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Pharmaco-Toxicological Effects of Novel Psychoactive Substances 2.0

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

Deadline for manuscript submissions: closed (11 November 2022) | Viewed by 14690

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Special Issue Editors

Dr. Matteo Marti

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Guest Editor

Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
Interests: pharmaco-toxicology of drug abuse; novel psychoactive substances; forensic toxicology; sex/gender differences; safety pharmacology studies
Special Issues, Collections and Topics in MDPI journals

Dr. Liana Fattore

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Guest Editor

National Research Council of Italy, Institute of Neuroscience, Cagliari, Italy
Interests: neuropsychopharmacology; behavioral neuroscience; neurobiology of drug abuse; psychiatric comorbidities; sex/gender differences
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Dr. Carlo Locatelli

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Istituti Clinici Scientifici Maugeri Spa – Società Benefit, 27100 Pavia, PV, Italy
Interests: toxicology; chemical exposure
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Dr. Monia Lenzi

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Guest Editor

Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
Interests: chemoprevention; genotoxicity; in vitro toxicology; bioactive molecules; natural compounds; flow cytometry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Novel psychoactive substances (NPS) are a broad range of substances not included in the United Nations drug control conventions and in recent years have increasingly been detected by police, hospitals and forensic laboratory networks. To date, more than 1000 NPS belonging to different pharmacological categories have been identified (e.g., synthetic cannabinoids and cathinones, hallucinogenic phenethylamines, synthetic opioids, new benzodiazepines and dissociative anaesthetics), which are usually sold via the internet. NPS detection in the context of seizures and in biological samples is challenging, and the legal status is often a grey zone, posing a real threat to public health due to their unpredictable toxicological effects, including lethal outcomes. Data on the prevalence and toxicity of these drugs and on their pharmacokinetics and pharmaco-toxicological effects are scarce. From a forensic and toxicological point of view, a relevant emerging problem is connected to NPSs’ severe adverse effects, the difficulty to manage acute toxicity and the complex identification of intoxication for both the forensic toxicologist and the medical examiner. Another aspect that has been more recently identified but is of great toxicological and social importance is represented by the possible genotoxic effects of NPS (and/or their metabolites) and the well-known long-term impact on human health.

Dr. Matteo Marti
Dr. Liana Fattore
Dr. Carlo Locatelli
Dr. Monia Lenzi
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

novel psychoactive substances
synthetic cannabinoids
synthetic cathinones
synthetic opioids
phenethylamines
dissociative anesthetics
new benzodiazepines
forensic toxicology
genotoxicity
neuropsychopharmacology
neurobiology of drug abuse

Published Papers (4 papers)

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Research

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14 pages, 2668 KiB

Open AccessArticle

The Genotoxicity of Acrylfentanyl, Ocfentanyl and Furanylfentanyl Raises the Concern of Long-Term Consequences

by Sofia Gasperini, Sabrine Bilel, Veronica Cocchi, Matteo Marti, Monia Lenzi and Patrizia Hrelia

Int. J. Mol. Sci. 2022, 23(22), 14406; https://doi.org/10.3390/ijms232214406 - 19 Nov 2022

Cited by 2 | Viewed by 1605

Abstract

Three fentanyl analogues Acrylfentanyl, Ocfentanyl and Furanylfentanyl are potent, rapid-acting synthetic analgesics that recently appeared on the illicit market of new psychoactive substances (NPS) under the class of new synthetic opioids (NSO). Pharmacotoxicological data on these three non-pharmaceutical fentanyl analogues are limited and studies on their genotoxicity are not yet available. Therefore, the aim of the present study was to investigate this property. The ability to induce structural and numerical chromosomal aberrations in human lymphoblastoid TK6 cells was evaluated by employing the flow cytometric protocol of the in vitro mammalian cell micronucleus test. Our study demonstrated the non-genotoxicity of Fentanyl, i.e., the pharmaceutical progenitor of the class, while its illicit non-pharmaceutical analogues were found to be genotoxic. In particular, Acrylfentanyl led to a statistically significant increase in the MNi frequency at the highest concentration tested (75 μM), while Ocfentanyl and Furanylfentnyl each did so at both concentrations tested (150, 200 μM and 25, 50 μM, respectively). The study ended by investigating reactive oxygen species (ROS) induction as a possible mechanism linked to the proved genotoxic effect. The results showed a non-statistically significant increase in ROS levels in the cultures treated with all molecules under study. Overall, the proved genotoxicity raises concern about the possibility of serious long-term consequences. Full article

(This article belongs to the Special Issue Pharmaco-Toxicological Effects of Novel Psychoactive Substances 2.0)

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29 pages, 3453 KiB

Open AccessArticle

In Vivo Bio-Activation of JWH-175 to JWH-018: Pharmacodynamic and Pharmacokinetic Studies in Mice

by Micaela Tirri, Raffaella Arfè, Sabrine Bilel, Giorgia Corli, Beatrice Marchetti, Anna Fantinati, Fabrizio Vincenzi, Fabio De-Giorgio, Cristian Camuto, Monica Mazzarino, Mario Barbieri, Rosa Maria Gaudio, Katia Varani, Pier Andrea Borea, Francesco Botrè and Matteo Marti

Int. J. Mol. Sci. 2022, 23(14), 8030; https://doi.org/10.3390/ijms23148030 - 21 Jul 2022

Cited by 6 | Viewed by 2847

Abstract

3-(1-Naphthalenylmethyl)-1-pentyl-1H-indole (JWH-175) is a synthetic cannabinoid illegally marketed for its psychoactive cannabis-like effects. This study aimed to investigate and compare in vitro and in vivo pharmacodynamic activity of JWH-175 with that of 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018), as well as evaluate the in vitro (human liver microsomes) and in vivo (urine and plasma of CD-1 male mice) metabolic profile of JWH-175. In vitro binding studies showed that JWH-175 is a cannabinoid receptor agonist less potent than JWH-018 on mouse and human CB1 and CB2 receptors. In agreement with in vitro data, JWH-175 reduced the fESPS in brain hippocampal slices of mice less effectively than JWH-018. Similarly, in vivo behavioral studies showed that JWH-175 impaired sensorimotor responses, reduced breath rate and motor activity, and increased pain threshold to mechanical stimuli less potently than JWH-018. Metabolic studies demonstrated that JWH-175 is rapidly bioactivated to JWH-018 in mice blood, suggesting that in vivo effects of JWH-175 are also due to JWH-018 formation. The pharmaco-toxicological profile of JWH-175 was characterized for the first time, proving its in vivo bio-activation to the more potent agonist JWH-018. Thus, it highlighted the great importance of investigating the in vivo metabolism of synthetic cannabinoids for both clinical toxicology and forensic purposes. Full article

(This article belongs to the Special Issue Pharmaco-Toxicological Effects of Novel Psychoactive Substances 2.0)

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15 pages, 3653 KiB

Open AccessArticle

Amitriptyline Accelerates SERT Binding Recovery in a Rat 3,4-Methylenedioxymethamphetamine (MDMA) Model: In Vivo 4-[¹⁸F]-ADAM PET Imaging

by Chi-Jung Tsai, Chuang-Hsin Chiu, Yu-Yeh Kuo, Wen-Sheng Huang, Tsung-Hsun Yu, Leo Garcia Flores II, Skye Hsin-Hsien Yeh and Kuo-Hsing Ma

Int. J. Mol. Sci. 2022, 23(13), 7035; https://doi.org/10.3390/ijms23137035 - 24 Jun 2022

Cited by 1 | Viewed by 2066

Abstract

Numerous studies have confirmed that 3,4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the density of the serotonin reuptake transporter (SERT). Amitriptyline (AMI) has been shown to exert neuroprotective properties in neuropathologic injury. Here, we used a SERT-specific radionuclide, 4-[¹⁸F]-ADAM, to assess the longitudinal alterations in SERT binding and evaluate the synergistic neuroprotective effect of AMI in a rat MDMA model. In response to MDMA treatment regimens, SERT binding was significantly reduced in rat brains. Region-specific recovery rate (normalized to baseline) in the MDMA group at day 14 was 71.29% ± 3.21%, and progressively increased to 90.90% ± 7.63% at day 35. AMI dramatically increased SERT binding in all brain regions, enhancing average ~18% recovery rate at day 14 when compared with the MDMA group. The immunochemical staining revealed that AMI markedly increased the serotonergic fiber density in the cingulate and thalamus after MDMA-induction, and confirmed the PET findings. Using in vivo longitudinal PET imaging, we demonstrated that SERT recovery was positively correlated with the duration of MDMA abstinence, implying that lower SERT densities in MDMA-induced rats reflected neurotoxic effects and were (varied) region-specific and reversible. AMI globally accelerated the recovery rate of SERT binding and increased SERT fiber density with possible neuroprotective effects. Full article

(This article belongs to the Special Issue Pharmaco-Toxicological Effects of Novel Psychoactive Substances 2.0)

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Review

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45 pages, 2884 KiB

Open AccessReview

Ketamine plus Alcohol: What We Know and What We Can Expect about This

by Natalia Harumi Correa Kobayashi, Sarah Viana Farias, Diandra Araújo Luz, Kissila Márvia Machado-Ferraro, Brenda Costa da Conceição, Cinthia Cristina Menezes da Silveira, Luanna Melo Pereira Fernandes, Sabrina de Carvalho Cartágenes, Vânia Maria Moraes Ferreira, Enéas Andrade Fontes-Júnior and Cristiane do Socorro Ferraz Maia

Int. J. Mol. Sci. 2022, 23(14), 7800; https://doi.org/10.3390/ijms23147800 - 15 Jul 2022

Cited by 6 | Viewed by 7607

Abstract

Drug abuse has become a public health concern. The misuse of ketamine, a psychedelic substance, has increased worldwide. In addition, the co-abuse with alcohol is frequently identified among misusers. Considering that ketamine and alcohol share several pharmacological targets, we hypothesize that the consumption of both psychoactive substances may synergically intensify the toxicological consequences, both under the effect of drugs available in body systems and during withdrawal. The aim of this review is to examine the toxicological mechanisms related to ketamine plus ethanol co-abuse, as well the consequences on cardiorespiratory, digestive, urinary, and central nervous systems. Furthermore, we provide a comprehensive discussion about the probable sites of shared molecular mechanisms that may elicit additional hazardous effects. Finally, we highlight the gaps of knowledge in this area, which deserves further research. Full article

(This article belongs to the Special Issue Pharmaco-Toxicological Effects of Novel Psychoactive Substances 2.0)

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