Analytical confirmation of synthetic cannabinoids in a cohort of 179 presentations with acute recreational drug toxicity to an Emergency Department in London, UK in the first half of 2015

Abouchedid, Rachelle; Hudson, Simon; Thurtle, Natalie; Yamamoto, Takahiro; Ho, James H; Bailey, George P.; Wood, Michelle; Sadones, Nele; Stove, Christophe; Dines, Alison; Archer, John R. H.; Wood, David M.; Dargan, Paul I.

doi:10.1080/15563650.2017.1287373

Cited by 54 publications

(50 citation statements)

References 31 publications

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“…Since 2014, numerous non‐fatal and fatal intoxications with the L‐ tert ‐leucine derivative MDMB‐CHMICA ( 9 ) have been reported . Subsequently, the UK government implemented the Psychoactive Substances Act in 2016 to counteract MDMB‐CHMICA‐related intoxications.…”

Section: Resultsmentioning

confidence: 99%

“…Besides MDMB‐CHMICA ( 9 ), the chemically closely related L‐valine derivative AB‐CHMINACA ( 14 ) has also frequently been encountered in forensic case work. It was identified amongst prevalently consumed drugs of abuse in patients presenting to an emergency department in London in the first half of 2015 . The use of these drugs has been associated with adverse effects including cardiovascular effects, neurotoxicity, and neuropsychiatric effects, potentially even more serious severe toxicity effects compared to the earlier generation SCRAs .…”

Section: Resultsmentioning

confidence: 99%

“…The intake of these highly potent drugs of abuse has caused considerable morbidity and mortality in the United States, Europe, and Japan, as well as in many other countries . Observed adverse effects include agitation, hypertension, acute kidney injury and tachycardia and may even result in fatalities …”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8] Observed adverse effects include agitation, hypertension, acute kidney injury and tachycardia and may even result in fatalities. [9][10][11][12][13][14][15][16] As xenobiotics, SCRAs undergo extensive metabolism and clearance, mainly by the liver, to remove these substances from the human body. The goal of drug metabolism is to detoxify potentially harmful compounds and excrete them from the body.…”

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confidence: 99%

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Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L‐valine or L‐tert‐leucine

Wouters

Mogler

Cannaert

et al. 2019

Drug Testing and Analysis

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Indole‐ and indazole‐based synthetic cannabinoid receptor agonists (SCRAs), featuring valine or tert‐leucine substituents, are commonly abused new psychoactive substances (NPS). A major metabolic pathway for these SCRAs is hydrolysis of the terminal amide or methylester functionalities. Although these hydrolysis products were already detected as main ingredients in some “legal highs,” these metabolites are often poorly characterized. Here, we report a systematic investigation of the activity of 7 common hydrolysis metabolites of 15 SCRAs featuring scaffolds based on L‐valine or L‐tert‐leucine in direct comparison to their parent compounds. An activity‐based cannabinoid receptor 1 (CB1) bio‐assay was used for activity profiling of SCRAs and their metabolites in a stable HEK293T cell system. The recruitment of β‐arrestin2 to the activated CB1 (each fused to one part of a split Nanoluciferase) was provoked by adding the (putative) SCRAs. Luminescence of the functionally complemented luciferase was monitored by a 96‐well plate‐reader. The major hydrolysis metabolites of 5F‐AB‐PINACA, ADB‐CHMICA, ADB‐CHMINACA, ADB‐FUBICA, and their methyl‐ and ethylester derivatives showed no detectable CB1 activation at concentrations up to 1 μM. On the other hand, metabolites of 5F‐ADB‐PINACA, AB‐CHMINACA, and ADB‐FUBINACA did retain activity, although significantly reduced as compared to the parent compounds (EC50 values >100 nM). Activity‐based characterization of SCRAs and their metabolites at CB1 may not only allow a better insight into the complex interplay between SCRAs and their metabolites in intoxications, but may also allow application of the concept of “activity equivalents” present in biological fluids or, alternatively, in confiscated materials.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L‐valine or L‐tert‐leucine

Wouters

Mogler

Cannaert

et al. 2019

Drug Testing and Analysis

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“…CUMYL-PINACA was identified in 3 cases of transdermal poisoning and 5F-CUMYL-PINACA in a case of hospital presentation; however, metabolism was not investigated in these cases. 13,14 The aim of the present study was to elucidate the main in vitro phase I metabolites of CUMYL-PINACA, 5F-CUMYL-PINACA, CUMYL-4CN-BINACA, 5F-CUMYL-P7AICA, and CUMYL-4CN-B7AICA, with a focus on the analytical differentiation and interpretation of the metabolites.…”

mentioning

confidence: 99%

In vitro metabolism of the synthetic cannabinoids CUMYL‐PINACA, 5F–CUMYL‐PINACA, CUMYL‐4CN‐BINACA, 5F–CUMYL‐P7AICA and CUMYL‐4CN‐B7AICA

Staeheli

Poetzsch

Veloso

et al. 2017

Drug Testing and Analysis

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Synthetic cannabinoid consumption trends underlie fast changes and provide several challenges to clinical and forensic toxicologists. Due to their extensive metabolism, parent compounds are hardly detectable in urine. Therefore, knowledge of the metabolism of synthetic cannabinoids is essential to allow their detection in biological matrices. The aim of the present study was the elucidation of the metabolism of CUMYL-PINACA, 5F-CUMYL-PINACA, CUMYL-4CN-BINACA, 5F-CUMYL-P7AICA, and CUMYL-4CN-B7AICA with a focus on the analytical and interpretational differentiation of the compounds. Microsomal assay mixtures containing cosubstrates, 10 μg/mL substrate and 1 mg/mL pooled human liver microsomes were incubated for 1 hour at 37°C. Investigation of the metabolites was performed on a Thermo Fischer Ultimate 3000 UHPLC system coupled to a Sciex 6600 QTOF System. Hydroxylation was observed to be a major biotransformation step for all 5 cumyl-derivatives, followed by dihydroxylation.For CUMYL-PINACA, a major metabolic pathway was hydroxylation at the pentyl moiety, followed by a second hydroxylation at that pentyl moiety or oxidation to ketone. A major metabolic pathway for the compounds containing a nitrile function was nitrile hydrolysis followed by carboxylation and further hydroxylation. For the fluorinated compounds, oxidative defluorination and carboxylation were abundant metabolic steps. Some of the metabolic transformations lead to structurally identical metabolites, which should not be used as marker for the intake of a particular parent compound. In addition, several constitutional isomers containing either an indazole or azaindole core structure were detected, which should be differentiated by retention time rather than by their mass spectra alone. KEYWORDSin vitro metabolism, new psychoactive substances NPS, synthetic cannabinoids

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Addictions and Substance Misuse

2021

The Maudsley Prescribing Guidelines in Psychiatry

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Analytical confirmation of synthetic cannabinoids in a cohort of 179 presentations with acute recreational drug toxicity to an Emergency Department in London, UK in the first half of 2015

Abstract: Synthetic cannabinoid receptor agonists were found in 10% of this cohort with acute recreational drug toxicity but self-reported in only half of these. This suggests that presentations to the ED with acute synthetic cannabinoid receptor agonist toxicity may be more common than reported.

Cited by 54 publications

References 31 publications

Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L‐valine or L‐tert‐leucine

Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L‐valine or L‐tert‐leucine

In vitro metabolism of the synthetic cannabinoids CUMYL‐PINACA, 5F–CUMYL‐PINACA, CUMYL‐4CN‐BINACA, 5F–CUMYL‐P7AICA and CUMYL‐4CN‐B7AICA

Addictions and Substance Misuse

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