Effect of Neurotropic and Immunotropic Drugs on Leukocyte Elastase Activity In Vitro.

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders.

Tranquilisers and sedatives misuse and associated factors among adolescents in Estonia: findings from cross-sectional ESPAD surveys, 2003-2019.

OBJECTIVES: This study aimed to (1) to describe trends of tranquilliser and sedative (TS) misuse in Estonia during 2003-2019 and (2) to analyse the associations between TS misuse and explanatory factors (perceived access to TS, medical use of TS, family-related, friends-related, school-related factors, risk behaviour and leisure time physical activity). DESIGN: A cross-sectional study. SETTING: Data were collected from the European School Survey Project on Alcohol and Other Drugs (ESPAD) from 2003 to 2019 in Estonia. PARTICIPANTS: Estonian schoolchildren aged 15-16 years old (n=11 328), 48.6% were boys. OUTCOME MEASURES: Prevalence, crude and adjusted ORs with 95% CIs for TS misuse. RESULTS: The prevalence of lifetime TS misuse significantly increased from 2003 (5.0% of boys and 12.6% of girls) to 2019 (11.3% and 17.5%, respectively) (p<0.001). Among boys, TS misuse increased significantly among those reporting medical use of TS from 21.1% to 41.4% in 2003-2019 (p=0.006). Medical use of TS multiplied the odds of misuse by 6.89 (95% CI 5.15 to 9.24) for boys and by 4.53 (95% CI 3.58 to 5.73) for girls. Perceived easy access to TS increased the odds of misuse by 6.57 (95% CI 4.13 to 10.46) times for boys and by 4.66 (95% CI 3.25 to 6.70) times for girls. Having many friends who misuse TS increased the odds of misuse by 3.27 (95% CI 2.16 to 4.95) times for boys and by 5.07 (95% CI 3.79 to 6.77) times for girls. Furthermore, higher odds of TS misuse were observed among adolescents who smoked cigarettes and engaged in less sports. CONCLUSIONS: TS misuse prevalence among Estonian adolescents increased significantly from 2003 to 2019. Misuse was strongly associated with medical use, perceived easy access and friends' TS misuse. These findings emphasise the need for targeted prevention strategies, including improving prescription practices, limiting TS access and promoting healthy behaviours and positive peer relationships among adolescents.

Cigarette and e-cigarette use trajectories and prospective prescription psychotherapeutic drug misuse among adolescents and young adults.

OBJECTIVE: This study aimed to determine the potential longitudinal impact of different cigarette and e-cigarette use trajectories among people aged 10-24 on prescription drug misuse of psychotherapeutic drugs. METHODS: Data came from waves 1-5 of the Population Assessment of Tobacco and Health (PATH) Study (2013-2019; n = 14,454). Group-based trajectory modeling identified groups of adolescents and young adults based on cigarette and e-cigarette use across the five waves. Weighted logistic regression models were fit to examine the association of group membership with two outcomes at all waves: 1) misuse of opioids, sedatives, and/or tranquilizers, and 2) misuse of Ritalin and/or Adderall, adjusting for background characteristics. RESULTS: Five trajectory groups emerged: (1) non-use (77.7 %); (2) early-onset cigarette use with reducing use (4.6 %); (3) ever-increasing e-cigarette use (6.1 %); (4) stable dual use of cigarettes and e-cigarettes (3.2 %); and (5) accelerating dual use of cigarettes and e-cigarettes (8.4 %). In comparison to the non-use group, all other groups had significantly higher odds of misuse of opioids, tranquilizers, and/or sedatives and all but the early-onset cigarette use with reducing use group had significantly higher odds of misuse of Ritalin and/or Adderall by the end of wave 5. DISCUSSION: Patterns of cigarette and e-cigarette use in adolescent and young adult populations may serve as important indicators for concurrent and prospective prescription psychotherapeutic drug misuse. Findings highlight the need for cigarette and e-cigarette use prevention, harm reduction, and/or cessation efforts among adolescents and young adults.

Prescription Psychotherapeutic Drug Use and Nicotine Use among Young People in the United States.

Background: While prescription psychotherapeutic drug use (PPDU) and nicotine use pose substantial problems in isolation, they pose an increased risk in combination. This study aimed to estimate the prevalence of PPDU for young people, stratified by nicotine use status. A trend analysis was used to examine changes in PPDU and nicotine use over time. Methods: We used a cross-sectional population-based sample of young people aged 16-25 years (n = 10,454) from the National Health and Nutrition Examination Survey (NHANES, 2003-2018). For each data cycle, the prevalence of self-reported PPDU and nicotine including pain relievers, sedatives, stimulants, and tranquilizers was estimated. Using Joinpoint regression, we tested for significant changes in trends using a log-linear model and permutation test approach and produced the average data cycle percentage change (ADCPC). Results: From 2003 to 2018, 6.7% of young people had PPDU and 27.3% used nicotine. The prevalence of cigarette smoking decreased while other nicotine product use increased (p's < 0.001). Those who used nicotine were more likely to have PPDU (8.2%; 95% CI = 6.5%, 9.8%) vs. non-nicotine use (6.1%; 95% CI = 5.1%, 7.0%; p = 0.01). Results indicated a decreasing trend for nicotine use (ADCPC = -3.8, 95% CI = -7.2, -0.3; p = 0.04), but not for PPDU (ADCPC = 1.3; 95% CI = -4.7, 7.8; p = 0.61). On further examination, opioid use decreased, sedative use remained stable, and stimulant and tranquilizer use increased over time. Conclusions: From 2003 to 2018, young people who used nicotine had a higher prevalence of PPDU than those who did not. Clinicians should communicate the association between nicotine use and prescription drugs when prescribing or managing young patients' medications.

The global distribution and epidemiology of alcohol and drug use among street-involved children and youth: a meta-analysis.

Background: Street-involved children and youth (SICY) who work and live on/of the streets are more likely to inject drugs and engage in psychoactive substance use.Objectives: The present study aimed to identify the prevalence, distribution, sociodemographic determinants, and risk-taking associated with alcohol and drug use among SICY.Methods: Studies published in English related to alcohol and drug use among SICY were searched for from December 1 1985 to July 1 2022, on PubMed, Scopus, Cochrane, and Web of Science.Results: After full-text paper evaluation, 73 studies were included in the meta-analysis. Results indicated that lifetime prevalence rates were 44% (alcohol), 44% (crack), 33% (inhalants), 44% (solvents), 16% (tranquilizer/sedatives), 22% (opioids), and 62% (polysubstance use). The current prevalence rates were 40% (alcohol), 21% (crack), 20% (inhalants), 11% (tranquilizer/sedatives), and 1% (opioids). Also, life-time and current prevalence of alcohol and crack use, current prevalence of tranquilizer/sedative use, and life-time prevalence of polysubstance use were higher among older age groups. Life-time prevalence of tranquilizer/sedative use was lower among older age groups.Conclusions: The high prevalence of using alcohol, crack, and inhalants is a major issue because they are used extensively among different age groups, including minors. Such findings are beneficial for policymakers, health authorities, and professionals in developing programs aimed at minimizing inhalant use and other types of substance use harms among this group. It is important to accurately monitor this risk-exposed population to understand the mechanisms that might help protect them from high-risk substance use.

Defining Prescription Drug Misuse: A Naturalistic Evaluation of National Survey on Drug Use and Health Data From 2012-2014 to 2015-2017.

OBJECTIVES: Prescription drug misuse (PDM) is a significant public health problem. As research has evolved, the definitions of misuse have varied over time, yet the implications of this variability have not been systematically studied. The objective of this study was to leverage a change in the measurement of PDM in a large population survey to identify its impact on the prevalence and correlates of this behavior. METHODS: Data from the National Survey on Drug Use and Health were compared before and after a change in the definition of PDM from one that restricted the source and motive for use to one that captured any misuse other than directed by a prescriber. Three-year cohorts were constructed, representing a restricted definition of PDM (2012-2014) and a broad definition of PDM (2015-2017). RESULTS: Segmented logistic regression models indicated a significant increase in PDM prevalence for all 3 drug types examined (opioids, tranquilizers, and sedatives). Although the magnitude of differences varied somewhat based on drug type, the broader definition was generally associated with older age, higher prevalence of health insurance, and higher odds of misusing one's own prescription. Some worsening of mental health indicators was observed, but results indicated few other clinical or substance use differences. CONCLUSIONS: Definitions of prescription drug misuse have a substantial impact on the prevalence of misuse and some impact on the characteristics of the population. Further research is needed to understand the optimal strategy for measuring this behavior, based on the scientific or public health question or interest.

Family history of substance use disorder and likelihood of prescription drug misuse in adults 50 and older.

OBJECTIVE: Individuals who are family history positive (FHP) for substance use problems have increased risk for substance use, substance use disorders (SUDs), and psychopathology. Links between FHP status and prescription drug misuse (PDM) have not been well investigated; this study examined PDM in adults 50 and older by FHP status. METHODS: Data were from the US NESARC-III (n = 14,667). Participants reported their opioid PDM, tranquilizer/sedative PDM, SUD, psychopathology, and family history status (i.e. first- and second-degree relatives with alcohol/substance use problems). Prevalence rates were estimated by FHP status, and logistic regressions compared FHP and family history negative (FHN) groups. RESULTS: FHP status was associated with significantly higher rates of PDM (e.g. past-year opioid PDM, FHP: 3.8%, FHN: 1.5%) and SUD from PDM (e.g. past-year SUD, FHP: 1.2%, FHN: 0.2%); also, prevalence varied by family history density, with the highest rates in those with three or more relatives with substance use problems (e.g. past-year opioid PDM: 5.5%). Overall, 32.2% of FHP individuals with past-year PDM had past-year co-occurring SUD and psychopathology diagnoses, versus 11.0% of FHN individuals. CONCLUSION: FHP status could inform treatment decisions in adults 50 and older with conditions for which prescription opioids or tranquilizer/sedatives are indicated.

Is anticholinergic and sedative drug burden associated with postdischarge institutionalization in community-dwelling older patients acutely admitted to hospital? A Norwegian registry-based study.

PURPOSE: Investigate the association between anticholinergic (AC) and sedative (SED) drug burden before hospitalization and postdischarge institutionalization (PDI) in community-dwelling older patients acutely admitted to hospital. METHODS: A cross-sectional study using data from the Norwegian Patient Registry and the Norwegian Prescription Database. We studied acutely hospitalized community-dwelling patients ≥70 years during 2013 (N = 86 509). Patients acutely admitted to geriatric wards underwent subgroup analyses (n = 1715). We calculated drug burden by the Drug Burden Index (DBI), use of AC/SED drugs, and the number of AC/SED drugs. Piecewise linearity of DBI versus PDI and a knot point (DBI = 2.45) was identified. Statistical analyses included an adjusted multivariable logistic regression model. RESULTS: In the total population, 45.4% were exposed to at least one AC/SED drug, compared to 52.5% in the geriatric subgroup. AC/SED drugs were significantly associated with PDI. The DBI with odds ratios (ORs) of 1.11 (95% CI 1.07-1.15) for DBI < 2.45 and 1.08 (95% CI 1.04-1.13) for DBI ≥ 2.45. The number of AC/SED drugs with OR of 1.07 (95% CI 1.05-1.09). The AC component of DBI with OR 1.23 and the number of AC drugs with OR 1.13. In the subgroup, ORs were closer to 1 for AC drugs. CONCLUSIONS: The use of AC/SED drugs was highly prevalent in older patients before acute hospital admissions, and significantly associated with PDI. The number, or just using AC/SED drugs, gave similar associations with PDI compared to applying the DBI. Using AC drugs showed higher sensitivity, indicating that to reduce the risk of PDI, a clinical approach could be to reduce the number of AC drugs.

Prevalence of the Consumption of Tranquilizers without a Medical Prescription and Associated Factors in School-Based Adolescents in Colombia / Prevalencia del consumo de tranquilizantes sin prescripción médica y factores asociados en adolescentes escolarizados de Colombia / Prevalência do uso de tranquilizantes sem prescrição médica e fatores associados em adolescentes em idade escolar na Colômbia

Introduction: Non-prescription tranquilizers are a specific group of benzodiazepines, used as drugs that act on the central nervous system and have an extensive effect in patients with anxiety disorders and problems in sleep stages. Objective: To determine the prevalence of the year and month of consumption of tranquilizers without a medical prescription and the associated factors, in adolescents in school in Colombia. Methods: It is a cross-sec-tional study with an analytical scope. The universe of the study consisted of 3,243,377 students, from grades 7 to 11 (aged between 12 and 18 years), the valid surveys were 80,018. The adolescent who declared having used tranquilizers during the last 30 days and the last 12 months was considered a consumer. All variables were self-re-ported by adolescents. Results: The prevalence of tranquilizer use without medical prescription was 1.02% and 1.97% (month and year, respectively). Adolescents who presented disciplinary problems are the most predisposed to use during the last month with an OR 2.79 (95% CI: 2.20­3.53) and last year an OR of 2.77 (95 % CI: 2.34­3.27). Conclusions: There is a higher prevalence of the consumption of tranquilizers without medical prescription in women between 14 and 17 years of age, from mixed schools and it is associated with academic and disciplinary performance problems, in the last year. In addition, as age increases, the consumption of substances without a medical prescription increases

Introducción: Los tranquilizantes sin prescripción médica son un grupo específico de benzodiacepinas, usados como medicamentos que actúan sobre el sistema nervioso central y cuentan con un extenso efecto en pacientes con trastornos de ansiedad y problemas en las etapas del sueño. Objetivo: Determinar la prevalencia de año y mes de consumo de tranquilizantes sin prescripción médica y los factores asociados en adolescentes escolarizados de Colombia. Métodos: Estudio transversal con alcance analítico. El universo del estudio estuvo constituido por 3 243 377 estudiantes de los gados 7.º a 11.º (con edades entre 12 y 18 años). Las encuestas válidas fueron 80 018. Se consideró consumidor al adolescente que declaró haber consumido tranquilizantes durante los últimos 30 días y los últimos 12 meses. Todas las variables fueron autorreportadas por los adolescentes. Resultados: La prevalencia de consumo de tranquilizantes sin prescripción médica fue del 1,02 % y del 1,97 % (mes y año, respectivamente). Los adolescentes que presentaron problemas disciplinarios son los más predispuestos al consumo durante el último mes con un OR de 2,79 (IC95 %: 2,20-3,53) y último año un OR de 2,77 (IC95 %: 2,34-3,27). Conclusiones: Existe mayor prevalencia de consumo de tranquilizantes sin prescripción médica en mujeres entre los 14 y los 17 años, de colegios mixtos, y se encuentra asociada con problemas de rendimiento académico y disciplinarios, en el último año. Además, a medida que aumenta la edad, se incrementa el consumo de sustancias sin prescripción médica

Introdução: Os tranquilizantes isentos de prescrição são um grupo específico de benzodiazepínicos, usados como medicamentos que atuam no sistema nervoso central e têm um efeito extenso em pa-cientes com transtornos de ansiedade e problemas no estágio do sono. Objetivo: Determinar a prevalência anual e mensal do uso de tranquilizantes sem prescrição médica e os fatores associados em adolescentes em idade escolar na Colômbia. Métodos: Estudo transversal com escopo analítico. O universo do estudo consistiu em 3243377 alunos da 7ª à 11ª série (com idades entre 12 e 18 anos). Foram realizadas 80018 pesquisas válidas. Um adolescente foi considerado usuário, o qual relatou ter usado tranquilizantes nos últimos 30 dias e nos últimos 12 meses. Todas as variáveis foram autorrelatadas pelos adolescentes. Resultados: A prevalência do uso de tranquilizantes sem prescrição médica foi de 1,02% e 1,97% (mês e ano, respectivamente). Os adolescentes com problemas disciplinares apresentaram maior pro-babilidade de uso no último mês, com um OR de 2,79 (IC95%: 2,20-3,53) e no último ano, com um OR de 2,77 (IC95%: 2,34-3,27). Conclusões: Há uma maior prevalência de uso de tranquilizantes sem prescrição médica em mulheres de 14 a 17 anos, de escolas mistas, e isso está associado a problemas de desempenho acadêmico e disciplinar no último ano. Além disso, com o aumento da idade, aumenta o uso de substâncias sem prescrição médica.

The Effects of Early Onset Tranquilizers, Sedatives, and Sleeping Pills Use on Recent Consumption Among Adolescents.

BACKGROUND: Adolescents' consumption of tranquilizers, sedatives, and sleeping pills (TSSp) has increased during the last few decades, and TSSp are currently among the substances with the lowest age-of-onset. We characterized current-use patterns of TSSp consumers by age when first taken. METHODS: This study used individualized secondary data retrieved from the 2016 Spanish State Survey on Drug Use in Secondary Education (16-18-year-olds), and included all subjects who reported having taken TSSp at any point, but excluded those who had started during the previous year (n = 1502). Logistic regression models were used to obtain adjusted odds ratios (aOR) for associations between early TSSp consumption (<14 years) and current TSSp use patterns, adjusted for sociodemographic factors. RESULTS: About 17.9% of respondents had taken TSSp (average age-of-onset = 13.7) and 45% of these without a prescription. TSSp consumption at <14 years was higher for males and nonrepeaters. Having begun to use TSSp < 14 years was associated with both higher probability of consumption in the last month (aOR = 1.41; 95%CI:1.12-1.77) and daily/almost daily consumption in the last month (aOR = 1.56; 95CI%:1.16-2.08). CONCLUSIONS: The results of this study show there is a high proportion of 16 to 18 TSSp student consumers - both prescribed and nonprescribed; it also establishes that early onset-of-use is associated with higher levels of intensive use later on.

Association of knowledge and attitudes with the misuse of tranquilizers in parents: a study in Beirut (Lebanon).

OBJECTIVE: To measure the association between knowledge, attitudes and practices of personal misuse of tranquilizers among parents of schoolchildren in Beirut (Lebanon). DESIGN: We carried out a cross-sectional study in 1396 adults recruited from parents of students of eleven public and private schools, from primary schools to high schools, using a Knowledge, Attitude and Practices (KAP) questionnaire of personal use of tranquilizers. MAIN OUTCOME MEASURES: We assessed five patterns of tranquilizers' misuse: unprescribed use, shortened treatment, stored leftovers, doubled forgotten doses or taken when remembered, changed dose without medical recommendation, and a sixth composite outcome: 'any misuse'. RESULTS: Sixty-three (62.2%) of 91 parents who used tranquilizers reported at least one misuse pattern. Higher odds of 'any misuse' were observed among parents who reported taking tranquilizers to sleep better, to enjoy themselves with their families or to work better [2.35 ≤ adjusted interquartile odds ratio (aIqOR) ≤ 1.99]. Storing tranquilizers for future need was strongly associated with misuse [aIqOR: 5.00 (95% CI: 3.30, 7.59)]. Greater awareness about hazards of tranquilizers and the importance of therapeutic compliance was associated with lower odds of specific misuse patterns (0.50 ≤ aIqOR ≤ 0.72). CONCLUSIONS: Poor knowledge and medically disapproved attitudes increase the likelihood of practices of tranquilizer misuse.

Prescription drug and alcohol simultaneous co-ingestion in U.S. young adults: Prevalence and correlates.

Simultaneous co-ingestion of prescription medication (e.g., opioid, tranquilizer/sedative, stimulant) and alcohol is associated with overdose and elevated substance use, but no studies have examined prescription drug misuse (PDM) and alcohol co-ingestion in U.S. young adults (18-25 years), despite the high rates of PDM in this age group. We used the 2015-19 National Survey on Drug Use and Health (young adult N = 69,916) to examine prevalence of past-month PDM-alcohol co-ingestion, PDM characteristics, and sociodemographic, physical health, mental health, and substance use correlates. Logistic regression examined correlates, comparing those without past-year PDM, those with past-year but not past-month PDM, those with past-month PDM without alcohol co-ingestion, and those with past-month PDM and alcohol co-ingestion. An estimated 585,000 young adults engaged in any past-month PDM-alcohol co-ingestion, or between 32.7% (opioids) and 44.6% (tranquilizer/sedatives) of those who were engaged in past-month PDM. Co-ingestion varied by educational status and was more common in males and white or multiracial young adults. All PDM-involved groups had elevated odds of suicidal ideation and other psychopathology, but substance use and substance use disorder (SUD) odds were significantly higher in young adults with co-ingestion, versus all other groups. To illustrate, 41.1% with opioid-alcohol co-ingestion had multiple past-year SUDs, versus 2.0% in those without past-year PDM. Young adults with co-ingestion are particularly likely to have problematic alcohol use and higher rates of SUD. Counseling about the risks of PDM-alcohol co-ingestion and screening for co-ingestion among those at risk are warranted to limit poor outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Racial-ethnic Differences in Reasons for Misuse of Prescription Medications Among US Adults.

OBJECTIVES: This study aims to investigate racial-ethnic differences in reasons for misuse of prescription medications among a nationally representative sample of US adults. METHODS: We analyzed data from the 2015-2019 National Surveys on Drug Use and Health. The study population includes US adults (18-49 years old) who reported misuse of 3 types of prescription drugs (stimulants [n = 6139], sedatives and tranquilizers [n = 5643], and pain relievers [n = 8780]) for 3 reasons: medical-only (eg, to help with pain), recreational-only (eg, to get high), or combined medical and recreational reasons. Multinomial logistic regressions assessed the association between reasons of misuse of prescription medications and self-identified race-ethnicity. RESULTS: Misuse of the 4 types of prescription medications was primarily motivated by medical reasons (63%-80%). Compared to non-Hispanic Whites, non-Hispanic Blacks (nHB), and Hispanics (H) were less likely to report misuse of pain relievers for combined (nHB: adjusted relative risk ratio [aRRR] = 0.6, 95% confidence interval [CI]: 0.4, 0.7; H; aRRR = 0.7, 95% CI: 0.5, 0.9) or recreational reasons (nHB: aRRR = 0.8, 95% CI: 0.6, 1.0; H; aRRR = 0.7, 95% CI: 0.6, 0.9) rather than medical-only reasons. The odds of misuse of sedatives and tranquilizers for recreational-only reasons as opposed to medical-only reasons were higher among nHB (aRRR = 1.9, 95% CI: 1.3, 2.7) and H (aRRR = 1.9, 95% CI: 1.4, 2.4) than among non-Hispanic Whites. CONCLUSIONS: The increased misuse of prescription pain relievers for medical reasons among racial-ethnic minority groups demonstrates a continued need to investigate underlying structural factors driving these behaviors. The higher odds of sedative and tranquilizer misuse for recreational purposes among racial-ethnic minority groups warrant further investigation.

Motivations for Prescription Drug Misuse Related to Mental Health Problems in Adults.

BACKGROUND: Prescription drug misuse (PDM) is a significant public health problem associated with mental health symptoms. OBJECTIVES: This project investigates the connections between PDM motivations and mental health to inform intervention efforts. METHODS: Using nationally representative adult data from the 2016-2018 National Survey on Drug Use and Health (N = 128,205; 53% female) this project investigated which motivations for misuse are related to past-year mental health problems including any mental illness, serious mental illness, major depressive episode, and suicidal thoughts. Complex samples logistic regression models of the main motivation of PDM for each mental health problem were conducted separately for each prescription drug class (i.e., opioids, tranquilizers, sedatives, and stimulants) while controlling for demographic characteristics. RESULTS: Adults that reported PDM were more likely than those with no PDM to endorse past year mental health problems. Compared to those that reported PDM of other medications, those misusing prescription opioids and tranquilizers to help with emotions and misusing sedatives to "relax or relieve tension" were more likely to have all categories of mental health problems. Those that misused prescription stimulants to "help study" had lower odds of all mental health problems. CONCLUSIONS: While there were differences based on prescription drug class, a range of motivations increased adults' likelihood to have mental health problems and common themes were found across drug classes. While causality is still undetermined, prevention and intervention efforts that are multifaceted and individualized, while broadly providing adults with other ways to cope with negative emotions are likely to help reduce PDM.

Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia.

BACKGROUND: Valproic acid (VPA) is frequently used with clozapine (CLZ) as mood stabilizer and/or seizure prophylaxis. Valproic acid is known to reduce N-desmethylclozapine (N-DMC) but not CLZ levels. This leads to the hypothesis that VPA induces the CLZ metabolism via non-N-desmethylation pathways. Therefore, we aimed to investigate the effect of concurrent VPA use on the serum concentrations of a spectrum of CLZ metabolites in patients, adjusting for smoking. METHODS: In total, 288 patients with an overall number of 737 serum concentration measurements of CLZ and metabolites concurrently using VPA (cases, n = 22) or no interacting drugs (controls, n = 266) were included from a routine therapeutic drug monitoring service. Linear mixed model analyses were performed to compare the dose-adjusted concentrations (C/D) of CLZ, N-DMC, CLZ 5N/N+-glucuronides, and metabolite-to-parent ratios in cases versus controls. RESULTS: After adjusting for covariates, the N-DMC (-40%, P < 0.001) and N+-glucuronide C/Ds (-78%, P < 0.001) were reduced in cases versus controls, while the CLZ C/D was unchanged (P > 0.7). In contrast, the 5N-glucuronide C/D (+250%, P < 0.001) and 5N-glucuronide-to-CLZ ratios (+120%, P = 0.01) were increased in cases versus controls. CONCLUSIONS: Our findings show that complex changes in CLZ metabolism underly the pharmacokinetic interaction with VPA. The lower levels of N-DMC seem to be caused by VPA-mediated induction of CLZ 5N-glucuronide formation, subsequently leading to reduced substrate availability for N-desmethylation. Whether the changes in CLZ metabolism caused by VPA affects the clinical outcome warrants further investigation.

Ganoderma lucidum promotes sleep through a gut microbiota-dependent and serotonin-involved pathway in mice.

Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative tranquilizing effects. However, the component of G. lucidum that promotes sleep has not been clearly identified. Here, the effect and mechanism of the acidic part of the alcohol extract of G. lucidum mycelia (GLAA) on sleep were studied in mice. Administration of 25, 50 and 100 mg/kg GLAA for 28 days promoted sleep in pentobarbital-treated mice by shortening sleep latency and prolonging sleeping time. GLAA administration increased the levels of the sleep-promoting neurotransmitter 5-hydroxytryptamine and the Tph2, Iptr3 and Gng13 transcripts in the sleep-regulating serotonergic synapse pathway in the hypothalamus during this process. Moreover, GLAA administration reduced lipopolysaccharide and raised peptidoglycan levels in serum. GLAA-enriched gut bacteria and metabolites, including Bifidobacterium, Bifidobacterium animalis, indole-3-carboxylic acid and acetylphosphate were negatively correlated with sleep latency and positively correlated with sleeping time and the hypothalamus 5-hydroxytryptamine concentration. Both the GLAA sleep promotion effect and the altered faecal metabolites correlated with sleep behaviours disappeared after gut microbiota depletion with antibiotics. Our results showed that GLAA promotes sleep through a gut microbiota-dependent and serotonin-associated pathway in mice.

Co-ingestion of prescription drugs and alcohol in US adults aged 50 years or older.

OBJECTIVE: To examine prevalence of past-month prescription drug misuse (PDM) and alcohol co-ingestion and its correlates in adults age 50 or older. METHODS: Data were from the 2015-2018 US National Survey on Drug Use and Health (n = 35,190). PDM-alcohol co-ingestion was defined as prescription opioid, tranquilizer/sedative, or stimulant misuse while "drinking alcohol or within a couple of hours of drinking." Co-ingestion prevalence was estimated, and logistic and negative binomial regressions examined the sociodemographic, physical health, mental health, substance use, and substance use disorder (SUD) correlates of co-ingestion. RESULTS: Over 344,000 adults aged 50 years or older (0.3%) engaged in past-month PDM-alcohol co-ingestion, or 27.4% of those with past-month PDM. Past-month co-ingestion was linked to greater past-month alcohol use frequency and elevated adjusted odds ratios (aORs) for all examined substance use outcomes (e.g., non-PDM SUD aOR = 21.8; 49.7% prevalence rate). The aOR for suicidal ideation was 506% higher in those with co-ingestion than those without past-year PDM. CONCLUSIONS: US adults aged 50 years or older with past-month PDM-alcohol co-ingestion are at high risk for SUD and concerning mental health symptoms. Screening for mental health and substance use treatment is warranted among aging adults with signs of PDM, especially involving co-ingestion.

The latent class structure of substance use in US adults 50 years and older.

OBJECTIVE: Substance use rates have increased in adults 50 years and older, and substance use in this population is associated with significant consequences. Given that little is known about their underlying substance use patterns, the objective was to identify latent classes of adults 50 years and older by past-year substance use, past-month substance use, and past-year substance use disorder (SUD) diagnosis. METHODS: The National Survey on Drug Use and Health is an annual nationwide cross-sectional U.S. survey. Participants were 35,229 civilian, non-institutionalized U.S. residents, 50 years and older. Past-year and past-month alcohol, tobacco, marijuana, heroin, cocaine, methamphetamine use, and opioid, stimulant, and tranquilizer/sedative prescription drug misuse (PDM) were captured, as was past-year DSM-IV SUD from these substances. Correlates included mental health, physical health, and healthcare utilization variables. RESULTS: Latent class analysis indicated four past-year or past-month substance use subgroups (Alcohol-Only, Alcohol-Tobacco-Marijuana, Cocaine-Polydrug, PDM-Polydrug), with SUD prevalence rising from 3.2% to 17.3%, 68.8%, and 78.5% by past-year subgroup; similarly, rates of past-year suicidal ideation increased from 2.1%, to 4.8%, 12.0%, and 20.4% by past-year subgroup. For SUD, there were three subgroups (Low Nicotine Dependence [ND], High Alcohol Use Disorder, Multiple SUDs). Over 90% of adults were in a low-risk subgroup (i.e., Alcohol-Only and Low ND), but members of Cocaine-Polydrug, PDM-Polydrug, or Multiple SUDs latent classes had high rates of mental and physical health concerns. CONCLUSIONS: Most adults 50 and older have lower risk profiles, but those engaged in PDM or cocaine use are heavily substance-involved and need screening and likely multi-disciplinary intervention.

Association of knowledge and attitudes with practices of misuse of tranquilizers: A cohort study in Spain.

BACKGROUND: Tranquilizer misuse represents a growing international public health problem with heavy social and economic consequences. We aimed to identify the psychosocial determinants of this misuse practice, focusing on modifiable factors including knowledge and attitudes towards these medications. METHODS: A prospective cohort study involving 847 adults accompanying children in primary care clinics was carried out in Spain. A validated Knowledge, Attitudes and Practices (KAP) questionnaire on tranquilizer use was self-administered at baseline, and then participants were followed-up bimonthly. A misuse event was defined as unprescribed intake of tranquilizers, storing/sharing leftovers of tranquilizers, and/or not adhering to the prescribed treatment period, timing or dosage. Poisson regression models were applied to estimate adjusted Incidence Rate Ratios (IRRs) of misuse and their 95 % Confidence Intervals (CIs). FINDINGS: Individuals' personal attitudes towards tranquilizers and treating physicians are strongly associated with the misuse of these drugs. These attitudes include: individuals' acceptance of taking tranquilizers to improve sleeping [IRR: 5.10 (95 %CI: 2.74-9.48)], to work better [IRR: 2.04 (95 %CI: 1.05-3.99)], or for recreational purposes [IRR: 1.85 (95 %CI: 1.04-3.32)]; willingness to prolong the course of tranquilizer treatment without medical consultation [IRR: 2.45 (95 %CI: 1.46-4.13)]; agreeing on storing tranquilizers for possible future need [IRR: 5.07 (95 %CI: 2.73-9.40)]; and untrusting the physician's decision about tranquilizer prescription [IRR: 1.92 (95 %CI: 1.12-3.30)]. The level of knowledge is marginally associated with tranquilizer misuse. CONCLUSIONS: There is a strong association between individuals' attitudes towards tranquilizers and the misuse practices of these drugs. Educational interventional studies could help reduce the incidence of tranquilizer misuse.