacts similar or identical to metabolism products, as reported for ADB‐CHMICA, MDMB‐CHMICA, BB‐22, 5F‐PB‐22, AB‐CHMINACA, AMB‐FUBINACA, and MDMB‐FUBINACA, that may be subsequently detectable in blood. Post‐mortem degradation of SCs by esterase activity in blood in the time between death and sampling or during storage may also contribute to the formation of hydrolyzed metabolites .…”

Section: Introductionmentioning

confidence: 99%

Simultaneous analysis of 29 synthetic cannabinoids and metabolites, amphetamines, and cannabinoids in human whole blood by liquid chromatography–tandem mass spectrometry – A New Zealand perspective of use in 2018

Ong

Kappatos

Russell

et al. 2019

Drug Testing and Analysis

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We describe the validation of a method for the simultaneous analysis of 29 synthetic cannabinoids (SCs) and metabolites, 4 amphetamines, and 2 cannabinoids in human whole blood. This method enables one analysis to cover what previously required multiple analyses for these classic and novel drugs-of-abuse with diverse physicochemical properties. The scope of targeted analytes was based on the most prevalent drugs-ofabuse and SCs encountered at the New Zealand border in 2017 and included parent compounds and metabolites belonging to the indole and indazole carboxamide, quinolinyl indole carboxylate, and naphthoylindole classifications. Samples were prepared by supported-liquid-extraction (SLE) followed by liquid chromatography −tandem mass spectrometry (LC−MS/MS) analysis with positive electrospray ionization (ESI). The method was validated with respect to selectivity, matrix effects, process efficiency, sensitivity, repeatability, extract stability, and carryover for qualitative confirmation. Linearity as well as accuracy and precision data at target decision concentrations were also evaluated. The limits of detection and confirmation ranged from 0.1 to 6.0 ng/mL and 1.0 to 6.0 ng/mL, respectively. The described method was successfully applied to the analysis of 564 ante-and post-mortem blood samples in 2018. There were 132 cases (23%) with positive findings of at least one SC, with the five most commonly detected SCs being AMB-FUBINACA and/or acid (61%), 5F-ADB and/or acid (40%), ADB-FUBINACA (11%), 5F-MDMB-PICA acid (6%), and MDMB-FUBINACA acid (6%). The results also demonstrate the predominant presence of metabolites at higher levels than the unchanged parent SCs in blood, highlighting the need to maintain forensic screening methods capable of the simultaneous detection of both parent compounds and metabolites.

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Toxic by design? Formation of thermal degradants and cyanide from carboxamide-type synthetic cannabinoids CUMYL-PICA, 5F-CUMYL-PICA, AMB-FUBINACA, MDMB-FUBINACA, NNEI, and MN-18 during exposure to high temperatures

Cited by 31 publications

References 37 publications

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Analysis of synthetic cannabinoid agonists and their degradation products after combustion in a smoking simulator

Simultaneous analysis of 29 synthetic cannabinoids and metabolites, amphetamines, and cannabinoids in human whole blood by liquid chromatography–tandem mass spectrometry – A New Zealand perspective of use in 2018

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