Toxicity of New Psychoactive Substance (NPS): Threo-4-methylmethylphenidate (4-Mmph) - Prediction of toxicity using in silico methods.

This study represents the first application of in silico methods to evaluate the toxicity of 4-methylphenidate (4-Mmph), a new psychoactive substance (NPS). Using advanced in silico toxicology tools, it was feasible to anticipate key aspects of 4-Mmph's toxicological profile, including acute toxicity (LD50), genotoxicity, cardiotoxicity, and possible endocrine disruption. The findings indicate significant acute toxicity with variability among species, a high potential for adverse effects in the gastrointestinal system and lungs, a low genotoxic potential, a significant likelihood of skin irritation, and a notable cardiotoxicity risk associated with hERG channel inhibition. Evaluation of endocrine disruption revealed a low likelihood that 4-Mmph interacts with the estrogen receptor alpha (ER-α), indicating minimal estrogenic activity. These insights, derived from in silico studies, play a crucial role in improving the comprehension of 4-Mmph in forensic and clinical toxicology. These initial toxicological inquiries establish the foundation for future investigations and help formulate risk assessment and management strategies regarding the use and abuse of NPS. This article is part of a larger project funded by the Polish Ministry of Education and Science, titled "Toxicovigilance, Poisoning Prevention, and First Aid in Poisoning with Xenobiotics of Current Clinical Importance in Poland" (Grant Number SKN/SP/570184/2023).

[Identification of Δ8-Tetrahydrocannabinol (THC) and Δ9-THC Analogs, with Different Lengths of Alkyl Chain at C-3 Position, in Oil Products Distributed on the Internet].

Since around 2021, products claiming to contain a Δ9-tetrahydrocannabinol (THC) analog with different lengths of alkyl chain at C-3 position have been sold on the internet in Japan. Δ9-THC has a pentyl group derived from the precursor olivetol at the C-3 position. These products include liquid cartridges for electronic cigarettes, herbal products, and gummy products. This study analyzed and determined the ingredients in five oil products distributed on the internet from 2022 to 2023 that claim to contain THC analogs. Samples of each product were used for GC-MS and LC-MS measurements. After isolating and purifying the unknown components from the products, structural analysis was performed by measuring 1H, 13C-NMR and various two-dimensional NMR [HH correlation spectroscopy (H-H COSY), heteronuclear multiple quantum coherence (HMQC), heteronuclear multiple-bond correlation (HMBC), and nuclear Overhauser effect spectroscopy (NOESY)]. The analysis identified Δ8-tetrahydrocannabivarin (THCV), Δ9-THCV, Δ8-tetrahydrocannabutol (THCB), Δ9-THCB, Δ8-tetrahydrocannabihexol (THCH), Δ9-THCH, Δ8-3-octyl-THC (THCjd) and Δ9-THCjd. These compounds were Δ8-THC or Δ9-THC analogs with different lengths of alkyl chain at C-3 position. Meanwhile, Δ4(8)-iso-THCV and Δ11-THCB were identified as minor components of the product, and were considered to be the reaction byproducts of the synthesis of the Δ8-THC or Δ9-THC analogs. In the future, there are concerns about the distribution of products containing new THC analogs. Therefore, continuous provision monitoring of newly detected in the products is important.

In vitro metabolic studies and machine learning analysis of mass spectrometry data: A dual strategy for differentiating alpha-pyrrolidinohexiophenone (α-PHP) and alpha-pyrrolidinoisohexanophenone (α-PiHP) in urine analysis.

Synthetic cathinones are some of the most prevalent new psychoactive substances (NPSs) globally, with alpha-pyrrolidinoisohexanophenone (α-PiHP) being particularly noted for its widespread use in the United States, Europe, and Taiwan. However, the analysis of isomeric NPSs such as α-PiHP and alpha-pyrrolidinohexiophenone (α-PHP) is challenging owing to similarities in their retention times and mass spectra. This study proposes a dual strategy based on in vitro metabolic experiments and machine learning-based classification modelling for differentiating α-PHP and α-PiHP in urine samples: (1) in vitro metabolic experiments using pooled human liver microsomes and liquid chromatography tandem quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) were conducted to identify the key metabolites of α-PHP and α-PiHP from the high-resolution MS/MS spectra. After 5 h incubation, 71.4 % of α-PHP and 64.7 % of α-PiHP remained unmetabolised. Nine phase I metabolites were identified for each compound, including primary ß-ketone reduction (M1) metabolites. Comparing the metabolites and retention times confirmed the efficacy of in vitro metabolic experiments for differentiating NPS isomers. Subsequently, analysis of seven real urine samples revealed the presence for various metabolites, including M1, that could be used as suitable detection markers at low concentrations. The aliphatic hydroxylation (M2) metabolite peak counts and metabolite retention times were used to determine α-PiHP use. (2) Classification models for the parent compounds and M1 metabolites were developed using principal component analysis for feature extraction and logistic regression for classification. The training and test sets were devised from the spectra of standard samples or supernatants from in vitro metabolism experiments with different incubation times. Both models had classification accuracies of 100 % and accurately identified α-PiHP and its M1 metabolite in seven real urine samples. The proposed methodology effectively distinguished between such isomers and confirmed their presence at low concentrations. Overall, this study introduces a novel concept that addresses the complexities in analysing isomeric NPSs and suggests a path towards enhancing the accuracy and reliability of NPS detection.

N,N-dimethylpentylone poisoning: Clinical manifestations, analytical detection, and metabolic characterization.

INTRODUCTION: The proliferation of new psychoactive substances (NPS) poses a significant challenge to clinical and forensic toxicology laboratories. N,N-dimethylpentylone, a novel synthetic cathinone, has emerged as a public health concern. The aims of this study are to describe the clinical presentation of N,N-dimethylpentylone poisoning, to describe detection methods, and to deduce its metabolic pathways. METHODS: Clinical data was collected and reviewed retrospectively from patients with confirmed N,N-dimethylpentylone exposure. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify N,N-dimethylpentylone and its metabolites in urine samples. The metabolic pathway was characterised by comparison of the detected substances with reference standards. RESULTS: Eight cases were included in the case series. Seven different metabolites of N,N-dimethylpentylone were identified in in vivo patient urine samples, where the two major metabolic pathways were proposed to be opening of the 5-membered ring and reduction of carboxide. All patients presented with neuropsychiatric and/or cardiovascular symptoms. Co-ingestion with other substances was reported in all cases. One patient requiring intensive care was described in detail. All patients eventually recovered. The analytical method allowed the simultaneous identification of N,N-dimethylpentylone, pentylone and bisdesmethyl-N,N-dimethylpentylone, as well as other drugs of abuse in patient samples. CONCLUSION: N,N-dimethylpentylone appears to be less potent than its metabolite pentylone. Co-ingestion with other drugs of abuse is common. Poisoning cases have neuropsychiatric and cardiovascular manifestations. An updated and comprehensive laboratory method is needed for its detection.

Toxicity of the New Psychoactive Substance (NPS) Clephedrone (4-Chloromethcathinone, 4-CMC): Prediction of Toxicity Using In Silico Methods for Clinical and Forensic Purposes.

This study reports the first application of in silico methods to assess the toxicity of 4-chloromethcathinone (4-CMC), a novel psychoactive substance (NPS). Employing advanced toxicology in silico tools, it was possible to predict crucial aspects of the toxicological profile of 4-CMC, including acute toxicity (LD50), genotoxicity, cardiotoxicity, and its potential for endocrine disruption. The obtained results indicate significant acute toxicity with species-specific variability, moderate genotoxic potential suggesting the risk of DNA damage, and a notable cardiotoxicity risk associated with hERG channel inhibition. Endocrine disruption assessment revealed a low probability of 4-CMC interacting with estrogen receptor alpha (ER-α), suggesting minimal estrogenic activity. These insights, derived from in silico studies, are critical in advancing the understanding of 4-CMC properties in forensic and clinical toxicology. These initial toxicological findings provide a foundation for future research and aid in the formulation of risk assessment and management strategies in the context of the use and abuse of NPSs.

2-Methyl-4'-(methylthio)-2-morpholinopropiophenone: A commercial photoinitiator being used as a new psychoactive substance.

Synthetic cathinones, which are novel psychoactive substances, have caused major social problems worldwide. A substance called 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MMMP), which is employed as a commercial industrial photoinitiator for triggering polymerization, has a basic cathinone backbone; however, few reports regarding MMMP have been published. In the current study, three potential metabolites of MMMP-namely hydroxy-MMMP (HO-MMMP), HO-MMMP-sulfoxide (HO-MMMP-SO), and HO-MMMP-sulfone (HO-MMMP-SO2)-were successfully synthesized, and MMMP and these three potential metabolites were used as standards to establish an analytic method based on liquid chromatography-tandem mass spectrometry for the quantitative analysis of urine. This analytic method and related parameters-including dynamic range, limit of quantification, selectivity, precision, accuracy, carryover effect, matrix effect, interference, and dilution integrity-were optimized and validated. Forty urine samples from 1,691 individuals who abused drugs were determined to contain MMMP, HO-MMMP, HO-MMMP-SO, or HO-MMMP-SO2; the results of this study indicate that approximately 2.37 % of drug abusers in Taiwan consumed MMMP in 2023. These 40 urine samples were analyzed to investigate the metabolism of MMMP in humans. The results indicate that HO-MMMP-SO is the main metabolite in human urine. This study recommends HO-MMMP-SO with a concentration of 2 ng/mL as a target and cutoff value, respectively, for identifying individuals who have consumed MMMP.

Predicting the new psychoactive substance activity of antitussives and evaluating their ecotoxicity to fish.

The misuse of antitussives preparations is a continuing problem in the world, and imply that they might have potential new psychoactive substances (NPS) activity. However, few study focus on their ecological toxicity towards fish. In the present study, the machine learning (ML) methods gcForest and random forest (RF) were employed to predict NPS activity in 30 antitussives. The potential toxic target, mode of action (MOA), acute toxicity and chronic toxicity to fish were further investigated. The results showed that both gcForest and RF achieved optimal performance when utilizing combined features of molecular fingerprint (MF) and molecular descriptor (MD), with area under the curve (AUC) = 0.99, accuracy >0.94 and f1 score > 0.94, and were applied to screen the NPS activity in antitussives. A total of 15 antitussives exhibited potential NPS activity, including frequently-used substances like codeine and dextromethorphan. The binding affinity of these antitussives with zebrafish dopamine transporter (zDAT) was high, and even surpassing that of some traditional narcotics and NPS. Some antitussives formed hydrogen bonds or salt bridges with aspartate (Asp) 95, tyrosine (Tyr) 171 of zDAT. For the ecotoxicity, the MOA of these 15 antitussives in fish was predicted as narcosis. The prenoxdiazin, pholcodine, codeine, dextromethorphan and dextrorphan exhibited very toxic/toxic to fish. It was necessary to pay close attention to the ecotoxicity of these antitussives. In this study, the integration of ML, molecular docking and ECOSAR approaches are powerful tools for understanding the toxicity profiles and ecological hazards posed by new pollutants.

In Vivo and In Vitro Metabolic Fate and Urinary Detectability of Five Deschloroketamine Derivatives Studied by Means of Hyphenated Mass Spectrometry.

Ketamine derivatives such as deschloroketamine and deschloro-N-ethyl-ketamine show dissociative and psychoactive properties and their abuse as new psychoactive substances (NPSs) has been reported. Though some information is available on the biotransformation of dissociative NPSs, data on deschloro-N-cyclopropyl-ketamine deschloro-N-isopropyl-ketamine and deschloro-N-propyl-ketamine concerning their biotransformation and, thus, urinary detectability are not available. The aims of the presented work were to study the in vivo phase I and II metabolism; in vitro phase I metabolism, using pooled human liver microsomes (pHLMs); and detectability, within a standard urine screening approach (SUSA), of five deschloroketamine derivatives. Metabolism studies were conducted by collecting urine samples from male Wistar rats over a period of 24 h after their administration at 2 mg/kg body weight. The samples were analyzed using liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS) and gas chromatography-mass spectrometry (GC-MS). The compounds were mainly metabolized by N-dealkylation, hydroxylation, multiple oxidations, and combinations of these metabolic reactions, as well as glucuronidation and N-acetylation. In total, 29 phase I and 10 phase II metabolites were detected. For the LC-HRMS/MS SUSA, compound-specific metabolites were identified, and suitable screening targets could be recommended and confirmed in pHLMs for all derivatives except for deschloro-N-cyclopropyl-ketamine. Using the GC-MS-based SUSA approach, only non-specific acetylated N-dealkylation metabolites could be detected.

Impurities in over-the-counter pseudoephedrine leading to methcathinone detection in urine.

Methcathinone, a psychoactive substance with stimulant properties, has raised concerns in recent years due to its presence in urine screenings, even among individuals with no history of drug abuse. To prevent misjudgment, this work aims to explore the source of methcathinone in urine. A total of 58 urine samples tested positive for methcathinone in the National Taiwan University Hospital cohort, with 27 linked to illicit drug use and 31 from individuals with no drug use history. Co-occurrence analysis revealed a strong association between methcathinone and over-the-counter cold medications containing pseudoephedrine or ephedrine. In an in vivo experiment, participants who consumed pseudoephedrine-containing drugs showed the presence of methcathinone in their urine, suggesting a connection between these substances. Additionally, tests on pharmaceutical products containing pseudoephedrine detected small amounts of methcathinone as impurities. The findings suggest that the presence of methcathinone in nonillicit drug users may be attributed to impurities in over-the-counter pseudoephedrine-containing medications. This raises concerns about potential misinterpretations of drug screening results and underscores the need for more comprehensive criteria for assessing drug use. This study contributes to our understanding of the origin of methcathinone in urine, which has implications for legal justice and drug screening practices.

Exploring the topic structure and abuse trends of new psychoactive Substance since the 21st century from a bibliometric perspective.

Nowadays, NPS abuse are continuing to expand in terms of harm and scope, due to its cheap and easy to manufacture anywhere in the world. This study reviewed articles related to seven heavily abused NPS to analyze the structure and trends of NPS abuse. A total of 2476 articles were retrieved based on the search strategy for bibliometric analysis. A significant trend of research in recent years was the increasing number of research on synthetic opioids and designer benzodiazepines, but synthetic cannabinoid and synthetic cathinone still dominate, which were mainly concerned with the development of metabolic models and determining methods as well as their abuse characteristics and reasons. However, with the introduction of class-wide ban on synthetic cannabinoid in China and a series of enhancements in other countries, the abuse of it might decrease to some extent, but more than 20 kinds of synthetic cannabinoid beyond the scope of ban in China still reminded researchers of their potential threats. As for synthetic cathinone, an important phenomenon was some of the drugs first identified during certain period might be more widely distributed in the future. Besides, several problems such as the regulation and prevention mode of emerging NPS, development of testing technologies as well as the interpretation and identification of multiple NPS combinations were also worth paying attention to. This study could help entrants better understand the structure of NPS abuse and provided direction for future research in forensic toxicology.

Understanding methiopropamine, a new psychoactive substance: an in-depth review on its chemistry, pharmacology and implications to human health.

Methiopropamine or 1-(thiophen-2-yl)-2-methylaminopropane (MPA) is a thiophene ring-based structural analogue of methamphetamine, first synthesized in 1942 but become popular when it started to be available for purchase on websites selling 'legal highs' since 2010. While it is legally controlled in many countries, it remains readily accessible and frequently encountered in recreational settings. The growing prevalence of MPA use results in new therapeutic challenges. Relatively few studies have focused on its pharmacodynamics and pharmacokinetics, making it important to better understand its potential risks and harmful effects in humans in terms of its toxicity. This review provides a comprehensive profiling of MPA toxicological properties, including its chemical properties, analytical methods, prevalence, patterns of use, and legal status. Additionally, it discusses the drug's effects on the central nervous system, its potential for addiction, and its adverse physical and mental health effects. Improving the understanding of safety aspects of MPA and how it imposes health threats for public health will guide the development of therapeutic approach of its intoxication and guide the authorities in deciding its legal status.

Factors Associated with Delta-8 THC Retail Availability in Fort Worth, Texas, 2021-2022.

Background: Delta-8 THC is a federally unregulated psychoactive cannabis product rising in popularity. However, little is known regarding its retail availability. Method: We assessed Delta-8 THC retail by calling locations with alcohol, tobacco, and/or consumable hemp retail licenses in Fort Worth, Texas, before and after Texas announced ongoing litigation surrounding Delta-8 THC legality. We linked census block area deprivation index (ADI) scores (1-10; 10 = most disadvantaged) to locations. Logistic regression models examined associations between license type, ADI, ADI*license type interaction, and Delta-8 availability at each time. Results: Retail availability was 11% at Time 1 (n = 133/1,223) and 9% at Time 2 (n = 94/1,026). Alcohol (aORTime1 = 0.18, 95%CI = 0.12,0.28; aORTime2 = 0.14, 95%CI = 0.08,0.24), tobacco (aORTime1 = 15.13, 95%CI = 6.78,33.74; aORTime2 = 12.39, 95%CI = 4.97,30.91), and consumable hemp licenses (aORTime1 = 21.85, 95%CI = 7.91,60.39; aORTime2 = 22.93, 95%CI = 6.92,75.98) were associated with Delta-8 THC retail availability; ADI scores were borderline but not statistically significant. The multiplicative interaction at Time 2 indicated locations with both high ADI scores and alcohol retail licenses had higher odds of selling Delta-8 THC. Differential associations between ADI and Delta-8 THC availability were observed based on those with (b = 0.007) or without (b = -0.023) alcohol retail licenses. Conclusions: Both timepoints had similar proportions of Delta-8 THC retailers, indicating that despite the uncertain legal landscape in Texas, interest in Delta-8 did not appear to be declining. Geographic socioeconomic disparities were observed among locations with alcohol retail licenses. Future regulations may include minimum distances from specific locations (e.g., schools), particularly in more disadvantaged areas. Increasing the compliance of Texas Delta-8 THC retailers to have the required hemp license is important for surveillance and product safety.

Comprehensive evaluation of drug cases in Seoul and its metropolitan areas - 2022.

In order to prepare a response strategy for future drug analyses, the number and results of drug cases handled by the Seoul Institute of National Forensic Service were comprehensively evaluated, with a focus on Seoul and its metropolitan areas. In 2022, the Seoul Institute received approximately 12,150 requests for drug testing related to drug abuse and possession, and the urine samples were tested for approximately 16,000 drug species. The most frequently requested test was for cannabis (Δ-9-THC and Δ-8-THC), followed by methamphetamine, MDMA, ketamine, and synthetic cannabinoids. ADB-5'Br-BUTINACA and propyl butylone were newly emerging substances in 2022. These results were consistent with the main drug detection findings of the confiscated materials. During this period, 24 cases of drug-related deaths were reported, of which 6 were suspected to be the result of acute overdose poisoning caused by methamphetamine, MDMA, fentanyl, and heroin. In addition to the controlled substances regulated by the Narcotics Control Act, new psychoactive substances are being found to be circulating, and various measures are required to address this issue. This study is expected to improve future drug analyses methods and assist in establishing drug policies, and responding to future investigations.

Characterization of the lysergic acid diethylamide analog, 1-(thiophene-2-carbonyl)-N,N-diethyllysergamide (1T-LSD) from a blotter product.

Recently, lysergic acid diethylamide (LSD) analogs have appeared worldwide as designer drugs. In this study, we identified a distributed LSD analog from a paper-sheet product. Gas chromatography-mass spectrometry (GC-MS), liquid chromatography-photodiode array-mass spectrometry (LC-PDA-MS), and liquid chromatography with hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) were used to analyze the sheet product. The sheet product claimed to contain 1-(1,2-dimethylcyclobutanoyl)-N,N-diethyllysergamide (1D-LSD). However, an unknown compound was detected in the product together with tryptamine and L-tryptophan methyl ester. This compound was isolated from the sheets and identified as 1-(thiophene-2-carbonyl)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8ß-carboxamide (1-thiophenoyl LSD; 1-(2-thienoyl)-LSD, 1T-LSD), using 1 H, 13 C nuclear magnetic resonance (NMR) spectroscopy and various two-dimensional NMR techniques. 1T-LSD was shown to have the thiophene-2-carbonyl group at the N1 position instead of the 1,2-dimethylcyclobutane-carbonyl group as claimed. The amount of 1T-LSD (free base) in three individual unit from one sheet was determined to be 87-100 µg per unit using a proton-specific quantitative NMR (1 H-qNMR) method. Deacylation of 1T-LSD to LSD was also observed to occur in methanol-d4 during NMR analysis. The UV spectrum of 1T-LSD differed from that of other LSD analogs, and the fluorescence sensitivity was much lower. Because of concerns about the future distribution of products containing new LSD analogs, continued monitoring of newly detected compounds in sheet products is encouraged.

Development of a vaccine against the synthetic opioid U-47700.

Opioid use disorders and overdose have become a major public health concern in recent years. U-47700, a New psychoactive substances (NPS) opioid, also known as "pinky" or "pink" has been identified as a new threat in the drug supply because of its potency and abuse potential. Conjugate vaccines that can produce antibodies against target drug molecules have emerged as a promising tool to treat substance use disorders. Herein, we report the design, synthesis, and in vivo characterization of a U-47700 vaccine. The vaccine demonstrated favorable results with rodents producing elevated levels of antibody titer and sub-micromolar affinity to U-47700. In addition, antibodies generated by the vaccine effectively mitigated drug-induced effects by preventing the drug from penetrating the blood-brain barrier, which was verified by antinociception and drug biodistribution studies. The development of a vaccine against U-47700 and other NPS opioids contributes to the continued advancement of non-conventional pharmacological treatments to address the global opioid epidemic.

Structural Analysis and Characterization of 4-F-α-PVP Analog 4-F-3-Methyl-α- PVP Hydrochloride.

OBJECTIVES: To identify 1-(4-fluorophenyl)-2-(1-pyrrolidinyl) pentan-1-one (4-F-α-PVP) analog 1-(4-fluoro-3-methyl phenyl)-2-(1-pyrrolidinyl) pentan-1-one (4-F-3-Methyl-α-PVP) hydrochloride without reference substance. METHODS: The direct-injection electron ionization-mass spectrometry (EI-MS), GC-MS, electrospray ionization-high resolution mass spectrometry (ESI-HRMS), ultra-high performance liquid chromatography-high resolution tandem mass spectrometry (UPLC-HRMS/MS), nuclear magnetic resonance (NMR), ion chromatography and Fourier transform infrared spectroscopy (FTIR) were integrated utilized to achieve the structural analysis and characterization of the unknown compound in the sample, and the cleavage mechanism of the fragment ions was deduced by EI-MS and UPLC-HRMS/MS. RESULTS: By analyzing the direct-injection EI-MS, GC-MS, ESI-HRMS and UPLC-HRMS/MS of the compound in the samples, it was concluded that the unknown compound was a structural analog of 4-F-α-PVP, possibly with one more methyl group in the benzene ring. According to the analysis results of 1H-NMR and 13C-NMR, it was further proved that the methyl group is located at the 3-position of the benzene ring. Since the actual number of hydrogen in 1H-NMR analysis was one more than 4-F-3-Methyl-α-PVP neutral molecule, it was inferred that the compound existed in the form of salt. Ion chromatography analysis results showed that the compound contained chlorine anion (content 11.14%-11.16%), with the structural analysis of main functional group information by FTIR, the unknown compound was finally determined to be 4-F-3-Methyl-α-PVP hydrochloride. CONCLUSIONS: A comprehensive method using EI-MS, GC-MS, ESI-HRMS, UPLC-HRMS/MS, NMR, ion chromatography and FTIR to identify 4-F-3-Methyl-α-PVP hydrochloride in samples is established, which will be helpful for the forensic science laboratory to identify this compound or other analog compounds.

Potential neonatal toxicity of new psychoactive substances.

Cannabis, cocaine, 3,4-methylenedioxymethamphetamine, and lysergic acid diethylamide are psychoactive substances with a significant increase in consumption during the 21st century due to their popularity in medicinal and recreational use. New psychoactive substances (NPSs) mimic established psychoactive substances. NPSs are known as being natural and safe to consumers; however, they are neither natural nor safe, causing severe adverse reactions, including seizures, nephrotoxicity, and sometimes death. Synthetic cannabinoids, synthetic cathinones, phenethylamines, and piperazines are all examples of NPSs. As of January 2020, nearly 1000 NPSs have become documented. Due to their low cost, ease of availability, and difficulty of detection, misuse of NPSs has become a familiar and growing problem, especially in adolescents and young adults in the past decade. The use of NPSs is associated with higher risks of unplanned sexual intercourse and pregnancy. As many as 4 in 100 women seeking treatment for substance abuse are pregnant or nursing. Animal studies and human clinical case reports have shown that exposure to certain NPSs during lactation periods has toxic effects on neonates, increasing various risks, including brain damage. Nevertheless, neonatal toxicity effects of NPSs are usually unrecognized and overlooked by healthcare professionals. In this review article, we introduce and discuss the potential neonatal toxicity of NPSs, emphasizing synthetic cannabinoids. Utilizing the established prediction models, we identify synthetic cannabinoids and their highly accumulative metabolites in breast milk.

Analytical characterization and differentiation between threo- and erythro-4-fluoroethylphenidate.

PURPOSE: Methylphenidate analogs appeared on the drug market during the last years. Its analogs contain two chiral centers and, thus, have potential varying configurations (i.e., threo and erythro forms). This study presents the analytical characterization of 4-fluoroethylphenidate (4-FEP) and its differentiation between threo- and erythro-4-FEP. METHODS: Analysis of the samples included high-performance liquid chromatography (HPLC), gas chromatography-electron ionization-mass spectrometry (GC-EI-MS), high-resolution mass spectrometry (HRMS) analyses, nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal structure analysis. RESULTS: NMR spectroscopic investigations confirmed the differences between threo- and erythro-4-FEP, and demonstrated that both isomers could be separated using HPLC and GC methods. Two samples obtained from one vendor in 2019 consisted of threo-4-FEP, whereas the other two samples obtained from a different vendor in 2020 consisted of a mixture of threo- and erythro-4-FEP. CONCLUSIONS: Several analytical approaches including HPLC, GC-EI-MS, HRMS analyses, NMR spectroscopy and X-ray crystal structure analysis enabled the unambiguous identification of threo- and erythro-4-FEP. The analytical data presented in this article will be useful for identifying threo- and erythro-4-FEP included in illicit products.

A UPLC-MS/MS methodological approach for the analysis of 75 phenethylamines and their derivatives in hair.

A rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the targeted analysis of 75 phenethylamines and their derivatives from the hair matrix. The monitored classes of phenethylamines included the 2C series, D series, N-benzyl derivatives, mescaline-derived compounds, MDMA analogs, and benzodifurans. Approximately 20 mg of hair was weighed and pulverized with 0.1% formic acid in methanol by cryogenic grinding. After ultrasonication, centrifugation, and filtration, the supernatant was analyzed by LC-MS/MS operating in the scheduled multiple reaction monitoring mode. Phenethylamines and their derivatives were separated in 13 min on a biphenyl column (2.6 µm, 100 Å, 100 × 3.0 mm) using a gradient eluting mobile phase composed of 0.1% formic acid in water and acetonitrile. The developed and validated method showed good selectivity, sensitivity (LOD: 0.5-10 pg/mg and LOQ: 1-20 pg/mg), linearity (R2 > 0.997), accuracy and precision (< 20%), and stability. The method also showed good recovery and acceptable matrix effects for most of the targeted compounds. This analytical approach was successfully applied for the identification and quantification of phenethylamines in hair from authentic forensic cases.