n‐Ethyl Pentylone‐Related Deaths in Alabama

n‐Ethyl pentylone (NEP) is a chemical substance derived from cathinone. Synthetic cathinones are an evolving group of drugs with stimulating, mind‐altering effects sometimes referred to as novel or new psychoactive substances (NPS). There is scarce information in the medical literature regarding forensic cases in which NEP is detected in toxicological testing. We present four fatalities involving NEP from Alabama in 2017. Deaths were attributed to NEP toxicity in two cases (peripheral blood concentrations of 0.121 and 0.953 mg/L) and injuries caused by gunshot wounds in two cases (peripheral blood concentrations of 0.045 and 0.031 mg/L). One case involving NEP described an individual who exhibited classic CNS‐stimulant induced erratic behavior before being found dead. These cases enhance the forensic literature regarding specific NPS like NEP and provide contextual reference for professionals considering the significance of NEP in toxicological interpretation.     

Sample Mining and Data Mining: Combined Real-Time and Retrospective Approaches for the Identification of Emerging Novel Psychoactive Substances

Novel psychoactive substances (NPS) are synthetic drugs that pose serious public health and safety concerns. A multitude of NPS have been identified in the United States, often implicated in forensic investigations. The most common and effective manner for identifying NPS is by use of mass spectrometry and the true utility lies within nontargeted acquisition techniques. During this study, a liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) assay was developed, validated, and implemented for forensic toxicology testing. A SCIEX TripleTOF™ 5600 + with SWATH^® acquisition was used. Resulting data were compared against an extensive library database containing more than 800 compounds. The LC-QTOF-MS assay was applied to the reanalysis of biological sample extracts to discover emergent NPS. More than 3,000 sample extracts were analyzed, and more than 20 emerging NPS were detected for the first time. Among these were isopropyl-U-47700, 3,4-methylenedioxy-U-47700, fluorofuranylfentanyl, N-methyl norfentanyl, 2F-deschloroketamine, 3,4-methylenedioxy-alpha-PHP, eutylone, and N-ethyl hexedrone.     

苯二氮卓类新精神活性物质去氯依替唑仑的定性检验方法研究

目的建立苯二氮卓类新精神活性物质去氯依替唑仑的气相色谱-质谱(GC-MS)和超高效液相色谱-四极杆-飞行时间质谱(UPLC-Q-TOF MS)定性检验方法。方法未知样品用甲醇和水提取,取上清液,采用GC-MS和UPLC-Q-TOF MS进行分析。结果经GC-MS检测,保留时间为17.73 min的未知组分的质谱碎片主要特征离子峰有m/z 279,308,239,252,225,77,126。经UPLC-Q-TOF MS检测,保留时间为4.781 min的未知组分的准分子离子峰为309.1173,碰撞诱导解离(CID)模式下二级质谱主要离子有m/z 280.0776,255.0952,240.0719,225.0604,206.0748。经缴获毒品分析科学工作组(Scientific Working Group for the Analysis of Seized Drugs,SWGDRUG)分析谱库检索和文献查询获得的信息资料进行比对,鉴定为去氯依替唑仑。结论该方法具有分析简便、快速的特点,可以用于实际案件的检测。     

In silico toxicity as a tool for harm reduction: A study of new psychoactive amphetamines and cathinones in the context of criminal science

The emergence of new psychoactive substances (NPS) has raised many issues in the context of law enforcement and public drug policies. In this scenario, interdisciplinary studies are crucial to the decision-making process in the field of criminal science. Unfortunately, information about how NPS affect people's health is lacking even though knowledge about the toxic potential of these substances is essential: the more information about these drugs, the greater the possibility of avoiding damage within the scope of a harm reduction policy. Traditional analytical methods may be inaccessible in the field of forensic science because they are relatively expensive and time-consuming. In this sense, less costly and faster in silico methodologies can be useful strategies. In this work, we submitted computer-calculated toxicity values of various amphetamines and cathinones to an unsupervised multivariate analysis, namely Principal Component Analysis (PCA), and to the supervised techniques Soft Independent Modeling of Class Analogy and Partial Least Square-Discriminant Analysis (SIMCA and PLS-DA) to evaluate how these two NPS groups behave. We studied how theoretical and experimental values are correlated by PLS regression. Although experimental data was available for a small amount of molecules, correlation values reproduced literature values. The in silico method efficiently provided information about the drugs. On the basis of our findings, the technical information presented here can be used in decision-making regarding harm reduction policies and help to fulfill the objectives of criminal science.     

Scheduling of new psychoactive substance the Swiss way: A review and critical analysis

Since the introduction of the European Early Warning System in 2005, >700 new psychoactive substances (NPS) have been listed. This review article presents for the first time the Swiss narcotic law in perspective of scheduling of NPS, and compares it to the regulations of the German speaking neighbours Austria and Germany.The Swiss way is a fast and effective way for scheduling NPS, with the purpose to restrict drug trafficking and for controlling the NPS drug market: the legal basis for scheduling substances of abuse is the “Law about narcotics and psychotropic substances” (BetmG, SR 812.121), which includes the “narcotic law directory (BetmVV-EDI, SR 812.121.11) suitable for listing all controlled substances. The BetmVV-EDI, SR 812.121.11 contains seven indices, with index e specifically designed for the fast scheduling of NPS. Newly appearing NPS can either be controlled under a structure analogues definition or by listing single substances. The list of single substances is updated at least once per year, and structure analogues definitions can be implemented, in order to keep track with new developments on the NPS market. The latest version from November 30th 2018 contains ten different structure analogue definitions and 207 single substances. Requirements to list NPS are their appearance on the NPS market, suspected psychotropic effects and their suggestions by Forensic professionals. As soon as substances are newly placed, on Schedule I of the 1961 Convention or Schedule II of the 1971 Convention by the Commission on Narcotic Drugs of the World Health Organization they can easily be transferred from index e to index a-d of the BetmVV-EDI, SR 812.121.11. The Austrian law uses a structure analogue and single substances approach (introduced in 2012, one update in 2016), whereas the German NPS law (established in 2016, no update yet) only lists two structure-analogue-definitions. All three legislations have defined which core structures, kinds and sites of substitutions are regulated.     

自主合成标准物质鉴定缴获物中的新精神活性物质ADB-FUBINACA

目的新精神活性物质在世界范围内蔓延迅速,但相关标准物质的短缺制约着其分析方法的研究和案件检验。本文以我国首次出现的N-(1-氨甲酰基-2,2-二甲基丙基)-1-(4-氟苄基)吲唑-3-甲酰胺(ADB-FUBINACA)制毒案件为例,介绍在无法及时获得商业化标准物质的情况下,不得不通过自主合成制备标准物质解决案件检验难题,建立该新精神活性物质检验的方法。方法建立气相色谱-质谱检验方法,分析条件:色谱柱为Aglient DB-5MS石英毛细管柱(30.00m×0.25mm×0.25μm);初始柱温60℃,按15℃/min升至300℃,保持15min;载气为氦,流速1.0mL/min,分流进样,进样量1.0μL,分流比20∶1;进样口温度280℃;电子轰击(EI)离子源,电子能量70eV,离子源温度230℃,四级杆温度150℃,传输线温度280℃,质量扫描范围m/z 40~500amu,全扫描模式(SCAN)采集总离子流图,溶剂延迟3.0min。案件缴获的送检未知样品经甲醇提取,超声、离心后,取上清液以GC-MS分析;将所得主要质谱特征碎片峰(m/z)通过NIST质谱库、SWGDRUG质谱数据库以及相关文献进行检索,初步确定待测目标物。采用有机合成技术制备ADB-FUBINACA标准物质,合成路线为:吲唑-3-甲酸甲酯与4-氟苄溴发生取代反应,生成1-(4-氟苄基)-1H-吲唑-3-甲酸甲酯;取代产物在碱性条件下经水解反应得到有机酸1-(4-氟苄基)-1H-吲唑-3-甲酸;在催化剂作用下,有机酸与L-叔亮酰胺发生酰化反应,制得化合物ADB-FUBINACA。经气相色谱-质谱(GC-MS)、液相色谱-离子阱-飞行时间质谱(LCMS-IT-TOF)、核磁共振(NMR)等分析,合成化合物的结构得以确证;同时采用超高效液相色谱-二极管阵列检测器(HPLC-PDA)进行分析,对其归一化纯度进行测定。将案件未知样品和合成标准物质分别用甲醇提取,超声、离心后,再行上清液GC-MS分析。结果经GC-MS分析,案件未知样品(RT=19.818min)的质谱特征碎片峰(m/z)信息为109.0(基峰)、253.1、338.1、309.1和145.0,经与合成标准物质的保留时间及质谱图检测比对,证实为N-(1-氨甲酰基-2,2-二甲基丙基)-1-(4-氟苄基)吲唑-3-甲酰胺;通过查阅相关资料,对上述质谱特征碎片峰的产生机制进行了推断,并对1H-NMR、13C-NMR和DEPT-135等一维核磁谱图的信号进行了归属分析。结论本文报道的新精神活性物质ADB-FUBINACA其GC-MS分析方法,可用于实际案件检验鉴定;合成化合物的结构表征方法也可用于固体ADB-FUBINACA的定性分析。基于有机合成技术的新精神活性物质制备与案件检验方法,可缓解有关标准物质短缺制约该类案件检验鉴定的现状。     

新精神活性物质检验鉴定面临的挑战和对策

新精神活性物质更新快,种类繁多,缺乏国际条约的监管,列入联合国管控目录困难,加之一些国家和国际社会对大麻等毒品管控降低,给我国在新精神活性物质类毒品的监管带来困难。具有成瘾性和社会危害性的新精神活性物质才能成为列管对象,毒物分析技术人员在列管程序中扮演极为重要的角色。我国对新精神活性物质的监管法规规定了相关列管程序,毒物分析技术人员应当增强参与新精神活性物质列管的责任意识,遵守新精神活性物质鉴定程序,研究和探索新精神活性物质检验方法。     

Illicit payments for illicit goods: noncontact drug distribution on Russian online drug marketplaces

The distribution or consumption of traditional drugs has become the subject of stringent penalties throughout most of the world and synthetic designer drugs have become the alternative. Novel psychoactive substances, also called ‘legal highs’, are highly varied in terms of chemical composition. These substances are advertised and distributed as an alternative to traditional drugs on the Internet, making identification of new substances and enforcement difficult. For this article, we downloaded and analysed 28 Russian-language online drug marketplaces which distribute traditional and novel psychoactive substances. All marketplaces used a noncontact drug dealing method where the seller and the buyer communicate through the Internet to arrange for payment and delivery of drugs without meeting face-to-face. Geographic information, price, amount, substance type and payment method data were extracted. Findings indicate such marketplaces are able to operate due to the ability of their clients to pay anonymously with the virtual currencies – Qiwi and Bitcoin.     

Excluding a psychoactive substance use disorder in forensic psychiatric evaluations

The forensic psychiatrist is sometimes asked to exclude that a person has a psychoactive substance use disorder, for example, in a security worker who has access to weapons, in a health care professional who may be alcohol/drug impaired, or in a parent, in a deprived child or custody hearing matter. After examining the data that are leading to the evaluation, these evaluations require corroborated background information to look for developmental and genetic antecedents that might be consistent with substance abuse and dependence; inquiry into the history of substance use; and an examination of areas, in which problems from substance use can occur, namely in family and other social relationships, at work, in legal settings, in physical health, and in personal and psychiatric reactions, for example, in suicidal behavior. Then a physical exam and laboratory evaluation are conducted to look for medical evidence of substance use and complications therefrom, and a mental status exam is performed and psychological testing is obtained as required, for example, a Minnesota Multiphasic Personality Inventory (MMPI) or neuropsychological testing. When such an evaluation is essentially negative, the examiner can say, within the limits of the evaluation, that a psychoactive substance use disorder does not exist.     

"Legal highs"-Toxicity in the clinical and medico-legal aspect as exemplified by suicide with bk-MBDB administration

The easily available "legal highs", which are products containing psychoactive substances, such as cathinones, piperazines and synthetic cannabinoids, are abused by adolescents in Poland and in the world as alternatives to classic drugs, such as amphetamines or marijuana. The majority of these potentially dangerous substances are still legal and they are associated with a risk of severe poisoning or even death, and provide new challenges in clinical and forensic toxicological practice. Investigations in the field of "designer drugs" may be well illustrated by the case of a suicide of a 21-year old male who ingested a specified dose of a preparation called "Amphi-bi-a" that contains bk-MBDB, chemically 2-methylamino-1-(3,4-methylenedioxyphenyl) butan-1-one, which belongs to the cathinone group, as a synthetic euphoric empathogen and psychoactive stimulant that is chemically similar to MDMA. It is one of more common components of "legal highs" examined in Poland and other countries. The documentation of the case includes a clinical assessment of the patient's health status performed during his almost 4-h hospitalization before death, autopsy and histological examinations supported by toxicological findings revealing bk-MBDB at extremely high concentrations (at 20mg/l in the blood and 33mg/kg in the liver); hence, this body of evidence contributes to knowledge in the field of "designer drugs". Inventions of designers of new psychoactive xenobiotics, which are much in demand, especially in view of the dynamic Internet marketing, which drums up narcobusiness, must be balanced by a national strategy developed by medical, legal and educational circles in the modern civilized world in order to prevent the spreading of the phenomenon.     

新精神活性物质发展与管制综述

新精神活性物质具有更迭快、种类多、毒性强的特点,业已成为继传统毒品和合成毒品之后的"第三代毒品"。新精神活性物质的出现对个人和公众健康构成越来越严峻的威胁,也对传统的毒品管制制度提出了巨大的挑战。为应对新精神活性物质问题,以联合国为平台的国际组织与国际社会均进行了一系列措施,我国于2015年出台《非药用类麻醉药品和精神药品列管办法》加强对新精神活性物质的管制,但由于其立法层级较低、缺配套措施等局限性,新精神活性物质的管控仍困境重重。为此,应在立足现有法律法规的基础上合理借鉴域外的经验和制度,通过加强宣传教育、加快列管步伐、完善监测预警等方式,推动新精神活性物质危机的有效解决。     

Fatal alcohol poisoning: medico-legal practices and mortality statistics

Compilation of mortality statistics from death certificate data is based on international and national conventions which in certain situations result in the underlying cause-of-death other than that established and reported by the physician. The present study compares all fatal alcohol poisonings in 1997 as registered on forensic toxicological grounds at the accredited central laboratory and as presented in the national cause-of-death statistics, according to the underlying cause-of-death, by applying international statistical rules and principles in ICD-10. Four groups were formed, and case frequencies in each group were obtained from forensic toxicological data, group "T51" for acute poisonings due to alcohol alone, and group "Comb" for acute alcohol poisonings combined with some drug, medicament or other biological substance, and from cause-of-death statistics data, group "X45", for deaths from alcohol poisoning, and group "F102" for those medico-legal fatal alcohol poisoning deaths which at the statistics office were inferred to be due to alcoholism. The study shows that in Finland the officially compiled statistics on fatal alcohol poisonings, when compared with medico-legal statements based on forensic toxicological examinations, were underrepresented by 31.4% in 1997. About two-thirds of this underrepresentation is explained by preferring, as the underlying cause-of-death, alcoholism to acute alcohol poisoning, and about one-third by preferring, in cases of acute combined poisonings, the drug component to the alcohol. From 1998 onwards, more emphasis has been put on the alcohol component when coding medico-legally proven accidental deaths from simultaneous poisoning with alcohol and a medicinal agent. This change in coding practices presumably explains the subsequent decline in the annual underrepresentation rate of alcohol poisoning in mortality statistics to the level of 15-16%. It is concluded that the present ICD rules inevitably lead to underrepresentation of alcohol poisonings in the mortality statistics, and conceptual and practical proposals for future procedures are made.     

The use of alcohol and other psychoactive substances by victims of traffic accidents in Greece.

Alcohol is one of the main causes of traffic accidents worldwide. Its use decreases significantly the driving ability of an individual as well as the reflexes of a pedestrian increasing in this way the possibilities of their involvement in motor-vehicle accidents. The above possibilities are increased when a psychoactive substance has been taken in combination with alcohol due to their synergistic effect. The Laboratory of Forensic Medicine and Toxicology of the University of Athens is authorized to perform the toxicological investigation of traffic accidents that happen in the major part of Greece. The findings of the toxicological analyses that were performed in our laboratory during the years 1995 to 1997 are classified according to the alcohol concentration and the kind of psychoactive substance detected as well as to the gender and the age of the victims, drivers or pedestrians. The results of the above classification are evaluated and the conclusions regarding alcohol, drugs and traffic accidents in Greece are discussed thoroughly.     

Fatalities temporally associated with the ingestion of ibogaine

Ibogaine is a naturally occurring psychoactive plant alkaloid that is used globally in medical and nonmedical settings for opioid detoxification and other substance use indications. All available autopsy, toxicological, and investigative reports were systematically reviewed for the consecutive series of all known fatalities outside of West Central Africa temporally related to the use of ibogaine from 1990 through 2008. Nineteen individuals (15 men, four women between 24 and 54 years old) are known to have died within 1.5-76 h of taking ibogaine. The clinical and postmortem evidence did not suggest a characteristic syndrome of neurotoxicity. Advanced preexisting medical comorbidities, which were mainly cardiovascular, and/or one or more commonly abused substances explained or contributed to the death in 12 of the 14 cases for which adequate postmortem data were available. Other apparent risk factors include seizures associated with withdrawal from alcohol and benzodiazepines and the uninformed use of ethnopharmacological forms of ibogaine.     

The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines

The illicit market for new psychoactive substances is forever expanding. Benzodiazepines and their derivatives are one of a number of groups of these substances and thus far their number has grown year upon year. For both forensic and clinical purposes it is important to be able to rapidly understand these emerging substances. However as a consequence of the illicit nature of these compounds, there is a deficiency in the pharmacological data available for these ‘new’ benzodiazepines. In order to further understand the pharmacology of ‘new’ benzodiazepines we utilised a quantitative structure-activity relationship (QSAR) approach. A set of 69 benzodiazepine-based compounds was analysed to develop a QSAR training set with respect to published binding values to GABA_A receptors. The QSAR model returned an R² value of 0.90. The most influential factors were found to be the positioning of two H-bond acceptors, two aromatic rings and a hydrophobic group. A test set of nine random compounds was then selected for internal validation to determine the predictive ability of the model and gave an R² value of 0.86 when comparing the binding values with their experimental data. The QSAR model was then used to predict the binding for 22 benzodiazepines that are classed as new psychoactive substances. This model will allow rapid prediction of the binding activity of emerging benzodiazepines in a rapid and economic way, compared with lengthy and expensive in vitro/in vivo analysis. This will enable forensic chemists and toxicologists to better understand both recently developed compounds and prediction of substances likely to emerge in the future.     

Determining the Toxicological Significance of Pregabalin in Fatalities

Pregabalin has become more widely prescribed and abused in recent years but is still not always included in laboratory analysis. An LC‐MS‐MS method has been developed and applied to measure pregabalin in 93 postmortem cases, including drug‐related deaths, alternative causes of death, and fatalities where pregabalin was likely to have contributed to death. Other drugs or alcohol was detected, and the most common drug types (in decreasing frequency) were antidepressants, opioids, benzodiazepines, opiates, alcohol, antipsychotics, cocaine, cardiac drugs, amphetamines, cannabis, anticonvulsants, and antihistamines. New psychoactive substances (methoxphenidine and synthetic cannabinoids) were only found in two cases. The results provide further data to assist in evaluating the significance of postmortem pregabalin concentrations and a toxicologically significant concentration of 25 mg/L is proposed. Pregabalin, especially with concomitant use of other CNS depressant drugs, presents a significant toxicological risk and existing laboratory protocols should be reviewed for their suitability to detect pregabalin.     

Drug Recognition Evaluation and Chemical Confirmation of a 25C‐NBOMe‐Impaired Driver

This case report details an individual arrested for drug‐impaired driving after leaving the scene of multiple motor vehicle collisions and evading police. The driver was examined by a drug recognition expert and failed the drug recognition evaluation. The driver admitted to using cocaine, marijuana, an antidepressant medication and “N‐bomb,” a novel psychoactive substance that possesses hallucinogenic properties. Toxicological analyses at the Centre of Forensic Sciences’ Toronto laboratory revealed only the substance 2‐[4‐chloro‐2,5‐dimethoxyphenyl]‐N‐[(2‐methoxyphenyl)methyl]ethanamine (25C‐NBOMe) in the accused's urine. This is the first report in which 25C‐NBOMe was identified through DRE and toxicological analyses in a drug‐impaired driver.     

Regulatory Risk Management of Psychoactive Substances

Congress and the Drug Enforcement Administration have assigned certain psychoactive substances to one of five schedules, based on assumed or demonstrated abuse potential. Although formidable difficulties exist in assessing the hazards of drug use, some of these assignments do not appear consistent with empirical estimates. This mismatch of assignment and abuse potential -possibly due to "radical" political ideology - obscures significant differences in drug effects, and therefore stifles meaningful public participation in evaluating the benefits, risks, and proper use (if any) of available psychoactive substances.     

Application of forensic toxicology to the problem of domestic violence.

The role of the forensic toxicologist in helping to determine causes of death or in aiding in the resolution of "driving under the influence" or similar cases is well known and clearly understood. Less clearly defined is the position of the forensic toxicologist vis-à-vis other socially significant problems. However, as the 21st century approaches, it is worth considering how forensic toxicology can help in unraveling some of these problems. The problem of violence between intimates--that is, domestic violence--is a social problem in which it has been long felt that alcohol has played a part. Until now, though, no carefully controlled toxicological studies have been conducted to substantiate this or to determine whether other drug use is associated with domestic violence. At the San Francisco Medical Examiner's Office, toxicological data from both the victim and the suspect in 20 cases of domestic violence that ended in homicide have been gathered. It was found that alcohol or other drugs or a combination of these factors was invariably present in the suspect, the victim, or both. The implications of these results and how they can be used to develop a toxicological strategy to help reduce the most serious consequences of domestic violence are presented.     

Driving under the influence in Greece: a 7-year survey (1998-2004)

Alcohol is one of the main causes of traffic accidents worldwide. Its use decreases significantly the driving ability of an individual increasing in this way the possibilities of their involvement in motor-vehicle accidents. The above possibilities are increased when a psychoactive substance has been taken in combination with alcohol due to their synergistic effect. The Laboratory of Forensic Medicine and Toxicology of the University of Athens is authorized to perform the toxicological investigation of traffic accidents that happen in the southern part of Greece. The objective of the present study was to identify the prevalence of alcohol and other psychoactive substances among drivers involved in road traffic accidents in Greece during the period 1998-2004. Alcohol was detected in the blood of about 37% of the drivers involved in traffic accident during the years 1998-2000. The detection of alcohol was lower (29%) in the years 2001-2004. Cannabis, benzodiazepines, opiates, and cocaine were found in 4%, 4%, 4% and 1% of the total number of cases, respectively. The above values were compared with those of a previous study concerning the period 1995-1997 and the reasons for the reduction of the number of alcohol-related traffic accidents during the last years are discussed.