Designer Drugs Research Articles

The challenges for psychiatric care posed by synthetic drugs

In addition to the drugs that have been known for decades, several hundred mainly synthetic substances have been identified as drugs for the first time in the last 20years. Presentation of the various groups of substances and their psychotropic effects, the epidemiology of their use and the legal and social background of this development. Narrative literature review. The most important new psychoactive substances (NPS) are synthetic cannabinoids, synthetic stimulants (cathinones), halluginogens and new synthetic opioids (NSO), in particular fentanyl and related substances. The new substances do not have any qualitatively new psychotropic effects. They were brought onto the market in particular as substitutes for substances subject to the Narcotics Act but are often associated with dangerous side effects and even mortality. The increasing availability of these substances has gone hand in hand with the establishment of the Internet as asource of knowledge (e.g. for synthesis routes) and as amarketplace. Substance group-related regulations have also been established in Germany (New Psychoactive Substances Act). In Germany the prevalence of NPS use is significantly lower than that of cannabis; however, there are indications that the production and distribution of synthetic drugs is more profitable for drug dealers than with conventional plant-based drugs, such as heroin. In the USA, for example, NSOs are the primarily drugs used for opioid addiction. It remains to be seen whether NPS and NSOs will replace conventional drugs. The availability of synthetic drugs is more difficult to reduce than that of plant-based drugs. Harm reduction measures should be expanded, e.g., early warning systems for new drugs, drug checking and naloxone programs.

High-performance liquid chromatography coupled to Orbitrap mass spectrometry for screening of common new psychoactive substances and other drugs in biological samples.

The complexity of the drug market and the constant updating of drugs have been challenging issues for drug regulatory authorities. With the emergence of new psychoactive substances (NPS) and the nonmedical use of prescription drugs, forensic and toxicology laboratories have had to adopt new drug screening methods and advanced instrumentation. Using high-performance liquid chromatography coupled with Orbitrap mass spectrometry, we developed a screening method for common NPS and other drugs. Two milliliters of mixed solvent of n-hexane and ethyl acetate (1:1, v:v) were added to 500 μL of blood or urine sample for liquid-liquid extraction, and methanol extraction was used for hair samples. The developed method was applied to 3897 samples (including 332 blood samples, 885 urine samples, and 2680 hair samples) taken from drug addicts in a province of China during 2019-2021. For urine and blood samples, the limits of detection (LODs) ranged from 1.68 pg/mL to 10.7 ng/mL. For hair samples, the LODs ranged from 3.30 × 10-5 to 4.21 × 10-3 ng/mg. The matrix effects of urine, blood, and hair samples were in the range of 47.6%-121%, 39.8%-139%, and 6.35%-118%, respectively. And the intra-day precision was 3.5%-6.0% and the inter-day precision was 4.18%-9.90%. Analysis of the actual samples showed an overall positive detection rate of 58.9%, with 5.32% of the samples indicating the use of multiple drugs.

Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid-induced excitotoxicity on the hippocampus.

Astrocytes play a multifaceted role regulating brain glucose metabolism, ion homeostasis, neurotransmitters clearance, and water dynamics being essential in supporting synaptic function. Under different pathological conditions such as brain stroke, epilepsy, and neurodegenerative disorders, excitotoxicity plays a crucial role, however, the contribution of astrocytic activity in protecting neurons from excitotoxicity-induced damage is yet to be fully understood. In this work, we evaluated the effect of astrocytic activation by Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on brain glucose metabolism in wild-type (WT) mice, and we investigated the effects of sustained astrocyte activation following an insult induced by intrahippocampal (iHPC) kainic acid (KA) injection using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) positron emission tomography (PET) imaging, along with behavioral test, nuclear magnetic resonance (NMR) spectroscopy and histochemistry. Astrocytic Ca2+ activation increased the 18F-FDG uptake, but this effect was not found when the study was performed in knock out mice for type-2 inositol 1,4,5-trisphosphate receptor (Ip3r2-/-) nor in floxed mice to abolish glucose transporter 1 (GLUT1) expression in hippocampal astrocytes (GLUT1ΔGFAP). Sustained astrocyte activation after KA injection reversed the brain glucose hypometabolism, restored hippocampal function, prevented neuronal death, and increased hippocampal GABA levels. The findings of our study indicate that astrocytic GLUT1 function is crucial for regulating brain glucose metabolism. Astrocytic Ca2+ activation has been shown to promote adaptive changes that significantly contribute to mitigating the effects of KA-induced damage. This evidence suggests a protective role of activated astrocytes against KA-induced excitotoxicity.

GAP43 Located on Corticostriatal Terminals Restrains Novelty-Induced Hyperactivity in Mice.

Growth-associated protein of 43 kDa (GAP43) is a key cytoskeleton-associated component of the presynaptic terminal that facilitates neuroplasticity. Downregulation of GAP43 expression has been associated to various psychiatric conditions in humans and evokes hippocampus-dependent memory impairments in mice. Despite the extensive studies conducted on hippocampal GAP43 in past decades, however, very little is known about its roles in modulating the excitatory versus inhibitory balance in other brain regions. We recently generated conditional knock-out mice in which the Gap43 gene was selectively inactivated in either telencephalic glutamatergic neurons (Gap43fl/fl ;Nex1Cre mice, hereafter Glu-GAP43-/- mice) or forebrain GABAergic neurons (Gap43fl/fl ;Dlx5/6Cre mice, hereafter GABA-GAP43-/- mice). Here, we show that Glu-GAP43-/- but not GABA-GAP43-/- mice of either sex show a striking hyperactive phenotype when exposed to a novel environment. This behavioral alteration of Glu-GAP43-/- mice was linked to a selective activation of dorsal-striatum neurons, as well as to an enhanced corticostriatal glutamatergic transmission and an abrogation of corticostriatal endocannabinoid-mediated long-term depression. In line with these observations, GAP43 was abundantly expressed in corticostriatal glutamatergic terminals of wild-type mice. The novelty-induced hyperactive phenotype of Glu-GAP43-/- mice was abrogated by chemogenetically inhibiting corticostriatal afferences with a Gi-coupled "designer receptor exclusively activated by designer drugs" (DREADDs), thus further supporting that novelty-induced activity is controlled by GAP43 at corticostriatal excitatory projections. Taken together, these findings show an unprecedented regulatory role of GAP43 in the corticostriatal circuitry and provide a new mouse model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity, a phenotypic shortfall that occurs in diverse psychiatric diseases.

Patterns and Emerging Trends in Acute Poisoning with Substances of Abuse Used for Recreational Purposes in Adolescents: A Six-Year Multicentre Study.

This six-year multicentre study investigated acute intentional poisoning with substances of abuse in adolescents to identify changes and patterns in substance use. Data from 562 adolescents were collected from three paediatric poison centres in Romania between January 2017 and December 2022. This study analysed the epidemiological and sociodemographic characteristics of the adolescents, including age, gender, place of residence, history of substance abuse, psychiatric history, and history of institutionalised care. The findings revealed that cannabis and new psychoactive substances (NPSs) are the most commonly implicated substances, each with distinct profiles among adolescents. Cannabis was involved in 46.1% of cases, with a significant association with urban residency. NPSs were identified as the second most prevalent substance, accounting for 39.3% of cases. These were more prevalent in rural areas and among patients with psychiatric disorders. Cannabis and NPSs were also the most commonly implicated substances in acute intentional poisoning cases with substances of abuse. These substances have distinct profiles among adolescents, including age, gender, residency area, history of substance abuse, psychiatric history, and institutional care. These findings underscore the necessity of targeted public health interventions and integrated care approaches to address substance use and related mental health issues in adolescents.

A simple electrochemical approach for the rapid determination of cannabinoid designer drug ADB‐BUTINACA

AbstractThis work reports, for the first time, a simple, rapid and sensitive square‐wave voltammetric method for the determination of ADB‐BUTINACA, which is currently one the most prevalent synthetic cannabinoids on the drug market in the European Union. The method is based on the direct electrochemical oxidation of ADB‐BUTINACA at a modification‐free boron‐doped diamond electrode in aqueous electrolyte solution. Studies indicated that the oxidation of ADB‐BUTINACA is pH‐independent, irreversible and controlled by diffusion. The best SWV response for ADB‐BUTINACA was obtained in 0.1 mol dm−3 KNO3 buffered to pH 3, at a frequency of 100 Hz, a step potential of 2 mV and an amplitude of 50 mV. Under these conditions, the linear response for ADB‐BUTINACA was obtained in the concentration range of 1.1–104 μmol dm−3, and calculated LOD and LOQ were 0.83 and 2.50 μmol dm−3, respectively. The peak current based intra‐ and inter‐day precision values were 2.9 and 4.8 %, respectively. The spike‐recovery results in e‐liquid samples ranged between 92 and 104 %, confirming the applicability and good performance of the proposed method.

Novel harm reduction measures at music festivals in Australia: Pilot implementation of the Emerging Drugs Network of Australia-Victoria toxicosurveillance methodology.

Harm reduction strategies at music festivals seek to create a safer environment for patrons. The Emerging Drugs Network of Australia-Victoria (EDNAV) project is a state-wide toxicosurveillance network that derives drug intelligence from a sample of patients presenting to hospital with illicit drug-related toxicity. This publication describes the preliminary outcomes of conducting toxicosurveillance for critically unwell festival patrons within on-site medical facilities. Blood samples were collected from patrons who presented with severe illicit drug-related toxicity across three festivals (2022/2023). Blood samples were analysed via liquid chromatography-tandem mass spectrometry for over 700 pharmaceutical and illicit drugs. There were 1603 individual medical encounters across the festivals, 228 of which were illicit drug related. A blood sample was collected for 24 patients, with a median age of 22 years (range 18-39 years). A median of two drugs (range 1-5 drugs) were reported and four drugs (range 0-8 drugs) were analytically confirmed per patient. The most frequently reported exposures were congruent with analytical results, 3,4-methylenedioxymethamphetamine (reported n = 17, detected n = 20), ketamine (reported n = 9, detected n = 13) and cocaine (reported n = 9, detected n = 12). An unreported illicit drug and/or new psychoactive substance (NPS) was detected in 18 patients, including methylamphetamine (n = 10), a cathinone (n = 7), benzodiazepine-type NPS (n = 6), N-ethylamphetamine (n = 1), 3-hydroxyphencyclidine (n = 1) and/or 4-hydroxy-N-methyl-N-isopropyltryptamine (n = 1). EDNAV toxicosurveillance serves as an additional tool within a multi-faceted approach to harm reduction at festivals. Continued data collection will allow for the characterisation of high-risk drug use patterns to provide evidence-based messaging to festival patrons and key stakeholders.

Mellitic Acid-Supported Synthesis of Anisotropic Nanoparticles Used as SERS Substrate.

A method for the synthesis of a new SERS substrate-anisotropic silver nanoparticles using mellitic acid as a new capping agent is presented. The synthesis is free of toxic substances and does not require special temperature or lighting conditions. Moreover, it is fast, easy, and inexpensive. Depending on the concentration of silver ions and nanoparticle seeds, four different colloids were obtained, representing the evolution of nanoparticle growth along different paths from the first common stage. One of the synthesized colloids consists mainly of triangular nanoplates, while the other consists of polyhedral NPs. The analysis of the synthesis process together with the observation of TEM images and UV-vis extinction spectra enabled the proposal of the mechanism of interaction of mellitic acid molecules as the capping agent. The ability of mellitic acid molecules to form a hydrogen bond network, together with a ratio of silver ions to the mellitic acid concentration, turned out to be crucial for determining the shape of the NPs. All obtained colloids strongly enhance the Raman spectra of analyte molecules, thus proving their applicability as efficient new SERS substrates. For the one that enhanced the spectra the most, the detection limit was set at 10-9 M. Using it as a SERS substrate enables the identification of a trace amount of a designer drug, i.e., 4-chloromethcathinone (4-CMC, clephedrone). For the first time, SERS spectra of this substance, illegal in many countries, are presented.

Toxicity of Bromo-DragonFLY as a New Psychoactive Substance: Application of In Silico Methods for the Prediction of Key Toxicological Parameters Important to Clinical and Forensic Toxicology.

Bromo-DragonFLY is a synthetic new psychoactive substance (NPS) that has gained attention due to its powerful and long-lasting hallucinogenic effects, legal status, and widespread availability. This study aimed to use various in silico toxicology methods to predict key toxicological parameters for Bromo-DragonFLY, including acute toxicity (LD50), genotoxicity, cardiotoxicity, health effects, and the potential for endocrine disruption. The results indicate significant acute toxicity with noticeable variations across different species, a low likelihood of genotoxic potential suggesting potential DNA damage, and a notable risk of cardiotoxicity associated with inhibition of the hERG channel. Evaluation of endocrine disruption suggests a low probability of Bromo-DragonFLY interacting with the estrogen receptor α (ER-α), indicating minimal estrogenic activity. These insights from in silico investigations are important for advancing our understanding of this NPS in forensic and clinical toxicology. These initial toxicological examinations establish a foundation for future research efforts and contribute to developing risk assessment and management strategies for using and misusing NPS.

Structure-Activity Relationship of Synthetic Cathinones: An Updated Review.

The escalating prevalence of new psychoactive substances (NPSs) poses a significant public health challenge, evidenced by the vast chemical diversity, with over 500 substances reported annually to the United Nations Office on Drugs and Crime-Early Warning Advisory (UNODC-EWA) in the past five years. Among NPSs, synthetic cathinones are gaining a lot of popularity among users. Notably, synthetic cathinones accounted for approximately 50% of the total quantity of NPSs reported as seized by EU Member States in 2021. Preliminary data from UNODC indicates that a total of 209 synthetic cathinones have been reported to date. As their popularity grows, studying the structure-activity relationship (SAR) of synthetic cathinones is essential. SAR studies elucidate how structural features impact biological effects, aiding in toxicity prediction, regulatory compliance, and forensic identification. Additionally, SAR studies play a pivotal role in guiding drug policies, aiding authorities in categorizing and regulating newly emerging synthetic cathinones, mitigate public health risks and offer valuable insights into potential therapeutic applications. Thus, our Review consolidates recent findings on the effects of different substitutions in the chemical scaffold of synthetic cathinones on their mechanism of action as well as pharmacological and toxicological effects of synthetic cathinones, thus enhancing understanding of the SAR of synthetic cathinones' pharmacology and potential implications.

Software-assisted automated detection and identification of "unknown" analogues of benzodiazepines in liquid chromatography mass spectrometry analysis.

Benzodiazepines (BZDs) construct a large group of psychoactive drugs acting as depressants of the central nervous system (CNS) and used in medicine as sedatives and anxiolytic and antiepileptic agents. The illicit use of these materials is a worldwide problem, and for many years, part of the benzodiazepines have been abused as rape drugs. For example, flunitrazepam (Rohypnol) is most commonly linked by media reports to drug-facilitated sexual assaults, more commonly referred to as "date rape." Furthermore, there are growing concerns for other misuses of these drugs. Over the last few years, there was an increase in the number, type, and availability of new psychoactive substances (NPS) belonging to the benzodiazepine group, challenging standard forensic labs to fully identify the chemical structure of new, unknown benzodiazepines. This work demonstrates a new application of the automated tool for the detection and identification of benzodiazepine analogues using high-resolution-accurate-mass LC-MS analysis, followed by "Compound Discoverer" (CD) software data processing, to automatically detect various benzodiazepine analogues by picking peaks and compare them to in silico calculated modifications made on a predefined basic backbone. Subsequently, a complete structural elucidation for the proposed molecular formula is obtained by MS/MS data analysis of the suspected component. This method was found to be useful for the automated detection and putative identification of a series of nine "unknown" benzodiazepine analogues, at concentrations in the low ng/mL range. We hereby present a general demonstration of this powerful tool for the forensic community in the detection and identification of hazardous unknown compounds.

Rasd2 regulates depression-like behaviors via DRD2 neurons in the prelimbic cortex afferent to nucleus accumbens core circuit.

Depressive symptoms, such as anhedonia, decreased social interaction, and lack of motivation, implicate brain reward systems in the pathophysiology of depression. Exposure to chronic stress impairs the function of brain reward circuits and is well-known to be involved in the etiology of depression. A transcriptomic analysis found that stress alters the expression of Rasd2 in mice prefrontal cortex (PFC). Similarly, in our previous study, acute fasting decreased Rasd2 expression in mice PFC, and RASD2 modulated dopamine D2 receptor (DRD2)-mediated antidepressant-like effects in ovariectomized mice. This research suggests the role of RASD2 in stress-induced depression and its underlying neural mechanisms that require further investigation. Here, we show that 5-day unpredictable mild stress (5-d UMS) exposure reduces RASD2 expression in both the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of mice, while overexpression (but not knock-down) of Rasd2 in the NAc core (NAcc) alleviates 5-d UMS-induced depression-like behaviors and activates the DRD2-cAMP-PKA-DARPP-32 signaling pathway. Further studies investigated neuronal projections between the mPFC (Cg1, PrL, and IL) and NAcc, labeled by the retrograde tracer Fluorogold. Depression-like behaviors induced by 5-d UMS were only related to inhibition of the PrL-NAcc circuit. DREADD (Designer receptors exclusively activated by designer drug) analysis found that the activation of PrL-NAcc glutaminergic projection alleviated depression-like behaviors and increased DRD2- and RASD2-positive neurons in the NAcc. Using Drd2-cre transgenic mice, we constructed mice with Rasd2 overexpression in DRD2PrL-NAcc neurons, finding that Rasd2 overexpression ameliorated 5-d UMS-induced depression-like behaviors. These findings demonstrate a critical role for RASD2 modulation of DRD2PrL-NAcc neurons in 5-d UMS-induced depression-like behaviors. In addition, the study identifies a new potential strategy for precision medical treatment of depression.

Imbalance between hippocampal projection cell and parvalbumin interneuron architecture increases epileptic susceptibility in mouse model of methyl CpG binding protein 2 duplication syndrome.

Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV+ neurons occur in the hippocampus of MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility. We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis. Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice. Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.

Synthetic cannabinoid identification in cases associated with blue lotus and valerian root vaping products.

Synthetic cannabinoids emerged in the early 21st century and have continued to evolve and flourish to present day. Like other novel psychoactive substances (NPS), synthetic cannabinoids have been sold under the guise of legitimate products. Some examples include "potpourri," "incense," and herbal material. Between May 2020 and December 2023, the United States Army Criminal Investigation Laboratory, Drug Chemistry Division (USACIL) received 29 seized drug cases mentioning "blue lotus" or "valerian root." In 90% of these cases, at least one exhibit contained one or more synthetic cannabinoids. During the same timeframe, the Armed Forces Medical Examiner System, Division of Forensic Toxicology received 65 toxicology cases that contained synthetic cannabinoids and/or their corresponding metabolites where case history mentioned "blue lotus." The most frequently observed synthetic cannabinoids between laboratories were 5F-MDMB-PICA, ADB-BUTINACA, and MDMB-4en-PINACA. Innocuous branding and marketing may deceive law enforcement, investigators, and healthcare providers into believing that the adverse effects of erratic behavior, sedation, slurred speech, and hallucinations are a result of toxicity from botanical extracts (e.g. apomorphine and nuciferine in blue lotus). Due to the dangerous nature of these NPS, synthetic cannabinoid screening is recommended for all cases where there is suspected use of vaping products suggested to contain "blue lotus" or "valerian root" as vendors continue to conceal the presence of these compounds.

Dexmedetomidine Promotes NREM Sleep by Depressing Oxytocin Neurons in the Paraventricular Nucleus in Mice.

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist with sedative effects on sleep homeostasis. Oxytocin-expressing (OXT) neurons in the paraventricular nucleus (PVN) of the hypothalamus (PVNOXT) regulate sexual reproduction, drinking, sleep-wakefulness, and other instinctive behaviors. To investigate the effect of DEX on the activity and signal transmission of PVNOXT in regulating the sleep-wakefulness cycle. Here, we employed OXT-cre mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in PVNOXT neurons. Combining chemogenetic methods with electroencephalogram (EEG) /electromyogram (EMG) recordings, we found that cannula injection of DEX in PVN significantly increased the duration of non-rapid eye movement (NREM) sleep in mice. Furthermore, the chemogenetic activation of PVNOXT neurons using i.p. injection of clozapine N-oxide (CNO) after cannula injection of DEX to PVN led to a substantial increase in wakefulness. Electrophysiological results showed that DEX decreased the frequency of action potential (AP) and the spontaneous excitatory postsynaptic current (sEPSC) of PVNOXT neurons through α2-adrenoceptors. Therefore, these results identify that DEX promotes sleep and maintains sleep homeostasis by inhibiting PVNOXT neurons through the α2-adrenoceptor.

Delphi method applicability in drug foresight

BackgroundThe aim of the current study was to assess the accuracy of expert predictions, which were derived using a Delphi panel foresight study between 2009 and 2011, on a variety of drug-related topics in Finland in 2020.MethodsThe material used to evaluate the accuracy of the predictions consists of published reports on statistics, survey results, official register data, wastewater analyses and official documents. Whenever possible, we used multiple information sources to ascertain possible changes related to the predictions.ResultsBetween 2009 and 2011, the majority – but not all – of the experts accurately predicted an increase in drug use. Indeed, more people experimented with or used drugs, and more drug residues were found in wastewater monitoring. The experts also correctly predicted an increase in population-level approval of drug use, but this development has been rather slow. Contrary to predictions, there was no marked increase in the use of new synthetic drugs. However, the misuse of buprenorphine increased during the 2010s. In the drug market, unit prices were surprisingly stable over the ten-year period. There were no changes in legislation related to the legal status of drugs, as was foreseen by the experts. However, enforcement moved in the direction foreseen by the experts: more lenient measures have been taken against users. Drug care system reforms favored a combination of mental health and addiction care units between 2009 and 2011, and 2020, as foreseen by the experts.ConclusionsIt seems to have been easier for the experts to foresee the continuation of existing trends, e.g., increasing use of drugs or widening approval of drugs, than to predict possible changes in the popularity of distinct groups of drugs such as new psychoactive substances (NPS). Even armed with the prediction that drug imports and wholesale would increasingly fall into the domain of organized crime, this undesirable development could not be stopped. Expert disagreement can also be seen as a valuable indication of uncertainty regarding the future. Foresight related to drug-related issues can produce relatively accurate and realistic views of the future at least up to ten years ahead.

Electrochemical classification of benzodiazepines: A comprehensive approach combining insights from voltammetry and liquid chromatography − mass spectrometry

The growing non-medical use of benzodiazepines (BZs) has led to the emergence of counterfeit BZ pills and new psycho-active substances (NPS) in the BZ class on the illicit market. Comprehensive analytical methods for BZ identification are required to allow law enforcement, first aid responders and drug-checking services to analyze a variety of sample types and contents to make timely decisions on the spot. In this work, the electrochemical behavior of diazepam (DZ), clonazepam (CZ) and alprazolam (AP) is studied on graphite screen-printed electrodes, both with and without dissolved oxygen in the solution, to link their redox signals to their chemical structure. After elucidation of their reduction mechanisms using liquid chromatography coupled to high-resolution mass spectrometry, three structural classes (Class 1, Class 2 and Class 3) were defined, each with different redox centers and electrochemical behavior. Subsequently, 22 confiscated pills containing 14 different BZs were correctly assigned to these three structural classes, with the deoxygenated conditions displaying the highest class selectivity. Finally, the three classes were successfully detected after being spiked into five alcoholic beverages in the context of drug-facilitated sexual assault. For analysis in red wine, which complicated the analysis by interfering with Class 1, a dual test strategy in pH 2 and pH 7 was proposed for accurate detection. Its rapid measurements, broad scope and lack of interference from diluents or colors makes this method a promising approach for aiding various services in combating problematic BZ use.

“Blocking-like” effects in attentional set-shifting: Redundant cues facilitate shifting in male rats with medial prefrontal cortex inactivation

Without a functioning prefrontal cortex, humans and other animals are impaired in measures of cognitive control and behavioral flexibility, including attentional set-shifting. However, the reason for this is unclear with evidence suggesting both impaired and enhanced attentional shifting. We inhibited the medial prefrontal cortex (mPFC) of rats while they performed a modified version of an attentional set-shifting task to explore the nature of this apparent contradiction.Twelve adult male Lister hooded rats received AAV5-CaMKIIa-hM4D(Gi)-mCherry viral vector bilaterally into mPFC to express inhibitory ‘Designer Receptors Exclusively Activated by Designer Drugs’ (iDREADDs). The receptors were activated by systemic clozapine N-oxide (CNO) to inhibit mPFC function. The rats were tested in the standard attentional set-shifting task four times: twice after i.p. administration and twice after oral administration of vehicle or CNO (10 mg/kg). They were then tested twice in a modified task, with or without oral CNO. The modified task had an extra stage before the extradimensional shift, in which the relevant exemplars remained relevant and new exemplars that were fully predictive but redundant replaced the previous irrelevant exemplars. These exemplars then became relevant at the subsequent ED stage.In the standard task, mPFC inactivation impaired attentional set-shifting, consistent with previous findings. However, in the modified task, mPFC inactivation abolished ED shift-costs. The results support the suggestion that the mPFC is needed for the downregulation of attention that prevents learning about redundant and irrelevant stimuli. With mPFC inactivated, the rat learns more rapidly when previously redundant exemplars become the only relevant information.

Hemp-based psychoactive use and risk among young adults: Trend theory, policy, and regulation beyond legality

BackgroundHemp-based psychoactives comprise a burgeoning legal substance market with rising trends in use across the U.S. and Canada as well as parts of Europe. Currently, scant empirical research on the use of these Novel Psychoactive Substances (NPS) exists. By examining policy, market conditions, consumer uptake, and related risks, this research extends theory on drug trends by describing the regulatory environments that shape the emergence and popularity of psychoactive hemp-based products among young adults. MethodsRelying on ethnographic fieldwork of hemp-based markets across 3 U.S. state hemp and cannabis policy contexts as well as in-depth interviews with 40 young adult cannabis consumers recruited across 10 U.S. states, we examined how regulatory conditions shape hemp-based psychoactive markets, trends in their use, and associated risks. ResultsYoung adults are motivated to consume hemp-based psychoactives due to the regulatory and market environments that facilitate the production of highly potent products that are inexpensive and easily accessible. States that regulate hemp-based psychoactives as cannabis, do not provide hemp markets with a competitive advantage and as such see minimal uptake. In the absence of hemp specific policies, substantial variations in product potencies, insufficient dosing information, and unscrupulous product packaging practices may increase related risks. ConclusionTrend theory provides insight into the complex relationships that exist between drug policy, markets, and the proliferation of legal highs. Understanding the contextual significance that both market and regulatory conditions have on legal drug production, distribution, and consumption may better inform approaches to reduce the risks commonly associated with novel psychoactive substances like hemp-based psychoactives.

Chemical composition of Ecstasy tablets seized in Poland between 2005 and 2020.

The most commonly associated substance found in Ecstasy tablets is MDMA (3,4-methylenedioxymethamphetamine). In our study, we showed how the composition of psychoactive ingredients in Ecstasy tablets seized on the drug market in Poland has changed in the years 2005-2020. The study material consisted of nearly 20,000 single Ecstasy tablets seized by representatives of law enforcement (the police, prosecutors) from 2005 to 2020 and analysed by the Institute of Forensic Research, Krakow, Poland. The analysis of the tablets was carried out by gas chromatography-mass spectrometry (GC-MS), high-performance liquid chromatography with diode array detection (HPLC-DAD) and ultra-high-performance liquid chromatography with photodiode array detection (UHPLC-PDA). Currently, new types of MDMA tablets are introduced onto the market, available in various colours and shapes. Our study showed that tablets sold on the street as Ecstasy have variable purity and sometimes contain little or no MDMA. The mean content of MDMA in one tablet seized in 2005-2011 decreased from 90 to 50mg. In 2013, Ecstasy tablets with a very high MDMA content (average 195mg per tablet) appeared on the market, but in the next 2years, the MDMA content decreased again. From 2016, the average MDMA content began to rise again, ranging from 60 to 280mg. Tablets sold as Ecstasy also contained completely different psychoactive substances, including new psychoactive substances (NPS) (found in almost 20% of all examined tablets sold as Ecstasy) belonging to different chemical groups or their dangerous combinations (i.e. phenylethylamines, piperazines, tryptamines, cathinones, arylalkylamines, arylcyclohexylamines and piperidines). Such a large variety of psychoactive substances in Ecstasy tablets is associated with a high risk for users unaware of their composition.