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Cumyl-PEGACLONE: A comparatively safe new synthetic cannabinoid receptor agonist entering the NPS market?

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... Particularly, 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido [4,3-b]indol-1-one (semisystematic name: Cumyl-PEGACLONE or SGT-151) was the first SC with a γ-carbolinone core structure detected in forensic casework and, since then, it has dominated the German SC-market [6][7][8]. It has indeed been detected in about 25% of herbal blends purchased in Germany during a monitoring program and has showed high prevalence in biological specimens [8]. ...
... Particularly, 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido [4,3-b]indol-1-one (semisystematic name: Cumyl-PEGACLONE or SGT-151) was the first SC with a γ-carbolinone core structure detected in forensic casework and, since then, it has dominated the German SC-market [6][7][8]. It has indeed been detected in about 25% of herbal blends purchased in Germany during a monitoring program and has showed high prevalence in biological specimens [8]. ...
... High, NPS likely to have contributed to toxicity/death, despite the detection of other drugs) is assigned [9]. Six cases of death related to the intake of Cumyl-PEGACLONE were reported, in none of which, according to the TSS, the substance seemed to have played a causative role [8]. Due to the relatively low occurrence of severe intoxications and of deaths caused by Cumyl-PEGACLONE, the compound has been suggested as a "comparatively safe drug" and a relative "low toxicity" of SCs bearing a γ-carbolinone core structure was considered possible [8]. ...
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Purpose Cumyl-PEGACLONE was the first synthetic cannabinoid (SC) with a γ-carbolinone core structure detected in forensic casework and, since then, it has dominated the German SC-market. Here the first four cases of death involving its fluorinated analog, 5F-Cumyl-PEGACLONE, a recently emerged γ-carbolinone derived SC, are reported. Methods Complete postmortem examinations were performed. Postmortem samples were screened by immunoassay, gas chromatography mass spectrometry (GC–MS) or liquid chromatography tandem mass spectrometry. For quantification of SCs, the standard addition method was employed. Herbal blends were analyzed by GC–MS. In each case of death, the Toxicological Significance Score (TSS) was assigned to the compound. Results 5F-Cumyl-PEGACLONE was identified at concentrations ranging 0.09–0.45 ng/mL in postmortem femoral blood. In case 1, signs of hypothermia and kidney bleedings were noted. Despite a possible tolerance due to long term SC use, a TSS of 3 was assigned. In case 2, an acute heroin intoxication occurred and a contributory role (TSS = 1) of 5F-Cumyl-PEGACLONE was suggested. In case 3, a prisoner was found dead. GC–MS analysis of herbal blends, retrieved in his cell together with paraphernalia, confirmed the presence of 5F-Cumyl-PEGACLONE and a causative role was deemed probable (TSS = 2). In case 4, the aspiration of gastric content due to a SC-induced coma was observed (TSS = 3). Conclusions 5F-Cumyl-PEGACLONE is an emerging and extremely potent SC which raises serious public health concerns. A comprehensive analysis of circumstantial, clinical, and postmortem findings, as well as an in-depth toxicological analysis is necessary for a valid interpretation and for the assessment of the toxicological significance.
... Cumyl-PEGACLONE initially appeared on the market in the form of herbal blends and e-liquids and became available as a pure 'research chemical' in July 2017. 6 Since then, several research groups have characterized this new compound, its metabolization and, to a lesser extent, its cannabinoid activity. The psychoactive effects, most desired by (ab)users, but also several adverse effects, mainly stem from CB 1 receptor activation. ...
... Not surprisingly, identification and case reports for both Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE have emerged since then. 6,[8][9][10][11][12] Initially, SCRAs containing a γ-carbolinone core structure were hypothesized to be relatively safe, as no lethalities were observed in cases with (over)consumption of Cumyl-PEGACLONE. However, several fatalities have been reported during the past few years. ...
... 10,13 Therefore, the relative 'safety' of γ-carbolinones can be questioned. 6,10,13 As fluorination can have a beneficial effect on a compound's activity, resulting in a higher potency, it could be hypothesized that this would lead to a higher toxicity of 5F-Cumyl-PEGACLONE. 7,14,15 However, no activity data are available to confirm this hypothesis. ...
Article
Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest groups of new psychoactive substances (NPS) monitored in Europe. SCRAs are known to typically exert higher cannabinoid activity than THC from cannabis, therefore entailing a greater health risk. Both Cumyl‐PEGACLONE and 5F‐Cumyl‐PEGACLONE were not controlled by the national legislation upon their first detection in Germany in 2016 and 2017, respectively, and have been linked to several fatalities. In this study, the CB1receptor activity of these compounds, together with two newly synthesized structural isomers (Cumyl‐PEGACLONE ethylbenzyl isomer and n‐propylphenyl isomer) was assessed using two different in vitro receptor‐proximal bio‐assays, monitoring the recruitment of either β‐arrestin2 or a modified G protein (mini‐Gαi) to the activated CB1receptor. Both in terms of potency and relative efficacy, Cumyl‐PEGACLONE and 5F‐Cumyl‐PEGACLONE were found to exert strong CB1activation, with sub‐nanomolar EC50values, and efficacy values exceeding those of the reference agonist JWH‐018 >3 fold (β‐arrestin2 assay) or almost 2‐fold (mini‐Gαiassay). The ethylbenzyl and n‐propylphenyl isomers showed a strongly reduced CB1activity (EC50 values >100 nM; efficacy <40% relative to JWH‐018), which is hypothesized to originate from steric hindrance in the ligand binding pocket. Therefore, their abuse potential seems less likely. None of the evaluated compounds showed significant biased agonism. In conclusion, the functional assays applied here allowed us to demonstrate that 5‐fluorination of Cumyl‐PEGACLONE is not linked to an intrinsically higher CB1activation potential, and that the ethylbenzyl and n‐propylphenyl isomers yield a strongly reduced CB1activitation.
... In-vivo-Metabolismus von 5F-Cumyl-PEGACLONE die 5-Fluorpentyl-Seitenkette und die γ-Carbolinon-Kernstruktur bevorzugt metabolisiert. Im Gegensatz zum Indol-Analogon 5F-Cumyl-PICA [162] und dem Indazol-Analogon 5F-Cumyl-PINACA [163] und Japan bisher nicht aufgetreten ist [164] . ...
... Kapitel 3.3), wurden für Cumyl-PEGACLONE bisher nur wenige Vergiftungsfälle [165] und keine Todesfälle beschrieben. Daher wurde diskutiert, ob es sich bei Cumyl-PEGACLONE um ein SC mit vergleichsweise niedriger Toxizität handelt [164] . Konsummarker-Metaboliten sind dem Anhang A-2 zu entnehmen). ...
... So zeigte sich in dieser Arbeit am Beispiel von Cumyl-PEGACLONE und 5F-Cumyl-PEGACLONE, dass ein als relativ untoxisch eingestuftes SC [164] nach dessen ............................................................................ 183 A-3 Neue-psychoaktive-Stoffe Gesetz (NpSG) ...................................................... 189 EG-018 ..................................... [54] Abbildung Anhang 3 Definition der Seitenkette nach NpSG in der Piktogramm Darstellung. Unter a) Beispiele typischer substituierter Seitenketten; b) Beispiele typischer Ringsysteme als Seitenketten. ...
Thesis
Synthetische Cannabinoide (SC) werden konsumiert, um die psychoaktiven Effekte von Cannabis nachzuahmen. Gesetzliche Verbote einzelner SC führten zu fortwährenden chemischen Veränderungen der bekannten Stoffe. Seit November 2016 reguliert das deutsche Neue-psychoaktive-Stoffe-Gesetz (NpSG) SC anhand modularer chemischer Strukturen. Es war somit anzunehmen, dass neuartige SC entwickelt und für Konsumenten verfügbar gemacht werden, um dieses Gesetz zu umgehen. Die Urinanalytik durch Flüssigkeitschromatographie-Tandemmassenspektrometrie (LC MS/MS) nimmt beim Konsumnachweis von SC eine besondere Rolle ein. SC werden in der Regel nur verstoffwechselt ausgeschieden, daher sind Metaboliten die Zielanalyten im Urin. In dieser Arbeit wurde der In-vitro-Metabolismus von SC an humanen Lebermikrosomen (HLM) erforscht und die routinemäßig durchgeführte LC MS/MS Screeningmethode vorerst mit möglichen Hauptmetaboliten erweitert. Die In-vivo-Bestätigung erfolgte an humanen Urinproben von SC-Konsumenten, wodurch die Eignung nachgewiesener SC-Metaboliten als Konsummarker evaluiert werden konnte. Das Ziel dieser Arbeit war die kontinuierliche Erweiterung der LC-MS/MS-Screeningmethode, um möglichst alle aktuell marktrelevanten SC in Urinproben nachweisen zu können. Hierfür sollte zu Beginn der Metabolismus von SC aufgeklärt werden, die aufgrund ihrer neuartigen Carbazol-Kernstruktur nicht vom NpSG erfasst werden. Kurz nach dem Inkrafttreten des NpSG wurde im Rahmen dieser Arbeit erstmalig ein SC mit einer neuartigen γ-Carbolinon-Kernstruktur identifiziert. Daher sollten in der Folge Nachweismethoden für die Urinanalytik dieser neuartigen Strukturklasse von SC entwickelt werden. Die Metabolismusstudien der untersuchten Carbazol-Derivate führten zur Evaluierung geeigneter Konsummarker für das Urinscreening. In dieser Arbeit ist die strukturelle Aufklärung und pharmakologische Charakterisierung des ersten γ-Carbolinon-Derivates als SC (Cumyl-PEGACLONE) beschrieben. Für die diese SC wurden charakteristische MS-Eigenschaften aufgedeckt und geeignete Metaboliten für deren Detektion in Urinproben postuliert. Durch zahlreiche weitere Metabolismusstudien neuartiger SC konnte das Urinscreening dem hochdynamischen SC-Markt während dieser Arbeiten angepasst werden. Die entwickelten Nachweismethoden, die evaluierten Konsummarker-Metaboliten sowie die Identifizierung der γ-Carbolinon basierten SC stellen wichtige Grundlagen für die forensisch-toxikologische Analytik neuartiger SC in der Zukunft dar.
... Cumyl-PEGACLONE has originally been reported to be a "comparatively safe new synthetic cannabinoid receptor agonist" [11]; however since then, deaths related to its fluorinated analogue, 5F-Cumyl-PEGACLONE, have been described [6,10,12], and more data is becoming available, suggesting that its use is not safe and death may result when a sufficient dose is taken, particularly in the context of underlying natural disease, or concurrent use of other drugs. A recent article by Janssens et al. demonstrated that Cumyl-PEGACLONE has the same CB1 receptor activation potential (in vitro) as its 5-fluorinated analogue [13]. ...
... In this case series, Cumyl-PEGACLONE was detected in preserved postmortem iliac vein blood at a range of 0.73 μg/L-3 μg/L. Halter et al. reported the concentrations of 27 cases of fatal and non-fatal intoxications associated with the consumption of Cumyl-PEGACLONE [11]. In their case series, Cumyl-PEGACLONE concentrations ranged between 0.12 ng/mL to 13 ng/mL for all cases (fatal and non-fatal intoxications), and between 0.12 ng/mL to 0.84 ng/mL for fatal intoxications. ...
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Suspected unnatural or unexpected deaths in the Northern Territory of Australia are reportable to the coroner, and investigation of such cases typically includes a post-mortem examination with comprehensive toxicological screening. An autopsy case series of five Cumyl-PEGACLONE-related fatalities over a recent eighteen-month period is presented. Databases of the Northern Territory coroner’s office and the Royal Darwin Hospital Forensic Pathology Unit were searched to identify deaths related to synthetic cannabis use between July 1, 2018 and December 31, 2020. Toxicological analysis was performed at Forensic Science South Australia using a combination of liquid chromatography, gas chromatography and mass spectrometry. Cumyl-PEGACLONE, a synthetic cannabinoid receptor agonist (SCRA) with a gamma-carbolinone core, was detected in five cases (range in post-mortem blood 0.73—3.0 μg/L). Concurrent alcohol use and underlying cardiovascular disease were considered relevant factors in most cases. Toxicological Significance Scoring was carefully considered in all five cases, and in four cases, the presence of Cumyl-PEGACLONE was considered to be highly significant (TSS = 3). Synthetic cannabis use has not previously been identified in Northern Territory drug trends, and only one fatality related to the use of gamma-carbolines was identified in a recent Australia-wide study on synthetic cannabinoid-related fatalities. Deaths related to Cumyl-PEGACLONE use are emerging in the Northern Territory of Australia; this has public health implications. Although the exact mechanism(s) of death related to Cumyl-PEGACLONE are not fully established, this additional descriptive case series reaffirm an association with underlying cardiovascular disease, and suggest that concurrent use with alcohol may be relevant.
... It has been suggested that some SCRAs possess comparatively lower toxicities, potentially accounting for discrepancies between their prevalence of use estimations and incidences of mortality (43). Indeed, whilst 30% of test purchases were positive for the SCRA cumyl-PEGACLONE in a recent German study, only one case was reported where cumyl-PEGACLONE was directly implicated in causing death, and even then this was in combination with other SCRAs (5F-ADB and 5F-MDMB-P7AICA) and underlying health conditions (44). Cumyl-PEGACLONE was first detected in the UK in 2016 (45), but no deaths involving this SCRA were reported to NPSAD at time of writing. ...
Article
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Aim: To identify drug-related death trends associated with synthetic cannabinoid receptor agonists (SCRAs) reported to the National Programme on Substance Abuse Deaths (NPSAD) from England. Design: Case reports from NPSAD (England) where a SCRA was detected in post-mortem tissue(s) and/or implicated in the death were extracted, analyzed, and compared against non-SCRA-related deaths that occurred over the same time period (2012–2019). Findings: One hundred sixty-five death SCRA-related reports were extracted, with 18 different SCRAs detected. Following the first death in 2012, a subsequent sharp increase in reporting is evident. Acute SCRA use was the underlying cause of death in the majority of cases (75.8%) with cardiorespiratory complications the most frequently cited underlying physiological cause (13.4%). SCRA users were predominantly found dead (68.6%), with a large proportion of those witnessed becoming unresponsive described as suddenly collapsing (81.6%). Psychoactive polydrug use was detected in 90.3% of cases, with alcohol the most commonly co-detected (50.3%), followed by opioids (42.2%), benzodiazepines/Z-drugs (32.1%), stimulants (32.1%, [28.5% cocaine]), and cannabis (24.8%). Compared to all non-SCRA-related NPSAD deaths occurring over the same time period, SCRA-related decedents were more predominantly male (90.3% vs. 72.0%; p<0.01), and lived in more deprived areas (p<0.01). While a comparatively significant proportion of decedents were homeless (19.4% vs. 4.1%), living in a hostel (13.3% vs. 2.3%) or in prison (4.9% vs. 0.2%) at time of death (all p<0.01), the greatest majority of SCRA-related decedents were living in private residential accommodations (57.6%). Conclusions: This is the largest dataset regarding SCRA-related mortalities reported to date. Reporting of SCRA-related deaths in England have increased considerably, with polydrug use a specific concern. Lack of effective deterrents to SCRA use under current UK legislation, compounded by limited knowledge regarding the physiological impacts of SCRA consumption and their interaction with other co-administered substances are contributory factors to the occurrence of SCRA-related mortalities in an increasingly deprived demographic.
... pg/mg [11]. Furthermore, 27 11intoxications with CUMYL-PEGACLONE in combination with 5F-CUMYL-P7AICA was described by Halter et al. [18], where three serum concentrations of coexisting 5F-CUMYL-P7AICA were described (0.03, 2.5, and 0.23 ng/mL, respectively) without validation. However, it is worth noting that these two synthetic cannabinoids may have caused an additive effect after simultaneous consumption, while, in their case #11, there have been found also lethal signs of violence to the victim's neck, probably caused by autoerotic accident. ...
Article
Purpose Establishment of ultra-high-performance liquid chromatography–triple quadrupole-tandem mass spectrometry method was essential for quantification of 5F-CUMYL-P7AICA in authentic biological specimens. This method was fully validated and applied to a fatal intoxication case, which occurred in late 2019, in Poland. Methods Blood, urine, and gastric content samples were extracted with ethyl acetate from alkaline medium (pH 9). The analysis was carried out using ultra-high-performance liquid chromatography–tandem mass spectrometry. JWH 018-d11 was used as internal standard. Validation criteria were evaluated for blank blood and urine at concentrations of 0.1, 1 and 10 ng/mL. Results The validation parameters were as follows: lower limit of quantification: 0.1 ng/mL for blood and urine; coefficients of determination: blood > 0.9991 and urine > 0.9988; intra- and interday accuracies and precisions for both matrices: not greater than 15%; recoveries for both matrices: 88–107%; matrix effects: 89–119%. In the present case of death associated with 5F-CUMYL-P7AICA consumption, the determined concentrations were 2.8 ng/mL in blood and 3.1 ng/mL in urine. In gastric contents, 5F-CUMYL-P7AICA could not be detected. Conclusions The developed method enabled for determination of 5F-CUMYL-P7AICA in human blood and urine with high sensitivity and selectivity. To our knowledge, this is the first report to quantify 5F-CUMYL-P7AICA in blood and urine of an authentic case with full validation.
... or activity at the hCB 1 are missing. While Cumyl-PEGACLONE seems to be a relatively benign SC 6 , a number of death cases involving 5F-Cumyl-PEGACLONE have been described recently 7 . ...
Article
Synthetic cannabinoids (SC) remain one of the largest groups of new psychoactive substances (NPS) on the European drug market. In December 2018, Cumyl-CH-MEGACLONE, a novel SC based on a γ-carboline-1-one core structure was firstly identified in Hungary, and later also other European countries. This work aims to reveal the pharmacological characteristics and phase-I metabolism of Cumyl-CH-MEGACLONE and compare the data to its analogs Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE. The purified substance was characterized by means of gas chromatography–mass spectrometry (GC–MS), liquid chromatophraphy–quadrupole-time-of-flight-mass-spectrometry (LC–QToF-MS), attenuated-total-reflection-infrared-spectroscopy (ATR-FTIR) and nuclear-magnetic-resonance-spectroscopy (NMR). Phase-I metabolites were identified by LC–QToF-MS analysis combined with a scheduled precursor ion list of authentic urine samples and confirmed by comparison with metabolites built in vitro by pooled human liver microsome assays (pHLM). Pharmacological data was obtained in a competitive ligand binding assay and a receptor activation assay at the human cannabinoid receptor 1 (hCB1). The structure of 5-cyclohexylmethyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (semisystematic name: Cumyl-CH-MEGACLONE) was identified in a herbal blend as the main active ingredient. Investigation of phase-I biotransformation of Cumyl-CH-MEGACLONE led to three monohydroxylated metabolites (M08, M10 and M13) as reliable urinary markers for proof of consumption. At the hCB1, Cumyl-CH-MEGACLONE shows high binding affinity with Ki = 1.01 nM (2.5-fold higher than JWH-018), an EC50 of 1.22 nM and high efficacy with EMAX = 143.4% above constitutive activity of the receptor (1.13-fold higher than JWH-018). Comparison to the analogs 5F-Cumyl-PEGACLONE and Cumyl-PEGACLONE (both are hCB1 full agonists carrying a 5-fluoropentyl or pentyl chain instead of the cyclohexylmethyl (CHM) moiety) suggests that Cumyl-CH-MEGACLONE is more likely to resemble the pharmacologic profile of the latter one.
... Other compounds, such as Cumyl-PEGACLONE, have been suggested as "relatively safe" due to the low number of poisonings despite the abundant presence in herbal blends (25-30% of tested products) and their widespread use (prevalence of 29% in samples positive for SCRAs, including testing for driving under the influence, insult, and threat, criminal offenses). Moreover, the role of the SCRA was deemed minor or contributory in the majority of death cases (15). ...
Article
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Background Synthetic cannabinoid receptor agonists (SCRAs) have become the largest group of new psychoactive substances monitored by the European Union Early Warning System. Despite the wide diffusion on the market, data regarding effects, toxicities, and mechanisms as well as toxic/lethal doses are still scarce.MethodsA comprehensive literature search for articles published up to January 2019 was performed in multiple electronic databases. Only cases of death in which toxicological analyses revealed the presence of SCRAs in blood or urine and at least an external examination was performed, including those occurred in emergency departments, were included.ResultsOf 380 studies identified, 354 were excluded, while 8 additional manuscripts were included through the screening of relevant references cited in the selected articles. A total number of 34 manuscripts (8 case series and 26 case reports) were included.Conclusions Typical toxic ranges for SCRAs have not been so far identified, and the results of toxicological analyses should be interpreted with caution. In death cases involving SCRAs, a thorough post-mortem examination is a prerequisite to assess the role of the substance use in the deceased and to identify a probable mechanism of death. Even after a comprehensive analysis of clinical, circumstantial, toxicological, and autoptic data, the cause and manner of death remain unclear in some cases.
Thesis
Synthetische Cannabinoide nehmen als Substanzen, welche die psychoaktive Wirkung von Cannabis nachahmen, seit nunmehr über 10 Jahren eine bedeutende Rolle unter den neuen psychoaktiven Stoffen (NPS) ein. Aufgrund der großen strukturellen Vielfalt dieser Stoffgruppe wurde im November 2016 das Neue-psychoaktive-Stoffe-Gesetz (NpSG) in Deutschland eingeführt, welches im Gegensatz zum Betäubungsmittelgesetz (BtMG) hinsichtlich der rechtlichen Regulierung der Substanzen einen generischen Ansatz mit Stoffgruppendefinitionen verfolgt. Auch hat der Nachweis synthetischer Cannabinoide in Blut und Blutserum im forensisch-toxikologischen Kontext große Relevanz, da sie aufgrund ihrer Potenz und Toxizität neben akuten Beeinträchtigungen auch mit zahlreichen Todesfällen in Verbindung gebracht werden. Ein Ziel dieser Arbeit war es den Einfluss rechtlicher Regulierungen, inbesondere durch das NpSG, auf das Angebot synthetischer Cannabinoide auf dem Onlinemarkt zu untersuchen. Hierfür wurden im Rahmen eines Marktmonitorings monatlich Testkäufe in Onlineshops durchgeführt und die Produkte sowohl qualitativ als auch quantitativ ausgewertet. Ferner sollte mittels einer Studie die Stabilität 32 ausgewählter, strukturell verwandter synthetischer Cannabinoide in fünf Matrices untersucht werden, um geeignete Metabolite für die Routineanalytik ausfindig zu machen, die in Abwesenheit der Muttersubstanz als Konsummarker herangezogen werden können. Im Rahmen des Onlinemonitorings konnten mehrere neue synthetische Cannabinoide identifziert werden. Für drei dieser Substanzen wurde die vollständige Strukturaufklärung mittels GC-EI-MS, LC-qToF-MS und NMR durchgeführt. Weiterhin konnten Einflüsse rechtlicher Regulierungen auf das Angebot verfügbarer synthetischer Cannabinoide auf dem Onlinemarkt beobachtet werden. Dabei spielten nationale gesetzliche Restriktionen ebenso eine Rolle wie internationale. Die Einführung des NpSG führte dazu, dass auf dem nationalen NPS-Markt neue Substanzen, die die Gesetzgebung umgehen, etabliert wurden. Weiterhin wurde eine Studie zur Quantifizierung der Wirkstoffe in Räuchermischungen durchgeführt. Hierbei zeigten sich in der Verteilung der Wirkstoffe signifikante Unterschiede zwischen den untersuchten Räuchermischungen der Onlineshops. Durch Vergleich der ermittelten Wirkstoffgehalte und pharmakologischer Literaturdaten konnte zudem ein Zusammenhang zwischen Wirkstoffgehalt der Räuchermischungen und Potenz der Substanzen gezeigt werden. Im letzten Teil der Arbeit wurde anhand einer Stabilitätsstudie gezeigt, dass neben dem Nachweis der Muttersubstanz auch die Detektion von Hydrolyseprodukten synthetischer Cannabinoide in verschiedenen Blut- und Serummatrices sinnvoll ist. Diese Ergebnisse konnten anhand von Daten aus der Routineanalytik bekräftigt werden.
Article
Introduction: Synthetic cannabinoids (SCs) are the largest and most diverse group of new psychoactive substances. Their influence on organism is unpredictable and often lead to intoxications, including fatal poisonings. The interpretation of blood concentrations of detected SC although complicated, can help to determine the effects of an administered drug. The interpretation of one’s own results usually requires a comparison to previously published cases, therefore, a referenced compilation of concentration ranges would be useful. Material and methods: The data collection was based on a search of PubMed and Google search engine. All the available data from articles and reports where SCs concentrations have been measured in whole blood, serum or plasma were included in the data analysis. Results: Presented table lists the observed concentrations in fatal and non-fatal cases involving 65 SCs. A reference list with original papers has been added for each compound, which makes it easy to find the source data. Conclusion: The observed concentrations of SCs vary widely and often have overlapping ranges for fatal and non-fatal cases. Conclusions regarding the cause of death are difficult based upon the concentrations alone and should include knowledge of the clinical situation in each case.
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This review paper covers the forensic-relevant literature in toxicology from 2016 to 2019 as a part of the 19th Interpol International Forensic Science Managers Symposium. The review papers are also available at the Interpol website at: https://www.interpol.int/content/download/14458/file/Interpol%20Review%20.Papers%202019.pdf.
Article
Synthetic cannabinoid receptor agonizts (SCRAs), also known as synthetic cannabinoids, are mostly consumed in the form of herbal mixtures available in online shops. These herbal mixtures are produced by soaking dried, crushed plant material in a solution of SCRAs or by spraying the solution on the plant material. Inhomogeneity in the distribution of the active ingredient can occur during the production process and pose a serious health risk for consumers of these drugs. In the present study 20 herbal mixtures containing Cumyl-PEGACLONE, one of the most prevalent SCRAs in Germany in 2017, were quantitatively analyzed by high-performance liquid chromatography with diode array detection (HPLC-DAD) after an initial screening by gas chromatography mass spectrometry. All investigated herbal mixtures were purchased in online shops during a systematic product monitoring carried out in the frame of the EU project "SPICE Profiling". The complete content of the packages was divided into aliquots without homogenization and extracted three times with methanol under ultrasonication. The combined extracts of each aliquot were filtered and quantified with a fully validated HPLC-DAD method using a 7-point calibration curve (1-50 μg/mL). The Cumyl-PEGACLONE content in the analyzed material ranged from 8.6 to 146 mg/g (median 29.4 mg/g, mean 38.5 mg/g). The intrapackage concentration variability was mostly below 10% RSD. Analyzed concentrations roughly correlated with product advisory (e.g., "strong") on the websites, if available. Aliquots at the bottom of a package generally tended to show higher levels of Cumyl-PEGACLONE than the upper aliquots. Packages of the same brand with different date of order did not always show the same mean concentrations. Compared to former studies, the SCRA concentrations are generally lower and the risk of extreme variation of intrapackage SCRA contents seems to have dropped.
Article
Synthetic cannabinoid receptor agonists (SCRAs) first appeared on the international recreational drug market in the early 2000s in the form of SCRA‐containing herbal blends. Due to the cannabimimetic effects associated with the consumption of SCRAs, they have acquired an ill‐informed reputation for being cheap, safe, and legal alternatives to illicit cannabis. Possessing high potency and affinity for the human cannabinoid receptor subtype‐1 (CB1) and ‐2 (CB2), it is now understood that the recreational use of SCRAs can have severe adverse health consequences. The major public health problem arising from SCRA use has pressed legislators around the world to employ various control strategies to curb their recreational use. To circumvent legislative control measures, SCRA manufacturers have created a wide range of SCRA analogues which contain, more recently, previously unencountered azaindole, γ‐carbolinone, or carbazole heterocyclic scaffolds. At present, little information is available regarding chemical syntheses of these newly emerging classes of SCRA, from a clandestine perspective. When compared with previous generations of indole‐ and indazole‐type SCRAs, current research suggests that many of these heterocyclic SCRA analogues maintain high affinity and efficacy at both CB1 and CB2 but largely evade legislative control. This review highlights the importance of continued research in the field of SCRA chemistry and pharmacology, as recreational SCRA use remains a global public health issue and represents a serious control challenge for law enforcement agencies.
Article
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 200‐350oC, and a major thermal degradation product, Npentyl‐ γ‐carbolinone, was subsequently identified. Unlike some other synthetic cannabinoids, the thermal degradation product of CUMYLPEGACLONE 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.
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Purpose: In the present study we characterized a series of synthetic cannabinoids containing various heterocyclic scaffolds that had been identified as constituents of "Spice", a preparation sold on the illicit drug market. All compounds were further investigated as potential ligands of the orphan receptors GPR18 and GPR55 that interact with some cannabinoids. Methods: The compounds were studied in radioligand binding assays to determine their affinity for human cannabinoid CB1 and CB2 receptors expressed in CHO cells, and in cAMP accumulation assays to study their functionality. Results: Structure-activity relationships were analyzed. The most potent CB1 receptor agonist of the present series MDMB-FUBINACA (12) (Ki = 98.5 pM) was docked into the human CB1 receptor structure, and a plausible binding mode was identified showing high similarity with that of the co-crystallized THC derivatives. MDMB-CHMCZCA (41) displayed a unique profile acting as a full agonist at the CB1 receptor subtype, but blocking the CB2 receptor completely. Only a few weakly potent antagonists of GPR18 and GPR55 were identified, and thus all compounds showed high CB receptor selectivity, mostly interacting with both subtypes, CB1 and CB2. Conclusions: These results will be useful to assess the compounds' toxicological risks and to guide legislation. Further studies on 41 are warranted.
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The number of new psychoactive substances (NPS) that have emerged on the European market has been rapidly growing in the last years, with a particularly high number of new compounds from the group of synthetic cannabinoid receptor agonists. There have been various political efforts to control the trade and the use of NPS worldwide. In Germany, the 'Act to control the distribution of new psychoactive substances' (NpSG) came into force in November 2016. In this new Act two groups of substances were defined, the group 'cannabimimetics/synthetic cannabinoids' covering indole, indazole and benzimidazole core structures, and a second group named 'compounds derived from 2-phenethylamine'. Shortly after, the first retailers of 'herbal blends' promoted new products allegedly not violating the German NpSG. We describe the identification and structural elucidation of one of the first synthetic cannabinoids not being covered by the NpSG, 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one. For isolation of the substance a flash chromatography separation was applied. The structure elucidation was performed using gas chromatography-mass spectrometry (GC-MS), gas chromatography-solid state infrared spectroscopy (GC-sIR), liquid chromatography-electrospray ionization-quadrupole time of flight-mass spectrometry (LC-ESI-qToF-MS) and nuclear magnetic resonance (NMR) analysis. Additionally, binding affinity towards the cannabinoid receptors CB1 and CB2 and efficacy in a cAMP accumulation assay was measured, showing full agonistic activity and high potency at both receptors. The new compound bears a γ-carboline core structure circumventing the German NpSG and also the generic definitions in other national laws. As a semi-systematic name for 2-cumyl-5-pentyl-gamma-carbolin-1-one CUMYL-PEGACLONE is suggested.
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Cannabis sativa has a long history of use for medical purposes despite marijuana's addictive potential. The discovery of the endogenous cannabinoid system as a neuromodulatory system composed of receptors, endogenous ligands (endocannabinoids), and enzymes responsible for their synthesis and degradation, together with recent advancements in the elucidation of cannabinoid pharmacology, has renewed interest in medicines acting on the endocannabinoid system. Synthetic cannabinoid agonists have been developed and used for treatment of different human pathologic conditions, and promising potent cannabinoid antagonists are currently under clinical evaluation. During the last decade, new generations of synthetic cannabinoids appeared on the global drug market, proposed as marijuana-like compounds and sold as herbal mixture also known as spice drugs or legal highs. Because activation of cannabinoid receptors may induce central and peripheral beneficial effects, the newest synthetic cannabinoids having full agonistic activity and high potency at cannabinoid type 1 and type 2 receptors might have therapeutic potential too. However, case reports of acute and fatal intoxications are accumulating and revealing that this is not the case because adverse effects of the latest generation of synthetic cannabinoids far exceed the desired ones.
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Indole, indazole or azaindole based synthetic cannabinoids (SCs), bearing a cumyl substituent are a widespread, recreationally used subgroup of new psychoactive substances (NPS). The latest cumyl-derivative, CUMYL-PEGACLONE, emerged in December 2016 on the German drug market. The substance features a novel γ-carboline core structure, which is most likely synthesized to bypass generic legislative approaches to control SCs by prohibiting distinct core structures. Using liquid chromatography tandem mass spectrometry and liquid chromatography high resolution mass spectrometry techniques, the main in vivo phase I metabolites of this new substance were detected. A pooled human liver microsome assay was applied to generate in vitro reference spectra of CUMYL-PEGACLONE phase I metabolites. Additionally, 30 urine samples were investigated leading to 22 in vivo metabolites. A metabolite mono-hydroxylated at the γ-carbolinone core system and a metabolite with an additional carbonyl group at the pentyl side chain were evaluated as highly specific and sensitive markers to proof CUMYL-PEGACLONE uptake. Moreover, three immunochemical assays commonly used for SC screening in urine were tested for their capability of detecting the new drug but failed due to insufficient cross-reactivity.
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Introduction: In 2014, the “European Monitoring Centre for Drugs and Drug Addiction” (EMCDDA) reported on 30 novel synthetic cannabinoids (SCs). Among these were indole- and indazole-based valine derivatives with a cyclohexylmethyl side chain (e.g., AB-CHMINACA and MDMB-CHMICA), which represent a new class of SCs. Methods: A prospective observational study of patients treated in emergency departments (EDs) after the intake of SCs was conducted. Clinical and laboratory data were combined and reported to a poison control centre. Serum and/or urine samples of ED patients were analyzed using LC–MS/MS. Results: Forty four patients (39 male, five female, 12–48 years) were included. AB-CHMINACA (MDMB-CHMICA) was identified in 20 (19) serum samples, and in 21 (25) urine samples, respectively. In 19 of the cases, more than one SC was present. Other psychoactive substances (mainly amfetamines) were identified in seven cases, but in five out of these in urine samples only. Based on the Poison Severity Score, severity of poisoning was minor (4), moderate (31) or severe (9). Most frequently reported neuropsychiatric symptoms were CNS-depression (n = 21, 61%), disorientation (n = 20, 45%), generalized seizures (n = 12, 27%), combativeness (n = 8, 18%) and extreme agitation (n = 7, 16%). Duration of symptoms lasting 24 hours or longer occurred in 15 cases (34%). Discussion: The prevalence of certain neuropsychiatric symptoms was higher in our study than in former reports after the intake of SCs of the aminoalkylindole-type (first generation) SCs. In addition, severe poisoning and duration of symptoms were also higher. Conclusions: In this study, the valine derivative AB-CHMINACA and the tert-leucine derivative MDMB-CHMICA (“third generation of SCs”) seem to be associated with more severe clinical toxicity than was previously reported in patients exposed to earlier generation SCs such as JWH-018. However, this observation needs to be confirmed with a larger cohort of patients with analytically confirmed abuse of third generation SCs. The rapid turnover of SCs on the drug market together with the occurrence of SCs such as AB-CHMINACA and MDMB-CHMICA is alarming, especially because of the unexpectedly high frequency of neuropsychiatric symptoms.
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The number of new psychoactive substances (NPS) has increased significantly, especially within the last 5 years. The EMCDDA conducts risks assessments of such substances, especially in relation to serious adverse events. Examination of the individual health risks of a substance is a fundamental requirement of the process. Based on a number of considerations, the Toxicological Significance Score has been developed to support the risk assessment of NPS by allowing the role of a substance in deaths to be better assessed and classified.
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The most frequent form of consumption of cannabinoid receptor agonists (CRAs), often referred to as synthetic cannabinoids, is smoking of herbal mixtures often obtained via the Internet. However, because the plant material is either sprayed with or soaked in a drug solution, one of the main health risks in using these products is made up by the inhomogeneity in the content of active ingredient(s) and distribution within the mixtures. In the present study, 311 herbal mixtures covering 31 different brands seized from an online retailer in 2012 were analyzed quantitatively by high-performance liquid chromatography with diode array detection after screening by gas chromatography–mass spectrometry. Both interpackage and intrapackage CRA content variation were investigated by sampling without prior homogenization to reflect drug user behavior. The results showed that it is impossible for the consumer to safely dose these drugs, and that two joints of herbal mixture prepared from the same package could contain significantly different amounts of the active substance. Therefore, accidental overdosing is likely to occur frequently. In some products, interpackage variability of up to 33 % [standard deviation (SD)] and intrapackage variability of up to 20 % (SD) were observed. Another major health risk is posed by the substitution of a CRA in a herbal mixture without changing the brand name. In almost all cases when such a substitution was observed, there was a pronounced difference in the binding affinities of the respective CRA without a noticeable change in the amount added to the plant material. These findings can partly explain the high number of unintended intoxications that require hospitalization after use of these drugs.
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New Zealand has recently attempted to address the underlying drivers of the escalating new psychoactive substances (NPS) ('legal highs') problem by establishing the world's first pre-market approval regulatory regime for NPS. NPS products which can be shown with clinical trial data to pose a 'low risk' of harm will be approved for legal manufacture and sale. This paper critically assesses the new regime, drawing on experience of the pharmaceutical sector and legal BZP market. A number of characteristics of the recreational use of NPS may not be well addressed by standard medical clinical trials, including binge use, polydrug use, use by vulnerable groups and high-risk modes of administration. The overt advertising and covert promotion of approved NPS products on the internet may make them fairly visible to young people. The black market for unapproved NPS may be difficult to suppress given that unapproved NPS will be physically identical to approved NPS. If the legal market for NPS encourages the use of NPS, alcohol and other drugs there may be an increase in drug-related harm. Alternatively, if the legal NPS market reduces the use of more harmful drugs, there may be a considerable public health benefit. The clinical trials required for NPS products should address the characteristics of recreational NPS use. Enforcement resources and technical solutions are required to clearly distinguish legal NPS products. The impact the new NPS regime has on other drug use is a key issue and demands further study.
The changing pattern of synthetic cannabinoid detection between
  • P Smith
  • G X Hudson S Chong
  • L Hikin
  • Morley
Smith P, Hudson S, Chong GX, Hikin L, Morley SR. The changing pattern of synthetic cannabinoid detection between April 2014 and April 2017 in the UK. TIAFT, 2018.