Abstract:During 2012–2018, the clandestine manufacture of new psychoactive substances (NPS) designed to circumvent substance control regulations increased exponentially worldwide, with concomitant increase in fatalities. This review focuses on three compound classes identified as synthetic opioids, synthetic amphetamines, and synthetic cannabinoids and highlights the medicinal chemistry precedents utilized by clandestine laboratories to develop new NPS with increased brain penetration, longer duration of action, and gr… Show more
“…Isotonitazene is structurally related to etonitazene, an opioid investigated for its analgesic properties but ultimately internationally controlled because of health threats ( 341 , 342 ). Isotonitazene was first developed in 1957 and later emerged on the illicit opioid market in 2019, likely in response to fentanyl analogue core-structure scheduling ( 343 ).…”
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.
“…Isotonitazene is structurally related to etonitazene, an opioid investigated for its analgesic properties but ultimately internationally controlled because of health threats ( 341 , 342 ). Isotonitazene was first developed in 1957 and later emerged on the illicit opioid market in 2019, likely in response to fentanyl analogue core-structure scheduling ( 343 ).…”
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.
“…Over the last few decades, we have witnessed a growing commodification of psychoactive substances, including a diverse range of new chemical entities not controlled under drug laws. During a time of increasing legalization and use of medicinal and recreational cannabis and cannabinoid concentrates, a concurrent drug phenomenon has become largely defined by both the growing number of novel synthetic chemicals being detected from increasingly broad chemical and pharmacological families and the open sale of many of these substances as ‘legal highs’, ‘bath salts’, or ‘research chemicals’ in commercial venues and online shops, as well as by individual street-level drug dealers [ 103 , 104 ]. Over 400 new psychoactive substances were detected in Europe’s drug market in 2019, with extremely potent synthetic cannabimimetics, cathinones, arylcyclohexylamines, and opioids being the most prevalent classes of compounds posing significant health and social impact concerns.…”
Section: The Ultimate Diversion Of Cannabimimetic Indoles: Spice/k2mentioning
The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines.
“…7 ), we identified as many as 16 of them with a long (> ethyl) alkyl side chain at the α position, 4 of them with an isobutyl chain, 1 with a phenyl ring, 1 with a cyclohexyl ring and only the remaining 7 derivatives with short alkyl side chains: 4 with a methyl chain and 3 with an ethyl chain. These finding indicate that the trend of synthesizing derivatives with long, extended side chains is continuing and for several years now most of the newly formed derivatives have had such long side chains [ 106 – 108 ]. Fig.…”
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.
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