Effects of cocaine, nicotine, and marijuana exposure in Drosophila Melanogaster development: A systematic review and meta-analysis.

Abuse-related drug usage is a public health issue. Drosophila melanogaster has been used as an animal model to study the biological effects of these psychoactive substances in preclinical studies. Our objective in this review is to evaluate the adverse effects produced by cocaine, nicotine, and marijuana during the development of D. melanogaster. We searched experimental studies in which D. melanogaster was exposed to these three psychoactive drugs in seven online databases up to January 2023. Two reviewers independently extracted the data. Fifty-one studies met eligibility criteria and were included in the data extraction: nicotine (n = 26), cocaine (n = 20), and marijuana (n = 5). Fifteen studies were eligible for meta-analysis. Low doses (∼0.6 mM) of nicotine increased locomotor activity in fruit flies, while high doses (≥3 mM) led to a decrease. Similarly, exposure to cocaine increased locomotor activity, resulting in decreased climbing response in D. melanogaster. Studies with exposure to marijuana did not present a profile for our meta-analysis. However, this drug has been less associated with locomotor changes, but alterations in body weight and fat content and changes in cardiac function. Our analyses have shown that fruit flies exposed to drugs of abuse during different developmental stages, such as larvae and adults, exhibit molecular, morphological, behavioral, and survival changes that are dependent on the dosage. These phenotypes resemble the adverse effects of psychoactive substances in clinical medicine.

Prenatal and postnatal cocaine exposure enhances the anxiety- and depression-like behaviors in rats during cocaine withdrawal.

Prenatal drug exposure is a public health problem, which results in profound behavioral problems during childhood and adolescence, mainly represented by an increase in the risk of cocaine abuse at an early age. In rodents, prenatal and postnatal cocaine exposure enhanced locomotor activity and cocaine- or nicotine-induced locomotor sensitization. Various authors consider that the adverse emotional states (anxiety and depression) that occur during cocaine withdrawal are the main factors that precipitate, relapse, and increase chronic cocaine abuse, which could increase the risk of relapse of cocaine abuse. Therefore, the objective of this study was to characterize anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal in rats born to females exposed prenatally and postnatally to cocaine. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine preexposure group), and another group of pregnant female rats was administered daily with saline (saline preexposure group). Of the litters resulting from the cocaine-pre-exposed and saline-pre-exposed pregnant female groups, only the male rats were used for the recording of the anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal The study found that prenatal and postnatal cocaine exposure dose-dependent enhanced anxiety- and depression-like behaviors. This suggests that prenatal and postnatal cocaine exposure can result in enhanced vulnerability to cocaine abuse in young and adult humans.

Cocaine-use disorder and childhood maltreatment are associated with the activation of neutrophils and increased inflammation.

BACKGROUND: Cocaine-use disorder (CUD) has been associated with early life adversity and activated cellular immune responses. Women are most vulnerable to complications from chronic substance disorders, generally presenting an intense feeling of abstinence and consuming significant drug amounts. Here, we investigated neutrophil functional activities in CUD, including the formation of neutrophil extracellular traps (NETs) and related intracellular signalling. We also investigated the role of early life stress in inflammatory profiles. METHODS: Blood samples, clinical data, and history of childhood abuse or neglect were collected at the onset of detoxification treatment of 41 female individuals with CUD and 31 healthy controls (HCs). Plasma cytokines, neutrophil phagocytosis, NETs, intracellular reactive oxygen species (ROS) generation, and phosphorylated protein kinase B (Akt) and mitogen-activated protein kinases (MAPK)s were assessed by flow cytometry. RESULTS: CUD subjects had higher scores of childhood trauma than controls. Increased plasma cytokines (TNF-α, IL-1ß, IL-6, IL-8, IL-12, and IL-10), neutrophil phagocytosis, and production of NETs were reported in CUD subjects as compared to HC. Neutrophils of CUD subjects also produced high levels of intracellular ROS and had more activated Akt and MAPKs (p38/ERK), which are essential signalling pathways involved in cell survival and NETs production. Childhood trauma scores were significantly associated with neutrophil activation and peripheral inflammation. CONCLUSION: Our study reinforces that smoked cocaine and early life stress activate neutrophils in an inflammatory environment.

El secuestro de la voluntad: bases moleculares de los cambios plásticos en la adicción / The hijacking of the will: molecular bases of plastic changes in addiction

Todas las drogas de abuso tienen en común la activación del sistema cerebral del placer. Los análisis imagenológicos han arrojado resultados de cambios estructurales en el cerebro de adictos a la cocaína e imágenes cerebrales en sujetos adictos muestran una disminución de la producción de dopamina que lleva a que la acción esté notoriamente amortiguada en relación con controles. Los estudios estructurales han mostrado reducciones de volumen de la sustancia gris y alteraciones circuitales de la sustancia blanca en el lóbulo frontal de adictos. La transición del uso recreativo a la adicción se asocia con cambios en la función de las neuronas que se acumulan con la administración repetida. La exposición crónica a la cocaína provoca aumentos de la arborización y de la densidad de las espinas dendríticas. El aumento de capacidad sináptica, ante el estímulo subcortical de una nueva presencia de la droga, toma el control de las funciones ejecutivas, «secuestrando¼ la capacidad de la voluntad consciente.

The activation of of the brain pleasure system is common to all abuse drugs. Imaging analyses have shown structural changes in the brain of cocaine addicts and a reduction of dopamine production which causes attenuation of its action when compared to control subjects. Structural studies in these patients show gray matter reduction and circuitry changes in frontal lobe white matter. Transition from recreational use to addiction is associated with changes in neuronal function which accumulate with repeated administration. Chronic exposure to cocaine leads to an increase in arborization and density of dendritic spines. When faced with new subcortical presence of the drug, the increase of synaptic capacity takes control of executive functions, "sequestering" the capacity for conscious will.

Trends and outcomes of trauma patients positive to marijuana and cocaine.

PURPOSE: Substance misuse has long been recognized as a major predisposing risk factor for traumatic injury. However, there still exists no clear scientific consensus regarding the impact of drug use on patient outcomes. Therefore, this study aims to evaluate the demographic profile, hospital-course factors, and outcomes of trauma patients based on their toxicology. METHODS: This is a non-concurrent cohort study of 3709 patients treated at the Puerto Rico Trauma Hospital during 2002-2018. The sample was divided into four groups according to their toxicology status. Statistical techniques used included Pearson's chi-square test, Spearman correlation, and negative binomial and logistic regressions. RESULTS: Admission rates for marijuana (rho = 0.87) and marijuana and cocaine positive (rho = 0.68) patients increased. Positive toxicology patients underwent surgery more often than negative testing patients (marijuana: 68.7%, cocaine: 65.6%, marijuana & cocaine: 69.8%, negative: 57.0%). Among patients with non-penetrating injuries, a positive toxicology for cocaine or marijuana was linked to a 48% and 42% increased adjusted risk of complications, 37% and 27% longer TICU LOS, and 32% and 18% longer hospital LOS, respectively. CONCLUSION: Our results show an association between positive toxicology for either marijuana, cocaine, or both with higher need for surgery. Additionally, our results show an increase in complications, TICU LOS, and hospital LOS among non-penetrating trauma patients testing positive for marijuana or cocaine. Therefore, this study provides valuable information on the clinical profile of patients with positive toxicology, suggesting they might benefit from more aggressive management.

Muerte accidental por consumo combinado de cocaína y etanol Revisión bibliográfica / Accidental death from combined cocaine and ethanol use. Literature review

La autopsia médico legal en Costa Rica, en casos sospechosos de intoxicación por cocaetileno se debe realizar bajo las normas establecidas en la Guía de estándares de trabajo para la Sección de Patología Forense del Departamento de Medicina Legal. El análisis del mecanismo fisiopatológico de cómo estas sustancias provocan alteraciones en el organismo que pueden conllevar a un eventual fallecimiento corresponde a parte del análisis requerido en la investigación ante la sospecha de esta causa de muerte. Por lo anterior, el objetivo de este artículo es describir los mecanismos fisiopatológicos que ocurren durante el consumo combinado de cocaína y etanol, los mecanismos que conllevan a la muerte de personas consumidoras de estas sustancias y las consideraciones médico legales a tomar en cuenta para el diagnóstico de esta causa de muerte. Se realizó revisión de artículos científicos, sobre los efectos del uso combinado de la cocaína y el etanol. La literatura describe que el uso combinado de cocaína y etanol potencia los efectos farmacocinéticos y bioquímicos de cada una de estas sustancias, que su derivado, el cocaetileno, es capaz de generar por sí mismo los mecanismos causantes de la muerte. Que los principales mecanismos fisiopatológicos que conllevan la muerte ante el uso combinado de estas sustancias son de origen cardiovascular y hepático. Como consideraciones médico legales a tomar en cuenta para el diagnóstico de esta manera de muerte accidental, en la Sección de Toxicología del Departamento de Ciencias Forenses de Costa Rica, la cuantificación del cocaetileno y las sustancias relacionadas no se realiza, aunque se encuentra actualmente en el desarrollo de un proyecto para la determinación de la estabilidad de las drogas en sangre bajo las condiciones de almacenamiento, con el fin de ofrecer la posibilidad de cuantificar ciertas drogas (en donde se podría incluir el cocaetileno) en un futuro próximo.

Medical-legal autopsy in Costa Rica, in suspected cases of cocaethylene poisoning must be performed under the regulations established in the Work Standards Guide for the Forensic Pathology Section of the Department of Legal Medicine. The analysis of the pathophysiological mechanism of how these substances cause alterations in the organism that can lead to eventual death corresponds to part of the analysis required in the investigation when this cause of death is suspected. Therefore, the objective of this article is to describe the pathophysiological mechanisms that occur during the combined consumption of cocaine and ethanol, the mechanisms that lead to the death of people who consume these substances, and the medico-legal considerations to be considered for the diagnosis. of this cause of death. A review of scientific articles was carried out on the effects of the combined use of cocaine and ethanol. The literature describes that the combined use of cocaine and ethanol enhances the pharmacokinetic and biochemical effects of each one of these substances, that its derivative, cocaethylene, can generate the mechanisms that cause death by itself. That the main pathophysiological mechanisms that lead to death in the combined use of these substances are of cardiovascular and hepatic origin. As legal medical considerations to take into account for the diagnosis of this type of accidental death, in the Toxicology Section of the Department of Forensic Sciences of Costa Rica, the quantification of cocaethylene and related substances is not carried out, although it is currently in the development of a project for the determination of the stability of drugs in blood under storage conditions, in order to offer the possibility of quantifying certain drugs (which could include cocaethylene) in the near future.

Oral changes in cocaine abusers: an integrative review.

INTRODUCTION: Cocaine is one of the most often used psychoactive drugs worldwide, being extracted from the leaves of Erytroxylus coca plant. Its abusive use can trigger several consequences for the human body, including the oral cavity. OBJECTIVE: To identify the oral disorders that are most commonly found in individuals who abuse cocaine, in addition to the main diagnostic and treatment methods. METHODS: An integrative review was carried out on the databases: LILACS, BBO, LIS, MEDLINE, SciELO, Science Direct and PubMed. The following keywords were used: "Cocaína", "Boca", "Palato" and "Odontologia", together with their synonyms and variations in English, obtained from DeCS and MeSH. The inclusion criteria were original articles, articles in Portuguese, English and Spanish, studies involving individuals, without restriction related to the year of publication. Animal studies, literature reviews, book chapters, theses and dissertations were excluded. RESULTS: In total, 1373 records were identified. Of these, 22 articles were selected to comprise the review. Several oral alterations caused by cocaine abuse were found, primarily perforation of the palate, predisposition to periodontal diseases, temporomandibular disorders, bruxism, damage to oral tissues, dental caries, destructive lesions of the facial midline, xerostomia and ageusia. Among the diagnostic methods used by the professionals, anamnesis, intraoral examinations and head and neck computed tomography were the most frequently mentioned. As for treatment, in patients with palatal perforation, the reconstruction of the affected area or the use of prosthetic obturators is carried out. CONCLUSION: The management of these patients is not an easy task, as many of the users do not even seek professional help. The health professionals must be able to recognize these manifestations and alterations to establish timely and accurate diagnosis and treatment planning.

Estudo de estabilidade de anfetaminas e produtos de biotransformação de cocaína e tetraidrocanabinol em amostras de urina seca em papel (dried urine spots) / Stability study of amphetamines, biotransformation products of cocaine and tetrahydrocannabinol in dried urine spots

O número de pessoas utilizando substâncias ilícitas de forma recreativa aumenta a cada ano, chamando a atenção de estudiosos de diversas áreas do conhecimento. Com isso, a demanda de exames toxicológicos exigida para trabalhadores, vítimas de crimes e esportistas também tem crescido. A amostra biológica mais utilizada para análises toxicológicas continua sendo a urina, visto que sua obtenção é menos invasiva, possibilita coletar grande volume de amostra e pode-se detectar substâncias até dias após ter ocorrido a exposição ou consumo. Entretanto, estas amostras necessitam de um grande volume físico para serem armazenadas e transportadas aos laboratórios, devendo ser mantidas em temperatura baixa e controlada para conservação. Outro ponto a se considerar é a quantidade de amostra insuficientemente coletada, ou extravasamento do conteúdo, contaminando outras amostras e muitas vezes, inviabilizando a análise. Uma alternativa recente para tais problemas é utilizar a técnica chamada de dried urine spots (DUS), onde poucos microlitros de urina são colocados em um papel absorvente e secos sob temperatura ambiente, preservando de agentes degradantes os componentes presentes na urina. Assim, o objetivo deste trabalho é avaliar a estabilidade das substâncias do presente estudo em alta temperatura, temperatura ambiente e em temperaturas de 4°C e -20°C. Para este fim, foi necessário desenvolver, validar e aplicar métodos de extração e determinação de anfetaminas e produtos de biotransformação de cocaína e tetraidrocanabinol carboxílico (THCCOOH) em amostras dried urine spot, utilizando cromatografia líquida acoplada à espectrometria de massas. Os picos foram identificados por UPLC-ESI-MS/MS, com tempo total de 5 mins utilizando fase A- água, formiato de amônio e 0,1% ácido fórmico, e B- metanol: acetonitrila (6:4) + 0,1% de ácido fórmico. A extração foi feita utilizando acetonitrila: metanol: acetona (1:1:1) +ácido fórmico 0,1%. Não foi possível iniciar a validação de THCCOOH, visto uma possível complexação do analito com o papel. Para as outras substâncias, o método cromatográfico desenvolvido se mostrou eficiente e seletivo, com LOD e LOQ de 10 ng/mL para todos os analitos, sendo linear até 1000 ng/mL, atendeu as especificações de precisão e exatidão e carryover. As amostras permaneceram estáveis ao longo de 32 dias nas temperaturas estudadas, demonstrando a segurança em se utilizar a técnica de DUS para armazenamento e transporte de amostras biológicas dentro da faixa de temperatura do estudo até 32 dias

The number of people using illegal substances in a recreational way increases each year, drawing the attention of scholars from different areas of knowledge. As a result, the demand for workplaces drug tests, toxicological tests for victims of crimes and dopping has also grown. The biological sample most used for toxicological tests remains urine, since obtaining it is less invasive, it is possible to collect a large volume of sample and it is possible to detect substances up to days after exposure or consumption has occurred. However, these samples require a large physical volume to be stored and transported to the laboratories, and must be kept at a low temperature for conservation. Another point to consider is the amount of sample insufficiently collected, or leakage of the content, causing contamination of other samples and often making the analysis unfeasible. A recent alternative to such problems is to use "dried urine spots" (DUS), where few microliters of urine are placed on absorbent paper and dried at room temperature, preserving the components present in the urine from degrading agents. Thus, the objective of this work is to evaluate the stability of the substances in this study at high temperature, room temperature and at temperatures of 4°C and -20°C. For this purpose, it was necessary to develop, validate and apply methods of extraction and determination of amphetamines and biotransformation products of cocaine and carboxylic tetrahydrocannabinol (THCCOOH) in dried urine spot samples, using liquid chromatography coupled to mass spectrometry (LC-MS). The peaks were identified liquid chromatography coupled to a mass spectrometer (UPLC-ESI-MS/MS), with a total time of 5 mins using phase A- water, ammonium formate and 0.1% formic acid, and B- methanol: acetonitrile (6:4) + 0.1% formic acid. Extraction was done using acetonitrile: methanol: acetone (1:1:1) + 0.1% formic acid. It was not possible to perform the validation of THCCOOH, given a possible complexation of the analyte with the paper. To the others substances, the chromatographic method developed proved to be efficient and selective, with LOD and LOQ of 10 ng/mL for all analytes, being linear up to 1000 ng/mL, meeting the specifications of precision and accuracy and carryover. The samples remained stable for 32 days at the temperatures studied, demonstrating the safety of using the DUS technique for storage and transport of biological samples until 32 days on temperature range studied

Repercussões cardiovasculares em usuários de cocaína: uma revisão integrativa / Cardiovascular repercussions in cocaine users: an integrative review

RESUMO: Introdução: O uso da cocaína é considerado um importante problema de saúde, sendo crescente o número de atendimentos nos serviços de emergência de pacientes que referem sintomas relacionados a alterações cardiovasculares após seu uso. Objetivo: Apresentar as repercussões cardiovasculares promovidas pela cocaína, associando o seu consumo a possíveis desfechos fatais, além de discutir as melhores maneiras de abordar o paciente na emergência. Método: Revisão integrativa da literatura nas bases de dados eletrônicas LILACS, MEDLINE, IBECS, SciELO, Secretaria Municipal de Saúde de São Paulo, Secretaria Estadual de Saúde de São Paulo, Coleciona SUS, disponíveis na BVS, bem como no PubMed. Resultados: Após análise criteriosa, 44 artigos atenderam aos critérios de inclusão. Foram estudos realizados na Europa (25%), Austrália (6,82%) e no continente americano (68,18%). Discussão: Abuso de cocaína é considerado um fator de risco isolado para doenças cardiovasculares, independente de outros. Por isso, pacientes jovens admitidos com dor torácica devem ser questionados sobre o consumo dessa droga. O tratamento do IAM associado ao uso de cocaína é semelhante ao realizado em paciente não usuário e, apesar da controvérsia existente sobre existir ou não contraindicação ao emprego de betabloqueador, diversos estudos indicam a utilização de drogas alfa e beta bloqueadores nesses pacientes. Conclusão: constatou-se que as principais repercussões cardiovasculares encontradas em pacientes usuários de cocaína que procuraram atendimento nas emergências hospitalares foram as emergências/urgências hipertensivas, taquicardia supraventricular, angina, infarto agudo do miocárdio, dissecção e aneurisma de aorta. (AU)

ABSTRACT: Introduction: The use of cocaine is considered an important health problem. An increasing number of patients in the emergency services report symptoms related to cardiovascular changes after its use. Objective: To present the cardiovascular repercussions promoted by cocaine, associating its consumption with possible fatal outcomes, besides discussing the best ways to approach the patient in the emergency. Method: Integrative literature review in the electronic databases LILACS, MEDLINE, IBECS, SciELO, Sao Paulo Municipal Health Department, State Health Secretariat of São Paulo, Coleciona UHS, available at the VHL, as well as PubMed. Results: After careful analysis, 44 articles met the inclusion criteria. Studies were conducted in Europe (25%), Australia (6.82%) and the American continent (68.18%). Discussion: Cocaine abuse is considered an isolated risk factor for cardiovascular disease, independent of others. Therefore, young patients admitted with chest pain should be asked about the use of this drug. The treatment of AMI associated with cocaine use is similar to that performed in a non-user patient. Despite the controversy over whether or not there is a contraindication to the use of beta-blockers; several studies indicate the use of alpha and beta-blocker drugs in these patients. Conclusion: it was found that the main cardiovascular repercussions found in cocaine users who sought care in hospital emergencies were hypertensive emergencies/urgencies, supraventricular tachycardia, angina, acute myocardial infarction, dissection, and aortic aneurysm (AU)

CB1R activation in nucleus accumbens core promotes stress-induced reinstatement of cocaine seeking by elevating extracellular glutamate in a drug-paired context.

Preclinical models of stress-induced relapse to drug use have shown that the dysregulation of glutamatergic transmission within the nucleus accumbens (NA) contributes notably to the reinstatement of cocaine-seeking behavior in rodents. In this sense, there has been increasing interest in the cannabinoid type-1 receptor (CB1R), due to its crucial role in modulating glutamatergic neurotransmission within brain areas involved in drug-related behaviors. This study explored the involvement of CB1R within the NA subregions in the restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP), as well as in the regulation of glutamatergic transmission, by using a pharmacological approach and the in vivo microdialysis sampling technique in freely moving rats. CB1R blockade by the antagonist/inverse agonist AM251 (5 nmol/0.5 µl/side) or CB1R activation by the agonist ACEA (0.01 fmol/0.5 µl/side), prevented or potentiated restraint stress-induced reinstatement of cocaine-CPP, respectively, after local administration into NAcore, but not NAshell. In addition, microdialysis experiments demonstrated that restraint stress elicited a significant increase in extracellular glutamate in NAcore under reinstatement conditions, with the local administration of AM251 or ACEA inhibiting or potentiating this, respectively. Interestingly, this rise specifically corresponded to the cocaine-associated CPP compartment. We also showed that this context-dependent change in glutamate paralleled the expression of cocaine-CPP, and disappeared after the extinction of this response. Taken together, these findings demonstrated the key role played by CB1R in mediating reinstatement of cocaine-CPP after restraint stress, through modulation of the context-specific glutamate release within NAcore. Additionally, CB1R regulation of basal extracellular glutamate was demonstrated and proposed as the underlying mechanism.

Personal Doses of Cocaine and Coca Paste are Adulterated in Cartagena de Indias (Colombia).

Knowledge of drug composition consumed on the streets and the identification and quantification of their adulterants is essential for understanding unexpected side effects, tracking routes, and drug profiling. Therefore, this work aimed to determine the purity and to identify and quantify the main adulterants found in personal doses of cocaine (perico) and coca paste (bazuco) in Cartagena de Indias (Colombia). The data collected in this study describe a first attempt to introduce the qualitative and quantitative analyses of adulterants present in street drugs in Cartagena de Indias to improve surveillance. Through gas chromatography coupled to mass spectrometry (GC-MS), the purity and adulterants were quantified in 45 personal doses of cocaine powder and coca paste. 100% of the personal doses in the city were adulterated; caffeine, phenacetin, and levamisole were the main adulterants identified in cocaine. Besides the above, lidocaine was also found in coca paste. The purity of cocaine varied from 8% to almost 70%, with caffeine ranging from 6% to 42%. In the case of coca paste, the maximum content of cocaine found was 60%, while some samples contained as little as 14%. The results are consistent with other research in terms of the widespread use of caffeine as an adulterant, but they also follow the growing trend of the use of levamisole and phenacetin. The wide range of cocaine content in samples sold in the illicit market could cause undesirable effects on cocaine users who do not know the exact intended dose for consumption; so, this study intends to make these results available not only to academic, public health, and national security agencies but also to tourists entering Cartagena de Indias, so that they are aware of what they are consuming and the risks to which they are exposed.

Pyoderma gangrenosum associated to the use of cocaine/levamisole. Series of three cases and literature review

Abstract Pyoderma gangrenosum associated to the use of cocaine/levamisole is a rare condition associated to their consumption. Cocaine use is frequent in Colombia, and the substance is contaminated with levamisole, an anthelmintic that increases the psychotropic effects and enhances its side effects. We present three clinical cases of patients with ulcerated lesions, in which the diagnosis was pyoderma gangrenosum secondary to the use of cocaine contaminated with levamisole. This called the attention of the health staff to investigate the abuse of substances in gangrenous pyoderma and also evidence that the interruption of consumption was the basis of management.

Pyoderma gangrenosum associated to the use of cocaine/levamisole. Series of three cases and literature review.

Pyoderma gangrenosum associated to the use of cocaine/levamisole is a rare condition associated to their consumption. Cocaine use is frequent in Colombia, and the substance is contaminated with levamisole, an anthelmintic that increases the psychotropic effects and enhances its side effects. We present three clinical cases of patients with ulcerated lesions, in which the diagnosis was pyoderma gangrenosum secondary to the use of cocaine contaminated with levamisole. This called the attention of the health staff to investigate the abuse of substances in gangrenous pyoderma and also evidence that the interruption of consumption was the basis of management.

The concomitant use of cannabis and cocaine coexists with increased LPS levels and systemic inflammation in male drug users.

Illicit drug use can cause a variety of effects including alterations in the immune system. The aim of this study was to investigate the effects of illicit drugs on circulating lipopolysaccharide (LPS), systemic inflammation and oxidative stress markers in drug users. We evaluated the levels of soluble CD14 (sCD14), LPS, inflammatory (TNF-α and IL-6) and regulatory (IL-10) cytokines, as well as C-reactive protein (CRP), lipid peroxidation (TBARS) and total thiols in the peripheral blood of 81 men included in groups of cannabis (n = 21), cocaine (n = 12), cannabis-plus-cocaine users (n = 27), and non-drug users (n = 21). The use of cannabis plus cocaine leads to higher systemic levels of LPS, CRP, IL-6 and higher IL-6/IL-10 ratio, characterizing a proinflammatory profile. In contrast, a regulatory profile as viewed by lower systemic TNF-α and IL-6 levels and lower TNF-α/IL-10 ratio were observed in cannabis users compared to the control group. Moreover, cocaine users presented a lower content of non-enzymatic antioxidant thiol compared to control group, cannabis group and cannabis plus cocaine group. In conclusion, our results indicate that the use of cannabis contributes to an anti-inflammatory/or regulatory profile while the concomitant cannabis plus cocaine consumption coexists with increased circulating amounts of LPS and proinflammatory status.

Simultaneous administration of cocaine and caffeine dysregulates HCN and T-type channels.

RATIONALE: The abuse of psychostimulants has adverse consequences on the physiology of the central nervous system. In Argentina, and other South American countries, coca paste or "PACO" (cocaine and caffeine are its major components) is massively consumed with deleterious clinical consequences for the health and well-being of the general population. A scant number of studies have addressed the consequences of stimulant combination of cocaine and caffeine on the physiology of the somatosensory thalamocortical (ThCo) system. OBJECTIVES: Our aim was to study ion conductances that have important implications regulating sleep-wake states 24-h after an acute or chronic binge-like administration of a cocaine and caffeine mixture following previously analyzed pasta base samples ("PACO"-like binge") using mice. METHODS: We randomly injected (i.p.) male C57BL/6JFcen mice with a binge-like psychostimulants regimen during either 1 day (acute) or 1 day on/1 day off during 13 days for a total of 7 binges (chronic). Single-cell patch-clamp recordings of VB neurons were performed in thalamocortical slices 24 h after the last psychostimulant injection. We also recorded EEG/EMG from mice 24 h after being systemically treated with chronic administration of cocaine + caffeine versus saline, vehicle. RESULTS: Our results showed notorious changes in the intrinsic properties of the VB nucleus neurons that persist after 24-h of either acute or chronic binge administrations of combined cocaine and caffeine ("PACO"-like binge). Functional dysregulation of HCN (hyperpolarization-activated cyclic nucleotide-gated) and T-type VGC (voltage-gated calcium) channels was described 24-h after acute/chronic "PACO"-like administrations. Furthermore, intracellular basal [Ca2+] disturbances resulted a key factor that modulated the availability and the activation of T-type channels, altering T-type "window currents." As a result, all these changes ultimately shaped the low-threshold spikes (LTS)-associated Ca2+ transients, regulated the membrane excitability, and altered sleep-wake transitions. CONCLUSION: Our results suggest that deleterious consequences of stimulants cocaine and caffeine combination on the thalamocortical physiology as a whole might be related to potential neurotoxic effects of soaring intracellular [Ca2+].

Cocaine-Related Aortic Dissection: what do we know?

INTRODUCTION: Cocaine use is known to be associated with an increased risk for vascular diseases. It is likely to trigger or increase the risk for an aortic dissection. We conducted an analysis of 45 cases of cocaine-related aortic dissection to further characterize the clinical features and outcomes of this patient cohort. METHODS: Our study cohort of 45 patients consisted of 11 cases from our institutional database and 34 published case reports. RESULTS: The observed cases of acute aortic dissection related to cocaine use showed a high proportion of young (41.3±8.67 years) and male (88.9%) patients. Most of the cases (75%) were classified as Stanford type A. Also, in 75% of the cases, cocaine use was prevalent for more than one year. Median time from last cocaine use to onset of symptoms was one hour. In-hospital mortality was 21.4%, while additional 11.9% of the cases died before arriving at the hospital. CONCLUSION: Acute aortic dissection related to cocaine use occurs in predominantly young male patients and has a dismal outcome when compared to all comer series.

Cocaine-related aortic dissection: what do we know?

Abstract Introduction: Cocaine use is known to be associated with an increased risk for vascular diseases. It is likely to trigger or increase the risk for an aortic dissection. We conducted an analysis of 45 cases of cocaine-related aortic dissection to further characterize the clinical features and outcomes of this patient cohort. Methods: Our study cohort of 45 patients consisted of 11 cases from our institutional database and 34 published case reports. Results: The observed cases of acute aortic dissection related to cocaine use showed a high proportion of young (41.3±8.67 years) and male (88.9%) patients. Most of the cases (75%) were classified as Stanford type A. Also, in 75% of the cases, cocaine use was prevalent for more than one year. Median time from last cocaine use to onset of symptoms was one hour. In-hospital mortality was 21.4%, while additional 11.9% of the cases died before arriving at the hospital. Conclusion: Acute aortic dissection related to cocaine use occurs in predominantly young male patients and has a dismal outcome when compared to all comer series.

Combined cocaine and clonazepam administration induces REM sleep loss and anxiety-like withdrawal behaviors in rats.

Misuse of prescription medications has risen to popularity. Reasons for this practice include the self-medication of sleep and psychiatric disorders and attempts to counteract the dysphoric side effects of stimulant drugs. Clonazepam, a commonly prescribed benzodiazepine, has been increasingly used as a countermeasure to cocaine side-effects, including sleep reduction and anxiety. As both substances may impair sleep and aggravate psychiatric conditions, this study aimed to evaluate the long-term effects of the interaction of clonazepam and cocaine on anxiety-like behavior, and the short-term effects of this drug combination on sleep using male Wistar rats. Animals received saline, cocaine (15 mg/kg), clonazepam (1.25 mg/kg) or both drugs for 16 days. Sleep recording was performed on the first day of treatment to evaluate acute treatment effects. One day after the end of the treatment period, the open field and elevated plus-maze tests were used to assess anxiety-like behavior. Blood samples were collected for analysis of corticosterone levels. Rats receiving both drugs presented an increase in impulsivity when moving between arms in the elevated plus-maze and a reduction in exploratory behavior in the open field test. These findings suggest the presence of a withdrawal behavioral syndrome, which can manifest as a paradoxical increase in exploratory activity after a period without receiving the drug and may indicate the development of dependence. Combined treatment reduced paradoxical sleep time and increased its onset latency. There was no significant difference regarding corticosterone levels across any group. Our results contribute to the understanding of the risks of combining cocaine and clonazepam. Association of these drugs may impair sleep architecture and aggravate the dependence symptoms already seen when these substances are used separately. These findings may be useful in helping to counteract the impairments resulting from the combined use of these 2 substances and to raise awareness of these associated risks.