Abstract Alcohol Use Disorder (AUD) is a highly prevalent condition worldwide that produces a wide range of pathophysiological consequences, with a critical impact on health and social issues. Alcohol influences gene expression through epigenetic changes mainly through DNA methylation. In this sense, levels of 5-methylcytosine (5-mC), namely Global DNA methylation (GMe), which can be influenced by environmental and hormonal effects, represent a putative biological mechanism underlying alcohol effects. Our aim was to investigate the influence of AUD diagnosis and alcohol patterns (i.e., years of addiction, use in the last 30 days, and alcohol severity) on GMe levels. The sample consisted of 256 men diagnosed with AUD and 361 men without AUD. DNA samples from peripheral blood were used to assess GMe levels, measured through the levels of 5-mC using high-performance liquid chromatography. Results from multiple linear regression analysis indicated that the presence of AUD was associated with lower GMe levels (beta=-0.155, p=0.011). Other alcohol-related outcomes were not associated with DNA methylation. Our findings are consistent with the hypothesis that the impact of chronic and heavy alcohol use in GMe could be a potential mechanism mediating the multiple organ damages related to AUD. (AUD consequences issues sense 5methylcytosine methylcytosine 5 5mC, 5mC mC , (5-mC) GMe, (GMe) effects i.e., ie i e (i.e. addiction 3 days severity 25 36 highperformance high performance chromatography beta=0.155, beta0155 beta beta= 0.155, 0 155 (beta=-0.155 p=0.011. p0011 p p=0.011 . 011 p=0.011) alcoholrelated (5-mC (GMe i.e. (i.e 2 beta=0.155 beta015 0155 0.155 15 (beta=-0.15 p001 p=0.01 01 i.e beta=0.15 beta01 015 0.15 1 (beta=-0.1 p00 p=0.0 beta=0.1 beta0 0.1 (beta=-0. p0 p=0. beta=0. 0. (beta=-0 p=0 beta=0 (beta=- p= (beta= (beta

Abstract Introduction High rates of early hospital discharge are often observed in crack cocaine users and are related to adverse outcomes and increased public spending. This study evaluated clinical and sociodemographic factors associated with early treatment discharge among crack users. Methods The sample comprised 308 men diagnosed with crack cocaine use disorder (crack only), aged 18 to 65 years, admitted between 2013 and 2017 to a male-only hospital unit to treat substance use disorders. Sociodemographic and clinical data were obtained using the Addiction Severity Index, 6th version, and a Sociodemographic Questionnaire. Results Early discharge (within 7 days) was significantly associated with lack of own income, insufficient family support, being single, and recent homelessness. Regarding drug use, lower treatment retention was related to younger age of crack use onset, recent alcohol use, and nicotine use. Factors such as age, skin color, and educational level showed no relation to the outcome. Conclusion Our findings suggest that presence of characteristics verifiable at the time of admission may be related to crack users’ treatment retention. Identification of these factors can contribute to target interventions in order to improve treatment adherence in crack cocaine users. spending 30 only, only , only) 1 6 years 201 maleonly male disorders Index th version Questionnaire within days income support single homelessness onset color outcome 3 20 2

Abstract Introduction Consumption of substances has been associated with cognitive impairment. The Mini Mental State Examination (MMSE) is an easy-to-apply screening tool used to assess cognitive functions. Objectives To evaluate the cognitive performance of individuals with alcohol (AUD) and/or crack cocaine use disorder (CUD) and polysubstance use using the MMSE and to investigate the impact of substance use profile and the moderation effect of educational level on MMSE performance. Methods Cross-sectional study with 508 adult male inpatients diagnosed with substance use disorders (245 with AUD, 85 with CUD, and 178 with polysubstance use). Cognitive performance was assessed using the MMSE scale (total and composite scores). Results Individuals with AUD had worse total MMSE scores and scored worse for all three MMSE components compared to individuals with polysubstance use (p < 0.001, oral/written language comprehension, p < 0.001, attention/memory, and p = 0.007, motor functions). MMSE scores were positively correlated with educational level (p < 0.017), but were not associated with age, recent drug use, or years of drug use. Educational level moderated the impact of substance use on MMSE performance, especially total score and composite language comprehension score. Individuals with a low educational level (≤ 8 years) had worse performance than those with a high educational level (≥ 9 years), mainly in individuals with AUD (p < 0.001). Discussion Individuals with a low educational level and alcohol use are more prone to present cognitive impairment than crack cocaine users, especially involving language aspects. Better-preserved cognitive function could impact treatment adherence and might guide the decision of therapeutic strategies. (MMSE easytoapply easy apply functions (AUD andor CUD (CUD Crosssectional Cross sectional 50 245 (24 17 . use) scores. scores) 0001 0 001 0.001 oralwritten oral written attentionmemory attention memory attention/memory 0007 007 0.007 functions) 0.017, 0017 0.017 , 017 0.017) age ≤ ( ≥ years, 0.001. 0.001) users aspects Betterpreserved Better preserved strategies 5 24 (2 1 000 00 0.00 0.01 01 2 0.0 0.

Abstract Objectives To assess alcohol use and perceived change in alcohol consumption (before and during the pandemic) in Brazilians during the COVID-19 pandemic, their correlates, and their associations with depressive, anxiety and co-occurring depressive and anxiety symptoms (D&A). Methods This is a cross-sectional study comprising 992 individuals in self-isolation. A self-report questionnaire was used to assess whether participants were drinking during self-isolation and whether they changed their drinking behavior (drinking less, more, or no change) from before to during the pandemic. D&A symptoms were assessed using the Beck Depression and Anxiety Inventories (BDI and BAI). Results A total of 68.5% of participants reported alcohol consumption during the pandemic, and 22.7% of these reported increased alcohol use. Smoking was positively associated with alcohol consumption during the pandemic. Alcohol consumption was associated with anxiety (OR = 1.40, 95%CI 1.06-1.85, p < 0.01) and D&A (OR = 1.38, 95%CI 1.02-1.87, p = 0.033) symptoms. Conclusions Drinking during self-isolation was prevalent and was associated with risk factors for alcohol use disorders. The long-term effects of high drinking rates and increased consumption should be proactively monitored and assessed. pandemic COVID19 COVID 19 COVID-1 correlates cooccurring co occurring D&A. DA . D (D&A) crosssectional cross sectional 99 selfisolation. selfisolation self isolation. isolation selfreport report less more BDI BAI. BAI BAI) 685 68 5 68.5 227 22 7 22.7 OR 140 1 40 1.40 95CI CI 95 1.061.85, 106185 1.06 1.85, 06 85 1.06-1.85 0.01 001 0 01 138 38 1.38 1.021.87, 102187 1.02 1.87, 02 87 1.02-1.87 0.033 0033 033 disorders longterm long term COVID1 COVID- (D&A 9 6 68. 2 22. 14 4 1.4 061 1.061.85 10618 106 1.0 185 1.85 8 1.06-1.8 0.0 00 13 3 1.3 021 1.021.87 10218 102 187 1.87 1.02-1.8 0.03 003 03 1. 1.061.8 1061 10 18 1.8 1.06-1. 0. 1.021.8 1021 1.02-1. 1.061. 1.06-1 1.021. 1.02-1 1.061 1.06- 1.021 1.02-

Objectives: To compare suicide rates observed in Brazil after the onset of the COVID-19 pandemic with the estimated rate based on suicide deaths between 2010 and 2020, and identify sociodemographic variables associated with this outcome. Methods: Ecological time-series study. Data were obtained from Brazilian Unified Health System Department of Information Technology (DATASUS), with the structural break of the data set in March 2020. The number of actual suicides observed and the number of expected suicides if there were no COVID-19 pandemic were analyzed through bayesian structural time series modeling. Results: The overall incidence of suicides in Brazil remained stable after the start of the COVID-19 pandemic compared to what would be expected. However, there was a significant increase in suicide deaths among women (6.9%) and older adult (9.1%). Analysis by macro-regions of the country showed significant increases in suicide deaths in the Center-West (7.4%), Northeast (5.7%), and Southeast (10%). Stratified analyses revealed differences according to age, sex, education, and skin color. Conclusions: Despite stability in the overall number of suicides, this phenomenon occurs heterogeneously among different population groups and regions of Brazil. Rates have increased in populations with a history of poor access to health, which may have been more severely impacted by the pandemic.

Objective: This study aimed to evaluate whether progression from first drug use to crack-cocaine use differs according to gender, and whether the report of sexual or physical violence impacts the time of progression. Methods: We interviewed 896 crack-cocaine users (548 men; 348 women) from addiction treatment units. Cox regression models evaluated the time of progression from first drug use to crack use. We analyzed gender differences according to the absence or presence of sexual or physical violence, also considering whether violence, when present, had occurred before or after the onset of crack use. Results: Women presented a faster progression to crack use regardless of exposure to sexual or physical violence (p < 0.05). Compared to unexposed men, there was a similar progression for men exposed to sexual or physical violence before the first use of crack (p = 0.167 and p = 0.393, respectively). In both genders, we observed a faster progression among individuals exposed to these types of violence after the onset of crack use (p < 0.01). Conclusions: We found a faster progression to crack use among women and among individuals exposed to sexual and physical violence after the onset of crack use. These results encourage differentiated treatment strategies, focused on gender and individual characteristics.

Objective: To assess differences in blood inflammatory cytokines between people with alcohol use disorder (AUD) and healthy controls (HC). Methods: Searches were performed from inception through April 14, 2021. Meta-analyses with random-effects models were used to calculate the standardized mean difference ([SMD], 95%CI), and potential sources of heterogeneity were explored trough meta-regressions and subgroup analysis. Results: The meta-analysis included 23 studies on the following 14 cytokines: tumor necrosis factor (TNF)-α, IL-1, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL15, interferon (IFN)-γ and sCD14. There were significantly higher concentrations of IL-6 (n=462 AUD and 408 HC; SMD = 0.523; 95%CI 0.136-0.909; p = 0.008) in AUD than HC. No significant differences were found in the other 13 cytokines. Conclusion: We found that IL-6 levels were significantly higher in individuals with AUD than HC and that other cytokines were not altered. This can be explained by the small number of studies, their methodological heterogeneity, and confounding factors (active use, abstinence, quantity, and physical or psychiatric illnesses, for example). Despite a great deal of evidence about alcohol and inflammatory diseases, studies assessing the role of neuroimmune signaling in the development and severity of AUD are still lacking.

Objective: To compare the prevalence and subtypes of childhood maltreatment (CM) between individuals with and without substance use disorder (SUD) and investigate the influence of different traumas on the preferential use of substances and the severity of dependence. Methods: The sample consisted of 1,040 men with SUD (alcohol users [n=315], crack-cocaine users [n=406], multiple-substance users [n=319]) and 201 controls. The Childhood Trauma Questionnaire (CTQ) and the Addiction Severity Index-6 (ASI-6) were used to assess CM and drug-use patterns. Results: Individuals with SUD had a higher prevalence of CM than controls (63.4 vs. 28.1%, respectively). Exposure to physical trauma was associated with alcohol use disorder and severity of alcohol use. In contrast, emotional trauma was associated with use of multiple substances and severity of drug use in crack-cocaine users. Conclusions: This study corroborates the association of CM with SUD susceptibility. Our results suggest that the type of CM may influence preferential substance use and addiction severity. In this sense, physical traumas are more associated with alcohol use, while emotional and sexual traumas favor use of multiple drugs, especially crack cocaine. These findings may help the development of tailored prevention and intervention strategies.

Abstract Introduction Changes in brain-derived neurotrophic factor (BDNF) have been linked to the neuroadaptative consequences of chronic alcohol use and associated with disease severity and prognosis. Few studies have evaluated the influence of drug withdrawal and clinical and sociodemographic data on BDNF levels in severe alcohol users. Objectives Our goals were (1) to evaluate variation in BDNF levels during alcohol withdrawal and, (2) to assess the influence of putative confounding factors on BDNF levels. Methods Our sample consists of 62 men with alcohol use disorder undergoing a detoxification process. Serum BDNF levels were measured using a commercial sandwich-ELISA kit, at two points: before and after the detoxification period. Results We found an increase in BDNF levels during alcohol withdrawal (25.4±9.6 at admission vs. 29.8±10.2 ng/ml at discharge; p < 0.001), even after controlling for potential confounders (positive family history, number of days between blood sample collections, and age) (Generalized Estimating Equation: coefficient = -4.37, 95% confidence interval [95%CI] -6.3; -2.4; p < 0.001). Moreover, individuals who had first-degree relative with alcohol dependence had smaller increases in BDNF levels than individuals with no family history (14.8 [95%CI -5.3; 35.6] vs. 35.3 [95%CI 15.4; 74.8]; p = 0.005). Conclusions In summary, variation in BDNF levels seems to be influenced by withdrawal in severe alcohol users. A positive family history of alcohol dependence could also be a factor that influences variation in this biomarker.

Abstract The COVID-19 pandemic is unquestionably impacting on the mental health of the population worldwide. Fear of contamination can both increase levels of stress in healthy individuals and intensify psychiatric symptoms in patients with pre-existing conditions, especially obsessive-compulsive disorder (OCD). During the COVID-19 pandemic, the imminent risk of contamination creates a logical need for self-surveillance and hygiene habits. However, this kind of information can have drastic implications for subjects with OCD, since cognitive distortions and compensatory strategies (cleansing rituals) are no longer irrational or oversized – rather, these ideas become legitimate and socially accepted, generating plausible validation for the intensification of compulsive cleaning rituals. Patients who presented remission of OCD symptoms would be more likely to have a relapse, and subclinical patients may scale up and ultimately be diagnosed with OCD due to the reinforcement of their habits, emotions and thoughts.

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.

Abstract Introduction Drug-related crimes, especially drug trafficking, account for a large part of incarcerations not only in Brazil, but also worldwide. It is not clear whether the change in the drug law has contributed to the increase in the number of drug trafficking prisoners. Few studies have investigated gender differences and the growth of drug trafficking offenses in the Brazilian southern state of Rio Grande do Sul. Objective To investigate the growth of the prison population in the state of Rio Grande do Sul, emphasizing incarcerations for drug trafficking and gender differences. Method This was an ecological study using secondary data collected from official databases of the Brazilian National Penitentiary Department (Departamento Penitenciário [DEPEN]), affiliated with the Brazilian Ministry of Justice. Results Between 2006 and 2015, incarcerations increased by 27% (25% men, 83% women). Incarcerations for drug trafficking accounted for 11% of total arrests in 2006 (11% men, 20% women) and 45% in 2015 (47% men, 91% women), corresponding to an increase of 427% (415% among men, 723% among women). Conclusions Imprisonment for drug trafficking has increased considerably, especially among women. This may be due to factors such as: increase of drug trafficking, increase in the numbers of gangs in the state, and changes in the Brazilian drug law. These results highlight an emerging challenge in public health from the perspective of human rights and gender.

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.