Search Results (43)

New psychoactive substances (NPS) are a heterogeneous group of recreational drugs that mimic the actions and psychoactive effects of existing pharmaceutical products or recreational drugs. As NPS can be highly potent, even exceeding their template compound’s potency, there are frequent reports of non-fatal and fatal intoxications. One principal target for hallucinogenic and psychedelic drugs, including NPS, is the 5-hydroxytryptamine receptor 2A (5-HT_2A). Since NPS are designed to evade legal restrictions, this drug market is quickly evolving, and researchers are playing catch-up, investigating these novel compounds for their toxicological and pharmacological properties. Receptor binding affinity (Ki) is an important property describing ligand–receptor interactions and is a prerequisite for receptor activation. Competitive in vitro assays can be used to assess Ki; this is a resource-intensive process. We used publicly available Ki data for the 5-HT_2A, calculated molecular descriptors and fingerprints, and trained five classification machine learning models. The predictive performance of the models had precisions and recalls up to 93% and 92%, respectively. We used explainable artificial intelligence, i.e., SHAP values and similarity maps, for model interpretation. The results are in line with previous experiments and support its suitability to predict the binding affinities of possible 5-HT_2A ligands. Full article

Novel psychoactive substances (NPSs) exhibit extremely strong pharmaco-toxicological activity, often leading to severe adverse effects that pose a serious risk to consumers’ health. Among these, synthetic cannabinoids (SCs) currently represent the majority of drug seizures in Europe. One such compound, AKB-48 (also known as APINACA), was first identified in Japanese herbal smoking blends in 2012. Although it mimics the effects of Δ9-THC, the primary psychoactive component of Cannabis sativa, AKB-48 can induce more severe and potentially life-threatening outcomes. Several in vivo studies investigating the acute administration of AKB-48 have reported profound behavioral, neurological, and neurochemical alterations, including disruptions of neurotransmission across multiple brain regions, thus confirming its neurotoxic potential. Given the recognized vulnerability of the cerebellum to NPS, and its critical role in integrating neural circuits affected by psychostimulant drugs, the present study evaluated the toxic effects of repeated AKB-48 exposure on the cerebellar cortex of adult male and female ICR-CD1^® mice. Particular attention was paid to the modulation of cell death pathways, alongside assessments of sensorimotor responses. The results demonstrate, for the first time, that repeated AKB-48 administration induces significant morphological, immunohistochemical, and ultrastructural changes in both male and female mice. These alterations included pronounced disruption of cerebellar architecture and marked modulation of cell death pathways, further corroborated by TEM-detected ultrastructural damage and a substantial reduction in the basal visual placing response. Overall, the findings provide clear evidence of AKB-48’s sex-independent neurotoxicity, leading to cerebellar alterations that ultimately result in neuroplasticity impairment. Full article

Introduction: The availability of toxicokinetic data is critical for detecting and monitoring the intake of psychoactive substances. Timely characterization of novel psychoactive substances (NPS) is particularly important to assess their abuse potential and inform public health responses. Methods: Toxicometabolomics offers a powerful approach to characterize xenobiotic metabolism through high-resolution profiling of biochemical transformations. It thus allows the finding of exogenous biomarkers, such as new drug metabolites, and endogenous biomarkers, which could be indications of acute drug ingestions or sample manipulation, as well as offering information on the mode of action of drugs. In this study, we applied a liquid chromatography–high-resolution mass spectrometry workflow to investigate the toxicometabolomics of two N1-sulfonated N,N-dimethyltryptamine derivatives with potential for both therapeutic use and recreational abuse. Results: Zebrafish (Danio rerio), an increasingly valuable model for preclinical pharmacology and toxicology studies, along with pooled human liver S9 fractions were used to elucidate metabolic pathways and identify key phase I and phase II biotransformations. Furthermore, untargeted metabolomics revealed significant downregulation of L-threonine associated with compound exposure. Conclusions: These findings advance the current understanding of tryptamine metabolism and underscore the utility of toxicometabolomics in the analytical evaluation of NPS. Full article

Background/Objectives: The rapidly evolving crisis of Novel Synthetic Opioids (NSOs) poses a serious and growing threat for global public health. NSOs include prescription/non-prescription opioids (fentanyl, non-fentanyl analogues), herbal derivatives, and other emerging analogues that are of critical concern due to their high potency, misuse potential, and addiction and intoxication risk. There remains an important gap in real-time, systematic monitoring of NSOs emergence, especially in online communities where these substances appear for the first time. This study aimed to employ the NPSfinder^® automated web-crawling tool to detect, monitor, analyse, and evaluate the evolving NSOs scene. Methods: Data were collected during two time-periods, i.e., 2017–2019 and 2023, from selected high traffic psychonaut online platforms to better understand trends in opioids market evolution and adaptability and compare NPSfinder^® findings with other well-known Early Warning Systems (EWSs) databases to assess detection overlap and early identification capacity. Results: Within the selected time-periods, a total of 446 NSOs were detected by NPSfinder^®; fentanyl analogues (n = 249) were dominant, with a notable rise in non-fentanyl analogues, especially nitazene-like compounds, in 2023. Over 57% of these NSOs were not captured by any of the other EWSs, confirming the tool’s strong capacity to identify early threats. Conclusions: Overall, the low overlap across EWS databases underscores the global challenges in comprehensive opioid detection and surveillance. Future studies should integrate web-crawler findings with real-world datasets. It will be vital to combine these efforts with toxicological, mortality, and clinical outcome analyses, especially for emerging research compounds, to inform targeted harm-reduction strategies. Full article

The rapid emergence of novel psychoactive substances (NPSs) after 2020 has created one of the most dynamic analytical challenges in modern forensic science. Hundreds of new synthetic cannabinoids, synthetic cathinones, synthetic opioids, hallucinogens, and dissociatives, appearing as hybrid or structurally modified analogues of conventional drugs, have entered the illicit market, frequently found in complex polydrug mixtures. This review summarizes recent advances in gas chromatography-mass spectrometry (GC-MS) for their detection, structural elucidation, and differentiation between 2020 and 2025 based on the ScienceDirect and Google Scholar databases. Due to its reproducible electron-ionization spectra, established reference libraries, and robustness toward complex matrices, GC-MS remains the primary tool for the separation and identification of emerging NPS. The current literature highlights significant improvements in extraction and pre-concentration procedures, derivatization strategies for thermally unstable analogues, and chromatographic optimization that enable discrimination between positional and stereoisomers. This review covers a wide range of matrices, including powders, herbal materials, vaping liquids, and infused papers, as well as biological specimens such as blood, urine, and hair. Chemometric interpretation of GC-MS data now supports automated classification and prediction of fragmentation pathways, while coupling with complementary spectroscopic techniques strengthens compound confirmation. The review emphasizes how continuous innovation in GC-MS methodology has paralleled the rapid evolution of the NPS landscape, ensuring its enduring role as a reliable, adaptable, and cost-effective platform for monitoring emerging psychoactive substances in seized materials. Full article

In recent years, the expansion of the illicit market for Novel Psychoactive Substances (NPS) has resulted in the emergence of numerous synthetic recreational drugs specifically designed to evade legal control and analytical detection. Among these, nitazenes represent one of the most potent classes of new synthetic opioids, although information regarding their toxicological properties remains limited. The present study aimed to assess the genotoxic potential of four nitazenes: clonitazene, etonitazene, isotonitazene and metonitazene in human lymphoblastoid TK6 cells using a flow cytometric version of the In Vitro Mammalian Cell Micronucleus Test, following OECD Guideline No. 487. Cells were exposed to concentrations ranging from 12.5 to 100 μM, and cytotoxicity, cytostasis, and apoptosis were evaluated to identify appropriate doses for micronucleus frequency assessment. Vinblastine, a well-established mutagen, was included as positive control. Our findings demonstrated that clonitazene and isotonitazene exhibit mutagenic potential, suggesting an increased long-term risk of developing chronic degenerative diseases. Furthermore, the results revealed that structurally related molecules can induce markedly different cellular effects, underscoring the importance of compound-specific toxicological evaluations to achieve a comprehensive understanding of the risks associated with their illicit use—risks often presumed to involve only addiction or acute toxicity. Full article

Numerous individuals suffer from mental health issues including depression and anxiety, resulting in substantial societal burden. Data suggests individuals are choosing to self-medicate with Novel Psychoactive Substances (NPS); however, this phenomenon is poorly understood. We aimed to investigate which NPS are being used to self-medicate, evaluate their perceived effectiveness and examine influencing factors. Data from respondents (n = 274) (Mean Age [SD] = 29.8 ± 9.1, Male = 71%, Female = 18%, non-binary 5%) were collected via an online survey, with five participants (male = 2; nonbinary = 3) undertaking further semi-structured interviews and the data examined using a Framework analysis. NPS used included bromazolam, etizolam, clonazolam, 1P-LSD and 2-FDCK. Individuals perceived self-medication to be more effective than conventional treatment (p < 0.001). A Framework analysis identified the following themes surrounding mood and anxiety disorder self-medication: (1) depression being chronic, treatment resistant and often comorbid; (2) individuals attempting to mimic existing treatments; (3) individuals having high levels of pharmacological knowledge; (4) difficulties in controlling benzodiazepine self-medication. This study brings important insight into self-medication practices with NPSs, adding to data demonstrating an increase in bromazolam use. Data suggests self-medication follows conventional treatment and, therefore, we outline the importance of affordable emerging treatment options for depression and anxiety. Full article

Over the past decade, more than a thousand new psychoactive substances (NPSs) have emerged worldwide. This rapid proliferation of “designer drugs” poses significant challenges for drug control, forensic analysis, and public health. Artificial intelligence (AI) has increasingly been applied to address these challenges in NPS design and analysis. This review provides a comprehensive overview of AI methodologies—including deep learning, generative models, and quantitative structure–activity relationship (QSAR) modeling—and their applications in the synthesis, prediction, and identification of NPSs. We discuss how AI-driven generative models have been used to design novel psychoactive compounds and predict their pharmacological activity, how QSAR models can forecast potency and toxicological profiles, and how machine learning is enhancing analytical chemistry workflows for NPS identification. Special emphasis is placed on mass spectrometry (MS)-based techniques, where AI algorithms (e.g., for spectral prediction and pattern recognition) are revolutionizing the detection and characterization of unknown NPSs. A dedicated section examines the legal and regulatory implications of AI-generated psychoactive substances in the European Union (EU) and United States (USA), highlighting current policies, potential gaps, and the need for proactive regulatory responses. The review concludes with a discussion of the benefits and limitations of AI in this domain and outlines future directions for research at the intersection of AI, analytical chemistry, and drug policy. Full article

Introduction: Novel psychoactive substances (NPSs) are substances not controlled by the United Nations’ 1961 Narcotic Drugs and 1971 Psychotropic Substances convention, which pose a threat to public health. The use of NPSs is growing among recreational drug users. NPSs mimic the effects of the existing illegal drugs; they are used as substitutes for the traditional drugs of use. NPSs are commonly marketed as safe substances. NPS abuse is especially risky among vulnerable individuals, such as children and adolescents. The Aim: This study aims to analyze the knowledge and attitudes of primary and high school students regarding NPSs, determining the frequency and patterns of NPS use, and examine motivational factors for their consumption. Methodology: The questionnaire was employed to primary and secondary school students of the city of Novi Sad in November 2024. The data were analyzed using the methods of descriptive and inferential statistics in the statistical software package JASP 0.18.1.0. Results: A total of 1095 participants took part in the survey (53.6% males and 46.4% females). The age range of participants was 11–18 years (mean age 14.637 years). The majority of pupils lived in the city (70.5%). The most numerous students were students with the highest overall grade. The proportion of students who were familiar with NPSs was 38.3%, while 61.7% of them were not aware of their existence. Living in cities correlated positively with the NPS knowledge. The NPS risk awareness was notably low. The proportion of students who tried one or more novel drugs was 1.918%. Conclusions: The abuse of novel psychoactive substances is a growing concern, particularly among young individuals, requiring increased awareness and education on their risks. Educational systems should provide accurate information to prevent false beliefs, while policymakers must legally regulate new drugs. A coordinated approach is crucial for effective prevention, involving education, media, and support from different organizations. Future studies should focus on the impact of education on attitudes towards NPSs. Full article

Background: Piperazines, synthetic compounds known for their stimulant and hallucinogenic effects, have gained prominence among novel psychoactive substances (NPS) and are frequently associated with adverse psychiatric outcomes, including psychosis. Methods: A systematic review of the literature available up to 23 May 2024 was conducted, using the PubMed, Scopus, and Web of Science databases, in addition to the related gray literature, utilizing the following search strategy: “piperazines” AND (“psychosis” OR “hallucination” OR “delusion” OR “schizophrenia” OR “delusional” OR “schizoaffective”) NOT review NOT animal. Data collection adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The research methods were registered with PROSPERO (CRD42024549204). Results: Out of a total of 4547 articles identified, 4 met the inclusion criteria. We observed an important relationship between piperazine abuse and the onset of acute psychotic episodes, marked by symptoms such as paranoia, auditory, and visual hallucinations. Conclusion: The complex polyreceptor action mechanism of piperazines may explain these psychopathological effects, similar to those observed with other NPS. Although studies confirm a link between piperazine use and psychosis, data on long-term outcomes are limited. Recovery is common following cessation and treatment. Further research into the effects of piperazine abuse and the development of specific treatment protocols for substance-induced psychosis is necessary. Full article

The widespread use of novel psychoactive substances (NPSs)—defined as new narcotic or psychotropic agents not classified under the Single Convention on Narcotic Drugs of 1961 or the Convention on Psychotropic Substances of 1971—poses a significant challenge to contemporary mental health paradigms due to their impact on psychiatric disorders. This study revisits and expands upon the theory of mental automatism as proposed by Gaëtan Gatian de Clérambault, aiming to elucidate the psychopathological mechanisms underlying substance-induced psychoses (SIP) and their distinction from non-induced psychoses (schizophrenia and related disorders). Through a phenomenological and clinical investigation, we explore the relevance of mental automatism in the development of toxic psychoses, drawing upon the historical and contemporary literature. This research highlights the psychopathological distinctions between induced and non-induced psychoses and the transition mechanisms from acute to chronic psychosis states. De Clérambault’s theory, supplemented by Janet, Jackson, and Bonhoeffer’s contributions, provides a foundational framework for understanding the genesis of SIP. Our findings suggest that NPS consumption, particularly among adolescents and psychiatric patients, significantly correlates with increased risks of SIP, marked by a transition to chronicity influenced by biological lesions triggered by substance use. Furthermore, we propose a comprehensive framework for SIP, integrating mental automatism, psychopathological distinctions, and transition mechanisms. This framework aims to refine diagnostic criteria and therapeutic approaches, addressing gaps in clinical practice and research. The study underscores the need for a nuanced understanding of SIP, advocating for a paradigm shift in psychiatric assessment and treatment approaches to better address the complexities of substance-induced mental health disorders. Full article

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. 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

5-(2-Aminopropyl)benzofuran (5-APB), also known as “Benzo Fury,” is a novel psychoactive substance (NPS) belonging to a new class of synthetic phenethylamines. It acts by disrupting serotonergic circuits as a serotonin–norepinephrine–dopamine reuptake inhibitor and is classified as an entactogen, similar to MDMA and MDA. Despite its popularity among users, recent toxicity events have been associated with the consumption of 5-APB and other benzofurans, highlighting the need for a better understanding of their pharmacodynamics and toxicity. One way to achieve this is by developing the synthesis of 5-APB metabolites as biomarkers of exposure. In this study, we present a six-step synthesis for one of the 5-APB metabolites, 2-(5-(2-aminopropyl)-2-hydroxyphenyl)acetic acid (1), involving methylation, formylation, Aldol-type condensation, reduction, and hydrolysis reactions. The compound was obtained in an overall yield of 11%. Full article

In January 2020, the World Health Organization (WHO) issued a Public Health Emergency of International Concern, declaring the COVID-19 outbreak a pandemic in March 2020. Stringent measures decreased consumption of some drugs, moving the illicit market to alternative substances, such as New Psychoactive Substances (NPS). A systematic literature search was performed, using scientific databases such as PubMed, Scopus, Web of Science and institutional and government websites, to identify reported intoxications and fatalities from NPS during the COVID-19 pandemic. The search terms were: COVID-19, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, intox*, fatal*, new psychoactive substance, novel psychoactive substance, smart drugs, new psychoactive substance, novel synthetic opioid, synthetic opioid, synthetic cathinone, bath salts, legal highs, nitazene, bath salt, legal high, synthetic cannabinoid, phenethylamine, phencyclidine, piperazine, novel benzodiazepine, benzodiazepine analogue, designer benzodiazepines, tryptamine and psychostimulant. From January 2020 to March 2022, 215 NPS exposures were reported in Europe, UK, Japan and USA. Single NPS class intoxications accounted for 25, while mixed NPS class intoxications represented only 3 cases. A total of 130 NPS single class fatalities and 56 fatalities involving mixed NPS classes were published during the pandemic. Synthetic opioids were the NPS class most abused, followed by synthetic cathinones and synthetic cannabinoids. Notably, designer benzodiazepines were frequently found in combination with fentalogues. Considering the stress to communities and healthcare systems generated by the pandemic, NPS-related information may be underestimated. However, we could not define the exact impacts of COVID-19 on processing of toxicological data, autopsy and death investigations. Full article