International Journal of Molecular Sciences

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Open AccessEditorial

Molecular Insights on New Psychoactive Substances (NPSs)

by Francesco Paolo Busardò and Simona Pichini

Int. J. Mol. Sci. 2022, 23(6), 3282; https://doi.org/10.3390/ijms23063282 - 18 Mar 2022

Cited by 6 | Viewed by 1782

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

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16 pages, 2844 KiB

Open AccessArticle

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://doi.org/10.3390/ijms22158277 - 31 Jul 2021

Cited by 21 | Viewed by 4543

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-HT_1A, 5-HT_2A, 5-HT_2B, and 5-HT_2C 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))

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20 pages, 2384 KiB

Open AccessArticle

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://doi.org/10.3390/ijms22136785 - 24 Jun 2021

Cited by 17 | Viewed by 4093

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))

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14 pages, 3907 KiB

Open AccessArticle

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://doi.org/10.3390/ijms22126320 - 12 Jun 2021

Cited by 12 | Viewed by 2593

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))

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21 pages, 1901 KiB

Open AccessArticle

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://doi.org/10.3390/ijms22084000 - 13 Apr 2021

Cited by 23 | Viewed by 4438

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))

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17 pages, 2802 KiB

Open AccessArticle

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://doi.org/10.3390/ijms22010230 - 28 Dec 2020

Cited by 21 | Viewed by 3698

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))

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14 pages, 1336 KiB

Open AccessArticle

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://doi.org/10.3390/ijms21249414 - 10 Dec 2020

Cited by 16 | Viewed by 4670

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))

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30 pages, 1436 KiB

Open AccessReview

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://doi.org/10.3390/ijms21239279 - 4 Dec 2020

Cited by 32 | Viewed by 12934

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-HT_2A 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))

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