Designer Drugs Research Articles

CBMAFF-Net: An Intelligent NMR-Based Nontargeted Screening Method for New Psychoactive Substances.

With the proliferation and rapid evolution of new psychoactive substances (NPSs), traditional database-based search methods face increasing challenges in identifying NPS seizures with complex compositions, thereby complicating their regulation and early warning. To address this issue, CBMAFF-Net (CNN BiLSTM Multistep Attentional Feature Fusion Network) is proposed as an intelligent screening method to rapidly classify unknown confiscated substances using 13C nuclear magnetic resonance (NMR) and 1H NMR data. Initially, we utilize the synergy of a convolutional neural network (CNN) and bidirectional long short-term memory network (BiLSTM) to extract the global and local features of the NMR data. These features are sequentially fused through a weighted approach guided by an attention mechanism, thoroughly capturing the essential NPS information. We evaluated the model on a generated simulated data set, where it performed with 99.8% accuracy and a 99.8% F1 score. Additionally, testing on 42 actual seizure cases yielded a recognition accuracy of 97.6%, significantly surpassing the performance of conventional database-based similarity search algorithms. These findings suggest that the proposed method holds substantial promise for the rapid screening and classification of NPSs.

Rapid sensorimotor adaptation to auditory midbrain silencing in free-flying bats.

Echolocating bats rely on rapid processing of auditory information to guide moment-to-moment decisions related to echolocation call design and flight path selection. The fidelity of sonar echoes, however, can be disrupted in natural settings due to occlusions, noise, and conspecific jamming signals. Behavioral sensorimotor adaptation to external blocks of relevant cues has been studied extensively, but little is known about adaptations that mitigate internal sensory flow interruption. How do bats modify their sensory-guided behaviors in natural tasks when central auditory processing is interrupted? Here, we induced internal sensory interruptions by reversibly inactivating excitatory neurons in the inferior colliculus (IC) using ligand-activated inhibitory designer receptors exclusively activated by designer drugs (DREADDs). Bats were trained to navigate through one of three open windows in a curtain to obtain a food reward, while their echolocation and flight behaviors were quantified with synchronized ultrasound microphone and stereo video recordings. Under control conditions, bats reliably steered through the open window, only occasionally contacting the curtain edge. Suppressing IC excitatory activity elevated hearing thresholds, disrupted overall performance in the task, increased the frequency of curtain contact, and led to striking compensatory sensorimotor adjustments. DREADDs-treated bats modified flight trajectories to maximize returning echo information and adjusted sonar call design to boost detection of obstacles. Sensorimotor adaptations appeared immediately and did not change over successive trials, suggesting that these behavioral adaptations are mediated through existing neural circuitry. Our findings highlight the remarkable rapid adaptive strategies bats employ to compensate for internal sensory interruptions to effectively navigate their environments.

Establishment of Broad-Specificity Monoclonal Antibody-Based Immunoassay for Rapid Detection of Indole-Type and Indazole-Type Synthetic Cannabinoids and Metabolites.

Synthetic cannabinoids (SCs) have emerged as one of the most severely abused categories of new psychoactive substances (NPS), exacerbating the global drug problem and posing significant threats to public health. Presently, a class of new amide-type SCs featuring an indazole or indole core has been identified in numerous cases of illegal drug use, but there is still a lack of comprehensive analysis methods of SC detection. Herein, monoclonal antibodies (mAbs) 2E4 and AE6 targeting 36 indole-type and indazole-type SCs and their metabolites with IC50 ranging from 0.14 to 85.28 ng/mL were prepared and the molecular mechanism of antibody recognition was elaborated. We established the indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) and gold immunochromatography assay (GICA) based on mAbs 2E4 and AE6 to detect indazole-type and indole-type SCs in urine and hair samples. Under optimal conditions, the proposed method detected ADB-BUTINACA (an indazole-type SC) with limits of detection (LODs) of 0.11 ng/mL for urine and 0.024 ng/mg for hair by ic-ELISA, and 1.02 ng/mL for urine and 0.046 ng/mg for hair by GICA; the LODs of 4F-MDMB-BUTICA (an indole-type SC) detection was 0.036 ng/mL for urine and 0.012 ng/mg for hair by ic-ELISA, and 0.54 ng/mL for urine and 0.03 ng/mg for hair by GICA. Collectively, our study provides a comprehensive foundation for the rapid screening and quantitation of SC derivatives in biological samples.

Synthesis, Analytical Characterization, and Human CB1 Receptor Binding Studies of the Chloroindole Analogues of the Synthetic Cannabinoid MDMB-CHMICA

Synthetic cannabinoids (SCs) are one of the largest groups of new psychoactive substances (NPSs). However, the relationship between their chemical structure and the affinity to human CB1 receptors (hCB1), which mediates their psychotropic activity, is not well understood. Herein, the synthesis of the 2-, 4-, 5-, 6- and 7-chloroindole analogues of the synthetic cannabimimetic MDMB-CHMICA, along with their analytical characterization via ultraviolet–visible (UV/VIS), infrared (IR), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry, is described. Furthermore, all five derivatives of MDMB-CHMICA were analyzed for their hCB1 binding affinities. Chlorination at position 4 and 5 of the indole core reduced the binding affinity compared to MDMB-CHMICA, while the test compounds chlorinated in positions 2, 6, and 7 largely retained their binding affinities relative to the non-chlorinated parent compound.

Portable near-infrared detection to replace color tests in an analytical scheme for forensic drug identification

In the ever-changing drug market the popularity and availability of substances is dynamic. In the Netherlands, ketamine and various cathinones have recently seen increased prevalence. It is crucial for law enforcement to quickly obtain an initial indication of the identity of a substance. This first test also serves as quality control for subsequent confirmation with GC–MS analysis. Traditionally, color tests have been used for these purposes. While these tests are quick and inexpensive, they have the disadvantage of reacting only to a few traditional drugs. Suitable color tests are not available for many new psychoactive substances (NPS). Near-infrared (NIR) spectroscopy is a rapid technique that provides a characteristic spectrum for organic compounds. This technique is more versatile than color tests and can adapt more quickly to market changes by incorporating reference spectra into the library. This study demonstrates the feasibility of obtaining a good quality NIR spectrum from a 20 mg sub-sample in a test tube. This was achieved by scanning the test tube through the glass bottom. In the routine analytical scheme, these test tubes were subsequently batchwise analyzed by GC–MS. From the NIR spectra, 84 % true positive and 100 % true negative results were achieved on 516 casework samples, including identification of substances without available color tests like ketamine. Missed false negatives primarily involved new substances absent from the library, emphasizing the need for continuous library updates. NIR’s adaptability to market changes is crucial, allowing the inclusion of new substances as they emerge. This method enhances law enforcement’s ability to make informed decisions, aiding in the indictment process.

Assessment of medical doctors' knowledge of new psychoactive substances and their neurobehavioural effects

New Psychoacve Substances (NPS), also known as designer drugs, pose significant public health risks due to their potent psychoacve properes and potenal neurobehavioural effects. Medical doctors play a crucial role in idenfying and addressing the health risks associated with NPS use. This study assessed medical doctors' knowledge of NPS and their neurobehavioral effects. A cross-seconal online survey of licensed medical doctors was conducted, revealing varying levels of awareness and knowledge regarding NPS. While respondents showed familiarity with NPS terminology and street names, gaps existed, parcularly concerning specific NPS categories. This underscores the importance of enhancing medical professionals' understanding of NPS to ensure comprehensive paent care and informed treatment decisions.

Towards better prepared prisons: monitoring and response to the use of new substances inside prison

Abstract The use of new psychoactive substances (NPS) became an emerging issue in prisons in a number of European countries in 2014-2015. Synthetic cannabinoids were the new psychoactive substances most often reported, followed by synthetic cathinones, synthetic opioids and new benzodiazepines. Quantitative qualitative data on prison and drugs provided by 27 European Member States, Norway and Turkey to the EMCDDA (European Monitoring Centre for Drugs and Drug Addiction). An exploratory study conducted in 2017 found signs of NPS use in prison in 22 countries. Based on 2021-2022 data from a few countries, the lifetime prevalence of NPS in prison ranges from <1 to 19%, with large variation by country. Anecdotal information from 2024 referred to the use of new strong synthetic opioids (nitazene) inside prison. A wide range of physical and mental health harms (e.g. psychosis, disorientation, suicidal ideation, aggressiveness to others or self-harm) has been associated with acute intoxication by, and chronic consumption of NPS inside prison. Recent overdoses associated with the use of nitazene were reported in some prisons in Ireland and the UK. Additionally, the use of NPS in prison can have a disturbing impact on prison management, internal violence and bullying. To date, interventions to tackle the problems related to the use of NPS in prison have tended to focus on supply reduction and controls. Health and social interventions have begun to emerge, but they remain limited. Despite signs of increasing challenges posed by the emergence of NPS since several years, prisons remain largely unprepared to monitor and respond to those challenges. A new key task of the revised EMCDDA mandate (EUDA - European Drug Agency from 2nd of July) is to be better prepared to monitor, forecast and respond to new challenges in the drug field. Prisons should be prepared to adequately address the new challenges posed by the NPS to benefit the health and security of people living and working in prison.

A novel murine model of stress-induced cardiomyopathy achieved by chemogenetic stimulation of the locus coeruleus-norepinephrine system

Abstract Background Takotsubo syndrome (TTS) is a stress-induced acute cardiomyopathy characterized by transient left ventricular (LV) dysfunction without obstructive coronary artery disease. TTS is often underdiagnosed and undertreated and typically occurs in middle-aged women who recover from initial symptoms within a few weeks. Despite the apparent recovery, TTS patients have a worse cardiovascular prognosis compared to healthy individuals. To date, the pathophysiology underlying TTS remains unclear. So far, preclinical models barely reflect the complete clinical picture of TTS observed in humans. Moreover, these models display several limitations, e.g., high mortality or disregarding the involvement of the central nervous system. Consequently, much of the current obscurity concerning the pathophysiology of TTS is due to the lack of appropriate preclinical models. Purpose The present study aimed to assess whether chemogenetic activation of the locus coeruleus-(LC)-norepinephrine-(NE) system in vivo can induce LV dysfunction similar to that observed in patients with TTS. For this purpose, we used the designer excitatory receptor activated exclusively by designer drug (DREADD) system. Methods 11-13 weeks-old female Cre-dependent DREADD mice were genetically modified to express a codon-improved Cre recombinase under the dopamine-beta-hydroxylase-(DBH) promoter. For this purpose, a designed excitatory receptor exclusively activated by designer drugs or a control vector was stereotactically delivered to the LC using adenoviral transfection. Restricted expression of DBH-positive noradrenergic neurons to the LC was validated using pupillometry. LC-NE was activated by administering low-dose clozapine 0.03 mg/kg/day intraperitoneally. Serial anatomical and functional assessments of the cardiac phenotype in these mice were performed at baseline, the end of stress induction, and after ten days and three months of the recovery phase using echocardiography and cardiac magnetic resonance imaging. Results Targeted stimulation of the LC-NE system resulted in apical LV wall motion abnormality in 70–83% of mice. A complete recovery of LV wall motion abnormality was observed after the recovery phase. Conclusions Chemogenetic stimulation of the LC-NE system in mice mimics LV wall abnormalities similar to those observed in patients with TTS and may, therefore, be a novel preclinical model to investigate the pathophysiology of TTS.

Reward system activation improves recovery from acute myocardial infarction

Abstract Introduction Psychological processes play a crucial role in the recovery from acute myocardial infarction (AMI), yet the underlying mechanisms of these effects remain elusive. Here, we focused on the reward system, which mediates positively valenced emotions, motivation, and expectation and is based mainly on dopaminergic neurotransmission from the ventral tegmental area (VTA). Purpose The study examines the impact of activating dopaminergic neurons in the VTA following AMI in mice, aiming to understand the extent and mechanisms through which motivational brain network contribute to cardiac recovery process. Methods We used Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) to target neuronal activity. We performed an AMI model and assessed cardiac function using cardiac magnetic resonance (CMR). We used histology, immunohistochemistry, proteomic analysis, ELISA, reverse transcription-PCR, endothelial tube formation assay, and pseudorabies-virus neuronal tracing to investigate the mechanism. Results Chemogenetic activation of dopaminergic neurons in the VTA significantly modified the remodeling processes by reducing scar tissue (Fig. 1a) and increased vascularization (Fig. 1b) 15 days following AMI, leading to improved left-ventricular performance compared to control (Fig. 1c). These effects were mediated through several physiological mechanisms, including alterations in immune activity, and reduced adrenergic inputs to the liver. We further demonstrate an anatomical connection between the VTA and the liver that follows AMI manifested by altered transcription of complement component 3 (C3). We established the essential role of C3 in endothelial tube formation in vitro and its necessity in the beneficial effects of VTA activation on the recovery from AMI in vivo (Fig.2). Conclusion These findings establish a causal connection between a motivational brain network and recovery from AMI, introducing potential new therapeutic avenues for intervention.Effects of VTA activation on cardiac recMechanism of VTA effects

Synthetic torpor confers cardioprotection against myocardial ischaemia/reperfusion injury in the rat

Abstract Introduction Torpor is a hypothermic, bradycardic, hypometabolic state enabling animals, such as mice, to survive in unfavourable environmental conditions such as cold exposure or reduced food availability. It is thought to be a cardioprotective state. There is interest in developing models that mimic aspects of torpor in clinical settings such as ischaemia-reperfusion injury. The preoptic area of the hypothalamus (POA) has emerged as a key centre for triggering torpor in the mouse. Purpose Induce a synthetic torpor-like state in a species that does not naturally enter torpor (the rat) by chemoactivation of neurons in the POA that correspond to those that induce torpor in the mouse. Test the cardioprotective effects of synthetic torpor in the Langendorff ischaemia-reperfusion preparation. Methods Designer receptors exclusively activated by designer drugs (DREADDs) were used to exogenously activate excitatory neurons in the POA of the rat hypothalamus. Viral vectors (pAAV-CaMKIIa-hM3D(Gq)-mCherry) were stereotaxically injected bilaterally into the POA under ketamine and medetomidine anaesthesia, resulting in expression of DREADDs in excitatory neurons. Control animals received a vector delivering the gene for a fluorescent protein only. DREADD receptors in transfected neurons were activated by subsequent injection of Clozapine-N-Oxide (CNO, 2mg/kg IP), which results in neuronal activation and induces synthetic torpor. Heart rate and core temperature were monitored using implanted telemeters. 2 weeks after vector injection, animals were anaesthetised using 5% isoflurane and culled by cervical dislocation. Hearts were excised and ex-vivo whole heart perfusion at 37°C was performed using the Langendorff apparatus. Hearts were subjected to 30 minutes of global warm ischaemia followed by 60 minutes of reperfusion. Hearts were stained using tetrazolium triphenyl chloride, and infarct size as a proportion of the total heart area calculated. Results Chemoactivation of rat POA neurons induced synthetic torpor characterised by bradycardia (pre: 341.0 ± 17.73bpm, post: 233.4 ± 20.47bpm, paired t (4) = 5.4791, p = .0054) and hypothermia (36.2 ±0.40°C vs 31.6 ± 0.55°C (paired t (4) = 7.9023, p = .0014). CNO had no effect on heart rate or core temperature in control animals. The mean infarct size was significantly lower in synthetic torpor (21.54 ±2.84%) compared to control hearts (29.62 ±2.59%) (unpaired t (23) = 2.1054, p = .0464). Conclusions Synthetic torpor, induced centrally in a species for which torpor is not a natural behaviour, confers striking cardioprotection in an ex-vivo ischaemia-reperfusion model. This novel approach to cardioprotection against myocardial ischaemia/reperfusion injury should be further investigated as a potential therapeutic target for use in clinical practice.

Unexpected macrophage-mediated myocardial cGas-STING activation in a novel mouse model of stress-related sleep disturbance

Abstract Background Delayed bedtime following stress disorder is prevalent in waves of pandemics and modern life. Considered to be a specific and important contributor to cardiovascular health, stress-related sleep disturbance has an unmet need in steady preclinical models. We previously found exciting corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH) area of mice could induce 3-hour-long wakefulness. Purpose This study aimed to induce reproducible phenotypes of stress-related sleep disturbance in mice and explore the potential impact on cardiac function. Methods The chemogenetic method of designer receptors exclusively activated by designer drugs (DREADD) system was adopted to mimic stress-related sleep disturbance. We transfected PVH CRH neurons with rAAV-hSyn-DIO-hM3Dq-mCherry and rAAV-Crh-CRE. Prolonged CRH neuron activation was induced by daily intraperitoneal injection of clozapine N-oxide (CNO, 3mg/kg) at 9 am. Bulk RNA-sequencing and bioinformatics analysis were conducted for mechanistic exploration. Results 2-week repeated chemogenetic activation of PVH CRH neurons induced a 5-fold corticosterone release, consistent with increased daily 3-hour wakefulness and corresponding decreases in both rapid eye movement (REM) as well as non-REM sleep. Over 30% of chronic CRH activation mice displayed difficulties in maintaining balance and experienced premature mortality. Mice subjected to prolonged CRH activation showed impaired left ventricular ejection fraction (67.9% versus 48.2%, p=0.0011), and a dilated appearance demonstrated by histological staining. Intriguingly, the number of circulating monocytes increased. Then, we performed bulk RNA-sequencing of heart and bone marrow from CRH-activated and control mice. Differential gene expression and gene set enrichment analysis (GSEA) indicated marked activation of interferon-beta-related pathways in both tissues. Cytosolic DNA-sensing pathway and related key effector genes (cGAS, Cxcl10, CCL5) were found up-regulated in the heart, while mitochondrial oxidative phosphorylation was suppressed. We adopted the CIBERSORT tool to estimate immune infiltration in heart tissues and characterized M1 macrophage as the main pro-inflammatory cell. Further, we screened a set of secreted factors and mediators, which might play active roles in inflamed hearts. Conclusion Taken together, we report a failing heart in a mouse model of stress-related sleep disturbance. The neuro-immune axis involvement and molecular mechanisms merit in-depth explorations.

Cholecystokinin-expressing neurons of the ventromedial hypothalamic nucleus control energy homeostasis.

The hypothalamus is the primary center of the brain that regulates energy homeostasis. The ventromedial hypothalamus (VMH) plays a central role in maintaining energy balance by regulating food intake, energy expenditure, and glucose levels. However, the cellular and molecular mechanisms underlying its functions are still poorly understood. Cholecystokinin (CCK) is one of many genes expressed in this hypothalamic nucleus. Peripheral CCK regulates food intake, body weight, and glucose homeostasis. However, current research does not explain the function of CCK neurons in specific nuclei of the hypothalamus and their likely roles in network dynamics related to energy balance and food intake. This study uses genetic and pharmacological methods to examine the role of CCK-expressing neurons in the VMH (CCKVMH). Namely, using a previously generated BAC transgenic line expressing Cre recombinase under the CCK promoter, we performed targeted manipulations of CCKVMH neurons. Histological and transcriptomic database analysis revealed extensive distribution of these neurons in the VMH, with significant heterogeneity in gene expression related to energy balance, including co-expression with PACAP and somatostatin. Pharmacogenetic acute inhibition via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) resulted in increased food intake and altered meal patterns, characterized by higher meal frequency and shorter intermeal intervals. Furthermore, diphtheria toxin-mediated ablation of CCKVMH neurons led to significant weight gain and hyperphagia over time, increasing meal size and duration. These mice also exhibited impaired glucose tolerance, indicative of disrupted glucose homeostasis. Our findings underscore the integral role of CCKVMH neurons in modulating feeding behavior, energy homeostasis, and glucose regulation. This study enhances our understanding of the neurohormonal mechanisms underlying obesity and metabolic disorders, providing potential targets for therapeutic interventions.

Drug Use during Incarceration: A Comprehensive Quality and Prevalence Study in Three Danish Prisons

Background Drug use in Danish prisons has previously not been investigated in detail using confirmatory, laboratory analysis. The objective of the present quality study, initiated by the Danish Prison and Probation Service, was to i) evaluate the performance of an initial, on-site drug screening strategy; ii) gain insights into emerging drug trends; and iii) suggest evidence-based strategies for future drug testing. Methods Over a two-year period, routine urine samples (n = 1952 from 710 inmates) from three Danish prisons were subjected to comprehensive drug testing. Immunoassay screening was conducted on-site. A parallel sample aliquot was forwarded to laboratory analysis by confirmatory methods: High-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS) and gas chromatography and mass spectrometry (GC-MS) targeting 56 drugs-of-abuse/medical drugs, 26 key metabolites, 41 new psychoactive substances (NPS), including specific biomarkers for heroin, crack cocaine, or ethanol (a total of 123 target analytes/sample). Results The on-site immunoassay method showed a sensitivity from 66 to 100%; specificity was above 98%; accuracy was above 95%. Laboratory analysis detected compounds not screened for including tramadol, oxycodone, buprenorphine, ketamine, MDMA, 4-fluoroamphetamine, and GHB. The prevalence of drug use was in the order: cannabis > ethanol > cocaine > benzodiazepines > amphetamine. Conclusion The performance of the immunoassay was found acceptable; however, the screening program was inadequate for detecting other significant substances. Based on these findings, a broader screening method will be implemented in future at Danish Prisons to minimize false negative results. The data did not indicate a trend of using NPS in Danish prisons.

Development and Validation of a Method for Detecting and Quantifying Mitragynine in Kratom Samples Using HPLC-PDA

Kratom (Mitragyna speciosa Korth) has been identified as a New Psychoactive Substance (NPS) by the United Nations Office on Drugs and Crime (UNODC) and included in the list of prohibited ingredients in food supplements and traditional medicine by Indonesian FDA. Therefore, a rapid, easy, and reliable analytical method is necessary to detect and quantify this plant and its products. This study developed a method for the detection and quantification of kratom products based on a unique compound, mitragynine, as a biomarker. A previous survey of determining mitragynine in Kratom using GC-MS, LC-MS/MS, UPLC, and HPLC-PDA. Previously, the HPLC-PDA method used a C8 column. Yet, for efficiency, it is also necessary to develop a test method using a C18 column. Analysis was performed using an HPLC - PDA system with Waters Atlantis T3-C18 (250 x 4.6 mm, 5 µm) column. The mobile phase comprises acetonitrile and formic acid 0.05%, pH 5.0 (75:25 v/v), delivered at a 1.0 mL/min flow rate. Detection was carried out at a wavelength of 225 nm. The analytical method was validated with test parameters of selectivity, system suitability, accuracy, precision, linearity, detection limit, and quantification limit. The validation study demonstrated an excellent linear concentration range of 1.96 - 6.01 µg/mL with a correlation coefficient of 0.9996; the detection limit is 0.14 µg/mL, while the limit of quantification is 0.45 µg/mL—accuracy method of 98.88 - 101.44% and a bias of 0.27%. The percent relative standard deviation for six independent assay determinations was 0.67%, and the intermediate precision was 1.56% on two days. The mitragynine amounts in these materials ranged from 6.01 to 6.31 mg/g of dried leaf material. Based on the research results, it can be concluded that the method developed provides quick, simple, reliable, accurate, and valid, and has an advantage over existing methods in terms of simplicity of sample preparation, short analysis time, and cost-effectiveness compared to GCMS and LCMS/MS and can be applied for future analysis in Kratom samples.

Double Designers: Detection of Bromazolam and Metonitazene in Postmortem Casework.

The identification of novel psychoactive substances (NPSs) in casework at the Los Angeles County Department of Medical Examiner (LACDME) is constantly evolving. The case detailed herein marks the first detection of metonitazene in forensic casework at the LACDME which occurred in August 2023. Furthermore, bromazolam was found in the decedent's system and both substances were identified in drug evidence collected at the death scene. No other drugs were detected and the manner and cause of death were determined as accidental due to effects of bromazolam and metonitazene. The concentrations detected were 1.6 ng/mL and 4.4 ng/mL of metonitazene in the jugular blood and femoral blood, respectively, and 93 ng/mL of bromazolam in the femoral blood. Constraints in screening techniques conducted by toxicology laboratories create challenges in which numerous NPSs available on the illicit drug market can go undetected. Even if labs detect an NPS in their screening methodology, confirmation methods might not cover every NPS, given the impracticality of labs keeping pace with validations as new NPSs emerge in casework. The significance of testing medical evidence collected at death scenes by drug chemistry analysis becomes crucial when initial toxicology results are negative. In cases where there is evidence of potential drug paraphernalia this is especially true as it can be pivotal in determining the cause and manner of death.

Uncovering the universe of New Psychoactive Substances (NPS): Understanding the mechanisms of action and adverse effects in an accessible and didactic way

New Psychoactive Substances (NPS) constitute a heterogeneous group of drugs associated with a range of health harms, producing more intense effects than traditional drugs. NPS pose a challenge for public health policies due to the limited information available about their effects on the body. Understanding the primary effects of NPS and their mechanisms of action is crucial for guiding healthcare professionals and raising awareness about the dangers associated with their use. In this context, the aim of this study was to gather the most current scientific information on the mechanisms of action and adverse effects of NPS, transforming it into a simple and accessible educational material for the public. Based on the information collected in this review, it was possible to develop a playful educational tool that not only informs about the effects of NPS but also provides clear information about the mechanisms of action of these substances in the CNS, as currently known for the wide variety of NPS. By making this information accessible and understandable, the booklet contributes to public awareness and empowers individuals to make informed and responsible decisions about the use of psychoactive substances. Additionally, it serves as a valuable educational tool for healthcare professionals and educators.

Waxy- or Putty-Like Materials as a Novel Drug Preparation for Synthetic Cannabinoid Receptor Agonists: Detection in Prisons and InVitro Cannabinoid Receptor Activity.

After the Scottish Prison Service (SPS) introduced mail photocopying procedures in December 2021, a shift in smuggling methods was observed for synthetic cannabinoid receptor agonists (SCRAs) and other new psychoactive substances (NPS) from drug-infused papers back to traditional sample matrices (e.g., tablets and powders), although new matrices also emerged. This study reports on waxy- or putty-like materials as a novel drug preparation for SCRAs and other drugs seized from UK prisons. In 2023, 22 of these new preparations were seized from Scottish prisons, with eight found in sealed vape pods. The materials were positive for SCRAs, phytocannabinoids, novel benzodiazepines, and/or gabapentinoids. Additionally, 11 preparations were seized from an English prison, all containing the SCRAs MDMB-4en-PINACA and MDMB-INACA. MDMB-INACA was pharmacologically characterized using invitro CB1 and CB2 bioassays, revealing moderate efficacy but low potency at CB1. Furthermore, the invitro CB1 bioassay was also used to evaluate the CB1 activating potential of extracts from eight seized samples. Six of these showed high CB1 activity, whereas the samples lacking SCRAs or containing only MDMB-INACA showed no or only weak CB1 activity, respectively. Lastly, applying the bioassay as an activity-based "untargeted" screening method effectively identified the presence of SCRAs in one waxy preparation, which was initially not detected by gas chromatography-mass spectrometry (GC-MS). This underscores the effectiveness of the bioassay for evaluating these new waxy- or putty-like materials for the presence of SCRAs.

Separate mechanisms regulating accumbal taurine levels during baseline conditions and following ethanol exposure in the rat

Ethanol-induced dopamine release in the nucleus accumbens (nAc) is associated with reward and reinforcement, and for ethanol to elevate nAc dopamine levels, a simultaneous increase in endogenous taurine is required within the same brain region. By employing in vivo microdialysis in male Wistar rats combined with pharmacological, chemogenetic and metabolic approaches, our aim with this study was to identify mechanisms underlying ethanol-induced taurine release. Our results demonstrate that the taurine elevation, elicited by either systemic or local ethanol administration, occurs both in presence and absence of action potential firing or NMDA receptor blockade. Inhibition of volume regulated anion channels did not alter the ethanol-induced taurine levels, while inhibition of the taurine transporter occluded the ethanol-induced taurine increase, putatively due to a ceiling effect. Selective manipulation of nAc astrocytes using Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) did not affect ethanol-induced taurine release. However, activation of Gi-coupled DREADDs, or metabolic inhibition using fluorocitrate, rather enhanced than depressed taurine elevation. Finally, ethanol-induced taurine increase was fully blocked in rats pre-treated with the L-type Ca2+-channel blocker nicardipine, suggesting that the release is Ca2+ dependent. In conclusion, while astrocytes appear to be important regulators of basal taurine levels in the nAc, they do not appear to be the main cells underlying ethanol-induced taurine release.

Trends in novel psychoactive substance use and the impact of Irish legislative efforts

Introduction: Novel Psychoactive Substances (NPS) are emerging at increasingly rapid rates, creating unpredictability in drug markets and ineffective drug policies. Ireland has a drug-induced mortality rate greater than three times the European average and the highest rate of NPS use. Given the scarcity of published literature, the National Advisory Committee on Drugs has recommended trends in NPS use be studied in order to facilitate appropriate public health measures. Objectives: To critically evaluate the published literature on NPS and establish the health risks associated with their use, trends in drug-induced fatalities, and the efficacy of legislative policies in reducing NPS consumption. Methods: A systematic search of Medline and PubMed was completed based on pre-defined inclusion criteria, and relevant studies were selected for comprehensive analysis. Results: Clinical experiences of NPS abusers predominantly involved neurological or psychological symptoms, coupled with cardiovascular effects. While the overall prevalence of NPS presentations in Europe remains low, fatal overdoses were primarily attributed to acute overdose and commonly involved ingestion of synthetic cathinones. Legislation in 2010 resulted in decreased rates of recent and problematic NPS use, along with higher rates of negative user experiences. No significant displacement towards established illicit drugs was reported. Conclusion: This systematic review has demonstrated the current state of knowledge regarding NPS within an Irish context. The trends in NPS prevalence and toxicity are important considerations for the development of effective drug monitoring or enforcement strategies. This knowledge is further relevant for emergency physicians and forensic pathologists in order to make accurate medical assessments.

A five-year retrospective review of fatalities involving novel psychoactive substances in Southern Ireland

Introduction: Novel psychoactive substances (NPS) are rapidly emerging and being reformulated to evade legislative controls, creating unpredictability in drug markets and ineffective drug policies. Given that Ireland has the highest self-reported NPS use within Europe and literature regarding health risks is lacking, the National Advisory Committee on Drugs has advocated for the surveillance of regional trends. Objectives: To elucidate the demographic and autopsy findings of fatal cases involving NPS in Southern Ireland as compared to deaths involving traditional drugs of abuse (TDOA). Methods: Post-mortem reports from the Cork-Kerry region with positive toxicology for illicit substances between 2012-2016 were retrospectively analyzed to compare NPS and TDOA cases with respect to circumstances surrounding death, toxicological results, and pathological findings. Results: Between 2012-2016, there were 164 cases involving illicit substances in the Cork-Kerry region. NPS accounted for 17 (10.4%) cases, with an average annual mortality rate of 34.8 per 100,000 population. NPS contributed to the cause of death in 70.6% of cases where detected, compared to 43.5% for TDOA only. In both cohorts, fatal abusers were predominantly young males. Importantly, cases involving NPS showed a higher proportion of mono-drug intoxication and presentation to hospital prior to death. Autopsy findings were non-specific but commonly featured pulmonary congestion, aspiration, and cerebral oedema. Conclusion: NPS are detected in a small proportion of medicolegal autopsies but contribute significantly to acute intoxication deaths. This study highlights the need for effective drug monitoring and enforcement strategies, along with improved management of drug toxicities presenting to hospital.