RESUMEN
Drug use is prevalent in prisons with drugs associated with depressant effects found to be more prevalent than stimulants. Synthetic cathinones (SCats; often sold as "bath salts", "ecstasy", "molly", and "monkey dust") are the second largest category of new psychoactive substances (NPS) currently monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and are commonly used as substitutes for regulated stimulants, such as amphetamine, cocaine, and MDMA. N,N-dimethylpentylone (also known as dimethylpentylone, dipentylone, and bk-DMBDP) was detected for the first time in the Scottish prisons in seven powder samples seized between January and July 2023. Samples were analyzed using gas chromatography-mass spectrometry (GC-MS), ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-QToF-MS), and nuclear magnetic resonance imaging (NMR). Dimethylpentylone was detected alongside other drugs in four samples, including the novel benzodiazepine desalkylgidazepam (bromonordiazepam) and the synthetic cannabinoid receptor agonists (SCRAs) MDMB-INACA and MDMB-4en-PINACA.
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Alcaloides , Cromatografía de Gases y Espectrometría de Masas , Drogas Ilícitas , Prisiones , Humanos , Alcaloides/análisis , Drogas Ilícitas/análisis , Drogas Ilícitas/química , Psicotrópicos/análisis , Psicotrópicos/química , Drogas de Diseño/análisis , Drogas de Diseño/química , Detección de Abuso de Sustancias/métodosRESUMEN
Hexahydrocannabinol (HHC), hexahydrocannabiphorol (HHCP) and their acetates, HHC-O and HHCP-O, respectively, are emerging in Europe as alternatives to tetrahydrocannabinol (THC). This study aimed to elucidate the metabolic pathways of the semi-synthetic cannabinoids HHC, HHCP, HHC-O and HHCP-O from incubation with human hepatocytes. The metabolites of HHC were also identified in authentic urine samples. HHC, HHCP, HHC-O and HHCP-O were incubated with primary human hepatocytes for 1, 3 and 5 h. Authentic urine samples from cases screened positive for cannabis in blood using ELISA but confirmed negative were analysed both non-hydrolysed and hydrolysed for HHC metabolites. Potential metabolites were identified using ultra-high performance liquid chromatography (UHPLC) coupled to a quadrupole time-of-flight mass spectrometer (QToF-MS). HHC and HHCP were primarily metabolised through monohydroxylation (monoOH), followed by oxidation to a carboxylic acid metabolite. HHC-O and HHCP-O were rapidly metabolised to HHC and HHCP, respectively. In authentic urine samples, 18 different metabolites were identified, and 99.3% of hydroxylated metabolites were glucuronidated. 11-OH-HHC, 5'OH-HHC and another metabolite with a monoOH on the side chain were the only metabolites present in all 16 urine samples. The metabolism of HHC and HHCP were similar, although the longer alkyl side chain of HHCP (heptyl) led to greater hydroxylation on the side chain than HHC (pentyl). The use of HHC and HHCP can be differentiated from the use of THC and other phytocannabinoids, but the use of the acetate analogues may not be differentiable from their non-acetate analogues.
RESUMEN
The administration of new psychoactive substances (NPS), in particular synthetic cannabinoid receptor agonists (SCRAs), via e-cigarettes, within prison settings has been well publicized. This study provides an overview of five e-cigarette case samples seized from Scottish prisons between May 2022 and July 2023 where the anabolic-androgenic steroids (AASs) mestanolone and oxandrolone were identified following gas chromatography-mass spectrometry (GC-MS) analysis. These e-cigarette samples represented 2.9% of all samples containing e-cigarette cartridges (n = 170) and 9.4% of all samples found to contain AASs (n = 53) seized during the same time period. The AASs were detected in combination with other drugs, including cocaine, Δ9-tetrahydrocannabinol (Δ9-THC), SCRAs and nicotine. This represents a new and novel route of administration for AASs.
Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Esteroides Anabólicos Androgénicos , Prisiones , Cromatografía de Gases y Espectrometría de Masas , Agonistas de Receptores de CannabinoidesRESUMEN
The rapidly evolving synthetic cannabinoid receptor agonist (SCRA) market poses significant challenges for forensic scientists. Since the enactment of a generic ban in China, a variety of new compounds have emerged capable of evading the legislation by carrying new structural features. One recent example of a SCRA with new linker and head moieties is CH-PIATA (CH-PIACA, CHX-PIATA, CHX-PIACA). CH-PIATA bears an additional methylene spacer in the linker moiety between the indole core and the traditional carbonyl component of the linker. This study describes detections in 2022 of this new SCRA in the United States, Belgium, and Scottish prisons. CH-PIATA was detected once in a seized powder by Belgian customs and 12 times in Scottish prisons in infused papers or resin. The metabolites of CH-PIATA were investigated via in vitro human liver microsome (HLM) incubations and eight metabolites were identified, dominated by oxidative biotransformations. A blood sample from the United States was confirmed to contain a mixture of SCRAs including CH-PIATA via presence of the parent and at least five of the metabolites identified from HLM incubations. Furthermore, this paper evaluates the intrinsic in vitro cannabinoid 1 and 2 (CB1 and CB2) receptor activation potential of CH-PIATA reference material and the powder seized by Belgian customs by means of ß-arrestin 2 recruitment assays. Both the reference and the seized powder showed a weak activity at both CB receptors with signs of antagonism found. Based on these results, the expected harm potential of this newly emerging substance remains limited.
Asunto(s)
Cannabinoides , Ácidos Indolacéticos , Humanos , Polvos , Agonistas de Receptores de Cannabinoides/química , Receptores de Cannabinoides , Receptor Cannabinoide CB1 , Receptor Cannabinoide CB2RESUMEN
Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS) and new structural scaffolds have emerged on the recreational drug market since the enactment of Chinese SCRA analog controls in 2021. This study reports the first SCRAs to be detected with a bromide at the 5 position (5'Br) on the phenyl ring of the indazole core and without a tail moiety. ADB-5'Br-INACA (ADMB-5'Br-INACA) and MDMB-5'Br-INACA were detected in seized samples from Scottish prisons, Belgian customs, and US forensic casework. The brominated analog with a tail moiety, ADB-5'Br-BUTINACA (ADMB-5'Br-BUTINACA), was also detected in Scottish prisons and US forensic casework. The metabolites of these compounds and the predicted compound MDMB-5'Br-BUTINACA were identified through incubation with primary human hepatocytes to aid in their toxicological identification. The bromide on the indazole remains intact on metabolites, allowing these compounds to be easily distinguished in toxicological samples from their non-brominated analogs. Glucuronidation was more common for tail-less analogs than their butyl tail-containing counterparts. Forensic toxicologists are advised to update their analytical methods with the characteristic ions for these compounds, as well as their anticipated urinary markers: amide hydrolysis and monoOH at tert-butyl metabolites (after ß-glucuronidase treatment) for ADB-5'Br-INACA; monoOH at tert-butyl and amide hydrolysis metabolites for ADB-5'Br-BUTINACA; and ester hydrolysis metabolites with additional metabolites for MDMB-5'Br-INACA and MDMB-5'Br-BUTINACA. Toxicologists should remain vigilant to the emergence of new SCRAs with halogenation of the indazole core and tail-less analogs, which have already started to emerge.
RESUMEN
Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5'Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5'Br-INACA (ADMB-5Br-INACA), MDMB-5'Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (S)-enantiomers of these substances, as well as of two predicted analogs MDMB-5'Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5'F-BUTINACA (ADMB-B-5F-INACA), using CB1 and CB2 ß-arrestin 2 recruitment assays and a CB1 intracellular calcium release assay. Surprisingly, the tail-less (S)-ADB-5'Br-INACA and (S)-MDMB-5'Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (S)-ADB-5'Br-BUTINACA and (S)-MDMB-5'Br-BUTINACA, respectively, which were potent and efficacious CB1 agonists. Also, at CB2 , tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((S)-ADB-INACA) resulted in a reduced activity at CB1 ; however, this effect was less prominent at CB2 . Looking at tailed analogs, replacing the bromine with a fluorine substitution ((S)-ADB-5'F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5'Br-INACA and MDMB-5'Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB1 receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5'Br-INACA and MDMB-5'Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected.
RESUMEN
Drug use within prisons is increasingly complex and unpredictable. Benzodiazepines are currently one of the most common drugs detected in individuals leaving Scottish prisons; however, understanding illicit benzodiazepine use within prisons and assessing the potential harm to individuals is challenging due to the lack of available analytical data on the substances circulating. Increasingly, materials, such as paper and clothing, infused with novel benzodiazepines have been identified as a smuggling route into Scottish prisons. Methods were developed for the qualitative and quantitative analysis of benzodiazepines using gas chromatography-mass spectrometry (GC-MS) and applied to 495 seized samples from 11 Scottish prisons, including papers, cards, blotters, powders, tablets, and clothing. Evolution in the benzodiazepines being detected was demonstrated, with etizolam being the most prevalent throughout 2020/2021 following which flubromazepam and bromazolam detections increased. Additionally, significant changes in the smuggling methods and drug formats detected occurred over time following policy changes within prisons. These data represent the first reported widescale etizolam quantitation data and demonstrate high levels of variability across all sample types, most notably within tablets (0.34-2.33 mg per tablet). Additionally, concentration mapping of a whole seized card sample revealed the total concentration of drug present (312.5 mg) and demonstrated variability across the surface of the card (1.16-1.87 mg/cm2 ). These data highlight the challenges of consistent dosing for individuals and the high risks of unintentional overdose. Increased understanding of the challenge of such drug smuggling and benzodiazepine use will aid in the development of strategies to reduce supply and mitigate harm.
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BACKGROUND: Ion mobility spectrometry is used for the rapid detection of drugs at points of security but are unable to differentiate some drugs leading to the instrument alarming for a drug not present in the sample. This can be particularly problematic for samples that alarm for fentanyl. In this study, fentanyl immunoassay strips were evaluated for use as a secondary test for fentanyl, including for the testing of alternative matrices, such as powders, e-liquids, and infused papers and textiles. METHODS: The limit of detection of fentanyl immunoassay strips was examined along with their selectivity to 18 fentanyl analogsand 72 other drugs and cutting agents. The effectiveness of the test strips at the detection of fentanyl in the presence of other drugs was examined by testing a series of concentrations of fentanyl in solution in combination with other drugs. The testing of alternative matrices was explored with laboratory prepared samples through sampling with cotton buds and extraction in water. RESULTS: The fentanyl immunoassay strips detected fentanyl at concentrations of 45 ng/mL and reacted with 16 of 18 tested fentanyl analogs with carfentanil and norfentanyl being the only analogs to not react. There was no reactivity with other drugs or cutting agents. The effectiveness of the fentanyl test strips was not reduced when fentanyl was mixed with other drugs. Fentanyl was successfully detected with high sensitivity in all alternative matrices. CONCLUSION: The fentanyl immunoassay strips were found to be an effective secondary test for fentanyl and at least 16 fentanyl analogs in seized drug samples, including when mixed with other drugs. The effectiveness of the sampling methods for alternative matrices should be further evaluated using fentanyl and fentanyl analog casework samples. The use of this method by law enforcement and other agencies should be examined to assess its effectiveness and ease of use in operational settings.
Asunto(s)
Analgésicos Opioides , Fentanilo , Humanos , Analgésicos Opioides/análisis , Fentanilo/análisis , Inmunoensayo/métodos , Límite de Detección , Detección de Abuso de Sustancias/métodosRESUMEN
The synthetic cannabinoid receptor agonist (SCRA) market is undergoing important changes since the enactment of the 2021 class-wide generic SCRA ban in China, one of the most important source countries for new psychoactive substances (NPS). Recently, various compounds with new structural features, synthesized to bypass this legislation, have entered the recreational drug market. Certain monocyclic pyrazole-carrying "FUPPYCA" SCRAs have been sporadically detected since 2015 without gaining further popularity. However, as evidenced by their recent detection in Scottish prisons, 5F-3,5-AB-PFUPPYCA and 3,5-ADB-4en-PFUPPYCA have re-emerged, potentially triggered by the new legislative ban. The aim of this study was to characterize the in vitro intrinsic CB1 and CB2 receptor activation potential of 5F-3,5-AB-PFUPPYCA and 3,5-ADB-4en-PFUPPYCA, as well as 4 analogs (5F-3,5-ADB-PFUPPYCA, 3,5-AB-CHMFUPPYCA, 5,3-AB-CHMFUPPYCA and 5,3-ADB-4en-PFUPPYCA) using live cell ß-arrestin 2 recruitment assays. Most analogs were essentially inactive at either CB1 or CB2, with only 3,5-AB-CHMFUPPYCA, 5,3-AB-CHMFUPPYCA and 5,3-ADB-4en-PFUPPYCA showing a limited activation potential at CB1. Furthermore, the importance of the position of the tail structure was demonstrated, with 5,3 regioisomers being more active than their 3,5 analogs. Moreover, all compounds exhibited antagonistic behavior at both receptors, which may be associated with their structural resemblance to cannabinoid antagonists and inverse agonists. Although the 3,5 regioisomers of these "FUPPYCA" SCRAs circumvent the Chinese ban, it is unlikely that these SCRAs will pose a major threat to public health, given the lack of pronounced CB receptor activity.
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Agonistas de Receptores de Cannabinoides , Drogas Ilícitas , Agonistas de Receptores de Cannabinoides/farmacología , Agonistas de Receptores de Cannabinoides/química , Agonismo Inverso de Drogas , Pirazoles/farmacología , China , Receptor Cannabinoide CB1 , Receptor Cannabinoide CB2RESUMEN
4'Cl-cumyl-PINACA (SGT-157), 4'F-cumyl-5F-PINACA (4F-cumyl-5F-PINACA, SGT-65) and 4'F-cumyl-5F-PICA (4F-cumyl-5F-PICA, SGT-64) are a series of new halogenated cumyl synthetic cannabinoid receptor agonists (SCRAs). Due to rapid metabolism, monitoring and screening for SCRAs in biological matrices requires identification of their metabolites. It is an essential tool for estimating their spread and fluctuations in the global illicit market. The purpose of this study was to identify human biotransformations of 4'Cl-cumyl-PINACA, 4'F-cumyl-5F-PINACA and 4'F-cumyl-5F-PICA in vitro and characterize for the first time the metabolic pathways of halogenated cumyl SCRAs. 4'Cl-cumyl-PINACA, 4'F-cumyl-5F-PINACA and 4'F-cumyl-5F-PICA were incubated with human hepatocytes in duplicates for 0, 1, 3 and 5 h. The supernatants were analysed in data-dependent acquisition on a UHPLC-QToF-MS, and the potential metabolites were tentatively identified. A total of 11 metabolites were detected for 4'Cl-cumyl-PINACA, 21 for 4'F-cumyl-5F-PINACA and 10 for 4'F-cumyl-5F-PICA. The main biotransformations were oxidative defluorination, followed by hydroxylation with dehydrogenation, N-dealkylation, dihydrodiol formation and glucuronidation. Hydroxylations were most common at the tail moieties with higher abundancy for indole than indazole compounds. N-dealkylations were more common for fluorinated tail chain compounds than the non-fluorinated 4'Cl-cumyl-PINACA. In conclusion, many metabolites retained halogen groups at the cumyl moieties which, in various combinations, may be suitable as analytical biomarkers.
Asunto(s)
Cannabinoides , Humanos , Espectrometría de Masas , Indazoles , Hepatocitos/metabolismo , Agonistas de Receptores de Cannabinoides/metabolismoRESUMEN
Early warning systems detect new psychoactive substances (NPS), while dedicated monitoring programs and routine drug and toxicology testing identify fluctuations in prevalence. We report the increasing prevalence of the synthetic cannabinoid receptor agonist (SCRA) ADB-BUTINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-butyl-1H-indazole-3-carbox-amide). ADB-BUTINACA was first detected in a seizure in Sweden in 2019, and we report its detection in 13 routine Swedish forensic toxicology cases soon after. In January 2021, ADB-BUTINACA was detected in SCRA-infused papers seized in Scottish prisons and has rapidly increased in prevalence, being detected in 60.4% of the SCRA-infused papers tested between January and July 2021. In this work, ADB-BUTINACA was incubated with human hepatocytes (HHeps), and 21 metabolites were identified in vitro, 14 being detected in authentic case samples. The parent drug and metabolites B9 (mono-hydroxylation on the n-butyl tail) and B16 (mono-hydroxylation on the indazole ring) are recommended biomarkers in blood, while metabolites B4 (dihydrodiol formation on the indazole core), B9, and B16 are suitable biomarkers in urine. ADB-4en-PINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[pent-4-en-1-yl]-1H-indazole-3-carboxamide) was detected in Scottish prisons in December 2020, but, unlike ADB-BUTINACA, prevalence has remained low. ADB-4en-PINACA was incubated with HHeps, and 11 metabolites were identified. Metabolites E3 (dihydrodiol formed in the tail moiety) and E7 (hydroxylation on the linked/head group) are the most abundant metabolites in vitro and are suggested as urinary biomarkers. The in vitro potencies of ADB-BUTINACA (EC50 , 11.5 nM and ADB-4en-PINACA (EC50 , 11.6 nM) are similar to that of MDMB-4en-PINACA (EC50 , 4.3 nM). A third tert-leucinamide SCRA, ADB-HEXINACA was also detected in prison samples and warrants further investigation.
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Cannabinoides , Prisiones , Agonistas de Receptores de Cannabinoides , Toxicología Forense , Humanos , IndazolesRESUMEN
The synthetic cannabinoid receptor agonist (SCRA) market is transnational, and the availability of individual SCRAs changes regularly in response to national and international legislative controls. This generates a cyclic pattern and near constant evolution of SCRA compounds. This study reports toxicology-based and/or seized sample-based prevalence data relating to SCRA use in prisons from Germany, the United Kingdom (UK; Scotland and Wales), and the United States (US), representing 4427 individual test results. The study examines SCRA detections in prisons from July 2018 to September 2020, and where possible, prison-based data are compared with SCRA prevalence data in the wider population. The relative influence of Chinese, other international, and national drug legislation on the prevalence of individual SCRAs in prisons is also considered. tert-Leucinate- and valinate-indole- and indazole-3-carboxamides were the most common SCRA detections, and MDMB-4en-PINACA was one of the most commonly detected SCRAs in all jurisdictions by September 2020. However, despite there being a global production and supply market, there were notable regional differences. Analog controls in German and US legislation may have led to increased compound diversity that is not reflected in the UK which has both analog controls and a blanket ban on psychoactive substances. While there were regional differences, SCRA prevalence in prisons closely aligned with the SCRAs detected on the local market, demonstrating that SCRA (and possibly other NPS) monitoring programs in prisons can act as early warning systems for the wider population in that given jurisdiction.
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Agonistas de Receptores de Cannabinoides/provisión & distribución , Drogas Ilícitas/provisión & distribución , Legislación de Medicamentos , Prisiones/estadística & datos numéricos , Alemania , Humanos , Drogas Ilícitas/legislación & jurisprudencia , Reino Unido , Estados UnidosRESUMEN
Synthetic cannabinoid receptor agonists (SCRAs), colloquially known as "spice," are commonly used in prisons and enter establishments via the mail in the form of infused papers. Many prisons use benchtop ion mobility spectroscopy (IMS) instruments to screen mail and seized materials for the presence of SCRAs and other controlled substances. The selectivity and sensitivity of Rapiscan Itemiser® 3E and Itemiser® 4DN Ion Trap Mobility Spectroscopy™ (ITMS™) systems were evaluated using 21 SCRA reference standards. Some differences in the SCRA reduced mobility (K0 ) values were observed between this study and those reported previously using IMS detection systems, particularly for cumyl and quinolinyl SCRAs (e.g., 5F-PB-22, Cumyl-4CN-BINACA, and 5F-Cumyl-PEGACLONE), although this was found to have little effect at an operational level. Operational reliability of the systems was evaluated by analyzing 392 paper and card samples with known drug content. ITMS™ system results (e.g., detect or nondetect) were in agreement with gas chromatography-mass spectrometry (GC-MS) analysis in up to 95% of samples tested. Overall, this study found the ITMS™ systems tested to be effective instruments when deployed for the rapid detection of SCRA-infused papers. Used effectively and with up-to-date substance libraries, they will help reduce the supply of SCRAs into prisons and identify emerging threats as they arise. Several emerging SCRAs (5F-MPP-PICA, 5F-EMB-PICA, and 4F-MDMB-BICA) were detected for the first time in Scottish prisons between May and August 2020 as a result of routine monitoring, and all were detected using the ITMS™ systems tested.
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Agonistas de Receptores de Cannabinoides/análisis , Drogas Ilícitas/análisis , Espectrometría de Movilidad Iónica/métodos , Agonistas de Receptores de Cannabinoides/química , Cromatografía de Gases y Espectrometría de Masas , Humanos , Drogas Ilícitas/química , Papel , Prisiones , Reproducibilidad de los Resultados , EscociaRESUMEN
Synthetic cannabinoid receptor agonists (SCRAs) elicit many of their psychoactive effects via type-1 human cannabinoid (CB1 ) receptors. Enantiomer pairs of eight tert-leucinate or valinate indole- and indazole-3-carboxamide SCRAs were synthesized and their CB1 potency and efficacy assessed using an in vitro ß-arrestin recruitment assay in a HEK239T stable cell system. A chiral high-performance liquid chromatography method with photodiode array and/or quadrupole time-of-flight-mass spectrometry detection (HPLC-PDA and HPLC-PDA-QToF-MS) was applied to 177 SCRA-infused paper samples seized in Scottish prisons between 2018 and 2020. In most samples, SCRAs were almost enantiopure (S)-enantiomer (>98% of total chromatographic peak area), although in some (n = 18), 2% to 16% of the (R)-enantiomer was detected. (S)-enantiomers are consistently more potent than (R)-enantiomers and often more efficacious. The importance of SCRA-CB1 receptor interactions in the "head" or "linked group" moiety is demonstrated, with the conformation of the "bulky" tert-leucinate group greatly affecting potency (by up to a factor of 374), significantly greater than the difference observed between valinate SCRA enantiomers. (S)-MDMB-4en-PINACA, (S)-4F-MDMB-BINACA, and (S)-5F-MDMB-PICA are currently the most prevalent SCRAs in Scottish prisons, and all have similar high potency (EC50 , 1-5 nM) and efficacy. Infused paper samples were compared using estimated intrinsic efficacy at the CB1 receptor (EIECB1 ) to evaluate samples with variable SCRA content. Given their similar potency and efficacy, any variation in CB1 receptor-mediated psychoactive effects are likely to derive from variation in dose, mode of use, pharmacokinetic differences, and individual factors affecting the user, rather than differences in the specific SCRA present.
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Agonistas de Receptores de Cannabinoides/análisis , Cromatografía Líquida de Alta Presión/métodos , Drogas Ilícitas/análisis , Espectrometría de Masas/métodos , Bioensayo/métodos , Agonistas de Receptores de Cannabinoides/síntesis química , Agonistas de Receptores de Cannabinoides/química , Células HEK293 , Humanos , Drogas Ilícitas/síntesis química , Drogas Ilícitas/química , Papel , Prisiones , Escocia , Estereoisomerismo , beta-Arrestinas/metabolismoRESUMEN
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.
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Agonistas de Receptores de Cannabinoides/análisis , Drogas Ilícitas/análisis , Papel , Psicotrópicos/análisis , Cannabinoides/análisis , Cromatografía Líquida de Alta Presión , Cromatografía de Gases y Espectrometría de Masas , Humanos , Espectroscopía de Resonancia Magnética , PrisionesRESUMEN
Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB1 and CB2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC50 (a measure of potency) and Emax (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB2 receptor than at the CB1 receptor and (S)-enantiomers had an enhanced potency to both receptors over the (R)-enantiomers. The relative potency of the enantiomers to the CB2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of (R)-enantiomers in seized samples. Lux® Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux® i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) ≥ 1.99. Achiral GC-MS analysis of seized herbal materials (n = 16), found 5F-MDMB-PINACA (<1.0-91.5 mg/g herbal material) and AMB-FUBINACA (15.5-58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the (S)-enantiomer predominated in all samples (93.6-99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the "intrinsic" potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.