Haploinsufficiency of the Parkinson's disease gene synaptojanin1 is associated with abnormal responses to psychomotor stimulants and mesolimbic dopamine signaling.

The synaptojanin-1 (SYNJ1) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice (Synj1 +/-) have impairments in dopaminergic synaptic vesicular recycling. However, less is known about how Synj1 deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine the role of the Synj1 gene in motivated behavior, we subjected male and female Synj1 +/- and Synj1 +/+ mice to a battery of behavioral tests evaluating hedonic responses, effortful responding, and responses to psychomotor stimulants. We observed that Synj1 +/- mice exhibit few differences in reward processing and motivated behavior, with normal hedonic responses and motivated responding for sucrose. However, male but not female Synj1 +/- demonstrated an attenuated conditioned place preference for cocaine that could not be attributed to deficits in spatial memory. To further understand the dopamine signaling underlying the attenuated response to cocaine in these mutant mice, we recorded nucleus accumbens dopamine in response to cocaine and observed that Synj1 +/- male and female mice took longer to reach peak dopamine release following experimenter-administered cocaine. However, female mice also showed slower decay in accumbens dopamine that appear to be linked to differences in cocaine-induced DAT responses. These findings demonstrate that SYNJ1 deficiencies result in abnormal mesolimbic DA signaling which has not previously been demonstrated. Our work also highlights the need to develop targeted therapeutics capable of restoring deficits in DAT function, which may be effective for reversing the pathologies associated with Synj1 mutations.

Categorical and dimensional aspects of stimulant medication effects in adult patients with ADHD and healthy controls.

Psychiatric disorders are categorized on the basis of presence and absence of diagnostic criteria using classification systems such as the international classification of diseases (ICD) and the diagnostic and statistical manual for mental disorders (DSM). The research domain criteria (RDoC) initiative provides an alternative dimensional framework for conceptualizing mental disorders. In the present paper, we studied neural and behavioral effects of central stimulant (CS) medication in adults with attention deficit hyperactivity disorder (ADHD) and healthy controls using categorical and dimensional stratifications. AX-Continuous Performance Task (AX-CPT) was utilized for the later purpose, and participants were classified as "reactive" or "proactive" based on their baseline proactive behavioral index (PBI). Out of the 65 individuals who participated (33 healthy controls and 32 patients with ADHD), 53 were included in the final analysis that consisted of 31 healthy controls and 22 ADHD patients. For the dimensional stratification, a median split of PBI scores divided participants into "reactive" and "proactive" groups irrespective of whether they had ADHD or not. Participants performed AX-CPT in conjunction with functional magnetic resonance imaging (fMRI) before and after CS medication. We found no significant within or between group CS effect when participants were categorically assigned as healthy controls and ADHD patients. For the dimensional stratification, however, CS selectively increased activation in frontoparietal cognitive areas and induced a shift towards proactive control mode in the reactive group, without significantly affecting the proactive group. In conclusion, the neural and behavioral effects of CS were more clear-cut when participants were stratified into dimensional groups rather than diagnostic categories.

Selenium Nanoparticle and Melatonin Treatments Improve Melon Seedling Growth by Regulating Carbohydrate and Polyamine.

Bio-stimulants, such as selenium nanoparticles and melatonin, regulate melon growth. However, the effects of individual and combined applications of selenium nanoparticles and melatonin on the growth of melon seedlings have not been reported. Here, two melon cultivars were sprayed with selenium nanoparticles, melatonin, and a combined treatment, and physiological and biochemical properties were analyzed. The independent applications of selenium nanoparticles, melatonin, and their combination had no significant effects on the plant heights and stem diameters of Jiashi and Huangmengcui melons. Compared with the controls, both selenium nanoparticle and melatonin treatments increased soluble sugars (6-63%) and sucrose (11-88%) levels, as well as the activity of sucrose phosphate synthase (171-237%) in melon leaves. The phenylalanine ammonia lyase (29-95%), trans cinnamate 4-hydroxylase (32-100%), and 4-coumaric acid CoA ligase (26-113%), as well as mRNA levels, also increased in the phenylpropanoid metabolism pathway. Combining the selenium nanoparticles and melatonin was more effective than either of the single treatments. In addition, the levels of superoxide dismutase (43-130%), catalase (14-43%), ascorbate peroxidase (44-79%), peroxidase (25-149%), and mRNA in melon leaves treated with combined selenium nanoparticles and melatonin were higher than in controls. The results contribute to our understanding of selenium nanoparticles and melatonin as bio-stimulants that improve the melon seedlings' growth by regulating carbohydrate, polyamine, and antioxidant capacities.

Trajectories of craving in the course of pharmacotherapy trials for methamphetamine use disorder.

AIMS: The aim of this study was to measure trajectories of craving for methamphetamine during the course of pharmacotherapy trials for methamphetamine use disorder. DESIGN, SETTING AND PARTICIPANTS: Craving trajectories were identified using Group-Based Trajectory Modeling. The association of craving trajectories with drug use trajectories was examined using a dual trajectory model. Association of craving trajectories with other health and social outcomes was also examined. The study used pooled data from five randomized controlled pharmacotherapy trials for methamphetamine use disorder. A total of 866 adults with methamphetamine use disorder participated in randomized controlled pharmacotherapy trials. MEASUREMENT: Craving was assessed weekly using the Brief Substance Craving Scale. Drug use was assessed using urine toxicology. Alcohol- and drug-related problems, as well as psychiatric, medical, legal, employment and relationship problems, were measured using the Addiction Severity Index. FINDINGS: A three-trajectory model with high, medium and low craving trajectories was selected as the most parsimonious model. Craving trajectories were associated with methamphetamine use trajectories in the course of trial; 88.4% of those in the high craving trajectory group had a consistently high frequency of methamphetamine use compared with 18.7% of those in the low craving group. High craving was also associated with less improvement in most other outcomes and higher rate of dropout from treatment. In turn, low craving was associated with a rapidly decreasing frequency of methamphetamine use, greater improvement in most other outcomes and a lower rate of dropout. Participants on modafinil daily and ondansetron 1 mg twice daily were less likely to be in the high craving group compared with those on placebo. CONCLUSIONS: Trajectories of methamphetamine craving in the course of clinical trials for methamphetamine use disorder appear to be both highly variable and strongly associated with greater frequency of drug use, other drug-related outcomes and dropout from trials. Two medications, modafinil daily and ondansetron at a dose of 1 mg two times daily, appear to be associated with greater reduction in craving in the course of treatment compared with placebo. A decrease in methamphetamine craving shows promise as an early indicator of recovery from methamphetamine use disorder.

Worsening trends in the frequency of methamphetamine and other stimulant use between treatment admission and discharge.

BACKGROUND: Treatment for methamphetamine and other stimulants can be effective but treatment attrition and continued use are very high. Abstinence is the conventional outcome used to evaluate treatment success, but defining treatment success in this way misses opportunities to promote improved health even when abstinence is not achieved. Reducing methamphetamine and stimulant use without abstinence is associated with many positive outcomes. However, little is known about drug use patterns during treatment or trends in use over time. METHODS: We used the Treatment Episode Dataset-Discharges (TEDS-D) to identify treatment episodes that had a stimulant drug indicated as the primary substance of use (2017-2021; N=251,841; methamphetamine, cocaine, other amphetamines, or other stimulants). Our outcome was the change in the frequency of drug use between admission and discharge (decreased use with abstinence, decreased use without abstinence, increased use). We used multiple logistic regression to model a change in drug use frequency, predicted by year, stimulant type, and their interaction. RESULTS: Nearly two-thirds of the sample (60 %) had methamphetamine indicated as the primary stimulant of use. There was a decrease in the predicted rate of abstinence over time and worsening trends were strongest among those using methamphetamine. Daily and periodic drug use at both admission and discharge (no change in use) became worse over time, particularly for those using methamphetamine. CONCLUSION: Treatment outcomes worsened over time and declined fastest among those reporting methamphetamine. Abstinence was rare and most treatment clients did not change their drug use behavior. We recommend a renewed focus on evidence-based harm reduction while the nation's treatment systems continue grappling with the stimulant crises.

Humic acid and grafting as sustainable agronomic practices for increased growth and secondary metabolism in cucumber subjected to salt stress.

Salinity stress poses a significant treat to crop yields and product quality worldwide. Application of a humic acid bio stimulant and grafting onto tolerant rootstocks can both be considered sustainable agronomic practices that can effectively ameliorate the negative effects of salinity stress. This study aimed to assess the above mentioned ameliorative effects of both practices on cucumber plants subjected to saline environments. To attain this goal a factorial experiment was carried out in the form of a completely randomized design with three replications. The three factors considered were (a) three different salinity levels (0, 5, and 10 dS m-1 of NaCl), (b) foliar application of humic acid at three levels (0, 100, and 200 mg L-1), and (c) both grafted and ungrafted plants. Vegetative traits including plant height, fresh and dry weight and number of leaf exhibited a significant decrease under increasing salinity stress. However, the application of humic acid at both levels mitigated these effects compared to control plants. The reduction in relative water content (RWC) of the leaf caused by salinity, was compensated by the application of humic acid and grafting. Thus, the highest RWC (86.65%) was observed in grafting plants with 0 dS m-1 of NaCl and 20 mg L-1 of humic acid. Electrolyte leakage (EL) increased under salinity stress, but the application of humic acid and grafting improved this trait and the lowest amount of EL (26.95%) was in grafting plants with 0 dS m-1 of NaCl and 20 mg L-1 of humic acid. The highest amount of catalase (0.53 mmol H2O2 g-1 fw min-1) and peroxidase (12.290 mmol H2O2 g-1 fw min-1) enzymes were observed in the treatment of 10 dS m-1 of NaCl and 200 mg L-1 humic acid. The highest amount of total phenol (1.99 mg g-1 FW), total flavonoid (0.486 mg g-1 FW), total soluble carbohydrate (30.80 mg g-1 FW), soluble protein (34.56 mg g-1 FW), proline (3.86 µg g-1 FW) was in grafting plants with 0 dS m-1 of NaCl and 200 mg L-1 of humic acid. Phenolic acids and phenylalanine ammonia lyase (PAL) and polyphenol oxidase (PPO) enzymes increased with increasing salinity and humic acid levels. Contrary to humic acid, salt stress increased the sodium (Na+) and chlorine (Cl-) and decreased the amount of potassium (K+) and calcium (Ca2+) in the root and leaf of ungrafted cucumber. However, the application 200 mg L-1 humic acid appeared to mitigate these effects, thereby suggesting a potential role in moderating physiological processes and improving growth of cucumber plants subjected to salinity stress. According to the obtained results, spraying of humic acid (200 mg L-1) and the use of salt resistant rootstocks are recommended to increase tolerance to salt stress in cucumber. These results, for the first time, clearly demonstrated that fig leaf gourd a new highly salt-tolerant rootstock, enhances salt tolerance and improves yield and quality of grafted cucumber plants by reducing sodium transport to the shoot and increasing the amount of compatible osmolytes.

Synthetic Alfalfa Infusion Odour Attracts Gravid Culex quinquefasciatus Under Laboratory Conditions.

Gravid culicine mosquitoes rely on olfactory cues for selecting breeding sites containing organic detritus. While this capacity of the mosquitoes is used for surveillance and control, the current methodology is unwieldy, unreliable and expensive in time and labour. This study evaluated the dose-dependent attraction and oviposition response of gravid Culex quinquefasciatus to alfalfa infusions. Through combined chemical and electrophysiological analyses, bioactive volatile organic compounds (VOCs) in the headspace of alfalfa infusions, eliciting attraction, were identified. While phenolic and indolic compounds were the most abundant bioactive VOCs, additional VOCs, including a monoterpene, were required to elicit a significant behavioural response to the synthetic odour blend of alfalfa infusions. Comparative analysis with the commercially available mosquito oviposition pheromone (MOP) was also conducted demonstrating that this standardised synthetic alfalfa infusion odour blend offers a promising lure for targeted surveillance and control of Culex mosquitoes, which may contribute to disease prevention and public health protection.

Trends in drug overdose deaths in Mexico (1999-2019). A national descriptive analysis and interstate comparison.

BACKGROUND: We assess trends in overdose mortality rates in Mexico from 1999 to 2019 and identify the states with the highest overdose mortality rates over time. METHODS: The analysis using mortality statistics examined deaths related to drug use. We estimated general overdose mortality rates at the national and state levels and calculated specific mortality rates associated with opioid and stimulant use using central rate estimation. We used joinpoint regression to analyse national and state-specific trends in overdose mortality from 1999 to 2019. FINDINGS: Nationally, the general overdose mortality rate increased annually by 10.49 % (p < 0.01, CI=11.4-18.9) from 2015 to 2019. The northern states of Baja California and Chihuahua were the states with the higher annual increases (18.6 %, p < 0.01, CI=4.2-29.6; and 15.6 %, p < 0.01, CI=12.9-19.7, respectively). By substance type, the national opioid-related mortality rate increased by 29.82 % per year from 2014 to 2019 (p < 0.01; CI=20.1-40.3), compared with an annual decrease of 11.43 % in the previous period (2005-2014) (p < 0.01; CI=-14.7- 8.0). Baja California was the state with the highest rise in opioid-related mortality from 2013 to 2019, with an annual increase of 15.84 % (p < 0.01; CI=1.4-32.3). Stimulant-related mortality increased by 21.79 % per year since 2013 (p < 0.01; CI=16.9-26.9), but it was not possible to calculate state-level trends. CONCLUSIONS: Drug-related mortality rates have increased in Mexico since 2015, particularly in the northern states of Baja California, Chihuahua, Sonora and Sinaloa. Improving harm reduction programmes and local surveillance of fatal and non-fatal overdoses is essential to address the silent escalation of overdose mortality.

"If it wasn't for them, I don't think I would be here": experiences of the first year of a safer supply program during the dual public health emergencies of COVID-19 and the drug toxicity crisis.

BACKGROUND: In response to the devastating drug toxicity crisis in Canada driven by an unregulated opioid supply predominantly composed of fentanyl and analogues, safer supply programs have been introduced. These programs provide people using street-acquired opioids with prescribed, pharmaceutical opioids. We use six core components of safer supply programs identified by people who use drugs to explore participant perspectives on the first year of operations of a safer supply program in Victoria, BC, during the dual public health emergencies of COVID-19 and the drug toxicity crisis to examine whether the program met drug-user defined elements of an effective safer supply model. METHODS: This study used a community-based participatory research approach to ensure that the research was reflective of community concerns and priorities, rather than being extractive. We interviewed 16 safer supply program participants between December 2020 and June 2021. Analysis was structured using the six core components of effective safer supply from the perspective of people who use drugs, generated through a prior study. RESULTS: Ensuring access to the 'right dose and right drugs' of medications was crucial, with many participants reporting success with the available pharmaceutical options. However, others highlighted issues with the strength of the available medications and the lack of options for smokeable medications. Accessing the safer supply program allowed participants to reduce their use of drugs from unregulated markets and manage withdrawal, pain and cravings. On components related to program operations, participants reported receiving compassionate care, and that accessing the safer supply program was a non-stigmatizing experience. They also reported receiving support to find housing, access food, obtain ID, and other needs. However, participants worried about long term program sustainability. CONCLUSIONS: Participants in the safer supply program overwhelmingly appreciated it and felt it was lifesaving, and unlike other healthcare or treatment services they had previously accessed. Participants raised concerns that unless a wider variety of medications and ability to consume them by multiple routes of administration became available, safer supply programs would remain unable to completely replace substances from unregulated markets.

Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life.

OBJECTIVE: We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect differs between stimulants and non-stimulants. METHOD: From the dataset of a published network meta-analysis (Cortese et al., 20181), updated on 27th February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multi-level meta-analytic models were conducted with R 4.3.1. RESULTS: We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedges g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults. CONCLUSION: In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and non-stimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and non-pharmacological interventions is likely to further improve QoL in people with ADHD. STUDY PREREGISTRATION INFORMATION: Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/;qvgps.

Contingency Management for Drug Use Disorders: Meta-Analysis and Application of Tolin's Criteria.

Several professional organizations and federal agencies recommend contingency management (CM) as an empirically supported treatment for drug use disorder. However, the release of the "Tolin criteria" warrants an updated recommendation. Using this methodology, five meta-analyses (84 studies, 11,000 participants) were reviewed. Two meta-analyses were rated moderate quality, and three were rated low or critically low quality. Comparator conditions included active treatment, placebo, treatment as usual, and no treatment. The primary outcome was abstinence. Considering only the moderate quality meta-analyses, the effect of CM versus control on posttreatment abstinence was d = 0.54 [0.43, 0.64] and follow-up abstinence was d=0.08 [0.00, 0.16]. A "strong" recommendation was provided for CM as an empirically supported treatment for drug use disorder.

Practice Pearls for Stimulant Treatment of Attention-Deficit/Hyperactivity Disorder in Youth.

Over half of youth with attention-deficit/hyperactivity disorder (ADHD) have co-occurring psychiatric or medical conditions that present treatment challenges. Stimulants are the most effective pharmacologic treatment of ADHD for preschoolers to adults but questions about safety with co-occurring conditions frequently arise. In addition, stigma surrounding diagnosis and treatment can negatively impact care. This manuscript presents evidence-based practice pearls to guide treatment decisions for youth with ADHD and common coexisting psychiatric and medical conditions. Recommendations address specific stimulant adverse effects (i.e., anxiety, cardiac, growth, mania, psychosis) along with management strategies. Pearls were developed for the most common clinical questions, controversial topics, or therapeutic issues that may not be widely known. The goals of this manuscript are to: 1) provide a detailed resource for interprofessional teams regarding stimulant use in youth with ADHD, 2) improve therapeutic outcomes for youth with ADHD and co-occurring psychiatric and/or medical conditions through evidence-based recommendations, and 3) decrease stigma associated with stimulant use through education.

Perceptions of stimulant and buprenorphine diversion and strategies to address it.

There is ongoing policy debate on the prescribing of controlled substances such as buprenorphine and stimulants via telemedicine. The goal of federal and state policymakers is to ensure access to care while limiting diversion risk. However, there is little evidence on how clinicians view and address diversion and on telemedicine's role in diversion. From December 2023 to January 2024, we conducted semi-structured interviews with 21 psychiatrists and primary care physicians engaged in hybrid (telemedicine and in-person) care models in which we explored perceptions of diversion and strategies used to monitor for diversion. Most physicians reported monitoring for diversion, but there was little consistency on how monitoring was done and reported strategies did not differ between telemedicine vs in-person care. When physicians suspected diversion, there was also wide variation in responses: some clinicians did not immediately take any action while others imposed more requirements on patients (e.g., more frequent visits), no longer prescribed the controlled substance, or terminated the patient from their practice. Few physicians had ever reported a case of suspected diversion to law enforcement. Our findings suggest that the Drug Enforcement Administration could clarify reporting requirements and professional societies could provide additional guidance on how to respond to suspected diversion, given the current variation in practice across clinicians could be exploited by individuals who want to divert.

The Impact of Stimulant Medication on the Relation Between Working Memory and Activity Level in ADHD.

There is a positive association between heightened activity levels and improved working memory performance (WM) in individuals with Attention-Deficit/Hyperactivity Disorder (ADHD). Recent research suggests that stimulant medications may have a simultaneous positive impact on WM and motor skills. Yet, it is unclear the specific connection between movement, WM, and stimulant use. We examined how visuospatial (VS) and phonological (PH) WM performance varied with children's stimulant medication usage and naturally occurring activity level. In a repeated measures design, children with ADHD (n = 43; 7-12 years old) completed WM tasks while wearing actigraphy watches to monitor activity level on and off stimulant medication. Significant large sized main effects were observed for medication condition on PH (p < .05, ηp2 = .14) and VS (p < .001, ηp2 = .30) WM. Activity level also had significant medium sized main effects on PH (p < .01, ηp2 = .09) and VS (p < .005, ηp2 = .10) WM. There was a significant medium sized interaction for VS WM (p < .005, ηp2 = .11), indicating that the effect of medication on performance was greatest in the highest activity level category. The findings suggest that a combination of stimulant medication and an "optimal" level of movement may be most effective for improving VS WM.

The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium.

INTRODUCTION: Adrenergic neurotransmitter reuptake inhibitors are gaining attention in treatment for attention-deficit hyperactivity disorder (ADHD). Due to their effects on norepinephrine, dopamine, and serotonin neurotransmission, they benefit both ADHD and comorbid disorders and have some other advantages including longer duration of action and fewer adverse effects compared to stimulants. There is continued interest in these agents with novel mechanisms of action in treatment of ADHD. AREAS COVERED: The authors conducted a PubMed literature search using the following key words: 'ADHD' AND 'adrenergic reuptake inhibitors' OR 'nonstimulants' OR 'atomoxetine' OR 'Viloxazine' OR 'Dasotraline' OR 'Centanafadine' OR 'PDC-1421' OR 'Reboxetine' OR 'Edivoxetine' OR 'Bupropion' OR 'Venlafaxine' OR 'Duloxetine.' They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD. EXPERT OPINION: Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor affinities and modulating effects support the unique benefits of individual agents.

Leveraging pooled medical examiner records to surveil complex and emerging patterns of polysubstance use in the United States.

BACKGROUND: The United States (US) is an extreme global outlier for drug-related death rates. However, data describing drug-related deaths are generally available only on an 8-13-month lag. Furthermore, granular details about substance-involvement are often not available, which particularly stymies efforts to track fatal polysubstance and novel psychoactive substance use. Detailed medical examiner records provide a powerful source of information for drug-related death surveillance, but have been underutilized. METHODS: We pooled medical examiner data from five US states and 14 counties that together comprise 18% of the US population to examine demographic, geographic, and drug-specific trends in polysubstance drug-related deaths. We employed mixed effects logistic regression to identify demographic factors associated with polysubstance rather than single substance drug-related deaths. We assessed the correlations between drug classes and described geographic variation in the prevalence of specific drugs and the presence of novel and emerging psychoactive substances. RESULTS: Our sample included 73,077 drug-related deaths from 2012 through early 2022. Nearly two-thirds of drug-related deaths were polysubstance-involved, with the number and percentage growing annually. High percentages of polysubstance drug-related deaths were observed in both urban and rural jurisdictions. After adjusting for year and jurisdiction, female, American Indian and Alaska Native, and White individuals had the most elevated odds of polysubstance drug-related deaths. Drug-related deaths involving benzodiazepines or opioids, whether pharmaceutical or illicit, and other pharmaceutical drugs were most likely to have polysubstance involvement, while methamphetamine-involved deaths were least likely to involve multiple substances. Strong correlations were observed between prescription opioids and prescription benzodiazepines, fentanyl and xylazine, and designer benzodiazepines and novel synthetic opioids. CONCLUSIONS: Analysis of detailed medical examiner records reveals the breadth and complexity of polysubstance drug-related deaths in the US. Future efforts to use this unique resource can improve population-based surveillance of drug-related deaths to better tailor interventions and solutions to this critical health crisis.

Mortality, morbidity, and predictors of death among amphetamine-type stimulant users - a longitudinal, nationwide register study.

Introduction: Use of amphetamine-type stimulants (ATS) contributes substantially to the global burden of disease. Large-scale follow-up studies of morbidity and mortality in ATS users are few. This study analysed morbidity, mortality, and potential predictors of all-cause mortality in a nationwide cohort of patients with ATS use disorder. Methods: Data was acquired from national Swedish registers. All Swedish residents 18 years or older, with a registered ATS use diagnosis in 2013-2014 were included (N = 5,018) and followed until December 31, 2017. Comorbid diagnoses and causes of death were assessed and potential predictors of all-cause mortality were examined through Cox regression. Results: Median age at inclusion was 36.6 years (interquartile range 27.4---48.1) and 70.5 % were men. The crude mortality rate was 24.6 per 1,000 person-years. The adjusted all-cause standardized mortality ratio was 12.4 (95 % CI [11.34-13.55]). The most common cause of death was overdose (28.9 %). Multiple drug use (hazard ratio 1.39, 95 % CI [1.14-1.70], p = 0.004), anxiety (hazard ratio 1.39, 95 % CI [1.11-1.72], p = 0.014), viral hepatitis (hazard ratio 1.85, 95 % CI [1.50-2.29], p = 0.004), and liver disease (hazard ratio 2.41, 95 % CI [1.55-3.74], p = 0.004) were predictors of all-cause mortality. Conclusions: Multiple drug use, anxiety disorders, viral hepatitis and liver diseases were identified as risk factors for death. Our findings call for better screening, prevention, and treatment of somatic and psychiatric comorbidity among ATS users to reduce mortality.

Racial/ethnic trends in opioid and polysubstance opioid overdose mortality in adolescents and young adults, 1999-2020.

OBJECTIVES: Previous reports have described variations in opioid overdose mortalities among different race/ethnicity groups. We have analyzed racial/ethnicity trends in opioid and polysubstance opioid overdose mortalities in adolescents and young adults to further characterize differences and potential sub-epidemics within this specific population. METHODS: We used mortality data from the U.S. Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (WONDER) Multiple Cause of Death file from 1999 to 2020. Drug overdose mortalities were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes. Joinpoint regression was used to examine mortality rates for all opioids, opioids with a stimulant, opioids with benzodiazepines, and opioids with alcohol among racial/ethnic groups (non-Hispanic white, non-Hispanic Black, Hispanic, non-Hispanic other) in adolescents and young adults. RESULTS: The Average Annual Percent Change (AAPC) for mortality due to opioid and polysubstance opioid overdose increased for all racial/ethnic groups where data was available for analysis from 1999 to 2020. For mortality due to any opioid and any opioid with a stimulant, the greatest AAPC was seen among non-Hispanic Blacks. CONCLUSIONS: Unprecedented increases in mortality due to opioid overdose occurred in the last two decades among adolescents and young adults. Heterogenous trends support the notion that the previously defined opioid overdose epidemic "waves" may not accurately depict the effects of the crisis in all race/ethnicity groups. Additionally, alarming increases in opioid-stimulant overdose mortality starting in 2012 further characterize the interrelated effects of the third and fourth waves.

What's in drugs freely used by Brazilian truck drivers - "Rebites"? Determination of target and nontarget compounds by high-resolution mass spectrometry and nuclear magnetic resonance.

Highways, the lifeline of the Brazilian economy, transport approximately 75% of the country's economic activity, highlighting its importance. However, professional drivers, accustomed to long daily journeys, make use of tablets widely available in Gas Station, which are known as "Rebites," which could contain a mixture of legal and illegal compounds. Thus, this study aims at the chemical characterization of these through different analytical methods. Initially, we performed a comprehensive screening of compounds present in seven samples collected across the country using high-resolution mass spectrometry (HRMS). The findings revealed caffeine as the main compound, alongside theophylline, lidocaine, and clobenzorex, among others. In the next step, we employ quantitative nuclear magnetic resonance (qNMR) to quantify the caffeine content in the tablets. The results indicated a caffeine concentration ranging between 14% and 31% (m/m), which may imply a daily overdose of this compound from around four tablets. In summary, this investigation provides a chemical characterization of real samples of "Rebites" freely obtained along Brazilian highways. Caffeine emerged as the predominant active compound, with its concentration determined by qNMR analysis. The notable presence of caffeine, combined with other stimulants, depressants, and hallucinogens, underscores the need for strict quality control measures regarding "Rebites" to safeguard public health.