Synthetic cannabinoid drug use as a cause or contributory cause of death

The total number of synthetic cannabinoids (SCs) – a group of new psychoactive substances (NPS) – is increasing every year. The rapidly changing market demands the latest analytical methods to detect the consumption of SCs in clinical or forensic toxicology. In addition, SC metabolites must also be included in a screening procedure, if detection in urine is asked for. For that purpose, an easy and fast qualitative liquid chromatography—tandem mass spectrometry (LC−MS/MS) urine screening method for the detection of 75 SCs and their metabolites was developed and validated in terms of matrix effects, recovery, and limits of identification for a selection of analytes. SC metabolites were generated using in vitro human liver microsome assays, identified by liquid chromatography−high resolution tandem mass spectrometry (LC−HRMS/MS) and finally included to the MS/MS spectra in‐house library. Sample preparation was performed using a cheap‐and‐easy salting‐out liquid–liquid extraction (SALLE) after enzymatic hydrolysis. Method validation showed good selectivity, limits of identification down to 0.05 ng/mL, recoveries above 80%, and matrix effects within ±25% for the selected analytes. Applicability of the method was demonstrated by detection of SC metabolites in authentic urine samples.

Section: Introductionmentioning

confidence: 97%

Liquid chromatography–tandem mass spectrometry screening method using information‐dependent acquisition of enhanced product ion mass spectra for synthetic cannabinoids including metabolites in urine

Staeheli

Veloso

Bovens³

et al. 2019

“…Even for the most well‐studied SCRA NPS, existing data pertain to the activity of these compounds in cellular systems or animal models, with very few human studies reported . Of greater concern is the trend for increasing potency of SCRA NPS, with the most recent examples frequently associated with serious adverse effects, including myocardial infarction, ischemic stroke, acute kidney injury, tonic–clonic convulsion, coma, and death …”

Section: Introductionmentioning

confidence: 99%

The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F‐PY‐PICA, 5F‐PY‐PINACA, and their analogs

Banister

Kevin

Martin

et al. 2019

5F‐PY‐PICA and 5F‐PY‐PINACA are pyrrolidinyl 1‐(5‐fluoropentyl)ind (az)ole‐3‐carboxamides identified in 2015 as putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS). 5F‐PY‐PICA, 5F‐PY‐PINACA, and analogs featuring variation of the 1‐alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography–quadrupole time‐of‐flight–mass spectrometry (LC–QTOF–MS). In competitive binding experiments against HEK293 cells expressing human cannabinoid receptor type 1 (hCB1) or type 2 (hCB2), all analogs showed minimal affinity for CB1 (pKi < 5), although several demonstrated moderate CB2 binding (pKi 5.45–6.99). In fluorescence‐based membrane potential assays using AtT20‐hCB1 or ‐hCB2 cells, none of the compounds (at 10 μM) produced an effect >50% of the classical cannabinoid agonist CP55,940 (at 1 μM) at hCB1, although several showed slightly higher relative efficacy at hCB2. Expansion of the pyrrolidine ring of 5F‐PY‐PICA to an azepane (8) conferred the greatest hCB2 affinity (pKi 6.99) and activity (pEC50 7.54, Emax 72%) within the series. Unlike other SCRA NPS evaluated in vivo using radio biotelemetry, 5F‐PY‐PICA and 5F‐PY‐PINACA did not produce cannabimimetic effects (hypothermia, bradycardia) in mice at doses up to 10 mg/kg.

“…8 The prohibition of 1 and 2 resulted in the release of newer analogs that were subsequently banned, and this iterative cycle has produced hundreds of SCs with increasing structural diversity. [13][14][15][16] The confirmation of novel SCs by forensic chemists and clinical toxicologists is hindered by the dynamic heterogeneity of SC products, and the latency between tentative SC identification and availability of suitable commercial reference standards. [13][14][15][16] The confirmation of novel SCs by forensic chemists and clinical toxicologists is hindered by the dynamic heterogeneity of SC products, and the latency between tentative SC identification and availability of suitable commercial reference standards.…”

Section: Introductionmentioning

confidence: 99%

The chemistry and pharmacology of synthetic cannabinoid SDB‐006 and its regioisomeric fluorinated and methoxylated analogs

Banister

Olson

Winchester

et al. 2018

Synthetic cannabinoids are the largest and most structurally diverse class of new psychoactive substances, with manufacturers often using isomerism to evade detection and circumvent legal restriction. The regioisomeric methoxy- and fluorine-substituted analogs of SDB-006 (N-benzyl-1-pentyl-1H-indole-3-carboxamide) were synthesized and could not be differentiated by gas chromatography-mass spectrometry (GC-MS), but were distinguishable by liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). In a fluorescence-based plate reader membrane potential assay, SDB-006 acted as a potent agonist at human cannabinoid receptors (CB EC = 19 nM). All methoxy- and fluorine-substituted analogs showed reduced potency compared to SDB-006, although the 2-fluorinated analog (EC = 166 nM) was comparable to known synthetic cannabinoid RCS-4 (EC = 146 nM). Using biotelemetry in rats, SDB-006 and RCS-4 evoked comparable reduction in body temperature (~0.7°C at a dose of 10 mg/kg), suggesting lower potency than the recent synthetic cannabinoid AB-CHMINACA (>2°C, 3 mg/kg).