ijms-logo

Journal Browser

Journal Browser

Molecular Insights of New Psychoactive Substances (NPS)

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (25 June 2021) | Viewed by 31999

Special Issue Editors

Department of Excellence of Biomedical Sciences and Public Health, University Politecnica delle Marche, 60121 Ancona, Italy
Interests: toxicology; forensic toxicology; drugs of abuse; legal medicine; hepatotoxicity
Special Issues, Collections and Topics in MDPI journals
National Centre on Addiction and Doping, National Institute of Health, 00161 Rome, Italy
Interests: clinical pharmacotoxicology; forensic pharmacotoxicology; psychoactive substances; doping agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

To date, more than 800 molecules are classified as New Psychoactive Substances (NPS) and it is reported that every year this number increases. The main chemical classes of substances illicitly commercialized are aminoidanes, synthetic cannabinoids, synthetic cathinones, phencyclidine type substances, piperazines, and tryptamines. Nevertheless, fentanyl analogues represent an increasing alarm for the public health due to the number of fatalities reported and the increasing rate of overdose cases related to their abuse.

To document exposure to NPSs, clinical and forensic toxicologists have been aiming at detecting their metabolites, which can be detected for a much longer time. However, new NPSs are emerging every year onto the drug market, and their pharmacokinetic properties are unknown when they first appear. The objective of this Special Issue is to collect original and review articles to provide the most updated molecular knowledge in the field of NPS.

Suggested topics include, but are not limited to:

  • Identification of prevailing metabolites of specific last-generation NPSs in humans to determine the best markers of exposure
  • Studies of incubation of NPS with human hepatocytes to simulate in vivo metabolism
  • Development and validation of analytical methods for the identification and quantification of NPS in conventional and non-conventional biological matrices
  • Studies and updated reviews on NPS-related toxicity
  • Metabolic pathways of new synthetic opioids

Prof. Dr. Francesco P. Busardó
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • New Psychoactive Substances (NPS)
  • new synthetic opioids
  • Liquid chromatography-high resolution mass spectrometry (LC-HRMS/MS)
  • Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS)
  • NPS-related toxicity

Published Papers (8 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

3 pages, 198 KiB  
Editorial
Molecular Insights on New Psychoactive Substances (NPSs)
by Francesco Paolo Busardò and Simona Pichini
Int. J. Mol. Sci. 2022, 23(6), 3282; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063282 - 18 Mar 2022
Cited by 6 | Viewed by 1401
Abstract
Currently, more than 1000 molecules have been classified as New Psychoactive Substances (NPSs), and it is reported that, every year, this number increases with new classes of compounds and/or newer generations of NPS families [...] Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS))

Research

Jump to: Editorial, Review

16 pages, 2844 KiB  
Article
The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative
by Karolina E. Kolaczynska, Jan Thomann, Marius C. Hoener and Matthias E. Liechti
Int. J. Mol. Sci. 2021, 22(15), 8277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158277 - 31 Jul 2021
Cited by 16 | Viewed by 3598
Abstract
Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and [...] Read more.
Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. All pyrovalerone cathinones were potent DAT (IC50 = 0.02–8.7 μM) and NET inhibitors (IC50 = 0.03–4.6 μM), and exhibited no SERT activity at concentrations < 10 μM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC50 = 0.17–0.18 μM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264–356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS))
Show Figures

Figure 1

20 pages, 2384 KiB  
Article
Human Neuronal Cell Lines as An In Vitro Toxicological Tool for the Evaluation of Novel Psychoactive Substances
by Valeria Sogos, Paola Caria, Clara Porcedda, Rafaela Mostallino, Franca Piras, Cristina Miliano, Maria Antonietta De Luca and M. Paola Castelli
Int. J. Mol. Sci. 2021, 22(13), 6785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136785 - 24 Jun 2021
Cited by 9 | Viewed by 3304
Abstract
Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing [...] Read more.
Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4′-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS))
Show Figures

Figure 1

14 pages, 3907 KiB  
Article
Evaluation of Cytotoxic and Mutagenic Effects of the Synthetic Cathinones Mexedrone, α-PVP and α-PHP
by Monia Lenzi, Veronica Cocchi, Sofia Gasperini, Raffaella Arfè, Matteo Marti and Patrizia Hrelia
Int. J. Mol. Sci. 2021, 22(12), 6320; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126320 - 12 Jun 2021
Cited by 12 | Viewed by 2098
Abstract
Mexedrone, α-PVP and α-PHP are synthetic cathinones. They can be considered amphetamine-like substances with a stimulating effect. Actually, studies showing their impact on DNA are totally absent. Therefore, in order to fill this gap, aim of the present work was to evaluate their [...] Read more.
Mexedrone, α-PVP and α-PHP are synthetic cathinones. They can be considered amphetamine-like substances with a stimulating effect. Actually, studies showing their impact on DNA are totally absent. Therefore, in order to fill this gap, aim of the present work was to evaluate their mutagenicity on TK6 cells. On the basis of cytotoxicity and cytostasis results, we selected the concentrations (35–100 µM) to be used in the further analysis. We used the micronucleus (MN) as indicator of genetic damage and analyzed the MNi frequency fold increase by flow cytometry. Mexedrone demonstrated its mutagenic potential contrary to the other two compounds; we then proceeded by repeating the analyzes in the presence of extrinsic metabolic activation in order to check if it was possible to totally exclude the mutagenic capacity for α-PVP and α-PHP. The results demonstrated instead the mutagenicity of their metabolites. We then evaluated reactive oxygen species (ROS) induction as a possible mechanism at the basis of the highlighted effects but the results did not show a statistically significant increase in ROS levels for any of the tested substances. Anyway, our outcomes emphasize the importance of mutagenicity evaluation for a complete assessment of the risk associated with synthetic cathinones exposure. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS))
Show Figures

Figure 1

21 pages, 1901 KiB  
Article
Ultra-High Performance Liquid Chromatography-High Resolution Mass Spectrometry and High-Sensitivity Gas Chromatography-Mass Spectrometry Screening of Classic Drugs and New Psychoactive Substances and Metabolites in Urine of Consumers
by Emilia Marchei, Maria Alias Ferri, Marta Torrens, Magí Farré, Roberta Pacifici, Simona Pichini and Manuela Pellegrini
Int. J. Mol. Sci. 2021, 22(8), 4000; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084000 - 13 Apr 2021
Cited by 17 | Viewed by 3391
Abstract
The use of the new psychoactive substances is continuously growing and the implementation of accurate and sensible analysis in biological matrices of users is relevant and fundamental for clinical and forensic purposes. Two different analytical technologies, high-sensitivity gas chromatography-mass spectrometry (GC-MS) and ultra-high-performance [...] Read more.
The use of the new psychoactive substances is continuously growing and the implementation of accurate and sensible analysis in biological matrices of users is relevant and fundamental for clinical and forensic purposes. Two different analytical technologies, high-sensitivity gas chromatography-mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) were used for a screening analysis of classic drugs and new psychoactive substances and their metabolites in urine of formed heroin addicts under methadone maintenance therapy. Sample preparation involved a liquid-liquid extraction. The UHPLC-HRMS method included Accucore™ phenyl Hexyl (100 × 2.1 mm, 2.6 μm, Thermo, USA) column with a gradient mobile phase consisting of mobile phase A (ammonium formate 2 mM in water, 0.1% formic acid) and mobile phase B (ammonium formate 2 mM in methanol/acetonitrile 50:50 (v/v), 0.1% formic acid) and a full-scan data-dependent MS2 (ddMS2) mode for substances identification (mass range 100–1000 m/z). The GC-MS method employed an ultra-Inert Intuvo GC column (HP-5MS UI, 30 m, 250 µm i.d, film thickness 0.25 µm; Agilent Technologies, Santa Clara, CA, USA) and electron-impact (EI) mass spectra were recorded in total ion monitoring mode (scan range 40–550 m/z). Urine samples from 296 patients with a history of opioid use disorder were examined. Around 80 different psychoactive substances and/or metabolites were identified, being methadone and metabolites the most prevalent ones. The possibility to screen for a huge number of psychotropic substances can be useful in suspected drug related fatalities or acute intoxication/exposure occurring in emergency departments and drug addiction services. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS))
Show Figures

Figure 1

17 pages, 2802 KiB  
Article
Pyrrolidinyl Synthetic Cathinones α-PHP and 4F-α-PVP Metabolite Profiling Using Human Hepatocyte Incubations
by Jeremy Carlier, Xingxing Diao, Raffaele Giorgetti, Francesco P. Busardò and Marilyn A. Huestis
Int. J. Mol. Sci. 2021, 22(1), 230; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010230 - 28 Dec 2020
Cited by 14 | Viewed by 2798
Abstract
For more than ten years, new synthetic cathinones (SCs) mimicking the effects of controlled cocaine-like stimulants have flooded the illegal drug market, causing numerous intoxications and fatalities. There are often no data on the pharmacokinetics of these substances when they first emerge onto [...] Read more.
For more than ten years, new synthetic cathinones (SCs) mimicking the effects of controlled cocaine-like stimulants have flooded the illegal drug market, causing numerous intoxications and fatalities. There are often no data on the pharmacokinetics of these substances when they first emerge onto the market. However, the detection of SC metabolites is often critical in order to prove consumption in clinical and forensic settings. In this research, the metabolite profile of two pyrrolidinyl SCs, α-pyrrolidinohexaphenone (α-PHP) and 4′′-fluoro-α-pyrrolidinovalerophenone (4F-α-PVP), were characterized to identify optimal intake markers. Experiments were conducted using pooled human hepatocyte incubations followed by liquid chromatography–high-resolution tandem mass spectrometry and data-mining software. We suggest α-PHP dihydroxy-pyrrolidinyl, α-PHP hexanol, α-PHP 2′-keto-pyrrolidinyl-hexanol, and α-PHP 2′-keto-pyrrolidinyl as markers of α-PHP use, and 4F-α-PVP dihydroxy-pyrrolidinyl, 4F-α-PVP hexanol, 4F-α-PVP 2′-keto-pyrrolidinyl-hexanol, and 4F-α-PVP 2′-keto-pyrrolidinyl as markers of 4F-α-PVP use. These results represent the first data available on 4F-α-PVP metabolism. The metabolic fate of α-PHP was previously studied using human liver microsomes and urine samples from α-PHP users. We identified an additional major metabolite (α-PHP dihydroxy-pyrrolidinyl) that might be crucial for documenting exposure to α-PHP. Further experiments with suitable analytical standards, which are yet to be synthesized, and authentic specimens should be conducted to confirm these results. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS))
Show Figures

Figure 1

14 pages, 1336 KiB  
Article
Determination of the Synthetic Cannabinoids JWH-122, JWH-210, UR-144 in Oral Fluid of Consumers by GC-MS and Quantification of Parent Compounds and Metabolites by UHPLC-MS/MS
by Nunzia La Maida, Manuela Pellegrini, Esther Papaseit, Clara Pérez-Mañá, Lourdes Poyatos, Mireia Ventura, Liliana Galindo, Francesco Paolo Busardò, Simona Pichini, Magí Farré and Emilia Marchei
Int. J. Mol. Sci. 2020, 21(24), 9414; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249414 - 10 Dec 2020
Cited by 14 | Viewed by 3607
Abstract
The consumption of synthetic cannabinoids (SCs) has significantly increased in the last decade and the analysis of SCs and their metabolites in human specimens is gaining interest in clinical and forensic toxicology. A pilot study has been carried out using a combination of [...] Read more.
The consumption of synthetic cannabinoids (SCs) has significantly increased in the last decade and the analysis of SCs and their metabolites in human specimens is gaining interest in clinical and forensic toxicology. A pilot study has been carried out using a combination of an initial last generation gas chromatography-mass spectrometry (GC-MS) screening method for the determination of JWH-122, JWH-210, UR-144) in oral fluid (OF) of consumers and an ultra-high performance liquid chromatography high resolution mass spectrometry (UHPLC-HRMS) confirmatory method for the quantification of the parent compounds and their metabolites in the same biological matrix. OF samples were simply liquid-liquid extracted before injecting in both chromatographic systems. The developed methods have been successfully validated and were linear from limit of quantification (LOQ) to 50 ng/mL OF. Recovery of analytes was always higher than 70% and matrix effect always lower than 15% whereas intra-assay and inter-assay precision and accuracy were always better than 16%. After smoking 1 mg JWH-122 or UR-144 and 3 mg JWH-210, maximum concentration of 4.00–3.14 ng/mL JWH-122, 8.10–7.30 ng/mL JWH-210 ng/mL and 7.40 and 6.81 ng/mL UR-144 were measured by GC-MS and UHPLC-HRMS respectively at 20 min after inhalation. Metabolites of JWH 122 and 210 were quantified in OF by UHPLC-HRMS, while that of UR144 was only detectable in traces. Our results provide for the first time information about disposition of these SCs and their metabolites in consumers OF. Last generation GC-MS has proven useful tool to identify and quantify parent SCs whereas UHPLC-HRMS also confirmed the presence of SCs metabolites in the OF of SCs consumers. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS))
Show Figures

Figure 1

Review

Jump to: Editorial, Research

30 pages, 1436 KiB  
Review
Toxicology and Analysis of Psychoactive Tryptamines
by Sara Malaca, Alfredo Fabrizio Lo Faro, Alice Tamborra, Simona Pichini, Francesco Paolo Busardò and Marilyn A. Huestis
Int. J. Mol. Sci. 2020, 21(23), 9279; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239279 - 04 Dec 2020
Cited by 27 | Viewed by 10389
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS))
Show Figures

Figure 1

Back to TopTop