Article

Severe Toxicity to the New Psychoactive Substances 3-Hydroxyphencyclidine and N-Ethylhexedrone: an Analytically Confirmed Case Report

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Abstract

Introduction 3-Hydroxyphencyclidine (3-HO-PCP) is a new psychoactive substance (NPS) and a hydroxy derivative of phencyclidine (PCP), and N-ethylhexedrone (Hexen) is a synthetic cathinone. We describe an analytically confirmed case of acute toxicity related to the use of both 3-hydroxyphencyclidine and N-ethylhexedrone. Case Report A 56-year-old male was brought to the Emergency Department by ambulance with hyperthermia (39.9 °C), sinus tachycardia (150 beats per minute), reduced consciousness, ocular clonus, and vertical nystagmus. He was treated with cooled intravenous (IV) fluids and IV benzodiazepines. Following 1 hour of treatment, his temperature fell to 37.7 °C, he developed rhabdomyolysis (creatine kinase peaked at 5999 IU (normal range < 229 IU)): he was managed with supportive measures and was discharged after 25 hours. The patient admitted regular use of Hexen and recent use of 3-HO-PCP. Analysis of urine and serum identified 3-hydroxyphencyclidine and metabolites, N-ethylhexedrone and metabolites, and clephedrone and metabolites. Discussion This is a case of analytically confirmed toxicity to 3-HO-PCP and N-ethylhexedrone. The acute toxicity reported in this patient is consistent with the use of 3-HO-PCP, but there were sympathomimetic and serotonergic features potentially consistent with the cathinone N-ethylhexedrone. The description of the acute toxicity of NPS, such as these, is vital to aid medical toxicologists and emergency medicine physicians treating patients who use them.

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... Dunlop et al. (72) describe a clinical case of a 56-year-old male who ingested 3-OH-PCP and hexene. A patient with a history of a heart attack and one stent in a coronary artery was regularly taking clopidogrel, simvastatin, atenolol, and lansoprazole. ...
... There are reports in the literature about the beneficial effects of Noopept, but they have not yet been scientifically proven. Hemodialysis and peritoneal dialysis seem to be ineffective in PCP poisoning (70,72). ...
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Background: In recent years, an increase in the frequency of hospitalizations of patients taking newer and newer psychoactive substances has been observed around the world. Each year, authors publish case reports of patients who consumed previously unknown NPS. Most publications of this type concern the period between 2014 and 2016. However, no publication systematically reviews the pharmacotherapy used in these cases. This study aims to review the case reports of patients taking NPS published between 2010 and 2019, as well as analyzing the pharmacotherapy used. Methods: We searched the Thomson (Web of Knowledge), PubMed/Medline, Science Direct, Scopus and Google Scholar databases. The search was performed using all possible combinations of the term “case report” describing the use of NPS, also referred to as designer medications, internet medications, research chemicals and herbal highs. Results: We analyzed 51 case reports on the intake of various types of NPS. Most of them ( p < 0.001) concerned the use of synthetic cannabinoids (41.2%) and cathinones (31.4%). The pharmacotherapy applied primarily ( p < 0.001) consisted of administering benzodiazepines to patients (62.7%), most of whom took only this group of medications (25.5%), followed by groups receiving benzodiazepines combined with neuroleptics (15.7%) and muscle relaxants (11.8%). Opioids were administered primarily to patients taking synthetic opioids ( p < 0.001). Of the 5 cases of deaths from NPS reported in the literature, three relate specifically to the synthetic opioid MT-45. The later the time period, the more medications patients were administered ( p = 0.02). Conclusion: In the pharmacotherapy for NPS poisoning, one should focus primarily on combating psychomotor agitation.
... 36 Single HEX-EN doses produce euphoria and increased talkativeness and creativity, but chronic consumption seems to result in psychological addiction. 37 A typical initial dose is about 50-60 mg of powder; however, because of the short duration of its effects, binge dosing of up to 350 mg may occur. 38 All HEX-EN deaths were reported as polydrug fatalities, including that of a young girl with 4-CMC, 4-MEC, and pentedrone also in her blood. ...
... 97 In this context, the authors noted that only 6 of 30 publications included a nontargeted or general unknown screening with GC-MS, LC-tandem MS (MS-MS), and ultra-high-performance (UHP) LC-QToF-MS detection that is essential for the detection of unexpected substances. 34,[37][38][39][40][41] In the United States, the Center for Forensic Science Research and Education reanalyzed deidentified biological sample extracts from forensic investigations and found previously unidentified SCs using high-resolution MS workflows for the nontargeted detection of NPSs. 98 In conclusion, additional research on the pharmacology SCs is urgently needed; however, the evaluation of SC fatalities, including observed antemortem and postmortem findings, provides critical data for the interpretation of new SC cases and on the prevalence of SC fatalities. ...
Article
Background: Synthetic cathinones (SCs) are designer analogs of the natural active principle of khat. Since their appearance on the black market in 2003, their popularity has increased annually, and they have become the most seized class of new psychoactive substances reported to the UNODC Early Warning Advisory system. The constant introduction of newly synthesized molecules makes this issue difficult to monitor. The authors reviewed the most recent SC-related fatalities worldwide to highlight new trends of consumption, reporting acute pharmacological and toxicological symptoms, scene investigations, analytical methods, and reported SC concentrations in diverse biological matrices. Methods: A literature search was performed using scientific databases such as PubMed, Scopus, Science Direct, Web of Science, and Research Gate to identify relevant scientific publications from 2017 to 2020. In addition, a search was conducted through the EU EWS. Results: From 2017 to 2020, 31 different SCs were identified in 75 reported fatal intoxications in the literature, alone or in combination with other substances. The most abused SCs were N-ethylpentylone, N-ethylhexedrone, and 4-chloromethcathinone. The EU EWS included less detail on 72 additional SC-related fatalities from 2017 to 2020. Conclusions: New SCs continuously replace older natural and synthetic stimulant drugs, making determining the cause of death difficult. Analytical methods and high-performance mass spectrometry instruments are essential to detect the low concentrations of these potent new SCs. Little data are available on the pharmacology of these new drugs; the evaluation of toxicological antemortem and postmortem findings provides critical data on the drug’s pharmacology and toxicology and for the interpretation of new SC cases.
... The recreational NPS use can cause serious toxicity and even death. Many cases of acute toxicity and fatal intoxication associated with recreational use of 3-HO-PCP, 6-APB, 3-MMC, and ADB-BUTINACA, etc. have been reported [22][23][24][25]. Dut to the random NPS type and content included, chocolate consumers will face huge health risks. ...
Article
For the first time, the identification and quantification of trace level of new psychoactive substances (NPS) in a complex chocolate matrix have been reported. Since the beginning of 2022, suspected NPS-infused chocolate samples confiscated in inbound packages have been continuously sent to our laboratory for analysis. The qualitative gas chromatography-mass spectrometry (GC-MS) results were verified by 1H nuclear magnetic resonance (1H NMR) and 19F NMR to distinguish between potential aromatic isomers. A total of 11 NPS including deoxymethoxetamine, 3-OH-PCP, 6-APB, 4-APB, 4-OH-MiPT, 3-FEA, 2-FEA, 3-MMC, bromazolam, 2-FDCK, and ADB-BUTINACA were detected in 65 seized chocolate samples. A general 1H quantitative NMR (1H qNMR) method for quantification of 297 types of NPS in complex chocolate matrixes was devised for the first time after rigorous analysis of various critical features of merit, including suitable deuterated solvent, internal standard, quantitative peaks, and instrument acquisition parameters. Validation of the method using six different types of NPS afforded limits of detection of 0.05-0.1 mg/mL, limits of quantification of 0.01-0.03 mg/mL, repeatability and reproducibility lower than 0.5% and 3.6%, recoveries of 91.7%∼104.4%, and absence of matrix effect. The quantitative analysis of 65 seized chocolate samples by 1H qNMR and 19F qNMR showed that the content of NPS was in the range of 0.5 mg/g∼44.1 mg/g. Generally, the developed qNMR method was simple, fast, precise, and can be performed without reference materials of NPS. Since the type and content of NPS are relatively random, chocolate consumers will face huge health risks. Therefore, this new trend of NPS-infused chocolate deserves and requires more attention from national NPS monitoring departments as well as forensic laboratories.
... Additionally, N-ethylhexedrone has neurotoxic properties and is toxic to microglia [128]. There are numerous descriptions in the literature of fatal [97,127,[129][130][131][132][133] and nonfatal [100,127,[134][135][136] poisoning cases where N-ethylhexedrone has been detected in biological material ( Table 1). The blood concentrations detected in fatal and non-fatal cases were in the ranges of 4-285 ng/mL and 1-84 ng/mL, respectively, and the poisoning effects described included symptoms typical of sympathomimetic and serotonergic toxidromes. ...
Article
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Purpose The emergence of novel psychoactive substances (NPS) has been being a continuous and evolving problem for more than a decade. Every year, dozens of new, previously unknown drugs appear on the illegal market, posing a significant threat to the health and lives of their users. Synthetic cathinones are one of the most numerous and widespread groups among NPS. The purpose of this work was to identify and summarize available data on newly emerging cathinones in very recent years. Methods Various online databases such as PubMed, Google Scholar, but also databases of government agencies including those involved in early warning systems, were used in search of reports on the identification of newly emerging synthetic cathinones. In addition, threads on various forums created by users of these drugs were searched for reports on the effects of these new substances. Results We have identified 29 synthetic cathinones that have been detected for the first time from early 2019 to mid-2022. We described their structures, known intoxication symptoms, detected concentrations in biological material in poisoning cases, as well as the countries and dates of their first appearance. Due to the lack of studies on the properties of the novel compounds, we compared data on the pharmacological profiles of the better-known synthetic cathinones with available information on the newly emerged ones. Some of these new agents already posed a threat, as the first cases of poisonings, including fatal ones, have been reported. Conclusions Most of the newly developed synthetic cathinones can be seen as analogs and replacements for once-popular compounds that have been declining in popularity as a result of legislative efforts. Although it appears that some of the newly emerging cathinones are not widely used, they may become more popular in the future and could become a significant threat to health and life. Therefore, it is important to continue developing early warning systems and identifying new compounds so that their widespread can be prevented.
... There was no distinction between quantitative toxicology concentrations for antemortem and postmortem cases. A nonfatal intoxication following 3-HO-PCP and NEH ingestion led to reduced consciousness, hyperthermia and tachycardia; a patient who was eventually discharged from the hospital also had rhabdomyolysis (113). ...
Article
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An important role of modern forensic and clinical toxicologists is to monitor the adverse events of novel psychoactive substances (NPS). Following a prior review from 2013-2016, this critical literature review analyzes and evaluates published case reports for NPS from January 2017 through December 2020. The primary objective of this study is to assist in the assessment and interpretation of these cases as well as provide references for confirmation methods. Chemistry, pharmacology, adverse events, and user profiles (e.g., polypharmacy) for NPS are provided including case history, clinical symptoms, autopsy findings, and analytical results. Literature reviews were performed in PubMed and Google Scholar for publications using search terms such as NPS specific names, general terms (e.g., "designer drugs," "novel psychoactive substances"), drug classes (e.g., "designer stimulants,"), and outcome-based terms (e.g., "overdose," "death"). Government and website drug surveillance databases and abstracts published by professional forensic science organizations were also searched. Toxicological data and detailed case information were extracted, tabulated, analyzed, and organized by drug category. Case reports included overdose fatalities (378 cases), clinical treatment and hospitalization (771 cases), and driving under the influence of drugs (170 cases) for a total of 1,319 cases providing details of adverse events associated with NPS. Confirmed adverse events with associated toxidromes of more than 60 NPS were reported to include synthetic cannabinoid, NPS stimulant, NPS hallucinogen, NPS benzodiazepine, and NPS opioid cases. Fifty of these NPS were reported for the first time in January 2017 through December 2020 as compared to the previous four years surveyed. This study provides insight and context of case findings described in the literature and in digital government surveillance databases and websites during a recent four-year period. This review will increase awareness of adverse events associated with NPS use to better characterize international emerging drug threats.
... The cathinone N-ethylhexedrone was also confirmed in the urine but not in the blood. The sample extraction and analytical method for 3-MeO-PCP and its main metabolite have been described in detail elsewhere (31). Briefly, the blood and urine samples were prepared for analysis with an HPLC system interfaced with a Thermo Q Exactive Focus HRAM mass spectrometer. ...
Article
The phencyclidine derivative 3-Methoxyphencyclidine (3-MeO-PCP) is a potent dissociative hallucinogen. Sought for recreational use as a novel psychoactive substance, it can also induce acute psychological agitation and pathophysiological cardiorespiratory effects. Due to the harms associated with its use, 3-MeO-PCP was added to the ‘Green List’ of materials covered by the 1971 Convention on Psychotropic Substances as a Schedule II substance by the United Nations Commission on Narcotic Drugs in April 2021. There have been 15 previous reports of fatal intoxications following 3-MeO-PCP use, but only one was attributable to 3-MeO-PCP intoxication alone. In this report we detail the first fatality due to 3-MeO-PCP intoxication to be reported in the UK, along with a review of the surrounding literature. Whilst the blood concentrations associated with 3-MeO-PCP toxicity and fatality remain unclear, by providing details of sample collection and storage conditions this case will aid in future interpretations. Furthermore, this case suggests that 3-MeO-PCP toxicity may be exacerbated by exercise. Users of 3-MeO-PCP should be cautioned against its use as a ‘club drug’ or in a similar setting where elevations in heart rate, body temperature and blood pressure may occur.
... An altered state of consciousness and tachycardia are the most frequent clinical manifestation observed with PCP-derivatives [4]. Co-intoxication with similar symptoms involving 3-OH-PCP and N-ethylhexedrone have recently been described [5], which emphasize the risk of multiple NPS consumption, as in our original case where an association of five NPS belonging to two different chemical families is reported with a clinical and biological description. Since 3-OH-PCP, 3-MeO-PCP, CMC, and N-ethylhexedrone were detected at low level (below the limit of quantification) in blood 4 d after intoxication, this allows us to estimate an elimination half-life shorter than 20 h. ...
Article
Background The recreational use of new psychoactive substances (NPS) is increasing worldwide. Among them, the arylcyclohexylamine family including phencyclidine (PCP) and ketamine derivatives is increasing. We report a non-fatal intoxication mainly due to arylcyclohexylamine compounds illustrated by molecular networking (MN). Case details A 37-year-old man with a history of drug abuse was discovered with several bags labeled as research chemicals around him and traces of powder on his nose. He was rehydrated, intubated, and admitted to the intensive care unit (ICU). Urine and drug were analyzed by liquid chromatography-mass spectrometry for NPS identification. Several NPS were quantified in urine: 3-OH-PCP at 12,085 mg/L, 3-MeO-PCP at 1100 mg/L, 2F-DCK at 147 mg/L, N-ethylhexedrone at 165 mg/L and CMC at 48 mg/L. Using a bioinformatic approach, a molecular network was built to confirm the consumption of powders contained in the bags by comparison with patient’s urine. Discussion This case illustrates the interest of MN to (i) perform sample-to-sample comparison, (ii) target quantification methods, and (iii) allow proper management to confirm the relevance of the treatment.
... Kovács et al. [15] described fatal intoxication with a combination of N-ethylhexedrone and ADB-FUBINACA; the concentration in the blood of N-ethylhexedrone was 285 ng/mL, while the concentration of ADB-FUBINACA was 0.08 ng/ mL. Dunlop et al. [33] discussed acute toxicity related to the use by a 56-year-old man of 3-hydroxyphencyclidine and N-ethylhexedrone. Apart from these two substances and their metabolites, clephedrone and its metabolites were detected in his serum and 3-methoxy-PCP and 11-nor-9-carboxy-THC in his urine. ...
Article
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Purpose We present a case of fatal intoxication with U-47700 in combination with other NPS ( N -ethylhexedrone, adinazolam, 4-chloro- N -isopropylcathinone (4-CIC), 4-chloromethcathinone (4-CMC) and sertraline) confirmed by identification and quantification in biological materials and evidences found at the scene in 2017 in Poland. Methods Blood and urine samples were extracted with ethyl acetate from alkaline medium (pH 9); powders/crystals were diluted with methanol. The analysis was carried out using ultra-high-performance liquid chromatography–tandem mass spectrometry. Validation criteria were evaluated for blood and urine at the concentrations of 10 and 100 ng/mL. Results The validation parameters of the method were within acceptable ranges. In the presented case, the determined concentrations of drugs were as follows, in blood: U-47700, 1470 ng/mL; N -ethylhexedrone, 58 ng/mL; adinazolam, 18 ng/mL; 4-CIC, 8.0 ng/mL; 4-CMC, 1.7 ng/mL; in urine: U-47700, 3940 ng/mL; N -ethylhexedrone, 147 ng/mL; adinazolam, 82 ng/mL; 4-CIC, 130 ng/mL; 4-CMC, 417 ng/mL. Sertraline (blood, 89 ng/mL; urine, 32 ng/mL) was also determined in both materials. The same substances were also found in 5 powders/crystals: U-47700 (12% by weight), N -ethylhexedrone (54%), adinazolam (14%), 4-CIC (23%), 4-CMC (26%). After 775 days of storage, biological samples at + 4 °C, the most stable substance was sertraline and the less, synthetic cathinones, especially 4-CIC and 4-CMC. Conclusions The described case of fatal intoxication with NPS presented postmortem concentrations of U-47700, 4-CMC, N -ethylhexedrone, adinazolam and 4-CIC for the first time in the literature. The paper also showed stability study of these substances stored at + 4 °C for 775 days.
... Only a few toxicological case reports on NEH have been published so far. Authors have reported non-fatal mixed intoxication, driving under the influence and-in fatalities-included traffic accidents and overdose in which both psychoactive substances and health conditions were co-factors in the fatal outcome (1,5,6). Moreover, in studies available in the scientific literature, there are no procedures describing the quantification of NEH by liquid chromatography-triple quadrupole-mass spectrometry (LC-MS-MS). ...
Article
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N-Ethylhexedrone [2-(ethyloamino)-1-phenylhexan-1-one; α-ethylaminohexanophenone; NEH] is one of the most recent synthetic cathinones that appeared on the illegal market in late 2015. The majority of information concerning the model of consumption of NEH and its impact on the body originates only from self-reports from grey literature websites and drug forums. There are only limited data associated with the concentrations of NEH in blood samples available in the literature. This article presents a case of fatal NEH intoxication and a method for the determination of this substance in whole blood. A 21-year-old man without any diagnosed diseases was admitted to the hospital due to disorientation, aggression and finally loss of consciousness. Hyperthermia (>41°C), tachycardia (>160 beats per minute), tachypnoe (20 breaths per minute), blood pressure (110/60 mmHg) and acute kidney failure were diagnosed. After a few hours of hospitalization, the patient died. A plastic bag with a white powder was found in his underwear. Analysis of the powder by another laboratory revealed cocaine hydrochloride; however, no cocaine or its metabolites were found in the biological material upon testing in our laboratory. Therefore, re-analysis of the powder was performed, and NEH was identified. Liquid-liquid extraction followed by LC-MS-MS analysis were used for the determination of NEH in blood. The validation parameters were as follows: calibration range 1-250 ng/mL, accuracy 106.5-109.9%, precision 3.5-6.3%, recovery 90.1-96.9%, LOD 0.07 ng/mL and LOQ 1 ng/mL. NEH was quantified in the blood at a concentration of 145 ng/mL. Additionally, amphetamine at low concentrations and THC-COOH were detected. Our study provided information on the possible lethal concentration and toxidrome that clinicians can observe for NEH-intoxicated patients and can be helpful during the preparation of toxicology analysis reports for a court of law for proper data interpretation.
... In addition, the EMCDDA also provides the annual European Drug Report that contains information regarding NPS trafficking (2). The illicit market constantly changes with many intoxications occurring worldwide (3)(4)(5)(6). As a result, multiple countries and recently the United Nations Office on Drugs and Crime (UNODC) monitor NPS and provide reports that benefit law enforcement, first responders and health-care providers around the world (1). ...
Article
New psychoactive substances (NPS) are a major public health problem, primarily due to the increased number of acute poisoning cases. Detection of these substances is a challenge. The aim of this research was to develop and validate a sensitive screening method for 104 drugs of abuse, including synthetic cannabinoids, synthetic cathinones, fentanyl analogues, phenethylamines, and other abused psychoactive compounds (i.e., THC, MDMA, LSD and their metabolites) in oral fluid by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The Quantisal™ oral fluid device was used to collect oral fluid samples. The oral fluid elution buffer mixture (500 μL sample) was extracted with t-butyl methyl ether (MTBE), and chromatographic separation was performed on a Raptor™ biphenyl column (100 mm x 2.1 mm ID, 2.7 μm), with a total run time of 13.5 min. Limits of detection were established at three concentrations (0.05, 0.1 or 1 ng/mL) for most analytes, except for acetyl norfentanyl and mescaline (5 ng/mL). Matrix effects were generally less than 20% and overall extraction recoveries greater than 60%. The highest matrix effect was observed within the synthetic cannabinoids group (PB-22, -55.5%). Lower recoveries were observed for 2C-T (47.2%) and JWH-175 (58.7%). Recoveries from the Quantisal™ device were also evaluated for all analytes (56.7 to 127%), with lower recoveries noted for 25I-NBOMe, valerylfentanyl and mCPP (56.7, 63.0 and 69.9%, respectively). Drug stability in oral fluid was evaluated at 15, 60 and 90 days and at 25 °C, 4 °C and - 20 °C. As expected, greater stability was observed when samples were stored at -20 °C, but even when frozen, some NPS (e.g., synthetic cannabinoids) showed more than 20% degradation. The method was successfully applied to the analysis of 7 authentic oral fluid samples positive for 16 different analytes. The method achieved good sensitivity and simultaneous detection of a wide range of NPS.
... Ciągle powstają nowe pochodne wymienionych substancji, najnowsze doniesienia z września 2019 roku informują o przypadku zatrucia 3-hydroksyfencyklidyną, która w połączeniu z innymi NPS (m.in. z grupy syntetycznych katynonów) spowodowała hipertermię oraz rabdomiolizę [32]. ...
Article
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Psychoactive substances have been around for a very long time. In the 1980’s, chemical engineers created new psychoactive substances as the answer to worldwide drug prohibition. So far, these legal highs have been proven to be worse than the „classical drugs”. In this article the authors try to present the most important new psychoactive substances including their groups, effects, side effects, mechanism of action, and all of those from view of medical doctor practicing in Poland. The article also presents the problem from the legal point of view and explains the most liberal approaches to illegal drugs in European Union. The need for further research is emerging.
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Cathinone, the main psychoactive compound found in the plant Catha edulis Forsk. (khat), is a β-keto analogue of amphetamine, sharing not only the phenethylamine structure, but also the amphetamine-like stimulant effects. Synthetic cathinones are derivatives of the naturally occurring cathinone that largely entered the recreational drug market at the end of 2000s. The former “legal status”, impressive marketing strategies and their commercial availability, either in the so-called “smartshops” or via the Internet, prompted their large spread, contributing to their increasing popularity in the following years. As their popularity increased, the risks posed for public health became clear, with several reports of intoxications and deaths involving these substances appearing both in the social media and scientific literature. The regulatory measures introduced thereafter to halt these trending drugs of abuse have proved to be of low impact, as a continuous emergence of new non-controlled derivatives keep appearing to replace those prohibited. Users resort to synthetic cathinones due to their psychostimulant properties but are often unaware of the dangers they may incur when using these substances. Therefore, studies aimed at unveiling the pharmacological and toxicological properties of these substances are imperative, as they will provide increased expertise to the clinicians that face this problem on a daily basis. The present work provides a comprehensive review on history and legal status, chemistry, pharmacokinetics, pharmacodynamics, adverse effects and lethality in humans, as well as on the current knowledge of the neurotoxic mechanisms of synthetic cathinones.
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A new generation of novel cathinone compounds has been developed as stimulant substitutes to avoid drug control laws and detection of use by blood tests. Dipentylone, N‐ethylhexedrone, 4‐chloroethcathinone (4‐CEC), and 4′‐methyl‐α‐pyrrolidinohexiophenone (MPHP) were tested for in vivo psychostimulant‐like effects to assess their abuse liability. Locomotor activity was assessed in an open‐field assay using Swiss–Webster mice to screen for locomotor stimulant effects and to identify behaviorally‐active dose ranges, times of peak effect, and durations of action. Discriminative stimulus effects were assessed in separate groups of Sprague–Dawley rats trained to discriminate cocaine or methamphetamine from vehicle. Dipentylone, N‐ethylhexedrone, 4‐CEC, and MPHP dose‐dependently increased locomotor activity. Dipentylone, N‐ethylhexedrone, and MPHP produced maximal stimulant effects similar to cocaine and methamphetamine. 4‐CEC was less efficacious, producing peak stimulant effects of about 74% of that of methamphetamine. The compounds were less potent than methamphetamine and approximately equipotent with cocaine. The doses of cocaine, methamphetamine, dipentylone, and 4‐CEC that produced peak effects lasted 2 to 3 h, the peak dose of N‐ethylhexedrone lasted 4 h, and the peak dose of MPHP lasted 6 h. All four compounds fully substituted for the discriminative stimulus effects of methamphetamine and cocaine, although full substitution by 4‐CEC occurred at doses that substantially decreased response rate. Only 4‐CEC fully substituted for MDMA. These data provide evidence that the novel cathinone compounds dipentylone, N‐ethylhexedrone, 4‐CEC, and MPHP demonstrate potential for abuse as psychostimulants, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine and cocaine.
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A molecularly imprinted polymer (MIP) has been prepared in presence of 3-hydroxy phencyclidine (3-OH PCP) as template by bulk polymerization using N,N-dimethylformamide, as porogenic solvent, for the selective solid-phase extraction (SPE) of arylcyclohexylamines from oral fluids. Experimental variables of the extraction procedure have been studied in order to increase both, extraction recovery of 3-OH PCP, used as model analyte, and imprinting factor. By modifying the composition of the washing solvent, the selectivity of the MIP extraction procedure can be tuned, moving from an arylcyclohexylamine selective method to a 3-OH PCP specific method. The applicability of the synthesized MIP was evaluated by the analysis of oral fluids spiked with 3-OH PCP at different concentration levels, extracted using both recommended SPE procedures and analysed by ion mobility spectrometry. Recovery values ranging from 70 to 101 % and a limit of detection of 15 μg L⁻¹ were obtained.
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The new psychoactive substance (NPS) 3‐HO‐PCP, a phencyclidine (PCP) analogue, was detected in a law enforcement seizure and in forensic samples in Denmark. Compared to PCP, 3‐HO‐PCP is known to be a more potent dissociative NPS, but no toxicokinetic investigations of 3‐HO‐PCP are yet available. Therefore, 3‐HO‐PCP was quantified in in vivo samples, and the following were investigated: plasma protein binding, in vitro and in vivo metabolites and metabolic targets. All samples were separated by liquid chromatography and analysed by mass spectrometry. The unbound fraction in plasma was determined as 0.72 ± 0.09. After in vitro incubation with pooled human hepatocytes, four metabolites were identified: a piperidine‐hydroxyl‐and piperidine ring opened N‐dealkyl‐COOH metabolite, and O‐glucuronidated‐ and O‐sulphate‐conjugated metabolites. In vivo, depending on sample and sample preparation, fewer metabolites were detected as the O‐sulphate‐conjugated metabolite was not detected. The N‐dealkylated‐COOH metabolite was the main metabolite in the deconjugated urine sample. In vivo analytical targets in blood and brain samples were 3‐HO‐PCP and the O‐glucuronidated metabolite, with 3‐HO‐PCP having the highest relative signal intensity. The drug levels of 3‐HO‐PCP quantified in blood were 0.013 and 0.095 mg/kg in a living and a deceased subject, respectively. 3‐HO‐PCP concentrations in deconjugated urine in a sample from a living subject and in post‐mortem brain were 7.8 and 0.16 mg/kg, respectively. The post mortem results showed a 1.5‐fold higher concentration of 3‐HO‐PCP in the brain tissue than in the post mortem blood sample.
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Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at μ-opioid receptors and γ-aminobutyric acid-A (GABAA) or GABAB receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-d-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.
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Rationale New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling. Objectives The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability. Methods Affinities to displace the radioligand [¹²⁵I]RTI-55 and potencies to inhibit [³H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [³H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. Results Most α-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83–360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4-Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters’ binding pockets that influence drug affinities. Conclusions The α-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity.
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Clinical and forensic toxicology laboratories are continuously confronted by analytical challenges when dealing with the new psychoactive substances phenomenon. In this study, the analytical characterization of nine synthetic cathinones is described: 2-(ethylamino)-1-phenylhexan-1-one (N-ethylhexedrone 1), 1-(4-chlorophenyl)-2-(methylamino)pentan-1-one (4-Cl-pentedrone 2), 1-(4-chlorophenyl)-2-(ethylamino)pentan-1-one (4-Cl-α-EAPP 3), 1-(3,4-methylenedioxyphenyl)-2-propylaminopropan-1-one (propylone 4), 1-(3,4-methylenedioxyphenyl)-2-ethylaminopentan-1-one (N-ethylnorpentylone 5), 1-(6-methoxy-3,4-methylenedioxyphenyl)-2-methylaminopropan-1-one (6-MeO-bk-MDMA 6), 4-methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PiHP 7), 1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)hexan-1-one (4-Cl-α-PHP 8), and 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)hexan-1-one (4-F-α-PHP 9). The identification was based on ultra-high-performance liquid chromatography–quadrupole time-of-flight–mass spectrometry (UHPLC–QTOF–MS), gas chromatography–mass spectrometry (GC–MS), and nuclear magnetic resonance spectroscopy (NMR). The mass-spectral fragmentations of these compounds following collision-induced dissociation (CID) and electron ionization (EI) were studied to assist forensic laboratories in identifying these compounds or other substances with similar structure in their case work. To our knowledge, no analytical data about the compounds 1–4, 7, and 8 have appeared until now, making this the first report on these compounds. The GC-MS data of 5, 6 and 9 has been reported, but this study added the LC-MS, FT–IR and NMR data for additional characterization. This article is protected by copyright. All rights reserved.
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PCP or phencyclidine was discovered in 1956 and soon became a popular street drug. Dissociatives including PCP, ketamine, and dextromethorphan have been used non-medically for their mind-altering effects for over 60 years. Many of these compounds have also been used clinically and in legitimate research. At least 14 derivatives of PCP were sold for non-medical and illict use from the late 1960s until the 1990s. With the advent of the Internet, the drug market underwent a dramatic evolution. While initially gray-market chemical vendors offering dextromethorphan and ketamine thrived, most recently the market has shifted to legal high and online-based research chemical vendors. Starting with the first dissociative research chemical, 4-MeO-PCP in 2008, the dissociative research chemical market has rapidly evolved and currently comprises at least 12 dissociatives, almost half of which were unknown in the scientific literature prior to their introduction. Several of these, including methoxetamine, have reached widespread use internationally. A historical account of non-medical use of over 30 dissociative compounds was compiled from a diverse collection of sources. The first complete portrait of this underground market is presented along with the relevant legal, technological, and scientific developments which have driven its evolution. Copyright © 2014 John Wiley & Sons, Ltd.
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1-[1-(3-Hydroxyphenyl)cyclohexyl]piperidine (PCP-3-OH) is one of the most potent analogs of phencyclidine (PCP). In the present study we describe the binding properties of 3H-PCP-3-OH to guinea pig brain membranes. Scatchard analysis of saturation binding studies revealed the existence of high (0.44nM) and low (17nM) affinity binding components. High affinity binding sites were completely blocked in the presence of (+)SKF 10047 (50nM). In competition studies PCP analogs compete for 3H-PCP-3-OH specific binding in a monophasic manner whereas psychotomimetic opioid ligands compete for this binding in a biphasic manner. Results from both saturation and competition experiments suggest the existence of a common high affinity binding site for psychotomimetic opioid ligands and PCP analogs and a low affinity binding component primarily for phencyclidines.
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Small modifications of the basic structure of phencyclidine have produced compounds with potent opioid analgesic actions. Detailed competition studies show that two of these phencyclidine derivatives, the 3'-hydroxy and the 4-phenyl-4-hydroxy analogs, displace 3H-opioid binding in a multiphasic manner. Approximately 25% of the total specific binding of all the radiolabeled opioids is displaced by low concentrations of the derivatives while the remainder of the binding is far less sensitive. The inclusion of these derivatives in saturation studies with [3H]dihydromorphine indicate that both compounds interact with highest affinity with mu1 sites. Furthermore, the prior in vivo administration of naloxonazine 24 h earlier reduces the analgesic potency of the 4-phenyl-4-hydroxy compound by 63% supporting a mu1 mechanism of action.
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The following monohydroxy derivatives of 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP) were synthesized: o-, m-, and p-phenols of PCP, 1-(1-phenylcyclohexyl)-4-piperidinol, and two stereoisomeric pairs of 3-phenyl-3-(1-piperidinyl)cyclohexanol and 4-phenyl-4-(1-piperidinyl)cyclohexanol. Inhibition of specific binding of tritiated PCP, morphine, or quinuclidinyl benzylate (QNB) in rat brain homogenates was measured for these compounds. Inhibition of PCP binding for selected compounds correlated with mouse rotarod assay activity. The most characteristic effects of hydroxylation of PCP on the cyclohexyl, piperidine, or phenyl moieties are the following: (i) it generally decreases its activity in inhibiting [3H]PCP binding by a factor of 10 to 80; (ii) it does not produce a large variation in the affinity for the morphine receptor; (iii) it produces a considerable decrease of the affinity for the muscarinic receptor. An important exception to these general observations was the metaphenolic derivative of PCP. This PCP derivative has an affinity for the [3H]PCP binding sites that is 8 times higher than that of PCP itself; its affinity for the muscarinic receptor is only twice lower than that of PCP, but its affinity for the morphine receptor is 430 times higher than that of PCP and only one order of magnitude lower than that of morphine itself.
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The pharmacological characteristics and the regional distribution of [3H]3-OH-PCP (1-[1(3-hydroxyphenyl)-cyclohexyl]piperidine) binding were investigated in rat brain by quantitative autoradiography. Kinetic analysis of [3H]3-OH-PCP binding revealed fast and slow components, in the association and dissociation studies. The regional distribution of binding closely corresponded to those of binding sites labeled by [3H]N-[l-(2-thienyl)-cyclohexyl]3,4-piperidine (TCP) and [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate (MK 801). High densities of [3H]3-OH-PCP binding sites were found in the stratum radiatum and orients of field CA1 in the hippocampus and in the outer layers of cerebral cortices. In contrast, low levels of binding were seen in the brain stem and the granular cell layer of the cerebellum. [3H]3-OH-PCP binding was strongly inhibited by MK 801 and 3-OH-PCP, while the potency of (+)-SKF 10047 in inhibiting [3H]3-OH-PCP binding was less in the cerebral cortex and hippocampus. The antagonists for the glutamate, glycine and polyamine recognition sites at the NMDA/PCP receptor complex displaced [3H]3-OH-PCP binding sites with a potency similar to that of [3H]MK 801. These findings suggest that the [3H]3-OH-PCP binding site is similar or identical to the PCP binding site labeled by [3H]TCP and [3H]MK 801.
Slovenia: National Forensic Laboratory
  • N F Laboratory
  • N Analytical Report
  • Ethylhexedrone
2-(ethylamino)-1-phenylhexan-1-one
  • N F Laboratory
  • Analytical Report