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International audience; Cannabis consumption during adolescence is an area of particular concern, owing to changes in the social and political perception of the drug, and presents a scientific, medical, and economic challenge. Major social and economic interests continue to push toward cannabis legalization as well as pharmaceutical development. As a result, shifting perceptions of both legal and illicit cannabis use across the population have changed the collective evaluation of the potential dangers of the product. The wave of cannabis legalization therefore comes with new responsibility to educate the public on potential risks and known dangers associated with both recreational and medical cannabis. Among these is the risk of long-term cognitive and psychological consequences, particularly following early-life initiation of use, compounded by high-potency and/or synthetic cannabis, and heavy/frequent use of the drug. Underlying these cognitive and psychiatric consequences are lasting aberrations in the development of synaptic function, often secondary to epigenetic changes. Additional factors such as genetic risk and environmental influences or nondrug toxic insults during development are also profound contributors to these long-term functional alterations following adolescent cannabis use. Preclinical studies indicate that exposure to cannabinoids during specific windows of vulnerability (e.g., adolescence) impacts neurodevelopmental processes and behavior by durably changing dendritic structure and synaptic functions, including those normally mediated by endogenous cannabinoids and neuronal circuits.

In the last two years, the number of shops selling CBD-rich THC-deprived cannabis flowers (CrTd) has increased considerably in France as in many European countries. The objective of this study was to determine the actual composition of the samples sold in these stores, and to discuss regulatory consequences that may affect users. Samples were provided from shops in the region Provence-Alpes Cote d'Azur (PACA), in France. Pictures of the samples were taken before they were weighed then crushed. Twenty milligrams were diluted in 10 mL heptane ethyl acetate (7:1; v:v) for analysis by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method was validated according to SWGTOX guidelines for the quantification of cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC) and cannabinol (CBN). Thirty-nine samples obtained between November 2021 and January 2022 in the PACA region were analyzed in this study. Mean content was 0.32% (0.03%-0.77%; STDV=0.17%; n=39) for THC, 2.23% (0.01%-5.97%; STDV=1.29%; n=39) for CBD and 0.01% (0.004%-0.025%; STDV=0.01%; n=19) for CBN. THC content over the threshold defined by the European legislation (0.3%) was found in 18 of the 39 samples analyzed together with a CBD content1% in 9 samples (23%). None of the products analyzed had health risk messages on the packaging. The consumption of these products may lead to the presence of THC in biological fluids which can be detected by screening. Users may then find themselves in breach of the law particularly when driving. Consumers should therefore be informed both about the actual composition of these products and about the legal and health risks they run.

Complex planned suicide is characterized by the simultaneous use of two or more methods to ensure that death occurs even if one method fails. The authors present an original combination of two self-killing methods. A 42-year-old cardiologist, with a major depressive syndrome and several suicide attempts, as well as cocaine addiction, was found dead at his home with a femoral catheter inserted in the right femoral artery. The autopsy concluded that death was due to major hemorrhagic process in a context of suicide. Toxicological analyses, performed in peripheral blood by gas chromatography coupled to mass spectrometry and by liquid chromatography-diode array detection, revealed the presence of ethanol (0.13 g/L), cocaine, and metabolites (cocaine: 432 µg/L, benzoylecgonine: 3286 µg/L, ecgonine methyl ester: 1195 µg/L, cocaethylene: 41 µg/L), a potentially lethal concentration of citalopram (1.03 mg/L), toxic concentrations of hydroxyzine (0.11 mg/L), bromazepam (2.06 mg/L), and lidocaine (7.30 mg/L). At the end of these analyses, the death was reclassified as planned complex suicide combining drug intoxication and catheterization of the femoral artery. The authors discuss the main aspects of this case and stress the importance of meticulous analysis of all available evidence: witness reports, victim's medical history and occupation, findings of at-the-scene examination, autopsy, and toxicological analyses, in order to exclude homicide and to understand the sequence of events that led to death.

Resume L’objectif de cet article est de presenter deux approches, l’une basee sur les analyses biochimiques et l’autre sur le dosage des oligo-elements dans les cheveux, afin d’explorer le statut nutritionnel d’enfants pour lesquels une denutrition est suspectee a l’autopsie. Nous presentons le cas d’une fillette de 9 mois decedee au domicile. Le corps est transporte a l’unite de mort inattendue du nourrisson le jour meme (j0) ou sont effectues differents prelevements. Des ecchymoses ayant ete constatees a l’examen du corps, un signalement est effectue et le corps transporte a l’institut medicolegal. L’autopsie effectuee a J1 revele un traumatisme crânien, cause du deces, et un retard staturoponderal majeur. Le magistrat ordonne, en plus de l’expertise toxicologique de reference, une evaluation du statut nutritionnel de l’enfant. Les analyses toxicologiques et biochimiques sont effectuees a partir des echantillons de serum preleve a J0 ainsi que de sang peripherique et de cheveux preleves a J1. Les analyses toxicologiques ne revelent aucune anomalie. Les parametres biochimiques doses dans le serum (albumine, pre-albumine, uree, creatinine, acide urique) et le sang total (β-hydroxybutyrate) sont normaux a l’exception d’une elevation de l’acide urique. Le dosage des oligo-elements dans les cheveux par ICP-MS montre des resultats comparables a ceux obtenus dans une population de sujets temoins et d’enfants de la meme tranche d’âge. L’examen anatomopathologique ne releve aucune lesion en faveur d’une denutrition. En conclusion, ces deux approches ont permis d’eliminer une denutrition. Bien que peu exploitee, l’approche par criblage des oligo-elements pourrait s’averer utile, notamment pour augmenter la fenetre de detection ou lorsque les prelevements necessaires aux analyses biochimiques ne sont pas disponibles. D’autres etudes de cas sont necessaires pour etayer cette hypothese.

International audience; Introduction: Suicide attempts have been associated with both cocaine use disorder (CocUD) and childhood trauma. We investigated how childhood trauma is an independent risk factor for serious and recurrent suicide attempts in CocUD. Method: 298 outpatients (23% women) with CocUD underwent standardized assessments of substance dependence (Diagnostic and Statistical Manual-mental disorders, fourth edition, text revised), impulsiveness, resilience, and childhood trauma, using validated tools. Suicide attempts history was categorized as single vs. recurrent or non-serious vs. serious depending on the lifetime number of suicide attempts and the potential or actual lethality of the worst attempt reported, respectively. Bivariate and multinomial regression analyses were used to characterize which childhood trauma patterns were associated with the suicide attempts groups. Results: 58% of CocUD patients reported childhood trauma. Recurrent and serious suicide attempts clustered together and were thus combined into "severe SA." Severe suicide attempt risk increased proportionally to the number of childhood traumas (test for trend, p = 9 × 10-7). Non-severe suicide attempt risk increased with impulsiveness and decreased with resilience. In multinomial regression models, a higher number of traumas and emotional abuse were independently and only associated with severe vs. non-severe suicide attempts (effect size = 0.82, AUC = 0.7). The study was limited by its cross-sectional design. Conclusion: These preferential associations between childhood trauma and severe suicide attempts warrant specific monitoring of suicide attempts risk in CocUD, regardless of the severity of addiction profiles.

Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity.Two hundred and forty-two non-psychotic and Caucasian lifetime cocaine users were included in a French multicentric study. Clinical variables and dopamine pathway genotype data were extracted and tested with CIH scores using a zero-inflated binomial model, which allows for the exploration of factors associated with occurrence and severity separately.Cocaine dependence (pOur study shows that CIH occurrence and severity are two distinct phenotypes, with shared clinical risk factors; however, they likely do not share the same genetic background.

Objectifs La question des cyanures en post-mortem est toujours delicate a traiter en termes d’interpretation, notamment du fait de problemes pre-analytiques (degradation/production). Nous illustrons ces difficultes en rapportant un cas complexe d’interpretation des cyanures dans le sang post-mortem et presentant la demarche utilisee pour l’interpretation. Methode Monsieur X., 67 ans, presentant une maladie de Parkinson tres evoluee traitee par rasagiline et levodopa, est retrouve en etat de mort apparente a 11 h 20 dans la cellule d’incarceration qu’il occupait seul. Il a ete vu vivant la derniere fois a 10 h 30. Une tentative de reanimation est effectuee sans succes. La levee de corps realisee a 14 h 30 ne montre que les stigmates de la reanimation. La temperature corporelle est a 37 °C pour une temperature dans la cellule de 30 °C. L’autopsie realisee le lendemain matin met en evidence des lesions atheromateuses diffuses sur l’ensemble du reseau vasculaire sans stenose coronaire significative. Des prelevements a visee anatomopathologique et toxicologique (sang cardiaque et peripherique sur tubes fluores, humeur vitree, contenu gastrique, cheveux) sont realises. Les prelevements toxicologiques sont immediatement places a +4 °C et conserves a cette temperature jusqu’a analyse. Les alcools ont ete recherches dans le sang peripherique par HS-GC/FID. Le taux de carboxyhemoglobine a ete mesure dans le sang peripherique par methode spectrophotometrique. Les cyanures sont doses apres par LC-MS/MS [1] . Ont ete realisees dans le sang peripherique une recherche large de principes actifs et/ou de metabolites de principes actifs de medicaments et autres toxiques par LC-HRMS ainsi qu’une recherche specifique de substances stupefiantes par LC-MS/MS. Resultats La recherche des alcools s’est averee negative. Le taux de carboxyhemoglobine mesure dans le sang peripherique est inferieur a 5 % de l’hemoglobine totale. La concentration de cyanures mesuree dans le sang peripherique est de 1,23 mg/L. Il n’a pas ete decele de principes actifs et/ou de metabolites de produit stupefiants, de medicaments ou toxiques dans le sang peripherique. L’examen anatomopathologique met en evidence des lesions de defaillance circulatoire prolongee avec des necroses cardiaques de bas debit sans remaniement significatif. La presence de corps de Lewy dans le locus niger confirme le diagnostic de maladie de Parkinson. Plusieurs hypotheses ont ete evoquees pour expliquer cette concentration de cyanures elevee. Compte tenu de l’etat cognitif de la victime, un suicide a ete immediatement ecarte. De la meme maniere, les donnees de l’enquete ont permis d’eliminer un homicide. Les donnees du dossier medical ont confirme que la victime ne fumait pas et n’avait pas eu de prescription recente de nitroprussiate. Le proces-verbal de fouille de la cellule a confirme l’absence de plantes ou aliments contenant des heterosides cyanogenetiques. Le dosage des cyanures dans l’echantillon de sang peripherique a ete verifie deux fois avec l’obtention des memes valeurs elevees. L’echantillon de sang cardiaque a alors ete analyse, avec un resultat a 0,044 mg/L. Le rapport des concentrations sang cardiaque/sang peripherique rendant peu probable l’hypothese d’une redistribution post-mortem [2] , l’hypothese la plus vraisemblable est une contamination de l’echantillon de sang peripherique par des bacteries cyanogenes. La PCR ARN16S effectuee sur les deux echantillons s’avere negative sur l’echantillon de sang cardiaque mais ininterpretable sur l’echantillon de sang peripherique pour lequel des cultures sont en cours. Conclusion L’interpretation des concentrations post-mortem d’ions cyanures demeure une source de difficultes potentielles et doit idealement s’appuyer sur des donnees analytiques dans differents echantillons sanguins (sang peripherique, sang cardiaque gauche et droit), des investigations complementaires ainsi que des donnees d’anamnese completes.

The prefrontal cortex (PFC) develops until early adulthood in rodents and humans, but how synaptic plasticity evolves throughout postnatal development is not known. Here, we used a cross-sectional approach to establish the postnatal maturational trajectories of intrinsic properties and synaptic plasticity in the PFC of rats of both sexes. We found that while layer 5 PFC pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases and resting potentials across all age groups, excitability was lower in female adults compared to the other developmental stages. NMDAR-dependent long-term potentiation and mGluR2/3-mediated long-term depression (LTD) were equally expressed at the juvenile, pubescent and adult developmental stages in animals of both sexes. However, the developmental course of endocannabinoid (eCB)-mediated LTD was sexually dimorphic. First, eCB-LTD emerged during the juvenile period in females. However, although CB1Rs were functional in both sexes at all developmental stages, eCB-LTD’s first emerged during pubescence in male. Second, eCB-LTD engaged distinct receptors in males and females depending on their developmental stages. Female rats employ both CB1R and TRPV1R to produce eCB-LTD at the juvenile stage but solely CB1R at pubescence followed by only TRPV1R at adulthood. In contrast, in pubescent and adult males eCB-LTD always and exclusively depended on CB1R. Pharmacological blockade of 2AG’s principal degrading enzyme allowed incompetent male juvenile synapses to express eCB-LTD. The data reveal different maturational trajectories in the PFC of male and female rats and provide new cellular substrates to the sex-specific behavioral and synaptic abnormalities caused by adolescent exposure to cannabinoids.

International audience; In animals, research in the past two decades has demonstrated the strong involvement of the endocannabinoid system (ECS) in numerous steps of the reproductive process, including ovarian physiology. Reproductive lifespan is closely related to the number of nongrowing ovarian follicles, called ovarian reserve (OR), which is definitively established during foetal life. Thus, OR damage may lead to poor reproductive outcomes and a shortened reproductive lifespan. We investigated whether prenatal ECS modulation had an effect on the OR at different ages in the rat offspring. Four groups of gestating female rats (F0) were exposed to the CB1-/CB2-receptor agonist WIN55212 (0.5 mg/kg), the CB1R inverse agonist SR141716 (3 mg/kg) or Δ9THC (5 mg/kg) and were compared to negative control groups. OR was histologically assessed at different postnatal timepoints (F1 individuals): postnatal day (PND) 6, PND40 and PND90. At PND6, prenatal exposure had no effect on OR. In the young adult group (PND90) exposed during gestation to WIN55212, we observed a CB1R-mediated delayed OR decrease, which was reversed by prenatal CB1R blockade by SR141716. Conversely, after prenatal SR141716 exposure, we observed higher OR counts at PND90. RT-PCR experiments also showed that prenatal ECS modulation perturbed the mRNA levels of ECS enzymes and OR regulation genes. Our findings support the role of the ECS in OR regulation during the foetal life of rats and highlight the need for further studies to elucidate its precise role in OR physiology.

International audience; New designer drugs, as synthetic cannabinoids (SCs), continuously appear on the market and are booming due to their cannabis-like effect. New generation of smokable SCs, structurally dissimilar from Δ9-tetrahydrocannabinol (THC), have isomers with distinguishable pharmacokinetic parameters and therefore different in vivo effects. The isoforms are misidentified using conventional techniques such as gas or liquid chromatography coupled to mass spectrometry - or tandem mass - spectrometry. The aim of this study was to differentiate three positional isomers (JWH-007, JWH-019 and JWH-122) in single human hair samples, which store numerous substances revealing a way of life and consumption style. Matrix-assisted laser desorption/ionization (MALDI) combined with imaging is an innovative and powerful tool used since few years, especially in forensic research. Herein, we propose an innovative method to monitor the drugs of abuse consumption through direct mapping of the compounds with a high spatial distribution in human hair samples, by state-of-art imaging MALDI-MSn. Three positional SC isomers (JWH-007, JWH-019 and JWH-122) were analysed using high and low fragmentation energy and the resulting MS/MS and even MS3 spectra differentiated the SCs. The MALDI-MS/MS and MS3 imaging was performed on hair soaked in a mixture of the three SCs as well as on hair from self-reported SC user, proving the potential of the technique for a forensic use. Keeping in mind that spatial distribution of organics from whole hair remains a challenge, the described methodology is a very promising analytical tool to probe the consumption of complex drugs and obtain correlation with its origin.

Because of inhomogeneous matrix-assisted laser desorption/ionization (MALDI) matrix crystallization and laser shot-to-shot variability, quantitation is not generally performed by MALDI mass spectrometry. Here we introduce a high-throughput MALDI method using an innovative high-density microarray for mass spectrometry (MAMS) technology, which allows semiquantitative measurement of cocaine and its metabolites, benzoylecgonine, cocaethylene, and ecgonine methyl ester. A MAMS slide containing lanes of hydrophilic spots and an automated slider to drag a sample droplet over several small spots can accomplish automatic sample aliquoting and lead to homogeneous crystallization of the matrix-analyte mixture and, thus, to a reproducible signal (average RSD 6%). Four hair samples of self-reported drug users were analyzed in parallel by MALDI-MS/MS and by a validated LC-MS/MS method. The consumption profiles as well as the metabolite-parent drug ratios obtained correlated well, confirming the effectiveness of the MALDI-MS/MS method to establish a calendar of consumption in only 1 mg of hair. The analysis time for 10 hair samples is below 40 min, with 12 replicates per sample. Since only 3 μL of a 20 μL extract is analyzed, complementary assays are possible, such as the detection of additional drugs. The semiquantitative MALDI method worked well with only a small amount of hair and gave results in less than 4 min per sample, including replicates. This was made possible by the use of MAMS slides for sample preparation, which thus present significant advantages over traditional methods in cases where results are required urgently or if samples are scarce.

Major self-mutilation (amputation, castration, self-inflicted eye injuries) is frequently associated with psychiatric disorders and/or substance abuse. A 35-year-old man presented with behavioral disturbances of sudden onset after oral cannabis consumption and major self-mutilation (attempted amputation of the right arm, self-enucleation of both eyes and impalement) which resulted in death. During the enquiry, four fragments of a substance resembling cannabis resin were seized at the victim's home. Autopsy confirmed that death was related to hemorrhage following the mutilations. Toxicological findings showed cannabinoids in femoral blood (tetrahydrocannabinol (THC) 13.5 ng/mL, 11-hydroxy-tetrahydrocannabinol (11-OH-THC) 4.1 ng/mL, 11-nor-9-carboxy-THC (THC-COOH) 14.7 ng/mL, cannabidiol (CBD) 1.3 ng/mL, cannabinol (CBN) 0.7 ng/mL). Cannabinoid concentrations in hair (1.5 cm brown hair strand/1 segment) were consistent with concentrations measured in chronic users (THC 137 pg/mg, 11-OH-THC 1 pg/mg, CBD 9 pg/mg, CBN 94 pg/mg). Analysis of the fragments seized confirmed that this was cannabis resin with high levels of THC (31–35%). We discuss the implications of oral consumption of cannabis with a very high THC content.

Suicide is one of the principal causes of mortality in a prison environment. Although suicide by medication overdose is less frequent than suicide by hanging, self-strangulation, or vein cutting, it raises questions as to how the medications are obtained, particularly in view of the specific organization of the medication circuit in prisons. We present three cases of suicide by medication overdose involving different therapeutic classes with different distribution circuits and review the regulatory requirements and the measures that could be taken to prevent such suicides.

Objectifs La pregabaline (Lyrica®) est indiquee chez l’adulte dans le traitement de l’epilepsie, des douleurs neuropathiques et de certains troubles anxieux. Bien que recent, l’usage detourne de cette molecule, seule ou en association avec d’autres composes psychoactifs, connait un developpement notable (hausse des demandes de prescription en detention, existence de marches de rue) du fait de ses effets euphorisants aux fortes doses [1] . Dans ce contexte, nous rapportons trois cas de deces pour lesquels l’analyse toxicologique met en evidence la prise concomitante de pregabaline et d’autres substances recreatives, discutons de la participation de ces associations dans le processus letal. Methode Les trois victimes (une femme de 51 ans [cas 1] et deux hommes de 30 et 43 ans [cas 2 et 3]), bien inseres socialement, ont ete retrouvees a leur domicile. Dans leurs antecedents, il est note une addiction a la cocaine associee a la prise a visee recreative d’autres depresseurs du systeme nerveux central (methadone, clonazepam, pregabaline, quetiapine et/ou alcool). L’autopsie a mis en evidence un syndrome asphyxique avec congestion viscerale chez l’ensemble des victimes. Les prelevements toxicologiques usuels ont ete effectues. Ont ete realises dans le sang peripherique une recherche large des principes actifs et/ou leurs metabolites de medicaments et autres toxiques par LC-MSHR apres precipitation par l’acide sulfosalicylique et extraction en ligne dans une colonne de type HLB (Richeval C, These de l’Universite de Lille, Lille, Septembre 2018), complete par une recherche des stupefiants par LC-MS/MS. Le dosage des alcools a ete realise par HS-GC/FID. Resultats Dans le cas 1, les analyses mettent en evidence dans le sang peripherique de la pregabaline (7680 μg/L), du diazepam (348 μg/L), des opiaces (morphine = 629 μg/L, codeine = 42 μg/L) et de la methadone (360 μg/L). Dans le cas2, les investigations toxicologiques ont confirme la presence de pregabaline (11 000 μg/L) Enfin, dans le cas 3, la pregabaline (18 500 μg/L) a egalement ete identifiee associee a la methadone (148 μg/L). Conclusion L’association pregabaline - depresseurs du SNC est tres probablement a l’origine du deces des trois victimes. En effet, la consommation concomitante de gabapentinoides et d’opioides (cas 1 et 3) augmenterait le risque de deces par depression respiratoire, meme pour des doses d’opioides non toxiques [2] . Les concentrations en pregabaline mesurees sont comparables aux concentrations post-mortem decrites dans la litterature dans une etude menee sur 70 echantillons sanguins [3] . Ces trois cas de deces, rapproches dans le temps, confirment les donnees epidemiologiques actuelles [4] quant aux consommations associees au Lyrica® et illustrent l’extension rapide de l’usage detourne de cette molecule ici comme ailleurs. Cependant, il est a noter que le profil des trois victimes ne correspond pas au profil « classique » du consommateur (jeunes isoles ou adultes originaires d’Europe de l’Est). Compte tenu de l’usage abusif de plus en plus repandu de la pregabaline en France, il conviendrait de sensibiliser davantage les prescripteurs a cette problematique. Par ailleurs, comme dans d’autres pays, une regulation des modalites de prescription et de delivrance des gabapentinoides pourrait etre envisagee afin de limiter ces pratiques recreatives.

Consumption of cannabis during pregnancy and the lactation period is a rising public health concern (Scheyer et al., 2019). We have previously shown that exposure to synthetic or plant-derived cannabinoids via lactation disrupts perinatal programming of the gamma-aminobutyric acid trajectory in the prefrontal cortex and early-life behaviors (Scheyer et al., 2020b). Recently, we described lasting behavioral and neuronal consequences of Δ9-tetrahydrocannabinol (THC) perinatal exposure via lactation (Scheyer et al., 2020a).Here, we extend upon these findings by testing the effects in offspring of maternal exposure to the synthetic cannabinoid agonist WIN 55,12,2 (WIN). The data demonstrate that rats exposed during lactation to WIN display social, cognitive and motivational deficits at adulthood. These behavioral changes were paralleled by a specific loss of endocannabinoid-mediated long-term depression in the prefrontal cortex and nucleus accumbens, while other forms of synaptic plasticity remained intact. Thus, similarly to THC, perinatal WIN exposure via lactation induces behavioral and synaptic abnormalities lasting into adulthood.

Resume Lors de l’analyse toxicologique de certaines expertises medicolegales, dans de rares cas, aucun milieu biologique conventionnel n’est disponible en post-mortem et seuls les vetements peuvent etre utilises. Nous presentons le cas d’un squelette retrouve partiellement devetu sous une dalle de beton. Le magistrat ayant refuse l’analyse des restes osseux, les vetements ont ete transmis au laboratoire pour expertise toxicologique. Les scelles contenaient un blouson, un reste de pantalon avec une ceinture et deux morceaux de tissu non identifies. Des pieces de 3 × 3 cm ont ete decoupees au niveau des zones susceptibles d’avoir ete en contact avec le revetement cutane ou les fluides corporels : une au niveau du col de la veste, deux au niveau de la braguette du pantalon, une au niveau de l’entre-jambe. Enfin, trois pieces ont ete decoupees dans les morceaux de tissu non identifies. Un screening est effectue par UPLC-MS/MS apres extraction liquide-liquide en milieu alcalin. Les analyses ont montre la presence de tiapride, venlafaxine et tramadol au niveau du col de la veste, et de tiapride et tramadol au niveau de la braguette. L’analyse des autres pieces de tissus s’est averee negative. Selon les informations recueillies par les enqueteurs, la victime ne suivait pas de traitement particulier et les molecules identifiees pourraient avoir contribue au deces. En conclusion, dans le cas present, l’analyse des vetements a permis de documenter une absorption ante-mortem de medicaments psychoactifs. Le screening realise dans les pieces de tissu peut donc permettre, lorsqu’aucun autre milieu biologique n’est disponible, de recueillir des informations necessaires au bon deroulement de l’enquete, et les textiles peuvent etre consideres comme une matrice alternative.

Resume Les concentrations obtenues a partir d’echantillons post mortem ne sont pas forcement le reflet des concentrations au moment du deces. Elles peuvent varier en fonction des differents sites de prelevement et/ou en fonction du delai entre le deces et les prelevements. Ces phenomenes sont regroupes sous le terme de redistribution post mortem. Les mecanismes presidant a ces phenomenes sont complexes et multifactoriels. Ils dependent en premier lieu de l’evolution des phenomenes cadaveriques. En periode post mortem precoce, certains organes, qualifies « d’organes reservoirs » peuvent relarguer les xenobiotiques concentres avant le deces. Il s’agit essentiellement du tractus gastro-intestinal, du foie, des poumons et du myocarde. La lyse cellulaire et plus tardivement la putrefaction favorisent egalement les phenomenes de redistribution. Le profil physico-chimique et pharmacocinetique des xenobiotiques semble etre egalement un facteur determinant, mais ces aspects sont moins bien connus. L’auteur presente les dernieres avancees dans le domaine.

Objectifs Presenter un cas de deces d’un nouveau-ne premature presentant des malformations congenitales et expose a la cocaine. Presentation du cas : le SAMU est appele pour un accouchement a domicile dans un contexte de deni de grossesse. Le nouveau-ne aurait crie et respire ; il est en arret cardio-respiratoire a l’arrivee du SMUR pediatrique et decede a son arrivee au CHU malgre la reanimation. L’autopsie revele qu’il s’agit d’un nouveau-ne de sexe masculin, mesurant 40 cm et pesant 1693 grammes. L’âge fœtal est estime a 33 SA. L’examen externe montre une dysmorphie des organes genitaux externes et des doigts, un pied bot a gauche, un omphalocele et une dysmorphie des oreilles. L’aspect des poumons a l’autopsie evoque une absence de respiration. Les prelevements a visee toxicologique (sang cardiaque, sang peripherique, poumon, foie, cerveau) et anatomopathologique sont effectues. Aucun diagnostic genetique n’est demande. L’interrogatoire de la mere revele que la grossesse n’a pas ete suivie et qu’elle a des antecedents d’avortement spontane et d’IVG. Methode Les alcools ont ete recherches dans le sang peripherique par HS-GC/FID. Le taux de carboxyhemoglobine a ete mesure par methode spectrophotometrique. Ont ete realisees dans le sang peripherique une recherche large de principes actifs et/ou de metabolites de principes actifs de medicaments et autres toxiques par LC-HRMS ainsi qu’une recherche specifique de substances stupefiantes par LC-MS/MS. Ces analyses ont ete completees par dosage de la morphine ainsi que de la cocaine et ses metabolites dans le sang cardiaque et l’exsudat de poumon, de cerveau et de foie par LC-MS/MS. Resultats Les analyses revelent la presence de morphine dans le sang cardiaque, le sang peripherique, les exsudats de foie, de cerveau et de poumon aux concentrations respectives (formes non conjuguees, en μg/L) de 210/160/179/11/89, ainsi que des marqueurs de la cocaine aux concentrations respectives dans les memes milieux biologiques (μg/L) : cocaine : 2,6/2/2,1/5,7/1,6 ; BZE : 645/431/1751/737/214 ; EME : 35/18/521/209/116. Le taux d’HbCO est de 5 %. L’examen anatomopathologique estime l’âge fœtal a 28 ± 2 SA, revele une immaturite tissulaire et la presence de membranes hyalines, temoignant de l’agression ante-mortem de l’epithelium respiratoire par l’oxygene en l’absence de surfactant. L’enfant a donc probablement respire spontanement mais s’est retrouve rapidement en incapacite ventilatoire du fait de l’immaturite pulmonaire. Conclusion La concentration de morphine mesuree dans le sang peripherique, compatible avec les concentrations therapeutiques decrites chez le premature [1] correspond a l’administration de morphine par le SMUR. La concentration de cocaine dans le sang peripherique est compatible avec celles mesurees dans le sang de cordon de nouveau-nes exposes [2] et le taux eleve d’HbCO est probablement en lien avec un tabagisme maternel. Si le deces semble directement cause par l’immaturite pulmonaire, la responsabilite de la cocaine dans le declenchement de l’accouchement et le syndrome poly-malformatif doit etre discutee. En effet, si le risque de prematurite et d’hypotrophie chez des fœtus exposes a la cocaine est admis [3] , le caractere teratogene de cette derniere est controverse. Dans le cas present, certaines des malformations presentees par le nouveau-ne sont compatibles avec celles decrites dans la litterature chez des enfants exposes in utero a la cocaine, et il n’existe pas d’element en faveur d’une pathologie genetique identifiee. Toutefois, seul un diagnostic genetique aurait permis de trancher cette question. En conclusion, il parait important, face a des situations complexes de ce type, de pouvoir disposer de toutes les investigations necessaires pour determiner de la cause du deces mais egalement approfondir les connaissances dans ce domaine.

Heavy cannabis consumption among adolescents is associated with significant and lasting neurobiological, psychological and health consequences that depend on the age of first use. Chronic exposure to cannabinoid (CB) agonists during adolescence alters social behavior and prefrontal cortex (PFC) activity in adult rats. However, sex differences on social behavior as well as PFC synaptic plasticity after acute CB activation remain poorly explored. Here, we determined the consequences of a single CB activation differently affects PFC in males and females by assessing social behavior and PFC neuronal and synaptic functions in rats during pubertal or adulthood periods, 24h after a single in-vivo cannabinoid exposure (SCE). During puberty, SCE reduced play behavior in females but not males. In contrast, SCE impaired sociability in both sexes at adulthood. General exploration and memory recognition remained normal at both ages and both sexes. At the synaptic level, SCE ablated endocannabinoid-mediated long-term depression (eCB-LTD) in the PFC of females of both ages and heightened excitability of PFC pyramidal neurons at adulthood, while males were spared. In contrast, SCE was associated to impaired long-term potentiation in adult males. Together, the data indicate behavioral and synaptic sex differences in response to a single in-vivo exposure to cannabinoid at puberty and adulthood.

International audience; Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing reports of cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here, we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/ 5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.

Cannabis is the most widely used illicit drug in the world, and its usage is increasing with its widespread legalization. Use of the drug by mothers during lactation may transfer active cannabinoids to the developing offspring, altering postnatal neurodevelopment during this critical period. During early life, GABA undergoes a functional switch from an excitatory to an inhibitory neurotransmitter due to reciprocal changes in expression of the K+/Cl- co-transporters KCC2 and NKCC1. Here, we characterize the functional GABA switch in the prefrontal cortex of both male and female rats. We show that treating rat dams with Δ9-THC or a synthetic cannabinoid during early lactation (PND01-10) retards KCC2 expression and delays the GABA switch in pups of both sexes via a CB1R-dependent mechanism. Our results indicate that the developmental trajectory of GABA in PFC neurons is significantly altered by perinatal exposure to cannabinoids through lactation during the early perinatal period.

Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.

Summary Zopiclone is a hypnotic agent belonging to a class of non-benzodiazepine hypnosedative drugs, the cyclopyrrolones. Fatal poisonings are mainly represented by suicides, often in combination with other drugs. To our knowledge, no deaths have been reported in children. We present here a double infanticide with premeditation by zopiclone administration and drowning. Two young boys, 2- and 5-year-old respectively, were found dead in a bathtub full of water. Suspicions quickly turned to the mother who rapidly confessed to having drowned her children after drugging them with zopiclone. Autopsies only revealed a small amount of water in the lungs and stomach of the eldest. Toxicological analyses, including hair testing of the mother, were performed. Benzodiazepines, Z-drugs, neuroleptics and other sedatives were determined in peripheral blood, urine and hair by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Zopiclone blood concentrations confirmed the massive intoxication of the two children (260 and 174 ng/mL, respectively). Hair analysis showed very low concentrations of zopiclone in all segments (maximum 45 pg/mg) in favor of regular exposure of the two victims during the 8 months preceding the deaths. The analysis of maternal hair confirms a regular exposure of z-drugs, as well as cyamemazine and amitriptyline.

Resume La cocaine se situe au deuxieme rang des produits illicites les plus consommes en France apres le cannabis. Elle est absorbee essentiellement par voie sniffee (sous forme chlorhydrate) ou fumee (sous forme base). Elle est fortement metabolisee dans l’organisme, ses principaux metabolites etant la benzoylecgonine (BZE) et l’ecgonine methylester (EME). Les methodes de dosage reposent sur des techniques separatives, soit liquide, soit gazeuse, couplees a une detection par spectrometrie de masse. Il est fortement conseille de doser la cocaine ainsi que la BZE et l’EME. En effet, la cocaine est relativement instable in vitro, et peut se degrader en ses metabolites sous l’action d’esterases erythrocytaires et plasmatiques. Un prelevement sur fluorure de sodium a 2,5 % permet de diminuer cette instabilite. Pour les memes raisons, la conservation des prelevements doit se faire a –20 °C plutot qu’a +4 °C, temperature a laquelle apparait une degradation apres 48 heures. Dans le cadre de la circulation routiere, certains pays quantifient dans le sang total, d’autres ont choisi le plasma ou le serum. Dans des conditions optimales de conservation, la cocaine va persister environ 3 a 8 heures dans le sang, et jusqu’a 24 heures dans les urines. Ces delais peuvent etre prolonges chez les consommateurs chroniques. La BZE est retrouvee classiquement jusqu’a 24 heures dans le sang et entre 40 et 60 heures dans les urines. Les seuils limites appliques sont variables en fonction des pays, correspondant a des seuils analytiques et non de dangerosite. Certains pays ont un seuil impose uniquement pour la cocaine, comme la France (50 μg/L), alors que d’autres ont egalement un seuil impose pour la BZE, comme la Belgique ou la Finlande. Il est actuellement admis que la cocaine perturbe la capacite de conduite automobile, mais il ne ressort pas clairement de seuil de dangerosite de l’etude de la litterature. Des experts de differentes nationalites ont propose des seuils sanguins au-dela duquel le risque d’avoir un accident ou une conduite perturbee est significativement augmente, variant de 2 a 50 μg/L, associe ou non a des valeurs seuils pour la BZE. En France, la SFTA a propose un seuil de 10 μg/L pour la cocaine. Dans la plupart des etudes, les concentrations salivaires de cocaine sont plus elevees que dans le sang, mais il n’existe pas de correlation entre ces deux milieux. Les effets de la cocaine dependent de la quantite consommee, de la voie d’administration, de la sensibilite du sujet et des substances associees. Le craving est une composante majeure de l’addiction. Les complications peuvent etre nombreuses, essentiellement de type cardiovasculaire, mais egalement pulmonaire, ORL, neurologique et psychiatrique.

A personal history of childhood trauma has been associated with the severity of psychotic symptoms in several disorders. We evaluated retrospectively cocaine-induced psychotic symptoms with the SAPS-CIP and childhood trauma with the CTQ in a clinical sample of 144 cocaine users. The SAPS-CIP score was not statistically associated with the presence or number or intensity of trauma, but was associated with rapid routes of administration (intravenous and smoked) and with frequent cocaine use.

Resume Objectif Les cannabinoides de synthese (CS) sont une large famille de molecules, presentant des structures chimiques tres diverses, qui ont pour caracteristique commune d’etre agonistes des recepteurs cannabinoides. Initialement synthetises a des fins medicales, leur usage recreatif s’est largement repandu depuis quelques annees. Les donnees epidemiologiques et cliniques demeurent encore tres fragmentaires. L’objectif de cet article est de faire le point des connaissances actuelles sur les aspects epidemiologiques, les modalites de consommation et les aspects cliniques. Materiels et methodes Revue de la litterature. Resultats Les donnees epidemiologiques recentes montrent que la prevalence de l’usage des cannabinoides de synthese reste faible en population generale. Les modalites de consommation sont tres variees. Les motivations principales pour consommer des CS sont leur statut legal, leur facilite d’acces, leur faible cout ainsi que la promesse d’effets positifs comparables, voire superieurs a ceux du cannabis. Paradoxalement, ces effets positifs semblent moins intenses et/ou de plus courte duree qu’avec le cannabis, alors que les complications psychiatriques et neurologiques sont beaucoup plus frequentes. Le potentiel addictif des cannabinoides de synthese semble moins important que celui du cannabis. Ces resultats doivent etre confirmes par des etudes cliniques et epidemiologiques prospectives sur des effectifs plus larges.

Background Drug concentrations obtained from post mortem samples do not necessarily reflect the concentrations at the time of death, and variations of concentration may be observed between different sites and/or different sampling times. These phenomena, collectively termed post mortem redistribution, concern numerous molecules (medications, drugs of abuse, gases, etc.) and can complicate the interpretation of toxicological analyses. Methods Literature review. Results The mechanisms that cause these phenomena are complex and often intricate. Certain organs, which concentrate the molecules before death, may release them very early in the vascular sector. The gastrointestinal tract, liver, lungs and myocardium are mainly concerned. Cell autolysis also plays a part in drug release. Furthermore, micro-organisms (mainly bacteria and yeasts) which colonize the organism during putrefaction may cause neoformation and/or the degradation of certain molecules. Lastly, it appears that the physicochemical and pharmacokinetic profile of xenobiotics, notably their lipophilic nature, their ionization state and their volume of distribution may be factors likely to influence redistribution phenomena. Some recommendations concerning anatomic sampling sites, sampling methods and sample storage make it possible to limit these phenomena.

Objectif Presenter un cas pour lequel les analyses toxicologiques effectuees sur des pieces de vetements, seule matrice disponible, ont permis d’apporter des elements d’orientation a l’enquete. Description Des ossements sont retrouves par un salarie d’EDF sous la dalle d’un regard d’acces a des câbles electriques. A la levee de corps, les medecins legistes constatent la presence d’un squelette, partiellement vetu, en decubitus lateral gauche. Aucun papier d’identite n’est retrouve a proximite du corps. Ces restes sont transportes a l’institut medico-legal. Une expertise anthropologique est ordonnee sur les pieces osseuses. Un fragment de 10 cm de diaphyse femorale gauche est preleve pour analyse genetique. Enfin, les vetements nous sont transmis pour expertise toxicologique. Methodes Les scelles contiennent un blouson, un reste de pantalon avec une ceinture et deux morceaux de tissu non identifies. Des pieces de 3 × 3 cm ont ete decoupees au niveau des zones susceptibles d’avoir ete en contact avec le revetement cutane ou les fluides corporels : une piece au niveau du col de la veste, deux au niveau de la braguette du pantalon (braguette 1 et 2), une au niveau de l’entrejambe. Enfin, trois pieces ont ete decoupees dans les morceaux de tissu non identifies (tissu 1 a 3) pouvant etre un tee-shirt. Un screening des pieces de tissus decoupees est effectue par chromatographie en phase liquide apres extraction en milieu alcalin par un melange dichloromethane/isopropanol/n-heptane (25:10:65, v/v/v), separation sur colonne en phase inverse Waters Acquity HSS C18 column (150 × 2,1 mm × 1,8 μm) et detection par spectrophotometre a barrette de diodes et par spectrometrie de masse en tandem sur un systeme Xevo TQD® (Waters). Resultats Les resultats des analyses pratiquees sur les pieces de tissus sont presentes dans le Tableau 1 . Parallelement, l’expertise anthropologique a permis de determiner que la victime est un adulte de sexe masculin, âge de plus de 60 ans, dont la stature est comprise entre 164 et 170 cm et dont le deces ne date probablement pas de plus de deux ans. Aucune trace de traumatisme expliquant le deces n’a ete mise en evidence lors de l’examen anthropologique. L’expertise genetique a permis d’identifier avec precision la victime, un homme de 67 ans, inscrit au fichier des personnes disparues depuis un an et recherche par la brigade financiere. Selon les informations recueillies par les enqueteurs, la victime ne suivait pas de traitement particulier et les molecules identifiees pourraient avoir contribue au deces. Conclusion L’analyse des textiles au contact du revetement cutane ou des fluides biologiques permet, lorsqu’aucun autre milieu biologique n’est disponible, de recueillir des informations necessaires au bon deroulement de l’enquete. Les auteurs presentent les aspects analytiques et les limites de l’interpretation de ces cas.