Search Results (31)

Background/Objectives: The emergence of cathinone-based psychostimulants necessitates ongoing research and analysis of the characteristics and properties of novel derivatives. The metabolic fate of five novel cathinone-derived substances (ASProp, MASProp, MASPent, PySProp, and PySPent) containing a selenophene moiety was investigated in vitro and in vivo. Methods: All compounds were incubated individually with pooled human liver S9 fraction. A monooxygenase activity screening investigating the metabolic contribution of eleven recombinant phase I isoenzymes was conducted. Rat urine after oral administration was prepared by urine precipitation. Liquid chromatography–high-resolution tandem mass spectrometry was used for the analysis of all samples. Reversed-phase liquid chromatography (RPLC) and zwitterionic hydrophilic interaction liquid chromatography (HILIC) were used to evaluate and compare the metabolites’ chromatographic resolution. Results: Phase I reactions of ASProp, MASProp, MASPent, PySProp, and PySPent included N-dealkylation, hydroxylation, reduction, and combinations thereof. The monooxygenase activity screening revealed the contribution of various isozymes. Phase II reactions detected in vivo included N-acetylation and glucuronidation. Both chromatographic columns complemented each other. Conclusions: All substances revealed metabolic reactions comparable to those observed for other synthetic cathinones. Contributions from isozymes to their metabolism minimized the risk of drug–drug interactions. The identified metabolites should be considered as targets in human biosamples, especially in urine screening procedures. RPLC and HILIC can both be recommended for this purpose. Full article

In this study, two isomeric cathinone derivatives, N-butyl-norbutylone and N-ethylhexylone, seized on the illicit drug market in Poland, were described and characterized by various instrumental analytical methods. The compounds were characterized by electrospray ionization mass spectrometry, high-resolution mass spectrometry, gas chromatography–mass spectrometry, and nuclear magnetic resonance spectroscopy. The two investigated compounds were confirmed as 1-(2H-1,3-benzodioxol-5-yl)-2-(butylamino)butan-1-one and 1-(2H-1,3-benzodioxol-5-yl)-2-(ethylamino)hexane-1-one, both of which were cathinone derivatives available on the new psychoactive substances (NPS) market. The obtained analytical data should be useful for forensic and toxicological purposes for quick and reliable compound identification. Full article

Khat, derived from the Catha edulis plant, is widely consumed in East Africa and the Arabian Peninsula, where it holds significant socio-cultural importance. This review examines the multifaceted effects of khat, particularly focusing on its cardiovascular implications. Khat’s active constituents, notably cathinone and cathine, exhibit stimulant and psychoactive properties akin to amphetamines, leading to heightened alertness and euphoria. However, chronic consumption is associated with adverse effects, including cardiovascular diseases such as hypertension, myocardial infarction, and cardiomyopathy. The review highlights the pharmacokinetics of khat, with cathinone being rapidly absorbed and leading to sympathomimetic effects. Studies indicate a correlation between chronic khat use and increased risks of hypertension, acute coronary syndromes, and cardiomyopathy. These cardiovascular conditions are exacerbated by prolonged hemodynamic stress, catecholamine release, and oxidative stress induced by khat’s active compounds. Additionally, khat’s impact extends beyond the cardiovascular system, affecting neurological, reproductive, and gastrointestinal health. Despite its legality in certain regions, khat is classified as a controlled substance in many countries, emphasizing the need for global awareness of its health risks. This review calls for longitudinal studies to elucidate the pathophysiological mechanisms of khat-induced cardiomyopathy and to identify potential biomarkers for its early detection. Furthermore, it advocates for culturally sensitive public health initiatives and clinical guidelines to mitigate the adverse health effects of khat consumption, especially among immigrant populations in developed nations. Recognizing and addressing khat’s cardiovascular implications is crucial for improving patient outcomes and guiding effective clinical practice. Full article

Cathinone and its synthetic derivatives belong to organic compounds with narcotic properties. Their structural diversity and massive illegal use create the need to develop new analytical methods for their identification in different matrices. NMR spectroscopy is one of the most versatile methods for identifying the structure of organic substances. However, its use could sometimes be very difficult and time-consuming due to the complexity of NMR spectra, as well as the technical limitations of measurements. In such cases, molecular modeling serves as a good supporting technique for interpreting ambiguous spectral data. Theoretical prediction of NMR spectra includes calculation of nuclear magnetic shieldings and sometimes also indirect spin–spin coupling constants (SSCC). The quality of theoretical prediction is strongly dependent on the choice of the theory level. In the current study, cathinone and its 12 fluorinated derivatives were selected for gauge-including atomic orbital (GIAO) NMR calculations using Hartree–Fock (HF) and 28 density functionals combined with 6-311++G** basis set to find the optimal level of theory for ¹H, ¹³C, and ¹⁹F chemical shifts modeling. All calculations were performed in the gas phase, and solutions were modeled with a polarized-continuum model (PCM) and solvation model based on density (SMD). The results were critically compared with available experimental data. Full article

The emergence of new psychoactive substances (NPS) in the global drug market since the 2000s has posed major challenges for regulators and law enforcement agencies. Among these, synthetic cathinones have gained prominence due to their stimulant effects on the central nervous system, leading to widespread recreational use. These compounds, often marketed as alternatives to illicit stimulants such as amphetamines and cocaine, have been linked to numerous cases of intoxication, addiction and death. The structural diversity and enantiomeric forms of synthetic cathinones further complicate their detection and regulation and pose challenges to forensic toxicology. In addition to their psychoactive and toxicological effects, new research suggests that cathinones may have antimicrobial properties. Compounds derived from Catha edulis (khat), including cathinone, have shown antimicrobial activity against multidrug-resistant bacteria such as Staphylococcus aureus and Escherichia coli, highlighting their potential role in the fight against antibiotic resistance. This article provides an overview of the chemistry, pharmacokinetics, pharmacodynamics, toxicological effects and potential antimicrobial applications of synthetic cathinones. The potential therapeutic use of cathinone-derived compounds to combat antimicrobial resistance represents an exciting new frontier in drug development, although further research is needed to balance these benefits with the psychoactive risks. Full article

Novel psychoactive substances (NPSs) are compounds plotted to modify the chemical structures of prohibited substances, offering alternatives for consumption and evading legislation. The prompt emergence of these substances presents challenges in health concerns and forensic assessment because of the lack of analytical standards. A viable alternative for establishing these standards involves leveraging in silico methods to acquire spectroscopic data. This study assesses the efficacy of utilizing infrared spectroscopy (IRS) data derived from density functional theory (DFT) for analyzing NPSs. Various functionals were employed to generate infrared spectra for five distinct NPS categories including the following: amphetamines, benzodiazepines, synthetic cannabinoids, cathinones, and fentanyls. PRISMA software was conceived to rationalize data management. Unsupervised learning techniques, including Hierarchical Cluster Analysis (HCA), Principal Component Analysis (PCA), and t-distributed stochastic neighbor embedding (t-SNE), were utilized to refine the assessment process. Our findings reveal no significant disparities among the different functionals used to generate infrared spectra data. Additionally, the application of unsupervised learning demonstrated adequate segregation of NPSs within their respective groups. In conclusion, integrating theoretical data and dimension reduction techniques proves to be a powerful strategy for evaluating the spectroscopic characteristics of NPSs. This underscores the potential of this combined methodology as a diagnostic tool for distinguishing IR spectra across various NPS groups, facilitating the evaluation of newly unknown compounds. Full article

Psychostimulants alter cellular morphology and activate neuroimmune signaling in a number of brain regions, yet few prior studies have investigated their persistence beyond acute abstinence or following high levels of voluntary drug intake. In this study, we examined the effects of the repeated binge-like self-administration (96 h/week for 3 weeks) of methamphetamine (METH) and 21 days of abstinence in female and male rats on changes in cell density, morphology, and cytokine levels in two addiction-related brain regions—the prefrontal cortex (PFC) and dorsal striatum (DStr). We also examined the effects of similar patterns of intake of the cocaine-like synthetic cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV) or saline as a control. Robust levels of METH and MDPV intake (~500–1000 infusions per 96 h period) were observed in both sexes. We observed no changes in astrocyte or neuron density in either region, but decreases in dendritic spine densities were observed in PFC pyramidal and DStr medium spiny neurons. The microglial cell density was decreased in the PFC of METH self-administering animals, accompanied by evidence of microglial apoptosis. Changes in microglial morphology (e.g., decreased territorial volume and ramification and increased cell soma volume) were also observed, indicative of an inflammatory-like state. Multiplex analyses of PFC and DStr cytokine content revealed elevated levels of various interleukins and chemokines only in METH self-administering animals, with region- and sex-dependent effects. Our findings suggest that voluntary binge-like METH or MDPV intake induces similar cellular perturbations in the brain, but they are divergent neuroimmune responses that persist beyond the initial abstinence phase. Full article

Synthetic cathinones, derived from cathinone found in the plant Catha edulis, represent the second largest and most frequently seized group of new psychoactive substances. They are considered as β-keto analogs of amphetamine, sharing pharmacological effects with amphetamine and cocaine. This review describes the neurotoxic properties of synthetic cathinones, encompassing their capacity to induce neuroinflammation, dysregulate neurotransmitter systems, and alter monoamine transporters and receptors. Additionally, it discusses the rewarding and abuse potential of synthetic cathinones drawing from findings obtained through various preclinical animal models, contextualized with other classical psychostimulants. The review also offers an overview of current abuse trends of synthetic cathinones on the illicit drug market, specifying the aspects covered, and underscores the risks they pose to public health. Finally, the review discusses public health initiatives and efforts to reduce the hazards of synthetic cathinones, including harm reduction methods, education, and current clinical management strategies. Full article

New Psychoactive Substances are currently a serious and growing problem affecting public health worldwide. By 2022, 1184 of these substances had been identified over a period of 16 years. Within these, α-pyrrolidinohexanophenone (α-PHP) and α-pyrrolidinoisohexanophenone (α-PiHP) have emerged, two synthetic cathinones from the pyrovalerone derivates subgroup that are positional isomers of each other. Alpha-PHP appeared on the Japanese illicit drug market in 2014 and, two years later, α-PiHP was identified for the first time in China. They were placed in schedule II on the list of Psychotropic Substances under International Control in 2020 and in March 2023, respectively. Both cathinones have no therapeutic potential for medical use and therefore are abused for recreational habits, which can lead to fatalities. The most frequent adverse effects reported are cardiac, psychiatric, and neurologic, and fatal intoxications have already been described. In Portugal, their consumption and consequent seizures are more prevalent on the archipelagos, which has been aggravating the health situation. In conclusion, these types of substances are a challenge for forensic toxicology since they are easily synthesized, modified, and placed on the market. Therefore, more studies to develop analytical methods to detect them and more comprehensive legislation should be applied. Thus, this review aimed to address the legislative, physicochemical, toxicological, and analytical aspects of both substances. Full article

The characteristic alkaloid component of the leaves of the catnip shrub (Catha edulis) is cathinone, and its synthetic analogs form a major group of recreational drugs. Cathinone derivatives are chiral compounds. In the literature, several chiral methods using cyclodextrins (CDs) have been achieved so far for diverse sets of analogs; however, a comprehensive investigation of the stability of their CD complexes has not been performed yet. To characterize the enantioselective complex formation, a systematic experimental design was developed in which a total number of 40 neutral, positively, and negatively charged CD derivatives were screened by affinity capillary electrophoresis and compared according to their cavity size, substituent type, and location. The functional groups responsible for the favorable interactions were identified in the case of para-substituted cathinone analog mephedrone, flephedrone, and 4-methylethcathinone (4-MEC) and in the case of 3,4-methylendioxy derivative butylone and methylenedioxypyrovalerone (MDPV). The succinylated-β-CD and subetadex exhibited the highest complex stabilities among the studied drugs. The complex stoichiometry was determined using the Job’s plot method, and the complex structures were further studied using ROESY NMR measurements. The results of our enantioselective complex formation study can facilitate chiral method development and may lead to evaluate potential CD-based antidotes for cathinone analogs. Full article

Increasing reports of neurological and psychiatric outcomes due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the understanding of neurotoxic mechanisms is still lacking, particularly for the under-investigated αPHP, one of the major MDPV derivatives. In particular, its effects on neural stem/progenitor cell cultures (NSPCs) are still unexplored. Therefore, in the current in vitro study, the effects of increasing αPHP concentrations (25–2000 μM), on cell viability/proliferation, morphology/ultrastructure, genotoxicity and cell death pathways, have been evaluated after exposure in murine NSPCs, using a battery of complementary techniques, i.e., MTT and clonogenic assay, flow cytometry, immunocytochemistry, TEM, and patch clamp. We revealed that αPHP was able to induce a dose-dependent significant decrease of the viability, proliferation and clonal capability of the NSPCs, paralleled by the resting membrane potential depolarization and apoptotic/autophagic/necroptotic pathway activation. Moreover, ultrastructural alterations were clearly observed. Overall, our current findings demonstrate that αPHP, damaging NSPCs and the morpho-functional fundamental units of adult neurogenic niches may affect neurogenesis, possibly triggering long-lasting, irreversible CNS damage. The present investigation could pave the way for a broadened understanding of SCs toxicology, needed to establish an appropriate treatment for NPS and the potential consequences for public health. Full article

The proliferation of new psychoactive substances (NPSs) in recent years has posed a significant challenge to public health. Traditional monitoring methods have proven insufficient in tracking these constantly evolving substances, leading to the development of alternative approaches such as wastewater-based epidemiology (WBE). The present study aims to utilize high-resolution mass spectrometry (HRMS)-based targeted and suspect screening to profile NPS, other illicit drugs, and drug-related compounds in a Taiwanese wastewater sample. For the targeted analysis, 8 out 18 standards of illicit drugs have been identified. The suspect screening approach based on approximately 3600 substances in the SWGDRUG library can further identify 92 compounds, including opiate analgesics, synthetic cathinones, phenylalkylamines derivatives, phenethylamine derivatives, tryptamine derivatives, steroids, and ephedrine-related compounds. Additionally, the presence of 5-methoxy-2-aminoindane (MEAI) in the wastewater indicates that drug dealers have recently sold this potential NPS to evade drug regulations. This study firstly reports the HRMS-based comprehensive profile of NPS, other illicit drugs, and drug-related compounds in Taiwan, which could be applied as biomarkers for estimating the consumption of drugs. Full article

In this paper, two cathinone derivatives, 4F-3Me-α-PVP and N-ethylheptedrone, seized on the illegal drug market in Poland, were described and characterized by various instrumental analytical methods. The compounds were characterized by electrospray ionization mass spectrometry, high-resolution mass spectrometry, gas chromatography–mass spectrometry, infrared spectroscopy, X-ray crystallography, thermogravimetric analysis, differential scanning calorimetry and nuclear magnetic resonance spectroscopy. The two tested compounds were confirmed as 1-(4-fluoro-3-methylphenyl)-2-(pyrrolidin-1-yl)pentan-1-one and N-ethyl-2-amino-1-phenylheptan-1-one hydrochlorides; both are cathinone derivatives available on the market for new psychoactive substances (NPS). The obtained analytical data should be useful for forensic and toxicological purposes in the rapid and reliable identification of compounds. Full article

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers’ stability up to 48 h at room temperature and 24 h at 37 °C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins—brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)—was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed. Full article

The enantioselective potential of two macrocyclic glycopeptide-based chiral stationary phases for analysis of 28 structurally diverse biologically active compounds such as derivatives of pyrovalerone, ketamine, cathinone, and other representatives of psychostimulants and antidepressants was evaluated in sub/supercritical fluid chromatography. The chiral selectors immobilized on 2.7 μm superficially porous particles were teicoplanin (TeicoShell column) and modified macrocyclic glycopeptide (NicoShell column). The influence of the organic modifier and different mobile phase additives on the retention and enantioresolution were investigated. The obtained results confirmed that the mobile phase additives, especially water as a single additive or in combination with basic and acidic additives, improve peak shape and enhance enantioresolution. In addition, the effect of temperature was evaluated to optimize the enantioseparation process. Both columns exhibited comparable enantioselectivity, approximately 90% of the compounds tested were enantioseparated, and 30% out of them were baseline enantioresolved under the tested conditions. The complementary enantioselectivity of the macrocyclic glycopeptide-based chiral stationary phases was emphasized. This work can be useful for the method development for the enantioseparation of basic biologically active compounds of interest. Full article