Investigation of the intrinsic cannabinoid activity of hemp-derived and semisynthetic cannabinoids with ß-arrestin2 recruitment assays-and how this matters for the harm potential of seized drugs.

Cultivation of industrial low-Δ9-tetrahydrocannabinol (Δ9-THC) hemp has created an oversupply of cannabidiol (CBD)-rich products. The fact that phytocannabinoids, including CBD, can be used as precursors to synthetically produce a range of THC variants-potentially located in a legal loophole-has led to a diversification of cannabis recreational drug markets. 'Hemp-compliant', 'hemp-derived' and 'semisynthetic' cannabinoid products are emerging and being advertised as (legal) alternatives for Δ9-THC. This study included a large panel (n = 30) of THC isomers, homologs, and analogs that might be derived via semisynthetic procedures. As a proxy for the abuse potential of these compounds, we assessed their potential to activate the CB1 cannabinoid receptor with a ß-arrestin2 recruitment bioassay (picomolar-micromolar concentrations). Multiple THC homologs (tetrahydrocannabihexol, THCH; tetrahydrocannabiphorol, THCP; tetrahydrocannabinol-C8, THC-C8) and THC analogs (hexahydrocannabinol, HHC; hexahydrocannabiphorol, HHCP) were identified that showed higher potential for CB1 activation than Δ9-THC, based on either higher efficacy (Emax) or higher potency (EC50). Structure-activity relationships were assessed for Δ9-THC and Δ8-THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB1 activity were established for various THC isomers (Δ7-THC, Δ10-THC) and analogs (HHC, HHCP). Evaluation of the relative abundance of 9(S)-HHC and 9(R)-HHC epimers in seized drug material revealed varying epimeric compositions between batches. Increased abundance of the less active 9(S)-HHC epimer empirically resulted in decreased potency, but sustained efficacy for the resulting diastereomeric mixture. In conclusion, monitoring of semisynthetic cannabinoids is encouraged as the dosing and the relative composition of stereoisomers can impact the harm potential of these drugs, relative to Δ9-THC products.

[Toxicology of synthetic cannabinoids]. / Toxicologie des cannabinoïdes de synthèse.

Synthetic cannabinoids (CS), or synthetic endocannabinoid receptor agonists, were initially synthesized for basic research into exocannabinoid signaling pathways, as well as in clinical research for their analgesic properties. The use of CS for recreational purposes is a recent phenomenon, but one that has grown very quickly in recent years, since these molecules now represent the main category of new synthetic products (NPS). This literature review aims to bring together current data regarding the use and effects caused by CS in humans. The relationship between the structure and activity of these CSs, the pharmacology and adverse effects of these CSs and finally the different methods of analyzing CSs. A better understanding of this phenomenon is essential to raise awareness among stakeholders in the health field.

Metaphedrone (3-Methylmethcathinone): Pharmacological, Clinical, and Toxicological Profile.

Introduction: Synthetic cathinones are a group of novel psychoactive substances used as an alternative to classical recreational drugs. As a result of legal prohibitions on older generations of these compounds, new formulations appeared on the drug market. One of them is metaphedrone (3-methylmethcathinone, 3-MMC), a structural isomer of 4-methylmethcathinone and a psychostimulant drug. Metaphedrone became popular in a large number of countries in a short period of time. The aim: The collection, analysis, and review of relevant research on the subject of metaphedrone in order to present information about the pharmacological, clinical, and toxicological profile of this compound. An assessment of the significance and role of metaphedrone in consumption patterns of novel psychoactive substances among recreational drug users. Methodology: By using search engines like Google Scholar and PubMed, the relevant literature on metaphedrone was looked for and analyzed. The search was not limited to a specific period of time. All information regarding the compound of interest was analyzed and presented. Key results and discussion: All novel psychoactive substances are abused due to their pronounced stimulatory, hallucinogenic, dissociative, and euphoric and/or relaxing characteristics. Users of 3-methylmethcathinone usually opt for this substance for recreational purposes and/or sexual stimulation. Metaphedrone has the potential to cause a psychological dependence to the users. It was determined in relevant studies that most users are from 17 to 50 years of age. Older users usually administer metaphedrone intravenously, while younger ones usually choose snorting and oral ingestion of the drug. In Serbia, metaphedrone is a legally controlled substance. The pharmacodynamic properties make metaphedrone similar to classical recreational drugs. The method of administration, mainly repeated administration in a single session, could be explained using the pharmacokinetic profile of the drug. The most reported symptoms of intoxication were those of a sympathomimetic nature, such as tachycardia, chest pain, hypertension, diaphoresis, and agitation. Most intoxications and fatal outcomes occurred to users who combined several psychoactive substances. The correlation between measured blood concentrations of the drug and outcomes of intoxication was not found. The mechanisms of metaphedrone's toxicity are not fully understood. Conclusions: There is an increasing trend of abuse of metaphedrone among recreational drugs users. Future studies should focus on pharmacological and toxicological effects of metaphedrone on animals and humans.

Cytogenotoxicity effects in addicts with multidrug consumption.

Drug abuse is considered a global health problem with serious social impact. In recent decades, changes in drug consumption patterns have shown a clear rising trend in the use of multiple drugs. Although the buccal micronucleus cytome (BMCyt) assay has evaluated cytotoxicity in drug abuse, there has not been an approach that takes into account this pattern of multiple drug use. Therefore, in this study, we evaluate for the first time the cytogenotoxic effects in multidrug users, and its correlation with the amount consumed and years of abuse. This study was conducted on 166 individuals by the BMCyt assay. A total of 83 individuals with a history of multiple licit (alcohol and tobacco) and at least one illicit drug abuse (marijuana, methamphetamines, cocaine, and/or inhalants), and 83 healthy individuals, non-drug abusers were analyzed. The results showed that drug abusers had higher frequencies of nuclear abnormalities nuclear buds, binucleated cells, pyknotic nuclei (PNs), karyorrhexis (KX), and abnormally condensed chromatin when compared with healthy controls. Moreover, results suggests that the use of licit and illicit drugs is related to cytogenotoxic damage, as was shown by an upward trend in the frequency of nuclear abnormalities identified in groups 1 (alcohol + tobacco + at least one illicit drug) and 2 (tobacco + at least one illicit drug). Furthermore, a positive correlation was found in the different groups, between the years and the amount of consumption of some drugs (alcohol, methamphetamine, and tobacco) with cytotoxicity markers such as KL, KX, and PNs.

Phencyclidine-Like Abuse Liability and Psychosis-Like Neurocognitive Effects of Novel Arylcyclohexylamine Drugs of Abuse in Rodents.

Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities, including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male National Institutes of Health Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl, and 4-MeO analogs, PCE and its 3-OH and 3-MeO analogs, and ketamine and its deschloro and 2F-deschloro analogs, in comparison with those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA. PCP-like interoceptive effects for all of these ACXs were determined using a food-reinforced drug discrimination procedure in adult male Sprague Dawley rats. A novel operant assay of rule-governed behavior incorporating aspects of attentional set-shifting was used to profile psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in rats, in comparison with cocaine and morphine. PCP-like ACXs were more effective locomotor stimulants than the amphetamines, PCE-like ACXs were as effective as the amphetamines, and ketamine-like ACXs were less effective than the amphetamines. Addition of -Cl, -OH, or -OMe at the 3-position on the aromatic ring did not impact locomotor effectiveness, but addition of -OMe at the 4-position reduced locomotor effectiveness. Lethal effects were induced by drugs with -OH at the 3-position or -OMe at the 3- or 4-position. All novel ACXs substituted at least partially for PCP, and PCP and 3-Cl-PCP elicited dose-dependent psychosis-like neurocognitive deficits in the rule-governed behavior task not observed with cocaine or morphine. Novel ACXs exhibit substantial abuse liability and toxicities not necessarily observed with their parent drugs. SIGNIFICANCE STATEMENT: Novel arylcyclohexylamine analogs of PCP, PCE, and ketamine are appearing on the illicit market, and abuse of these drugs poses risks for toxicities, including adverse neurocognitive effects. These studies demonstrate that the novel ACXs exhibit PCP-like abuse liability in the drug discrimination assay, elicit varied locomotor stimulant and lethal effects in mice, and induce psychosis-like neurocognitive effects in rats.

Daphnia magna an emerging environmental model of neuro and cardiotoxicity of illicit drugs.

Cocaine, methamphetamine, ectasy (3,4-methylenedioxy amphetamine (MDMA)) and ketamine are among the most consumed drugs worldwide causing cognitive, oxidative stress and cardiovascular problems in humans. Residue levels of these drugs and their transformation products may still enter the aquatic environment, where concentrations up to hundreds of ng/L have been measured. In the present work we tested the hypothesis that psychotropic effects and the mode of action of these drugs in D. magna cognitive, oxidative stress and cardiovascular responses are equivalent to those reported in humans and other vertebrate models. Accordingly we expose D. magna juveniles to pharmacological and environmental relevant concentrations. The study was complemented with the measurement of the main neurotransmitters involved in the known mechanisms of action of these drugs in mammals and physiological relevant amino acids. Behavioural cognitive patters clearly differentiate the 3 psychostimulant drugs (methamphetamine, cocaine, MDMA) from the dissociative one ketamine. Psychostimulant drugs at pharmacological doses (10-200 µM), increased basal locomotion activities and responses to light, and decreased habituation to it. Ketamine only increased habituation to light. The four drugs enhanced the production of reactive oxygen species in a concentration related manner, and at moderate concentrations (10-60 µM) increased heartbeats, diminishing them at high doses (200 µM). In chronic exposures to environmental low concentrations (10-1000 ng/L) the four drugs did not affect any of the behavioural responses measured but methamphetamine and cocaine inhibited reproduction at 10 ng/L. Observed effects on neurotransmitters and related metabolites were in concern with reported responses in mammalian and other vertebrate models: cocaine and MDMA enhanced dopamine and serotonin levels, respectively, methamphetamine and MDMA decreased dopamine and octopamine, and all but MDMA decreased 3 MT levels. Drug effects on the concentration of up to 10 amino acids evidence disruptive effects on neurotransmitter synthesis, the urea cycle, lipid metabolism and cardiac function.

Acute, chronic, and post-mortem toxicity: a review focused on three different classes of new psychoactive substances.

PURPOSE: New psychoactive substances (NPS) are not controlled under the Single Convention on Narcotic Drugs of 1961 or the 1971 Convention, but they may pose a public health threat. Knowledge of the main properties and toxicological effects of these substances is lacking. According to the current Drugs Law (Law n. 11.343/2006), the Brazilian Surveillance Agency issues directives for forbidden substances in Brazil, and structural classes of synthetic cannabinoids, cathinones, and phenylethylamines are considered illicit drugs. Considering that data on these controlled substances are scattered, the main objective of this work was to collect and organize data to generate relevant information on the toxicological properties of NPS. METHODS: We carried out a literature review collecting information on the acute, chronic, and post-mortem toxicity of these classes of NSP. We searched info in five scientific databases considering works from 2017 to 2021 and performed a statistical evaluation of the data. RESULTS: Results have shown a general lack of studies in this field given that many NPS have not had their toxicity evaluated. We observed a significant difference in the volume of data concerning acute and chronic/post-mortem toxicity. Moreover, studies on the adverse effects of polydrug use are scarce. CONCLUSIONS: More in-depth information about the main threats involving NPS use are needed.

Accuracy of substance exposure history in patients attending emergency departments after substance misuse; a comparison with biological sample analysis.

CONTEXT: Acute toxicity caused by illicit substance use is a common reason for emergency department (ED) presentation. Knowledge of the substances involved is helpful for predicting and managing potential toxicity, but limited information is available about the accuracy of patient-reported substance exposure. This study assessed the accuracy of the history of exposure in those reporting use of a single substance by comparison with those identified by detailed toxicological analysis, focusing on synthetic cannabinoid receptor agonists (SCRA). METHODS: Adults (≥16 years) presenting between March 2015 and July 2021 to participating UK hospitals with toxicity after reporting use of a single illicit substance were included. Exposure details were documented from medical records and blood and/or urine samples analysed using high-resolution accurate mass liquid chromatography-mass spectrometry (HRAM LCMS). Sensitivity, specificity, and positive and negative predictive values of the exposure history were calculated by comparison with biological sample analysis ("gold standard"). RESULTS: Single substance exposure was reported for 474 (median age 33 years, IQR: 18 range 16-75, 80% males) patients. Analysis commonly identified multiple substances (Median 3, IQR 2-5). A history of exposure was documented for 121 of 151 patients where a SCRA or metabolite was detected on analysis (sensitivity 80.1%, 95% CI 72.9, 86.2%). Corresponding proportions were lower for 3,4-methylenedioxymethamphetamine (MDMA, 44/70, 62.9%., 95% CI 50.5%, 74.1%), heroin 41/108 (38.0% 95% CI 28.8-47.8%) and cocaine (22/56, 31.3%, 95% CI 20.9, 43.6%). CONCLUSIONS: Multiple undeclared substances were detected analytically in most patients reporting single substance use. Clinicians should be alert to the potential presence and toxicity of unreported substances when managing patients presenting after substance misuse.

Renal manifestations of recreational drugs: A narrative review of the literature.

Drug abuse has become a major problem of the modern world where drug-induced kidney injury can be caused by both prescribed drugs for clinical conditions and illegal (illicit) drugs or drugs of abuse. Heroin, cocaine, nicotine and alcohol are the most commonly abused drugs but with the emergence of various synthetic drugs, numerous novel descriptions of their nephrotoxic effects have been described. This review summarizes the key renal manifestations of recreational drugs as reported in case reports and case. A comprehensive review of published case reports and case series in English language of renal toxicity related to recreational drugs/drugs of abuse was conducted using search engines like PubMed/Medline. Publications which reported renal injury with raised creatinine levels, clinically symptomatic patients, those with oliguria and with renal biopsies are chosen. The medical literature on recreational drugs is full of claims of renal complications including different glomerular diseases, acute kidney injury, rhabdomyolysis, interstitial nephritis, and debilitating irreversible conditions like renal infarction and end stage renal disease, even though the pathogenesis of drug- related renal manifestations are not available for all the newer agents. The outcome of this review paper will help multidisciplinary physicians to understand the renal side effects of recreational drugs, their pathophysiology, and most importantly, the clinical presentations of renal dysfunction in relation each drug. Emphasizing these adverse effects will prevent future unfavorable outcomes.

Synthetical effect of microplastics and chiral drug amphetamine on a primary food source algae Chlorella pyrenoids.

The biological effects and fate of the chiral illicit drug amphetamine in the presence and absence of microplastics on freshwater algae (Chlorella pyrenoids), including acute toxicity, growth inhibition, photosynthetic pigment content, oxidative stress, lipid peroxidation, and enantioselective fate were assessed. An agglomeration and the shading effects of microplastics in algae suspension were also determined. Microplastics were observed to increase the toxicity of amphetamine to algae and reduce algae cell growth. Exposed Chlorella pyrenoids exhibited a reduced algae cell counts in an agglomeration test, wherein algae cells decreased between 18% and 56% among treatment groups exposed to 5-50 mg L-1 of microplastics. The agglomeration test suggested that microplastics might significantly increase the adverse effect on algae. Furthermore, our experiments demonstrated enantioselective degradation of amphetamine in algae, and demonstrated that the S-enantiomer was preferably degraded by algae cells. Adding microplastics to the algae suspension significantly reduced the enantioselectivity, with an EF value of 0.41 compared with amphetamine-alone group (0.34) after 21 d exposure. These results demonstrated the first evidence of microplastics acting as a vehicle to enhance amphetamine toxicity to Chlorella pyrenoids, as well as provided new insights into the co-effect of microplastics and organic contaminants on food source.

Induction of CYP450 by illicit drugs: Studies using an in vitro 3D spheroidal model in comparison to animals.

Information regarding the metabolism of illicit drugs is under urgent need for toxicological assessment. Its development, however, is limited by the currently available animal models. To this end, we proposed three-dimensional (3D) HepaRG spheroids as an in vitro model to study the effects of illicit drugs on hepatic cytochrome P450 (CYP450) enzymes and potential drug-drug interactions (DDIs). By comparing the results from animal and cell experiments, we confirmed the significant impact of heroin, morphine, tetrahydrocannabinol, and fentanyl on CYP450 enzymes, and the 3D spheroids results were in good agreement with the animal results for 2B6, 2C19, 2D6. Using 3D HepaRG spheroids, we demonstrated DDIs between heroin as a 2B6 perpetrator and clinical medicine for cancer, depression, and illicit drug withdrawal. Specifically, the clearance rate of 5.4 µM bupropion was increased by 214 % under DDI with 5 µM heroin, highlighting the importance of DDI pre-screening and individualized medication guidance for illicit drug users. This research contributes to the growing body of evidence regarding the metabolic toxicity of illicit drugs and suggests 3D HepaRG spheroids as a high-throughput and cost-efficient platform for DDI analysis.

Nitrous oxide abuse induced subacute combined degeneration despite patient initiated B12 supplementation.

INTRODUCTION: Nitrous oxide (N2O) is a commonly used inhaled anesthetic that is legal to purchase as a food additive and is popular as a recreational euphoric drug. Abuse causes a functional B12 deficiency, leading to clinical features and imaging consistent with subacute combined spinal cord degeneration (SCD). CASES: Poison Center medical records from four patients are reviewed in this series. Four patients presented with lower extremity weakness, paresthesias and gait abnormalities in the setting of chronic N2O abuse. Each reported using 50-150 N2O cartridges ("whippets") almost daily for months to years, and reported supplementing with oral B12 at the recommendation of other users and online forums. None reported prior B12 deficiency or dietary restrictions, and none exhibited hematologic abnormalities. RESULTS: All patients had clinical signs of neurotoxicity including weakness and ataxia. Additionally, all had elevated methylmalonic acid and homocysteine concentrations with normal B12 indicating a functional B12 deficiency. Three had imaging consistent with SCD despite home supplementation The MRI in the fourth case was inconclusive due to movement artifact. CONCLUSION: We report four cases of subacute combined degeneration induced by recreational nitrous oxide abuse despite self-administered vitamin B12 supplementation.

Toxicokinetics of U-47700, tramadol, and their main metabolites in pigs following intravenous administration: is a multiple species allometric scaling approach useful for the extrapolation of toxicokinetic parameters to humans?

New synthetic opioids (NSOs) pose a public health concern since their emergence on the illicit drug market and are gaining increasing importance in forensic toxicology. Like many other new psychoactive substances, NSOs are consumed without any preclinical safety data or any knowledge on toxicokinetic (TK) data. Due to ethical reasons, controlled human TK studies cannot be performed for the assessment of these relevant data. As an alternative animal experimental approach, six pigs per drug received a single intravenous dose of 100 µg/kg body weight (BW) of U-47700 or 1000 µg/kg BW of tramadol to evaluate whether this species is suitable to assess the TK of NSOs. The drugs were determined in serum and whole blood using a fully validated method based on solid-phase extraction and LC-MS/MS. The concentration-time profiles and a population (pop) TK analysis revealed that a three-compartment model best described the TK data of both opioids. Central volumes of distribution were 0.94 L/kg for U-47700 and 1.25 L/kg for tramadol and central (metabolic) clearances were estimated at 1.57 L/h/kg and 1.85 L/h/kg for U-47700 and tramadol, respectively. The final popTK model parameters for pigs were upscaled via allometric scaling techniques. In comparison to published human data, concentration-time profiles for tramadol could successfully be predicted with single species allometric scaling. Furthermore, possible profiles for U-47700 in humans were simulated. The findings of this study indicate that unlike a multiple species scaling approach, pigs in conjunction with TK modeling are a suitable tool for the assessment of TK data of NSOs and the prediction of human TK data.

Caracterización del estilo de vida en la etapa de recuperación de adolescentes adictos a drogas ilegales / Characterization of the lifestyle in the recovery stage of adolescents addicted to illegal drugs

Introducción: El consumo de drogas ilegales por los adolescentes se considera en la actualidad, como un problema de salud pública a nivel mundial. Cuba no está exenta de esta problemática. Una vez instaurada la adicción, el estilo de vida que desarrolle cada individuo es determinante para el proceso de recuperación. Objetivo: Caracterizar el estilo de vida de adolescentes adictos a drogas ilegales en la etapa de recuperación. Métodos: La investigación se basó en un diseño mixto y consistió en el estudio de los 26 adolescentes adictos a drogas ilegales que fueron atendidos en el Departamento de Salud Mental del municipio Playa, La Habana, Cuba, durante el primer trimestre de 2018. Se aplicó el Cuestionario de Estilo de Vida Promotor de Salud y se realizaron cuatro grupos focales. Resultados: Los 26 sujetos evaluados presentaron una conducta irresponsable ante la salud y el cuidado de sí mismo. No obstante, el soporte interpersonal fue adecuado en 76,9 por ciento de los casos estudiados, y 46,15 por ciento de ellos presentó habilidades para manejo adecuado del estrés. Fue identificada la carencia de hábitos adecuados de ejercitación física (73,1 por ciento) y de comportamientos nutricionales y de autoactualización (69,2 por ciento). Conclusiones: Las adicciones constituyen un trastorno crónico y el tratamiento para la recuperación tiene entre sus pilares principales la modificación del estilo de vida. El apoyo interpersonal y las habilidades para manejar el estrés que logre desarrollar el paciente adicto pueden ayudarlo asumir su estilo de vida, y su salud con más responsabilidad. Para que el proceso de recuperación concluya satisfactoriamente y se eviten recaídas desmoralizantes, debe procurarse la adecuación de la autoestima, el compromiso con proyectos de vida realistas y la satisfacción con su situación personal(AU)

Introduction: The use of illegal drugs by adolescents is nowadays considered as a global public health problem. Cuba is not an exception of this problem. Once the addiction is established, the lifestyle developed by each individual is determinant for the recovery process. Objective: Characterize the lifestyle of adolescents addicted to illegal drugs in the recovery stage. Methods: The research was based in mixed design and consisted in the study of 26 adolescents addicted to illegal drugs whom were attended in the Mental Health Service of Playa municipality, Havana, Cuba during the first quarter of 2018. It was applied the Questionnaire of Lifestyle - Health Promoter and four focus groups were formed. Results: The 26 patients assessed showed an irresponsible behaviour towards health and self-care. However, the interpersonal support was adequate in 76,9percent of the studied cases, and 46,15percent of them presented skills for an adequate management of stress. It was identified lack of adequate habits of physical activity (73,1percent) and of nutritional behaviours and auto-updating (69,2percent). Conclusions: Addictions are a chronic disorder and the treatment for recovery has among its pillars the modification of lifestyle. Interpersonal support and skills to manage stress that the addict patient is able to develop would help to assume his-her lifestyle and health with more responsibility. In order that the recovery process ends up satisfactorily and to avoid that demoralizing relapses occur, it must be seek the adequacy of self-steem, the commitment with realistic life projects and satisfaction with the personal situation(AU)

Clinical Pharmacology, Toxicity, and Abuse Potential of Opioids.

Opioids were the most common drug class resulting in overdose deaths in the United States in 2019. Widespread clinical use of prescription opioids for moderate to severe pain contributed to the ongoing opioid epidemic with the subsequent emergence of fentanyl-laced heroin. More potent analogues of fentanyl and structurally diverse opioid receptor agonists such as AH-7921 and MT-45 are fueling an increasingly diverse illicit opioid supply. Overdose from synthetic opioids with high binding affinities may not respond to a typical naloxone dose, thereby rendering autoinjectors less effective, requiring higher antagonist doses or resulting in a confusing clinical picture for health care providers. Nonscheduled opioid drugs such as loperamide and dextromethorphan are associated with dependence and risk of overdose as easier access makes them attractive to opioid users. Despite a common opioid-mediated pathway, several opioids present with unique pharmacodynamic properties leading to acute toxicity and dependence development. Pharmacokinetic considerations involve half-life of the parent opioid and its metabolites as well as resulting toxicity, as is established for tramadol, codeine, and oxycodone. Pharmacokinetic considerations, toxicities, and treatment approaches for notable opioids are reviewed.

Uso de club drugs entre estudantes de graduação: prevalência, características associadas e a influência dos pares / Club drugs use among undergraduate students: prevalence, associated characteristics and peer influence

OBJETIVO: Medir a prevalência do uso na vida, no último ano e no último mês de duas club drugs ­ o ecstasy e o LSD ­, bem como as características associadas ao uso dessas substâncias, no último mês, entre estudantes de graduação de uma universidade no Sul do Brasil. MÉTODOS: Trata-se de um estudo transversal conduzido no ano de 2015 com amostragem aleatória sistemática por conglomerados. Participaram 1.423 estudantes de graduação. Foi utilizado um modelo de análise multivariável em três níveis hierárquicos por meio da regressão de Poisson com ajuste robusto da variância. RESULTADOS: As prevalências de uso na vida, no último ano e no último mês de club drugs foram de 12,7%, 7,8% e 3,8%, respectivamente. Indivíduos do sexo masculino, com orientação sexual homossexual ou bissexual, mais jovens, que moravam com seus pares, solteiros, e que relataram uso no último mês de tabaco e maconha apresentaram maior probabilidade de ter feito uso no último mês de alguma club drug. Entretanto, a variável mais fortemente associada a esse desfecho foi ter algum amigo que já fez uso de alguma droga ilícita na vida (RP = 19,54). CONCLUSÕES: O ambiente universitário parece ser um terreno fértil para a difusão do uso de club drugs. O fortalecimento de uma rede de apoio institucional da universidade, capaz de propor atividades de prevenção, bem como de identificar, acolher e encaminhar casos em que haja abuso e dependência dessas substâncias, pode ser uma estratégia importante para lidar com essa problemática.

OBJECTIVE: To measure the prevalence of lifetime, last-year, and last-month use of two club drugs ­ ecstasy and LSD ­, as well as the characteristics associated with the last-month use of these substances among undergraduate students at a university in southern Brazil. METHODS: This was a cross-sectional study conducted in 2015 with a clustered systematic sampling strategy. Overall, 1,423 undergraduate students participated. A three-level hierarchical multivariate analysis model was used through Poisson regression with robust adjustment of variance. RESULTS: Prevalence of lifetime, last-year, and lastmonth use of club drugs were 12.7%, 7.8% and 3.8%, respectively. Male participants, with homosexual or bisexual sexual orientation, younger, who lived with their peers, who were single, and who reported last-month use of tobacco and marijuana had higher probability of last-month use club drugs. However, the variable most strongly associated with this outcome was having a friend with lifetime use of illicit drugs (PR = 19.54). CONCLUSIONS: University environment seems to be a fertile ground for the spread of the use of club drugs. The strengthening of the university's institutional assistance network, capable of proposing prevention activities, as well as identifying, supporting and referring cases where there is abuse and dependence on these substances can be an important strategy to deal with this problem.

Synthetic Cannabinoids and Cathinones Cardiotoxicity: Facts and Perspectives.

New psychoactive substances (NPS) constitute a group of psychotropic substances, designed to mimic the effects of traditional substances like cannabis, cocaine, MDMA, khat, which was not regulated by the 1961 United Nations Convention on Narcotics or the 1971 United Nations Convention on Psychotropic Substances. Illegal laboratories responsible for their production regularly developed new substances and placed them on the market to replace the ones that have been banned; for this reason, during the last decade this class of substances has represented a great challenge for the public health and forensic toxicologists. The spectrum of side effects caused by the intake of these drugs of abuse is very wide since they act on different systems with various mechanisms of action. To date most studies have focused on the neurotoxic effects, very few works focus on cardiotoxicity. Specifically, both synthetic cannabinoids and synthetic cathinones appear to be involved in different cardiac events, including myocardial infarction and sudden cardiac death due to fatal arrhythmias. Synthetic cannabinoids and cathinones cardiotoxicity are mainly mediated through activation of the CB1 receptor present on cardiomyocyte and involved with reactive oxygen species production, ATP depletion and cell death. Concerns with the adrenergic over-stimulation induced by this class of substances and increasing oxidative stress are mainly reported. In this systematic review we aim to summarize the data from all the works analyzing the possible mechanisms through which synthetic cannabinoids and synthetic cathinones damage the myocardial tissue.

Assessment of aversive effects of methylone in male and female Sprague-Dawley rats: Conditioned taste avoidance, body temperature and activity/stereotypies.

Methylone's rewarding effects have been well characterized; however, little is known about its aversive effects and how such effects may be impacted by sex. In this context, the present study investigated the aversive effects of methylone (vehicle, 5.6, 10 or 18 mg/kg, IP) in 35 male and 31 female Sprague-Dawley rats assessed by conditioned taste avoidance and changes in body temperature and activity/stereotypies. Methylone induced significant taste avoidance, changes in temperature and increased activity and stereotypies in both males and females. Similar to work with other synthetic cathinones, methylone has aversive effects as indexed by significant taste avoidance and changes in temperature and activity (two characteristics of methylone overdose in humans). The only endpoint for which there were significant sex differences was in general activity with males displaying a faster onset and females displaying a longer duration. Although sex was not a factor with taste avoidance and temperature, separate analyses for males and females revealed different patterns, e.g., males displayed a more rapid acquisition of taste avoidance and females displayed changes in temperature at lower doses. Males displayed a faster onset and females displayed a longer duration of activity (consistent with the analyses considering sex as a factor), while time- and dose-dependent stereotypies did not show consistent pattern differences. Although sex differences were relatively limited when sex was specifically assessed as a factor (or only evident when sex comparisons were made in the patterns of effects), sex as a biological variable in the study of drugs should be made to determine if differences exist and, if evident, the basis for these differences.

Comparison of N-methyl-2-pyrrolidone (NMP) and the "date rape" drug GHB: behavioral toxicology in the mouse model.

N-methyl-2-pyrrolidone (NMP) and γ-hydroxybutyrate acid (GHB) are synthetic solvents detected in the recreational drug market. GHB has sedative/hypnotic properties and is used for criminal purposes to compromise reaction ability and commit drug-facilitated sexual assaults and other crimes. NMP is a strong solubilizing solvent that has been used alone or mixed with GHB in case of abuse and robberies. The aim of this experimental study is to compare the acute pharmaco-toxicological effects of NMP and GHB on neurological signs (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, and motor activity (bar, drag, and accelerod test) in CD-1 male mice. Moreover, since cardiorespiratory depression is one of the main adverse effects related to GHB intake, we investigated the effect of NMP and GHB on cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in mice. The present study demonstrates that NMP inhibited sensorimotor and motor responses and induced cardiorespiratory depression, with a lower potency and efficacy compared to GHB. These results suggest that NMP can hardly be used alone as a substance to perpetrate sexual assault or robberies.

Synthetic cathinone poisoning from ingestion of drug-laced "instant coffee packets" in Taiwan.

BACKGROUND: Synthetic cathinone abuse is a global health issue. Synthetic cathinones emerged in Taiwan in 2009, and their prevalence rapidly rose. They are usually made into "instant coffee packets," and these so-called "toxic coffee packets" may also contain psychoactive drugs other than synthetic cathinones. Due to the diversity of the ingredients, clinical presentations can be complex. METHODS: Retrospective analysis of emergency department (ED) patients who reported ingesting toxic coffee packets at three Chang-Gung Memorial Hospitals located in northern Taiwan between January, 2015 and December, 2019. RESULTS: Sixty patients were included. Their mean age was 28.85 ± 9.24 years and 47(78.33%) were male. The most common presentations were palpitation, agitation, hallucination, and altered consciousness. Tachycardia and hypertension were common, while hyperthermia was observed in only three patients. Three patients (5%) developed rhabdomyolysis, and one underwent transient hemodialysis. Most patients were discharged from the ED, but 15(25%) were admitted, of whom nine (15%) were admitted to the intensive care unit (ICU), and one eventually died. Confirmation tests (mass-spectrometry-based analysis) were available in 10 patients; all reported positive for at least one type of synthetic cathinone. Polysubstance exposure was common. In multivariate logistic regression analyses, Glasgow coma scale ≤13 and the presence of seizure were associated with ICU admission. CONCLUSION: Patients who report ingesting toxic coffee packets are very likely to have been exposed to synthetic cathinones. Polysubstance exposure is common following ingestion. Cardiovascular and neurological symptoms are the main presentations, and severe complications such as rhabdomyolysis and life-threatening dysrhythmia can occur.