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Molecular Insights of New Psychoactive Substances (NPS) 2.0
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Molecular Insights of New Psychoactive Substances (NPS) 2.0

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 (20 June 2023) | Viewed by 18859

Special Issue Editors

Prof. Dr. Francesco Paolo Busardò

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Guest Editor
Faculty of Medicine and Surgery, University “Politecnica delle Marche” of Ancona, Via Tronto 71, 60124 Ancona, Italy
Interests: forensic toxicology; analytical toxicology; drugs; pharmacology; chromatography/mass Spectrometry
Special Issues, Collections and Topics in MDPI journals
Dr. Simona Pichini

E-Mail Website
Guest Editor
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
Dr. Angelo Montana

E-Mail Website
Guest Editor
Legal Medicine, Department of Medical, Surgical and Advanced Technologies, “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
Interests: AASs; anabolic androgenic steroids; organ damage; toxicity; injury; chronic administration; phorate; acute toxicity; chronic toxicity; histopathological kidney; toxicological examination
Dr. Fabrizio Lo Faro

E-Mail Website
Guest Editor
Department of Excellence of Biomedical Science and Public Health, University “Politecnica delle Marche” of Ancona, Via Tronto 10/a, 60124 Ancona, Italy
Interests: drugs of abuse; new psychoactive substances; pharmacokinetics; pharmacodinamics
Dr. Annagiulia Di Trana

E-Mail Website
Guest Editor
Department of Excellence of Biomedical Science and Public Health, University “Politecnica delle Marche” of Ancona, Via Tronto 10/a, 60124 Ancona, Italy
Interests: drugs of abuse; new psychoactive substances; pharmacokinetics; pharmacodinamics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue "Molecular Insights of New Psychoactive Substances (NPS)".

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 Paolo Busardò
Dr. Simona Pichini
Dr. Angelo Montana
Dr. Fabrizio Lo Faro
Dr. Annagiulia Di Trana
Guest Editors

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 (7 papers)

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Editorial

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3 pages, 204 KiB  
Editorial
Molecular Insights of New Psychoactive Substances (NPS) 2.0
by Annagiulia Di Trana, Angelo Montana, Alfredo Fabrizio Lo Faro, Francesco Paolo Busardò and Simona Pichini
Int. J. Mol. Sci. 2023, 24(24), 17492; https://doi.org/10.3390/ijms242417492 - 14 Dec 2023
Viewed by 761
Abstract
The New Psychoactive Substances (NPS) phenomenon represents an ever-changing global issue, with a number of new molecules entering the illicit market every year in response to international banning laws [...] Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS) 2.0)

Research

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15 pages, 1930 KiB  
Article
GC–MS/MS Determination of Synthetic Cathinones: 4-Chloromethcathinone, N-Ethyl Pentedrone, and N-Ethyl Hexedrone in Oral Fluid and Sweat of Consumers under Controlled Administration: Pilot Study
by Melani Nuñez-Montero, Claudia Lombroni, Nunzia La Maida, Maria Concetta Rotolo, Simona Pichini, Esther Papaseit, Olga Hladun, Mireia Ventura, Lourdes Poyatos, Clara Pérez-Mañá, Magí Farré and Emilia Marchei
Int. J. Mol. Sci. 2023, 24(11), 9387; https://doi.org/10.3390/ijms24119387 - 27 May 2023
Cited by 2 | Viewed by 1819
Abstract
This study presents a validated GC-MS/MS method for the detection and quantification of 4-chloromethcathinone or clephedrone (4-CMC), N-ethyl Pentedrone (NEP), and N-ethyl Hexedrone (NEH, also named HEXEN) in oral fluid and sweat and verifies its feasibility in determining human oral fluid concentrations and [...] Read more.
This study presents a validated GC-MS/MS method for the detection and quantification of 4-chloromethcathinone or clephedrone (4-CMC), N-ethyl Pentedrone (NEP), and N-ethyl Hexedrone (NEH, also named HEXEN) in oral fluid and sweat and verifies its feasibility in determining human oral fluid concentrations and pharmacokinetics following the administration of 100 mg of 4-CMC orally and 30 mg of NEP and NEH intranasally. A total of 48 oral fluid and 12 sweat samples were collected from six consumers. After the addition of 5 μL of methylone-d3 and 200 μL of 0.5 M ammonium hydrogen carbonate, an L/L extraction was carried out using ethyl acetate. The samples, dried under a nitrogen flow, were then derivatized with pentafluoropropionic anhydride and dried again. One microliter of the sample reconstituted in 50 μL of ethyl acetate was injected into GC-MS/MS. The method was fully validated according to international guidelines. Our results showed how, in oral fluid, the two cathinones taken intranasally were absorbed very rapidly, within the first hour, when compared with the 4-CMC which reached its maximum concentration peak in the first three hours. We observed that these cathinones were excreted in sweat in an amount equivalent to approximately 0.3% of the administered dose for 4-CMC and NEP. The total NEH excreted in sweat 4 h after administration was approximately 0.2% of the administered dose. Our results provide, for the first time, preliminary information about the disposition of these synthetic cathinones in the consumers’ oral fluid and sweat after controlled administration. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS) 2.0)
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9 pages, 771 KiB  
Communication
Sweat Testing for the Detection of Methylone after Controlled Administrations in Humans
by Alessandro Di Giorgi, Giorgia Sprega, Lourdes Poyatos, Esther Papaseit, Clara Pérez-Mañá, Annagiulia Di Trana, Maria Rosaria Varì, Francesco Paolo Busardò, Simona Pichini, Simona Zaami, Alfredo Fabrizio Lo Faro and Magí Farré
Int. J. Mol. Sci. 2023, 24(8), 7395; https://doi.org/10.3390/ijms24087395 - 17 Apr 2023
Cited by 2 | Viewed by 1034
Abstract
The aim of this study was to determine the excretion of methylone and its metabolites in sweat following the ingestion of increasing controlled doses of 50, 100, 150 and 200 mg of methylone to twelve healthy volunteers involved in a clinical trial. Methylone [...] Read more.
The aim of this study was to determine the excretion of methylone and its metabolites in sweat following the ingestion of increasing controlled doses of 50, 100, 150 and 200 mg of methylone to twelve healthy volunteers involved in a clinical trial. Methylone and its metabolites 4-hydroxy-3-methoxy-N-methylcathinone (HMMC) and 3,4-methylenedioxycathinone (MDC) were analyzed in sweat patches by liquid chromatography–tandem mass spectrometry. Methylone and MDC were detected in sweat at 2 h and reached their highest accumulation (Cmax) at 24 h after the administration of 50, 100, 150 and 200 mg doses. In contrast, HMMC was not detectable at any time interval after each dose. Sweat proved to be a suitable matrix for methylone and its metabolites’ determination in clinical and toxicological studies, providing a concentration that reveals recent drug consumption. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS) 2.0)
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23 pages, 8306 KiB  
Article
Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS
by Uliana De Simone, Patrizia Pignatti, Laura Villani, Luciana Alessandra Russo, Azzurra Sargenti, Simone Bonetti, Eleonora Buscaglia and Teresa Coccini
Int. J. Mol. Sci. 2023, 24(2), 1421; https://doi.org/10.3390/ijms24021421 - 11 Jan 2023
Cited by 2 | Viewed by 1989
Abstract
There is growing concern about the consumption of synthetic cannabinoids (SCs), one of the largest groups of new psychoactive substances, its consequence on human health (general population and workers), and the continuous placing of new SCs on the market. Although drug-induced alterations in [...] Read more.
There is growing concern about the consumption of synthetic cannabinoids (SCs), one of the largest groups of new psychoactive substances, its consequence on human health (general population and workers), and the continuous placing of new SCs on the market. Although drug-induced alterations in neuronal function remain an essential component for theories of drug addiction, accumulating evidence indicates the important role of activated astrocytes, whose essential and pleiotropic role in brain physiology and pathology is well recognized. The study aims to clarify the mechanisms of neurotoxicity induced by one of the most potent SCs, named MAM-2201 (a naphthoyl-indole derivative), by applying a novel three-dimensional (3D) cell culture model, mimicking the physiological and biochemical properties of brain tissues better than traditional two-dimensional in vitro systems. Specifically, human astrocyte spheroids, generated from the D384 astrocyte cell line, were treated with different MAM-2201 concentrations (1–30 µM) and exposure times (24–48 h). MAM-2201 affected, in a concentration- and time-dependent manner, the cell growth and viability, size and morphological structure, E-cadherin and extracellular matrix, CB1-receptors, glial fibrillary acidic protein, and caspase-3/7 activity. The findings demonstrate MAM-2201-induced cytotoxicity to astrocyte spheroids, and support the use of this human 3D cell-based model as species-specific in vitro tool suitable for the evaluation of neurotoxicity induced by other SCs. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS) 2.0)
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13 pages, 819 KiB  
Article
Methylone and MDMA Pharmacokinetics Following Controlled Administration in Humans
by Lourdes Poyatos, Alfredo Fabrizio Lo Faro, Diletta Berardinelli, Giorgia Sprega, Sara Malaca, Simona Pichini, Marilyn A. Huestis, Esther Papaseit, Clara Pérez-Mañá, Francesco Paolo Busardò and Magí Farré
Int. J. Mol. Sci. 2022, 23(23), 14636; https://doi.org/10.3390/ijms232314636 - 23 Nov 2022
Cited by 9 | Viewed by 2461
Abstract
The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in [...] Read more.
The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d5, MDA-d5 and methylone-d3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with 0.1 mL acidified methanol and evaporated under nitrogen. Samples were reconstituted with a mobile phase and injected into the LC-MS/MS instrument. The method was fully validated according to OSAC guidelines (USA). Methylone plasma concentrations increased in a dose-proportional manner, as demonstrated by the increasing maximum concentration (Cmax) and area under the curve of concentrations (AUC). Methylone Cmax values were reported as 153, 304, 355 and 604 ng/mL, AUC0–24 values were reported as 1042.8, 2441.2, 3524.4 and 5067.9 h·ng/mL and T1/2 values as 5.8, 6.4, 6.9 and 6.4 h following the 50, 100, 150 and 200 mg doses, respectively. Methylone exhibited rapid kinetics with a Tmax of 1.5 h for the 50 mg dose and 2 h approximately after all the other doses. HMMC exhibited faster kinetics compared to methylone, with a Cmax value that was 10–14-fold lower and an AUC0–24 value that was 21–29-fold lower. Methylone pharmacokinetics was linear across 50–200 mg oral doses in humans, unlike the previously described non-linear oral MDMA pharmacokinetics. An LC-MS/MS method for the quantification of methylone, MDMA and their metabolites in human plasma was achieved. Methylone exhibited linear pharmacokinetics in humans with oral doses of 50–200 mg. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS) 2.0)
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Review

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48 pages, 4248 KiB  
Review
Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review
by Gloria Daziani, Alfredo Fabrizio Lo Faro, Vincenzo Montana, Gaia Goteri, Mauro Pesaresi, Giulia Bambagiotti, Eva Montanari, Raffaele Giorgetti and Angelo Montana
Int. J. Mol. Sci. 2023, 24(7), 6230; https://doi.org/10.3390/ijms24076230 - 25 Mar 2023
Cited by 10 | Viewed by 5419
Abstract
According to the EU Early Warning System (EWS), synthetic cathinones (SCs) are the second largest new psychoactive substances (NPS) class, with 162 synthetic cathinones monitored by the EU EWS. They have a similar structure to cathinone, principally found in Catha Edulis; they have [...] Read more.
According to the EU Early Warning System (EWS), synthetic cathinones (SCs) are the second largest new psychoactive substances (NPS) class, with 162 synthetic cathinones monitored by the EU EWS. They have a similar structure to cathinone, principally found in Catha Edulis; they have a phenethylamine related structure but also exhibit amphetamine-like stimulant effects. Illegal laboratories regularly develop new substances and place them on the market. For this reason, during the last decade this class of substances has presented a great challenge for public health and forensic toxicologists. Acting on different systems and with various mechanisms of action, the spectrum of side effects caused by the intake of these drugs of abuse is very broad. To date, most studies have focused on the substances’ cardiac effects, and very few on their associated neurotoxicity. Specifically, synthetic cathinones appear to be involved in different neurological events, including increased alertness, mild agitation, severe psychosis, hyperthermia and death. A systematic literature search in PubMed and Scopus databases according to PRISMA guidelines was performed. A total of 515 studies published from 2005 to 2022 (350 articles from PubMed and 165 from Scopus) were initially screened for eligibility. The papers excluded, according to the criteria described in the Method Section (n = 401) and after full text analyses (n = 82), were 483 in total. The remaining 76 were included in the present review, as they met fully the inclusion criteria. The present work provides a comprehensive review on neurotoxic mechanisms of synthetic cathinones highlighting intoxication cases and fatalities in humans, as well as the toxic effects on animals (in particular rats, mice and zebrafish larvae). The reviewed studies showed brain-related adverse effects, including encephalopathy, coma and convulsions, and sympathomimetic and hallucinogenic toxidromes, together with the risk of developing excited/agitated delirium syndrome and serotonin syndrome. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS) 2.0)
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28 pages, 1131 KiB  
Review
Molecular Insights and Clinical Outcomes of Drugs of Abuse Adulteration: New Trends and New Psychoactive Substances
by Annagiulia Di Trana, Diletta Berardinelli, Eva Montanari, Paolo Berretta, Giuseppe Basile, Marilyn A. Huestis and Francesco Paolo Busardò
Int. J. Mol. Sci. 2022, 23(23), 14619; https://doi.org/10.3390/ijms232314619 - 23 Nov 2022
Cited by 4 | Viewed by 4608
Abstract
Adulteration is a well-known practice of drug manufacturers at different stages of drug production. The intentional addition of active ingredients to adulterate the primary drug may enhance or mask pharmacological effects or may produce more potent drugs to increase the number of available [...] Read more.
Adulteration is a well-known practice of drug manufacturers at different stages of drug production. The intentional addition of active ingredients to adulterate the primary drug may enhance or mask pharmacological effects or may produce more potent drugs to increase the number of available doses and the dealer’s profit. Adulterants found in different drugs change over time in response to different factors. A systematic literature search in PubMed and Scopus databases and official international organizations’ websites according to PRISMA guidelines was performed. A total of 724 studies were initially screened, with 145 articles from PubMed and 462 from Scopus excluded according to the criteria described in the Method Section. The remaining 117 records were further assessed for eligibility to exclude articles without sufficient data. Finally, 79 studies were classified as “non-biological” (n = 35) or “biological” (n = 35 case reports; n = 9 case series) according to the samples investigated. Although the seized samples analyses revealed the presence of well-established adulterants such as levamisole for cocaine or paracetamol/acetaminophen for heroin, the reported data disclosed new adulteration practices, such as the use of NPS as cutting agents for classic drugs of abuse and other NPS. For example, heroin adulterated with synthetic cannabinoids or cocaine adulterated with fentanyl/fentalogues raised particular concern. Notably, adulterants play a role in some adverse effects commonly associated with the primary drug, such as levamisole-adulterated cocaine that may induce vasculitis via an autoimmune process. It is essential to constantly monitor adulterants due to their changing availability that may threaten drug consumers’ health. Full article
(This article belongs to the Special Issue Molecular Insights of New Psychoactive Substances (NPS) 2.0)
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