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Plasma acylethanolamides (NAEs), including the endocannabinoid anandamide (AEA), have been proposed as circulating biomarkers of substance use disorders. However, the concentration of these lipid transmitters might be influenced by the use of drugs prescribed for either the treatment of addiction or the associated psychiatric co-morbidities such as psychosis. As an example, neuroleptics, used for attenuation of psychotic symptoms and sedation, might theoretically interfere with the monoamine-mediated production of NAEs, obstructing the interpretation of plasma NAEs as clinical biomarkers. To solve the lack of information on the impact of neuroleptics on the concentration of NAEs, we evaluated the concentrations of NAEs in a control group and compared them to those present in (a) substance use disorders (SUD) patients that are not prescribed with neuroleptics, and (b) SUD patients (both alcohol use disorder and cocaine use disorder patients) using neuroleptics. The results demonstrate that SUD patients exhibited greater concentrations of NAEs than the control population, affecting all species with the exception of stearoylethanolamide (SEA) and palmitoleoylethanolamide (POEA). Neuroleptic treatment enhanced the concentrations of NAEs, especially those of AEA, linoleoylethanolamide (LEA), and oleoylethanolamide (OEA). This effect of neuroleptic treatment was observed independently of the drug addiction that motivated the demand for treatment (either alcohol or cocaine). This study remarks the need to control the current use of psychotropic medication as a potential confounding variable when considering the use of NAEs as biomarkers in SUD.

Background: Neurologic impairment persisting months after acute severe SARS-CoV-2 infection has been described because of several pathogenic mechanisms, including persistent systemic inflammation. The objective of this study is to analyze the selective involvement of the different cognitive domains, it impacts on quality of life and the possible existence of related biomarkers.Methods: Cross-sectional study of patients who survived severe infection with SARS-CoV-2 consecutively recruited from 13 neurology services in Spain between 90 and 120 days after hospital discharge. All patients underwent an exhaustive study of cognitive functions as well as plasma determination of pro-inflammatory factors (chemokines), and neurotrophic factors and light-chain neurofilaments. A Principal Component Analysis extracted the main independent characteristics of the syndrome.Results: 152 patients were recruited. The results of our study show a pattern of cognitive impairment with preferential involvement of episodic and working memory, executive functions, and attention and relatively less affectation of information processing speed, denomination, verbal fluency, and other cortical functions. In addition, psychiatric affectation such as anxiety and depression pictures are constant in our cohort. Several plasma chemokines concentrations were elevated compared with both, a non-SARS-Cov2 infected cohort of neurological outpatients or a control healthy general population, suggesting a pro-inflammatory chronic state derived of viral infection.Conclusion: The neurologic Subacute Impairment in severe Covid-19 consist in an amnesic and dysexecutive syndrome with neuropsychiatric manifestations. We do not know if the deficits detected can persist in the long term and, in this case, if this can trigger or accelerate the onset of neurodegenerative diseases.

For a long time, Substance Use Disorders (SUDs) were not considered a component in the etiology of dementia. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders introduced substance-induced neurocognitive disorders, incorporating this notion to clinical practice. However, detection and monitoring of neurodegenerative processes in SUD patients remain a major clinical challenge, especially when early diagnosis is required. In the present study, we aimed to investigate new potential biomarkers of neurodegeneration that could predict cognitive impairment in SUD patients: the circulating concentrations of Neurofilament Light chain protein (NfL) and Brain-Derived Neurotrophic Factor (BDNF). Sixty SUD patients were compared with twenty-seven dementia patients and forty healthy controls. SUD patients were recruited and assessed using the Psychiatric Research Interview for Substance and Mental (PRISM) and a battery of neuropsychological tests, including the Montreal Cognitive Assessment test for evaluation of cognitive impairment. When compared to healthy control subjects, SUD patients showed increases in plasma NfL concentrations and NfL/BDNF ratio, as well as reduced plasma BDNF levels. These changes were remarkable in SUD patients with moderate–severe cognitive impairment, being comparable to those observed in dementia patients. NfL concentrations correlated with executive function and memory cognition in SUD patients. The parameters “age”, “NfL/BDNF ratio”, “first time alcohol use”, “age of onset of alcohol use disorder”, and “length of alcohol use disorder diagnosis” were able to stratify our SUD sample into patients with cognitive impairment from those without cognitive dysfunction with great specificity and sensibility. In conclusion, we propose the combined use of NfL and BDNF (NfL/BDNF ratio) to monitor substance-induced neurocognitive disorder.

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

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.

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.

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.

Descripción de los objetivos Los trastornos por uso de alcohol (TUA) se relacionan con problemas cognitivos, específicamente con dificultades en funciones ejecutivas y memoria. El ácido lisofosfatídico (LPA) es un lípido bioactivo estrechamente vinculado a procesos de desarrollo neurológico. El objetivo consiste en evaluar cambios en niveles circulantes de las especies relevantes de LPA asociadas con las características clínicas y neuropsicológicas de los TUA. Material y métodos Un total de 55 pacientes con TUA en abstinencia que fueron evaluados clínica y cognitivamente y pareados en edad sexo e IMC con 34 controles sanos. Se cuantificaron las medias de LPA total, y de las siguientes especies: 16:0-, 18:0-, 18:1-, 18:2- y 20:4- y se compararon con medidas de factores de crecimiento asociados a neuroplasticidad: brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and -2 (IGF-2). Resultado y conclusiones Los pacientes con TUA mostraron síndrome disejecutivo (22,4%) y déficit en la memoria (32,6%). Las concentraciones plasmáticas de LPA total, 18:0- y 18:1-LPA estaban disminuidos en pacientes TUA comparados con el grupo control. El 22,4% de los pacientes TUA mostró déficit en funciones ejecutivas y un 32,6% déficits relacionados con la memoria. Las puntuaciones en tareas ejecutivas en pacientes con TUA correlacionan positivamente con las especies de LPA en plasma. Además, las concentraciones del LPA total y las especies LPA 18:2- y 20:4- correlacionaron positivamente con niveles plasmáticos de BDNF. Por el contrario, se encuentra correlación negativa entre IGF-1 y la mayoría de las especies LPA, así como entre IGF-2 y 18:1-. Estos resultados sugieren que los déficits cognitivos evaluados en los TUA pueden estar relacionados con la desregulación de especies LPA, especialmente 18:0- y 18:1-LPA. Se propone estudiar la relación entre 18:1-LPA y BDNF en plasticidad y neurogénesis en la búsqueda de marcadores biológicos de deterioro cognitivo.

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.