Search Results (20)

Synthetic cathinones represent the second most frequently reported group of new psychoactive substances identified annually, according to the United Nations. It remains unknown whether specific derivatives differ in the onset of effects related to absorption kinetics. Clephedrone (4-chloromethcathinone, 4-CMC) has been among the most frequently seized cathinones in recent years; however, available data on its pharmacology and abuse potential remain scarce. A non-controlled, prospective, observational study was conducted involving eight healthy volunteers (six women) who self-administered a single oral dose of clephedrone (100 or 150 mg). Study variables were assessed at baseline and over a 5-h period following administration, including vital signs and subjective effects. Oral fluid concentrations of clephedrone and cortisol were determined. For comparison, this article also presents previously unpublished data from a pilot study in which 12 healthy male participants received 150 or 200 mg of methylone under comparable conditions to evaluate effects. Results indicated that both clephedrone and methylone produced stimulant-like subjective effects. However, clephedrone exhibited a delayed onset and peak of effects compared with methylone, indicating a clinically relevant pharmacokinetic difference. Both substances were detected in oral fluid, with peak concentrations occurring later following clephedrone administration, consistent with its delayed pharmacodynamic profile. Full article

Synthetic cathinones (SCs), commonly referred to as “bath salts”, are a class of novel psychoactive substances (NPSs) that elicit amphetamine-like effects and severe cardiovascular outcomes, including myocardial infarction and sudden cardiac death. Despite these risks, the mechanisms underlying SC-induced cardiotoxicity remain poorly studied. This study investigated the in vitro cardiotoxicity of two prevalent SCs—methylone and 3,4-dimethylmethcathinone (3,4-DMMC)—in H9c2 rat cardiomyoblasts, focusing on oxidative stress and the potential protective role of antioxidants. Cells were exposed to methylone (0.01–4.0 mM) or 3,4-DMMC (0.0005–0.8 mM) for 24 and 48 h, and cytotoxicity was assessed by an MTT assay. Intracellular reactive oxygen/nitrogen species (ROS/RNS) were quantified by fluorescence, and antioxidant effects were evaluated using ascorbic acid, N-acetylcysteine, and Trolox. Both SCs caused concentration-dependent cytotoxicity, with 3,4-DMMC showing higher potency than methylone (IC₅₀: 0.28 vs. 0.98 mM, p = 0.0013). ROS/RNS levels increased in a concentration- and time-dependent manner for both compounds, reflecting early and sustained redox imbalance. Of the antioxidants, only ascorbic acid significantly improved cell viability. Taken together, these findings demonstrate for the first time that methylone and 3,4-DMMC exert cardiotoxic effects in vitro, with oxidative stress as a key contributor. The protective effect of ascorbic acid highlights its potential as a therapeutic candidate against SC-induced cardiac injury. Full article

Drug abuse presents a significant global health challenge as the illicit drug market progresses from classic drugs to a growing prevalence of New Psychoactive Substances (NPS), particularly synthetic cathinones, which, although illegal, are often falsely marketed as safe and legal alternatives. The rapid increase in the use of these drugs complicates the assessment of their safety and effects on human health. However, they pose unique toxicological concerns that remain largely uncharacterized. This study investigated the toxic effects of three synthetic cathinones, namely, methylone, pentedrone, and 4-methylethcathinone (4-MEC), using the model organism C. elegans. We assessed the impact of these substances on animal survival, development, reproductive behavior, and longevity. Our results showed that short-term exposure (24 h) to concentrations of 5.0 mM or higher significantly reduced animal survival rates, while prolonged exposure (72 h) led to more pronounced toxicity, significantly reducing survival rates at concentrations as low as 1.0 mM. Moreover, sublethal concentrations resulted in developmental arrest. Additionally, pentedrone impaired reproductive capacity, while 4-MEC significantly shortened C. elegans lifespan. These findings highlight the urgent need for further investigation into the implications of synthetic cathinone use on human health through in vivo models as their prevalence in the illicit drug market continues to rise. Full article

Structural modifications to synthetic psychoactive cathinones (SPCs), a class of drugs that contain a β-keto modification of the phenethylamine pharmacophore of amphetamine, induce differences in dopamine transporter (DAT) activity. Here, in vivo retrodialysis was utilized to deliver the SPCs 3,4-methylenedioxypyrovalerone (MDPV, a DAT inhibitor) or methylone (a DAT substrate) into the caudate putamen of male Sprague-Dawley rats. Dialysate samples were collected prior to and post drug administration, and temporal changes in dopamine concentration were quantified using HPLC-EC methods. Methylone elicited a 200% increase and MDPV a 470% increase in dopamine levels at the 10 min time point. The findings demonstrate that in vivo retrodialysis can be used to evaluate the effects of SPCs on neurotransmission in the brain. Full article

The increasing number of new psychoactive substances (NPS) entering the illicit drug market, especially synthetic cathinones, as well as the risk of cardiovascular complications, is intensifying the need to quickly assess their cardiotoxic potential. The present study aims to evaluate the cardiovascular toxicity and lethality induced by first-generation synthetic cathinones (mephedrone, methylone, and MDPV) and more classical psychostimulants (cocaine and MDMA) in zebrafish embryos using a new approach methodology (NAM). Zebrafish embryos at 4 dpf were exposed to the test drugs for 24 h to identify drug lethality. Drug-induced effects on ventricular and atrial heart rate after 2 h exposure were evaluated, and video recordings were properly analyzed. All illicit drugs displayed similar 24 h LC₅₀ values. Our results indicate that all drugs are able to induce bradycardia, arrhythmia, and atrial-ventricular block (AV block), signs of QT interval prolongation. However, only MDPV induced a different rhythmicity change depending on the chamber and was the most potent bradycardia and AV block-inducing drug compared to the other tested compounds. In summary, our results strongly suggest that the NAM presented in this study can be used for screening NPS for their cardiotoxic effect and especially for their ability to prolong the QT intervals. Full article

The enantioselective separation of synthetic cathinones via capillary electrophoresis with ultraviolet detection (CE-UV) was successfully achieved using an acidic formate buffer with the ionic liquid tetrabutylammonium chloride (TBAC) and beta-cyclodextrin (β-CD) as co-additives. Synthetic cathinones (also known as “bath salts”) belong to a class of unregulated drugs labeled new psychoactive substances (NPS). These drugs are readily available and can cause paranoia, confusion, violence, and suicidal thoughts. The stereochemistry of synthetic cathinones, as with other drugs, can influence their potency, toxicity, metabolism, and interaction with other molecules. Thus, it is important to be able to effectively separate different types of synthetic cathinone as well as to resolve enantiomers of each. A study of buffer additives, pH, and counter ions was conducted to identify a system yielding complete enantioselective separation of synthetic cathinones by capillary electrophoresis. Buffer additives TBAC and β-CD, when used separately, did not afford the desired separation; however, when employed as co-additives, enantiomers of each of six different bath salt standards (pentylone, 4-MEC, methylone, MDPBP, MDPV, and naphyrone) were resolved. Achieving this separation of a complex mixture of closely related illicit drugs by CE using an ionic liquid and cyclodextrin together, as buffer co-additives, may provide a new starting point from which to approach the enantiomeric analysis of other drug samples as syntheses of NPS continue to rapidly evolve to evade regulation and law enforcement. Full article

This study presents a validated GC-MS/MS method for the detection and quantification of 4-chloromethcathinone or clephedrone (4-CMC), N-ethyl Pentedrone (NEP), and N-ethyl Hexedrone (NEH, also named HEXEN) in oral fluid and sweat and verifies its feasibility in determining human oral fluid concentrations and pharmacokinetics following the administration of 100 mg of 4-CMC orally and 30 mg of NEP and NEH intranasally. A total of 48 oral fluid and 12 sweat samples were collected from six consumers. After the addition of 5 μL of methylone-d₃ and 200 μL of 0.5 M ammonium hydrogen carbonate, an L/L extraction was carried out using ethyl acetate. The samples, dried under a nitrogen flow, were then derivatized with pentafluoropropionic anhydride and dried again. One microliter of the sample reconstituted in 50 μL of ethyl acetate was injected into GC-MS/MS. The method was fully validated according to international guidelines. Our results showed how, in oral fluid, the two cathinones taken intranasally were absorbed very rapidly, within the first hour, when compared with the 4-CMC which reached its maximum concentration peak in the first three hours. We observed that these cathinones were excreted in sweat in an amount equivalent to approximately 0.3% of the administered dose for 4-CMC and NEP. The total NEH excreted in sweat 4 h after administration was approximately 0.2% of the administered dose. Our results provide, for the first time, preliminary information about the disposition of these synthetic cathinones in the consumers’ oral fluid and sweat after controlled administration. Full article

The aim of this study was to determine the excretion of methylone and its metabolites in sweat following the ingestion of increasing controlled doses of 50, 100, 150 and 200 mg of methylone to twelve healthy volunteers involved in a clinical trial. Methylone and its metabolites 4-hydroxy-3-methoxy-N-methylcathinone (HMMC) and 3,4-methylenedioxycathinone (MDC) were analyzed in sweat patches by liquid chromatography–tandem mass spectrometry. Methylone and MDC were detected in sweat at 2 h and reached their highest accumulation (C_max) at 24 h after the administration of 50, 100, 150 and 200 mg doses. In contrast, HMMC was not detectable at any time interval after each dose. Sweat proved to be a suitable matrix for methylone and its metabolites’ determination in clinical and toxicological studies, providing a concentration that reveals recent drug consumption. Full article

Background: Prior work has reported that a drug’s aversive effects (as indexed by taste avoidance conditioning) are attenuated when the pre-exposure and conditioning drugs are the same or different. The latter, otherwise known as cross-drug pre-exposure, is especially interesting as it has been used as a tool to assess mechanisms underlying the aversive effects of drugs. We previously reported that methylone pre-exposure differentially impacted the aversive effects of MDPV and MDMA (MDPV > MDMA), a difference consistent with the dopaminergic mediation of methylone’s aversive effects. To examine the possible role of serotonin (5-HT) in methylone’s aversive effects, the present study assessed the effects of methylone pre-exposure on taste avoidance induced by the 5-HT reuptake inhibitor fluoxetine. Methods: Male and female Sprague-Dawley rats were exposed to 10 mg/kg of methylone every 4th day (for a total of 5 injections) prior to taste avoidance training with 10 mg/kg of fluoxetine. Results: Fluoxetine induced significant taste avoidance (each p < 0.05) that was independent of sex. Methylone pre-exposure had no impact on avoidance produced by fluoxetine in either males or females (each p > 0.05). Conclusions: Methylone pre-exposure had no impact on fluoxetine-induced avoidance. These findings suggest that it is unlikely that 5-HT mediates the aversive effects of methylone. The implications of the present results for the mechanisms mediating methylone’s aversive effects were discussed. Understanding such mechanisms is important in predictions relevant to drug history and abuse liability as a variety of subject and experiential factors known to affect (reduce) a drug’s aversive effects may increase its use and potential for abuse. Full article

The aim of this study was to investigate methylone and its metabolites concentration in oral fluid following controlled increasing doses, focusing on the effect of oral fluid pH. Samples were obtained from a clinical trial where twelve healthy volunteers participated after ingestion of 50, 100, 150 and 200 mg of methylone. Concentration of methylone and its metabolites 4-hydroxy-3-methoxy-N-methylcathinone (HMMC) and 3,4-methylenedioxycathinone in oral fluid were measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Pharmacokinetic parameters were estimated, and the oral fluid-to-plasma ratio (OF/P) at each time interval was calculated and correlated with the oral fluid pH using data from our previous study in plasma. Methylone was detected at all time intervals after each dose; MDC and HMMC were not detectable after the lowest dose. Oral fluid concentrations of methylone ranged between 88.3–503.8, 85.5–5002.3, 182.8–13,201.8 and 214.6–22,684.6 ng/mL following 50, 100, 150 and 200 mg doses, respectively, peaked between 1.5 and 2.0 h, and were followed by a progressive decrease. Oral fluid pH was demonstrated to be affected by methylone administration. Oral fluid is a valid alternative to plasma for methylone determination for clinical and toxicological studies, allowing for a simple, easy and non-invasive sample collection. Full article

Herein, the Hirshfeld surfaces analysis of the crystalline methylone hydrochloride was performed in order to analyze NH⋯Cl, CH⋯Cl, and CH⋯O intermolecular interactions and study the formation of the NН₂⁺–Cl⁻ salt fragment in methylone hydrochloride crystal. There are two isomeric dimers with parallel and side-by-side orientation extracted from the crystal packing to model the IR spectrum of the crystalline methylone hydrochloride within the framework of density functional theory (DFT) and B3LYP/6-31G(d,p) method. We have assigned and interpreted all observed IR bands in the experimental spectrum of the 3,4-methylenedioxymethcathinone hydrochloride standard crystal sample that is important for forensic-medical examination. It was shown that intermolecular interactions between the NН₂⁺ and Cl⁻ ionic moieties occur in crystalline samples that confirm the presence of the ionized form of the methylone hydrochloride compound with the NН₂⁺Cl⁻ fragment. Full article

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d₅, MDA-d₅ and methylone-d₃ internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with 0.1 mL acidified methanol and evaporated under nitrogen. Samples were reconstituted with a mobile phase and injected into the LC-MS/MS instrument. The method was fully validated according to OSAC guidelines (USA). Methylone plasma concentrations increased in a dose-proportional manner, as demonstrated by the increasing maximum concentration (Cmax) and area under the curve of concentrations (AUC). Methylone Cmax values were reported as 153, 304, 355 and 604 ng/mL, AUC0–24 values were reported as 1042.8, 2441.2, 3524.4 and 5067.9 h·ng/mL and T_1/2 values as 5.8, 6.4, 6.9 and 6.4 h following the 50, 100, 150 and 200 mg doses, respectively. Methylone exhibited rapid kinetics with a Tmax of 1.5 h for the 50 mg dose and 2 h approximately after all the other doses. HMMC exhibited faster kinetics compared to methylone, with a Cmax value that was 10–14-fold lower and an AUC0–24 value that was 21–29-fold lower. Methylone pharmacokinetics was linear across 50–200 mg oral doses in humans, unlike the previously described non-linear oral MDMA pharmacokinetics. An LC-MS/MS method for the quantification of methylone, MDMA and their metabolites in human plasma was achieved. Methylone exhibited linear pharmacokinetics in humans with oral doses of 50–200 mg. Full article

Liver damage is a common issue associated with synthetic cathinones abuse. Indeed, human stem cell-derived hepatocyte-like cells (HLCs) have been used as alternative in vitro models for hepatotoxicity studies, due to their ability to maintain a stable hepatic-specific phenotype. Furthermore, all cathinone derivatives are chiral, and their biological effects can differ for each enantiomer. Thus, the aim of this work was to evaluate the cytotoxicity and metabolism of pentedrone and methylone enantiomers using HLC models. Human neonatal mesenchymal stem cells were differentiated into HLCs by a three-step differentiation protocol and maintained under 2D and 3D culture conditions. Subsequently, pentedrone and methylone enantiomers were isolated by HPLC using a chiral stationary phase. Cell viability was evaluated through the CellTiter-Glo assay and the formation of methylone and pentedrone metabolites was analyzed by GS-MS. The racemates of pentedrone and methylone exhibited potential hepatotoxicity in a concentration-dependent manner in both models. Different cytotoxic profiles for pentedrone enantiomers were observed in HLC 3D, with R-(-)-pentedrone being the most cytotoxic. Concerning HLC 2D metabolic assays, S-(-)-methylone was preferentially metabolized via N-demethylation, whereas R-(+)-methylone was metabolized by O-demethylation and N-hydroxylation. However, in HLC 3D assays, R-(+)-methylone was preferentially metabolized by all metabolic pathways, except for O-demethylation. Regarding pentedrone enantiomers, the metabolic pathways studied were more pronounced for R-(-)-pentedrone, namely N-demethylation and β-keto reduction in both models. Overall, this study revealed stereoselectivity in cytotoxicity and metabolism pathways for pentedrone and methylone. Full article

Pentedrone and methylone can express stereoselectivity in toxicokinetic and toxicodynamic processes. Similarly, their chiral discrimination in metabolism, which was not yet evaluated, can result in different metabolic profiles and subsequent hepatotoxic effects. Therefore, the aim of this work was to assess, for the first time, both the hepatic cytotoxic and metabolic profile of pentedrone and methylone enantiomers using physiologically relevant in vitro models. The hepatotoxicity of these compounds was observed in a concentration-dependent manner in human stem-cell-derived hepatocyte-like cells (HLCs) cultured under 3D (3D-HLCs) and 2D (2D-HLCs) conditions. Enantioselectivity, on the other hand, was only shown for pentedrone (1 mM) in 3D-HLCs, being R-(−)-pentedrone the most cytotoxic. Furthermore, the metabolic profile was initially evaluated in human liver microsomes (HLM) and further demonstrated in 3D-HLCs and 2D-HLCs applying a gas chromatography coupled to a mass spectrometer (GC–MS) technique. Methylone and pentedrone showed distinct and preferential metabolic routes for their enantiomers, resulting in the production of differentiated metabolites; R-(+)-methylone and R-(−)-pentedrone are the most metabolized enantiomers. In conclusion, the results demonstrated enantioselectivity for pentedrone and methylone in the metabolic processes, with enantioselectivity in cytotoxicity for pentedrone. Full article

Introduction and objective: Assessing the abuse potential of new substances with central nervous system activity is essential for preventing possible risks of misuse and addiction. The same methodology is recommended for the evaluation of the abuse potential of recreational drugs. This systematic review aims to assess the pharmacological effects related to the abuse potential and pharmacokinetics of cathinones, which are evaluated in both experimental and prospective observational studies in humans. Materials and Methods: A systematic search of the published literature was conducted to retrieve studies that had administered cathinone, mephedrone, methylone, and diethylpropion to evaluate their acute pharmacological effects related to abuse potential. Results: The search yielded 583 results, 18 of which were included to assess the abuse potential of cathinone (n = 5), mephedrone (n = 7), methylone (n = 1), and diethylpropion (n = 5). All four substances induce stimulant and euphorigenic effects that resemble those of amphetamines and MDMA, and their different intensities may be associated with varying levels of abuse potential. Conclusions: Cathinone, mephedrone, methylone, and diethylpropion induce a range of desirable and reinforcing effects that may, to some extent, result in abuse potential. Further investigation is needed to minimize and prevent their impact on society and public health. Full article