A combined toxicokinetic and metabolic approach to investigate deschloro-N-ethylketamine exposure in a multidrug user.

The use of new psychoactive substances derived from ketamine is rarely reported in France. A chronic GHB, 3-MMC, and methoxetamine consumer presented a loss of consciousness in a chemsex context and was referred to the intensive care unit with a rapid and favorable outcome. To investigate the chemicals responsible for the intoxication, a comprehensive analysis was conducted on the ten plasma samples collected over a 29.5-hour period, urine obtained upon admission, a 2-cm hair strand sample, and a seized crystal. These analyses were performed using liquid chromatography hyphenated to high resolution tandem mass spectrometry operating in targeted and untargeted modes. Additionally, analyses using gas chromatography coupled to mass spectrometry and nuclear magnetic resonance were conducted to probe the composition of the seized crystal. The molecular network-based approach was employed for data processing in non-targeted analyses. It allowed to confirm a multidrug exposure encompassing GHB, methyl-(aminopropyl)benzofuran (MAPB), (aminopropyl)benzofuran (APB), methylmethcathinone, chloromethcathinone, and a new psychoactive substance belonging to the arylcyclohexylamine family namely deschloro-N-ethyl-ketamine (O-PCE). Molecular network analysis facilitated the annotation of 27 O-PCE metabolites, including phase II compounds not previously reported. Plasma kinetics of O-PCE allowed the estimation of the elimination half-life of ∼5 hours. Kinetics of O-PCE metabolites was additionally characterized, possibly useful as surrogate biomarkers of consumption. We also observed marked alterations in lipid metabolism related to poly consumption of drugs. In conclusion, this case report provides a comprehensive analysis of exposure to O-PCE in a multidrug user including kinetic and metabolism data in human.

Assessment of 19 years of a prospective national survey on drug-facilitated crimes in France.

Drug facilitated-crime or chemical submission (DFC/CS) is defined as the concealed or forced administration of psychoactive substances to a victim for criminal purposes. This is a national program set up in the early 2000 s in the form of a prospective multicenter survey, the results of which this manuscript presents. Over this 19-year period, 5487 cases were collected, analyzed and classified into 54 % of suspected cases, 29 % of chemical vulnerability (CV) cases and 17 % of proven DFC/CS cases. In the overall data, the most prevalent victims were female (81 %), with an average age of 27 years. Sexual assault was the most frequent aggression (77 %), followed by theft (14 %). Victims of proven DFC/CS cases were from of all ages including children and elderly. In 934 victims of DFC/CS, 100 various psychoactive substances were detected mostly represented by benzodiazepines and z-drugs (55 %), various sedatives including antihistamines (16 %) and non-therapeutic substances (16 %). Gamma-hydroxybutyric acid (GHB) was found in 4 % cases. In CV cases, alcohol (90 %) and cannabis (32 %) intake were mainly involved. In France, despite prevention messages, DFC/CS has been an epidemic for many years and has been proven by our national study. This national program has the aim to identifying the substances used but unfortunately not the goal to fight against this phenomenon. Since 2009, we observed a new modus operandi of the aggressors who pose as taxi drivers facilitating the reception of the victims leaving nightclubs. We can emphasize that GHB is not the "date rape drug" but rather the benzodiazepine class is.

Trends in Fatal Poisoning Among Drug Users in France From 2011 to 2021: An Analysis of the DRAMES Register.

Importance: The DRAMES (Décès en Relation avec l'Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses. Objective: To describe drug-related deaths in France and report trends over an 11-year period. Design, Setting, and Participants: This case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022. Main Outcomes and Measures: Demographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports. Results: Among the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin-44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%). Conclusions and Relevance: This case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored.

Trends in the Pharmaceutical Design of New Psychoactive Substances Detected in Oral Fluid OF Drivers Around a Music Festival in South-West France: Comparison 2019/2017.

OBJECTIVE: New psychoactive substance use (NPS) is a reality in France, including among drivers. This work aims (i) to report the pharmaceutical design of NPS detected in oral fluid (OF) from drivers initially screened for drugs around a music festival in 2019 and (ii) to compare obtained results with those of a previous similar study carried out in 2017 in the same situation (and the same music festival) and according to the same methodology. METHODS: OF specimens were recovered from the user devices of the salivary immunochemical tests used by the police during the controls carried out at the entering and leaving the festival. These OF were analyzed using liquid chromatography coupled with tandem mass spectrometry and high-resolution mass spectrometry methods using mass spectra libraries of approximately 1700 substances, including (in 2020) more than 650 NPS and metabolites. RESULTS: NPS was detected in 14 out of the 265 collected OF specimens. Ten NPS were identified (number of identification): APINACA (1), AB-Chminaca (1), 5F-AMB (1), 5F-PB-22 (5), 2C-D (1), methoxetamine (2), ketamine (1), x-CMC (1), 4-MEC (2), ethylone (2). The prevalence of NPS detection in OF (5.2%) is in the same order as the observed one in 2017 (6.8%), but these results are marked by the majority and increasing proportion of synthetic cannabinoids (47% of identified NPS in 2019 vs. 25% in 2017), an increase also in the proportion of cathinone derivatives (29% in 2019 vs. 6% in 2017), and a decrease in cyclohexanones (17% in 2019 vs. 43% in 2017). CONCLUSION: These pharmaceutical design trends (2019 vs. 2017) observed in a population of drivers around a music festival seem to reflect those that can be seen in more general populations in France, with probably a rise in the consumption of synthetic cannabinoids.

Hair Analysis of Methoxphenidine in a Forensic Chemsex Case.

Methoxphenidine (MXP, 2-MeO-diphenidine) is a dissociative anesthetic drug of the diarylethylamine type, recently introduced for recreational purposes through the online-based sale of new psychoactive substances (NPSs). The concentration of MXP in hair has never been reported, either in cases of chemsex use or in fatal cases. A 55-year-old man was found dead at his home the morning after a chemsex party. Toxicological analyses indicated high concentrations of MXP in femoral blood (606 µg/L), cardiac blood (254 µg/L) and hair (13 ng/mg). We also identified 3-methylmethcathinone (3-MMC) in femoral blood (traces) and urine (238 µg/L). The concentrations of all other drugs were consistent with living subjects. This case highlights the risk of MXP poisoning in the context of chemsex and emphasizes the importance of including NPS in postmortem toxicology examinations.

Complete Post-mortem Investigations in a Death Involving Clenbuterol After Long-term Abuse.

The body of a 61-year-old man was found at his home by his wife, lying on the floor, near the bathroom, around midnight. He was known to be training for bodybuilding, using anabolic steroids. Police investigations revealed the presence of two types of tablets at home, one supposed to contain clenbuterol (0.040 mg) and the other stanozolol (10 mg). Testing the tablets revealed different dosages from what was expected, i.e., 0.073 and 11.5 mg/tablet, for clenbuterol and stanozolol, respectively. External body examination and autopsy, which was performed the next day, revealed generalized organ congestion and lack of any traumatic injury (confirmed by radiology). Cardiomegaly, with a heart weighing 692 g, was obvious. Anatomic pathology tests did not reveal evidence of malformations, but atheromatous plaque was identified in the coronaries during complete histology investigations. Femoral blood, urine, bile, gastric contents and two strands of hair (6 cm) were collected for toxicology. These specimens were submitted to standard analyses, but also to a specific LC-MS-MS method for clenbuterol and stanozolol testing. Clenbuterol was identified in all the tissues, including femoral blood (1.1 ng/mL), urine (7.2 ng/mL), bile (2.4 ng/mL), gastric content (3.2 ng/mL) and hair (23 pg/mg). Stanozolol only tested positive in hair (11 pg/mg). All other analyses were negative, including blood alcohol and drugs of abuse. The pathologists concluded to cardiac insufficiency with support of cardiomegaly, in a context involving repetitive abuse of anabolic drugs. This case indicates that more attention should be paid to clenbuterol, a drug widely used as a stimulant by people who want to lose weight, athletes and bodybuilding practitioners.

New psychoactive substances in oral fluid of drivers around a music festival in south-west France in 2017.

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.

A Rare Case of Poisoning with a Volatile Substance: Quantitative Determination of n-Butane in Postmortem Tissue.

Poisoning with volatile substances remains exceptional. Authors report the case of a married couple who were found in a car with a butane gas bottle: the woman was dead and her husband alleged it was an unsuccessful suicide pact. A specific research of volatile substances on postmortem samples with headspace gas chromatography-mass spectrometry following a quantitative determination was performed. The n-butane concentrations detected were composed of 610 µg/L (cardiac blood), 50 µg/kg (brain), 134 µg/kg (lungs), 285 µg/kg (liver), and 4090 µg/kg (heart) and were compatible with the rare lethal concentrations evoked in the literature. The cause of death was determined to be asphyxiation through n-butane criminal poisoning. Authors recommendation therefore is to take samples immediately and place them in properly sealed containers and hence analyzing the samples as soon as possible after collecting them or storing them under -30°C (-22°F) if analyses cannot be performed immediately.

Drug-facilitated sexual assault and analytical toxicology: the role of LC-MS/MS A case involving zolpidem.

The use of a drug to modify a person's behavior for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused alarm in the general public. Drugs involved can be pharmaceuticals, such as benzodiazepines (flunitrazepam, lorazepam, etc.), hypnotics (zopiclone, zolpidem), sedatives (neuroleptics, some histamine H1-antagonists) or anaesthetics (gamma-hydroxybutyrate, ketamine), drugs of abuse, such as cannabis, ecstasy or lysergide, or more often ethanol. Drugs said to be used to facilitate sexual assaults can be difficult to detect (active products at low dosages, chemical instability), possess amnesic properties and can be rapidly cleared from the body (short half-life). We present here a case involving a 23-year old girl that declared a sexual assault 6 days after the event was said to have occurred. To the Police, the victim claimed a total amnesia of the offense associated with intense sedation. Toxicological analyses for unknown sedative drugs achieved by LC-MS/MS revealed the presence of zolpidem (Stilnox), a non-benzodiazepine hypnotic. Concentrations after 6 days were 16 and 32 pg/mL in blood and urine, respectively. The drug tested also positive in the corresponding hair segment at 0.75 pg/mg. The requested extraordinary sensitivity of LC-MS/MS appears as a pre-requisite to document any case involving drug-facilitated sexual assault.

Methadone as a chemical weapon: two fatal cases involving babies.

Methadone is largely used for the substitution management of opiate-dependent individuals but can also be easily found on the black market. The first cases involving repetitive sedation linked to the use of methadone and subsequent death of 2 babies are reported. At the autopsy, no particular morphologic changes were noted except for pulmonary and visceral congestion. There was no evidence of violence, and the pathologist in both cases found no needle marks. Toxicological analyses, as achieved by GC/MS, demonstrated both recent and repetitive methadone exposure. In case 1, a 14-month-old girl was found dead at home. Blood concentrations were 1071 and 148 ng/mL for methadone and EDDP, respectively. Hair (6 cm) tested positive at 1.91 and 0.82 ng/mg for methadone and EDDP, respectively. In case 2, a 5-month-old girl was taken to hospital in a pediatric unit for coma. Antemortem blood analysis demonstrated methadone exposure (142 ng/mL), and the baby was declared dead 12 days after admission. Hair analysis (5 cm) by segmentation was positive for methadone in the range 1.0 (root) to 21.3 ng/mg (end). The death of the babies was attributed to accidental asphyxia ina situation where methadone was considered as a chemical weapon. The mothers, who were the perpetrators in both cases, did not deny the use of methadone as a sedative drug.