Antioxidants Supplementation in Acute Amitriptyline Abuse for Pain.

The fundamental aim of this study is to establish the role of antioxidant supplementation in alleviating acute amitriptyline induced oxidative stress. The effect of supplementation was compared on treatment of acute amitriptyline intoxication cases for pain management, with alpha lipoic acid (ALA) alone or with vitamin C, with that of healthy individuals (group I), and those receiving only routine standard treatment (RST) as control (group II). A total of 132 human subjects divided into 5 groups were supplemented with either placebo, RST, RST with vitamin C, RST with ALA, or RST with vitamin C, and ALA. Results of this study revealed that the decrease in the level of oxidative stress and enzyme activity was observed among those supplemented with either alpha lipoic acid alone or along with vitamin C, with a slightly more decrease in the latter group. P value of < 0.001 was considered statistically significant. The percentage of benefit of treatment on supplementation with vitamin C and alpha lipoic acid showed a marked increase in group V cases after supplementation with both in combination. The results provided that the oxidative stress induced by acute amitriptyline poisoning is comparatively decreased by supplementation with antioxidants like alpha lipoic acid and vitamin C, than those only on routine standard treatment.

Improvements in Toxicology Testing to Identify Fentanyl Analogs and Other Novel Synthetic Opioids in Fatal Drug Overdoses, Connecticut, January 2016-June 2019.

OBJECTIVES: Drug overdose deaths in Connecticut increasingly involve a growing number of fentanyl analogs and other novel nonfentanyl synthetic opioids (ie, novel synthetics). Current postmortem toxicology testing methods often lack the sophistication needed to detect these compounds. We examined how improved toxicology testing of fatal drug overdoses can determine the prevalence and rapidly evolving trends of novel synthetics. METHODS: From 2016 to June 2019, the Connecticut Office of the Chief Medical Examiner increased its scope of toxicology testing of suspected drug overdose deaths in Connecticut from basic to enhanced toxicology testing to detect novel synthetics. The toxicology laboratory also expanded its testing panels during this time. We analyzed toxicology results to identify and quantify the involvement of novel synthetics over time. RESULTS: From 2016 to June 2019, 3204 drug overdose deaths received enhanced toxicology testing; novel synthetics were detected in 174 (5.4%) instances. Ten different novel synthetics were detected with 205 total occurrences. Of 174 overdose deaths with a novel synthetic detected, most had 1 (n = 146, 83.9%) or 2 (n = 26, 14.9%) novel synthetics detected, with a maximum of 4 novel synthetics detected. Para-fluorobutyrylfentanyl/FIBF, furanylfentanyl, and U-47700 were most identified overall, but specific novel synthetics came in and out of prominence during the study period, and the variety of novel synthetics detected changed from year to year. CONCLUSIONS: Enhanced toxicology testing for drug overdose deaths is effective in detecting novel synthetics that are not identified through basic toxicology testing. Identifying emerging novel synthetics allows for a timely and focused response to potential drug outbreaks and illustrates the changing drug market.

The Relationships between HIV-1 Infection, History of Methamphetamine Use Disorder, and Soluble Biomarkers in Blood and Cerebrospinal Fluid.

Methamphetamine (METH) use disorder is highly prevalent among people with HIV (PWH) and is a significant public health problem. HIV and METH use are each associated with immune system dysfunction; however, the combined effects on the immune system are poorly understood. This cross-sectional project measured soluble immune biomarkers in plasma and cerebrospinal fluid (CSF) collected from a control group, people with a history of a METH use disorder (METH+), PWH with no history of METH use disorder (HIV+), and PWH with a history of METH use disorder (HIV+/METH+). HIV, METH, and immune dysfunction can also be associated with affective and cognitive deficits, so we characterized mood and cognition in our participants. Two factor analyses were performed for the plasma and CSF biomarkers. Plasma IL-8, Ccl2, VEGF, and 8-isoprostane loaded onto one factor that was highest in the HIV+/METH+ group (p < 0.047) reflecting worse inflammation, vascular injury, and oxidative stress. This plasma factor was also negatively correlated with delayed recall (R = -0.49, p = 0.010), which was worst in the HIV+/METH+ group (p = 0.030 compared to the control group). Overall, these data implicate that combined HIV-1 infection and METH use may exacerbate inflammation, leading to worse cognition.

Increased Nectin-4 levels in chronic ketamine abusers and the relationship with lower urinary tract symptoms.

Persistent ketamine use causes susceptibility to addiction and bladder toxicity. We examined the association of lower urinary tract symptoms and levels of Nectin-4, a member of the cell adhesion molecules that is essential for maintaining the urothelium barrier in chronic ketamine abusers. We measured the plasma levels of Nectin-4 in 88 patients with ketamine dependence and 69 controls. Patients with ketamine dependence were assessed for ketamine use variables, psychological symptoms, and lower urinary tract symptoms. We found Nectin-4 levels were increased in ketamine-dependent patients compared to the controls (p < 0.0001). Patients with urinary tract symptoms exhibited lower Nectin-4 levels than those without (p = 0.021). Our results suggest an up-regulation of Nectin-4 following chronic and heavy ketamine use. Patients with ketamine dependence with a compromised upregulation of Nectin-4 are likely to have more severe urinary tract symptoms. The mechanisms underlying the involvement of Nectin-4 in ketamine addiction and bladder toxicity warrant future investigation.

Plasma concentrations of granulocyte colony-stimulating factor (G-CSF) in patients with substance use disorders and comorbid major depressive disorder.

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 < 0.001) but not in the patients with MDD. G-CSF concentrations were lower in patients with SUD than in controls (p < 0.05), specifically in the cocaine subgroup (p < 0.05). Patients with SUD and comorbid MDD had lower G-CSF concentrations than patients with SUD but not comorbid MDD or controls (p < 0.05). In contrast, patients with MDD but not SUD showed no differences compared with their controls. The negative association between G-CSF concentrations and age in the sample was not observed in patients with MDD. G-CSF concentrations were decreased in patients with SUD and comorbid MDD but not in patients with MDD. Therefore, G-CSF may be useful to improve the stratification of patients with dual diagnosis seeking treatment. Further investigation is needed to explore the impact of sex and type of drug on the expression of G-CSF.

Association of urinary ketamine and APOA1 levels with bladder dysfunction in ketamine abusers revealed via proteomics and targeted metabolite analyses.

Chronic ketamine abuse is associated with bladder dysfunction and cystitis. However, the effects of ketamine abuse on the urinary proteome profile and the correlations among urinary proteins, urinary ketamine (and metabolites) and clinicopathological features of ketamine-induced bladder dysfunction remain to be established. Here, we recruited 56 ketamine abusers (KA) and 40 age-matched healthy controls (HC) and applied the iTRAQ-based proteomics approach to unravel quantitative changes in the urine proteome profile between the two groups. Many of the differentially regulated proteins are involved in the complement and coagulation cascades and/or fibrotic disease. Among them, a significant increase in APOA1 levels in KA relative to control samples (392.1 ± 59.9 ng/ml vs. 13.7 ± 32.6 ng/ml, p < 0.0001) was detected via ELISA. Moreover, urinary ketamine, norketamine and dehydronorketamine contents (measured via LC-SRM-MS) were found to be positively correlated with overactive bladder syndrome score (OABSS) and APOA1 levels with urinary RBC, WBC, OABSS and numeric pain rating scale in KA. Collectively, our results may aid in developing new molecular tool(s) for management of ketamine-induced bladder dysfunction. Moreover, information regarding the differentially regulated proteins in urine of KA provides valuable clues to establish the molecular mechanisms underlying ketamine-induced cystitis.

The 5-HT2C receptor as a therapeutic target for alcohol and methamphetamine use disorders: A pilot study in treatment-seeking individuals.

Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5-HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10-mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment-emergent events, incidence of methamphetamine or alcohol withdrawal-related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self-reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self-reported alcohol and amphetamine-type substance use and craving in AUD and MUD participants, respectively. Self-reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5-HT2C receptors as a therapeutic target for drug and alcohol abuse.

Plasma C-reactive protein is lower among marijuana using HIV-negative individuals but not among persons living with HIV.

The use of marijuana is highly prevalent among young men who have sex with men (YMSM). Past work has also shown that inflammation is elevated among YMSM, independent of HIV status. Here, we aim to examine the relationship between marijuana use and inflammation among this high-risk cohort, relative to use of other substances. Data were collected among YMSM aged 16-29 in Chicago. Multiplex cytokine and inflammatory biomarker assays were run on plasma from all persons living with HIV (PLWH) (n = 195) and a subset of HIV-negative participants (n = 489). Bivariate analyses and multivariable models assessed relationships between various substances and inflammatory biomarkers. Models were stratified by HIV status and adjusted for demographic characteristics. Most participants reported use of marijuana in the past 30 days (416, 60.8%). Mean blood C-reactive protein (CRP) levels were above the upper limit of normal (3.0 mg/L), indicative of increased risk for cardiovascular disease (mean CRP was 3.9 mg/L; SD = 8.5). In adjusted, stratified analyses, CRP was significantly lower among participants reporting frequent marijuana use (≥ 6 times per month), relative to those reporting never using marijuana, (ß = - 0.38; 95% CI: - 0.73, - 0.03). However, this was entirely accounted for by an association among the HIV-negative participants and there was no significant association between marijuana use and blood CRP level among the PLWH. In summary, YMSM had markedly elevated marijuana use and blood CRP levels. Frequent marijuana use was associated with lower inflammation among only those not diagnosed with HIV. Further research is needed to explicate why there are differences between HIV-negative participants and PLWH and to leverage this information to characterize biological mechanisms by which marijuana decreases inflammation.

Sex differences in circulating inflammatory mediators as a function of substance use disorder.

BACKGROUND: Substance use disorders (SUD) with comorbid depression and anxiety are linked to poor treatment outcome and relapse. Although some depressed individuals exhibit elevated blood-based inflammation (interleukin-6 [IL-6] and C reactive protein [CRP]), few studies have examined whether the presence of SUD exacerbates inflammation. METHODS: Treatment-seeking individuals with major depressive disorder (MDD), anxiety disorders, and/or SUD (N = 160; 80 % with MDD) recruited into the Tulsa 1000 study provided blood samples, participated in clinical interviews, and completed a questionnaire battery querying symptoms of current psychopathology and emotional processing. Analyses followed a multistep process. First, groups were created on the presence versus absence of 1+ lifetime SUD diagnoses: SUD+ (37 F, 43 M) and SUD- (60 F, 20 M). Second, a principal component analysis (PCA) of questionnaire data resulted in two factors, one indexing negative emotionality/withdrawal motivation and one measuring positive emotionality/approach motivation. Third, SUD groups, extracted PCA factors, and nuisance covariates (age, body mass index [BMI], nicotine use, psychotropic medication [and hormone/contraception use in females]) were entered as simultaneous predictors of blood-based inflammation (IL-6, IL-8, IL-10, tumor necrosis factor-α, and CRP). RESULTS: Within females, SUD + exhibited higher IL-8 and IL-10 but lower CRP levels than SUD-. In contrast, SUD was not associated with biomarker levels in males. Across sexes, higher BMI was linked to higher IL-6 and CRP levels, and within the five biomarkers, IL-6 and CRP shared the most variance. CONCLUSION: These findings point to sex-specific inflammatory profiles as a function of SUD that may provide new targets for intervention.

Effect of Anabolic-Androgenic Steroid Abuse on the Contact Activation System.

The effect of anabolic-androgenic steroid (AAS) abuse on the contact activation system (CAS) is not known in detail. We hypothesized that current AAS abuse reduces the kallikrein-generating capacity of CAS significantly and investigated the impact of AAS on the proteins and capacity of CAS in current and former AAS abusers and healthy age-matched controls. Men 18 to 50 years of age were included as current AAS abusers, former AAS abusers, or controls. Blood samples were collected after overnight fasting. Kallikrein generation (lag time, peak height, and endogenous kallikrein potential [EKP]), coagulation factor XII (FXII), prekallikrein, high-molecular-weight kininogen (HK), and Complement C1 esterase inhibitor (C1inh) were assessed. Groups were compared by analysis of variance or Kruskal-Wallis test and probabilities were corrected for multiple comparisons. Associations were evaluated by linear regression models. The EKP was significantly reduced in current (n = 37) AAS abusers (984 ± 328 nmol/L × min) compared with former (n = 33) abusers (1,543 ± 481 nmol/L × min) and controls (n = 30) (1,521 ± 339 nmol/L × min), p < 0.001. Current abusers had higher levels of FXII and C1inh and lower levels of prekallikrein and HK than controls, p ≤ 0.025. Stepwise regression analysis showed that EKP was associated with C1inh and prekallikrein in current AAS abusers, R 2 = 0.70, p < 0.001. We conclude that current AAS abuse reduces the kallikrein-generating capacity of CAS by increasing the concentration of C1inh and reducing the concentration of prekallikrein. These changes may contribute to the anti-inflammatory effect of testosterone.

Epigenome-wide analysis uncovers a blood-based DNA methylation biomarker of lifetime cannabis use.

Cannabis use is highly prevalent and is associated with adverse and beneficial effects. To better understand the full spectrum of health consequences, biomarkers that accurately classify cannabis use are needed. DNA methylation (DNAm) is an excellent candidate, yet no blood-based epigenome-wide association studies (EWAS) in humans exist. We conducted an EWAS of lifetime cannabis use (ever vs. never) using blood-based DNAm data from a case-cohort study within Sister Study, a prospective cohort of women at risk of developing breast cancer (Discovery N = 1,730 [855 ever users]; Replication N = 853 [392 ever users]). We identified and replicated an association with lifetime cannabis use at cg15973234 (CEMIP): combined p = 3.3 × 10-8 . We found no overlap between published blood-based cis-meQTLs of cg15973234 and reported lifetime cannabis use-associated single nucleotide polymorphism (SNPs; p < .05), suggesting that the observed DNAm difference was driven by cannabis exposure. We also developed a multi-CpG classifier of lifetime cannabis use using penalized regression of top EWAS CpGs. The resulting 50-CpG classifier produced an area under the curve (AUC) = 0.74 (95% CI [0.72, 0.76], p = 2.00 × 10-5 ) in the discovery sample and AUC = 0.54 ([0.51, 0.57], p = 2.87 × 10-2 ) in the replication sample. Our EWAS findings provide evidence that blood-based DNAm is associated with lifetime cannabis use.

Perfil toxicológico dos suicídios no Rio Grande do Sul, Brasil, 2017 a 2019 / Perfil toxicológico de los casos de suicidio en Rio Grande do Sul (Brasil), 2017-2019 / Toxicology of suicide cases in the state of Rio Grande do Sul, Brazil, 2017 to 2019

RESUMO Objetivo. Descrever o perfil toxicológico de todas as vítimas de suicídio no Rio Grande do Sul, Brasil, de 2017 a 2019. Métodos. Neste estudo descritivo e transversal, foram consultados todos os laudos periciais e as ocorrências policiais relacionados aos óbitos por suicídio no estado. Foram realizadas análises de correspondência múltipla e construídos modelos independentes de regressão logística, tendo como variáveis dependentes o etanol, os ansiolíticos, os antidepressivos, as substâncias ilícitas e os agentes tóxicos não medicamentosos. Resultados. Foram realizados 2 978 exames de alcoolemia, com resultado positivo em 28,5%. A chance de resultados positivos para alcoolemia foi 0,5 (IC95%: 1,1 a 2,2) vez maior para suicídio durante a noite, 1,0 (IC95%: 1,4 a 2,9) vez maior para suicídio aos finais de semana e 0,9 (IC95%: 1,3 a 2,7) vez maior na presença de antecedentes criminais. A pesquisa de psicotrópicos (2 900 amostras) detectou algum medicamento em 30,4%. Os ansiolíticos foram a classe mais frequente, com chance 1,5 (IC95%: 1,6 a 4,1) vez maior em mulheres e 0,8 (IC95%: 1,2 a 2,7) vez maior para suicídios ocorridos no outono-inverno. As substâncias ilícitas (n = 338) tiveram chance 4,1 (IC95%: 1,9 a 14,4) vezes maior de detecção na macrorregião de Pelotas em relação à de Passo Fundo e 1,2 (IC95%: 1,3 a 3,6) vez maior em pessoas com resultados positivos para etanol. Não houve diferença significativa entre adolescentes e adultos. Conclusões. Embora sem evidência de causalidade, os resultados mostram um vínculo entre o suicídio e diversos psicoativos. Os médicos legistas devem ser orientados quanto à necessidade de realização de exames toxicológicos em todos os casos de suicídio.

ABSTRACT Objective. To describe the toxicology of suicide cases recorded in the state of Rio Grande do Sul, Brazil, from 2017 to 2019. Method. The present descriptive, cross-sectional study examined all the medico-legal reports and police records related to suicide deaths in the state. Multiple correspondence analyses were performed along with independent logistic regression models having ethanol, anxiolytic and antidepressant drugs, illicit drugs, and non-medical substances as dependent variables. Results. Ethanol was investigated in 2 978 samples, with positive results in 28.5%. The odds of a positive ethanol finding were 0.5 time higher (95%CI: 1.1; 2.2) for suicides occurring at night, 1.0 (95%CI: 1.4; 2.9) time higher for suicides occurring on weekends, and 0.9 (95%CI: 1.3; 2.7) time higher in individuals with a prior criminal record. Investigation of psychotropic drugs (2 900 samples) was positive in 30.4% samples. Anxiolytics were the most common medication detected, with 1.5 (95%CI: 1.6; 4.1) time higher odds of occurrence in women and 0.8 time higher odds (95%CI: 1.2; 2.7) for suicides occurring in the fall-winter. The odds of detecting illicit drugs (n = 338) were 4.1 times higher (95%CI: 1.9; 14.4) in the regions of Pelotas (south of the state) vs. Passo Fundo (north), and 1.2 (95%CI: 1.3; 3.6) time higher in cases with positive ethanol results, without significant difference between adolescents and adults. Conclusions. Despite the lack of evidence on causality, the present results support a link between suicide and several psychoactive drugs. Medico-legal experts should be guided regarding the need to perform toxicological tests in all suicide cases.

RESUMEN Objetivo. Describir el perfil toxicológico de todas las víctimas de suicidio en Rio Grande do Sul desde el 2017 hasta el 2019. Métodos. En este estudio descriptivo y transversal se consultaron todos los informes periciales y policiales sobre las muertes por suicidio en el estado. Se realizaron análisis de correspondencia múltiple y se crearon modelos independientes de regresión logística, con empleo de etanol, productos ansiolíticos y antidepresivos, sustancias ilícitas y agentes tóxicos no medicamentosos como variables dependientes. Resultados. Se realizaron 2 978 exámenes de alcoholemia, con resultado positivo en un 28,5%. La probabilidad de obtener resultados positivos para alcoholemia aumentó 0,5 (IC95%: 1,1-2,2) en casos de suicidio durante la noche, 1,0 (IC95%: 1,4-2,9) en casos de suicidio en los fines de semana y 0,9 (IC95%: 1,3-2,7) cuando había antecedentes penales. En la investigación de productos psicotrópicos (2 900 muestras) se detectó algún medicamento en un 30,4%. Los ansiolíticos fueron la clase detectada con más frecuencia, con un aumento de la probabilidad de 1,5 (IC95%: 1,6-4,1) en las mujeres y de 0,8 (IC95%: 1,2-2,7) en casos de suicidio durante el otoño y el invierno. El aumento de la probabilidad de detección de sustancias ilícitas (n = 338) fue de 4,1 (IC95%: 1,9-14,4) en la macrorregión de Pelotas en comparación con la de Passo Fundo y de 1,2 (IC95%: 1,3-3,6) en personas con resultados positivos en la prueba de detección de etanol, sin que hubiera ninguna diferencia significativa entre adolescentes y adultos. Conclusiones. Aun sin haberse comprobado la causalidad, los resultados muestran que existe un vínculo entre el suicidio y diversos productos psicoactivos. Es preciso orientar a los médicos legistas con respecto a la necesidad de realizar exámenes toxicológicos en todos los casos de suicidio.

The effect of maternal alcohol and drug abuse on first trimester screening analytes: a retrospective cohort study.

BACKGROUND: The purpose of this study was to determine whether first trimester trisomy screening (FTS) parameters are affected by alcohol and drug use. METHODS: A routine combined FTS including measurements of maternal serum levels of free ß-human chorionic gonadotropin subunit (free ß-hCG) and pregnancy-associated plasma protein A (PAPP-A) were measured at 9-11 weeks of gestation, and fetal nuchal translucency thickness (NTT) at 11-13 weeks of gestation. In total 544 women with singleton pregnancies [71 alcohol and drug abusers, 88 smokers, 168 non-smokers delivering a small for gestational age (SGA) child, and 217 unexposed control women] were assessed. RESULTS: Free ß-hCG levels were higher in alcohol and drug abusing than in unexposed pregnant women [mean 1.5 vs. 1.2 multiples of medians (MoM); P = 0.013]. However, stepwise multiple linear regression analyses suggested that smoking could explain increased free ß-hCG. Additionally, we observed lower PAPP-A levels in the smoking mothers (0.9 vs. 1.2 MoM; P = 0.045) and in those giving birth to an SGA child compared to the controls (1.1 vs.. 1.2 MoM; P < 0.001). Fetal NTT did not differ significantly between any of the groups. CONCLUSIONS: The present study shows increased free ß-hCG levels in alcohol and drug abusers, but maternal smoking may explain the result. Maternal serum PAPP-A levels were lower in smoking than non-smoking mothers, and in mothers delivering an SGA child. However, FTS parameters (PAPP-A, free ß-hCG and NTT) seem not to be applicable for the use as alcohol biomarkers because of their clear overlap between alcohol abusers and healthy controls.

Professional perception of clozapine use in patients with dual psychosis.

INTRODUCTION: Patients with psychotic disorders often have substance use disorders and other addictions. The objective of this study was to know the current treatment situation of these patients focusing on clozapine, which was proposed in most consensus as antipsychotic of first choice in this indication. MATERIAL AND METHODS: A survey with 14 questions on aspects related to the treatment and management of the dual disorders was developed, emphasizing the role of clozapine in this disease. RESULTS: The survey was answered by 199 experts in mental illnesses (90.5% physicians and 9.5% psychologists). A total of 88.4% of experts were able to prescribe clozapine, but the majority (89.4%) administered the drug to patients with resistant schizophrenia without considering a dual disorder. Only 30.8% considered the use of clozapine in patients with dual psychosis. The underutilization of clozapine in these patients was mainly attributed to controls of the pharmacovigilance plan, including frequent leukocyte count (57.1%), and lack of drug education (35.6%). The main measures proposed to increase its use are fewer blood tests (29.3%), more training (27.8%), and fewer administrative problems (25.1%). CONCLUSIONS: In order to improve the treatment of patients with dual psychosis, it is necessary to simplify the therapy and increase the training of professionals in the use of atypical antipsychotics, especially clozapine, designed to be the drug of choice in the main expert consensus.

Aspiration in lethal drug abuse-a consequence of opioid intoxication.

AIMS: The primary objective of this study was to investigate whether the fatalities of opioid abuse are not only related to respiratory depression but also as a result of other side effects such as emesis, delayed gastric emptying, a reduction of the cough reflex, and impaired consciousness leading to the aspiration of gastric contents, a finding regularly observed in drug-related deaths. DESIGN: A retrospective exploratory study analyzing heroin/morphine/methadone-related deaths submitted to court-ordered autopsy. SETTING: Center for Forensic Medicine, Medical University of Vienna, Austria (2010-2015). PARTICIPANTS: Two hundred thirty-four autopsy cases were included in the study: morphine (n = 200), heroin (n = 11), and methadone (n = 23) intoxication. FINDINGS: Analyses revealed that 41.88% of all deceased showed aspiration of gastric contents with equal gender distribution (p = 0.59). Aspiration was more frequent in younger deceased (χ2 = 8.7936; p = 0.012) and in deceased with higher body mass index (BMI) (χ2 = 6.2441; p = 0.044). Blood opioid concentration was lower in deceased with signs of aspiration than in non-aspirators (p = 0.013). Toxicological evaluation revealed a high degree of concomitant substance abuse (91%)-benzodiazepines (61.6%) and/or alcohol (21.8%). CONCLUSIONS: There are lower opioid concentrations in deceased with signs of aspiration, a fact which strongly points to aspiration as alternative cause of death in opioid-related fatalities. Furthermore, this study highlights the common abuse of slow-release oral morphine in Vienna and discusses alternative medications in substitution programs (buprenorphine/naloxone or tamper-resistant slow-release oral morphine preparations), as they might reduce intravenous abuse and opioid-related deaths.

High-Sensitivity Cardiac Troponin I and T Response Following Strenuous Activity is Attenuated by Smokeless Tobacco: NEEDED (North Sea Race Endurance Exercise Study) 2014.

Background Use of snus, a smokeless tobacco product, is increasing in Scandinavia. Strenuous physical activity is associated with an acute increase in high-sensitivity cardiac troponin (swhs-cTn) concentrations. Current smoking is associated with lower hs-cTn, but whether this also holds true for smokeless tobacco and whether tobacco affects the hs-cTn response to exercise remain unknown. Methods and Results We measured hs-cTnI and hs-cTnT concentrations in 914 recreational athletes before and 3 and 24 hours after a 91-km bicycle race. Self-reported snus tobacco habits were reported as noncurrent (n=796) and current (n=118). The association between snus use and change in log-transformed hs-cTnI and hs-cTnT concentrations (ie, the differences between concentrations at baseline and 3 hours and 24 hours ) were assessed by multivariable linear regression analysis. Concentrations of hs-cTn at baseline were lower in current than in noncurrent snus users (hs-cTnI median, 1.7 ng/L; Q1 to Q3: 1.6-2.3 versus 2.0 ng/L; Q1 to Q3: 1.6-3.2 [P=0.020]; and hs-cTnT: median, 2.9 ng/L, Q1 to Q3: 2.9-3.5 versus 2.9 ng/L, Q1 to Q3: 2.9-4.3 [P=0.021]). In fully adjusted multivariable models, use of snus was associated with lower change in hs-cTn concentrations from baseline to 3 hours (hs-cTnI: -29% [P=0.002], hs-cTnT: -18% [P=0.010]) and 24 hours (hscTnI: -30% [P=0.010], hs-cTnT -19%, [P=0.013]). Conclusions Resting hs-cTn concentrations are lower and the exercise-induced cardiac troponin response is attenuated in current users of smokeless tobacco compared with nonusers. Further insight into the pathophysiological processes underlying the attenuated cardiac troponin response to exercise in tobacco users is needed. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02166216.

Impact of polysubstance use on high-sensitivity cardiac troponin I over time in homeless and unstably housed women.

INTRODUCTION: The use of controlled substances like cocaine increases the risk of cardiovascular disease (CVD) and myocardial infarction (MI). However, outside of alcohol and tobacco, substance use is not included in CVD risk assessment tools. We identified the effects of using multiple substances (nicotine/cotinine, cannabis, alcohol, cocaine, methamphetamine, heroin and other opioids) on cardiac injury measured by high-sensitivity troponin (hsTnI) in homeless and unstably housed women. METHODS: We recruited 245 homeless and unstably housed women from shelters, free meal programs and street encampments. Participants completed six monthly study visits. Adjusting for traditional CVD risk factors, we examined longitudinal associations between substance use and hsTnI. RESULTS: Median participant age was 53 years and 74 % were ethnic minority women. At baseline, 76 % of participants had hypertension, 31 % were HIV-positive, 8% had a history of a prior MI and 12 % of prior stroke. The most commonly used substances were cotinine/nicotine (80 %), cannabis (68 %) and cocaine (66 %). HsTnI exceeding the 99th percentile (14.7 ng/L) - a level high enough to signal possible MI - was observed in 14 participants during >1 study visit (6%). In adjusted analysis, cocaethylene and fentanyl were significantly associated with higher hsTnI levels. CONCLUSIONS: Fentanyl use and the co-use of cocaine and alcohol are associated with myocardial injury, suggesting that the use of these substances may act as long-term cardiac insults. Whether risk counseling on these specific substances and/or including their use in CVD risk stratification would improve CVD outcomes in populations where substance use is high merits further investigation.

"Residual blood THC levels in frequent cannabis users after over four hours of abstinence: A systematic review."

BACKGROUND: Tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, causes psychomotor impairment and puts drivers at increased risk of motor vehicle collisions. Many jurisdictions have per se limits for THC, often 2 or 5 ng/mL, that make it illegal to drive with THC above the "legal limit". People who use cannabis regularly develop partial tolerance to some of its impairing effects. Regular cannabis users may also have persistent elevation of THC even after a period of abstinence. Some stakeholders worry that current per se limits may criminalize unimpaired drivers simply because they use cannabis. We conducted a systematic review of published literature to investigate residual blood THC concentrations in frequent cannabis users after a period of abstinence. METHODS: We identified relevant articles by combining terms for "cannabis" and "blood" and "concentration" and "abstinence" and searching MEDLINE, EMBASE, PsycINFO, and Web of Science. We included studies that reported THC levels in frequent cannabis users after more than 4 h of abstinence. RESULTS: Our search identified 1612 articles of which 8 met our inclusion criteria. After accounting for duplicate publications, we had identified 6 independent studies. These studies show that blood THC over 2 ng/mL does do not necessarily indicate recent cannabis use in frequent cannabis users. Five studies reported blood THC >2 ng/mL (or plasma THC >3 ng/mL) in some participants after six days of abstinence and two reported participants with blood THC >5 ng/mL (or plasma THC > 7.5 ng/mL) after a day of abstinence. CONCLUSIONS: Blood THC >2 ng/mL, and possibly even THC >5 ng/mL, does not necessarily represent recent use of cannabis in frequent cannabis users.

Serum proteomic profiling of patients with amphetamine use disorder.

BACKGROUND: Amphetamine use disorder has been recently classified as an epidemic condition. Amphetamine use/abuse has been associated with several neurological and inflammatory effects. However, the exact mechanism involved in these effects warrants further investigation. The aim of this study was to determine any alterations in the serum proteome of individuals classified as patients with amphetamine use disorder compared to that of control subjects. METHODS: An untargeted proteomic approach employing two-dimensional difference in gel electrophoresis coupled with mass spectrometry was used to identify the patterns of differentially expressed proteins. Serum samples were collected from 20 individuals (males) including 10 subjects with amphetamine use disorder and 10 healthy controls for the present study. RESULTS: The analysis revealed 78 proteins with a significant difference in protein abundance between the amphetamine-addicted subjects and controls. Among them, 71 proteins were upregulated while 7 proteins remained downregulated in the amphetamine-addicted group. These proteins were further analyzed by ingenuity pathway analysis (IPA) to investigate their correlation with other biomarkers. IPA revealed the correlation of altered proteins with mitogen-activated protein kinase (MAP2K1/K2), p38MAPK, protein kinase-B (PKB; Akt), extracellular signal-regulated kinase (ERK1/2), and nuclear factor-κB signaling pathways. Importantly, these pathways are highly involved in neurological diseases, inflammatory responses, and cellular compromise. CONCLUSIONS: Our data suggest that the changes in the levels of serum proteins between amphetamine and control groups might affect cellular compromise, inflammatory response, and neurological diseases.

Tryptophan degradation is associated with risk-taking propensity in methamphetamine users with treated HIV infection.

Few studies have examined neuroimmune pathways that could contribute to impulsivity in people living with HIV who use substances. Eighty-four methamphetamine-using, sexual minority men with an undetectable HIV viral load were administered the Balloon Analogue Risk Task (BART), a behavioral measure of risk-taking propensity. We examined the associations between kynurenine/tryptophan ratio and phenylalanine/tyrosine ratio with BART scores using multiple linear regression. A higher kynurenine/tryptophan ratio was independently associated with greater BART scores (beta = 0.25; 95% CI = 0.05-1.23; p = 0.034). The phenylalanine/tyrosine ratio was not significantly associated with BART scores. Findings support the need for further research to elucidate the neuroimmune mechanisms linking tryptophan degradation with impulsivity to catalyze the development novel pharmacologic treatments for people living with HIV who use methamphetamine.