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Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel...
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Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids

A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (15 September 2020) | Viewed by 45678

Special Issue Editor

Prof. Dr. Maria Antonietta De Luca

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Cagliari, Via Università, 40, 09124 Cagliari CA, Italy
Interests: Liquid Chromatography; Neurobiology; Neurophysiology; Learning and Memory
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Novel Psychoactive Substances (NPS) are a broad variety of drugs not regulated by present legislation. The advent of NPS has contributed to the appearance and growth of a new ‘drug scenario’ characterized by an increased number of drug users among youth and the consumption of drugs with unknown effects or safety profiles. Preclinical and clinical findings have shown that at lower doses NPS may produce effects comparable to those of illicit psychoactive drugs, such as cannabis, heroin, cocaine and MDMA, however, with more severe consequences. The first wave of NPS came to Europe in the early 2000s in the form of synthetic cannabinoids followed by synthetic cathinones and phenethylamines. From 2016, a rise in the availability of novel synthetic opioids (NSO) was registered in Europe. NSO are the most dangerous NPS since they mimic morphine and heroin and are many times more potent than these opioids in producing acute toxicity. Moreover, they are effective by the intranasal and oral route. Consequently, their use is likely to become the primary source of NPS-associated deaths in Europe, given their increasing prevalence, as opposed to that of other NPS classes. This Special Issue aims to provide an up-to-date overview of pharmacology, structure–activity relationships, and toxicology of NPS and NSO, and the detrimental effects associated with their intake.

Dr. Maria Antonietta De Luca
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). 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

  • NPS
  • cannabis
  • heroin
  • cocaine
  • MDMA
  • opioids
  • NSO
  • pharmacology
  • structure–activity relationships
  • toxicology

Published Papers (8 papers)

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Editorial

Jump to: Research, Review

4 pages, 187 KiB  
Editorial
Analyzing the Open/Deep Web to Better Understand the New/Novel Psychoactive Substances (NPS) Scenarios: Suggestions from CASSANDRA and NPS.Finder Research Projects
by Fabrizio Schifano
Brain Sci. 2020, 10(3), 146; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10030146 - 04 Mar 2020
Cited by 8 | Viewed by 2764
Abstract
New/novel psychoactive substances (NPS) are defined as new narcotic/psychotropic drugs which are not controlled by the United Nations’ 1961 Narcotic Drugs/1971 Psychotropic Substances conventions, but which may pose a public health threat [...] Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids)

Research

Jump to: Editorial, Review

14 pages, 1268 KiB  
Article
Neurochemical and Behavioral Characterization after Acute and Repeated Exposure to Novel Synthetic Cannabinoid Agonist 5-MDMB-PICA
by Aurora Musa, Nicola Simola, Gessica Piras, Francesca Caria, Emmanuel Shan Onaivi and Maria Antonietta De Luca
Brain Sci. 2020, 10(12), 1011; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10121011 - 18 Dec 2020
Cited by 10 | Viewed by 3236
Abstract
Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability [...] Read more.
Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability to the central effects of drugs. Despite growing concerns about the negative effects of the use of SCs, newly synthetized compounds are increasingly detected in drugs seized by the authorities, posing a serious threat to public health. 5F-MDMB-PICA has been recently detected and classified as a highly potent agonist of CB1 and CB2 cannabinoid receptors. Here, we first investigated the rewarding properties of 5F-MDMB-PICA in C57BL/6 adolescent and adult mice by in vivo brain microdialysis. Data showed that acute administration of a selected dose of 5F-MDMB-PICA (0.01 mg/kg i.p.) stimulates the release of dopamine in the nucleus accumbens shell of adolescent, but not of adult, mice. To further investigate the consequences of repeated exposure to this dose of 5F-MDMB-PICA, a separate group of adolescent mice was treated for 14 consecutive days and evaluated for behavioral abnormalities at adulthood, starting from 7 days after drug discontinuation. Data showed that this group of adult mice displayed an anxiety-like and compulsive-like state as revealed by an altered performance in the marble burying test. Our study suggests an alarming vulnerability of adolescent mice to the effects of 5F-MDMB-PICA. These findings provide a useful basis for understanding and evaluating both early and late detrimental effects that may derive from the use of SCs during adolescence. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids)
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20 pages, 1515 KiB  
Article
Acute DOB and PMA Administration Impairs Motor and Sensorimotor Responses in Mice and Causes Hallucinogenic Effects in Adult Zebrafish
by Micaela Tirri, Luisa Ponzoni, Sabrine Bilel, Raffaella Arfè, Daniela Braida, Mariaelvina Sala and Matteo Marti
Brain Sci. 2020, 10(9), 586; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10090586 - 24 Aug 2020
Cited by 6 | Viewed by 3076
Abstract
The drastic increase in hallucinogenic compounds in illicit drug markets of new psychoactive substances (NPS) is a worldwide threat. Among these, 2, 5-dimetoxy-4-bromo-amphetamine (DOB) and paramethoxyamphetamine (PMA; marketed as “ecstasy”) are frequently purchased on the dark web and consumed for recreational purposes during [...] Read more.
The drastic increase in hallucinogenic compounds in illicit drug markets of new psychoactive substances (NPS) is a worldwide threat. Among these, 2, 5-dimetoxy-4-bromo-amphetamine (DOB) and paramethoxyamphetamine (PMA; marketed as “ecstasy”) are frequently purchased on the dark web and consumed for recreational purposes during rave/dance parties. In fact, these two substances seem to induce the same effects as MDMA, which could be due to their structural similarities. According to users, DOB and PMA share the same euphoric effects: increasing of the mental state, increasing sociability and empathy. Users also experienced loss of memory, temporal distortion, and paranoia following the repetition of the same thought. The aim of this study was to investigate the effect of the acute systemic administration of DOB and PMA (0.01–30 mg/kg; i.p.) on motor, sensorimotor (visual, acoustic, and tactile), and startle/PPI responses in CD-1 male mice. Moreover, the pro-psychedelic effect of DOB (0.075–2 mg/kg) and PMA (0.0005–0.5 mg/kg) was investigated by using zebrafish as a model. DOB and PMA administration affected spontaneous locomotion and impaired behaviors and startle/PPI responses in mice. In addition, the two compounds promoted hallucinatory states in zebrafish by reducing the hallucinatory score and swimming activity in hallucinogen-like states. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids)
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18 pages, 615 KiB  
Article
Focus on Clozapine Withdrawal- and Misuse-Related Cases as Reported to the European Medicines Agency (EMA) Pharmacovigilance Database
by Stefania Chiappini, Fabrizio Schifano, John Martin Corkery and Amira Guirguis
Brain Sci. 2020, 10(2), 105; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10020105 - 16 Feb 2020
Cited by 21 | Viewed by 5454
Abstract
Background: Clozapine is of high clinical relevance for the management of both treatment-resistant schizophrenia and psychotic disturbances with concurrent drug misuse. Although the molecule presents with a range of well-known side-effects, its discontinuation/withdrawal syndrome has been only anecdotally described. Aims: the 2005–2018 European [...] Read more.
Background: Clozapine is of high clinical relevance for the management of both treatment-resistant schizophrenia and psychotic disturbances with concurrent drug misuse. Although the molecule presents with a range of well-known side-effects, its discontinuation/withdrawal syndrome has been only anecdotally described. Aims: the 2005–2018 European Medicines Agency (EMA) dataset of Adverse Drug Reactions (ADRs) was analyzed to identify and describe possible clozapine withdrawal- and misuse-/abuse-/dependence-related issues. Method: A descriptive analysis of clozapine-related ADRs was performed when available, data on ADRs’ outcome, dosage, and possible concomitant drug(s) were considered. Results: Out of 11,847 clozapine-related ADRs, some 599 (5.05%) were related to misuse/abuse/dependence/withdrawal issues, including 258 withdrawal-related (43.1%); 241 abuse-related (40.2%); and 80 intentional product misuse-related (13.3%) ADRs. A small number of overdose- and suicide-related ADRs were reported as well. Clozapine was typically (69.2%) identified alone, and most (84.7%) fatalities/high-dosage intake instances were reported in association with a history of substance abuse. Conclusions: Previous suggestions about the possibility of a clozapine discontinuation/withdrawal occurrence are here supported, but further studies are needed. However, the misuse/abuse cases here identified might be difficult to interpret, given the lack of studies highlighting the possible recreational use of clozapine. The high-dosage intake, fatal outcomes and clozapine/polydrug abuse issues reported here may, however, be a reason for concern. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids)
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13 pages, 760 KiB  
Article
Antinociceptive and Abuse Potential Effects of Cannabinoid/Opioid Combinations in a Chronic Pain Model in Rats
by Mohammad Alsalem, Ahmad Altarifi, Mansour Haddad, Sara A. Aldossary, Heba Kalbouneh, Nour Aldaoud, Tareq Saleh and Khalid El-Salem
Brain Sci. 2019, 9(11), 328; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci9110328 - 17 Nov 2019
Cited by 13 | Viewed by 3691
Abstract
Chronic pain is a persistent and debilitating health problem. Although the use of analgesics such as opioids is useful in mitigating pain, their prolonged use is associated with unwanted effects including abuse liability. This study assesses the antinociceptive effect of combining subtherapeutic doses [...] Read more.
Chronic pain is a persistent and debilitating health problem. Although the use of analgesics such as opioids is useful in mitigating pain, their prolonged use is associated with unwanted effects including abuse liability. This study assesses the antinociceptive effect of combining subtherapeutic doses of two opioids (morphine or tramadol) with the synthetic cannabinoid CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan -2-yl)phenol). It also evaluates the associated adverse effects of these drugs and combinations. Adult male rats were injected with intraplantar complete Freund’s adjuvant (CFA) to produce mechanical allodyia. Antinociceptive effect of morphine, tramadol, the synthetic cannabinoid CP55940, or their combinations was evaluated three to nine days post-CFA injections. Intracranial self-stimulation (ICSS) was utilized to evaluate the abuse liability of these drugs or their combinations. All drugs alone produced a dose-dependent antinociceptive effect. Morphine produced minimal effect on ICSS, but both tramadol and CP55940 produced dose-dependent depression of ICSS. Morphine at a dose of 0.32 mg/kg enhanced the antinociceptive effects of CP55940, in that, CP55940 produced antinociception at a lower dose (0.1 mg/kg) when compared to the vehicle. The aforementioned combinations did not change CP55940-induced depression of ICSS. On the other hand, tramadol failed to enhance the antinociceptive effect of CP55940. Our data suggest that combining CP55940 with morphine, but not tramadol, shows a better antinociceptive profile with no additional risk of abuse liability, which represents a potential pain management approach. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids)
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Review

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30 pages, 1369 KiB  
Review
U-47700 and Its Analogs: Non-Fentanyl Synthetic Opioids Impacting the Recreational Drug Market
by Michael H. Baumann, Graziella Tocco, Donna M. Papsun, Amanda L. Mohr, Melissa F. Fogarty and Alex J. Krotulski
Brain Sci. 2020, 10(11), 895; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10110895 - 23 Nov 2020
Cited by 28 | Viewed by 14104
Abstract
The recreational use of opioid drugs is a global threat to public health and safety. In particular, an epidemic of opioid overdose fatalities is being driven by illicitly manufactured fentanyl, while novel synthetic opioids (NSOs) are appearing on recreational drug markets as standalone [...] Read more.
The recreational use of opioid drugs is a global threat to public health and safety. In particular, an epidemic of opioid overdose fatalities is being driven by illicitly manufactured fentanyl, while novel synthetic opioids (NSOs) are appearing on recreational drug markets as standalone products, adulterants in heroin, or ingredients in counterfeit drug preparations. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a prime example of a non-fentanyl NSO that is associated with numerous intoxications and fatalities. Here, we review the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection, and forensic toxicology of U-47700 and its analogs. An up-to-date summary of the human cases involving U-47700 intoxication and death are described. The evidence demonstrates that U-47700 is a potent μ-opioid receptor agonist, which poses a serious risk for overdosing and death. However, most analogs of U-47700 appear to be less potent and have been detected infrequently in forensic specimens. U-47700 represents a classic example of how chemical entities from the medicinal chemistry or patent literature can be diverted for use in recreational drug markets. Lessons learned from the experiences with U-47700 can inform scientists, clinicians, and policymakers who are involved with responding to the spread and impact of NSOs. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids)
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Graphical abstract

21 pages, 427 KiB  
Review
Sex and Gender Differences in the Effects of Novel Psychoactive Substances
by Liana Fattore, Matteo Marti, Rafaela Mostallino and Maria Paola Castelli
Brain Sci. 2020, 10(9), 606; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10090606 - 03 Sep 2020
Cited by 29 | Viewed by 8295
Abstract
Sex and gender deeply affect the subjective effects and pharmaco-toxicological responses to drugs. Men are more likely than women to use almost all types of illicit drugs and to present to emergency departments for serious or fatal intoxications. However, women are just as [...] Read more.
Sex and gender deeply affect the subjective effects and pharmaco-toxicological responses to drugs. Men are more likely than women to use almost all types of illicit drugs and to present to emergency departments for serious or fatal intoxications. However, women are just as likely as men to develop substance use disorders, and may be more susceptible to craving and relapse. Clinical and preclinical studies have shown important differences between males and females after administration of “classic” drugs of abuse (e.g., Δ9-tetrahydrocannabinol (THC), morphine, cocaine). This scenario has become enormously complicated in the last decade with the overbearing appearance of the new psychoactive substances (NPS) that have emerged as alternatives to regulated drugs. To date, more than 900 NPS have been identified, and can be catalogued in different pharmacological categories including synthetic cannabinoids, synthetic stimulants (cathinones and amphetamine-like), hallucinogenic phenethylamines, synthetic opioids (fentanyls and non-fentanyls), new benzodiazepines and dissociative anesthetics (i.e., methoxetamine and phencyclidine-derivatives). This work collects the little knowledge reached so far on the effects of NPS in male and female animal and human subjects, highlighting how much sex and gender differences in the effects of NPS has yet to be studied and understood. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids)
14 pages, 330 KiB  
Review
Targeting the Orexin System for Prescription Opioid Use Disorder
by Alessandra Matzeu and Rémi Martin-Fardon
Brain Sci. 2020, 10(4), 226; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10040226 - 10 Apr 2020
Cited by 14 | Viewed by 4093
Abstract
Prescription opioids are potent analgesics that are used for clinical pain management. However, the nonmedical use of these medications has emerged as a major concern because of dramatic increases in abuse and overdose. Therefore, effective strategies to prevent prescription opioid use disorder are [...] Read more.
Prescription opioids are potent analgesics that are used for clinical pain management. However, the nonmedical use of these medications has emerged as a major concern because of dramatic increases in abuse and overdose. Therefore, effective strategies to prevent prescription opioid use disorder are urgently needed. The orexin system has been implicated in the regulation of motivation, arousal, and stress, making this system a promising target for the treatment of substance use disorder. This review discusses recent preclinical studies that suggest that orexin receptor blockade could be beneficial for the treatment of prescription opioid use disorder. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of New Psychoactive Substances: Focus on Novel Synthetic Opioids)
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