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Introduction: Hypomagnesemia (hypoMg) has not yet been extensively studied in alcohol use disorder (AUD) . We hypothesize that chronic, excessive alcohol consumption favors oxidative stress and pro-inflammatory alterations that may be exacerbated by hypoMg. The objective of this study was to analyze the prevalence and associations of hypoMg in AUD.Patients and Methods: Cross-sectional study in patients admitted for a first treatment of AUD in six tertiary centers between 2013 and 2020. Socio-demographic, alcohol use characteristics, and blood parameters were ascertained at admission.Results: 753 patients (71% men) were eligible; age at admission was 48 years [IQR, 41-56 years]. Prevalence of hypoMg was 11.2%, higher than that observed for hypocalcemia (9.3%), hyponatremia (5.6%), and hypokalemia (2.8%). HypoMg was associated with older age, longer duration of AUD, anemia, higher erythrocyte sedimen-tation rate, gamma-glutamyl transpeptidase, glucose levels, advanced liver fibrosis (FIB-4 >= 3.25) and estimated glomerular filtration rate (eGFR) < 60 mL/min. In multivariate analysis, advanced liver fibrosis (OR, 8.91; 95% CI, 3.3-23.9) and eGFR < 60 mL (OR, 5.2; 95% CI, 1.0-26.2) were the only factors associated with hypoMg.Conclusions: Mg deficiency in AUD is associated with liver damage and glomerular dysfunction suggesting that both comorbidities should be assessed in the course of serum hypoMg.

Gender significantly influences sociodemographic, medical, psychiatric and addiction variables in cocaine outpatients. Educational level may be a protective factor showing less severe addictive disorders, longer abstinence periods, and better cognitive performance. The aim was to estimate gender-based differences and the influence of educational level on the clinical variables associated with cocaine use disorder (CUD). A total of 300 cocaine-consuming patients undergoing treatments were recruited and assessed using the Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Women developed CUD later but exhibited more consumption of anxiolytics, prevalence of anxiety disorders, eating disorders, and major depressive disorders. Alcohol and cannabis use disorders were more frequent in men. A predictive model was created and identified three psychiatric variables with good prognosis for distinguishing between women and men. Principal component analysis helped to describe the different profile types of men and women who had sought treatment. Low educational levels seemed to be a risk factor for the onset, development, and duration of CUD in both genders. Women and men exhibited different clinical characteristics that should be taken into account when designing therapeutic policies. The educational level plays a protective/risk role in the onset, development and progression of CUD, thus prolonging the years of compulsory education and implementing cognitive rehabilitation programmes could be useful.

Lysophosphatidic acid (LPA) is an endogenous lysophospholipid and a bioactive lipid that is synthesized by the enzyme autotaxin (ATX). The ATX–LPA axis has been associated with cognitive dysfunction and inflammatory diseases, mainly in a range of nonalcoholic liver diseases. Recently, preclinical and clinical evidence has suggested a role of LPA signaling in alcohol use disorder (AUD) and AUD-related cognitive function. However, the ATX–LPA axis has not been sufficiently investigated in alcoholic liver diseases. An exploratory study was conducted in 136 participants, 66 abstinent patients with AUD seeking treatment for alcohol (alcohol group), and 70 healthy control subjects (control group). The alcohol group was divided according to the presence of comorbid liver diseases (i.e., fatty liver/steatosis, alcoholic steatohepatitis, or cirrhosis). All participants were clinically evaluated, and plasma concentrations of total LPA and ATX were measured using enzyme-linked immunosorbent assays. Data were primarily analyzed using analysis of covariance (ANCOVA) while controlling for age, body mass index, and sex. Logistic regression models were created to assess the association of the ATX–LPA axis and AUD or liver disease. LPA and ATX were log10-transformed to fit the assumptions of parametric testing.The main results were as follows: total LPA and ATX concentrations were dysregulated in the alcohol group, and patients with AUD had significantly lower LPA (F(1,131) = 10.677, p = 0.001) and higher ATX (F(1,131) = 8.327, p = 0.005) concentrations than control subjects, patients with AUD and liver disease had significantly higher ATX concentrations (post hoc test, p &lt, 0.05) than patients with AUD but not liver disease, significant correlations between AUD-related variables and concentrations of LPA and ATX were only found in the non-liver disease subgroup (the duration of alcohol abstinence with LPA and ATX (r = +0.33, p &lt, 0.05), and the severity of AUD with ATX (rho = −0.33, p &lt, 0.05)), and a logistic regression model with LPA, ATX, and AUD-related variables showed an excellent discriminative power (area under the curve (AUC) = 0.915, p &lt, 0.001) for distinguishing patients with AUD and comorbid liver disease. In conclusion, our data show that the ATX–LPA axis is dysregulated in AUD and suggest this lipid signaling, in combination with relevant AUD-related variables, as a reliable biomarker of alcoholic liver diseases.

Granulocyte colony–stimulating factor (G-CSF) has raised much interest because of its role in cocaine addiction in preclinical models. We explored the plasma concentrations of G-CSF in patients diagnosed with substance use disorder (SUD) and highly comorbid psychiatric disorders. In particular, we investigated the association between G-CSF concentrations and comorbid major depressive disorder (MDD) in patients with cocaine and alcohol use disorders (CUD and AUD, respectively). Additionally, patients with MDD but not SUD were included in the study. Three hundred and eleven participants were enrolled in this exploratory study: 136 control subjects, 125 patients with SUD (SUD group) from outpatient treatment programs for cocaine (N = 60, cocaine subgroup) and alcohol (N = 65, alcohol subgroup), and 50 patients with MDD but not SUD (MDD group) from primary-care settings. Participants were assessed based on DSM-IV-TR criteria, and a blood sample was collected to examine the plasma concentrations of G-CSF. G-CSF concentrations were negatively correlated with age in the entire sample (r = − 0.233, p p p p

The lack of effective treatments and a high rate of relapse in cocaine addiction constitute a major health problem. The present study was conducted to examine the expression of tryptophan-derived metabolites in the context of cocaine addiction and psychiatric comorbidity, which is common in addicted subjects. Abstinent patients with cocaine use disorder (CUD) and control subjects were recruited for a cross-sectional study. Participants were assessed with a semi-structured diagnostic interview (PRISM) based on DSM-IV-TR for substance and mental disorders. Plasma concentrations of tryptophan metabolites and their association with relevant CUD-related variables and psychiatric comorbidity were explored. We observed decreased plasma kynurenic acid concentrations in the cocaine group, however no associations between CUD-related variables and tryptophan-derived metabolites were found. In contrast, 5-HT concentrations were increased in CUD-patients and the diagnosis of different psychiatric disorders in the cocaine group was related to higher plasma 5-HT concentrations compared with non-comorbid patients. Therefore, while changes in plasma kynurenic acid concentrations appear to be directly associated with lifetime CUD, changes in 5-HT concentrations are associated with psychiatric comorbidity. These results emphasize the need to find potential biomarkers for a better stratification of cocaine-addicted patients in order to develop therapeutic approaches to prevent cocaine relapse.

Cognitive reserve (CR) is the capability of an individual to cope with a brain pathology through compensatory mechanisms developed through cognitive stimulation by mental and physical activity. Recently, it has been suggested that CR has a protective role against the initiation of substance use, substance consumption patterns and cognitive decline and can improve responses to treatment. However, CR has never been linked to cognitive function and neurotrophic factors in the context of alcohol consumption. The present cross-sectional study aims to evaluate the association between CR (evaluated by educational level), cognitive impairment (assessed using a frontal and memory loss assessment battery) and circulating levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in patients with alcohol use disorder (AUD). Our results indicated that lower educational levels were accompanied by earlier onset of alcohol consumption and earlier development of alcohol dependence, as well as impaired frontal cognitive function. They also suggest that CR, NT-3 and BDNF may act as compensatory mechanisms for cognitive decline in the early stages of AUD, but not in later phases. These parameters allow the identification of patients with AUD who are at risk of cognitive deterioration and the implementation of personalized interventions to preserve cognitive function.

Addiction is characterized by compulsive substance seeking and use, underlying neuroadaptations in the reward and stress systems, and executive function. Clinically, addiction is defined as severe substance use disorder (SUD) with a high prevalence of psychiatric comorbidity, especially depression. Despite it is difficult to establish causality or directionality between SUD and major depressive disorder, the cooccurrence of depression has been focused on distinguishing primary from substance-induced depression because depressed mood and anhedonia are commonly observed during drug intoxication and withdrawal. Neuroinflammation has been attributed to the pathogenesis of addiction and depression. However, not only the neuroinflammation occurs but a chronic systemic inflammatory state is observed in both disorders, involving dysregulation of neuroendocrine pathways and disruption of the intestinal and blood-brain barriers. In the brain, neuroimmune response to drugs and stressors is characterized by the activation of microglia that results in the production of proinflammatory factors such as cytokines and chemokines, and the generation of reactive oxygen and nitrogen species, which interact with neurotransmitters in relevant brain circuits.

Antecedentes: El consumo de cocaína es un creciente problema de salud en todo el mundo. Además, los pacientes con trastorno por consumo de cocaína (TCC) presentan una alta comorbilidad con el trastorno depresivo mayor (TDM). Estos pacientes pueden presentar dos tipos de TDM: trastorno depresivo mayor primario (TDM-P) y trastorno depresivo mayor inducido por cocaína (TDM-IC). El objetivo de este estudio es evaluar las diferencias en la sintomatología depresiva (TDM-P vs. TDM- IC) en los pacientes con TCC para mejorar su tratamiento. Métodos: Se llevó a cabo un análisis secundario en una muestra transversal de 160 pacientes que presentaban TCC y algún TDM. La evaluación clínica, así como el diagnóstico diferencial entre TDM-P y TDM-IC, se realizó utilizando la entrevista PRISM. Resultados: Los hombres representaron el 80% de la muestra con una edad media de 38,61 años y el 64,5% sólo tenía estudios primarios. El diagnóstico de TDM-IC (61,3%) fue más frecuente que el de TDM-P (38,7%). Los pacientes con TDM-IC mostraron una edad de aparición más temprana para el TCC. El 79,4% de los pacientes cumplían criterios para otro trastorno por consumo de sustancias. Únicamente el criterio “Cambios en el peso o en el apetito” fue estadísticamente más prevalente (57,1%) en los pacientes con TDM-P. Conclusiones: Existen diferencias en el criterio “Cambios en el peso o en el apetito” entre TDM-P y TDM-IC. Se necesita más investigación a fin de obtener un diagnóstico diferencial entre los dos tipos de depresión y proporcionar un mejor tratamiento para los pacientes con TCC.

Lysophosphatidic acid (LPA) species are bioactive lipids participating in neurodevelopmental processes. The aim was to investigate whether the relevant species of LPA were associated with clinical features of alcohol addiction. A total of 55 abstinent alcohol use disorder (AUD) patients were compared with 34 age/sex/body mass index-matched controls. Concentrations of total LPA and 16:0-LPA, 18:0-LPA, 18:1-LPA, 18:2-LPA and 20:4-LPA species were quantified and correlated with neuroplasticity-associated growth factors including brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and IGF-2, and neurotrophin-3 (NT-3). AUD patients showed dysexecutive syndrome (22.4%) and memory impairment (32.6%). Total LPA, 16:0-LPA, 18:0-LPA and 18:1-LPA concentrations, were decreased in the AUD group compared to control group. Total LPA, 16:0-LPA, 18:2-LPA and 20:4-LPA concentrations were decreased in men compared to women. Frontal lobe functions correlated with plasma LPA species. Alcohol-cognitive impairments could be related with the deregulation of the LPA species, especially in 16:0-LPA, 18:1-LPA and 20:4-LPA. Concentrations of BDNF correlated with total LPA, 18:2-LPA and 20:4-LPA species. The relation between LPA species and BDNF is interesting in plasticity and neurogenesis functions, their involvement in AUD might serve as a biomarker of cognitive impairment. The present study has been supported by the following programs and research projects: Subprograma Redes Temáticas RETICS (Red de Trastornos Adictivos RD16/0017/001 and RD12/0028/0021) funded by Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad (MINECO) and the European Regional and European Regional Development Funds/European Social Fund (ERDF/ESF); Proyectos de Investigación en Salud (PI16/01953, PI16/01698 and PI17/02026) funded by ISCIII and ERDF/ESF; Proyectos de Investigación en Drogodependencias (PND2017/043, PND2018/033, PND2018/044 and PND2019/040) funded by Delegación del Gobierno para el Plan Nacional sobre Drogas, Ministerio de Sanidad, Secretaría de Estado de Sanidad and ERDF/ESF; Proyecto de Investigación en Salud (PI-0140-2018) funded by Consejería de Salud y Bienestar Social, Junta de Andalucía and ERDF/ESF. NGM holds a “Sara Borrell” research contract (CD19/00019) funded by ISCIII and ERDF/ESF. FJP, AS and JS hold a “Miguel Servet II” research contract (CPII19/00022, CPII19/00031 and CPII17/00024, respectively) funded by ISCIII and ERDF/ESF. RTF holds a Grant (2017 SGR 138) funded by Departament d’Economia i Coneixement de la Generalitat de Catalunya (CIBEROBN), ISCIII and ERDF/ESF. Yes

Background:Recent studies have demonstrated that alcohol consumption can modulate the immune system by directly activating natural immunity and triggering inflammatory processes in the central nervous system and in peripheral organs, such as the liver and pancreas. Patients with alcohol use disorders have an elevated frequency of comorbid mental disorders and gut diseases (i.e. fatty liver and pancreatitis) that complicate diagnosis, treatment and prognosis.Aims:The present study aims to explore possible associations in circulating plasma cytokine concentrations in abstinent patients diagnosed with alcohol use disorders.Methods:To this end, 85 abstinent subjects with alcohol use disorders from an outpatient setting and 55 healthy subjects were evaluated for both substance and mental disorders. The plasma levels of cytokines interleukin 1 beta, interleukin 4, interleukin 6, interleukin 17A, interferon gamma and tumour necrosis alpha were determined and their association with (a) history of alcohol consumption, (b) psychiatric comorbidity and (c) liver/pancreas comorbidities was explored.Results:We found that plasma concentrations of interleukin 1 beta, interleukin 6 and tumour necrosis alpha were increased, whereas plasma concentrations of interleukin 4, interleukin 17A and interferon gamma were decreased in abstinent alcohol use disorder patients as compared with control subjects. Moreover, we found that changes in interleukin 6 and interleukin 17A plasma concentrations in alcohol use disorder patients were associated with the presence of liver and pancreatic diseases.Conclusion:The present results suggest alcohol use disorder is associated with alterations of plasma cytokines, being interleukin 6 and interleukin 17A potential biomarkers of the presence of comorbidities of digestive organs. The clinical relevance of these findings is discussed in the context of alcohol-induced inflammatory processes.

Cocaine use is a growing global health problem and patients with cocaine use disorders (CUD) present several complications, including high rates of major depression. These subjects present two types of major depressive disorder (MDD): primary major depressive disorder (P-MDD) and cocaine-induced major depressive disorder (CI-MDD). To improve treatment, it is necessary to distinguish between both types. The aim of this study was to assess the differences in depressive symptomatology criteria (P-MDD vs CI-MDD) in CUD patients.Secondary data analysis was carried out with a cross-sectional sample of 160 patients presenting CUD and MDD. Clinical assessment was performed using the Psychiatric Research Interview for Substance and Mental Disorders (PRISM). A differential diagnosis was obtained between P-MDD and CI-MDD.Men represented 80% of the sample, the mean age was 38.61 years, and 64.5% had elementary studies. CI-MDD diagnosis (61.3%) was more frequent than P-MDD (38.7%). There was a younger age of CUD onset in CI-MDD patients. In addition, 79.4% of the patients had another substance use disorder diagnosis. The criterion "Changes in weight or appetite" was more prevalent (57.1%) in P-MDD group.We found differences in the criterion "Changes in weight or appetite". Further research is needed in this field to establish a differential diagnosis and thus provide better treatment for CUD patients.Antecedentes: El consumo de cocaína es un creciente problema de salud en todo el mundo. Además, los pacientes con trastorno por consumo de cocaína (TCC) presentan una alta comorbilidad con el trastorno depresivo mayor (TDM). Estos pacientes pueden presentar dos tipos de TDM: trastorno depresivo mayor primario (TDM-P) y trastorno depresivo mayor inducido por cocaína (TDM-IC). El objetivo de este estudio es evaluar las diferencias en la sintomatología depresiva (TDM-P vs. TDM- IC) en los pacientes con TCC para mejorar su tratamiento. Métodos: Se llevó a cabo un análisis secundario en una muestra transversal de 160 pacientes que presentaban TCC y algún TDM. La evaluación clínica, así como el diagnóstico diferencial entre TDM-P y TDM-IC, se realizó utilizando la entrevista PRISM. Resultados: Los hombres representaron el 80% de la muestra con una edad media de 38,61 años y el 64,5% sólo tenía estudios primarios. El diagnóstico de TDM-IC (61,3%) fue más frecuente que el de TDM-P (38,7%). Los pacientes con TDM-IC mostraron una edad de aparición más temprana para el TCC. El 79,4% de los pacientes cumplían criterios para otro trastorno por consumo de sustancias. Únicamente el criterio “Cambios en el peso o en el apetito” fue estadísticamente más prevalente (57,1%) en los pacientes con TDM-P. Conclusiones: Existen diferencias en el criterio “Cambios en el peso o en el apetito” entre TDM-P y TDM-IC. Se necesita más investigación a fin de obtener un diagnóstico diferencial entre los dos tipos de depresión y proporcionar un mejor tratamiento para los pacientes con TCC.

How the presence of inflammation has repercussions for brain function is a topic of active research into depression. Signals released from immune system-related cells, including chemokines, might be indicative of active depression and can, hypothetically, serve as biomarkers of response to interventions, both pharmacological and psychological. The objective of this study is to analyze the peripheral plasma concentrations of CXCL12, CCL11, CX3CL1 and CCL2 in a cohort of depressed primary-care patients, as well as their evolution after an internet-based cognitive-behavioral intervention. The concentrations of those chemokines were measured in 66 primary-care patients with mild and moderate depression, before and after the intervention, as well as 60 controls, using multiplex immunoassays. Concentrations of CXCL12 and CCL2 were significantly higher in the clinical sample in comparison with controls. A stable multivariate discriminative model between both groups was found. Concentrations of all chemokines decreased after the internet-based psychological intervention. These findings support the implication of chemokines in depression, even in a sample of patients with mild and moderate severity. Furthermore, they demonstrate the need for further multidisciplinary research that confirms how biomarkers such as plasma chemokines can serve as a marker for depression and are sensitive to non-pharmacological interventions.

Descripción de los objetivos Los trastornos por uso de alcohol (TUA) alteran el desarrollo cerebral afectando a las funciones ejecutivas, a los procesos estratégicos de recuerdo y a las capacidades visoespaciales. Estas alteraciones constituyen factores predictivos de deterioro de la memoria. El objetivo consiste en examinar el funcionamiento de la memoria episódica y visual en pacientes con TUA según la gravedad de los criterios diagnósticos. Material y métodos Se llevó a cabo una evaluación psicopatológica de 35 pacientes con TUA en abstinencia utilizando criterios DSM-5 y para la evaluación neuropsicológica se aplicaron el Test de Aprendizaje Verbal España-Complutense (TAVEC), la Figura Compleja de Rey y el Trail Making test (TMT). Se seleccionaron pacientes con criterios diagnósticos leve/moderado (n=17) y se compararon con aquellos con criterios diagnósticos grave (n=18). Las diferencias sociodemográficas y clínicas se determinaron mediante Chi-cuadrado (χ²) y t de Student (t-test). El análisis de las pruebas neuropsicológicas se llevó a cabo mediante ANCOVAS univariantes controlando la variable edad. Resultado y conclusiones El 86% de la muestra eran hombres con una media de 43 años y con estudios secundarios (46%) sin diferencias sociodemográficas ni clínicas entre los dos grupos de TUA. Encontramos diferencias significativas en la ejecución de la memoria episódica a corto plazo (p=0,003) y a largo plazo (p=0,029) pero no en el recuerdo inmediato. También existen diferencias significativas en las estrategias seriales del recuerdo inmediato (p=0,008) y en la interferencia proactiva (p=0,013), con menor ejecución en el grupo TUA con mayor gravedad de criterios diagnósticos. No encontramos diferencias entre los dos grupos en memoria visual. La gravedad de los TUA se relaciona con la afectación de la memoria episódica. Existiría una relación entre un procesamiento superficial poco efectivo de la información que dificulta la entrada de nueva información a la memoria a largo plazo y los TUA.

Chronic alcohol consumption is associated with neurocognitive and memory deficits, dramatically affecting plasticity and connectivity, with maximal expression as dementia. Neurotrophic factors may contribute to alcohol-related cognitive decline. For further investigation, a cross-sectional study was performed to evaluate the association of cognitive impairment, by using frontal assessment battery, and memory loss, using memory failures everyday, with the circulating levels of the neurotrophin brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in abstinent subjects with alcohol use disorders (AUDs, N = 58, average of 17.9 years of problematic use and 4.3 months of abstinence) compared with healthy control subjects (N = 22). This association was also explored in a pre-clinical model of adolescent rats chronically exposed to alcohol up to adulthood (~77 days old) in a three-bottle free-choice (5-10-20 percent), repeated abstinence and relapse paradigm. AUD subjects had low educational level and cognitive impairment associated with teenage consumption and lower circulating levels of BDNF and NT-3. Only BDNF concentration showed a positive correlation with frontal assessment battery in AUD patients. In the ethanol-exposed rats, the plasma levels of BDNF and NT-3 were also decreased, and a negative correlation between hippocampal Bdnf mRNA levels and recognition memory was found. The ethanol-exposed rat hippocampus showed a decrease in the mRNA levels of neurotrophic (Bdnf and Ntf-3) and neurogenic (Mki67, Sox2, Dcx, Ncam1 and Calb1) factors, associated to a deactivation of the neurogenic regulator mitogen-activated protein kinase extracellular signal-regulated kinase. Results suggest a relevant role of BDNF/extracellular signal-regulated kinase 2 signaling in alcohol-induced cognitive impairment and suggest that early alcohol exposure-derived effects on cognition are associated with neurotrophin signaling deficits.

Cocaine continues to be a worldwide public health concern in Europe. To improve prognosis and intervention, it is necessary to understand the characteristics of the patients who depend on the services where they receive care. The objective is to analyze the differences among patients who use cocaine and between ambulatory and residential resources to better adapt treatment. This is a descriptive, observational study of two populations of cocaine users in treatment: the ambulatory therapeutic community (ATC) and the therapeutic community (TC). The PRISM diagnostic interview was used for both groups. An analysis of both populations indicates a high prevalence of cocaine, heroin, cannabis, sedative, psychostimulant, and hallucinogen use disorders in the TC population compared to the ATC. In alcohol use disorder, differences between both mental health services were not observed. The degree of severity of cocaine use disorders (CUD) is greater in the TC population. The prevalence of psychiatric comorbidity is not statistically significant between the two populations, except for primary psychotic disorders, which are more prevalent in the TC population. This difference in the prevalence of psychotic disorders may be related to the high prevalence of cannabis use disorders in TC patients. Differences in the prevalence of substance use disorders, severity of CUD, and psychiatric comorbidity may limit the efficiency of mental health services involved in substance use disorder therapeutics. These results suggest the need for careful and extensive phenotyping of patients to improve intervention and prognosis in a clinical resource-dependent manner.

Cocaine induces neuroinflammatory response and interleukin-1 beta (IL1β) is suggested a final effector for many cocaine-induced inflammatory signals. Recently, the chemokine fractalkine (CX

Major depressive disorder (MDD) is the most prevalent comorbid mental disorder among people with substance use disorders. The MDD can be both primary and substance-induced and its accurate diagnosis represents a challenge for clinical practice and treatment response. Recent studies reported alterations in the circulating expression of inflammatory mediators in patients with psychiatric disorders, including those related to substance use. The aim of the study was to explore TNF-alpha, IL-1 beta, CXCL12, CCL2, CCL11 (eotaxin-1) and CX3CL1 (fractalkine) as potential biomarkers to identify comorbid MDD and to distinguish primary MDD from substance-induced MDD in patients with substance disorders. Patients diagnosed with cocaine (CUD, n = 64) or alcohol (AUD, n = 65) use disorders with/without MDD were recruited from outpatient treatment programs [ CUD/non-MDD (n = 31); CUD/primary MDD (n = 18); CUD/cocaine-induced MDD (N = 15); AUD/non-MDD (n = 27); AUD/primary MDD (n = 16) and AUD/alcohol-induced MDD (n = 22)]. Sixty-two healthy subjects were also recruited as control group. Substance and mental disorders were assessed according to "Diagnostic and Statistical Manual of Mental Disorders, 4 th edition, text revision" (DSM-IV-TR) and a blood sample was collected for determinations in the plasma. The cocaine group showed lower TNF-alpha (p

Oleoylethanolamide (OEA) is a non-cannabinoid acylethanolamide with multiple physiological roles that has been proposed to have antidepressant-like activity in preclinical models. OEA shares biosynthetic pathways with anandamide (AEA) a transmitter involved in affective disorders and anxiety in humans. However, although the participation of OEA in depression has been proposed, both, the contribution of OEA to the depressive phenotype and the effect of antidepressant therapy on circulating levels of this and related non-cannabinoid acylethanolamides in humans are basically unknown. The main objective of this study is to compare the plasma concentrations of OEA and related acylethanolamides in a sample of primary care patients with depression (n = 69) with those of healthy non-depressed patients (n = 47). At the time of admission to the study, 22 patients were under selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and 47 patients were not receiving any type of intervention. In addition, plasma concentrations of the endocannabinoid 2-AG and two related monoacylglycerols were monitored. Plasma OEA concentrations were found to be elevated in depressed patients and to correlate with somatic symptoms of depression. Plasma concentrations of both, AEA and 2-AG, were found to be elevated also in depressed patients. Further analysis demonstrated that the elevation observed in the plasma concentrations of both, OEA and 2-AG, was associated to SSRI antidepressant therapy at the time of recruitment. Further clinical research is needed to understand whether SSRI-induced elevations in OEA levels contribute to the response to SSRI in depressed patients as described in preclinical models.

Cocaine addiction is a chronic brain disease in which the drug seeking habits and profound cognitive, emotional and motivational alterations emerge from drug-induced neuroadaptations on a vulnerable brain. Therefore, a 'cocaine addiction brain circuit' has been described to explain this disorder. Studies in both cocaine patients and rodents reveal the hippocampus as a main node in the cocaine addiction circuit. The contribution of the hippocampus to cocaine craving and the associated memories is essential to understand the chronic relapsing nature of addiction, which is the main obstacle for the recovery. Interestingly, the hippocampus holds a particular form of plasticity that is rare in the adult brain: the ability to generate new functional neurons. There is an active scientific debate on the contributions of these new neurons to the addicted brain. This review focuses on the potential role(s) of adult hippocampal neurogenesis (AHN) in cocaine addiction. Although the current evidence primarily originates from animal research, these preclinical studies support AHN as a relevant component for the hippocampal effects of cocaine.

Acylethanolamides are a family of endogenous lipid mediators that are involved in physiological and behavioral processes associated with addiction. Recently, oleoylethanolamide (OEA) has been reported to reduce alcohol intake and relapse in rodents but the contribution of OEA and other acylethanolamides in alcohol addiction in humans is unknown. The present study is aimed to characterize the plasma acylethanolamides in alcohol dependence. Seventy-nine abstinent alcohol-dependent subjects (27 women) recruited from outpatient treatment programs and age-/sex-/body mass-matched healthy volunteers (28 women) were clinically assessed with the diagnostic interview PRISM according to the DSM-IV-TR after blood extraction for quantification of acylethanolamide concentrations in the plasma. Our results indicate that all acylethanolamides were significantly increased in alcohol-dependent patients compared with control subjects (p < 0.001). A logistic model based on these acylethanolamides was developed to distinguish alcohol-dependent patients from controls and included OEA, arachidonoylethanolamide (AEA) and docosatetraenoylethanolamide (DEA), providing a high discriminatory power according to area under the curve [AUC = 0.92 (95%CI: 0.87-0.96), p < 0.001]. Additionally, we found a significant effect of the duration of alcohol abstinence on the concentrations of OEA, AEA and DEA using a regression model (p < 0.05, p < 0.01 and p < 0.001, respectively), which was confirmed by a negative correlation (rho = -0.31, -0.40 and -0.44, respectively). However, acylethanolamides were not influenced by the addiction alcohol severity, duration of problematic alcohol use or diagnosis of psychiatric comorbidity. Our results support the preclinical studies and suggest that OEA, AEA and DEA are altered in alcohol-dependence during abstinence and that might act as potential markers for predicting length of alcohol abstinence.

Alterations in tryptophan (TRP) metabolism has been linked to drug exposure and mental disorders. However, most of studies have been performed without considering the co-occurrence of both disorders in the context of addiction. This cross-sectional study examines TRP metabolism through the serotonin (5-HT) and kynurenine (KYN) pathways in subjects with alcohol use disorders (AUD) and high prevalence of psychiatric comorbidity.For this purpose, male and female abstinent AUD patients (N = 130) and healthy controls (N = 80) were clinically evaluated for substance use and mental disorders, and blood samples were collected to determine plasma concentrations of TRP, 5-HT, KYN and kynurenic acid (KA) using high performance liquid chromatography. Clinical and biochemical variables were analyzed for potential associations considering AUD, psychiatric comorbidity and sex.TRP concentrations were significantly associated with an interaction effect between AUD diagnosis and sex (p .01): TRP concentrations were lower in male AUD patients but higher in female AUD patients compared with their controls. KYN and KA concentrations were significantly associated with AUD diagnosis (p .01 and p .05, respectively). Thus, AUD patients showed significantly higher KYN concentrations and lower KA concentrations than controls. Regarding 5-HT concentrations, there were sex differences in the alcohol group (p .05) and female AUD patients showed lower 5-HT concentrations than male AUD patients. Moreover, there was a significant interaction effect between psychiatric comorbidity and sex on TRP concentrations in the alcohol group (p .01). Whereas male patients with both comorbid substance use and mental disorders showed lower TRP concentrations than male non-comorbid patients, female patients with comorbid mental disorders showed higher TRP concentrations than female non-comorbid patients.While alterations in the KYN pathway appear to be directly associated with a history of AUD, altered TRP concentrations are associated with the presence of comorbid psychiatric disorders. Finally, sex differences in TRP metabolism must be considered in future studies.

Cocaine induces neuroinflammatory response and interleukin-1 beta (IL1β) is suggested a final effector for many cocaine-induced inflammatory signals. Recently, the chemokine fractalkine (CX3CL1) has been reported to regulate hippocampus-dependent neuroinflammation and synaptic plasticity via CX3C-receptor 1 (CX3CR1), but little is known about the impact of cocaine. This study is mainly focused on the characterization of CX3CL1, IL1β and relevant inflammatory signal transduction pathways in the hippocampus in acute and repeated cocaine-treated male mice. Complementarily, the rewarding properties of cocaine were also assessed in Cx3cr1-knockout (KO) mice using a conditioned place preference (CPP). We observed significant increases in CX3CL1 and IL1β concentrations after cocaine, although repeated cocaine produced an enhancement of CX3CL1 concentrations. CX3CL1 and IL1β concentrations were positively correlated in acute (r = +0.61) and repeated (r = +0.82) cocaine-treated mice. Inflammatory signal transduction pathways were assessed. Whereas acute cocaine-treated mice showed transient increases in p-ERK1/2/ERK1/2 and p-p65/p65 NFκB ratios after cocaine injection, repeated cocaine-treated mice showed transient increases in p-ERK1/2/ERK1/2, p-p38/p38 MAPK, p-NFκB p65/NF-κB p65 and p-CREB/CREB ratios. Baseline p-p38/p38 MAPK and p-CREB/CREB ratios were downregulated in repeated cocaine-treated mice. Regarding the cocaine-induced CPP, Cx3cr1-KO mice showed a notably impaired extinction but no differences during acquisition and reinstatement. These results indicate that cocaine induces alterations in CX3CL1 concentrations, which are associated with IL1β concentrations, and activates convergent inflammatory pathways in the hippocampus. Furthermore, the CX3CL1/CX3CR1 signaling could mediate the processes involved in the extinction of cocaine-induced CPP.

Chronic alcohol consumption is associated with neurocognitive and memory deficits, dramatically affecting plasticity and connectivity, with maximal expression as dementia. Neurotrophic factors may contribute to alcohol-related cognitive decline. For further investigation, a cross-sectional study was performed to evaluate the association of cognitive impairment, by using frontal assessment battery, and memory loss, using memory failures everyday, with the circulating levels of the neurotrophin brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in abstinent subjects with alcohol use disorders (AUDs, N = 58, average of 17.9 years of problematic use and 4.3 months of abstinence) compared with healthy control subjects (N = 22). This association was also explored in a pre-clinical model of adolescent rats chronically exposed to alcohol up to adulthood (~77 days old) in a three-bottle free-choice (5-10-20 percent), repeated abstinence and relapse paradigm. AUD subjects had low educational level and cognitive impairment associated with teenage consumption and lower circulating levels of BDNF and NT-3. Only BDNF concentration showed a positive correlation with frontal assessment battery in AUD patients. In the ethanol-exposed rats, the plasma levels of BDNF and NT-3 were also decreased, and a negative correlation between hippocampal Bdnf mRNA levels and recognition memory was found. The ethanol-exposed rat hippocampus showed a decrease in the mRNA levels of neurotrophic (Bdnf and Ntf-3) and neurogenic (Mki67, Sox2, Dcx, Ncam1 and Calb1) factors, associated to a deactivation of the neurogenic regulator mitogen-activated protein kinase extracellular signal-regulated kinase. Results suggest a relevant role of BDNF/extracellular signal-regulated kinase 2 signaling in alcohol-induced cognitive impairment and suggest that early alcohol exposure-derived effects on cognition are associated with neurotrophin signaling deficits.

The identification of growth factors as potential biomarkers in alcohol addiction may help to understand underlying mechanisms associated with the pathogenesis of alcohol use disorders (AUDs). Previous studies have linked growth factors to neural plasticity in neurocognitive impairment and mental disorders. In order to further clarify the impact of chronic alcohol consumption on circulating growth factors, a cross-sectional study was performed in abstinent AUD patients (alcohol group, N = 91) and healthy control subjects (control group, N = 55) to examine plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and IGF-1 binding protein-3 (IGFBP-3). The association of these plasma peptides with relevant AUD-related variables and psychiatric comorbidity was explored. The alcohol group was diagnosed with severe AUD and showed an average of 13 years of problematic use and 10 months of abstinence at the moment of participating in the study. Regarding common medical conditions associated with AUD, we observed an elevated incidence of alcohol-induced liver and pancreas diseases (18.7%) and psychiatric comorbidity (76.9%). Thus, AUD patients displayed a high prevalence of dual diagnosis (39.3%) [mainly depression (19.9%)] and comorbid substance use disorders (40.7%). Plasma BDNF and IGF-1 concentrations were significantly lower in the alcohol group than in the control group (p

Recent studies have linked changes in peripheral chemokine concentrations to the presence of both addictive behaviors and psychiatric disorders. The present study further explore this link by analyzing the potential association of psychiatry comorbidity with alterations in the concentrations of circulating plasma chemokine in patients of both sexes diagnosed with alcohol use disorders (AUD). To this end, 85 abstinent subjects with AUD from an outpatient setting and 55 healthy subjects were evaluated for substance and mental disorders. Plasma samples were obtained to quantify chemokine concentrations [C-C motif (CC), C-X-C motif (CXC), and C-X3-C motif (CX3C) chemokines]. Abstinent AUD patients displayed a high prevalence of comorbid mental disorders (72%) and other substance use disorders (45%). Plasma concentrations of chemokines CXCL12/stromal cell-derived factor-1 (p

La adicción al alcohol se asocia con una elevada comorbilidad psiquiátrica que complica el tratamiento, siendo necesaria una fenotipación clínica objetiva de estos pacientes para optimizar la atención y mejorar el pronóstico. El presente estudio aborda este problema mediante los siguientes objetivos: a) estimar la prevalencia y tipos de comorbilidad psiquiátrica de una muestra de pacientes que buscan tratamiento por uso de alcohol, b) describir las diferencias de género en su presentación y c) analizar los valores plasmáticos de 2-acilgliceroles (incluyendo el endocannabinoide 2-araquidonilglicerol), estudiando su posible valor como biomarcador de alcoholismo y/o comorbilidad psiquiátrica. Para ello se reclutaron 162 pacientes evaluados con la entrevista semiestructurada PRISM, para evaluar la presencia de comorbilidad y su carácter primario o inducido. Los resultados obtenidos indican que la presencia de psicopatología se asoció a un mayor número de criterios de abuso y dependencia de alcohol Se encontraron diferencias de género tanto en la comorbilidad psiquiátrica, especialmente en trastornos del estado de ánimo. La prevalencia de comorbilidad psiquiátrica encontrada a lo largo de la vida fue del 68,5%, destacando los trastornos del estado ánimo (37%), y seguidos por el trastorno por déficit de atención (24,7%, monitorizado específicamente por la entrevista WURS) y los trastornos de ansiedad (17,9%). Entre los trastornos del estado de ánimo y psicóticos fueron más frecuentes los inducidos, mientras que en los trastornos de ansiedad los primarios fueron más prevalentes. Además, se encontraron concentraciones disminuidas significativamente de 2-acilgliceroles en pacientes con trastornos de ansiedad comórbidos diagnosticados en el último año. Alcohol addiction is associated with high psychiatric comorbidity. Objective stratification of patients is necessary to optimize care and improve prognosis. The present study is designed to gain insights into this challenge by addressing the following objectives: a) to estimate the prevalence of psychiatric comorbidities in a sample of outpatients seeking treatment for alcohol use disorder, b) to describe the existence of gender differences and c) to validate 2-acyl-glycerols as biomarkers of alcohol use disorder and/or psychiatric comorbidity. One hundred and sixty-two patients were recruited and evaluated with the semi-structured interview PRISM. The presence of psychopathology was associated with a greater number of criteria for alcohol abuse and dependence according to DSM-IV-TR. We found gender differences in psychiatric comorbidity, e.g., mood disorder, as well as in comorbid substance use disorders. The prevalence of lifetime psychiatric comorbidity was 68.5%, with mood disorders the most frequent (37%), followed by attention deficit disorder (24.7%) and anxiety disorders (17.9%). Substance-induced disorders were more frequent in mood and psychotic disorders, whereas the primary disorders were more prevalent in patients with comorbid anxiety disorders. We found that 2-acyl-glycerols were significantly decreased in comorbid anxiety disorders in alcohol dependent patients in the last year, which makes them a potential biomarker for this psychopathological condition. El presente estudio ha sido financiado por Instituto de Salud Carlos III (ISC-III), Red de Trastornos Adictivos UE-FEDER 2012 (RD12/0028); Ministerio de Economía y Competitividad (PI13/02261); Plan Nacional sobre Drogas 049/2009 y 049/2013; Consejería de Economía, Innovación y Ciencia, Junta de Andalucía UE-FEDER (CTS-433); Consejería de Salud y Bienestar Social, Junta Andalucía (PI0228-2013 y PI0823-2012). Contratos “Miguel Servet” del Instituto de Salud Carlos III y Fondo Europeo de Desarrollo Regional FEDER/EU-ERDF (CP14/00212 y CP14/00173). Contrato “Río Hortega” del Instituto de Salud Carlos III (CM13/0115)

Cocaine use is significantly associated with psychiatric co-morbidities of which psychotic symptoms are the most typical. The primary goal of this study is to estimate the life-time prevalence of cocaine-induced psychotic symptoms (CIPS) in a sample of patients without a history of primary psychosis, who attended specific out-patient drug-dependence treatment centres (ODDTCs). This is an observational, cross-sectional design and a consecutive sampling technique. The Scale for Assessment of Positive Symptoms-Cocaine Induced Psychosis (SAPS-CIP) was used to interview 114 patients who request treatment at specific ODDTCs for problems related to cocaine use. Most patients, 89.5% (95% CIs: 83.8-95.2%) had dependence of cocaine and 84.2% (95% CIs: 77.5-90.9%) showed at least one CIPS. Patients with CIPS had used cocaine more times throughout their lives and had a more frequency of use during the period of higher abuse severity in the last year, had higher severity of dependence score and had fewer abstinence periods greater than 30 days compared with those without CIPS. Cocaine dependency severity scale scores were significantly greater in patients with CIPS compared with those without CIPS.

The treatment for cocaine use constitutes a clinical challenge because of the lack of appropriate therapies and the high rate of relapse. Recent evidence indicates that the immune system might be involved in the pathogenesis of cocaine addiction and its co-morbid psychiatric disorders. This work examined the plasma pro-inflammatory cytokine and chemokine profile in abstinent cocaine users (n = 82) who sought outpatient cocaine treatment and age/sex/body mass-matched controls (n = 65). Participants were assessed with the diagnostic interview Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Tumor necrosis factor-alpha, chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 and chemokine (C-X-C motif) ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) were decreased in cocaine users, although all cytokines were identified as predictors of a lifetime pathological use of cocaine. Interleukin-1 beta (IL-1β), chemokine (C-X3-C motif) ligand 1 (CX3CL1)/fractalkine and CXCL12/SDF-1 positively correlated with the cocaine symptom severity when using the DSM-IV-TR criteria for cocaine abuse/dependence. These cytokines allowed the categorization of the outpatients into subgroups according to severity, identifying a subgroup of severe cocaine users (9-11 criteria) with increased prevalence of co-morbid psychiatric disorders [mood (54%), anxiety (32%), psychotic (30%) and personality (60%) disorders]. IL-1β was observed to be increased in users with such psychiatric disorders relative to those users with no diagnosis. In addition to these clinical data, studies in mice demonstrated that plasma IL-1β, CX3CL1 and CXCL12 were also affected after acute and chronic cocaine administration, providing a preclinical model for further research. In conclusion, cocaine exposure modifies the circulating levels of pro-inflammatory mediators. Plasma cytokine/chemokine monitoring could improve the stratification of cocaine consumers seeking treatment and thus facilitate the application of appropriate interventions, including management of heightened risk of psychiatric co-morbidity. Further research is necessary to elucidate the role of the immune system in the etiology of cocaine addiction.