[Changes in Test Methods for Internationalization in the Japanese Pharmacopoeia (Part 2): Establishment of a Quantitative Method for Lorazepam Using HPLC Analysis].

The Japanese Pharmacopoeia (JP) is an official normative publication that is referred to, for establishing the authenticity and properties and maintaining the quality of pharmaceutics in Japan. Partial amendments are periodically made to these guidelines to keep up with the progress of science and technology, and the international harmonization is revised every 5 years. Thus, "Internationalization of the JP" is one of the more important issues to address for the revision of the JP. For example, the incorporation of the test methods that have been used in other pharmacopeias, such as the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP), into the JP is a useful approach. In light of this, we have recently reported changes in test methods in the 17th JP, "Establishment of a quantitative test method for clonidine hydrochloride from using a potentiometric titration method to using HPLC". As a part of our ongoing research to change test methods for internationalization, we selected lorazepam. Lorazepam is analyzed using a potentiometric titration method as listed in the 17th JP; however, both the USP and EP use HPLC for quantitative analysis of this drug. In this study, we synthesized the related impurities of lorazepam listed in the USP and the EP and determined their purities using quantitative NMR. The separation conditions of these compounds, including lorazepam, were examined using HPLC and simultaneous analyses were performed. In addition, lorazepam extracted from the tablets was analyzed using conditions similar to those used for the analysis of the related impurities.

Synthetic drugs of abuse.

Synthetic drugs of abuse contain various psychoactive substances. These substances have recently emerged as novel drugs of abuse in public; thus, they are known as novel psychoactive substances (NPS). As these compounds are artificially synthesized in a laboratory, they are also called designer drugs. Synthetic cannabinoids and synthetic cathinones are the two primary classes of NPS or designer drugs. Synthetic cannabinoids, also known as "K2" or "Spice," are potent agonists of the cannabinoid receptors. Synthetic cathinones, known as "Bath salts," are beta-keto amphetamine derivatives. These compounds can cause severe intoxication, including overdose deaths. NPS are accessible locally and online. NPS are scheduled in the US and other countries, but the underground chemists keep modifying the chemical structure of these compounds to avoid legal regulation; thus, these compounds have been evolving rapidly. These drugs are not detectable by traditional drug screening, and thus, these substances are mainly abused by young individuals and others who wish to avoid drug detection. These compounds are analyzed primarily by mass spectrometry.

Pharmacology and adverse effects of new psychoactive substances: synthetic cannabinoid receptor agonists.

Over the last decade, new psychoactive substances (NPS) have continuously been the focus of the international society since their emergence on the illicit drug market. NPS can be classified into six groups including; synthetic cannabinoid receptor agonists (SCRAs), stimulants, opioids, dissociatives, sedatives/hypnotics, and classic hallucinogens with psychoactive effects. These are sold as "herbal incense," "bath salts," "legal highs," and "research chemicals". They can be synthesized easily with slight changes in the chemical moieties of known psychoactive substances. NPS are sold worldwide via on- and off-line markets without proper scientific evaluation regarding their safety or harmfulness. Abuse of NPS poses a serious public health issue, and systematic studies on their adverse effects are lacking. Therefore, it would be meaningful to collect currently available data in order to understand NPS and to establish viable solutions to cope with the various health issues related to them. In this article, we reviewed the general pharmacological characteristics, recent findings, and adverse effects of representative NPS; SCRAs. SCRAs are known as the most commonly abused NPS. Most SCRAs, cannabinoid receptor 1 and cannabinoid receptor 2 agonists, are often associated with severe toxicities, including cardiotoxicity, immunotoxicity, and even death, unlike natural cannabinoid Δ9-Tetrahydrocannabinol.

Toxicology and Analysis of Psychoactive Tryptamines.

Our understanding of tryptamines is poor due to the lack of data globally. Tryptamines currently are not part of typical toxicology testing regimens and their contribution to drug overdoses may be underestimated. Although their prevalence was low, it is increasing. There are few published data on the many new compounds, their mechanisms of action, onset and duration of action, toxicity, signs and symptoms of intoxication and analytical methods to identify tryptamines and their metabolites. We review the published literature and worldwide databases to describe the newest tryptamines, their toxicology, chemical structures and reported overdose cases. Tryptamines are 5-HT2A receptor agonists that produce altered perceptions of reality. Currently, the most prevalent tryptamines are 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 5-methoxy-N,N- diallyltryptamine (5-MeO-DALT) and dimethyltryptamine (DMT). From 2015 to 2020, 22 new analytical methods were developed to identify/quantify tryptamines and metabolites in biological samples, primarily by liquid chromatography tandem mass spectrometry. The morbidity accompanying tryptamine intake is considerable and it is critical for clinicians and laboratorians to be informed of the latest data on this public health threat.

Use of new psychoactive substances to mimic prescription drugs: The trend in France.

Among the expanding world of New Psychoactive Substances (NPS), Designer Medicines (DM) are designed to mimic psychoactive drugs and might lead to adverse events of various severity. The DM category includes designer benzodiazepines (DB), phenmetrazine, modafinil, methylphenidate analogs, and novel synthetic opioids (NSO). To investigate DM-related complications in France, all data on NPS collected in the French Addictovigilance network database through spontaneous reports (SRs) and the annual survey on deaths related to the abuse of licit and illicit psychoactive substances (DRAMES survey) between 2009 and 2017 were analyzed. From 2009-2017, about 800 cases of NPS-related abuse or somatic complications were reported to the French Addictovigilance Network, including 71 fatal cases (9%). DM use progressively increased over the years, particularly after 2013 (4% of all SRs on NPS in 2011 versus 14 % in 2017). Moreover, DM were implicated in 17 % of NPS-related deaths in France, just after cathinones (43 %) and dissociative drugs (22 %). NSO, DB and phenidate analogs were identified in 42 %, 25 % and 25 % of all DM-related death reports, respectively. DM seem to interest a new target group of users that includes mainly patients and healthy people rather than substance users. The availability on the Internet of compounds mimicking therapeutic drugs is a worrying phenomenon that could lead to their uncontrolled use.

Synthetic cathinones - From natural plant stimulant to new drug of abuse.

As recreational substances, synthetic cathinones started to be used at the beginning of the 21st century. There is still limited data on these compounds, introduced to the illicit drug market for the most part after 2009. Considering that synthetic cathinones are currently the second largest group of new psychoactive and dangerous substances among over 670 new psychoactive substances identified in Europe and monitored by the EMCDDA, research on them should be regarded as extremely important. This review focuses on the availability of synthetic cathinones on the illicit drug market, presentation of current trends in the use of these substances, and their mechanisms of action and toxicity. The authors discuss cases of intoxication with synthetic cathinones and post-mortem diagnostics as well as the problem of combined used of synthetic cathinones with other psychoactive substances. Literature as well as clinical and forensic data indicate the need for further research on the metabolism, toxicokinetics, toxicodynamics, clinical effects, and addictive potential of synthetic cathinones, especially in the context of potential threats caused by increased consumption of this group of drugs in future.

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

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.

Seizures as a complication of recreational drug use: Analysis of the Euro-DEN Plus data-set.

Seizures are a recognized and potentially serious complication of recreational drug use. This study examined a large international data set of presentations to Emergency Departments with acute recreational drug toxicity, the European Drug Emergencies Plus (Euro-DEN Plus) Network, to compare presentations with and without seizures and estimate incidence and associated drugs. Amongst 23,947 presentations between January 2014 and December 2017, there were 1013 (4.2%) with reported seizures. Clinical and demographic features were similar between individuals who had a seizure and those who did not, although rates of coma, cardiac arrest, intubation, intensive care admission, and death were significantly higher in those with seizures. There was a significant association between specific drugs and a higher seizure incidence, including fentanyl (odds ratio 2.63, 95% confidence interval 1.20-5.80), and synthetic cannabinoids (OR 2.90, 95% CI 2.19-3.84). Other drugs were associated with a lower seizure incidence, including heroin (OR 0.46, 95% CI 0.35-0.61), clonazepam (OR 0.22, 95% CI 0.06-0.91), and cannabis (OR 0.65, 95% CI 0.50-0.86). This substantiates observations that the synthetic cannabinoids as a group of novel psychoactive substances are clinically different in consequence of intoxication than cannabis, and that individuals who suffer a seizure in the context of recreational drug intoxication are likely to have worse outcomes overall. Utilising this information of what substances have a greater risk of seizures, could provide tailored harm reduction and education strategies to users to reduce the risk of seizures and their associated complications.

Syntheses and analytical characterizations of the research chemical 1-[1-(2-fluorophenyl)-2-phenylethyl]pyrrolidine (fluorolintane) and five of its isomers.

A number of substances based on the 1,2-diarylethylamine template have been investigated for various potential clinical applications whereas others have been encountered as research chemicals sold for non-medical use. Some of these substances have transpired to function as NMDA receptor antagonists that elicit dissociative effects in people who use these substances recreationally. 1-[1-(2-Fluorophenyl)-2-phenylethyl]pyrrolidine (fluorolintane, 2-F-DPPy) has recently appeared as a research chemical, which users report has dissociative effects. One common difficulty encountered by stakeholders confronting the appearance of new psychoactive substances is the presence of positional isomers. In the case of fluorolintane, the presence of the fluorine substituent on either the phenyl and benzyl moieties of the 1,2-diarylethylamine structure results in a total number of six possible racemic isomers, namely 2-F-, 3-F-, and 4-F-DPPy (phenyl ring substituents) and 2"-F-, 3"-F-, and 4"-F-DPPy (benzyl ring substituents). The present study reports the chemical syntheses and comprehensive analytical characterizations of the two sets of three positional isomers. These studies included various low- and high-resolution mass spectrometry platforms, gas- and liquid chromatography (GC and LC), nuclear magnetic resonance (NMR) spectroscopy and GC-condensed phase and attenuated total reflection infrared spectroscopy analyses. The differentiation between each set of three isomers was possible under a variety of experimental conditions including GC chemical ionization triple quadrupole tandem mass spectrometric analysis of the [M + H - HF]+ species. The latter MS method was particularly helpful as it revealed distinct formations of product ions for each of the six investigated substances.

An expanding world of new psychoactive substances-designer benzodiazepines.

The abuse of new psychoactive substances (NPS) has been increasing dramatically since the late 2000s worldwide. Between 2009 and 2017, a total of 803 individual NPS were reported to the United Nations Office of Drugs and Crime by 111 countries and territories. Although the most popular compounds are synthetic cannabinomimetics and psychostimulatory derivatives of cathinone (so-called ß-keto-amphetamines), novel benzodiazepines have recently emerged on the recreational drug market. The misuse/abuse of "designer benzodiazepines" (DBZD), a common name for the benzodiazepine class NPS, has become an increasing problem in many countries. The DBZD group includes pharmaceutical drug candidates that have never been approved for medical use, compounds that were synthesized by a simple structural modification of a registered drug, and some active metabolites of registered benzodiazepines. This survey presents members of the DBZD group, describes the epidemiological trends and clinical effects associated with DBZD use, and discusses available data on their metabolism. Special emphasis is given to cases of intoxications involving these compounds.

The Evolving Landscape of Designer Drugs.

Since 2008 there has been an onslaught of new drugs in the illicit marketplace. Often referred to as "research chemicals," "designer drugs," or "novel psychoactive substances" (NPS), these substances are used for their pharmacological effects which are often similar to more widely known drugs such as ecstasy or heroin. In some cases users specifically seek out these new chemicals, in other cases they are simply purchasing what they believe to be their normal drug of choice from a dealer, but the product is not what it is purported to be. Implementation of national and international systems to monitor the appearance of new compounds enables laboratories to be prepared with validated tests to detect them in biological specimens. The most common classes of NPS are synthetic cannabinoids, novel opioids, novel benzodiazepines, stimulants, and hallucinogens. Within these groups the compounds may be drugs that were originally synthesized for research purposes during the pursuit of new therapeutic agents such as the synthetic cannabinoid JWH-018 and the designer opioid U47700. Others like etizolam are compounds used in other countries but not commonly seen in the USA. Some are drugs synthesized specifically to circumvent legal controls. In all cases, these compounds present a unique challenge to forensic toxicology laboratories which must quickly develop and validate analytical methods for the identification and quantification in biological matrices.This chapter is a condensed and updated version of an article originally published in Clinical and Forensic Toxicology News.

The synthetic cannabinoid XLR-11 induces in vitro nephrotoxicity by impairment of endocannabinoid-mediated regulation of mitochondrial function homeostasis and triggering of apoptosis.

Synthetic cannabinoids (SCBs)-related intoxications and deaths have been increasingly reported, turning its widespread recreational use into a major public health concern. Specifically, a direct link between SCBs and acute kidney injury (AKI) has been established. XLR-11 is an SCB commonly found in the toxicological analysis of patients with SCB-associated AKI. However, the pathophysiology of AKI among SCB consumers remains unknown. This work thus represents the first in vitro assessment of SCB nephrotoxicity, as a first approach to identify its cellular targets. We demonstrate that XLR-11, at biologically relevant concentrations (in the nanomolar range), primarily targets mitochondrial function in human proximal tubule (HK-2) cells, inducing a transient hyperpolarization of the mitochondrial membrane and increasing ATP production, accompanied by Bax translocation from cytosol into mitochondria. These phenomena further triggered energy-dependent apoptotic cell death pathways, indicated by increased caspase-3 activity and chromatin condensation. Experiments using SR141716A and SR144258, specific antagonists for CB1 and CB2 receptors, respectively, as well as HEK293T cells (which do not express CBRs) highlighted these processes' dependence on CBR activation. Nevertheless, ATP formation seemed to follow a CBR-independent pathway. Our findings using specific inhibitors of endogenous cannabinoids biosynthesis (i.e. MAFP and THL) further evidenced the involvement of the endocannabinoid system in the regulation of these processes, as XLR-11 binding to CBRs seemed to compromise endocannabinoid-mediated preservation of mitochondrial function. Nevertheless, the exact mechanisms involved require further clarification.

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

Chiral Resolution and Enantioselectivity of Synthetic Cathinones: A Brief Review.

Chiral discrimination has become one of the most important fields in analytical and medicinal chemistry, and forensic toxicology. The enantiomers may have different binding to proteins that may lead to many pharmacological and toxicological differences between them, including kinetic (at the absorption, distribution, metabolism and excretion level) or dynamic (level of potency and efficacy or even differences in mechanism of action) variations. Cathinone derivatives are chiral compounds, sold via the internet for recreational use, and little is known about their enantiomeric selectivity. Consequently, it is of crucial importance for the development of resolution methods to obtain pure enantiomers to study their biological effects. In the last few years, techniques for chiral drug analysis, as chromatography, have been developed and some works related to the analytical enantiomeric resolution of synthetic cathinones were described. However, information about synthetic cathinones in the literature is scarce specially concerning single enantiomers. In this mini-review, analytical chiral resolution and biological differences between enantiomers of cathinone derivatives will be addressed.

Examination of Synthetic Cannabinoid and Cathinone Use among a Drug-Using Offender Sample, 2013-2015.

Use of novel psychoactive substances (NPS) such as synthetic cannabinoids (e.g., "Spice," "Serenity") and cathinones (e.g., "bath salts") has proliferated in recent years; however, there is a gap in research examining prevalence among offender samples. This study examined demographics, drug use, mental health characteristics, and criminal histories of NPS users compared to non-NPS users within an offender sample entering drug treatment. Using logistic regression analysis, combined 2013-2015 assessment data were examined (N = 8,791). NPS users offended more often (x̄ = 10.3), were more likely to have experienced homelessness (12.2%), and to have lived in a metro area (59.0%). NPS users reported significantly more past-year drug use, including substances not readily detected by standard urine analysis (e.g., hallucinogens, alcohol, and inhalants). Individuals with higher anxiety symptom counts (OR = 1.07; p < .001) and those who reported drinking to intoxication (OR = 1.30; p < .001) had an increased likelihood of NPS use. Older individuals (OR = 0.95; p < .001) and those who began using drugs at an older age (OR = 0.95; p < .001) were less likely to report NPS use. NPS use may be a marker of more severe using patterns in an offender sample. Future investigation should focus on NPS use as a possible method for bypassing drug testing measures.

Advances in new psychoactive substances identification: the U.R.I.To.N. Consortium.

Identification of new psychoactive substances (NPS) in biological and non-biological samples represents a hard challenge for forensic toxicologists. Their great chemical variety and the speed with which new NPS are synthesised and spread make stringent the need of advanced tools for their detection based on multidisciplinary approaches. For this reason, in August 2016, the "Unit of Research and Innovation in Forensic Toxicology and Neuroscience of Addiction" (U.R.I.To.N.) was founded by the Forensic Toxicology Division of the University of Florence. In this Research Unit, various professionals (i.e. forensic toxicologists, chemists, physicians) collaborate to study all the aspects of drugs of abuse, especially NPS. Herein, we describe the multidisciplinary approach comprising liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), gas chromatography hyphenated to mass spectrometry (GC-MS) and solution nuclear magnetic resonance analysis that allowed the identification of three NPS such as 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 2-amino-1-(4-bromo-2,5-dimethoxyphenyl)ethan-1-one (bk-2C-B), and 3-(2-aminopropyl)indole (α-methyltryptamine) in seized materials.

Neuropsychiatric and General Interactions of Natural and Synthetic Cannabinoids with Drugs of Abuse and Medicines.

BACKGROUND & OBJECTIVE: Cannabis is the most widely used illicit drug. The two most important natural cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The THC content of cannabis has been increasing during the last years and recently appeared in the market as a series of synthetic cannabinoids with potent agonist activity. Recreational users frequently combine cannabis with other drugs of abuse as alcohol, amphetamines and derivatives, nicotine and cocaine. In addition, these subjects can be taking medicines for acute and chronic medical conditions. The increasing use of medicinal cannabis for chronic pain and neurological and psychiatric disorders can produce potential interactions with medications used for the symptomatic treatment of these or other diseases. CONCLUSION: THC and CBD are metabolized mainly in the liver by cytochrome P-450 isoenzymes (mainly CYP2Cs and CYP3A4). In vitro studies indicate that THC and CBD both inhibit CYP1A1, 1A2 and 1B1 enzymes, and recent studies have indicated that CBD is also a potent inhibitor of CYP2C19 and CYP3A4. Both cannabinoids may interact with other medications metabolized by the same pathway or by inducers/inhibitors of the isoenzymes. Cannabis produces sedation, impairs psychomotor performance, and increases blood pressure and heart rate. Pharmacodynamic interactions with other sedatives can potentiate the central effects but can be decreased by psychostimulants. This review focuses on the interactions between cannabinoids and alcohol, other drugs of abuse, and prescription medicines.

Synthetic Cannabinoids: Psychopharmacology, Clinical Aspects, Psychotic Onset.

BACKGROUND: Synthetic Cannabinoids (SC) are the widest and most diffused class of Novel Psychoactive Substances. The short- and long- term health risks associated with the consumption of SC are often unknown to both users and health professionals. This review aims to provide a synthesis of the most recent and relevant insights on the pharmacology, clinical and psychopathological aspects of SC. METHOD: A structured search of two bibliographic databases (PubMed and Scopus) was undertaken according to inclusion/exclusion criteria. The following terms "synthetic cannabinoid*", "synthetic cannabimimetic*", "synthetic cannabis", "synthetic marijuana" and "Spice AND cannabinoid*" were used as search strings. RESULTS: 162 relevant results, mainly published in the past two years were revealed. Most results emerged for the keyword "synthetic cannabinoid*", followed by the combination "Spice* AND "cannabinoid*". Most papers were epidemiological, forensic, toxicologic, or analytical. The results of studies were systematized according their contribution to the comprehension of pharmacological, clinical and psychopathological effects of SC. Fifteen SC-related fatality cases were reviewed according to their histories, pathology and toxicology findings. CONCLUSION: The findings of this review confirm the importance of prompt and reliable information available for health professionals More specific analytic techniques and designed preventive strategies are required to face unprecedented SC challenge.

The Isoxazole Ring and Its N-Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics.

Mental disorders are neuropsychiatric conditions that are marked by unusual or irregular thinking, feelings, or behavior, and lead to distress and/or impaired functions. Major psychiatric conditions are depression, anxiety, and psychoses of various types. Their etiopathogeneses, of a primary or secondary origin, are associated with genetic and environmental factors. They are commonly treated with psychoactive drugs (also known as psychotropics), which target serotonin, dopamine, norepinephrine, glutamate, and nuclear receptors (NRs), including retinoic acid receptor-related orphan receptors (RORs) and other receptors in the central nervous system (CNS). Herein we present a diverse array of isoxazole derivatives, among which are some prominent marketed drugs. Some of the derivatives and forms, including N-oxides, are under either (pre)clinical evaluation or patent protection as new generation of psychotropics, and a few have effective blood-brain barrier (BBB) permeability. Various drug-like isoxazol(in)es and their structural features and efficiency, modified through scaffold hopping, are described and discussed in the context of treating neuropsychiatric conditions.