Synthetic cannabinoid receptor agonists: classification and nomenclature.

Introduction: The emergence of novel psychoactive substances has changed the epidemiology of drugs used recreationally throughout Europe and have posed significant challenges for clinicians, researchers and regulators. Synthetic cannabinoid receptor agonists have made up a large proportion of these novel psychoactive substances. Developed for legitimate scientific research, synthetic cannabinoid receptor agonists are potent agonists at CB1 and CB2 receptors and there have been many case reports of severe or fatal toxicity following their recreational use. At least 180 analytically confirmed compounds belonging to this group of drugs have been reported in Europe as of January 2019. Synthetic cannabinoid receptor agonists have a complex molecular structure, consisting of four pharmacophore components termed the 'core', 'tail', 'linker' and 'linked' groups. This structural complexity offers multiple opportunities for chemical modification to evade drug control legislation based on chemical structure, and this explains the large numbers of individual products that have been detected.Objectives: To discuss the chemical structure of synthetic cannabinoid receptor agonists and to describe the different nomenclature used to identify individual compounds thereby increasing understanding of their chemical heterogenicity and the potential relevance of their molecular structure to the risk of toxicity.Methods: The European Database on New Drugs (EDND) and EMCDDA-Europol annual implementation reports (2010-2017) was searched for compounds with known agonist activity at CB1 and/or CB2 receptors. Information on the different names and chemical structures of each compound was extracted and analysed for patterns. PUBMED, Google Scholar and MEDLINE databases were searched, in addition to non-peer reviewed sources, for data on structure, structure-activity relationships and nomenclatures for each compound.Nomenclature of synthetic cannabinoid receptor agonists: The structural complexity of synthetic cannabinoid receptor agonists presents challenges for nomenclature. There are several nomenclature systems in use.Colloquial and clandestine names: Non-scientific names (e.g. AKB-48, 2NEI, XLR-11) have been used to refer to specific compounds and most have probably been invented by vendors, presumably for the purpose of successful marketing of recreational products, however such names do not convey useful information about structure.Systematic chemical names: Each compound has a systematic chemical name that describes its exact structure; however, it is complex, unwieldy, inaccessible to non-chemists and not suitable for routine communication or clinical use.Serial names: Represent iterative designations assigned to compounds produced as a series in a laboratory (e.g. 'WIN-', 'HU-', 'CP-', 'JWH-' and 'AM-'). This nomenclature does not provide structural information or reflect structural similarities between compounds.Systematic abbreviated names: Succinctly describe each compound utilising structural pharmacophores. The chemical motif in each pharmacophore group is assigned a unique code-letter and assembled into a name with the format of 'Linked Group - TailCoreLinker'. Frequently encountered groups include indole and indazole cores, amino-acid-like like groups, most notably methyl-3,3-dimethylbutanoate (MDMB), methanone linker groups and pentyl, 5-fluoropentyl and 4-fluorobenzyl tails. There has been inconsistent usage of this nomenclature, likely due to a lack of consensus and identification of code-letters for several chemical motifs.Emerging compounds and practices: Tricyclic carbazole and γ-carbolinone core analogues have been identified and may represent the next significant structural analogues to emerge onto the recreational market. There is a need to establish basic pharmacological and toxicological data for these analogues.Conclusions: There is a need for international consensus on the nomenclature used to name synthetic cannabinoid receptor agonists to ensure precise and effective communication between professional groups in the clinic and for the purposes of research and regulation, especially with the emergence of analogues of existing compounds and novel structural motifs. A well-defined nomenclature system also supports quick and accurate communication of the structure-activity of these compounds, potentially highlighting compounds that carry a significant risk of toxicity.

Drogas emergentes y de diseño: nuevos retos para la atención y cuidado de las drogodependencias / Emerging and synthetic drugs: new challenges for the attention and care of drug addictions

Introducción. Pese a que el consumo de drogas se remonta a tiempo inmemoriales, con la ilegalización de éstas están surgiendo sustancias con efectos similares aprovechando vacíos legales, donde la enfermera tiene un papel muy importante en el proceso de prevención, tratamiento y desintoxicación de las mismas. Objetivos. Analizar los grupos de drogas emergentes más relevantes según su popularidad y perjuicios para la salud. Metodología. Se realizó una búsque-da bibliográfica en CINAHL, Medline, Dialnet, Scielo, la biblioteca virtual de la Universidad de Huelva, Google Académico y en la web del Observatorio Español de Drogas y toxicomanías basada en las palabras claves: dro-gas, emergentes, emergencia, enfermera, adicciones, drogas de diseño, prehistoria, tratamiento, MDMA, bath salts, Flakka, Mefedrona, marihuana sintética, cannabinoides sintéticos, Kratom, Metoxetamina, Poppers, Salvia Divinorum, así como sus equiva-lentes en inglés. Resultados. Los cannabinoides sin-téticos son sustancias mucho más potentes que la marihuana. Las catinonas sintéticas o sales de baño suelen provocar efectos adversos varios y muy peligrosos, llegando a existir gran variedad de sales de baño. El kratom y la Salvia Divinorum son sustancias de origen vegetal provenientes de países tropicales en los que tradicionalmente se les ha dado uso terapéutico. En occidente se está consumiendo con fines de ocio. La metoxetamina es una droga que ha surgido para reemplazar a la ketamina, ya que no posee tantos efectos secundarios. Los poppers son sus-tancias volátiles que se suelen inhalar y suelen usarse a la hora de mantener relaciones sexuales. Conclusiones. Se necesita más investigación acerca de estas sustancias en continua evolución. El papel de la enfermera en el ámbito de las adicciones resulta fundamental para alcanzar resultados deseables

Introduction. Although Drug consumption dates back to time immemorial, nowadays, with the outlawing of these drugs, emerging substances with similar effects are taking advantage of legal gaps, where the nurse has an important role in the process of prevention, treatment and drug detoxification. Objectives. To analyze the most relevant emerging drug groups according to their popularity and health damages. Methodology. A bibliographic search was carried out in CINAHL, Medline, Dialnet, Scielo, the virtual library of the University of Huelva, Google Scholar and on the website of the Spanish Observatory of Drugs and Addiction, based on the keywords: drugs, emergencies, emergency, nurse, addictions, designer drugs, prehistory, treatment, MDMA, bath salts, Flakka, Mephedro-ne, synthetic marijuana, synthetic cannabinoids, Kratom, Methoxyethamine, Poppers, Salvia Divinorum. Results. Synthetic cannabinoids are much more potent substances than marijuana. Synthetic cathinones or bath salts usually cause several and very dangerous adverse effects, reaching to a wide variety of bath salts. Kratom and Salvia Divinorum are substances of vegetable origin from tropical countries, where they have been traditionally used for therapy. In the West it is being consumed for leisure purposes. Methoxetamine is a drug that has arisen to replace ketamine because it has not many secondary effects. Poppers are volatile substances that are usually inhaled and often used to have sex. Conclusions. More research is needed on these continually evolving substances. The role of the nurse in the field of addiction is essential to achieve desirable results

Schedules of Controlled Substances: Temporary Placement of N-Ethylpentylone in Schedule I. Temporary amendment; temporary scheduling order.

The Acting Administrator of the Drug Enforcement Administration is issuing this temporary scheduling order to schedule the synthetic cathinone, 1- (1,3-benzodioxol-5-yl)-2-(ethylamino)- pentan-1-one (N-ethylpentylone, ephylone) and its optical, positional, and geometric isomers, salts, and salts of isomers in schedule I. This action is based on a finding by the Acting Administrator that the placement of Nethylpentylone in schedule I of the Controlled Substances Act (CSA) is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle N-ethylpentylone.

Schedules of Controlled Substances: Temporary Placement of Acetyl Fentanyl Into Schedule I. Final order.

The Administrator of the Drug Enforcement Administration is issuing this final order to temporarily schedule the synthetic opioid, N-(1-phenethylpiperidin-4-yl)-N-phenylacetamide (acetyl fentanyl), and its optical, positional, and geometric isomers, salts and salts of isomers, into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act. This action is based on a finding by the Administrator that the placement of this opioid substance into schedule I of the Controlled Substances Act is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, import, export, engage in research, or possess), or propose to handle, acetyl fentanyl.

Schedules of controlled substances: temporary placement of 10 synthetic cathinones into Schedule I. Final order.

The Deputy Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule 10 synthetic cathinones into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act (CSA). The 10 substances are: 4-methyl-N-ethylcathinone (``4-MEC''); 4-methyl-alpha-pyrrolidinopropiophenone (``4-MePPP''); alpha-pyrrolidinopentiophenone (``[alpha]-PVP''); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butan-1-one (``butylone''); 2-(methylamino)-1-phenylpentan-1-one (``pentedrone''); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1-one (``pentylone''); 4-fluoro-N-methylcathinone (``4-FMC''); 3-fluoro-N-methylcathinone (``3-FMC''); 1-(naphthalen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one (``naphyrone''); and alpha-pyrrolidinobutiophenone (``[alpha]-PBP''). This action is based on a finding by the Deputy Administrator that the placement of these synthetic cathinones and their optical, positional, and geometric isomers, salts and salts of isomers into schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, import, export, engage in research, conduct instructional activities, and possess), or propose to handle these synthetic cathinones.

Enantiomeric separation of 13 new amphetamine-like designer drugs by capillary electrophoresis, using modified-B-cyclodextrins.

An easy-to-prepare chiral CE method for the enantiomeric separation of 13 new amphetamine-like designer drugs, using CDs as chiral selectors, was developed. Sulfated-ß-CD was found to be the best chiral selector among the three used (sulfated-ß-CD, caroboxymethyl-ß-CD, dimethyl-ß-CD). The separation of the analytes was achieved in a fused-silica gel capillary at 20 °C using an applied voltage of +25 kV. The optimized background electrolyte consisted of 63.5 mM H3 PO4 and 46.9 mM NaOH in water. Several electrophoretic parameters such as CD type, CD concentration (1 - 40 mg/mL), buffer pH (2.6, 3.6, 5.0, 6.0), length of the capillary (70 - 40 cm total length), amount of the organic solvent (methanol and acetonitrile) were investigated and optimized.

Substituted cathinone products: a new trend in "bath salts" and other designer stimulant drug use.

There is a growing concern about the availability of a new generation of "designer drug" stimulants that are marketed as "bath salts" and other household products. The products are not true bath salts and contain substituted cathinone stimulant substances, such as methylenedioxypyrovalerone (MDPV) and mephedrone. Calls to the American Association of Poison Control Centers regarding "bath salts" consumption began in 2010 and have continued since that time. Few reports of systematic epidemiologic surveillance or definitive clinical effects of toxicity specifically associated with "bath salts" consumption have been reported in the medical literature. The current narrative review describes the growing trend of designer substituted cathinone use, pharmacology, clinical effects, and recent regulatory changes. It is hoped that a greater understanding of the clinical effects and use patterns will help inform policy and practice.

Schedules of controlled substances: extension of temporary placement of methylone into schedule I of the Controlled Substances Act. Final order.

This Final Order is issued by the Administrator of the Drug Enforcement Administration (DEA) to extend the temporary scheduling of methylone (3,4-methylenedioxy-N-methylcathinone) including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible, into Schedule I of the Controlled Substances Act (CSA). The temporary scheduling of methylone is due to expire on October 20, 2012. This document will extend the temporary scheduling of methylone to April 20, 2013, or until rulemaking proceedings are completed, whichever occurs first.

Analysis of psychoactive and intoxicating substances in legal highs.

"Legal highs" known also as "smarts", "legal drugs" or "boosters" contain in their composition psychoactive substances the production, sale and possession of which are not prohibited in legislation. They are offered for sale under the cover of collectors' items, a salt bath, aroma sticks, or plant fertilizer. Marketing was the reason for such high sales of these "highs" in Poland. The phenomenon became of concern when information became available about the first cases of tragic health consequences. Raising the awareness of youth about the level of imminent danger and serious consequences associated with the use of legal highs may be a very effective way to develop appropriate attitudes of young people, and in the light of their own health can help them take proper life decisions."Legal highs" are substances of natural or synthetic origin having psychostimulating properties. These compounds may differ in chemical structure, potency, half-life, metabolism and severity of side effects. Their pharmacological activity is associated with changes in the neurotransmitter system. After higher doses of "legal highs" psychotic symptoms may occur: visual and auditory hallucinations resembling schizophrenic endogenous psychoses. An alarming fact is the underestimation of the adverse effect of these substances on human health. Any actions aimed at improving this situation are extremely important; therefore, in one of the key projects undertaken at the Institute of Rural Health in Lublin, in cooperation with other scientific institutes, concerned the analysis of a selected series of "legal highs". This research was meant top serve as a source of information for science and medicine, and for popularizing knowledge about legal highs.

Schedules of controlled substances: temporary placement of three synthetic cathinones in Schedule I. Final Order.

The Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule three synthetic cathinones under the Controlled Substances Act (CSA) pursuant to the temporary scheduling provisions of 21 U.S.C. 811(h). The substances are 4-methyl-N-methylcathinone (mephedrone), 3,4-methylenedioxy-N-methylcathinone (methylone), and 3,4-methylenedioxypyrovalerone (MDPV). This action is based on a finding by the Administrator that the placement of these synthetic cathinones and their salts, isomers, and salts of isomers into Schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the full effect of the CSA and its implementing regulations including criminal, civil and administrative penalties, sanctions and regulatory controls of Schedule I substances will be imposed on the manufacture, distribution, possession, importation, and exportation of these synthetic cathinones.

Clinical toxicology of newer recreational drugs.

INTRODUCTION: Novel synthetic 'designer' drugs with stimulant, ecstasy-like (entactogenic) and/or hallucinogenic properties have become increasingly popular among recreational drug users in recent years. The substances used change frequently in response to market trends and legislative controls and it is an important challenge for poisons centres and clinical toxicologists to remain updated on the pharmacological and toxicological effects of these emerging agents. AIMS: To review the available information on newer synthetic stimulant, entactogenic and hallucinogenic drugs, provide a framework for classification of these drugs based on chemical structure and describe their pharmacology and clinical toxicology. METHODS: A comprehensive review of the published literature was performed using PUBMED and Medline databases, together with additional non-peer reviewed information sources, including books, media reports, government publications and internet resources, including drug user web forums. EPIDEMIOLOGY: Novel synthetic stimulant, entactogenic or hallucinogenic designer drugs are increasingly available to users as demonstrated by user surveys, poisons centre calls, activity on internet drug forums, hospital attendance data and mortality data. Some population sub groups such as younger adults who attend dance music clubs are more likely to use these substances. The internet plays an important role in determining the awareness of and availability of these newer drugs of abuse. CLASSIFICATION: Most novel synthetic stimulant, entactogenic or hallucinogenic drugs of abuse can be classified according to chemical structure as piperazines (e.g. benzylpiperazine (BZP), trifluoromethylphenylpiperazine), phenethylamines (e.g. 2C or D-series of ring-substituted amfetamines, benzodifurans, cathinones, aminoindans), tryptamines (e.g. dimethyltryptamine, alpha-methyltryptamine, ethyltryptamine, 5-methoxy-alphamethyltryptamine) or piperidines and related substances (e.g. desoxypipradrol, diphenylprolinol). Alternatively classification may be based on clinical effects as either primarily stimulant, entactogenic or hallucinogenic, although most drugs have a combination of such effects. CLINICAL TOXICOLOGY: Piperazines, phenethylamines, tryptamines and piperidines have actions at multiple central nervous system (CNS) receptor sites, with patterns of effects varying between agents. Predominantly stimulant drugs (e.g. benzylpiperazine, mephedrone, naphyrone, diphenylprolinol) inhibit monoamine (especially dopamine) reuptake and are characteristically associated with a sympathomimetic toxidrome. Entactogenic drugs (e.g. phenylpiperazines, methylone) provoke central serotonin release, while newer hallucinogens (e.g. 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 2,5-dimethoxy-4-bromoamfetamine (DOB)) are serotonin receptor agonists. As a result, serotoninergic effects predominate in toxicity. CONCLUSIONS: There are limited reliable data to guide clinicians managing patients with toxicity due to these substances. The harms associated with emerging recreational drugs are not fully documented, although it is clear that they are not without risk. Management of users with acute toxic effects is pragmatic and primarily extrapolated from experience with longer established stimulant or hallucinogenic drugs such as amfetamines, 3,4-methylenedioxymethamfetamine (MDMA) and lysergic acid diethylamide (LSD).

Legal highs - legal aspects and legislative solutions.

In recent years the attention of society, the media and politicians has focused on the negative phenomenon of the occurrence of an enormous amount of new psychoactive substances flooding the European market. In Poland and in Europe they are known under the name 'legal highs' or 'smart drugs'. In many countries these compounds present a serious social and health problem. The core of the problem is the fact that in the light of the law these substances are legal, while actually they imitate the eff ect of illegal narcotics. Smart drugs are sold allegedly as 'products not intended for human consumption', under the cover of 'collector's commodities', 'incense sticks' or 'bath salts'. Efforts undertaken by many countries, including Poland, are biased towards gaining control over this pathological phenomenon by placing the subsequent substances on the list of prohibited agents. However, the resilient chemical and pharmaceutical industry still remains one step ahead by introducing new derivatives of already banned products, practically identical in action. The presented article is an attempt to bring closer the problem of smart drugs in Poland, from the occurrence of this alarming phenomenon, through the spread of sales in shops all over Poland, to a series of changes in the Polish anti-narcotic law, drastic actions of closing the shops throughout the entire country, and transferring the sale of smart drugs to the internet.

Bioanalysis of new designer drugs.

Since the late 1990s the illicit drug market has undergone considerable change: along with the traditional drugs of abuse that still dominate, more than 100 psychotropic substances designed to bypass controlled substances legislation have appeared and led to intoxications and fatalities. Starting from the huge class of phenylalkylamines, containing many subgroups, the spectrum of structures has grown from tryptamines, piperazines, phenylcyclohexyl derivates and pyrrolidinophenones to synthetic cannabinoids and the first synthetic cocaine. Due to the small prevalence and high number of unknown substances, the detection of new designer drugs is a challenge for clinical and forensic toxicologists. Standard screening procedures might fail because a recently discovered or yet unknown substance has not been incorporated in the library used. Nevertheless, many metabolism studies, case reports, screening methods and substance-profiling papers concentrating on single compounds have been published. This review provides an overview of the developed bioanalytical and analytical methods, the matrices used, sample-preparation procedures, concentration of analytes in case of intoxication and also gives a résumé of immunoassay experiences. Additionally, six screening methods for biological matrices with a larger spectrum of analytes are described in more detail.

Producción científica nacional e internacional en drogas de diseño (1988-1997) / National and International scientific production on designer drugs (1988-1997)

Introducción: El conocimiento de las fuentes de información científica es imprescindible para el abordaje del problema del consumo de drogas de diseño. El objetivo de este trabajo es analizar la producción científica nacional e internacional sobre esta conducta, a partir del análisis bibliométrico de las publicaciones. Material y método: La producción científica sobre drogas de diseño se ha obtenido de las bases de datos IME, MEDLINE, ISOC y teseo durante el período 1988-1997. También se revisaron las referencias bibliográficas de los artículos recuperados en la base de datos IME. Los artículos obtenidos se distribuyeron por años, tipo documental, revista de publicación y temática, instituciones y países de procedencia, idiomas y temas tratados. Resultados: En las revistas españolas se publicaron 34 artículos y en las extranjeras 2.181. Los principales aspectos tratados se refieren a la toxicidad, concepto y clasificación y actividad farmacológica de las drogas de diseño. Las áreas temáticas más productivas son la neuropsiquiatría, la farmacología y la medicina general e interna. Conclusiones: El análisis muestra que existen escasos estudios experimentales y epidemiológicos publicados en España. Las revistas son de drogodependencias, temática general, neuropsiquiatría y farmacología, lo que pone de relieve la multidisciplinariedad de esta conducta adictiva. Predominan los estudios sobre la 1-metil-4-fenil-1,2,3,6-tetrahidropiridina y los análogos y derivados de la MDMA (AU)

'Designer drugs'. Treating the damage caused by basement chemists.

Use of "designer drugs" has created a new dilemma for physicians. Generally, it is possible to recognize symptoms and signs of intoxication that fit a specific class of substances, such as amphetamine-like effects for the phenylethylamines and opioid effects for the fentanyl analogues. Designer compounds have crossed these boundaries, and toxicology laboratories cannot readily identify them. For now, physicians must rely on clinical presentation and treat accordingly.

Substance abuse: the designer drugs.

Designer drugs, chemically altered compounds derived from federally controlled substances, have become a major cause of addiction and overdose deaths. These drugs include mescaline analogs, synthetic opioids, arylhexylamines, methaqualone derivatives and crack, a new form of cocaine. Sudden changes in mood, weight loss, depression, disturbed sleep patterns, deteriorating school or work performance, marital problems, and loss of interest in friends and social activities may be signs of drug addiction. Life-threatening complications of acute intoxication, such as hyperthermia, seizures, combative and psychotic behavior, and cardiorespiratory collapse, require prompt diagnosis and supportive intervention.