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Viral hepatitis C (HCV) remains a major global health challenge, and psychoactive substance use disorders (SUD) significantly compound its burden. However, national mortality trends from comorbid HCV and psychoactive SUD are not well characterized. This study aimed to examine temporal, demographic, and regional patterns in mortality associated with comorbid HCV and psychoactive SUD in the United States. A descriptive analysis of CDC WONDER death certificate data from 1999-2023 was performed. Deaths were identified using International Statistical Classification of Diseases and Health Related Problems - 10th revision codes B17.1 and B18.2 for HCV and F10-F19 for psychoactive SUD. Age-adjusted mortality rates (AAMRs) per 100,000 persons and annual percent change (APC) with 95% confidence intervals were calculated and stratified by sex, age, race/ethnicity, U.S. geographic region, and urban-rural status. A total of 80,403 deaths occurred between 1999 and 2023. Mortality rose in 1999-2003 (APC + 16.0), declined in 2003-2009 (-2.2), increased again in 2009-2014 (+8.6), and fell after 2020 (-8.9). Males consistently had higher AAMRs, peaking at 1.6 in 2016 vs 0.6 in females. The steepest rise occurred in ages 55-74 years, while younger adults (25-44) increased after 2012. Non-Hispanic American Indians/Alaska Natives had the highest AAMRs (2.0), followed by non-Hispanic Blacks (1.2). The West and South had the greatest burden, with Colorado, Louisiana, Montana, Oklahoma, Oregon, and DC in the highest mortality decile. Rural mortality exceeded urban mortality. Comorbid HCV and psychoactive substance use disorder mortality has fluctuated over time, showing recent declines but persistent disparities by sex, race/ethnicity, and geography. Integrated prevention and treatment approaches remain urgently needed.

Earlier studies have documented psychoactive substance use and nicotine exposure among commercial drivers in Ghana. However, those studies relied solely on self-reported questionnaires, which are prone to recall and response bias. This study aimed to provide a more accurate estimate by using a chromatographic immunoassay urine drug test. This exploratory cross-sectional study was conducted between January and August 2024 in the Tamale metropolitan area of Ghana. The study included 70 consenting commercial drivers aged from 26 to 78 years. Sociodemographic, anthropometric and occupational factors were collected using a semi-structured questionnaire. Urine samples were then obtained from the participants and tested for Amphetamine (AMP), Barbiturates (BAR), Benzodiazepines (BZO), Cocaine (COC), Tetrahydrocannabinol (THC), Morphine (MOP), Opiates (OPI), nicotine exposure using Cotinine (COT), Tramadol (TML), and Tricyclic Antidepressants (TCA) using the 10-panel Multi-Drug One Step chromatographic immunoassay test kit. The total urine prevalence of psychoactive substances and nicotine exposure was 61.4%, consisting of COT (37.1%), THC (24.3%), BZO (11.4%), Tramadol (5.7%) and AMP (2.9%). While the self-reported smoking prevalence was 10%, the urine cotinine prevalence was 37.1%. In addition, 14(20%) of the urine samples tested positive for two substances. Contrary to expectations, commercial drivers with no history of accident were more likely to test positive for TML [AOR = 8.667(95%CI: 1.025-73.249)], or two substances [AOR = 5.000(95%CI: 1.051-23.789)]. The urine samples of commercial drivers tested positive for psychoactive substances and nicotine exposure. However, positivity for a psychoactive substance or nicotine exposure may not be associated with a history of road traffic accidents. Further studies are recommended.

To examine the associations of chronotype and sleep quality with psychoactive substance use among adolescents attending schools with different schedules and patterns associated with chronotype-school schedule combinations. A cross-sectional study was conducted in 1311 adolescents aged 11-19 years from public and private schools. Chronotype was assessed using the Children's Morningness-Eveningness Questionnaire, sleep quality using the Pittsburgh Sleep Quality Index, and psychoactive substance use through structured questionnaires. Logistic regression models examined the independent and joint associations of chronotype and sleep quality with psychoactive substance use. Formal Chronotype &#xd7; School Schedule interactions were also tested. Most adolescents reported insufficient sleep (65&#x202f;% slept <8&#x202f;h/night) and regular or poor sleep quality (80&#x202f;%). Morning-shift students reported shorter sleep duration than evening-shift students. In separate adjusted models, evening chronotype and poor sleep quality were associated with higher odds of alcohol, tobacco, and cannabis use. In fully adjusted models, sleep quality remained the most consistent predictor across substance categories, whereas chronotype associations were substantially attenuated. Formal Chronotype &#xd7; School Schedule interactions were not statistically significant for alcohol, tobacco, or cannabis use. However, analyses using a combined chronotype-school schedule variable identified significant differences in alcohol, tobacco, and cannabis use patterns across chronotype-school schedule groups. Sleep quality showed the most consistent associations with psychoactive substance use across multiple substance categories. Although the school schedule did not significantly modify chronotype-related associations, chronotype-school schedule combinations were associated with distinct substance-use patterns. These findings highlight sleep health as a potential target for adolescent substance-use prevention.

Objective: Mental and behavioral disorders due to psychoactive substance use, as defined by ICD-10 codes F10-F19, include a spectrum of substance use disorders such as acute intoxication, withdrawal, harmful use, and dependence related to alcohol, opioids, stimulants, cannabis, tobacco, and other substances. These conditions significantly increase the risk of suicide, yet national trends in suicide-related mortality among affected individuals remain underexplored. This study aimed to evaluate national trends in suicide and self-harm mortality among individuals with these disorders from 1999 to 2023. Methods: We conducted a retrospective analysis of U.S. death certificate data from the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) database (1999-2023). Decedents with mental and behavioral disorders due to psychoactive substance use were identified using ICD-10 codes F10-F19, encompassing acute intoxication, withdrawal, harmful use, and dependence. Suicide and self-harm deaths were defined by ICD-10 codes U03, X60-X84, and Y87. Age-adjusted mortality rates (AAMRs) per million and average annual percentage changes (AAPCs) were estimated using Joinpoint regression. Analyses were stratified by sex, age, race/ethnicity, and metropolitan status. Results: Between 1999 and 2023, 37,473 suicide-related deaths were identified among U.S. individuals with mental and behavioral disorders due to psychoactive substance use. AAMRs increased from 2.2 to 5.7 per million (AAPC: 3.31; p < .01). Males had higher mortality than females (6.6 vs. 2.9), though females had a steeper rate of increase over time. Middle-aged adults had the highest AAMR (8.2), followed by younger (6.9), older adults (3.4) and children and adolescents (1.1). Non-Hispanic (NH) American Indian/Alaska Native individuals (AI/AN) had the highest AAMR (13.5), followed by NH White (6.2), Hispanic/Latino (1.6), NH Black (1.6), and NH Asian/Pacific Islander (API) (1.4). From 1999 to 2000, non-metropolitan areas had higher AAMRs than metropolitan areas (6.5 vs. 4.3), with significant increases in both settings. Conclusions: Suicide-related mortality among individuals with mental and behavioral disorders due to psychoactive substance use has increased significantly increased in the United States from 1999 to 2023, demonstrating substantial disparities by sex, age, race/ethnicity, and geographic region. These findings highlight the critical need for integrated approaches in suicide prevention and substance-related treatment settings.

Maternal psychoactive substance use during pregnancy represents a major threat to placental integrity and fetal development. As the central interface for maternal-fetal exchange, the placenta is highly susceptible to psychoactive substances, including alcohol, tobacco, cannabis, cocaine, opioids, and synthetic drugs, which can cross the placental barrier and induce structural and functional alterations. This review synthesizes current evidence on the biological mechanisms, diagnostic approaches, and forensic relevance of psychoactive substances-induced placental pathology. We summarize how different substances disrupt placental vascularization, oxidative balance, epigenetic regulation, and cellular viability, leading to impaired nutrient and oxygen transfer and increasing the risk of adverse outcomes such as intrauterine growth restriction, preterm birth, congenital anomalies, and long-term neurodevelopmental impairment. We further discuss the role of placental tissue in identifying prenatal drug exposure and reconstructing exposure timelines. Beyond its clinical relevance, placental examination provides objective evidence with potential forensic value in cases of suspected maternal substance use, while also informing non-punitive, evidence-based interventions. Overall, integrating placental pathology into reproductive health research and prenatal care offers a multidisciplinary framework to improve maternal-fetal outcomes and guide public health strategies addressing substance use during pregnancy.

Early adolescent psychoactive substance use poses major health and social risks. School-based programs enhancing psychosocial skills are effective for prevention. This study aims to develop, implement, and evaluate "HOPE", a school-based program to prevent substance use and promote health among first-year middle school students in Fez, Morocco. A stratified cluster randomized controlled trial will be conducted across 12 middle schools, enrolling 1,000 first-year students (500 intervention, 500 control) and 60-90 parents. Stratified cluster randomization based on sociodemographic characteristics will ensure group balance. The intervention will be delivered over two years through 22 structured in-person group sessions (15 for students, 7 for parents) at participating schools. Data collection will involve structured student questionnaires and parent focus groups to assess a range of outcomes, including knowledge acquisition, attitude change, development of psychosocial skills, substance use patterns, and related behavioral and psychological effects. Measurable objectives include improvements in knowledge and psychosocial competencies, as well as reductions in substance use and associated harms. Expected outcomes include delayed initiation of substance use and enhanced student well-being. We expect that the program will help to prevent and/or delay psychoactive substance use among first-year middle school students by reinforcing protective factors and reducing risk factors. We anticipate a reduction in current substance use, a decreased risk of abuse, and diminished physical and psychological effects. This study will evaluate the effectiveness of the "HOPE" program in reducing substance use and improving the physical and mental health of first-year middle school students in Fez. Its multi-year structure and potential positive outcomes could serve as a foundation for a national school-based prevention initiative in Morocco. Pan African Clinical Trial Registry PACTR202401711272288 (Registered on January 26, 2024).

Cocaine use disorder (CUD) remains a major global health concern, with no FDA-approved pharmacological treatments currently available. Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa L., has shown promising preclinical effects in disrupting the consolidation and retrieval of drug-associated memories, thereby attenuating relapse-like behaviors. The present study evaluated the effects of a low-THC CBD-rich cannabis extract (NPCE) on the reinstatement and reconsolidation of cocaine-induced conditioned place preference (CPP) in male CD1 (ICR) mice, an approach not previously investigated. The extract was administered at a dose equivalent to 20 mg/kg of CBD. Treatment significantly attenuated both priming- and stress-induced reinstatement of cocaine-induced CPP. Reinstatement was triggered either by a cocaine priming injection or by acute stress exposure, whereas reconsolidation-like processes were assessed by administering the extract following memory reactivation sessions and subsequently evaluating the persistence of cocaine-associated preference over time. NPCE showed a consistent result with disruption of reconsolidation-like processes of cocaine-associated memory, with effects persisting for at least two weeks. The extract alone did not induce conditioned preference or aversion. These findings suggest that NPCE modulates drug-associated memory processes involved in relapse-like behavior. However, the underlying mechanisms were not directly evaluated and remain to be elucidated. Further studies are warranted to include both sexes, evaluate effects across multiple behavioral paradigms, directly compare full-spectrum extracts with isolated cannabinoids, and incorporate receptor-specific approaches to clarify the mechanisms of action.

Novel psychoactive substances (NPS) are synthetic compounds designed to mimic illicit drugs while circumventing international drug regulations. Commonly marketed as "research chemicals" or "legal highs", these substances remain poorly understood, with limited evidence regarding their pharmacology, risks, and therapeutic potential. Current drug policies often place NPS in the strictest legal schedules, restricting the clinical and pharmacological research needed to assess both harms and possible medical benefits. This paper advocates for a public health-oriented regulatory framework that balances harm reduction with controlled scientific access. Existing clinical evidence indicates that some NPS present significant risks, whereas others may possess therapeutic value. To address this complexity, an evidence-based four-stage scheduling framework is proposed: Early Surveillance to identify emerging substances and harms; Provisional Scheduling to permit access to regulated research; Controlled Research to investigate pharmacology, safety, subjective and neurocognitive effects, abuse liability, and therapeutic potential; and Reclassification based on integrated clinical, toxicological, and public health evidence. This approach would reduce research barriers and support more adaptive, evidence-based regulation and more balanced drug policies. None.

Histamine receptors (H1R-H4R) are G protein-coupled receptors with large physiological and therapeutic relevance. Despite extensive research, a systematic and cross-database overview of ligands is missing. This review integrates the Psychoactive Drug Screening Program (PDSP) Ki database and the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to Pharmacology, both having different scopes and curation principles, and evaluates concordance of HxR ligands across databases and experimental systems. Binding affinities (Ki) for 302 ligands targeting recombinant human HxR were extracted from the PDSP Ki database (accessed January 2026) and converted to pKi. A total of 302 ligands with relevant binding affinities were identified, including approved drugs and experimental compounds. Functional annotations and further binding affinities were retrieved from the IUPHAR/BPS Guide to Pharmacology and complementary literature, revealing missing or incomplete functional characterization for 69 ligands. Although most ligands were selective for a single HxR, others displayed multireceptor affinity. Cross-database comparisons found limited overlap in ligands, differences in primary literature, and pKi deviations. Comparisons with native human tissues and nonhuman species demonstrated substantial variability, with deviations of up to pKi 4.2 in human brain tissues and up to pKi 3.2 across species. This database-driven analysis highlights strengths and limitations of the PDSP Ki database (broad data aggregation) and the IUPHAR/BPS Guide to Pharmacology (curated representative selection). Although together they provide extensive coverage of HxR ligands, incomplete overlap and selective data inclusion limit direct comparability and may give the impression of missing data despite substantial experimental data. Systematic integration is essential to improve data reliability, summarize knowledge, and support future drug development. SIGNIFICANCE STATEMENT: This review provides a systematic overview of ligand binding affinities and functional profiles across all 4 HxR. It integrates data from the PDSP Ki database and the IUPHAR/ BPS Guide to Pharmacology and compares recombinant human HxR with native tissues and several species. Substantial data gaps, inconsistencies, and context-dependent variability are revealed. The PDSP Ki database has large potential for use in scientific research and in the support of drug development.

Novel psychoactive substances (NPSs), due to rapid emergence and evolving use patterns, pose a significant public health surveillance challenge. Traditional surveillance lags street-level reality, necessitating the exploration of novel strategies and data sources like Reddit for continuous NPS trend monitoring and presenting a public dashboard. We mined data from 60,601 subreddits between January 2015 and June 2025 for seven NPSs (kratom, xylazine, medetomidine, nitazenes, tianeptine, bromazolam, and 2C-B) using keyword-variants. We performed Mann-Kendall trend tests to assess temporal patterns, computed correlations to compare post volumes with National Forensic Laboratory Information System (NFLIS) drug report counts (2015-2024), conducted cross-correlation analyses at &#xb1;2-year lags to identify lead-lag relationships, and created a public dashboard for data visualization. The dataset comprised 328,223 posts from 139,901 accounts. We observed moderate to strong correlations between Reddit volumes and three out of five NPSs with NFLIS reports: bromazolam (&#x3c1; = 0.81, p&#x2009;<&#x2009;0.001), tianeptine (&#x3c1; = 0.48, p&#x2009;=&#x2009;0.04), xylazine (&#x3c1; = 0.60, p&#x2009;<&#x2009;0.001). Cross-correlation analyses indicated Reddit discussions preceded NFLIS reports for medetomidine (&#x3c1; = 0.93, lag = -2 years), bromazolam (&#x3c1; = 0.86, lag = -1year), tianeptine (&#x3c1; = 0.81, lag = -2years), and xylazine (&#x3c1; = 0.62, lag = -2years), suggesting Reddit discussions as a potential leading indicator. Co-mention of other substances with NPSs often matched known trends from retrospective data. Reddit-based surveillance provides timely and complementary signals to traditional forensic systems for NPS monitoring. Interactive visualizations and downloadable aggregated statistics are available via our dashboard.

MDMB-4en-PINACA and ADB-BUTINACA are indazole-derived synthetic cannabinoids that have increasingly been encountered in forensic toxicology, partly due to their potent cannabinoid receptor activity and their association with severe intoxication cases involving agitation, hallucinations, paranoia, and psychosis-like symptoms. In this study, a simplified and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method incorporating a simple and rapid sample preparation based on methanol-assisted protein precipitation followed by dispersive liquid-liquid extraction (DLLE) was developed and validated for the simultaneous determination of MDMB-4en-PINACA, ADB-BUTINACA, and their major metabolites, MDMB-4en-PINACA butanoic acid and ADB-BUTINACA N-butanoic acid, in blood and urine. The method provided effective separation and quantification of all analytes over a linear range of 1-100&#x202f;ng/mL, with limits of detection between 0.51 and 1.20&#x202f;ng/mL. No significant matrix interferences were observed, confirming adequate selectivity. The validated method was successfully applied to real forensic case samples, in which the inclusion of metabolite monitoring improved the confirmation of exposure particularly in cases where parent compounds were present at low concentrations or were no longer detectable. The results demonstrate that the proposed DLLE-LC-MS/MS method is a simple, robust, and reliable approach for the simultaneous determination of these synthetic cannabinoids and their metabolites in routine forensic toxicology, especially in investigations involving suspected synthetic cannabinoid-related neuropsychiatric manifestations such as acute psychosis.

Dementia, termed major neurocognitive disorder in the DSM-5-TR, and substance use disorders (SUD) are major and increasingly overlapping public health concerns in the United States. However, population-level trends examining their combined contribution to mortality remain limited. This study evaluates national mortality trends involving both conditions. We conducted a retrospective analysis of the CDC WONDER Multiple Cause of Death database (2000-2023). Deaths listing both dementia and SUD as underlying or contributing causes were identified using ICD-10 codes. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated using the 2000 U.S. standard population. Trends were analyzed using Joinpoint regression, reporting annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). A total of 283,206 deaths were identified. The overall AAMR increased significantly from 0.58 in 2000 to 7.63 in 2023 (AAPC: 13.29%; 95% CI: 10.42-16.23; p<0.001). Sex-stratified analysis showed higher mortality in males (AAMR: 0.87&#x2192;9.61) than females (0.41&#x2192;6.23), although females demonstrated a greater relative increase (AAPC: 14.07% vs 12.55%; both p<0.001). By race, non-Hispanic (NH) White individuals had the highest absolute rates (AAMR: 0.60&#x2192;8.57), while NH Black individuals exhibited the highest long-term burden (AAPC: 12.69%; p<0.001). Hispanic individuals showed lower rates but consistent increases (AAMR: 0.22&#x2192;3.33; p<0.001). Age-stratified analysis demonstrated increasing age-adjusted mortality rates among individuals aged 45-64 years (0.14&#x2192;0.61; p<0.001). Among older adults (&#x2265;65 years), mortality rates initially increased substantially (2.79&#x2192;41.94) through 2020 (p<0.001), then declined sharply, reaching 0.61 in 2023 (p<0.001). Regionally, the Midwest had the highest mortality (AAMR: 0.58&#x2192;10.8; AAPC: 14.38%; p<0.001), while the Northeast had the lowest rates (0.29&#x2192;4.95; p<0.001). All regions showed significant upward trends (p<0.001). Urbanization analysis revealed increasing mortality in metropolitan (0.56&#x2192;3.5) and non-metropolitan areas (0.71&#x2192;3.8), with stronger growth in non-metropolitan regions (AAPC: 16.72% vs 15.82%; p<0.001). Mortality involving both dementia and substance use disorders has increased substantially in the United States over the past two decades, with significant disparities across sex, race, geography, and urbanization. These findings highlight the growing burdens of neurodegenerative disease and substance use, emphasizing the need for integrated public health strategies targeting both conditions.