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Pharmaco-Toxicological Effects of Novel Psychoactive Substances

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 25205

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Dr. Matteo Marti

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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
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Dr. Liana Fattore

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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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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
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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 900 NPS belonging to different pharmacological categories have been identified (e.g., synthetic cannabinoids and cathinones, hallucinogenic phenethylamines, synthetic opioids, new benzodiazepines and dissociative anesthetics), which are usually sold via the internet as “bath salts”, “plant food” or “legal highs”. 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 their possible genotoxic effects and the well-known long-term impact on human health.

Dr. Matteo Marti
Dr. Liana Fattore
Dr. Carlo A. Locatelli
Dr. Monia Lenzi
Guest Editors

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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 (9 papers)

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Research

12 pages, 2391 KiB

Open AccessArticle

Genotoxicological Characterization of (±)cis-4,4′-DMAR and (±)trans-4,4′-DMAR and Their Association

by Monia Lenzi, Sofia Gasperini, Veronica Cocchi, Micaela Tirri, Matteo Marti and Patrizia Hrelia

Int. J. Mol. Sci. 2022, 23(10), 5849; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105849 - 23 May 2022

Cited by 3 | Viewed by 1464

Abstract

The novel psychoactive substance (NPS) 4-Methyl-5-(4-methylphenyl)-4,5-dihydroxazol-2-amine (4,4′-DMAR) shows psychostimulant activity. Data on the acute toxicity of 4,4′-DMAR are becoming increasingly available, yet the long-term effects are still almost unknown. In particular, no data on genotoxicity are available. Therefore, the aim of the present study was to evaluate its genotoxic potential using the “In Vitro Mammalian Cell Micronucleus Test” (MNvit) on (±)cis-4,4′-DMAR and (±)trans-4,4′-DMAR and their associations. The analyses were conducted in vitro on human TK6 cells. To select suitable concentrations for MNvit, we preliminarily evaluated cytotoxicity and apoptosis. All endpoints were analysed by flow cytometry. The results reveal the two racemates’ opposite behaviours: (±)cis-4,4′-DMAR shows a statistically significant increase in micronuclei (MNi) frequency that (±)trans-4,4′-DMAR is completely incapable of. This contrast confirms the well-known possibility of observing opposite biological effects of the cis- and trans- isomers of a compound, and it highlights the importance of testing single NPSs that show even small differences in structure or conformation. The genotoxic capacity demonstrated stresses an additional alarming toxicological concern related to this NPS. Moreover, the co-treatments indicate that consuming both racemates will magnify the genotoxic effect, an aspect to consider given the unpredictability of illicit drug composition. Full article

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

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18 pages, 2804 KiB

Open AccessArticle

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

by Núria Nadal-Gratacós, Esther Lleixà, Mónica Gibert-Serramià, Roger Estrada-Tejedor, Xavier Berzosa, Xavier Batllori, David Pubill, Jordi Camarasa, Elena Escubedo and Raúl López-Arnau

Int. J. Mol. Sci. 2022, 23(4), 2226; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042226 - 17 Feb 2022

Cited by 8 | Viewed by 4294

Abstract

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives. Full article

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

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14 pages, 5039 KiB

Open AccessArticle

Alteration of Ethanol Reward by Prior Mephedrone Exposure: The Role of Age and Matrix Metalloproteinase-9 (MMP-9)

by Pawel Grochecki, Irena Smaga, Marta Marszalek-Grabska, Malgorzata Lopatynska-Mazurek, Tymoteusz Slowik, Ewa Gibula-Tarlowska, Ewa Kedzierska, Joanna Listos, Malgorzata Filip and Jolanta H. Kotlinska

Int. J. Mol. Sci. 2022, 23(4), 2122; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042122 - 14 Feb 2022

Cited by 4 | Viewed by 1951

Abstract

Mephedrone, a synthetic cathinone, is widely abused by adolescents and young adults. The aim of this study was to determine: (i) whether prior mephedrone exposure would alter ethanol reward and (ii) whether age and matrix metalloproteinase-9 (MMP-9) are important in this regard. In our research, male Wistar rats at postnatal day 30 (PND30) received mephedrone at the dose of 10 mg/kg, i.p., 3 times a day for 7 days. To clarify the role of MMP-9 in the mephedrone effects, one mephedrone-treated group received minocycline, as an MMP-9 antagonist. Animals were then assigned to conditioned place preference (CPP) procedure at PND38 (adolescent) or at PND69 (adult). After the CPP test (PND48/79), expression of dopamine D1 receptors (D1R), Cav1.2 (a subtype of L-type calcium channels), and MMP-9 was quantified in the rat ventral striatum (vSTR). The influence of mephedrone administration on the N-methyl-D-aspartate glutamate receptors (NMDAR) subunits (GluN1, GluN2A, and GluN2B) was then assessed in the vSTR of adult rats (only). These results indicate that, in contrast with adolescent rats, adult rats with prior mephedrone administration appear to be more sensitive to the ethanol effect in the CPP test under the drug-free state. The mephedrone effect in adult rats was associated with upregulation of D1R, NMDAR/GluN2B, MMP-9, and Cav1.2 signaling. MMP-9 appears to contribute to these changes in proteins expression because minocycline pretreatment blocked mephedrone-evoked sensitivity to ethanol reward. Thus, our results suggest that prior mephedrone exposure differentially alters ethanol reward in adolescent and adult rats. Full article

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

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16 pages, 2423 KiB

Open AccessArticle

Comparative Neuropharmacology and Pharmacokinetics of Methamphetamine and Its Thiophene Analog Methiopropamine in Rodents

by Silja Skogstad Tuv, Marianne Skov-Skov Bergh, Jannike Mørch Andersen, Synne Steinsland, Vigdis Vindenes, Michael H. Baumann, Marilyn A. Huestis and Inger Lise Bogen

Int. J. Mol. Sci. 2021, 22(21), 12002; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222112002 - 05 Nov 2021

Cited by 6 | Viewed by 3029

Abstract

Methiopropamine is a novel psychoactive substance (NPS) that is associated with several cases of clinical toxicity, yet little information is available regarding its neuropharmacological properties. Here, we employed in vitro and in vivo methods to compare the pharmacokinetics and neurobiological effects of methiopropamine and its structural analog methamphetamine. Methiopropamine was rapidly distributed to the blood and brain after injection in C57BL/6 mice, with a pharmacokinetic profile similar to that of methamphetamine. Methiopropamine induced psychomotor activity, but higher doses were needed (E_max 12.5 mg/kg; i.p.) compared to methamphetamine (E_max 3.75 mg/kg; i.p.). A steep increase in locomotor activity was seen after a modest increase in the methiopropamine dose from 10 to 12.5 mg/kg, suggesting that a small increase in dosage may engender unexpectedly strong effects and heighten the risk of unintended overdose in NPS users. In vitro studies revealed that methiopropamine mediates its effects through inhibition of norepinephrine and dopamine uptake into presynaptic nerve terminals (IC₅₀ = 0.47 and 0.74 µM, respectively), while the plasmalemmal serotonin uptake and vesicular uptake are affected only at high concentrations (IC₅₀ > 25 µM). In summary, methiopropamine closely resembles methamphetamine with regard to its pharmacokinetics, pharmacodynamic effects and mechanism of action, with a potency that is approximately five times lower than that of methamphetamine. Full article

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

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21 pages, 5981 KiB

Open AccessArticle

Effects of β-Phenylethylamine on Psychomotor, Rewarding, and Reinforcing Behaviors and Affective State: The Role of Dopamine D1 Receptors

by In Soo Ryu, Oc-Hee Kim, Ji Sun Kim, Sumin Sohn, Eun Sang Choe, Ri-Na Lim, Tae Wan Kim, Joung-Wook Seo and Eun Young Jang

Int. J. Mol. Sci. 2021, 22(17), 9485; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179485 - 31 Aug 2021

Cited by 10 | Viewed by 2924

Abstract

Beta-phenylethylamine (β-PEA) is a well-known and widespread endogenous neuroactive trace amine found throughout the central nervous system in humans. In this study, we demonstrated the effects of β-PEA on psychomotor, rewarding, and reinforcing behaviors and affective state using the open-field test, conditioned place preference (CPP), self-administration, and ultrasonic vocalizations (USVs) paradigms. We also investigated the role of the dopamine (DA) D1 receptor in the behavioral effects of β-PEA in rodents. Using enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, we also determined the DA concentration and the DA-related protein levels in the dorsal striatum of mice administered with acute β-PEA. The results showed that acute β-PEA increased stereotypic behaviors such as circling and head-twitching responses in mice. In the CPP experiment, β-PEA increased place preference in mice. In the self-administration test, β-PEA significantly enhanced self-administration during a 2 h session under fixed ratio (FR) schedules (FR1 and FR3) and produced a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement in rats. In addition, acute β-PEA increased 50-kHz USV calls in rats. Furthermore, acute β-PEA administration increased DA concentration and p-DAT and TH expression in the dorsal striatum of mice. Finally, pretreatment with SCH23390, a DA D1 receptor antagonist, attenuated β-PEA-induced circling behavior and β-PEA-taking behavior in rodents. Taken together, these findings suggest that β-PEA has rewarding and reinforcing effects and psychoactive properties, which induce psychomotor behaviors and a positive affective state by activating the DA D1 receptor in the dorsal striatum. Full article

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

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25 pages, 2979 KiB

Open AccessArticle

Worsening of the Toxic Effects of (±)Cis-4,4′-DMAR Following Its Co-Administration with (±)Trans-4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice

by Micaela Tirri, Paolo Frisoni, Sabrine Bilel, Raffaella Arfè, Claudio Trapella, Anna Fantinati, Giorgia Corli, Beatrice Marchetti, Fabio De-Giorgio, Cristian Camuto, Monica Mazzarino, Rosa Maria Gaudio, Giovanni Serpelloni, Fabrizio Schifano, Francesco Botrè and Matteo Marti

Int. J. Mol. Sci. 2021, 22(16), 8771; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168771 - 16 Aug 2021

Cited by 4 | Viewed by 2382

Abstract

4,4’-Dimethylaminorex (4,4’-DMAR) is a new synthetic stimulant, and only a little information has been made available so far regarding its pharmaco-toxicological effects. The aim of this study was to investigate the effects of the systemic administration of both the single (±)cis (0.1–60 mg/kg) and (±)trans (30 and 60 mg/kg) stereoisomers and their co-administration (e.g., (±)cis at 1, 10 or 60 mg/kg + (±)trans at 30 mg/kg) in mice. Moreover, we investigated the effect of 4,4′-DMAR on the expression of markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2), apoptosis (Smac/DIABLO and NF-κB), and heat shock proteins (HSP27, HSP70, HSP90) in the cerebral cortex. Our study demonstrated that the (±)cis stereoisomer dose-dependently induced psychomotor agitation, sweating, salivation, hyperthermia, stimulated aggression, convulsions and death. Conversely, the (±)trans stereoisomer was ineffective whilst the stereoisomers’ co-administration resulted in a worsening of the toxic (±)cis stereoisomer effects. This trend of responses was confirmed by immunohistochemical analysis on the cortex. Finally, we investigated the potentially toxic effects of stereoisomer co-administration by studying urinary excretion. The excretion study showed that the (±)trans stereoisomer reduced the metabolism of the (±)cis form and increased its amount in the urine, possibly reflecting its increased plasma levels and, therefore, the worsening of its toxicity. Full article

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

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14 pages, 1816 KiB

Open AccessArticle

Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice

by Laia Alegre-Zurano, Raúl López-Arnau, Miguel Á. Luján, Jordi Camarasa and Olga Valverde

Int. J. Mol. Sci. 2021, 22(15), 8304; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158304 - 02 Aug 2021

Cited by 4 | Viewed by 2668

Abstract

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the “bath salts”. Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed. Full article

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

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31 pages, 5371 KiB

Open AccessArticle

In Vitro and In Vivo Pharmaco-Toxicological Characterization of 1-Cyclohexyl-x-methoxybenzene Derivatives in Mice: Comparison with Tramadol and PCP

by Sabrine Bilel, Micaela Tirri, Raffaella Arfè, Chiara Sturaro, Anna Fantinati, Virginia Cristofori, Tatiana Bernardi, Federica Boccuto, Marco Cavallo, Alessandro Cavalli, Fabio De-Giorgio, Girolamo Calò and Matteo Marti

Int. J. Mol. Sci. 2021, 22(14), 7659; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147659 - 17 Jul 2021

Cited by 6 | Viewed by 2176

Abstract

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm. Full article

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

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12 pages, 974 KiB

Open AccessArticle

Single Exposure to the Cathinones MDPV and α-PVP Alters Molecular Markers of Neuroplasticity in the Adult Mouse Brain

by Lucia Caffino, Francesca Mottarlini, Sabrine Bilel, Giorgia Targa, Micaela Tirri, Coralie Maggi, Matteo Marti and Fabio Fumagalli

Int. J. Mol. Sci. 2021, 22(14), 7397; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147397 - 09 Jul 2021

Cited by 3 | Viewed by 2968

Abstract

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity. Full article

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

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