New Psychoactive Substances - Metabolism and Metabolomics

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: closed (30 December 2020) | Viewed by 23837

Special Issue Editor

Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, Germany
Interests: hyphenated mass spectrometry; drugs of abuse; new psychoactive substances; toxicokinetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

New psychoactive substances (NPS) are – according to the WHO - “substances of abuse, …, that are not controlled by the 1961 Single Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but which may pose a public health threat. The term “new” does not necessarily refer to new inventions — several NPS were first synthesized 40 years ago — but to substances that have recently become available on the market.” An NPS intake can lead to serious unwanted effects such as arrythmia, seizures, or acute psychosis. There are usually no toxicodynamic and toxicokinetic data including long-term effects available.

This Special Issue of Metabolites, "New Psychoactive Substances - Metabolism and Metabolomics", will be dedicated to studies, new analytical techniques, and innovations dealing with the elucidation of the NPS toxicometabolomics. This means metabolism of NPS, besides answering related metabolomics questions. Specific areas include, but are not limited to, the identification of NPS biomarkers of exposure e.g. in the context of clinical and forensic toxicology and doping control.

Prof. Markus R. Meyer
Guest Editor

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Keywords

  • new psychoactive substances
  • metabolomics
  • metabolism
  • toxicometabolomics
  • analytical toxicology

Published Papers (8 papers)

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Research

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18 pages, 840 KiB  
Article
25CN-NBOMe Metabolites in Rat Urine, Human Liver Microsomes and C. elegans—Structure Determination and Synthesis of the Most Abundant Metabolites
by Anna Šuláková, Jitka Nykodemová, Petr Palivec, Radek Jurok, Silvie Rimpelová, Tereza Leonhardt, Klára Šíchová, Tomáš Páleníček and Martin Kuchař
Metabolites 2021, 11(4), 212; https://doi.org/10.3390/metabo11040212 - 31 Mar 2021
Cited by 9 | Viewed by 2778
Abstract
N-Benzylphenethylamines are novel psychedelic substances increasingly used for research, diagnostic, or recreational purposes. To date, only a few metabolism studies have been conducted for N-2-methoxybenzylated compounds (NBOMes). Thus, the available 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) metabolism data are limited. Herein, we investigated the metabolic [...] Read more.
N-Benzylphenethylamines are novel psychedelic substances increasingly used for research, diagnostic, or recreational purposes. To date, only a few metabolism studies have been conducted for N-2-methoxybenzylated compounds (NBOMes). Thus, the available 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) metabolism data are limited. Herein, we investigated the metabolic profile of 25CN-NBOMe in vivo in rats and in vitro in Cunninghamella elegans (C. elegans) mycelium and human liver microsomes. Phase I and phase II metabolites were first detected in an untargeted screening, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification of the most abundant metabolites by comparison with in-house synthesized reference materials. The major metabolic pathways described within this study (mono- and bis-O-demethylation, hydroxylation at different positions, and combinations thereof, followed by the glucuronidation, sulfation, and/or N-acetylation of primary metabolites) generally correspond to the results of previously reported metabolism of several other NBOMes. The cyano functional group was either hydrolyzed to the respective amide or carboxylic acid or remained untouched. Differences between species should be taken into account in studies of the metabolism of novel substances. Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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21 pages, 9250 KiB  
Article
Untargeted Metabolic Profiling of 4-Fluoro-Furanylfentanyl and Isobutyrylfentanyl in Mouse Hepatocytes and Urine by Means of LC-HRMS
by Camilla Montesano, Flaminia Vincenti, Federico Fanti, Matteo Marti, Sabrine Bilel, Anna Rita Togna, Adolfo Gregori, Fabiana Di Rosa and Manuel Sergi
Metabolites 2021, 11(2), 97; https://doi.org/10.3390/metabo11020097 - 10 Feb 2021
Cited by 5 | Viewed by 2438
Abstract
The diffusion of new psychoactive substances (NPS) is highly dynamic and the available substances change over time, resulting in forensic laboratories becoming highly engaged in NPS control. In order to manage NPS diffusion, efficient and innovative legal responses have been provided by several [...] Read more.
The diffusion of new psychoactive substances (NPS) is highly dynamic and the available substances change over time, resulting in forensic laboratories becoming highly engaged in NPS control. In order to manage NPS diffusion, efficient and innovative legal responses have been provided by several nations. Metabolic profiling is also part of the analytical fight against NPS, since it allows to identify the biomarkers of drug intake which are needed for the development of suitable analytical methods in biological samples. We have recently reported the characterization of two new analogs of fentanyl, i.e., 4-fluoro-furanylfentanyl (4F-FUF) and isobutyrylfentanyl (iBF), which were found for the first time in Italy in 2019; 4F-FUF was identified for the first time in Europe and was notified to the European Early Warning System. The goal of this study was the characterization of the main metabolites of both drugs by in vitro and in vivo experiments. To this end, incubation with mouse hepatocytes and intraperitoneal administration to mice were carried out. Samples were analyzed by means of liquid chromatography-high resolution mass spectrometry (LC–HRMS), followed by untargeted data evaluation using Compound Discoverer software with a specific workflow, designed for the identification of the whole metabolic pattern, including unexpected metabolites. Twenty metabolites were putatively annotated for 4F-FUF, with the dihydrodiol derivative appearing as the most abundant, whereas 22 metabolites were found for iBF, which was mainly excreted as nor-isobutyrylfentanyl. N-dealkylation of 4F-FUF dihydrodiol and oxidation to carbonyl metabolites for iBF were also major biotransformations. Despite some differences, in general there was a good agreement between in vitro and in vivo samples. Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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12 pages, 2493 KiB  
Article
Investigation of Biotransformation Products of p-Methoxymethylamphetamine and Dihydromephedrone in Wastewater by High-Resolution Mass Spectrometry
by Juliet Kinyua, Aikaterini K. Psoma, Nikolaos I. Rousis, Maria-Christina Nika, Adrian Covaci, Alexander L. N. van Nuijs and Νikolaos S. Τhomaidis
Metabolites 2021, 11(2), 66; https://doi.org/10.3390/metabo11020066 - 25 Jan 2021
Cited by 6 | Viewed by 2404
Abstract
There is a paucity of information on biotransformation and stability of new psychoactive substances (NPS) in wastewater. Moreover, the fate of NPS and their transformation products (TPs) in wastewater treatment plants is not well understood. In this study, batch reactors seeded with activated [...] Read more.
There is a paucity of information on biotransformation and stability of new psychoactive substances (NPS) in wastewater. Moreover, the fate of NPS and their transformation products (TPs) in wastewater treatment plants is not well understood. In this study, batch reactors seeded with activated sludge were set up to evaluate biotic, abiotic, and sorption losses of p-methoxymethylamphetamine (PMMA) and dihydromephedrone (DHM) and identify TPs formed during these processes. Detection and identification of all compounds was performed with target and suspect screening approaches using liquid chromatography quadrupole-time-of-flight mass spectrometry. Influent and effluent 24 h composite wastewater samples were collected from Athens from 2014 to 2020. High elimination rates were found for PMMA (80%) and DHM (97%) after a seven-day experiment and degradation appeared to be related to biological activity in the active bioreactor. Ten TPs were identified and the main reactions were O- and N-demethylation, oxidation, and hydroxylation. Some TPs were reported for the first time and some were confirmed by reference standards. Identification of some TPs was enhanced by the use of an in-house retention time prediction model. Mephedrone and some of its previously reported human metabolites were formed from DHM incubation. Retrospective analysis showed that PMMA was the most frequently detected compound. Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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14 pages, 2366 KiB  
Article
Liquid Chromatography-High-Resolution Mass Spectrometry-Based In Vitro Toxicometabolomics of the Synthetic Cathinones 4-MPD and 4-MEAP in Pooled Human Liver Microsomes
by Sascha K. Manier, Florian Schwermer, Lea Wagmann, Niels Eckstein and Markus R. Meyer
Metabolites 2021, 11(1), 3; https://doi.org/10.3390/metabo11010003 - 23 Dec 2020
Cited by 10 | Viewed by 2169
Abstract
Synthetic cathinones belong to the most often seized new psychoactive substances on an international level. This study investigated the toxicometabolomics, particularly the in vitro metabolism of 2-(methylamino)-1-(4-methylphenyl)-1-pentanone (4-MPD) and 2-(ethylamino)-1-(4-methylphenyl)-1-pentanone (4-MEAP) in pooled human liver microsomes (pHLM) using untargeted metabolomics techniques. Incubations were [...] Read more.
Synthetic cathinones belong to the most often seized new psychoactive substances on an international level. This study investigated the toxicometabolomics, particularly the in vitro metabolism of 2-(methylamino)-1-(4-methylphenyl)-1-pentanone (4-MPD) and 2-(ethylamino)-1-(4-methylphenyl)-1-pentanone (4-MEAP) in pooled human liver microsomes (pHLM) using untargeted metabolomics techniques. Incubations were performed with the substrates in concentrations ranging from 0, 12.5, and 25 µM. Analysis was done by means of high-performance liquid chromatography coupled to high-resolution mass spectrometry (HPLC-HRMS/MS) in full scan only and the obtained data was evaluated using XCMS Online and MetaboAnalyst. Significant features were putatively identified using a separate parallel reaction monitoring method. Statistical analysis was performed using Kruskal-Wallis test for prefiltering significant features and subsequent hierarchical clustering, as well as principal component analysis (PCA). Hierarchical clustering or PCA showed a distinct clustering of all concentrations with most of the features z-scores rising with the concentration of the investigated substances. Identification of significant features left many of them unidentified but revealed metabolites of both 4-MPD and 4-MEAP. Both substances formed carboxylic acids, were hydroxylated at the alkyl chain, and formed metabolites after combined hydroxylation and reduction of the cathinone oxo group. 4-MPD additionally formed a dihydroxy metabolite and a hydroxylamine. 4-MEAP was additionally found reduced at the cathinone oxo group, N-dealkylated, and formed an oxo metabolite. These findings are the first to describe the metabolic pathways of 4-MPD and to extend our knowledge about the metabolism of 4-MEAP. Findings, particularly the MS data of the metabolites, are essential for setting up metabolite-based toxicological (urine) screening procedures. Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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15 pages, 2070 KiB  
Article
Comparison of Three Untargeted Data Processing Workflows for Evaluating LC-HRMS Metabolomics Data
by Selina Hemmer, Sascha K. Manier, Svenja Fischmann, Folker Westphal, Lea Wagmann and Markus R. Meyer
Metabolites 2020, 10(9), 378; https://doi.org/10.3390/metabo10090378 - 21 Sep 2020
Cited by 17 | Viewed by 4617
Abstract
The evaluation of liquid chromatography high-resolution mass spectrometry (LC-HRMS) raw data is a crucial step in untargeted metabolomics studies to minimize false positive findings. A variety of commercial or open source software solutions are available for such data processing. This study aims to [...] Read more.
The evaluation of liquid chromatography high-resolution mass spectrometry (LC-HRMS) raw data is a crucial step in untargeted metabolomics studies to minimize false positive findings. A variety of commercial or open source software solutions are available for such data processing. This study aims to compare three different data processing workflows (Compound Discoverer 3.1, XCMS Online combined with MetaboAnalyst 4.0, and a manually programmed tool using R) to investigate LC-HRMS data of an untargeted metabolomics study. Simple but highly standardized datasets for evaluation were prepared by incubating pHLM (pooled human liver microsomes) with the synthetic cannabinoid A-CHMINACA. LC-HRMS analysis was performed using normal- and reversed-phase chromatography followed by full scan MS in positive and negative mode. MS/MS spectra of significant features were subsequently recorded in a separate run. The outcome of each workflow was evaluated by its number of significant features, peak shape quality, and the results of the multivariate statistics. Compound Discoverer as an all-in-one solution is characterized by its ease of use and seems, therefore, suitable for simple and small metabolomic studies. The two open source solutions allowed extensive customization but particularly, in the case of R, made advanced programming skills necessary. Nevertheless, both provided high flexibility and may be suitable for more complex studies and questions. Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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20 pages, 2300 KiB  
Article
Comparative Untargeted Metabolomics Analysis of the Psychostimulants 3,4-Methylenedioxy-Methamphetamine (MDMA), Amphetamine, and the Novel Psychoactive Substance Mephedrone after Controlled Drug Administration to Humans
by Andrea E. Steuer, Daria Kaelin, Martina I. Boxler, Lisa Eisenbeiss, Friederike Holze, Patrick Vizeli, Joanna Czerwinska, Paul I. Dargan, Vincenzo Abbate, Matthias E. Liechti and Thomas Kraemer
Metabolites 2020, 10(8), 306; https://doi.org/10.3390/metabo10080306 - 27 Jul 2020
Cited by 17 | Viewed by 4330
Abstract
Psychoactive stimulants are a popular drug class which are used recreationally. Over the last decade, large numbers of new psychoactive substances (NPS) have entered the drug market and these pose a worldwide problem to human health. Metabolomics approaches are useful tools for simultaneous [...] Read more.
Psychoactive stimulants are a popular drug class which are used recreationally. Over the last decade, large numbers of new psychoactive substances (NPS) have entered the drug market and these pose a worldwide problem to human health. Metabolomics approaches are useful tools for simultaneous detection of endogenous metabolites affected by drug use. They allow identification of pathways or characteristic metabolites, which might support the understanding of pharmacological actions or act as indirect biomarkers of consumption behavior or analytical detectability. Herein, we performed a comparative metabolic profiling of three psychoactive stimulant drugs 3,4-methylenedioxymethamphetamine (MDMA), amphetamine and the NPS mephedrone by liquid chromatography-high resolution mass spectrometry (LC-HRMS) in order to identify common pathways or compounds. Plasma samples were obtained from controlled administration studies to humans. Various metabolites were identified as increased or decreased based on drug intake, mainly belonging to energy metabolism, steroid biosynthesis and amino acids. Linoleic acid and pregnenolone-sulfate changed similarly in response to intake of all drugs. Overall, mephedrone produced a profile more similar to that of amphetamine than MDMA in terms of affected energy metabolism. These data can provide the basis for further in-depth targeted metabolome studies on pharmacological actions and search for biomarkers of drug use. Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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Review

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14 pages, 999 KiB  
Review
Metabolic Alterations Associated with γ-Hydroxybutyric Acid and the Potential of Metabolites as Biomarkers of Its Exposure
by Suryun Jung, Suji Kim, Yujin Seo and Sooyeun Lee
Metabolites 2021, 11(2), 101; https://doi.org/10.3390/metabo11020101 - 10 Feb 2021
Cited by 9 | Viewed by 2934
Abstract
γ-Hydroxybutyric acid (GHB) is an endogenous short chain fatty acid that acts as a neurotransmitter and neuromodulator in the mammalian brain. It has often been illegally abused or misused due to its strong anesthetic effect, particularly in drug-facilitated crimes worldwide. However, proving its [...] Read more.
γ-Hydroxybutyric acid (GHB) is an endogenous short chain fatty acid that acts as a neurotransmitter and neuromodulator in the mammalian brain. It has often been illegally abused or misused due to its strong anesthetic effect, particularly in drug-facilitated crimes worldwide. However, proving its ingestion is not straightforward because of the difficulty in distinguishing between endogenous and exogenous GHB, as well as its rapid metabolism. Metabolomics and metabolism studies have recently been used to identify potential biomarkers of GHB exposure. This mini-review provides an overview of GHB-associated metabolic alterations and explores the potential of metabolites for application as biomarkers of GHB exposure. For this, we discuss the biosynthesis and metabolism of GHB, analytical issues of GHB in biological samples, alterations in metabolic pathways, and changes in the levels of GHB conjugates in biological samples from animal and human studies. Metabolic alterations in organic acids, amino acids, and polyamines in urine enable discrimination between GHB-ingested animals or humans and controls. The potential of GHB conjugates has been investigated in a variety of clinical settings. Despite the recent growth in the application of metabolomics and metabolism studies associated with GHB exposure, it remains challenging to distinguish between endogenous and exogenous GHB. This review highlights the significance of further metabolomics and metabolism studies for the discovery of practical peripheral biomarkers of GHB exposure. Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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1 pages, 150 KiB  
Addendum
Addendum: Hemmer, S., et al. Comparison of Three Untargeted Data Processing Workflows for Evaluating LC-HRMS Metabolomics Data. Metabolites 2020, 10, 378
by Selina Hemmer, Sascha K. Manier, Svenja Fischmann, Folker Westphal, Lea Wagmann and Markus R. Meyer
Metabolites 2020, 10(11), 432; https://doi.org/10.3390/metabo10110432 - 27 Oct 2020
Viewed by 1309
Abstract
The authors wish to make the following comment to this paper [...] Full article
(This article belongs to the Special Issue New Psychoactive Substances - Metabolism and Metabolomics)
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