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Rett syndrome and its “early-onset seizure” variant are severe neurodevelopmental disorders associated with mutations within the MECP2 and the CDKL5 genes. Antidepressants and drugs of abuse induce the expression of the epigenetic factor MeCP2, thereby influencing chromatin remodeling. We show that increased MeCP2 levels resulted in the repression of Cdkl5 in rat brain structures in response to cocaine, as well as in cells exposed to serotonin, or overexpressing MeCP2. In contrast, Cdkl5 was induced by siRNA-mediated knockdown of Mecp2 and by DNA-methyltransferase inhibitors, demonstrating its regulation by MeCP2 and by DNA methylation. Cdkl5 gene methylation and its methylation-dependent binding to MeCP2 were increased in the striatum of cocaine-treated rats. Our data demonstrate that Cdkl5 is a MeCP2-repressed target gene providing a link between genes the mutation of which generates overlapping symptoms. They highlight DNA methylation changes as a potential mechanism participating in the long-term plasticity triggered by pharmacological agents.

Introduction: Abuse/dependence and acute use of ethanol and illicit drug are considered risk factors for suicide. The risk is also influenced by demographic conditions and/or psychiatric comorbidity. The aim of the study was to test the association between presence of ethanol, illicit substances and prescribed drugs in suicide decedents and controls., Materials and Methods: Case-control study of autopsies performed in the Biscay Forensic Pathology Service, Basque Country, Spain from 01/01/2010 to 30/06/2021 in subjects between 15 and 55 years old. Suicide deaths (n=481) with completed autopsy were evaluated. Concurrent natural deaths were chosen as controls (n=330). The risk for suicide according to demographic, toxicological and psychiatric variables was analyzed using logistic regression., Results: Ethanol was present in 21% and illicit drugs, mainly cannabis, cocaine and amphetamine, in 27% of suicide deaths. Illicit drugs were more frequent among males. In 63% of suicide cases, prescribed psychotropic drugs were detected. In a multivariate analysis, the main risk factors for suicide were psychiatric diagnosis of illicit drug abuse/dependence (OR=5.56, 95% CI 2.74-11.30) or another mental disease as mood or psychotic disorders (OR=13.05, 95% CI 8.79-19.37). Acute presence of ethanol (OR=4.22, 95% CI 2.52-7.08), recent use of cocaine (OR=2.52, 95% CI 1.05-6.07) and age <35 years (OR=2.50, 95% CI 1.62-3.87) were also associated with suicide deaths., Conclusions: The presence of drugs of abuse in suicide deaths of people ≤55 years old is high. Recent use of ethanol and cocaine is significantly associated with an increased suicide risk. Specific prevention strategies against exposition to substances of abuse should be promoted, especially in psychiatric patients., (Copyright © 2023 The Author(s). Published by Elsevier España S.L.U. All rights reserved.)

The concentrations of 17 drugs of abuse, including cocaine, several amphetamines, opioid drugs, and 2 metabolites-benzoylecgonine, a metabolite of cocaine, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine, a metabolite of methadone-were investigated in an urban watershed that is heavily impacted by discharges of municipal wastewater. The artificial sweetener sucralose was also monitored as a persistent tracer of contamination from municipal wastewater. Monitoring was conducted in a municipal wastewater treatment plant (WWTP) and at sites upstream and downstream of the WWTP discharge, as well as in a drinking water treatment plant (DWTP) located 19 km downstream of the WWTP discharge that withdraws raw water from the river. Drug concentrations were monitored with polar organic chemical integrative samplers deployed for 2 wk in the river and in the WWTP and DWTP. Several of the investigated compounds exhibited a decrease in concentration with distance downstream from the wastewater discharge into the river, but there was little attenuation of sucralose, cocaine, benzoylecgonine, morphine, acetylmorphine, acetylcodeine, and oxycodone. Heroin and methadone were not detected at any sample locations. Amphetamine, methamphetamine, 3,4-methylenedioxy-methamphetamine, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine were not detected in the samples collected at the drinking water intake. Many of the drugs of abuse were not removed effectively in the DWTP, including cocaine, benzoylecgonine, methylenedioxyamphetamine, ephedrine, and several prescription opioids, most probably because the DWTP was operating at or above its rated treatment capacity. These data indicate that there can be transport of drugs of abuse from wastewater sources into drinking water in urban watersheds. Environ Toxicol Chem 2016;35:843-849. © 2015 SETAC [ABSTRACT FROM AUTHOR]

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 24-h 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. These data could inspire new strategies to treat drug addiction, considering circadian timing as a principal factor. [ABSTRACT FROM AUTHOR]

The use of smoked illicit drugs has spread dramatically, but few studies use proper devices to expose animals to inhalational abused drugs despite the availability of numerous smoking devices that mimic tobacco exposure in rodents. Therefore, the present study developed an inexpensive device to easily expose laboratory animals to smoked drugs. We used crack cocaine as the drug of abuse, and the cocaine plasma levels and the behaviors of animals intoxicated with the crack cocaine were evaluated to prove inhaled drug absorption and systemic activity. We developed an acrylic device with two chambers that were interconnected and separated by a hatch. Three doses of crack (100, 250, or 500 mg), which contained 63.7% cocaine, were burned in a pipe, and the rats were exposed to the smoke for 5 or 10 min (n = 5/amount/period). Exposure to the 250-mg dose for 10 min achieved cocaine plasma levels that were similar to those of users (170 ng/mL). Behavioral evaluations were also performed to validate the methodology. Rats (n = 10/group) for these evaluations were exposed to 250 mg of crack cocaine or air for 10 min, twice daily, for 28 consecutive days. Open-field evaluations were performed at three different periods throughout the experimental design. Exposed animals exhibited transient anorexia, increased motor activity, and shorter stays in central areas of the open field, which suggests reduced anxiety. Therefore, the developed model effectively exposed animals to crack cocaine, and this model may be useful for the investigation of other inhalational abused drugs. [ABSTRACT FROM AUTHOR]

We present a series of forensic cases measuring concentrations in hair of γ-hydroxybutyric acid (GHB) and its glucuronide. The compounds were extracted from hair by incubation for 1.5 h in a 25:25:50 (v/v/v) mixture of methanol/acetonitrile/2 mM ammonium formate (8 % acetonitrile, pH 5.3). The compounds were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The limits of quantitation (LOQ) were 0.32 and 0.48 ng/mg hair for GHB and its glucuronide, respectively, and linearity up to 50 ng/mg. Extraction recoveries were 62-92 % for the analytes, and the accuracy was 90-108 %. Precision values expressed as relative standard deviations (%) obtained from daily controls were 9.1-11.3 % for GHB and 12.2-17.9 % for GHB glucuronide. Endogenous levels were up to 1.0 ng/mg for GHB and 1.2 ng/mg for GHB glucuronide in control subjects. In two GHB abusers, GHB was highly elevated (461-591 ng/mg), whereas GHB glucuronide was only slightly elevated in one of the subjects (1.7-3.1 ng/mg) and below the LOQ in the other. Thus, GHB glucuronide is not incorporated in hair in any appreciable amounts in GHB abusers and does not contribute diagnostically with regard to detection of exogenous exposure. To our knowledge, this is the first report to present GHB glucuronide in human hair. [ABSTRACT FROM AUTHOR]

Background and Objective: Road traffic injuries are among the most important causes of death and disability in Iran, and the country has one of the highest prevalence of opioid drug use, especially among drivers. The effect of different situations related to opioid use needs great attention. The purpose of this study was to estimate the effect of driving in the withdrawal phase on the occurrence of traffic accidents leading to injury.Materials and Methods: This is a Case-Crossover study on injured drivers of crashed motor vehicles in Kerman. Drivers having skipped one habitual drug dose within one hour of the driving session were considered as being in withdrawal. We compared the drivers' situation at the time of accident with their regular driving habits.Results: Among 75 drivers who had history of regular use of opium, 15 were in withdrawal phase at the time of accident. The relative rate of occurrence of traffic injuries while driving in these circumstances was 2.67 (95% confidence interval: 1.52 - 4.68).Conclusion: According to these findings we can conclude that habitual opioid users are at greater risk of traffic accidents while driving in withdrawal status; this risk is more than two-fold relative to not being in withdrawal status.

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.

Synthetic cannabinoids are an emerging class of drugs of abuse and are of a great concern for transport control and usage regulation. In this study, we have developed rapid analytical methods using a miniature mass spectrometer for the identification of synthetic cannabinoids, as the traces of bulk powders on surfaces or substances in blood and urine. Significantly simplified work flows were developed by employing two ambient ionization methods, the paper spray and extraction spray ionization. Using five synthetic cannabinoids as examples, a limit of detection of 2 ng was estimated for the detection of trace powders on a bench surface and limits of quantitation as good as 10 ng/mL were obtained for the analysis of blood and urine samples. [ABSTRACT FROM AUTHOR]

We report the development of a simple and accurate analytical method to detect aminopyrine in seized cocaine samples using a platinum electrode. The quantification of aminopyrine was performed using square wave voltammetry (SWV), where the peak current response was found to increase linearly with aminopyrine concentration over the range 100–1000 μmol L − 1 . The repeatability of the electrode response was determined to be 2.4% (n = 15), and the detection limit of the proposed method was estimated to be 22 μmol L − 1 (3σ/slope). The accuracy of the proposed method was evaluated comparing the measured aminopyrine concentration in seized cocaine sample to the value obtained by gas chromatography coupled to flame ionization detector (GC-FID). An addition and recovery protocol in seized cocaine samples was also performed. [ABSTRACT FROM AUTHOR]

A new pyrazole-carboxamide type synthetic cannabinoid, AB-CHFUPYCA ( 1), was detected in illegal herbal products by our ongoing survey in Japan. The structure of 1 was identified by gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-high-resolution-mass spectrometry (LC-HR-MS) and nuclear magnetic resonance (NMR) analyses. Compound 1 showed a molecular weight of 400, and accurate mass measurement using LC-HR-MS revealed its molecular formula to be CHNOF. The MS and NMR spectrometric data revealed that the structure of 1 was N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1 H-pyrazole-5-carboxamide. Compound 1, which is a new type of synthetic cannabinoid, has a 3-(4-fluorophenyl)-1 H-pyrazole group in place of a 1 H-indazole group of AB-CHMINACA. To our knowledge, data on the chemistry and pharmacology of compound 1 have never been reported, and we therefore named compound 1 'AB-CHFUPYCA.' [ABSTRACT FROM AUTHOR]

Rationale: Thousands of adolescents start smoking daily but information on the effects of tobacco exposure on this age group is scarce. Moreover, the available animal models rely on the effects of nicotine, neglecting other neuroactive components of tobacco. Objectives: We investigated the effects of exposure of adolescent mice to tobacco smoke generated from cigarettes containing either high or low levels of nicotine on novelty seeking and anxiety-like behaviors. Methods: From postnatal day (PN) 30 to 45, male and female Swiss mice were exposed to tobacco smoke (whole body exposure, 8 h/day, 7 days/week) generated from 2R1F (HighNic group: 1.74 mg nicotine/cigarette) or 4A1 (LowNic group: 0.14 mg nicotine/cigarette) research cigarettes, whereas control mice were exposed to ambient air. By the end (PN44-45), shortly (PN49-50), or long after (PN74-75) exposure, mice were tested on the elevated plus maze and on the hole board. Results: While HighNic mice presented an increased number of head-dips (increased novelty-seeking) and decreased grooming (increased anxiety-like behavior) by the end of adolescent exposure, only the latter effect persisted shortly after its end. Distinctively, LowNic mice presented reduced head-dips both by the end and shortly after exposure as well as decreased grooming shortly and long after the end of exposure. Interestingly, only HighNic mice presented detectable cotinine (nicotine metabolite) serum levels (109.1 ± 24.0 ng/ml). Conclusion: Our results demonstrate that even adolescent exposure to tobacco smoke with very low nicotine content can have significant short- and long-term behavioral effects, supporting the hypothesis that adolescents can be particularly vulnerable to the effects of cigarette consumption. [ABSTRACT FROM AUTHOR]

Hair analysis of drugs of abuse has been a subject of growing interest from a clinical, social and forensic perspective for years because of the broad time detection window after intake in comparison to urine and blood analysis. Over the last few years, hair analysis has gained increasing attention and recognition for the retrospective investigation of drug abuse in a wide variety of contexts, shown by the large number of applications developed. This review aims to provide an overview of the state of the art and the latest trends used in the literature from 2005 to the present in the analysis of drugs of abuse in hair, with a special focus on separation analytical techniques and their hyphenation with mass spectrometry detection. The most recently introduced sample preparation techniques are also addressed in this paper. The main strengths and weaknesses of all of these approaches are critically discussed by means of relevant applications. [ABSTRACT FROM AUTHOR]

Introduction. Methoxphenidine is a novel dissociative designer drug of the diarylethylamine class which shares structural features with phencyclidine (PCP), and is not at present subject to restrictive regulations. There is very limited information about the acute toxicity profile of methoxphenidine and the only sources are anonymous internet sites and a 1989 patent of the Searle Company. We report a case of analytically confirmed oral methoxphenidine toxicity. Case details. A 53-year-old man was found on the street in a somnolent and confusional state. Observed signs and symptoms such as tachycardia (112 bpm), hypertension (220/125 mmHg), echolalia, confusion, agitation, opisthotonus, nystagmus and amnesia were consistent with phencyclidine-induced adverse effects. Temperature (99.1°F (37.3°C)) and peripheral oxygen saturation while breathing room air (99%) were normal. Laboratory analysis revealed an increase of creatine kinase (max 865 U/L), alanine aminotransferase (72 U/L) and gamma-glutamyl transpeptidase (123 U/L). Methoxphenidine was identified by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction in plasma and urine samples collected on admission. The clinical course was favourable and signs and symptoms resolved with symptomatic treatment. Conclusion. Based on this case report and users' web reports, and compatible with the chemical structure, methoxphenidine produces effects similar to those of the arylcyclohexylamines, as PCP. [ABSTRACT FROM AUTHOR]

Rationale: We have recently shown that chronic exposure to 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') of adolescent mice exacerbates dopamine neurotoxicity and neuroinflammatory effects elicited by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the substantia nigra and striatum at adulthood. Objectives: The present study investigated whether the amplification of MPTP effects by previous treatment with MDMA extends to the limbic and cortical regions and consequently affects cognitive performance. Methods: Mice received MDMA (10 mg/kg, twice a day/twice a week) for 9 weeks, followed by MPTP (20 mg/kg × 4 administrations), starting 2 weeks after MDMA discontinuation. Complement type 3 receptor (CD11b) and glial fibrillary acidic protein (GFAP) were evaluated by immunohistochemistry in both the hippocampus and the medial prefrontal cortex (mPFC) to measure microglia and astroglia activation. These neurochemical evaluations were paired with an assessment of cognitive performance by means of the novel object recognition (NOR) and spontaneous alternation tasks. Results: MPTP administration to MDMA-pretreated mice elicited a stronger activation of CD11b and GFAP in both the hippocampus and the mPFC compared with either substance administered alone. Furthermore, NOR performance was lower in MDMA-pretreated mice administered MPTP compared with mice that received either substance alone. Conclusions: These results demonstrate that MDMA-MPTP negative interactions extend to the limbic and cortical regions and may result in cognitive impairment, providing further evidence that exposure to MDMA may amplify the effects of later neurotoxic insults. [ABSTRACT FROM AUTHOR]

Purpose: To understand bladder contractility changes induced by chronic ketamine treatment, noting the prevalence of its abuse worldwide. Methods: A mouse model of chronic ketamine treatment was used and detrusor strip contractility was measured. Rising and falling phases of contractile responses as well as maximal, average sustained and phasic contractions were measured. Results: While maximal contractility of ketamine-treated strips was identical to the saline controls, the former displayed slower contraction rates under K-Krebs, carbachol and electrical stimulation. The decay phase of electrically stimulated responses was also slower at most stimulation frequencies in the ketamine-treated strips. Greater sensitivity to varying the strengths of stimuli was observed in the ketamine-treated strips. Conclusions: Altered contractility characteristics of the bladder after chronic ketamine treatment were revealed, which could potentially be useful in the development of improved treatment regimens. [ABSTRACT FROM AUTHOR]

Abstract: Damage to lungs may occur from systemic as well as inhalational exposure to various illegal drugs of abuse. Aspiration pneumonia probably represents the most common pulmonary complication in relation to consciousness impairment. Some pulmonary consequences may be specifically related to one given drug. Prolonged smoking of marijuana may result in respiratory symptoms suggestive of obstructive lung disease. Non-cardiogenic pulmonary edema has been attributed to heroin, despite debated mechanisms including attempted inspiration against a closed glottis, hypoxic damage to alveolar integrity, neurogenic vasoactive response to stress, and opiate-induced anaphylactoid reaction. Naloxone-related precipitated withdrawal resulting in massive sympathetic response with heart stunning has been mistakenly implicated. In crack users, acute respiratory syndromes called “crack-lung” with fever, hemoptysis, dyspnea, and pulmonary infiltration on chest X-rays have been reported up-to 48h after free-base cocaine inhalation, with features of pulmonary edema, interstitial pneumonia, diffuse alveolar hemorrhage, and eosinophil infiltration. The high-temperature of volatilized cocaine and the presence of impurities, as well as cocaine-induced local vasoconstriction have been suggested to explain alveolar damage. Some other drug-related pulmonary insults result from the route of drug self-administration. In intravenous drug users, granulomatous pneumonia with multinodular patterns on thoracic imaging is due to drug contaminants like talcum. Septic embolism from right-sided endocarditis represents an alternative diagnosis in case of sepsis from pulmonary origin. Following inhalation, pneumothorax, and pneumomediastinum have been attributed to increased intrathoracic pressure in relation to vigorous coughing or repeated Valsalva maneuvers, in an attempt to absorb the maximal possible drug amount. In conclusion, pulmonary consequences of illicit drugs are various, resulting in both acute life-threatening conditions and long-term functional respiratory sequelae. A better understanding of their spectrum and the implicated mechanisms of injury should help to improve patient management. [Copyright &y& Elsevier]

• Herbal blends have been commonly used for the trafficking of synthetic cannabinoids. • This study presents the findings of a case report in which free-base cocaine was found dispersed on such herbal blends. • These findings seem to indicate a new form of drug trafficking for free-base cocaine in São Paulo, Brazil. This case report deals with an unusual seized drugs case, in which cocaine, more commonly found in powder form or as crack cocaine, was found in herbs similar to those used to deliver synthetic cannabinoids. A comparison with expected physical appearance and chemical results for a genuine coca leaf is also presented. [ABSTRACT FROM AUTHOR]

Consumption of illicit narcotic drugs and fatal or criminal activities under their influence has become an utmost concern worldwide. These drugs influence an individual's feelings, perceptions, and emotions by altering the state of consciousness and thus can result in serious safety breaches at critical workplaces. Point-of-care drug-testing devices have become the need-of-the-hour for many sections such as the law enforcement agencies, the workplaces, etc. for safety and security. This review focuses on the recent progress on various electrochemical and optical nanosensors developed for the analysis of the most common illicit drugs (or their metabolites) such as tetrahydrocannabinol (THC), cocaine (COC), opioids (OPs), amphetamines & methamphetamine, and benzodiazepine (BZDs). The paper also highlights the sensitivity and selectivity of various sensing modalities along with evolving parameters such as real-time monitoring and measurement via a smart user interface. An overall outlook of recent technological advances in point of care (POC) devices and guided insights and directions for future research is presented. [Display omitted] • Detection of illicit drugs at roadside, workplace or clinical laboratories is of prime importance. • Nano-analytical methods have emerged as potential tools to detect illicit drugs down to picomolar to nanomolar level. • Electrochemical and optical platforms demonstrate potential towards development of highly sensitive and selective nanosensor. • Efforts are needed to translate the illicit drug detection nanobioassays into integrated real-time POCdiagnostics devices. [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 [ABSTRACT FROM AUTHOR]

Methylmethaqualone is a sedative designer drug created by adding a methyl group to the 3-phenyl ring of methaqualone, and is at present not subject to restrictive regulation in many countries. To our knowledge, no case of methylmethaqualone abuse has been published to date in the scientific literature, and the only sources of information are users' reports on Web discussion forums and data from preclinical animal studies. We report a case of oral methylmethaqualone abuse confirmed by liquid chromatography tandem mass spectrometry in a 24-year-old previously healthy Caucasian male. Observed symptoms and signs such as central nervous system depression alternating with excitation, psychomotor agitation, muscle hyperactivity, and tachycardia were compatible with methaqualone-induced adverse effects. Except for the mild tachycardia (115 beats/min), other vital signs were normal: blood pressure 134/89 mmHg, body temperature 36.2°C (97.16°F), and peripheral oxygen saturation 99% while breathing room air. The ECG showed no prolongation of the QT interval and the QRS duration was normal. Laboratory analysis revealed a slight increase in creatine kinase (368 U/L) and alanine aminotransferase (90 U/L) serum concentrations. Blood alcohol concentration was 0.32 g/L. Methylmethaqualone was identified in a serum sample collected on admission which was analyzed by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction. After a few days the patient ingested the same amount of substance with identical symptoms. Based on the chemical structure and animal data, and according to this case report and users' Web reports, methylmethaqualone appears to have a similar acute toxicity profile to methaqualone, with marked psychomotor stimulation. Symptoms of acute toxicity can be expected to resolve with supportive care. [ABSTRACT FROM AUTHOR]

In our survey of designer drugs in the Japanese market, a cannabimimetic indole was identified as a new active compound in a herbal product. The structure of this compound was elucidated by liquid chromatography-photodiode array-mass spectrometry (LC-PDA-MS), gas chromatography-mass spectrometry (GC-MS), high-resolution MS, and nuclear magnetic resonance (NMR) analyses. The compound was finally identified as (4-ethyl-1-naphthalenyl)(2-methyl-1-pentyl-1 H-indol-3-yl)methanone (JWH-213), an indole-based cannabinoid receptor ligand. To our knowledge, this is the first finding of JWH-213 as a designer drug in a herbal product. The quantitative LC-PDA analysis showed that the JWH-213 content in the product was 252 mg/pack. [ABSTRACT FROM AUTHOR]

Drugs impact brain reward circuits, causing dependence and addiction, in a condition currently described as substance use disorders. Mechanisms of synaptic plasticity in these circuits are crucial in the development of addictive behaviour, and endocannabinoids, particularly anandamide and 2-arachidonyl-glycerol, participate in normal neuroplasticity. Substance use disorders are known to be associated with disruption of endocannabinoid-mediated synaptic plasticity, among other phenomena. Endocannabinoids mediate neuroplasticity in the short and the long term. In the short term, we may stress "inhibitory" phenomena, such as depolarisation-induced suppression of inhibition and depolarisation-induced suppression of excitation, and such "disinhibitory" phenomena as long-lasting disinhibition of neuronal activity, particularly in the striatum, and suppression of hippocampal GABA release. Drugs of abuse can also disrupt normal endocannabinoid-mediated long-term potentiation and long-term depression. Endocannabinoids are also involved in the development of drug-induced hypofrontality and sensitisation. In summary, substance abuse causes a disruption in the synaptic plasticity of the brain circuits involved in addiction, with the alteration of normal endocannabinoid activity playing a prominent role. This facilitates abnormal changes in the brain and the development of the addictive behaviours that characterise substance use disorders., (Copyright © 2019 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

The history of the chemical synthesis and animal/human pharmacology of phencyclidine is documented. From its early use as a general anesthetic, chemical model of schizophrenia, and drug of abuse, phencyclidine has had a checkered history. Research with this agent and its chemical derivatives like ketamine have provided a solid foundation for just a beginning to understanding the neuropathology of schizophrenia. [ABSTRACT FROM PUBLISHER]

Treatment of Parkinson's disease with dopaminergic agents, such as L-DOPA, is frequently compromised by disabling side effects, particularly dyskinesia and a shortening in duration of antiparkinsonian action. Studies in animal models and anecdotal evidence from a patient with Parkinson's disease show that the illicit drug ecstasy (MDMA) can alleviate these side effects, though with many drawbacks (e.g., psychoactivity). MDMA itself thus has little therapeutic potential. On the basis of known structure-psychoactivity relationships, we designed a series of α-substituted MDMA analogues, one of which, bearing an α-cyclopropyl substituent (UWA-101), enhanced the quality of L-DOPA actions in animal models. Indeed, UWA-101 was more effective than MDMA.Unlike MDMA, UWA-101 did not reduce viability of serotonergic cells, exhibit psychoactive properties, or reduce food intake, and did not substitute for MDMA in drug discrimination assays. UWA-101 displayed a unique receptor/ transporter binding profile relative to MDMA, with a >5-fold decrease in affinity for NET and 5-HT2A receptors and a 10-fold increase in affinity for DAT. Furthermore, in a functional reuptake assay, UWA-101 inhibited both 5-HT and dopamine reuptake, while having no effect on the reuptake of noradrenaline. UWA-101 is the first selective DAT/SERT inhibitor described with comparable affinities for these two sites. These data identify a new class of therapeutic in Parkinson's disease and highlight the potential benefits of studying illicit drugs that in themselves would never be considered safe for long-term therapy. [ABSTRACT FROM AUTHOR]

Abstract: Environmental and health safety requires thorough determination of hazardous compounds and drugs of abuse. In determinations of these analytes, traditional instrumental analytical techniques often suffer from tedious assay procedures. Biosensors are simpler to construct and faster in use, so they can better meet the analytical demands in determination of these biohazards. However, their stability and reproducibility when operating under harsh conditions are poor, so artificial recognition units have become attractive as replacements for natural receptors in sensing applications. Molecular imprinting is one of the most powerful tools for preparing materials that can bind analytes reversibly and selectively in the presence of their interferents. This review critically evaluates the development of chemical sensing of biohazards and drugs of abuse using the molecular-imprinting approach to recognition in combination with different ways of analytical signal transduction. We compile analytical parameters of the molecularly-imprinted receptors, identify difficulties in the determinations encountered and highlight proposed solutions to problems. [Copyright &y& Elsevier]

Abstract: This review discusses recent research of mood disorders associated with the cessation of psychoactive substances, with an emphasis on preclinical studies that have been published in the last decade. Animal models exhibiting anhedonic and depressive-like behaviours associated with drug withdrawal have been used to study the neurobiology of mood disorders and have culminated in the identification of novel targets for the treatment of depressive-like symptoms. This review will introduce the behavioural as well as the neurochemical and plasticity changes in depressed patients and several animal models of depression. Following, we provide a more in-depth discussion of the role of serotonergic neurotransmission and Hypothalamic-Pituitary-Adrenal (HPA) axis regulation as well as the neurogenic changes occurring after chronic drug intake focusing on the withdrawal associated depression. Although we mainly focus on animal data, some relevant human studies are also discussed. Establishing the commonalities of depression and drug-seeking behaviour will allow us to elucidate the factors driving the high co-morbidity between mood disorders and drug dependence. [Copyright &y& Elsevier]

This article describes the synthesis and identification of urinary metabolites of 4-iodo-2,5-dimethoxyphenethylamine (2C-I), a new psychoactive drug. 2C-I hydrochloride was administered orally to male Sprague-Dawley rats, and the urinary extracts were analyzed by gas chromatography/mass spectrometry (GC/MS), then five putative 2C-I metabolites were synthesized in our laboratory. In the synthetic process of the 2C-I metabolites, iodination of the aromatic ring was successfully carried out using iodine and orthoperiodic acid as the iodination reagent, and selective debenzylation of aryl benzyl ether was accomplished by the acid hydrolysis method using trifluoroacetic acid and thioanisole. The synthesized metabolites were well separated and detected by GC/MS after valeryl derivatization. The results showed that 2C-I underwent O-demethylation, N-acetylation, and deamination, followed by oxidation to the corresponding carboxylic acid in rats. The data presented in this study will be very useful for the analysis of 2C-I and its metabolites in forensic samples. [ABSTRACT FROM AUTHOR]

Abstract: Gas chromatography coupled to high-resolution time-of flight mass spectrometry (GC-HR-TOF-MS) is a powerful analytical technique with excellent capabilities due to its high sensitivity in full-spectrum-acquisition mode together with its resolving power and accurate-mass measurements. These features make this technique very attractive in qualitative analysis, especially for wide-scope screening of a large number of organic contaminants and residues at trace levels. Full-spectrum MS allows data processing, in principle, of an unlimited number of compounds in samples, as no analyte-specific information is required before the injection. Also, as all data remain available, retrospective analysis is always possible without the need to reinject the sample – an important advantage of full-spectrum MS techniques. Despite these advantages, GC-HR-TOF-MS has rarely been applied, so we expect promising results in different applied fields in the years ahead. We discuss in detail the characteristics and the potential of GC-HR-TOF-MS. We describe different analytical strategies from wide-scope target screening to investigation of unknowns in biology, the environment and food safety. Recent instrumental developments (e.g., high-speed analog-to-digital converter or soft ionization sources) and advances in software for processing the huge amount of data available open up new prospects, making GC-TOF-MS one of the most promising techniques to investigate the presence of organic compounds in different fields. [Copyright &y& Elsevier]

During our careful survey of unregulated drugs in Tokyo, a new compound was disclosed as an adulterant in herbal and powder products. This compound was found to have a molecular weight of 335 by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry, and the accurate mass measurement suggested an elementary composition of CHNO. Using these mass data together with those obtained by nuclear magnetic resonance analysis, the compound was identified as 1-pentyl-3-(2-methoxyphenylacetyl)indole (JWH-250), which had been reported by Huffman and coworkers in 2005. This compound was classified as a phenylacetylindole and a cannabinoid receptor agonist. For quantitation of the compound in herbal and powder products, each product was extracted with methanol under ultrasonication to prepare the solution for analysis by liquid chromatography with ultraviolet detection. The contents of JWH-250 in five products ranged from 77.4 to 165 mg per pack. [ABSTRACT FROM AUTHOR]

Abstract: Daily restricted feeding entrains the circadian rhythm of mouse clock gene expression in the central nervous system, excluding the suprachiasmatic nucleus (SCN), as well as in the peripheral tissues such as the liver, lung, and heart. In addition to entrainment of the clock genes, daily restricted feeding induces a locomotor activity increase 2–3h before the restricted feeding time initiates. The increase in activity is called the food-anticipatory activity (FAA). In addition to FAA, daily restricted feeding can also entrain peripheral circadian clocks in other organs such as liver, lung, and heart. This type of oscillator is called the food-entrainable peripheral oscillator (FEPO). At present, the mechanisms for restricted feeding-induced entrainment of locomotor activity (FAA) and/or peripheral clock (FEPO) are still unknown. In this review, we describe the role of the central nervous system and peripheral tissues in FAA performance and also in the entrainment of clock gene expression. In addition, the mechanism for entrainment of circadian oscillators by the abuse of drugs, such as methamphetamine, is discussed. [ABSTRACT FROM AUTHOR]

Abstract: Rett syndrome and its “early-onset seizure” variant are severe neurodevelopmental disorders associated with mutations within the MECP2 and the CDKL5 genes. Antidepressants and drugs of abuse induce the expression of the epigenetic factor MeCP2, thereby influencing chromatin remodeling. We show that increased MeCP2 levels resulted in the repression of Cdkl5 in rat brain structures in response to cocaine, as well as in cells exposed to serotonin, or overexpressing MeCP2. In contrast, Cdkl5 was induced by siRNA-mediated knockdown of Mecp2 and by DNA-methyltransferase inhibitors, demonstrating its regulation by MeCP2 and by DNA methylation. Cdkl5 gene methylation and its methylation-dependent binding to MeCP2 were increased in the striatum of cocaine-treated rats. Our data demonstrate that Cdkl5 is a MeCP2-repressed target gene providing a link between genes the mutation of which generates overlapping symptoms. They highlight DNA methylation changes as a potential mechanism participating in the long-term plasticity triggered by pharmacological agents. [Copyright &y& Elsevier]

Abstract: Popularity of γ-hydroxybutyric acid (GHB) is fairly stable among drug users, while the consumption of its chemical precursor, γ-butyrolactone (GBL), is a growing phenomenon. Although conventional analytical methods allow to detect this substance in various matrices, linking a trace and a source is still a difficult challenge. However, as several synthesis pathways and chemical precursors exist for the production of GBL, its carbon isotopic signature may vary extensively. For that purpose, a method has been developed to determine the carbon isotopes content of GBL by means of gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). The δ 13C-values of 19 bulk samples purchased worldwide were in the range from −23.1 to −45.8‰ (SD<0.3‰). Furthermore, testing on the purification of GBL by distillation has not been found to be consistent with such a large range of δ 13C-values, which are likely to result from the isotopic composition of the organic precursors used to produce GBL together with the kinetic isotope effect associated with the synthesis routes. Finally, inter- and intra-variability measurements of the δ 13C-values demonstrated the high potential of IRMS for discriminating between seizures of GBL and for source determination. [Copyright &y& Elsevier]

Several reports suggest that 3,4-methylenedioxymethamphetamine (MDMA) induces neurotoxic effects and gliosis. Since recreational use of MDMA is often associated with caffeinated beverages, we investigated whether caffeine interferes with MDMA-induced astroglia and microglia activation, thus facilitating its neurotoxicity. MDMA (4 × 20 mg/kg) was acutely administered to mice alone or in combination with caffeine (10 mg/kg). CD11b and GFAP immunoreactivity were evaluated as markers of microglia and astroglia activation in the substantia nigra pars-compacta (SNc) and striatum. MDMA was associated with significantly higher CD11b and GFAP immunoreactivity in striatum, whereas only CD11b was significantly higher than vehicle in SNc. Caffeine potentiated the increase in CD11b and GFAP in the striatum but not in the SNc of MDMA-treated mice. The abuse of MDMA is a growing worldwide problem; the results of this study suggest that combination of MDMA plus caffeine by increasing glial activation might have harmful health consequences. [ABSTRACT FROM AUTHOR]

Abstract: This review covers methods for determination of medicines and drugs of abuse in three biological specimens – meconium, nails and tears – based on the literature since 1998. It starts with general descriptions of specimens, sample-collection methods and sample-preparation procedures. The key questions addressed relate to drug analysis in meconium, nails and tears. [Copyright &y& Elsevier]

The analysis of drugs of abuse in human specimens is essential in forensic medicine. This study evaluated the use of Cozart DDS for postmortem screening of some drugs of abuse in vitreous humor (VH) prior to forensic autopsies. The Cozart DDS is an on-site drug detection system that has been validated for oral fluid. Seventy-one VH specimens were obtained from cadavers. Causes of death included injury, drug poisoning, natural disorders, and traffic accidents. The samples were tested for cannabis, cocaine, opiate, amphetamine, and methamphetamine. Thirty-three of 71 samples were positive for drugs of abuse (42% for cocaine, 28% for cannabis, 26% for opiates, and 3% for methamphetamine). The positive specimens for opiates and methamphetamine were reexamined by gas chromatography-mass spectrometry (GC-MS); benzoylecgonine (cocaine product) was detected by liquid chromatography-tandem mass spectrometry (LC-MS-MS). All positive results for cocaine or its products and opiates by the Cozart test were confirmed by MS analysis, whereas one positive result for methamphetamine was negative by MS. The Cozart DDS system is generally a useful screening test for VH specimens prior to autopsies, because of its simplicity and rapidness. [ABSTRACT FROM AUTHOR]

Abstract: A rapid and cleanup-free microwave-assisted extraction (MAE) method is proposed for the simultaneous extraction of six illegal drugs of abuse – cocaine, benzoylecgonine (BZE), cocaethylene (CCE), morphine, 6-monoacethylmorphine (6AM) and codeine – from human hair samples. The analytes were determined using high performance liquid chromatography (HPLC) with photodiode array UV detection. The influence of several variables on the efficiency of the MAE procedure was investigated in detail by a multi-objective optimization approach based on a hybrid experimental design (17 experiments) and desirability functions. Six drugs were successfully extracted from human hair with recoveries close to 100% and good reproducibility (<3.6% RSD) under the optimal MAE conditions: 11mL dichloromethane (DCM) extraction solvent, 60°C extraction temperature, 9min extraction time and 0.5mL of methanol (MeOH) added to 50mg of the hair sample in the extraction vessels. Limits of quantification of 0.2ngmg−1 were found for the studied compounds. A comparison of sample preparation procedures, including MAE, enzymatic digestion and digestion by aqueous acids, was also conducted. The results indicated that the global behaviour of sample procedures provided similar satisfactory recoveries ranging from 86 to 100%. Indeed, the MAE procedure resulted in a reduction of extraction time by 100-fold and the elimination of cleanup steps. Slightly higher recoveries of morphine, 6AM, BZE and CCE, at 1ngmg−1 concentration level and cocaine at 40ngmg−1 concentration level, were achieved using MAE. Lastly, the proposed MAE method was applied to several human hair samples from multidrug abusers. [Copyright &y& Elsevier]

Nandrolone is an anabolic-androgenic steroid (AAS) that is highly abused by individuals seeking enhanced physical strength or body appearance. Supraphysiological doses of this synthetic testosterone derivative have been associated with many physical and psychiatric adverse effects, particularly episodes of impulsiveness and overt aggressive behavior. As the neural mechanisms underlying AAS-induced behavioral disinhibition are unknown, we investigated the status of serotonergic system-related transcripts in several brain areas of mice receiving prolonged nandrolone administration. Male C57BL/6J mice received 15 mg/kg of nandrolone decanoate subcutaneously once daily for 28 days, and different sets of animals were used to investigate motor-related and emotion-related behaviors or 5-HT-related messenger RNA (mRNA) levels by real-time quantitative polymerase chain reaction. AAS-injected mice had increased body weight, were more active and displayed anxious-like behaviors in novel environments. They exhibited reduced immobility in the forced swim test, a higher probability of being aggressive and more readily attacked opponents. AAS treatment substantially reduced mRNA levels of most investigated postsynaptic 5-HT receptors in the amygdala and prefrontal cortex. Interestingly, the 5-HT1B mRNA level was further reduced in the hippocampus and hypothalamus. There was no alteration of 5-HT system transcript levels in the midbrain. In conclusion, high doses of AAS nandrolone in male mice recapitulate the behavioral disinhibition observed in abusers. Furthermore, these high doses downregulate 5-HT receptor mRNA levels in the amygdala and prefrontal cortex. Our combined findings suggest these areas as critical sites for AAS-induced effects and a possible role for the 5-HT1B receptor in the observed behavioral disinhibition. [ABSTRACT FROM AUTHOR]

[Display omitted] • High-throughput screening method for the identification of the predatory use of scopolamine in beverage samples. • Ultra-fast simultaneous determination of scopolamine and butylscopolamine. • Possibility of analysis without sample preparation step. • A useful method to identify the formation of scopolamine from butylscopolamine. Scopolamine is a natural tropane alkaloid widely used for medicinal purposes due to its anticholinergic and antispasmodic effects. However, this compound is also used as a potent sedative that facilitates sexual crimes when it is intentionally mixed into drinks. Butylscopolamine – active ingredient of buscopan® – is a safer compound derived from scopolamine and commonly used for treatments of abdominal pain and intestinal spasms. Although scopolamine can be purchased only with medical prescription, it has been reported cases where scopolamine can be produced from butylscopolamine (non-medical prescription drug) by simple heating, which increases the risk of contamination or enable easy access to scopolamine. The present study describes, for the first time, a method based on capillary electrophoresis with capacitively coupled contactless conductivity detection for rapid (∼17 injections h−1) and simultaneous quantification of scopolamine and butylscopolamine using a buffer solution composed by 20 mmol L−1 butyric acid and 7 mmol L−1 NaOH (pH = 4.5). The developed method presents several desirable characteristics: (i) simple sample preparation step (dissolution, filtration and dilution in water), (ii) wide linear range (10 to 1000 µmol L−1), (iii) adequate recovery values (104 ± 6% and 99 ± 6% for scopolamine and butylscopolamine, respectively) and, (iv) adequate limits of detection (LOD): 2.4 and 2.8 µmol L−1 for scopolamine and butylscopolamine, respectively. The method has been successfully applied as fast screening tool for detection of scopolamine (psychoactive compound) in adulterated beverages and butylscopolamine (anti-muscarinic drug) in pharmaceutical formulations. Most importantly, the CE method has great potential as simple, rapid and, low-cost diagnostic tool to discern between both compounds. [ABSTRACT FROM AUTHOR]

Abstract: In recent years, analytical chemists have developed analytical methodologies to account for the presence of drugs of abuse (DAs) and their human metabolites in surface and sewage water, where these compounds are at detectable levels (μg/L–ng/L). All these analytical procedures are based on liquid chromatography separation and tandem mass spectrometry detection. In this article, we review aspects of these protocols, including sample preservation, pretreatment and extraction, detection conditions, and matrix effects. Monitoring these emerging contaminants in the environment provides valuable information for investigating their fate and their potential effects in aquatic ecosystems. Concentrations measured in influent sewage water can be used to estimate overall usage of DAs in different locations. We discuss this approach, the concentrations of the most relevant DAs and their metabolites in water, and other relevant data for the calculation of usage from concentrations in water (e.g., drug doses and excretion rates), and we compile correction factors. [Copyright &y& Elsevier]

The "loló" stands out among the most used inhalant drugs in Brazil. This drug is a non-specific blend of organic solvents, traditionally composed of ether and chloroform. Reports in the literature and forensic practice have revealed changes in the composition profile of this drug, based on availability of acquisition. This diversity has an effect on the efficiency of the preliminary tests used to detect illicit substances in situations that require rapid response time from the criminal investigations, such as arrests in the act. Considering the diversity of volatile substances with potential use as inhalant drugs and the limited detection abilities of preliminary exams routinely used by forensic laboratories, this present work applied NIR spectroscopy associated with chemometric models to detect the presence of organic solvents in samples of "loló". Initially, the chemical profile of the seized samples was surveyed in the geographic region of study (Paraiba State, Brazilian northeast), and from the observation of the prevalent substances, classification models were produced using samples made in the laboratory and samples from real apprehensions. Then, an analysis protocol was developed, based on SIMCA models, to detect the predominant solvents in the regional composition profile (dichloromethane, trichloroethene and chloroform). The proposed analysis protocol obtained an overall accuracy of 94.7% in detecting halogenated hydrocarbons in suspect samples and 100% accuracy in characterizing the composition of samples composed exclusively of the studied halogenated hydrocarbons and their binary mixtures. Considering that the colorimetric tests used in the routine of forensic laboratories do not detect many components, the proposed method was technically and economically viable in preliminary tests for samples seized as suspicious of being "loló". [ABSTRACT FROM AUTHOR]