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Background: Finding new strategies to treat cognitive disorders is a challenging task. Medication must defeat the blood-brain barrier. Cannabidiol (CBD), a nonintoxicating compound of the cannabis plant, has gained recognition as a nutraceutical for its potential effectiveness in treating anxiety, oxidative stress, convulsions, and inflammation. However, the dose, tolerable upper intake, formulation, administration routes, comorbidities, diet, and demographic factors to reverse cognitive impairments have not been completely explored. Trials using CBD as a primary intervention have been conducted to alleviate cognitive issues. This review evaluates the benefits of CBD supplementation, research design, formulations, and outcomes reported in randomized clinical trials. Methods: An evidence-based systematic literature review was conducted using PUBMED and the Florida International University Research Library resources. Fourteen randomized trials were selected for review, and their designs and outcomes were compared conceptually and in the form of resume tables. Results: CBD showed improvement in anxiety and cognitive impairments in 9 out of 16 analyzed trials. However, the variability could be justified due to the diversity of the trial designs, underpowered studies, assayed population, uncontrolled results for comorbidities, medications, severity of drug dependence, compliances, and adherences. Overall, oral single doses of 200 mg-1,500 mg or vaporized 13.75 mg of CBD were shown to be effective at treating anxiety and cognition with a good safety profile and no drug addiction behaviors. Conversely, results that did not have a significant effect on treating cognitive impairments can be explained by various factors such as THC or other abuse drugs masking effect, low dose, and unknown purity of CBD. Furthermore, CBD shows potential properties that can be tested in the future for Alzheimer's disease. Conclusion: As medical cannabis becomes more accessible, it is essential to understand whether medication rich in CBD exerts a beneficial effect on cognitive disorders. Our study concludes that CBD is a promising candidate for treating neurocognitive disorders; however, more studies are required to define CBD as a therapeutic candidate for managing cognitive disorders. [ABSTRACT FROM AUTHOR]

BackgroundFinding new strategies to treat cognitive disorders is a challenging task. Medication must defeat the blood–brain barrier. Cannabidiol (CBD), a non-intoxicating compound of the cannabis plant, has gained recognition as a nutraceutical for its potential effectiveness in treating anxiety, oxidative stress, convulsions, and inflammation. However, the dose, tolerable upper intake, formulation, administration routes, comorbidities, diet, and demographic factors to reverse cognitive impairments have not been completely explored. Trials using CBD as a primary intervention have been conducted to alleviate cognitive issues. This review evaluates the benefits of CBD supplementation, research design, formulations, and outcomes reported in randomized clinical trials.MethodsAn evidence-based systematic literature review was conducted using PUBMED and the Florida International University Research Library resources. Fourteen randomized trials were selected for review, and their designs and outcomes were compared conceptually and in the form of resume tables.ResultsCBD showed improvement in anxiety and cognitive impairments in 9 out of 16 analyzed trials. However, the variability could be justified due to the diversity of the trial designs, underpowered studies, assayed population, uncontrolled results for comorbidities, medications, severity of drug dependence, compliances, and adherences. Overall, oral single doses of 200 mg–1,500 mg or vaporized 13.75 mg of CBD were shown to be effective at treating anxiety and cognition with a good safety profile and no drug addiction behaviors. Conversely, results that did not have a significant effect on treating cognitive impairments can be explained by various factors such as THC or other abuse drugs masking effect, low dose, and unknown purity of CBD. Furthermore, CBD shows potential properties that can be tested in the future for Alzheimer’s disease.ConclusionAs medical cannabis becomes more accessible, it is essential to understand whether medication rich in CBD exerts a beneficial effect on cognitive disorders. Our study concludes that CBD is a promising candidate for treating neurocognitive disorders; however, more studies are required to define CBD as a therapeutic candidate for managing cognitive disorders.

Background: Hair samples are recognized as alternative biological specimens in forensic and clinical toxicology for detecting drug abuse and poisoning. Forensic testing for opioids in hair has become a useful diagnostic measure for assessing chronic drug usage through segmental analysis. However, accurate, sensitive and specific analytical methods are needed. The aim of this study was to introduce a simple, sensitive and specific GC-MS method for the identification and quantitation of selected and commonly abused opioids (tramadol, methadone, morphine, and codeine) in hair samples. Methods: After external decontamination, a 50 mg portion of powdered hair sample was combined with hydrochloric acid (0.1 M) and incubated on a magnetic stirrer at 56°C for 16 hours. Then, 1 mL of sodium hydroxide (0.1 M) and 2 mL of phosphate buffer (1 M, pH=8.4) were added. Chloroform-isopropanol (ratio: 80:20 V/V) was utilized as the extracting solvent and the sample was homogenized and centrifuged for 5 minutes (at 3500 rpm). After centrifugation, the organic phase was dried using dry nitrogen gas. The sample was derivatized with N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA). The blank, standards, and real samples were subsequently analyzed by GC-MS. Results: The limits of detection in the linearity experiments ranged from 0.12 to 0.21 ng/mg. According to the validation results, the method exhibited linearity in the concentration range of 0.1-2.5 ng/mg for all analytes, with calibration curve slopes ranging from R2=0.98 to 0.99. Good inter and intra-day precision relative standard deviations (RSDs) were observed to be

Unhealthy behaviors such as use of alcohol and drug usually begin during adolescence. Izmir is on transit route for illicit substance due to geographical situation. Children and adolescents are the most important threatened group in terms of alcohol and substance abuse. In this study, it was aimed to investigate alcohol and substance use profile of children and adolescents in Izmir/Turkey with the toxicological analysis results obtained from Addiction Toxicology Laboratory. Urine and blood samples of 4524 cases at and under the age of 18 years coming from various departments to the laboratory in 2015–2016 were analyzed by enzymatic immunoassay. Information and analysis results of the cases were obtained by retrospective analysis of the hospital system. 83,3% of the cases were male and the mean age was 16,69 ± 1,63. Alcohol and/or substance use was determined in 13,2% of the cases. Among the cases with positive results of analysis, cannabis (33%) was mostly detected and was followed by amphetamine type stimulants (ATS, 15%), polysubstance use (15%) and alcohol (13%). While cannabis, polysubstance use and ATS were the most common in male, ethyl alcohol, ATS and benzodiazepine were mostly detected in female. There was a significant increase in the substance use rate in 2016 compared to the previous year. A substance use profile was obtained through drug testing in adolescents who are in the risk group for substance use. In this context, our data will be indicative for the development of new and more effective preventive strategies targeting children and adolescents. [ABSTRACT FROM AUTHOR]

Workplace drug testing (WDT) is essential to prevent drug abuse disorders among the workforce because it can impair work performance and safety. However, WDT is limited by many challenges, such as urine adulteration, specimen selection, and new psychoactive substances (NPS). This review examined the issues related to WDT. Various scientific databases were searched for articles on WDT for drug detection published between 1986 (when WDT started) and January 2024. The review discussed the history, importance, and challenges of WDT, such as time of specimen collection/testing, specimen adulteration, interference in drug testing, and detection of NPS. It evaluated the best methods to detect NPS in forensic laboratories. Moreover, it compared different techniques that can enhance WDT, such as immunoassays, targeted mass spectrometry, and nontargeted mass spectrometry. These techniques can be used to screen for known and unknown drugs and metabolites in biological samples. This review assessed the strengths and weaknesses of such techniques, such as their validation, identification, library search, and reference standards. Furthermore, this review contrasted the benefits and drawbacks of different specimens for WDT and discussed studies that have applied these techniques for WDT. WDT remains the best approach for preventing drug abuse in the workplace, despite the challenges posed by NPS and limitations of the screening methods. Nontargeted techniques using high-resolution liquid chromatography-mass spectrometry (MS)/gas chromatography–tandem MS can improve the detection and identification of drugs during WDT and provide useful information regarding the prevalence, trends, and toxicity of both traditional and NPS drugs. Finally, this review suggested that WDT can be improved by using a combination of techniques, multiple specimens, and online library searches in case of new NPS as well as by updating the methods and databases to include new NPS and metabolites as they emerge. To the best of the author's knowledge, this is the first review to address NPS as an issue in WDT and its application and propose the best methods to detect these substances in the workplace environment.

Forensic toxicology plays a pivotal role in elucidating the presence of drugs of abuse in both biological and solid samples, thereby aiding criminal investigations and public health initiatives. This review article explores the significance of sensor technologies in this field, focusing on diverse applications and their impact on the determination of drug abuse markers. This manuscript intends to review the transformative role of portable sensor technologies in detecting drugs of abuse in various samples. They offer precise, efficient, and real-time detection capabilities in both biological samples and solid substances. These sensors have become indispensable tools, with particular applications in various scenarios, including traffic stops, crime scenes, and workplace drug testing. The integration of portable sensor technologies in forensic toxicology is a remarkable advancement in the field. It has not only improved the speed and accuracy of drug abuse detection but has also extended the reach of forensic toxicology, making it more accessible and versatile. These advancements continue to shape forensic toxicology, ensuring swift, precise, and reliable results in criminal investigations and public health endeavours. [ABSTRACT FROM AUTHOR]

The direct coupling of solid-phase microextraction (SPME) to mass spectrometry (MS) (SPME-MS) has proven to be an effective method for the fast screening and quantitative analysis of compounds in complex matrices such as blood and plasma. In recent years, our lab has developed three novel SPME-MS techniques: SPME-microfluidic open interface-MS (SPME-MOI-MS), coated blade spray-MS (CBS-MS), and SPME-probe electrospray ionization-MS (SPME-PESI-MS). The fast and high-throughput nature of these SPME-MS technologies makes them attractive options for point-of-care analysis and anti-doping testing. However, all these three techniques utilize different SPME geometries and were tested with different MS instruments. Lack of comparative data makes it difficult to determine which of these methodologies is the best option for any given application. This work fills this gap by making a comprehensive comparison of these three technologies with different SPME devices including SPME fibers, CBS blades, and SPME-PESI probes and SPME-liquid chromatography-MS (SPME-LC-MS) for the analysis of drugs of abuse using the same MS instrument. Furthermore, for the first time, we developed different desorption chambers for MOI-MS for coupling with SPME fibers, CBS blades, and SPME-PESI probes, thus illustrating the universality of this approach. In total, eight analytical methods were developed, with the experimental data showing that all the SPME-based methods provided good analytical performance with R2 of linearities larger than 0.9925, accuracies between 81% and 118%, and good precision with an RSD% ≤ 13%.

The direct coupling of solid-phase microextraction (SPME) to mass spectrometry (MS) (SPME-MS) has proven to be an effective method for the fast screening and quantitative analysis of compounds in complex matrices such as blood and plasma. In recent years, our lab has developed three novel SPME-MS techniques: SPME-microfluidic open interface-MS (SPME-MOI-MS), coated blade spray-MS (CBS-MS), and SPME-probe electrospray ionization-MS (SPME-PESI-MS). The fast and high-throughput nature of these SPME-MS technologies makes them attractive options for point-of-care analysis and anti-doping testing. However, all these three techniques utilize different SPME geometries and were tested with different MS instruments. Lack of comparative data makes it difficult to determine which of these methodologies is the best option for any given application. This work fills this gap by making a comprehensive comparison of these three technologies with different SPME devices including SPME fibers, CBS blades, and SPME-PESI probes and SPME-liquid chromatography-MS (SPME-LC-MS) for the analysis of drugs of abuse using the same MS instrument. Furthermore, for the first time, we developed different desorption chambers for MOI-MS for coupling with SPME fibers, CBS blades, and SPME-PESI probes, thus illustrating the universality of this approach. In total, eight analytical methods were developed, with the experimental data showing that all the SPME-based methods provided good analytical performance with R 2 of linearities larger than 0.9925, accuracies between 81% and 118%, and good precision with an RSD% ≤ 13%. [Display omitted] • Rapid screening and quantitative analysis were achieved by SPME-MS direct coupling. • SPME with different geometries including fiber, blade and probe were studied. • Three SPME-MS techniques including MOI-MS, CBS-MS and PESI-MS has been investigated. • High throughput SPME were achieved by automated 96 Concept system. • The methods showed good analytical performance for drugs of abuse analysis. [ABSTRACT FROM AUTHOR]

Forensic toxicology plays a pivotal role in elucidating the presence of drugs of abuse in both biological and solid samples, thereby aiding criminal investigations and public health initiatives. This review article explores the significance of sensor technologies in this field, focusing on diverse applications and their impact on the determination of drug abuse markers. This manuscript intends to review the transformative role of portable sensor technologies in detecting drugs of abuse in various samples. They offer precise, efficient, and real-time detection capabilities in both biological samples and solid substances. These sensors have become indispensable tools, with particular applications in various scenarios, including traffic stops, crime scenes, and workplace drug testing. The integration of portable sensor technologies in forensic toxicology is a remarkable advancement in the field. It has not only improved the speed and accuracy of drug abuse detection but has also extended the reach of forensic toxicology, making it more accessible and versatile. These advancements continue to shape forensic toxicology, ensuring swift, precise, and reliable results in criminal investigations and public health endeavours.

New psychoactive substances (NPS) are uncontrolled analogues of existing drugs or newly synthesized chemicals that exhibit psychopharmacological effects. Due to their diverse nature, composition, and increasing prevalence, they present significant challenges to the healthcare system and drug control policies. In response, healthcare system laboratories have developed analytical methods to detect NPS in biological samples. As a Regional Reference Centre, the Sicilian CRQ Laboratory (Regional Laboratory for Quality Control) developed and conducted an External Quality Assessment (EQA) study to assess, in collaboration with the Istituto Superiore di Sanità (ISS), the ability of different Italian laboratories to identify NPS and traditional drugs of abuse (DOA) in biological matrices. Two blood samples were spiked with substances from various drug classes, including synthetic cannabinoids, cathinones, synthetic opiates, and benzodiazepines, at concentrations ranging from 2 to 10 ng/mL. The blood samples were freeze-dried to ensure the stability of DOA and NPS. Twenty-two laboratories from the Italian healthcare system participated in this assessment. The information provided by the laboratories during the registration in an in-house platform included a general description of the laboratory, analytical technique, and the chosen panels of analytes. The same platform was employed to collect and statistically analyze the data and record laboratory feedback and comments. The evaluation of the results revealed that the participating laboratories employed three different techniques for analyzing the samples: GC-MS, LC-MS, and immunoenzymatic methods. Approximately 90 % of the laboratories utilized LC-MS techniques. Around 40 % of false negative results were obtained, with the worst results in the identification of 5-chloro AB PINACA. The results showed that laboratories that used LC-MS methods obtained better specificity and sensitivity compared to the laboratories using other techniques. The results obtained from this first assessment underscore the importance of external quality control schemes in identifying the most effective analytical techniques for detecting trace molecules in biological matrices. Since the judicial authorities have not yet established cut-off values for NPS, this EQA will enable participating laboratories to share their analytical methods and expertise, aiming to establish common criteria for NPS identification. • NPS pose challengesto healthcare and drug control policies due to their diverse nature and increasing prevalence. • EQA study to evaluate the identification NPS and traditional drugs of abuse in biological matrices in Italian laboratories. • GC-MS, LC-MS, and immunoenzymatic methodswere reported, with LC-MS showing higher specificity and sensitivity. • The absence of cut-off values for NPS emphasizes the need to establish common criteria for their identification. [ABSTRACT FROM AUTHOR]

Background: Finding new strategies to treat cognitive disorders is a challenging task. Medication must defeat the blood-brain barrier. Cannabidiol (CBD), a non-intoxicating compound of the cannabis plant, has gained recognition as a nutraceutical for its potential effectiveness in treating anxiety, oxidative stress, convulsions, and inflammation. However, the dose, tolerable upper intake, formulation, administration routes, comorbidities, diet, and demographic factors to reverse cognitive impairments have not been completely explored. Trials using CBD as a primary intervention have been conducted to alleviate cognitive issues. This review evaluates the benefits of CBD supplementation, research design, formulations, and outcomes reported in randomized clinical trials., Methods: An evidence-based systematic literature review was conducted using PUBMED and the Florida International University Research Library resources. Fourteen randomized trials were selected for review, and their designs and outcomes were compared conceptually and in the form of resume tables., Results: CBD showed improvement in anxiety and cognitive impairments in 9 out of 16 analyzed trials. However, the variability could be justified due to the diversity of the trial designs, underpowered studies, assayed population, uncontrolled results for comorbidities, medications, severity of drug dependence, compliances, and adherences. Overall, oral single doses of 200 mg-1,500 mg or vaporized 13.75 mg of CBD were shown to be effective at treating anxiety and cognition with a good safety profile and no drug addiction behaviors. Conversely, results that did not have a significant effect on treating cognitive impairments can be explained by various factors such as THC or other abuse drugs masking effect, low dose, and unknown purity of CBD. Furthermore, CBD shows potential properties that can be tested in the future for Alzheimer's disease., Conclusion: As medical cannabis becomes more accessible, it is essential to understand whether medication rich in CBD exerts a beneficial effect on cognitive disorders. Our study concludes that CBD is a promising candidate for treating neurocognitive disorders; however, more studies are required to define CBD as a therapeutic candidate for managing cognitive disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Yndart Arias, Vadell, Vashist, Kolishetti, Lakshmana, Nair and Liuzzi.)

Xylazine, a non-opioid veterinary anaesthetic tranquillizer that is not licensed for human use, has been linked to an increase in overdose fatalities worldwide. The study delves into the forensic aspects of xylazine usage, emphasizing on chemical, clinical and toxicological analyses of drug seizures, bodily fluids and tissues. It advocates for validated analytical methods for determining xylazine. This study provides supporting material to pave the path for the usage and development of relevant and verified alternative screening and confirmation methods for laboratories. Google Scholar, Scopus, Science Direct and PubMed were searched for relevant articles and case reports in relation to xylazine misuse and established analytical methods for forensic investigation until April 2023. A total of 79 articles were evaluated, and 40 publications met the inclusion criteria. The most prevalent xylazine exposures recorded were incidental and intentional misuse/abuse. Common symptoms upon presentation were hypotension, bradycardia, drowsiness and lethargy, although mortality was less prevalent. Solid-phase extraction and liquid-liquid extraction are two extensively used sample preparation techniques. These techniques are used to extract desired analytes from complex matrices. Several analytical techniques have been stated, including GC-MS, LC-MS/MS, HPLC-DAD and others. The analytical procedures used are determined by the matrices involved, the amount of xylazine present, interfering compounds, the degree of precision required and the laboratory infrastructure. In the present context, the LC-MS/MS methods are preferred as the gold standard. In the near future, many analytical techniques such as capillary electrophoresis, PSI-MS, immuno-analytical techniques and SERRS may show significant potential., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This study aimed to investigate a miniaturized extraction methodology with analysis by GC-MS for simultaneous detection and quantification of cocaine (COC), benzoylecgonine (BZE) and cocaethylene (CE) in hair to monitor drug addicts. The process was done following the international guide of the Scientific Task Force on Forensic Toxicology. After sample extraction, derivatizing solution was added, clean-up was done by the Hollow Fiber Liquid Phase Microextraction (HF-LPME) and adapted to use the ultrasonic bath, a simple and easy-to-handle device. Isobutylchloroformate was first used as derivatization reagent to convert benzoylecgonine to isobutylbenzoylecgonine. Analytes quantification occurred within a linear range of 0.1 to 20 ng mg-1 for COC and 0.05 to 5 ng mg-1 for BZE and CE, with a correlation coefficient of r > 0.99. Limits of detection were 0.05; 0.03 and 0.03 ng mg-1, whereas limits of quantification were 0.1; 0.05 and 0.05 ng mg-1 for COC; BZE and CE, respectively. There was no matrix effect interference. Intra and inter-day precision and accuracy were acceptable according to international guidelines. The analytical method HF-LPME-GC-MS was successfully applied to 14 hair samples from patients admitted in drugs detoxification programs. All samples resulted positive for cocaine (0.80-> 20 ng mg-1) and benzoylecgonine (0.20-> 5 ng mg-1), 11 samples were positive for cocaethylene (0.10-> 0.60 ng mg-1).

Workplace drug testing (WDT) is essential to prevent drug abuse disorders among the workforce because it can impair work performance and safety. However, WDT is limited by many challenges, such as urine adulteration, specimen selection, and new psychoactive substances (NPS). This review examined the issues related to WDT. Various scientific databases were searched for articles on WDT for drug detection published between 1986 (when WDT started) and January 2024. The review discussed the history, importance, and challenges of WDT, such as time of specimen collection/testing, specimen adulteration, interference in drug testing, and detection of NPS. It evaluated the best methods to detect NPS in forensic laboratories. Moreover, it compared different techniques that can enhance WDT, such as immunoassays, targeted mass spectrometry, and nontargeted mass spectrometry. These techniques can be used to screen for known and unknown drugs and metabolites in biological samples. This review assessed the strengths and weaknesses of such techniques, such as their validation, identification, library search, and reference standards. Furthermore, this review contrasted the benefits and drawbacks of different specimens for WDT and discussed studies that have applied these techniques for WDT. WDT remains the best approach for preventing drug abuse in the workplace, despite the challenges posed by NPS and limitations of the screening methods. Nontargeted techniques using high-resolution liquid chromatography-mass spectrometry (MS)/gas chromatography–tandem MS can improve the detection and identification of drugs during WDT and provide useful information regarding the prevalence, trends, and toxicity of both traditional and NPS drugs. Finally, this review suggested that WDT can be improved by using a combination of techniques, multiple specimens, and online library searches in case of new NPS as well as by updating the methods and databases to include new NPS and metabolites as they emerge. To the best of the author's knowledge, this is the first review to address NPS as an issue in WDT and its application and propose the best methods to detect these substances in the workplace environment. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a drug of abuse used by millions worldwide. MDMA human abuse and dependence is well described, but addictive properties are not always consistent among studies. This amphetamine is a substrate type releaser, binding to monoamine transporters, leading to a pronounced release of serotonin and noradrenaline and to a minor extent dopamine. The toxicity of MDMA is well studied at the pre-clinical level, with neurotoxicity and hepatotoxicity being particularly described.In this review, we describe the most relevant MDMA effects at the mitochondrial level found in in vitro and in vivo models, these later conducted in mice and rats. Most of these reports focus on the mitochondria of brain or liver. In in vitro models, MDMA causes depletion of ATP levels and inhibition of mitochondrial complex I and III, loss in mitochondrial membrane potential (ΔΨm) and induction of mitochondrial permeability transition. The involvement of mitochondria in the apoptotic cell death evoked by MDMA has also been shown, such as the release of cytochrome c. Additionally, MDMA or its metabolites impaired mitochondrial trafficking and increased the fragmentation of axonal mitochondria. In animal studies, MDMA decreased mitochondrial complex I activity and decreased ATP levels. Moreover, MDMA-evoked oxidative stress has been shown to cause deletion on mitochondrial DNA and impairment in mitochondrial protein synthesis.Although the concentrations and doses used in some studies do not always correlate to the human scenario, the mitochondrial abnormalities evoked by MDMA are well described and are in part responsible for its mechanism of toxicity.

Abstract Analysis of hair provides useful information regarding drug addiction history or drug toxicity. Keeping in view some important applications of hair analysis, a lot of work done in the past few decades has been reviewed in this article. When compared with other biological samples, hair provides a larger window for drug detection. Drugs get deposited in hair through blood circulation by various mechanisms, after its administration. The deposited drug is much stable and can be detected after a longer period of time as compared with other biological samples, e.g., saliva, blood, and urine. Moreover, segmental analysis can depict multiple or single drug administration by using sensitive analytical techniques. Complex methods for drug extraction and the high cost of analysis are some drawbacks of hair analysis. LC-MS and GC-MS are the prominent among other techniques of choice due to high sensitivity. In this review, detailed knowledge about the drug deposition, extraction, analysis, and application of results in forensic and clinical cases have been discussed.

• U-47700) is a selective μ–opioid receptor agonist several times more potent than morphine. • Despite its growing abuse, psychopharmacological profile of U-47700 remains poorly understood. • The zebrafish is an important model species for CNS disease modeling and drug discovery. • Acute (1-50 mg/L) doses of U-47700 evoke robust sedation in adult zebrafish. • Chronic (0.1-1 mg/L) U-47700 causes hyperlocomotor and anxiolytic-like effects in zebrafish. 3,4-Dichloro- N -[2-(dimethylamino)cyclohexyl]- N -methylbenzamide (U-47700) is a selective μ–opioid receptor agonist originally synthesized as a prospective analgesic drug. Several times more potent than morphine, U-47700 has high abuse potential and may cause clinical neurotoxicity, euphoria, respiratory depression and occasional mortality. U-47700 also evokes analgesia, sedation and euphoria-like states in both humans and rodents. Despite the growing use and abuse of U-47700, its psychopharmacological and toxicological profiles in vivo remain poorly understood. The zebrafish (Danio rerio) is rapidly becoming a popular aquatic model organism for central nervous system (CNS) disease modeling and drug discovery. Here, we examine acute (1, 5, 10, 25 and 50 mg/L for 20-min) and chronic (0.1, 0.5 and 1 mg/L for 14 days) effects of U-47700 in adult zebrafish. Overall, we found overt sedation evoked in fish by acute, and hyperlocomotion with an anxiolytic-like action by chronic, drug treatments. Acute treatment with 1 and 10 mg/L U-47700 also resulted in detectable amounts of this drug in the brain samples, supporting its permeability through the blood-brain barrier. Collectively, these findings emphasize complex dose- and treatment-dependent CNS effects of U-47700 following its acute and chronic administration. Our study also supports high sensitivity of zebrafish to U-47700, and suggests these aquatic models as promising in-vivo screens for probing potential CNS effects evoked by novel synthetic opioid drugs. [ABSTRACT FROM AUTHOR]

Recent animal research on substance-use disorders (SUDs) has emphasized learning models and the identification of 'addiction-prone' animals. Meanwhile, basic neuroscientific research has elucidated molecular, cellular, and circuit functions with increasing sophistication. However, SUD-related research is hampered by continued arguments over which animal models are more 'addiction like', as well as the facile assignment of behaviors to a given brain region and vice versa. We argue that SUD-related research would benefit from a 'bottom-up' approach including: (i) the characterization of different brain circuits to understand their normal function as well as how they respond to drugs and contribute to SUDs; and (ii) a focus on the use patterns and neurobiological effects of different substances to understand the range of critical SUD-related in vivo phenotypes. Behavioral models of compulsive drug use and progress in techniques for cell and circuit measurement and manipulation are advancing substance abuse research. A circuit information-based approach to substance use disorder (SUD)-related research can take full advantage of these developments. This approach moves beyond the assignment of behavior to a particular brain region towards understanding how an area can contribute to the computations performed. We discuss examples from research on the corticothalamic–basal ganglia circuit that highlight the usefulness of circuit information-based research on SUDs. Consideration should also be given to divergent actions of different drugs of abuse in animal model-based research on circuit roles in SUDs. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop and to validate a toxicological untargeted screening relying on LC-HRMS in meconium including the detection of the four main classes of drugs of abuse (DoA; amphetamines, cannabinoids, opioids and cocaine). The method was then applied to 29 real samples. Analyses were performed with a liquid chromatography system coupled to a benchtop Orbitrap operating in a data-dependent analysis. The sample amount was 300 mg of meconium extracted twice by solid phase extraction following two distinct procedures. Raw data were processed using the Compound Discoverer 3.2 software (Thermo). The method was evaluated and validated on 15 compounds (6-MAM, morphine, buprenorphine, norbuprenorphine, methadone, EDDP, amphetamine, MDA, MDMA, methamphetamine, cocaine, benzoylecgonine, THC, 11-OH-THC, THC-COOH). Limits of detection were between 0.5 and 5 pg/mg and limits of identification between 5 and 50 pg/mg. Mean matrix effect was between −79 and −19% (n = 6) and mean overall recovery between 18 and 73% (n = 6) at 100 pg/mg. The application allows the detection of 88 substances, including 47 pharmaceuticals and 15 pharmaceutical metabolites, cocaine and its metabolites, THC and its metabolites, and natural (morphine, codeine) and synthetic (methadone, buprenorphine, tramadol, norfentanyl) opioids. This method is now used routinely for toxicological screening in high-risk pregnancies

A method for separation and determination of 32 fentanyl‐related substances, including seven sets of isomeric fentanyl analogues, was developed using ultra‐high‐performance liquid chromatography coupled with quadrupole‐orbitrap high‐resolution mass spectrometry. The collision energy, chromatographic column, and mobile phase were optimized. All compounds were efficiently flushed out of a universal C18 column with a soft gradient consisting of solvent A (2 mM ammonium formate and 0.1% formic acid in water) and solvent B (2 mM ammonium formate and 0.1% formic acid in methanol) in only 20 min, achieving excellent resolution. Detection and analysis were carried out simultaneously in the positive ion mode using the full scan and data‐dependent tandem mass spectrometry modes with a normalized collision energy of 40. The method was validated in terms of limit of detection, limit of quantification, linearity, accuracy, and precision. For all fentanyl‐related substances, the limit of detection (0.5 ng/mL) and limit of quantification (1 ng/mL) were adequate for screening and quantification in daily drug control. Calibration curves for all compounds were established in the range of 1–500 ng/mL. The intra‐ and interday precision (RSD%) were within 0.4–2.3 and 0.7‐2.7%, respectively. The accuracy ranged from 99 to 106%. The method was applied to analyze seized drug samples. [ABSTRACT FROM AUTHOR]

Drugs of abuse can be investigated in dried blood spot (DBS) samples to evaluate the intake of psychoactive drugs. We have developed the validated liquid chromatography–tandem mass spectrometry method to determine drug of abuse in whole blood with DBS. The mass spectrometer was performed using multiple reaction monitoring via positive electro-spray ionization. The analysis procedure was applied to real positive blood samples of the 59 cases brought to Forensic Toxicology Laboratory in Faculty of Medicine of Cukurova University by law enforcement agencies. The method based on liquid–liquid extraction and liquid chromatography tandem mass spectrometry was fully validated according to international guidelines and then applied to authentic positive blood samples. Overall, polydrug usage was determined in 24 real samples and one or more psychoactive drugs were found positive in 51 of 59 real samples, which were found to be positive via performing routine whole blood analysis and selected for DBS analysis. Our method developed could applicate as an alternative to conventional analytical and sampling techniques and respond to some of the present issues concerning the different forensic toxicological investigations. [ABSTRACT FROM AUTHOR]

OBJECTIVE: New psychoactive substances (NPS), are a range of drugs designed to mimic the effects of established illicit drugs, being legal at the time of their distribution in illicit markets. The review aims to shed a light on the growing threat caused by NPS, and on the dynamics and developments that have led to their spread, including the risk of new adulteration practices which can cause a serious health threat, due to their increased toxicity, e.g., through fentanyl and its analogs. MATERIALS AND METHODS: An overview of statistical trends relative to NPS use has been provided, in addition to regulatory and legislative approaches in several countries and recommendations and data from International institutions: UN Office on Drugs and Crime, United Nations Commission on Narcotic Drugs, WHO, European Parliament, European Monitoring Centre for Drugs and Drug Addiction, Europol and international collaborative efforts such as the Trans European Drug Information (TEDI) project and the Spanish Energy Control. RESULTS: Given the elusive nature of NPS, spontaneous pharmacovigilance reporting systems are needed to identify new trends of drug abuse. Broad-ranging legislative initiatives are needed in order to set common international standards (e.g., the European Parliament Regulation 2017/2101, with information exchange, an early warning system and risk assessment procedure for NPS) to tackle a potentially catastrophic and growing threat. CONCLUSIONS: By virtue of all the complexities and hurdles that have to be overcome in the fight against NPS, and to assist national governments in their identification and reporting, supranational organizations can come to play a key role. Only through international measures, supplementing national legislative initiatives, can this multi-faceted problem be effectively addressed and information about NPS be gathered and disseminated in a timely fashion. [ABSTRACT FROM AUTHOR]

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

Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP). These compounds' main physiological targets are monoamine transporters, where they promote addiction by potentiating dopaminergic neurotransmission. This chapter describes techniques used to study the pharmacodynamic properties of cathinones at monoamine transporters in vitro. Biochemical techniques described include uptake inhibition and release assays in rat brain synaptosomes and in mammalian expression systems. Electrophysiological techniques include current measurements using the voltage clamp technique. We describe a Ca 2+ mobilization assay wherein voltage-gated Ca 2+ channels function as reporters to study the action of synthetic cathinones at monoamine transporters. We discuss results from systematic structure-activity relationship studies on simple and complex cathinones at monoamine transporters with an emphasis on identifying structural moieties that modulate potency and selectivity at these transporters. Moreover, different profiles of selectivity at monoamine transporters directly predict compounds associated with behavioral and subjective effects within animals and humans. In conclusion, clarification of the structural aspects of compounds which modulate potency and selectivity at monoamine transporters is critical to identify and predict potential addictive drugs. This knowledge may allow prompt allocation of resources toward drugs that represent the greatest threats after drugs are identified by forensic laboratories., (Copyright © 2024. Published by Elsevier Inc.)

Curcumin (CUR), a natural polyphenol extracted from rhizome of the Curcuma longa L, has received great attention for its multiple potential health benefits as well as disease prevention. For instance, CUR protects against toxic agents acting on the human body, including the nervous system. In detail, CUR possesses, among others, strong effects as an autophagy activator. The present study indicates that CUR counteracts methamphetamine (METH) toxicity. Such a drug of abuse is toxic by disturbing the autophagy machinery. We profited from an unbiased, low variable cell context by using rat pheochromocytoma PC12 cell line. In such a system, a strong protection was exerted by CUR against METH toxicity. This was associated with increased autophagy flux, merging of autophagosomes with lysosomes and replenishment of autophagy vacuoles with LC3, which instead is moved out from the vacuoles by METH. This is expected to enable the autophagy machinery. In fact, while in METH-treated cells the autophagy substrates α-synuclein accumulates in the cytosol, CUR speeds up α-synuclein clearance. Under the effects of CUR LC3 penetrate in autophagy vacuoles to commit them to cell clearance and promotes the autophagy flux. The present data provide evidence that CUR counteracts the neurotoxic effects induced by METH by promoting autophagy.

Methamphetamine is, worldwide, one of the most consumed drugs of abuse. One important side effect is neurodegeneration leading to a decrease in life expectancy. The aim of this paper was to check whether the drug affects one of the receptors involved in neurodegeneration/neuroprotection events, namely the adenosine A2A receptor (A2AR). First, we noticed that methamphetamine does not affect A2A functionality if the receptor is expressed in a heterologous system. However, A2AR becomes sensitive to the drug upon complexes formation with the cannabinoid CB1 receptor (CB1R) and the sigma 1 receptor (σ1R). Signaling via both adenosine A2AR and cannabinoid CB1R was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the A2AR–CB1R heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the A2AR- and the CB1R-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σ1R, alters the expression and function of two interacting receptors, A2AR, which is a therapeutic target for neuroprotection, and CB1R, which is the most abundant G protein-coupled receptor (GPCR) in the brain.

Abstract Xylazine is marketed as a veterinary drug and used for sedative and analgesic purposes; it is not approved for human use due to various side effects. In recent years, xylazine has emerged as a drug of abuse and has been associated with drug-facilitated sexual assaults. Herein, we describe, for the first time, the electrochemical study of xylazine in aqueous and organic media and proposed a quantification method using glassy carbon electrode. The simple and accurate quantification method was performed using differential pulse voltammetry. Under the optimized experimental conditions, a linear analytical curve was obtained for xylazine concentrations ranging from 0.5 to 256 μmol L−1, with an estimated detection limit of 120 nmol L−1. The proposed method was applied to determination of xylazine in pharmaceutical formulation. Furthermore, to forensic scenario, a standard addition technique on urine samples exhibited recovery values in the range of 93–103%, demonstrating the potentiality to forensic and clinical analysis of xylazine intoxication. Graphical abstract Image 1 Highlights • Forensic oriented sensor towards the drug-facilitated crime detection. • First electroanalytical method for xylazine quantification is reported. • The proposed method is simple, sensitive, and accurate for clinical and forensic applications. • Electrochemical mechanism for the oxidation of xylazine in aqueous and organic media. • The proposed method was successfully applied for the analysis of pharmaceutical and urine samples. [ABSTRACT FROM AUTHOR]

DNA sequence is a powerful tool that can be used for an individual’s identification and investigation of various abnormalities in the genome. However, recent studies have identified other heritable changes by epigenetic mechanisms that cause changes in gene expression without altering the DNA sequence itself. In particular, DNA methylation mediates long-lasting changes in gene promoters, which makes it an appealing epigenetic mechanism to study variation in methylation status that characterizes the extent of drug abuse. We summarize recent findings on methylation alterations in a number of genes caused by various drugs including cocaine, opioids, cannabinoids, amphetamine, phenobarbital, and alcohol in various human and animal model studies. Additionally, a minimal discussion of the basic concepts of methylation is provided. The determination of possible DNA methylation alterations can assist in finding the cause and circumstances of death or ailment, and gene markers can be potentially used as biomarkers in the future. [ABSTRACT FROM AUTHOR]

Carfentanil and related fentanyl analogs have been linked to a number of overdose deaths from drug users in several cities across North America. Diagnosis of carfentanil exposure requires a very high index of clinical suspicion, especially because available laboratory narcotic screens do not detect this agent. We describe a 34-year-old man admitted with depressed level of consciousness and in respiratory failure after recreational exposure to a white powder later inferred to contain carfentanil. Urine and whole blood samples were obtained for conventional preliminary drug screen immunoassays for unknown exposures, in addition to utilizing a high-pressure liquid chromatography-tandem mass spectrometry assay for quantification of carfentanil and its metabolite. The patient was intubated and required mechanically assisted ventilation for 31 hours until he was able to breathe safely on his own. Pharmacokinetic modeling of three timed blood samples identified the elimination half-life as 5.7 hours for carfentanil and 11.8 hours for the norcarfentanil metabolite. Awakening and breathing spontaneously corresponded to an interpolated blood carfentanil concentration of 0.52 ng/ml. This is the first pharmacokinetic and pharmacodynamic case report on the recreational use of carfentanil. Critical care clinicians should anticipate long periods of ventilatory support in the care of patients exposed to carfentanil. [ABSTRACT FROM AUTHOR]

Achievements of supercritical fluid chromatography with mass spectrometric detection made in the field of forensic science during the last decade are reviewed. The main topics include analysis of traditional drugs of abuse (e.g. cannabis, methamphetamine) as well as new psychoactive substances (synthetic cannabinoids, cathinones and phenethylamines), doping agents (anabolic steroids, stimulants, diuretics, analgesics etc.) and chemical warfare agents. Control of food authenticity, detection of adulteration and identification of toxic substances in food are also pointed out. Main aspects of an analytical workflow, such as sample preparation, separation and detection are discussed. A special attention is paid to the performance characteristics and validation parameters of supercritical fluid chromatography-mass spectrometric methods in comparison with other separation techniques. [ABSTRACT FROM AUTHOR]

In this study, a passive sampling technique, diffusive gradients in thin films (DGT) was developed to simultaneously measure two drugs, methcathinone (MC) and ephedrine (EPH) in surface water. Four types of binding gels and four types of filter membranes were tested for the optimal configuration. XAD18 agarose binding gel and agarose diffusive gel, together with polyethersulfone filter membrane were used for measuring MC and EPH in the DGT device. 5% NH 3 in acetonitrile was used as the elution solvent, with the elution efficiency for MC and EPH higher than 71%. At 25 °C, the diffusion coefficients of MC and EPH in the diffusive gel were 7.60 × 10 − 6 cm 2 s − 1 and 6.62 × 10 − 6 cm 2 s − 1 , respectively. The DGT was effective in a wide range of pH (4–11) and ionic strength (NaCl: 0.001–0.5 M). The DGT device was deployed in Beijing urban surface water for successive 7 days to measure the time-weighted concentrations of MC and EPH. Results showed that EPH was detected in all samples, while MC was below its detection limit. DGT concentrations were comparable to the concentrations determined by SPE. This study demonstrated that the developed DGT method was effective to monitor the two drugs in surface water in situ . [ABSTRACT FROM AUTHOR]

Due to its continuing development after birth, the cerebellum represents a unique model for studying the postnatal orchestration of interneuron migration. The combination of fluorescent labeling and ex/in vivo imaging revealed a cellular highway network within cerebellar cortical layers (the external granular layer, the molecular layer, the Purkinje cell layer and the internal granular layer). During the first two postnatal weeks, saltatory movements, transient stop phases, cell-cell interaction/contact and degradation of the extracellular matrix mark out the route of cerebellar interneurons, notably granule cells and basket/stellate cells, to their final location. In addition, cortical-layer specific regulatory factors such as neuropeptides (pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin) or proteins (tissue-type plasminogen activator (tPA), insulin growth factor-1 (IGF-1)) have been shown to inhibit or stimulate the migratory process of interneurons. These factors show further complexity because somatostatin, PACAP or tPA have opposite or no effect on interneuron migration depending on which layer or cell type they act upon. External factors originating from environmental conditions (light stimuli, pollutants), nutrients or drug of abuse (alcohol) also alter normal cell migration, leading to cerebellar disorders. [ABSTRACT FROM AUTHOR]

An increased rate of drug abuse is a major social problem worldwide. The dried blood spot (DBS) sampling technique offers many advantages over using urine or whole blood sampling techniques. This study developed a simple and efficient ultra-high-performance liquid chromatography-ion booster-quadrupole time-of-flight mass spectrometry (UHPLC-IB-QTOF-MS) method for the analysis of abused drugs and their metabolites using DBS. Fifty-seven compounds covering the most commonly abused drugs, including amphetamines, opioids, cocaine, benzodiazepines, barbiturates, and many other new and emerging abused drugs, were selected as the target analytes of this study. An 80% acetonitrile solvent with a 5-min extraction by Geno grinder was used for sample extraction. A Poroshell column was used to provide efficient separation, and under optimal conditions, the analytical times were 15 and 5 min in positive and negative ionization modes, respectively. Ionization parameters of both electrospray ionization source and ion booster (IB) source containing an extra heated zone were optimized to achieve the best ionization efficiency of the investigated abused drugs. In spite of their structural diversity, most of the abused drugs showed an enhanced mass response with the high temperature ionization from an extra heated zone of IB source. Compared to electrospray ionization, the ion booster (IB) greatly improved the detection sensitivity for 86% of the analytes by 1.5–14-fold and allowed the developed method to detect trace amounts of compounds on the DBS cards. The validation results showed that the coefficients of variation of intra-day and inter-day precision in terms of the signal intensity were lower than 19.65%. The extraction recovery of all analytes was between 67.21 and 115.14%. The limits of detection of all analytes were between 0.2 and 35.7 ng mL −1 . The stability study indicated that 7% of compounds showed poor stability (below 50%) on the DBS cards after 6 months of storage at room temperature and −80 °C. The reported method provides a new direction for abused drug screening using DBS. [ABSTRACT FROM AUTHOR]

A simple, sensitive and precise HPTLC (high performance thin layer chromatography) method has been developed for quantitative estimation of ketamine in bulk and pharmaceutical formulations. The separation of ketamine was achieved over HPTLC glass plate of silica GF-254 by using cyclohexane:toluene:diethylamine (5:3:2 v/v) solvent system. Densitometric evaluation was carried out in the UV region at wavelength of 254. The method was found to be accurate (98.92-100.26%) and precise (CV = 0.43-0.67 for intra-day and CV = 0.58-1.45 for inter-day) within the corresponding linear range. The limit of detection (LOD) and limit of quantification (LOQ) of sample have been found to be 100 ng/spot and 303 ng/spot, respectively. [ABSTRACT FROM AUTHOR]

An advantage of differential mobility spectrometry (DMS) is it provides an orthogonal mechanism to mass spectrometry (MS). The DMS-MS/MS detects analytes in the gas phase on the basis of differences in ion mobility in low and high electric fields, which makes DMS-MS/MS an alternative to chromatographic separation-MS. One drawback of DMS is its limited resolution and sensitivity, especially for detecting small molecules when using a nonpolar inert gas as the carrier gas. The present work has evaluated the effects on peak capacity of adding chemical modifiers to inert carrier gases (nitrogen, helium, argon and carbon dioxide). Use of a methanol-helium mixture gave improvements in both separation and sensitivity. Nine structurally similar amphetamine-type stimulants were determined in urine without pretreatment of the samples before analysis. After optimization of carrier gas, nature and concentration of chemical modifier, and DMS temperature, limits of detection ranging from 1.1 to 2.7 ng mL −1 , with a linear range of three orders of magnitude (5–5000 ng mL −1 ) were achieved. Precision was <15% and the accuracy of the quality control samples was 87.6–113.7%. For the quantitation of urine samples from drug abusers, data obtained using DMS-MS/MS showed reasonable agreement (within ±19.5%) with that obtained using LC-MS/MS. The analysis time for DMS-MS/MS was only 1.1 min and a paired sample t -test between the two methods gave a p -value of 0.0894, which indicates that DMS-MS/MS is a reliable method, with comparable precision and sensitivity to LC-MS/MS. [ABSTRACT FROM AUTHOR]

A ampla disponibilidade e o baixo custo de Compostos Orgânicos Voláteis (COV) têm contribuído para o aumento do uso recreacional dessas substâncias em festas populares no Brasil. Nos últimos cinco anos, o consumo da droga popularmente conhecida como “lança-perfume” tornou-se crescente no Carnaval da Bahia. Diante desse cenário, somente em 2015 foram apreendidas pela polícia local durante o carnaval em Salvador, 61 ampolas de vidro contendo líquidos voláteis, em um período de cinco dias de festa. Após as análises das amostras de “lança-perfume” apreendidas, foram identificados 11 diferentes COVs, com a predominância de compostos halogenados (clorofluorcarbonos), especialmente o diclorofluorometano (HCFC 21) que estava presente em 18% das amostras analisadas e não é uma substância proscrita de acordo com a Portaria nº 344/98 SVS/MS.

Drug addiction is a brain disease involving alterations in anatomy and functional neural communication. Drug intake and toxicity show daily rhythms in both humans and rodents. Evidence concerning the role of clock genes in drug intake has been previously reported. However, the implication of a timekeeping brain locus is much less known. The epithalamic lateral habenula (LHb) is now emerging as a key nucleus in drug intake and addiction. This brain structure modulates the activity of dopaminergic neurons from the ventral tegmental area, a central part of the reward system. Moreover, the LHb has circadian properties: LHb cellular activity (i.e., firing rate and clock genes expression) oscillates in a 24h range, and the nucleus is affected by photic stimulation and has anatomical connections with the main circadian pacemaker, the suprachiasmatic nucleus. Here, we describe the current insights on the role of the LHb as a circadian oscillator and its possible implications on the rhythmic regulation of the dopaminergic activity and drug intake. This data could inspire new strategies to treat drug addiction, considering circadian timing as a principal factor.