Continuous development and rapid turnover of drug market of new psychoactive substances (NPS) make it difficult to obtain up-to-date analytical methods for efficient detection of intoxication cases ...with new substances: no analytical data and no previously published concentration values in biological samples are indeed available. In this context, we aim to report the first fatal case involving two newly emerging arylcyclohexylamine derivatives (a group of dissociative ketamine-based substances): 2-fluoro-deschloroketamine (2F-DCK) and 3-methoxyeticyclidine (3-MeO-PCE). A 42-year-old man was found dead at his home with three plastic bags of “research chemicals” powders near him. Comprehensive screenings of drugs and toxic compounds as well as more selective assays (performed using NMR, HS-GC-FID, LC-MS/MS and LC-HRMS methods) allowed (1) to identify the three unknown powders, 2F-DCK, 3-MeO-PCE, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT, a hallucinogenic tryptamine-related NPS), with purity above 95%, and (2) to determine peripheral blood (1780, 90, and 52 µg/L), urine (6.1, 6.3, and 2.2 mg/L), bile (12, 3.5, and 1.7 mg/L), and vitreous humour (1500, 66 and 155 µg/L) concentrations of 2F-DCK, 3-MeO-PCE and 5-MeO-DMT, respectively. In addition, toxicological results also revealed recent use of cannabis, cocaine, and amphetamine by the victim, and hair analysis draw pathway of addiction (including experiments with various other NPS) for several months before death. This fatality was considered as the consequence of respiratory depression in a poly-drug user due to a “cocktail effect” of concurrent intakes of 2F-DCK (mainly), 3-MeO-PCE, 5-MeO-DMT, amphetamine, and cocaine. In addition, this case report provides analytical data that could support subsequent toxicological result interpretation in forensic cases involving such arylcyclohexylamine derivatives.
This work first aims to investigate metabolites of 2‐fluoro‐deschloroketamine (2F‐DCK), a new arylcyclohexylamine derivatives (a group of dissociative ketamine‐based substances) using two in vitro ...experimental approaches, and to compare obtained results by means of molecular networking. Metabolites of 2F‐DCK were investigated using both human liver microsomes (HLMs) and hepatic (HepaRG) cell line incubates using molecular networking approach: 2F‐DCK pure substance was incubated with HLMs for up to 1 h at two concentrations (100 and 500 μM) and with HepaRG cells for two time periods (8 and 24 h) at one concentration (20 μM). In vitro obtained results were subsequently applied to a 2F‐DCK‐related fatality case. In vitro‐produced metabolites were investigated using high‐resolution accurate mass spectrometry using Orbitrap mass analyzer technology. Thirteen metabolites were in vitro produced and several metabolic pathways can be postulated. Seven additional metabolites were found in post‐mortem samples (bile and urine) of the case, comprising three Phase II metabolites, which appear to be minor in vivo metabolites. HLMs and HepaRG cell models appear to be complementary and obtained data allowed the identification of several specific 2F‐DCK metabolites in biological samples. In practical terms, observed metabolic ratios suggested that nor‐2F‐DCK (208.1137 m/z) and a hydrogenated metabolite (224.1443 m/z) could be proposed as reliable metabolites to be recorded in HRMS libraries in order to improve detection of 2F‐DCK use.
Molecular network approach (1) allows 2F‐DCK metabolic profile proposal with evaluation using authentic post‐mortem samples and (2) suggests not ‐2F‐DCK and dihydro‐nor‐FDCK metabolites as robust, specific, and sensitive biomarkers of 2F‐DCK use.
Today, new psychoactive substances (NPS) producers increasingly appear to be targeting new synthetic opioids (NSOs), and the recent emergence of NSOs is causing considerable concern in North America ...and in Europe. For toxicologists, NSO detection in a forensic context presents three additional difficulties to the general NPS analytical detection challenge: (i) high frequency of new products, (ii) low concentrations (in μg/L range and under) in biological samples related to their high opioid potency, and (iii) extensive metabolism. In this context, the present work aims to highlight the relevance of NSO metabolite detection in potential intoxication cases. Illustration is given with U-47700, an emerging NSO, (i) that was identified in a powder recently collected in France and in a fatality case, (ii) whose metabolites were in vitro produced using human liver microsomes and their mass spectra (MS) added in our MS/MS and HRMS libraries, and (iii) for which metabolism data were compared to those of the literature: U-47700 was identified in the powder and at 3040 μg/L in peripheral blood in the fatality case. In addition, high amounts of several U-47700 metabolites, especially
N
-desmethyl-U-47700, were observed in urine. Even if metabolite formation may largely depend on the enzymatic activity as well as on the length of the survival time, confrontation of these results to data found in the literature strongly suggests that this metabolite is regularly a better blood and (mainly) urine biomarker of U-47700 intake than U-47700 itself. Indeed, in this fatality and in other previous reports,
N
-desmethyl-U-47700 produced the main observed chromatographic signal (i) systematically in vitro and (ii) commonly in vivo, especially in urines.
N
,
N
-Didesmethyl-U-47700 is also sometimes a better biomarker of U-47700 intake than U-47700 itself. Accordingly, we suggest adding
N
-desmethyl-U-47700 (and
N
,
N
-didesmethyl-U-47700) in mass spectrum databases used for toxicological screening in order to reduce the risk of false-negative results in intoxication cases involving U-47700.
The metabolism of urapidil to 2‐MeOPP induces the risk of detection of 2‐MeOPP in biological samples (blood, urine and hair) in case of urapidil treatment. This is supported by two case reports and ...an in vitro study of urapidil metabolism.
Mayotte Island, a French department located in the Mozambique Channel, has for several years been faced with the consumption of “La Chimique” (LC), reputed (but extremely poorly documented) to be a ...mixture of tobacco and synthetic cannabinoid receptor agonists (SCRAs). One of the objectives of the CHASSE‐MAREE protocol is to assess the composition and heterogeneity of LC products through successive LC sample collection campaigns among users. Currently underway, we present here the first analytical results (samples collected in 2022). Between September and December 2022, 80 samples were collected throughout the island over three periods: 70 in the usual form of LC (small folded papers containing a plant‐like sample, mostly tobacco), 6 powders, and 4 cigarettes. Analysis was performed using liquid chromatography with high‐resolution mass spectrometry. The detected substances (number of detections) included SCRAs (MDMB‐4en‐PINACA 35, ADB‐FUBIATA 25, MDMB‐INACA 16, ADB‐BUTINACA 15, AFUBIATA 11, 4F‐MDMD‐BICA 7, CH‐PIATA 14, 5C‐APINACA 3, BZO‐HEXOXIZID 2, and 4F‐ABINACA 1), nicotine (68), tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) (2), medications (amantadine 11, cyamemazine 6, and acetaminophen 3), and a designer benzodiazepine (bromazolam 4). The SCRAs currently in use are varied, and the market for “cooks” (those who prepare LC) is dispersed according to where and when samples are collected. These preliminary results will be supplemented by analysis of samples collected in the first half of 2023 and by an improved description of the current panorama of consumption of LC in Mayotte (mapping, effects felt and dependence, etc.).
Mayotte Island, a French department, has for several years been faced with the consumption of a drug called “La Chimique.” The CHASSE‐MAREE protocol aims to assess the composition of “La Chimique” products through successive sample collection campaigns. The first analytical results (80 samples collected in 2022) revealed that, as suspected, the main psychoactive constituents of this drug are SCRAs. This overview of SCRAs often includes associations and seems to vary from month to month and according to geographical location.
An 11-month-old boy was found dead. Autopsy findings (cyanosis and polyvisceral congestion) and blood tramadol (TR) concentration of 6240 μg/L were consistent with an acute TR intoxication. In this ...poisoning situation, owing to the mother's statements (TR addiction leading to daily TR-orange juice mixture preparation accidentally used for the baby bottle preparation by the mother's partner), and the question of possible previous TR administrations to the infant, hair and/or nails (infant, mother, partner, 6-year-old sister) analysis was performed. Hair (2-cm-long hair segments from proximal S1 to distal S3) and nails concentrations (pg/mg; nd: not detected) were as follows: Infant (hair: TR 1420 S1, 1622 S2, 2736 S3; O-DMT 16-38; N-DMT 34-100 TR in significant quantities in the hair decontamination bath-toenails: TR 584; O-DMT 8; N-DMT 15), mother (hair: TR 2340 S1, 2150 S2, 2500 S3; O-DMT 704-1170; N-DMT 827-1360), mother's partner (fingernails: TR 72; O-DMT nd; N-DMT nd) and sister (hair: TR 261 S1, 524 S2; O-DMT 15 S1, 16 S2; N-DMT 20 S1, 38 S2). Metabolite ratio (infant and sister hair) was comparable to those observed in hair of pharmaceutical industry employees manufacturing tramadol. TR in washing baths, low observed nail concentrations (infant and partner) confirm (i) TR-related mother's addiction and (ii) external contamination issues (TR in sweat of the child at the time of death and in living environment) to explain the infant's keratinized samples results. This case report illustrates the interest of analyzing keratinized matrices of the whole family in such a situation.
Designer benzodiazepines have emerged as recreational drugs. They are available via the Internet without control and are found in the form of falsified (fake) medicines. For some of them, limited ...information concerning their effects, their toxicity, and their detection in bio fluids is available in the literature. For others, nothing has been published, as in the case of flunitrazolam (FNTZ). To gain preliminary data on its elimination parameters in urine and to investigate its metabolism, one of the authors ingested one pink tablet bought on the Internet, after confirming the absence of other compounds and agreement with the labeled dosage (0.25 mg) by nuclear magnetic resonance (NMR). A software algorithm (MetaboLynx, Waters, Milford, MA, USA) was used to predict FNTZ biotransformation and four potential metabolites were proposed: 4‐hydroxy‐FNTZ, desnitro‐FNTZ, 7‐amino‐FNTZ, and 7‐acetamido‐FNTZ. Urine samples were collected over 72 hours following oral administration of one tablet. After liquid/liquid extraction at pH 9.5, FNTZ concentrations were determined using ultra performance liquid chromatography–triple quadrupole–mass spectrometry (UPLC–QqQ–MS/MS). FNTZ remained detectable in hydrolyzed urine for 21 hours after ingestion, with concentrations ranging between 1 and 18 ng/mL. About 3% of the initial dose was excreted in urine as total unchanged FNTZ during this period. In vitro experiments (HLM incubations) were performed using ultra performance liquid chromatography–quadrupole time of flight‐mass spectrometry (UPLC–QTOF–MS) in order to investigate the potential CYP‐ and UGT‐dependent metabolites where only 7‐amino‐FNTZ was detected as the only metabolite. However, in the urine specimens, desnitro‐FNTZ, 7‐acetamido‐FNTZ and 7‐amino‐FNTZ were the main detected compounds. The identification of FNTZ metabolites dramatically improves the detection windows of the drug up to 37 hours.
Flunitrazolam is a designer benzodiazepine for which no information is available in the scientific literature. In order to gain data on its elimination in urine and to investigate its metabolism, one subject ingested one tablet (0.25 mg) bought on the Internet. Flunitrazolam remained detectable in hydrolyzed urine for 21 hours and its metabolites (7‐amino‐ flunitrazolam and 7‐acetamido‐flunitrazolam) improve the detection windows of the drug up to 37 hours.
The use of 3,4-methylenedioxymethamphetamine (MDMA) in drug-facilitated sexual assault (DFSA) is not uncommon. Indeed, the effects associated with the use of this substance may lead to disinhibition. ...Several synthetic cathinones, such as mephedrone or methylone, also possess marked entactogenic properties. This manuscript aims to (i) report a DFSA case involving a novel cathinone derivative, namely N-ethyl-pentedrone (NEPD) and (ii) review previously reported DFSA cases involving synthetic cathinones. Using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), NEPD was detected in both plasma and urine collected from a 36-year-old male who had been victim of DFSA. Furthermore, an exhaustive, non-period-specific English-language literature search was performed using several different electronic databases to identify DFSA cases involving synthetic cathinones. Overall, five synthetic cathinones have been associated with DFSA:methylenedioxypyrovalerone, 4-methylethcathinone, α -pyrrolidinopentiophenone, mephedrone, α –pyrrolidinohexiophenone, and methylone, which appears to be the most frequently reported. Methylone is the β-keto analog of MDMA, with which it shares substantial pharmacological similarities. Indeed, the pharmacological effects of methylone are similar to those associated with MDMA. By contrast, little is known regarding NEPD’s pharmacological effects in humans. Based on subjective reports, NEPD can produce both positive and negative effects in human. Unlike what is reported in the case of methylone or mephedrone, only a small minority of NEPD users report slightly entactogenics effects. Such properties theoretically make NEPD more suitable for use in a chemsex context than in DFSA context; even though, the boundary between these two specific forms of sexualized drug use can sometimes appear tenuous.
•The use of psychostimulants is not uncommon in DFSA cases.•These cases particularly involve MDMA, an entactogenic substance.•Here, a DFSA case involving a novel cathinone derivative, namely N-ethyl-pentedrone is reported.•Further, other reported DFSA cases involving synthetic cathinones has been reviewed.
Display omitted
Driving under the influence of drugs (DUID) is a worldwide problem with potentially major forensic and life-threatening consequences. Although it is obvious that new psychoactive ...substances (NPS) could lead to impaireddriving, the prevalence of NPS use in a DUID context is unknown as the applied roadside screening tests for drugs of abuse (DOA) are not adapted for NPS detection. This works aims to tested oral fluid (OF) specimens for NPS in French drivers circulating around two music festivals (Artsenik 2017 and Garorock 2017) in order to assess the prevalence of consumption and the kind of used NPS in this particular population. OF samples consisted in dried saliva spots obtained from used Drugwipe-5S® tests (after a positive or negative roadside screening test for DOA). These OF were analyzed using a liquid chromatography coupled with tandem mass spectrometry or high-resolution mass spectrometry method. NPS were detected in 17 out of the 229 OF collected specimens (7.4%). Eleven various NPS were identified (number of identification): 5F-AKB48 (2), MAM2201 (1), JWH122 (1), 4F-PVP (1), 3- or 4-MMC (2), fluoromethamphetamine (1), ketamine (3), MXE (3), methoxyketamine (1), 6-APB (2) and 25C-NBOMe (1). There is an apparent effect of the music festival proximity on the prevalence of NPS in OF from this controlled driver population compared to that of 140 controlled drivers from Northern France analyzed in the same period (7.4% versus 3%). The variety of used NPS appears to be increasing (e.g. large proportion of cyclohexanones). In addition, 5% of drivers initially roadside-tested negative for DOA were in fact driving after NPS use in this specific population. From a forensic perspective, these results confirm the reality of driving after NPS use in French drivers, notably in those driving to or from a music festival.
PDF