N,N-dimethylpentylone poisoning: Clinical manifestations, analytical detection, and metabolic characterization.

INTRODUCTION: The proliferation of new psychoactive substances (NPS) poses a significant challenge to clinical and forensic toxicology laboratories. N,N-dimethylpentylone, a novel synthetic cathinone, has emerged as a public health concern. The aims of this study are to describe the clinical presentation of N,N-dimethylpentylone poisoning, to describe detection methods, and to deduce its metabolic pathways. METHODS: Clinical data was collected and reviewed retrospectively from patients with confirmed N,N-dimethylpentylone exposure. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify N,N-dimethylpentylone and its metabolites in urine samples. The metabolic pathway was characterised by comparison of the detected substances with reference standards. RESULTS: Eight cases were included in the case series. Seven different metabolites of N,N-dimethylpentylone were identified in in vivo patient urine samples, where the two major metabolic pathways were proposed to be opening of the 5-membered ring and reduction of carboxide. All patients presented with neuropsychiatric and/or cardiovascular symptoms. Co-ingestion with other substances was reported in all cases. One patient requiring intensive care was described in detail. All patients eventually recovered. The analytical method allowed the simultaneous identification of N,N-dimethylpentylone, pentylone and bisdesmethyl-N,N-dimethylpentylone, as well as other drugs of abuse in patient samples. CONCLUSION: N,N-dimethylpentylone appears to be less potent than its metabolite pentylone. Co-ingestion with other drugs of abuse is common. Poisoning cases have neuropsychiatric and cardiovascular manifestations. An updated and comprehensive laboratory method is needed for its detection.

The surge of bromazolam-related fatalities replacing other novel designer benzodiazepines-related fatalities in San Francisco.

BACKGROUND AND AIM: Bromazolam, a novel designer benzodiazepine (NBD), exhibits potent sedative, hypnotic and anxiolytic effects, raising concerns regarding its potential for misuse and fatal outcomes, particularly when combined with opioids such as fentanyl. Despite limited documented fatalities globally, its use poses a significant threat, exacerbated by under-reporting and a lack of routine testing. This study analysed NBD-related deaths in a major US city over a 4-year period. METHODS: Analysis of accidental overdose deaths involving NBDs in San Francisco, CA, USA from 2020 to 2023, was performed utilizing medico-legal death investigations including comprehensive forensic toxicology, pathology and demographic information. San Francisco conducts thorough investigations into all non-natural and sudden unexpected deaths, including routine alcohol and drug testing of decedents under its jurisdiction, including etizolam, flualprazolam, flubromazolam and bromazolam analysis. RESULTS: There was a sudden surge in bromazolam-related deaths, with 44 fatalities documented in 2023, contrasting with relatively fewer deaths related to other NBDs. Bromazolam fatalities frequently involved co-ingestion with opioids, primarily fentanyl, and stimulants such as methamphetamine and cocaine. Demographic characteristics indicated a predominance of males, with a significant proportion lacking fixed addresses. Blood concentrations of bromazolam increased during the study period, suggesting heightened availability and/or purity in the community. CONCLUSION: There was a surge in bromazolam-related deaths during 2023 in San Francisco, CA, USA, contrasting with relatively stable numbers of deaths associated with other NBDs over the preceding years. The findings underscore the urgency for enhanced death investigation, testing and reporting to facilitate targeted harm reduction strategies for individuals at risk of bromazolam-related morbidity and mortality.

Alpha-methyltryptamine and 5-(2-methylaminopropyl)-benzofuran (5-MAPB) fatal co-intoxication: case report and review of literature.

The scientific literature contains little reliable data regarding new psychoactive substances and designer drugs, making it difficult to assess toxic blood levels and potentially lethal threshold. Here, we report a fatal co-intoxication involving two uncommon drugs ‒ alpha-methyltryptamine (AMT) and 5-(2-methylaminopropyl)-benzofuran (5-MAPB) ‒ combined with exposure to benzodiazepines, ephedrine, and norephedrine. AMT and 5-MAPB were quantified using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC/MS-MS), revealing concentrations of AMT 4690 ng/mL and 5-MAPB 101 ng/mL in postmortem peripheral blood. We additionally reviewed the literature to help interpret the likely roles of these molecules in the occurrence of death.

Two Fatalities Involving Mebroqualone.

Mebroqualone is an analogue of methaqualone, and there is a very little published information regarding the toxicity of this designer drug. We describe two cases with non-lethal levels of mebroqualone in blood collected at autopsy. Case 1 was an accidental death that involved a house fire, and the decedent was found to have a blood mebroqualone concentration of 10,228 ng/mL. Case 2 was a completed suicide by train, and the decedent was found to have a blood concentration of 115 ng/mL. To our knowledge, this is the first report in the scientific literature to compare two postmortem blood concentrations of mebroqualone. Mebroqualone was extracted from postmortem blood using a simple liquid-liquid extraction procedure and analyzed via gas chromatography-mass spectrometry.

Intoxication cases associated with the novel designer drug 3',4'-methylenedioxy-α-pyrrolidinohexanophenone and studies on its human metabolism using high-resolution mass spectrometry.

Among the increasing number of new psychoactive substances, 3',4'-methylenedioxy-α-pyrrolidinohexanophenone (MDPHP) belongs to the group of synthetic cathinones, which are the derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant. Currently, only limited data are available for MDPHP, and no information is available on its human metabolism. We describe the toxicological investigation of nine cases associated with the use of MDPHP during the period February-June 2019. Serum MDPHP concentrations showed a high variability ranging from 3.3 to 140 ng/mL (mean 30.3 ng/mL and median 16 ng/mL). Intoxication symptoms of the described cases could not be explained by the abuse of MDPHP alone because in all cases the co-consumption of other psychotropic drugs with frequent occurrence of opiates and benzodiazepines could be verified. Therefore, the patients showed different clinical symptoms, including aggressive behaviour, delayed physical response, loss of consciousness and coma. Liquid chromatography-high-resolution mass spectrometry was successfully used to investigate the human in vivo metabolism of MDPHP using authentic human urine samples. The metabolism data for MDPHP were further substantiated by the analysis of human urine using gas chromatography-mass spectrometry (GC-MS, a widely used systematic toxicological analysis method appropriate for the toxicological detection of MDPHP intake), which revealed the presence of seven phase I metabolites and three phase II metabolites as glucuronides. GC-MS spectral data for MDPHP and metabolites are provided. The identified metabolite pattern corroborates the principal metabolic pathways of α-pyrrolidinophenones in humans.

Fatal α-PVP and amphetamine poisoning during a sauna and autoerotic practices.

We describe the sudden death of a middle-aged man while having a sauna under the influence of α-pyrrolidinovalerophenone (α-PVP) (PM blood concentration: 0.8 mg/L), amphetamine (0.34 mg/L), and other drugs (buprenorphine, benzodiazepines), and engaging in solitary sexual activities. The drugs' effects on the cardio-circulatory system and on body thermoregulation combined with the high temperatures are likely to have been central mechanisms leading to death. The high levels of adrenaline triggered by sexual arousal and the respiratory depression caused by buprenorphine, in association with benzodiazepines, may have also contributed to his death. This previously unreported type of accidental autoerotic death illustrates the risk of using amphetamine-like sympathomimetic drugs (e.g. cathinone derivates) in hot environments such as a sauna, and during sexual activities therein.

Clonazolam a new designer benzodiazepine intoxication confirmed by blood concentration.

BACKGROUND: Recently the number of new psychoactive substances have significantly increased, becoming popular among experienced users of designer drugs. A significant group includes benzodiazepine derivatives, which have not been introduced as medications but are abused by people experimenting with new and classical psychoactive substances. CASE PRESENTATION: The aim of this paper was to present the case of a clonazolam ingestion by a person who was not habituated to benzodiazepines. The intake caused only prolonged coma, decreased muscle tone, and deep tendon reflexes without any other concomitant toxicity and cardio-respiratory failure. CONCLUSIONS: Clonazolam concentrations in patient's blood, measured three times were 0.077 mg/L, 0.015 mg/L, 0.009 mg/L after 4, 8 and 12 h, respectively. Clonazolam's human toxicity has not been well established, so any case of poisoning should be closely monitored.

Femoral blood concentrations of flualprazolam in 33 postmortem cases.

Flualprazolam is a novel designer benzodiazepine, structurally related to alprazolam, flubromazolam and triazolam. In the last couple of years, it has been frequently detected in seizures and in forensic cases in Sweden and Finland. However, there is a lack of published blood concentrations for the drug, which presents difficulties when assessing its relevance for the cause of death. A quantitative method for the determination of flualprazolam in post-mortem blood was developed and validated, and subsequently used to analyse samples from 33 deaths previously screened as testing positive for flualprazolam in Sweden and Finland. Most of the cases in the study were accidental deaths (61 %) or suicides (18 %). The median (range) flualprazolam concentration was 18.0 (3.0-68) ng/g. The majority of the deceased were male (82 %) and the median age was 30 years. The median age in the Swedish cases was significantly higher (35 years) than in the Finnish cases (23 years) (p< 0.05). Poly-drug use and particularly the concomitant use of flualprazolam and opioids were very common in the study population. Most of the cases that were positive for flualprazolam were fatal poisonings by a drug (N=23), and in 13 cases, flualprazolam was implicated in the cause of death. Combining the resources of two countries in which all post-mortem toxicology is centralised provided a more comprehensive insight into the toxicology of flualprazolam. Research on novel psychoactive substances, such as flualprazolam, is required in order to be able to provide scientific evidence on the risks of these new substances for drug administration and potential users.

Intoxication with 3-MeO-PCP alone: A case report and literature review.

RATIONALE: 3-Methoxyphencyclidine (3-MeO-PCP) is a new psychoactive substance derived from phencyclidine. Although it can lead to severe intoxications, the main manifestations and optimal management have not been well characterized. Here, we report 2 cases of 3-MeO-PCP intoxication in the same patient, and summarize the manifestations of this intoxication reported in literature. PATIENT CONCERNS: A 17-year-old male purchased a bag of 3-MeO-PCP on the Internet but took an oral dose (200 mg) that corresponds to the less active isomer 4-MeO-PCP. He developed high blood pressure (158/131 mm Hg), tachycardia (100 bpm), and neurological manifestations (confusion, hypertonia, nystagmus, and then agitation). A maculopapular rash appeared, although this may have been related to the administration of midazolam. Hyperlactatemia (2.6 mmol/L) was the main laboratory finding. Seven days later, he returned to the emergency department after sniffing 50 mg of 3-MeO-PCP. High blood pressure, tachycardia, and neurological manifestations (psychomotor impairment and dysarthria) were present but less severe than after the first intoxication. DIAGNOSIS: In the first intoxication, the blood and urine 3-MeO-PCP concentrations were, respectively, 71.1 ng/mL and 706.9 ng/mL. Conventional toxicity tests were all negative. In the second intoxication, biological samples were not available. INTERVENTIONS: In the first intoxication, treatment consisted of intravenous hydration and midazolam. The patient was transferred to an intensive care unit for monitoring. After the second intoxication, he was monitored for 12 hours. OUTCOMES: The patient's condition improved quickly in both cases. LESSONS: These cases provide additional information on the manifestations of 3-MeO-PCP intoxication. These manifestations are mainly cardiovascular (high blood pressure, tachycardia) and neurological. The fact that second (50 mg) intoxication was less severe than the first (200 mg) is suggestive of a dose-effect relationship for 3-MeO-PCP. The first case also emphasizes the risk of dosing errors caused by the similarity between the names "3-MeO-PCP" and "4-MeO-PCP."

Acute poisoning among children and adolescents in southern Norway. / Akutt forgiftning blant barn og ungdom i Agder.

BACKGROUND: Self-inflicted poisoning is common in adolescents and is a risk factor for suicide. The aim of this study was to survey the circumstances surrounding hospitalisations due to acute poisoning in patients aged up to 18 years. MATERIAL AND METHOD: All hospitalisations in the Departments of Paediatric and Adolescent Medicine, Sørlandet Hospital Trust (Arendal and Kristiansand) due to acute poisoning in the period 1 August 2014-31 July 2015 were prospectively recorded with the aid of a form completed during the admission. RESULTS: There were 88 hospitalisations distributed among 68 adolescents (mean age 15.5 years, SD 1.5) and 13 children (mean age 2.8 years, SD 2.8). The poisoning was categorised as self-harm behaviour in 32 (47 %) of the adolescents, and as substance misuse-related in 35 (52 %). In total, 37 (54 %) of the adolescents had been or were under treatment at the Department of Child and Adolescent Psychiatry. Fifteen (22 %) of the adolescents were deemed to be suicidal. Thirty (94 %) of the adolescents who reported self-harm as the intention behind their poisoning were offered further follow-up at the Department of Child and Adolescent Psychiatry, along with 7 (20 %) of the group with substance misuse-related poisoning. INTERPRETATION: Adolescents who reported self-harm as their intention were usually offered further follow-up, whereas adolescents with substance misuse-related poisoning were rarely offered follow-up.

Fatalities related to new psychoactive substances in Singapore-A case series.

The use of New Psychoactive Substances (NPS) has become a serious global issue with increasing number of reports of their toxicities and fatalities. Likewise, in Singapore, the number of exhibits containing NPS detected had increased 80% from 2011 to 2014. This is a case series of the first four autopsy cases of fatalities due to or related to the use of NPS in Singapore. In one case, we present the first reported case of death due directly to ADB-FUBINACA toxicity (post-mortem blood concentration of 56ng/ml). Another case was due to 25B-NBOMe toxicity (post-mortem blood concentration of 10ng/ml) while the last two cases were deaths related to 5-Fluoro ADB, where the metabolites of the drug were detected.

Mono-/polyintoxication with 5F-ADB: A case series.

5F-ADB is an indazole-based synthetic cannabinoid. In recent years, it has been detected in legal high products as well as in biological samples and is associated with serious adverse health, behavioral effects and even death. Due to the fast pace of the market of synthetic cannabinoids, data on such newly appearing substances are scarce. As pharmacological properties are often investigated in vitro or by using animal experiments, reports on synthetic cannabinoid findings in human samples along with corresponding case history descriptions are valuable for the interpretation of upcoming routine cases. Herein we report five cases with verified 5F-ADB consumption, including three fatalities, a case of driving under the influence of drugs as well as a case of grievous bodily harm. In four cases, 5F-ADB could be detected in blood or plasma. Concentrations were in the range of 0.11-0.57 µg/L. In one instance 5F-ADB consumption was verified by the detection of 5F-ADB metabolites in postmortem body fluids. The described cases illustrate various adverse effects including confusion (possibly even psychosis), collapse, loss of consciousness, unsafe driving style or changing moods that might be attributed to 5F-ADB.

Fatal intoxication of a regular drug user following N-ethyl-hexedrone and ADB-FUBINACA consumption.

In Hungary, N-ethyl-hexedrone (NEH) was the most frequently seized stimulant designer drug in 2017, while among synthetic cannabinoids ADB-FUBINACA and AB-FUBINACA were the most popular. Symptoms of intoxication by these substances are well known but less is known about the pathology of overdose-related death. NEH-induced fatal intoxication has not been described in the literature and knowledge surrounding the particular circumstances of death could be useful better public education of risk and more adequate treatment of overdose patients. In this report, we characterize the case of a 23-year-old male regular drug user who died a few hours after NEH and ADB-FUBINACA consumption. His medical history showed arrhythmia in childhood, and some seizures. Autopsy found he had a BMI of 42.9, a hypertrophic and dilated heart, severe atherosclerosis of the valves, coronaries and the arteries, and edema of the internal organs. Histology confirmed those findings. Postmortem blood levels of NEH were 285 ng/ml, along with 0.08 ng/ml ADB-FUBINACA and five ADB-FUBINACA metabolites. Based on the blood concentrations measured in suspected drug users (≤83.9 ng/ml) we hypothesize that NEH intoxication was the cause of death in this case, with heart disease being a co-factor and that the synthetic cannabinoid effect might have been accompaniment. This case also offered the opportunity to identify the metabolites of ADB-FUBINACA in the blood. We identified metabolites in the post-mortem blood by comparing them to human liver microsomal enzyme metabolites in vitro. Three major and two minor metabolites were found in the blood, of which two could only be derived from ADB-FUBINACA, as opposed to other cannabinoids. The case highlights the importance of the complex analysis of drug related deaths by medico-legal autopsy, histopathology and toxicology.

The risk of emerging new psychoactive substances: The first fatal 3-MeO-PCP intoxication in The Netherlands.

Structural analogs of classic drugs, also called designer drugs, are a booming market due to the easy accessibility on the internet and their legal status. One of those 'legal highs' is an analog of phencyclidine, namely 3-methoxyphencyclidine (3-MeO-PCP). Very few fatalities have been reported where 3-MeO-PCP contributed to the death of an individual. We present the first fatal case in the Netherlands and one of the few worldwide. Postmortem biological samples and the presumed abused unknown substance, sold as ant poison, were obtained. 3-MeO-PCP was detected, and the resulting concentration was 152 µg/l in whole blood. The presumed taken unknown sample was identified as 3-MeO-PCP and thus linked to the victim. The cause of death was a combination of 3-MeO-PCP, amphetamine, and alcohol. Improved diagnostic skills are necessary to face these emerging novel psychoactive substances also in light of public health and social risks.

A fatal case of poisoning of a 19-year-old after taking 3-MMC.

The significant increase in the number of new psychoactive substances on the drug market has recently been a serious problem. The manuscript presents a fatal case of suicide poisoning with 3-MMC (3-methylmethcathinone). The biological material collected during the autopsy of a 19-year-old woman, transferred to the toxicological Laboratory in Katowice ToxLab, was subjected to a chemical and toxicological analysis. The toxicological analysis of blood, vitreous humor and gastric contents revealed 3-methylmetcatinone at a concentration of 800 ng/ml, 153 ng/ml and 5,5 mg, respectively. The presence of 3-MMC has also been confirmed in physical evidence secured on site. 3-methylmethcathinone is a dangerous psychoactive substance that caused the death of the 19-year-old.

Toxic lifespan of the synthetic opioid U-47,700 in Finland verified by re-analysis of UPLC-TOF-MS data.

U-47,700 is a synthetic opioid that emerged on the novel psychoactive substance market a few years ago. After incorporating the substance into the urine UPLC-TOF-MS screening used in post-mortem toxicology, the drug was detected in 10 autopsy cases within routine case work. In all cases, the cause of death was accidental poisoning by U-47,700 alone or in combination with other psychoactive substances. The concentration of U-47,700 in the blood samples ranged between 0.15-2.0 mg/L with a median of 0.30 mg/L. In one of the cases with a U-47,700 concentration of 0.27 mg/L, no other psychoactive substances were detected. The stored TOF-MS analytical data from the year preceding the incorporation of U-47,700 into the screening was reprocessed in order to search for more positive cases. The data-independent acquisition of the original screening allowed for retrospective re-analysis of the full-scan data without additional experiments on the actual sample. The retrospective data-analysis revealed two additional cases positive for U-47,700. The first mention of U-47,700 on a Finnish internet discussion forum was in March 2015. After having been detected in several death cases, the drug was put under national control in November 2016 and the last fatality occurred in 2017. The toxic lifespan of U-47,700 thus lasted for approximately 2 years in Finland. Forensic and clinical laboratories need to rapidly adjust their screening procedures in order to adapt to the continuously expanding field of novel psychoactive substances. Retrospective data-analysis is a practical tool for monitoring the emergence of new substances onto the market.

Occurrence and time course of NPS benzodiazepines in Sweden - results from intoxication cases in the STRIDA project.

CONTEXT: In recent years, many unclassified benzodiazepines (BZD) have appeared through online sale as new psychoactive substances (NPS). This study describes bioanalytical and clinical data related to intoxications involving NPS BZD ("designer BZD") in the Swedish STRIDA project. STUDY DESIGN: Case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals all over Sweden for emergency treatment in 2012-2016. PATIENTS AND METHOD: Urine samples collected in the STRIDA project were analyzed for 28 NPS BZD, using immunoassay and liquid chromatography-high-resolution mass spectrometry . Data of patient's age, gender, reported substance exposure, clinical signs, and treatment were obtained from medical and Poisons Information Center (PIC) records. RESULTS: A total of fifteen different NPS BZD were analytically confirmed in 217 of 1913 (11%) cases involving patients (81% men) aged 15-66 (mean 28) years. The frequency of positive samples increased from 4% in 2012 to 19% in 2015. Etizolam (20 cases) was the first detected NPS BZD (January 2012), and it was followed by metizolam (four cases), estazolam (two), pyrazolam (33), flubromazepam (33), nifoxipam (five), diclazepam (four), meclonazepam (26), bromazepam (one), flubromazolam (92), deschloroetizolam (one), clonazolam (16), 3-hydroxyphenazepam (eight), ketazolam (one), and phenazepam (one). Most cases (89%) also involved other drugs. Use of NPS BZD was rarely (15%) reported during PIC consultation. In 24 patients exposed only to NPS BZD, CNS depression was the most prominent clinical sign, seven were observed in the intensive care unit, and they responded positively to flumazenil treatment. CONCLUSIONS: An increasing use of NPS BZD in Sweden was detected in acute intoxication cases, sometimes leading to intensive care monitoring and support needs.

Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014-2017.

IMPORTANCE: Exposures to novel psychoactive substances are reported with increasing frequency in both the medical literature and the lay press. While the majority of reports describe synthetic cannabinoids and cathinones, a lesser understood family is the "designer benzodiazepines". The current literature describing human exposures to these compounds is comprised of case reports and small case series. OBJECTIVE: The primary objectives of this study are to describe epidemiologic trends and clinical effects of designer benzodiazepine use. METHODS: Data regarding single agent exposures to designer benzodiazepines between 1 January 2014 and 31 December 2017 was obtained from the National Poison Data System. Substances queried include: adinazolam, clonazolam, cloniprazepam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, nifoxipam, norflurazepam, and pyrazolam. Data was summarized descriptively. RESULTS: 234 single agent exposures in 40 states were reported during the study period. The annual number of exposures increased each year, from 26 in 2014 to 112 in 2017, amounting to a 330% increase. The most common exposures were etizolam (n = 162) and clonazolam (n = 50). The most common clinical effects were drowsiness/lethargy (65%), and slurred speech (17%). 3% required intubation, 36% of cases required hospital admission, 22% to the intensive care unit. There was 1 death in the study population. CONCLUSIONS: The incidence of exposures to designer benzodiazepines is rising. Clinical effects are generally consistent with a sedative-hypnotic toxidrome. Severe effects, including death, seemed relatively uncommon in the study population.

A fatal blood concentration of 5-APB.

For the new psychoactive drug 5-(2-aminopropyl) benzofuran (5-APB), very limited knowledge is available regarding lethal concentrations. We present a case and report the post mortem blood concentration of a fatal outcome for a 25 year old man related to the consumption of 5-APB. After intake, he became unconscious and stopped breathing. Cardiopulmonary resuscitation was started without success. After 30min he was declared dead at the scene. During autopsy, whole blood from the femoral vein was collected and screened for a wide range of medicinal drugs and drugs of abuse. 5-APB was initially identified by ultra high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) and subsequently confirmed by using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The only toxicological findings were ethanol 0.6g/L, tetrahydrocannabinol (THC) 0.0024mg/L and 5-APB 0.86mg/L. The cause of death was attributed to intake of 5-APB. Only one previous report of a fatal 5-APB concentration as the main toxicological agent exist in the literature, and the present concentration indicated that 5-APB could be lethal in lower concentrations than previously reported.