Modulation of neuropeptide Y levels is impaired in crack withdrawal patients

Abstract Introduction The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has a key role in drug addiction susceptibility. In addition to the well-known relationship between cortisol and the HPA axis, other molecules are involved with stress response and could modify the HPA activation, such as the neuropeptide Y (NPY), which has anxiolytic proprieties. There are few studies evaluating the effect of NPY levels on addiction, especially in crack cocaine dependence. Objective To evaluate NPY in crack users during early withdrawal to determine its relationship with drug use and cortisol levels. Methods We analyzed 25 male inpatient crack users. Serum NPY levels were measured at admission and discharge (mean of 24 days). Morning salivary cortisol was measured at admission. Results Serum NPY levels at admission and discharge were very similar. Lower NPY levels at discharge were associated with higher lifetime crack use. Also, a negative correlation was found between morning cortisol and delta NPY (NPY discharge - NPY admission). Conclusion These preliminary findings indicate that crack use influences the modulation of NPY levels and modifies stress response. The NPY pathway may play an important role in the pathophysiology of crack addiction, and the anxiolytic effect of NPY may be impaired in crack users. Future studies should consider NPY as a measurable indicator of the biological state in addiction.

Effects of childhood trauma on BDNF and TBARS during crack-cocaine withdrawal

Objective: To evaluate the association between childhood trauma (CT) and serum levels of brain-derived neurotrophic factor (BDNF) and thiobarbituric acid-reactive substances (TBARS) during crack-cocaine withdrawal. Method: Thirty-three male crack-cocaine users were recruited at admission to a public addiction treatment unit. Serum BDNF and TBARS levels were evaluated at intake and discharge. Information about drug use was assessed by the Addiction Severity Index-6th Version (ASI-6); CT was reported throughout the Childhood Trauma Questionnaire (CTQ). CTQ scores were calculated based on a latent analysis model that divided the sample into low-, medium-, and high-level trauma groups. Results: There was a significant increase in BDNF levels from admission to discharge, which did not differ across CT subgroups. For TBARS levels, we found a significant time vs. trauma interaction (F2,28 = 6.357, p = 0.005,ηp 2 = 0.312). In participants with low trauma level, TBARS decreased, while in those with a high trauma level, TBARS increased during early withdrawal. Conclusion: TBARS levels showed opposite patterns of change in crack-cocaine withdrawal according to baseline CT. These results suggest that CT could be associated with more severe neurological impairment during withdrawal.

Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents

Objective: Cocaine use disorders (CUDs) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, who had concomitant cocaine and crack dependence, and healthy controls. Methods: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. Results: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs; adjusted p-value [adjP] < 10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that the EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1, and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. Conclusion: The investigation of DNA methylation patterns may contribute to a better understanding of the biological mechanisms involved in CUD.

TBARS and BDNF levels in newborns exposed to crack/cocaine during pregnancy: a comparative study

Objectives: To compare levels of a marker of lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and brain-derived neurotrophic factor (BDNF) in umbilical cord blood (UCB) between newborns exposed to crack/cocaine in utero (exposed newborns [EN], n=57) and non-exposed newborns (NEN, n=99), as well as in maternal peripheral blood at delivery. Methods: This was a cross-sectional study. Potential confounders, including perinatal parameters, psychopathology, and use of other substances, were assessed. Results: After adjusting for potential confounders, adjusted mean BDNF was significantly higher in EN (3.86 ng/mL, 95% confidence interval [95%CI] 2.29-5.43) than in NEN (0.85 ng/mL, 95%CI 0.47-1.23; p < 0.001; Cohen effect size: 1.12), and significantly lower in crack/cocaine mothers than in control mothers (4.03 ng/mL, 95%CI 2.87-5.18 vs. 6.67 ng/mL, 95%CI 5.60-7.74; p = 0.006). The adjusted mean TBARS level was significantly lower in EN (63.97 µM MDA, 95%CI 39.43-88.50) than NEN (177.04 µM MDA, 95%CI 140.93-213.14; p < 0.001; effect size = 0.84), with no difference between mother groups (p = 0.86). Conclusions: The changes in TBARS levels observed in EN suggest that fetuses exposed to cocaine mobilize endogenous antioxidant routes since very early stages of development. The increase in BDNF levels in EN might indicate changes in fetal development, whereas the changes in BDNF levels in mothers provide evidence of the complex metabolic processes involved in drug use during pregnancy.

IL-6 and IL-10 levels in the umbilical cord blood of newborns with a history of crack/cocaine exposure in utero: a comparative study / Níveis de IL-6 e IL-10 no sangue de cordão umbilical de recém-nascidos com história de exposição intrauterina ao crack/cocaína: um estudo comparativo

Introduction Prenatal cocaine exposure (PCE) is associated with neurobehavioral problems during childhood and adolescence. Early activation of the inflammatory response may contribute to such changes. Our aim was to compare inflammatory markers (IL-6 and IL-10) both in umbilical cord blood and in maternal peripheral blood at delivery between newborns with history of crack/cocaine exposure in utero and non-exposed newborns. Methods In this cross-sectional study, 57 newborns with a history of crack/cocaine exposure in utero (EN) and 99 non-exposed newborns (NEN) were compared for IL-6 and IL-10 levels. Sociodemographic and perinatal data, maternal psychopathology, consumption of nicotine and other substances were systematically collected in cases and controls. Results After adjusting for potential confounders, mean IL-6 was significantly higher in EN than in NEN (10,208.54, 95% confidence interval [95%CI] 1,328.54-19,088.55 vs. 2,323.03, 95%CI 1,484.64-3,161.21; p = 0.007; generalized linear model [GLM]). Mean IL-10 was also significantly higher in EN than in NEN (432.22, 95%CI 51.44-812.88 vs. 75.52, 95%CI 5.64-145.39, p = 0.014; GLM). Adjusted postpartum measures of IL-6 were significantly higher in mothers with a history of crack/cocaine use (25,160.05, 95%CI 10,958.15-39,361.99 vs. 8,902.14, 95%CI 5,774.97-12,029.32; p = 0.007; GLM), with no significant differences for IL-10. There was no correlation between maternal and neonatal cytokine levels (Spearman test, p ≥ 0.28 for all measures). Conclusions IL-6 and IL-10 might be early biomarkers of PCE in newborns. These findings could help to elucidate neurobiological pathways underlying neurodevelopmental changes and broaden the range of possibilities for early intervention.

Introdução A exposição pré-natal à cocaína está associada a problemas neurocomportamentais durante a infância e adolescência. A ativação precoce da resposta inflamatória pode contribuir para tais alterações. Nosso objetivo foi comparar marcadores inflamatórios (IL-6 e IL-10) no sangue do cordão umbilical e no sangue periférico materno na hora do parto, entre recém-nascidos expostos ao crack intraútero e recém-nascidos não expostos. Métodos Neste estudo transversal, 57 recém-nascidos expostos ao crack intraútero (RNE) e 99 recém-nascidos não expostos (RNNE) foram comparados quanto aos níveis de IL-6 e IL-10. Dados sociodemográficos e perinatais, psicopatologia materna, consumo de nicotina e outras substâncias foram sistematicamente coletados em casos e controles. Resultados Após o ajuste para potenciais confundidores, a média de IL-6 foi significativamente maior nos RNE em comparação aos RNNE [10.208,54, intervalo de confiança (IC95%) 1.328,54-19.088,55 versus2.323,03, IC95% 1.484,64-3.161,21; p = 0,007; modelo linear generalizado (MLG)]. A média ajustada de IL-10 foi significativamente maior nos RNE do que nos RNNE (432,2189, IC95% 51,44-812,88 versus 75,52, IC95% 5,64-145,39, p = 0,014; MLG). Medidas pós-parto ajustadas de IL-6 foram significativamente maiores nas mães que usaram de crack/cocaína (25.160,05, IC95% 10.958,15-39.361,99 versus 8.902,14, IC95% 5.774,97-12.029,32; p = 0,007; MLG), sem diferenças significativas para IL-10. Não houve correlação entre níveis maternos e neonatais de citocinas (teste de Spearman, p ≥ 0,28 para todas as medidas). Conclusões IL-6 e IL-10 podem ser biomarcadores precoces da exposição pré-natal a cocaína em recém-nascidos. Esses resultados podem ajudar a elucidar as vias neurobiológicas subjacentes a alterações do desenvolvimento e aumentar a gama de possibilidades para intervenção precoce.

Descripción de los hallazgos en el perfil lipídico y proteico de pacientes dependientes a cocaína, en abstinencia reciente / Serum lipid levels in a group of cocaine dependent subjects in recent abstinence

Background: Chronic cocaine users develop multiple potentially lethal ischemic vascular complications associated with accelerated atherosclerosis. Aim: To assess biochemical and lipid profiles among cocaine dependent subjects in recent abstinence. Material and Methods: A blood sample to measure blood count, biochemical and lipid profiles was obtained from 78 patients aged 19 to 53 years (78% males) who complied with DSM-IV criteria for cocaine dependency. Laboratory results were compared with a group of normal subjects. Results: All cases had positive urinary cocaine, with a mean consumption lapse of 7.6 years. The frequency of smoking was higher in cases. Dependent males had higher body mass index than controls. Compared to controls, dependent females had significantly higher triglyceride (TG) levels and lower HDL cholesterol. Therefore the relation total/HDL cholesterol was higher (p = 0.0365). Dependent males had higher TG levels than their normal counterparts. Dependent subjects consuming cocaine base-paste had higher TG levels. Total proteins, albumin, urea and blood urea nitrogen were lower in dependent subjects. Among males, serum creatinine was lower and blood urea was positively correlated with the daily amount of cocaine use (p = 0.03). After a month of strict abstinence, lipid profile was repeated in 27 patients and remained unchanged. Conclusions: Chronic cocaine use was associated with higher TG in both genders and lower HDL cholesterol in women when compared with a group of healthy counterparts.

Lesões destrutivas da linha média induzidas por cocaína com ANCA positivo mimetizando a granulomatose de Wegener / Cocaine-induced midline destruction lesions with positive ANCA test mimicking Wegener's granulomatosis

O uso crônico de cocaína por inalação pode causar lesões destrutivas de linha média (LDLMIC), que podem ser difíceis de distinguir das lesões da granulomatose de Wegener (GW) nos ouvidos, nariz e garganta. Descrevemos o caso de uma paciente de 43 anos admitida com história de dois anos de obstrução nasal e rinorreia. Ela havia recebido o diagnóstico de GW há cinco meses e estava em tratamento com prednisona e ciclofosfamida. Ao exame físico apresentava perfuração de septo nasal e palato. Exames de laboratório mostraram elevação das proteínas de fase aguda e teste p-ANCA positivo. Ensaios ELISA antiproteinase 3 e mieloperoxidase foram negativos. Tomografia computadorizada (TC) dos seios paranasais mostrou destruição de septo nasal e palato, bem como sinusite maxilar bilateral. TC de tórax resultou normal. Biópsia da mucosa nasal revelou infiltrado inflamatório sem granuloma ou vasculite. Quando questionada, admitiu ser usuária de cocaína há cinco anos. Os imunossupressores foram suspensos e a paciente não mais fez uso da droga. Ela está sendo monitorada há seis meses e não desenvolveu novas lesões ou sintomas de outros órgãos. O diagnóstico diferencial em pacientes com LDLMIC pode ser desafiador. A avaliação deve incluir pesquisa de uso intranasal de cocaína. Embora o teste de ANCA não diferencie claramente o ANCA encontrado em alguns pacientes com LDLMIC daqueles em pacientes com GW, o envolvimento localizado e os achados de biópsia não típicos de vasculite granulomatosa de pequenos vasos devem ser reconhecidos como características das lesões induzidas por cocaína.

Chronic use of cocaine by inhalation may induce midline destructive lesions (CIMDL), which can sometimes be difficult to distinguish from the ear, nose and throat lesions of Wegener's Granulomatosis (WG). We describe the case of a 43-year-old female patient admitted with a two-year history of nasal obstruction and rhinorrhea. She had been diagnosed with WG for five months, being on prednisone and cyclophosphamide. On her physical examination, perforation of her nasal septum and palate was observed. Laboratory tests showed elevated acute phase proteins and a positive p-ANCA test. ELISA assays anti-proteinase 3 and myeloperoxidase were negative. The paranasal sinus computed tomography (CT) showed destruction of the nasal septum and palate, in addition to bilateral maxillary sinusitis. Chest CT was normal. Nasal mucosal biopsy revealed an inflammatory infiltrate, with neither granuloma nor vasculitis. When questioned, she admitted being a cocaine user for five years. Medical therapy and cocaine use were withdrawn. She has been followed up for six months and no other lesion or other organ symptoms occurred. Differential diagnosis in patients with midline destructive lesions can be very challenging. Evaluation should include enquiry about intranasal use of cocaine. Although ANCA testing does not clearly differentiate the ANCA found in some patients with CIMDL from those found in WG patients, the localized involvement and the biopsy findings non-characteristic of small vessel granulomatous vasculitis should be recognized as features for cocaine-induced lesions.

Brain injury markers (S100B and NSE) in chronic cocaine dependents

OBJECTIVE: Studies have shown signs of brain damage caused by different mechanisms in cocaine users. The serum neuron specific enolase and S100B protein are considered specific biochemical markers of neuronal and glial cell injury. This study aimed at comparing blood levels of S100B and NSE in chronic cocaine users and in volunteers who did not use cocaine or other illicit drugs. METHOD: Twenty subjects dependent on cocaine but not on alcohol or marijuana, and 20 non-substance using controls were recruited. Subjects were selected by consecutive and non-probabilistic sampling. Neuron specific enolase and S100B levels were determined by luminescence assay. RESULTS: Cocaine users had significantly higher scores than controls in all psychiatric dimensions of the SCL-90 and had cognitive deficits in the subtest cubes of WAIS and the word span. Mean serum S100B level was 0.09 ± 0.04 µg/l among cocaine users and 0.08 ± 0.04 µg/l among controls. Mean serum neuron specific enolase level was 9.7 ± 3.5 ng/l among cocaine users and 8.3 ± 2.6 ng/l among controls. CONCLUSIONS: In this first study using these specific brain damage markers in cocaine users, serum levels of S100B and neuron specific enolase were not statistically different between cocaine dependent subjects and controls.

OBJETIVO: Estudos têm demonstrado sinais de lesão cerebral causadas por diferentes mecanismos em usuários de cocaína. A enolase sérica neurônio-específica e a proteína S100B são consideradas marcadores bioquímicos específicos de lesão neuronal e glial. Este estudo objetivou comparar os níveis sangüíneos de S100B e enolase sérica neurônio-específica em usuários crônicos de cocaína e em voluntários que não usam cocaína ou outras drogas ilícitas. MÉTODO: Vinte sujeitos dependentes de cocaína, mas não dependentes de álcool, maconha ou outra droga, e 20 sujeitos controles não usuários de drogas foram recrutados. Os sujeitos foram selecionados por amostragem consecutiva e não-probabilística e os níveis de enolase neurônio-específica e S100B foram determinados por ensaio de luminescência. RESULTADOS: Os usuários de cocaína tiveram escores significativamente maior que os controles em todas as dimensões psiquiátricas do SCL-90 e apresentaram prejuízos cognitivos no subteste cubos do WAIS e no span de palavras. Os níveis de S100B foram em média 0,09 ± 0,04 µg/l nos usuários de cocaína e 0,08 ± 0,04 µg/l nos controles. Os níveis de enolase neurônio-específica foram em média 9,7 ± 3,5 ng/l nos usuários e 8,3 ± 2,6 ng/l nos controles. CONCLUSÃO: Neste primeiro estudo utilizando esses marcadores específicos de lesão cerebral em usuários de cocaína, os níveis séricos de S100B e enolase específica do neurônio não foram significativamente diferentes entre dependentes de cocaína e controles.

Brazilian female crack users show elevated serum aluminum levels

OBJECTIVE: There is no information in the literature on the impact of crack smoking using crushed aluminum cans as makeshift pipes, a common form of crack use in Brazil. Since aluminum intake is associated with neurological damage, we measured serum aluminum levels in crack smokers. The objective of this study was to ascertain the levels of aluminum in crack users who smoke on makeshift aluminum pipes. METHOD: 71 female crack smokers, their mean age being 28.0 (± 7.7), provided information about their drug use, and had blood samples tested for serum aluminum level. RESULTS: 56 (79 percent) subjects smoked crack from crushed can pipes, while 15 (21 percent) smoked from other containers. Fifty-two (73.2 percent) out of the 71 subjects presented a serum aluminum level of 2 æg/l and 13 (18.3 percent) had a serum aluminum level of 6 æg/l cut-off point, which is above the reference value. When compared to non-drug users matched by their mean age and gender, they had similar median values and interquartile ranges for serum aluminum level [3 (2-4.6) for crack smokers; 2.9 (1.6-4.1) for controls], but with different means and standard deviations (4.7 ± 4.9 and 2.9 ± 1.7, respectively). DISCUSSION: Crack smokers have high serum aluminum level, but we are unsure of its complete association with aluminum cans. Further studies are needed. If such association is proven true in future research, further issues will be raised in dealing with this important disorder, including proper planning and evaluation of public health policies in this area.

OBJETIVO: Não há informação na literatura sobre o impacto do uso de crack fumado em latas de alumínio utilizadas como cachimbos improvisados, uma forma comum de uso de crack no Brasil. Uma vez que a ingestão de alumínio está associada a dano neurológico, nós medimos alumínio sérico em usuários de crack. O objetivo deste estudo foi avaliar os níveis de alumínio em usuários de crack que fumam em cachimbos improvisados de lata de alumínio. MÉTODO: Setententa e uma usuárias de crack, com média de idade de 28,0 anos (± 7,7), forneceram informação sobre seu uso de drogas e tiveram amostras de seu sangue testadas para níveis séricos de alumínio. RESULTADOS: Cinqüenta e seis (79 por cento) sujeitos fumaram crack usando cachimbos de lata e 15 (21 por cento) fumaram em outros formatos. Cinqüenta e dois (73,2 por cento) dos 71 sujeitos apresentaram níveis de alumínio sérico de 2 æg/l e 13 (18,3 por cento) tinham níveis no ponto de corte 6 æg/l, o que está acima dos valores de referência. Quando comparados com não-usuários pareados por média de idade e do mesmo gênero, os sujeitos tiveram valores medianos e intervalos inter-quartil para níveis séricos similares [3 (2-4,6) para usuários de crack; 2,9 (1,6-4,1) para os controles], porém com médias e desvios-padrão diferentes (4,7 ± 4,9 e 2,9 ± 1,7, respectivamente). DISCUSSÃO: Usuários de crack apresentam altos níveis de alumínio sérico, mas não temos certeza disto estar associado completamente com as latas de alumínio. Mais estudos são necessários. Se tal associação se mostrar verdadeira em pesquisa no futuro, questões terão que ser debatidas a respeito deste problema, incluindo planejamento apropriado e avaliação das políticas públicas nesta área.