Pharmacotherapy with stimulant or nonstimulant medications is recommended as first-line treatment for attention-deficit/hyperactivity disorder (ADHD). Among patients prescribed stimulants, concomitant opioid use may increase the risk of drug dependence, exacerbate comorbid conditions, and compromise treatment adherence. However, limited evidence exists on the risk factors for initial opioid prescription in this population. To identify factors associated with incident opioid prescriptions among patients with ADHD prescribed stimulant therapy. We conducted a retrospective cohort study using the Merative® MarketScan® Commercial Claims and Encounters Database (2010-2020). We identified patients with ADHD who initiated stimulant therapy and followed them for 1 year to assess incident opioid prescription. Cox proportional hazards models were used to evaluate factors associated with opioid initiation. Among 380 494 patients with ADHD initiating stimulants (mean age: 21.2 years; 56.5% male), 14.2% received an opioid prescription within 1 year. Factors significantly associated with incident opioid prescription included age ≥35 years (adjusted hazard ratio [aHR]: 10.84; 95% CI: 10.43-11.26), gender(aHR [female]:1.29; 95% CI: 1.27-1.31), geographic region (aHR [West]: 1.58; 95% CI: 1.52-1.64), multiple chronic conditions (aHR: 1.61; 95% CI: 1.54-1.67), anxiety (aHR: 1.19; 95% CI: 1.17-1.22), depression (aHR: 1.16; 95% CI: 1.14-1.19), severe mental illnesses (aHR: 1.18; 95% CI: 1.13-1.23), substance use disorders (SUDs) (aHR: 1.69; 95% CI: 1.63-1.75). Receipt of behavioral therapy before ADHD pharmacotherapy (aHR: 0.89; 95% CI: 0.87-0.92) was associated with a lower risk of receiving incident opioid prescriptions. Several demographic factors (e.g., age, gender, geographic region) and clinical factors (e.g., history of mental health conditions and SUDs) are associated with opioid initiation among stimulant-treated patients with ADHD. These findings may inform clinical strategies to mitigate unnecessary opioid exposure and associated harms.

Abstract Background Spinal anesthesia-induced hypotension is a common complication during cesarean delivery, often requiring vasopressor support, and is associated with maternal discomfort. Caffeine, a central nervous system stimulant with well-documented cardiovascular effects, may provide a simple adjunct to enhance hemodynamic stability. We aimed to evaluate the efficacy of a single preoperative 200 mg oral caffeine dose in reducing the incidence and severity of hypotension following spinal anesthesia in healthy patients undergoing elective cesarean delivery. Methods In this randomized controlled trial, 90 patients classified as ASA II and scheduled for elective cesarean delivery under spinal anesthesia were assigned to receive either 200 mg oral caffeine or a placebo 30 min before the procedure. Hemodynamic parameters, the incidence and severity of hypotension, baseline and 60 min post-administration serum caffeine levels, ephedrine requirements, incidence of postoperative nausea and vomiting, and post-dural puncture headache were recorded and analyzed. Results Caffeine administration significantly reduced the incidence of hypotension (9% vs. 33%, p < 0.05). Severe hypotension was not observed in the caffeine group. Patients in the caffeine group demonstrated greater hemodynamic stability, with a delayed onset of hypotension and reduced ephedrine requirements. No significant differences were observed in the incidence of bradycardia, tachycardia, or reactive hypertension. Neonatal outcomes were comparable between the groups. Additionally, caffeine was associated with lower rates of postoperative nausea and vomiting (2% vs. 20%) and post-dural puncture headache (2% vs. 16%) at 24 h. Conclusion Preoperative administration of 200 mg oral caffeine is a cost-effective strategy for reducing spinal anesthesia-induced hypotension, the incidence of postoperative nausea and vomiting, and post-dural puncture headache in healthy patients undergoing elective cesarean delivery. These findings support further investigation of the role of caffeine as an adjunct in obstetric anesthesia. Trial registration The study was registered by the principal investigator (M. Helmy) at ClinicalTrials.gov under the identifier NCT07076654 on July 11, 2025. Graphical Abstract

The extract of Carica papaya L. leaves contains phytochemical compounds such as flavonoids, alkaloids, phenolics, and saponins that play a role in biological activities, including antioxidants, anti-inflammatory, analgesic, and modulation of the nervous system. This study aims to evaluate the effects of fresh papaya leaf extract on the central nervous system (CNS) and autonomic nervous system based on varying extract concentrations. The study used test animals with treatment groups consisting of negative control, positive control, and extracts at concentrations of 4%, 8%, and 16%. Parameters observed included parasympathomimetic (PSM), parasympatholytic (PSL), sympathomimetic (SM), sympatholytic (SL), analeptic effects (ANA), CNS stimulation (SSSP), CNS depression (DSSP), and muscle relaxation (RO). The results showed that the 16% concentration produced the highest PSM activity (46.82%) and dominant CNS stimulation (38.59%), while DSSP and RO decreased at higher concentrations. This phenomenon indicates that increasing the extract concentration does not always enhance CNS depression, but rather leads to stimulation. These findings support the potential of papaya leaf extract as a neuroprotective and multifunctional agent. Further research is needed to confirm its molecular mechanisms and clinical effectiveness as a phytotherapy candidate.

Stimulant and non-stimulant ADHD medication prescriptions for homeless veteran service users with mental illness.

Tracking law enforcement-associated fatalities is complicated by an absence of a national database. Death certificates often fail to report deaths due to law enforcement activity. Adopting recommendations by the National Association of Medical Examiners, the present study was conducted using records from the King County Medical Examiner's Office of all deaths associated with law enforcement, including deaths in correctional facilities, from 1995 to 2024. A total of 566 deaths were categorized as Pre-Custody (299) or In-Custody (267). Pre-Custody deaths were subcategorized into: Shooting (178), Vehicular Pursuit (57), Restraint (24), and Other (40). An altercation with law enforcement (40 deaths) or with other individuals (11 deaths) was the most common circumstance preceding the fatal event in the Pre-Custody/Shooting subcategory. In the Pre-Custody/Restraint group, multiple factors contributed to the deaths of all but 5, and stimulant drug intoxication contributed to the deaths of 19. No deaths were caused by tasers or pepper spray. In the In-Custody category, manners of death and demographics differed between deaths from jails and prisons. Racial and ethnic disproportionalities, relative to the county population, were evident in both Pre- and In-Custody deaths. Death certificates mentioned law enforcement involvement in 74% of the Pre-Custody/Shooting deaths and in only 12% of In-Custody deaths due to injuries. As public policies evolve to guide modern policing, creating a national database is imperative. Medical examiners and coroners have an important role in this effort by providing appropriate descriptions in the Describe How Injury Occurred section of death certificates.

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition defined by persistent patterns of inattention, hyperactivity, and impulsivity that impair functioning across multiple settings [1]. Symptoms typically emerge in childhood and frequently persist into adulthood, although their expression may change over time. ADHD is clinically heterogeneous, with substantial variability in symptom severity, cognitive profiles, and comorbidity patterns [2]. Global prevalence estimates suggest that approximately five percent of children are affected, with lower rates observed in adults largely reflecting partial symptom remission rather than resolution [3]. The diagnosis of ADHD is based on behavioral criteria and includes three clinical presentations: predominantly inattentive, predominantly hyperactive impulsive, and combined [1]. ADHD commonly co-occurs with anxiety disorders, depression, learning disabilities, and autism spectrum disorder, contributing to diagnostic complexity and increased clinical burden [2]. These overlaps suggest shared biological mechanisms rather than discrete disease boundaries. Neurobiological studies have consistently implicated fronto striatal and fronto cerebellar circuits involved in executive control, attention regulation, and inhibitory processes [4]. Structural and functional neuroimaging studies report delayed cortical maturation, altered cortical thickness, and differences in large scale brain connectivity, particularly in prefrontal regions [5]. At the neurochemical level, dysregulation of dopamine and norepinephrine signaling plays a central role in ADHD pathophysiology and provides the mechanistic basis for stimulant medications, which remain first line treatment [6]. Genetic factors represent one of the strongest contributors to ADHD risk. Family and twin studies consistently report heritability estimates between seventy and eighty percent, placing ADHD among the most heritable psychiatric disorders [7]. However, ADHD does not follow a single gene or Mendelian inheritance pattern. Instead, it reflects the cumulative effects of many common genetic variants of small effect, consistent with a highly polygenic architecture [8]. Early candidate gene studies focused on dopaminergic pathway genes such as DRD4, DRD5, SLC6A3, and COMT, but these explained only a small fraction of genetic risk. The field advanced substantially with large genome wide association studies. The first genome wide significant ADHD loci were identified by Demontis and colleagues, implicating genes involved in neurodevelopment, synaptic organization, and transcriptional regulation [9]. Subsequent work demonstrated substantial genetic overlap between ADHD and other neuropsychiatric and behavioral traits, including autism spectrum disorder, schizophrenia, educational attainment, and risk-taking behaviors, supporting shared biological pathways across conditions [10,11]. Rare genetic variants, including copy number variations affecting neurodevelopmental genes, also contribute to ADHD risk, particularly in individuals with more severe or persistent symptoms [9]. Environmental exposures such as prenatal smoking, low birth weight, and early life psychosocial adversity interact with genetic susceptibility, influencing symptom expression rather than acting as primary causes. Future ADHD research is increasingly oriented toward integrative and precision-based approaches. Polygenic risk scores summarizing genome wide genetic liability are being developed, although their predictive value at the individual level remains limited [7]. Combining genomic data with neuroimaging, cognitive phenotyping, and environmental measures may enable biologically informed stratification of ADHD, addressing long standing heterogeneity in diagnosis and treatment response. Precision medicine represents a key future goal. Pharmacogenomic research seeks to identify genetic predictors of medication response and adverse effects, potentially improving treatment selection and tolerability [12]. Additionally, there is growing recognition of the need for ancestry diverse and lifespan focused research. Most genetic studies to date have focused on populations of European ancestry, limiting generalizability. Expanding global representation and longitudinal study designs will be essential for equitable translation of genetic discoveries into clinical practice. In summary, ADHD is a complex neurodevelopmental disorder with a strong genetic foundation and substantial biological overlap with other psychiatric traits. Continued integration of genomics, neuroscience, and clinical research is likely to reshape ADHD classification and management, moving toward more precise and individualized care.

Adult ADHD is increasingly recognized in clinical practice, especially in private healthcare, leading to more patient presentations. However, accurate diagnosis remains challenging due to overlapping symptoms with other mental health issues. Thorough assessments beyond self-reports are crucial to avoid both over- and underdiagnosis, which can impact patient safety and treatment outcomes.A major challenge is the rising number of patients requesting stimulant medications, sometimes with fixed expectations. Clinicians must carefully weigh the benefits against risks such as side effects, misuse, and dependence, balancing patient autonomy with ethical prescribing.This case series from Australia and Sri Lanka high-lights the complexities in diagnosing and managing adult ADHD, emphasizing diagnostic uncertainty, prescribing pressures, treatment risks, and the vital role of psychological support. It advocates for a multidisciplinary approach combining clinical judg-ment, structured assessments, and psychological input for responsible, effective care.

Cognitive enhancers (CE) are substances frequently used to enhance cognitive capabilities, especially in demanding environments, such as medical schools. Accordingly, this study aimed to investigate students’ knowledge, attitudes toward, and usage of CEs. Data was collected from 350 medical students through an online questionnaire. Around (22.3%) of participants were found to be users of prescription pills as CEs, with beta-blockers and nasal decongestants being the most frequently abused substances (16.3%). Lifetime usage of prescription pills as CEs was associated with usage of natural supplements (p < 0.05, OR: 2.01), tobacco smoking (p < 0.05, OR: 2.79) and low concentration rating (p < 0.05, OR: 0.66). The majority (66.9%) first heard about CEs from the internet or their family and friends. While around (38%) considered using CEs to improve their attention and concentration, around (35.1%) refused to due to concerns regarding their safety. Our study has shown that Jordanian medical students use cognitive enhancers in their various forms, including psychostimulant drugs. However, given their unproven efficacy, safety and possible ethical and public health implications of their usage, concerns arise as these students will become medical practitioners and in charge of drug prescriptions. Accordingly, this should prompt policymakers to implement educational initiatives to spread awareness.

Background: Adults with attention-deficit/hyperactivity disorder (ADHD) often have comorbid substance use disorders (SUDs). In Italy, individuals with both ADHD and heroin use disorder (HUD) are usually treated in addiction services with opioid agonist therapy (OAT), but stimulant medications are rarely prescribed. This may create a treatment gap for core ADHD symptoms. Aim: This study examined the clinical and behavioural profiles of ADHD patients with HUD who receive OAT but no stimulant treatment, compared to ADHD patients without opioid use disorder (ADHD/NoHUD) on standard pharmacotherapy. All participants were considered treatment responders in their respective services. Methods: Data were collected from two outpatient clinics and included 103 adult ADHD patients assessed using validated tools for symptom severity, emotional dysregulation, and global functioning. Differences between groups were analysed using univariate tests and logistic regression. Results: The ADHD+HUD group was significantly older and showed higher levels of emotional dysregulation, impulsivity, and current cocaine use. Despite clinical stability, these individuals presented a more severe psychopathological profile than their ADHD/NoHUD counterparts, who received stimulant-based treatment. Conclusions: Although limited by its cross-sectional nature and setting-related confounders, the study indicates that OAT alone may not be sufficient to manage neurodevelopmental symptoms in ADHD+HUD patients. Further research is necessary to assess the safety and efficacy of integrated stimulant-based treatments, ideally within dual disorder services combining psychiatric and addiction expertise.

Females represent a growing proportion of adults with ADHD yet remain understudied in the literature compared to males. An important aspect of the experience of females with ADHD is the impact of the menstrual cycle and ovarian hormones on both the symptoms of ADHD and effects of stimulant medications on treating these symptoms. In the present pilot study, female participants being treated with amphetamine salts for ADHD (n = 30) were recruited to complete 35 daily online surveys to track ADHD symptoms, mood, and medication use through the menstrual cycle. Results indicated that the degree of ADHD symptoms was significantly associated with menstrual cycle phase with ADHD symptoms being most severe in the menstruation phase and comparatively milder ADHD symptoms in the mid-follicular phase. This difference was positively correlated with subjective changes in negative mood. These results indicate that ADHD symptoms vary across the menstrual cycle among females being treated with amphetamine salts for their ADHD, a finding that could inform clinical and prescribing practices for physicians caring for females with ADHD.

Noninvasive deep-tissue calcium imaging of live mammals with high sensitivity and resolution is challenging owing to light scattering experienced by traditional calcium ion (Ca2+) indicators with excitation and emission wavelengths within 400-750 nm. Here, we report near-infrared II (NIR-II) calcium imaging beyond 1000 nm by exploring a natural protein derived from a bacterium (Thermochromatium tepidum) living in a calcium carbonate-rich environment. This highly photostable fluorescent protein enables NIR-II imaging of intracellular Ca2+ responses to stimulant drugs in cultured mammalian cells with sensitivity comparable to that of visible Ca2+ indicators. We achieve in vivo NIR-II imaging of Ca2+ transients in response to two different tumor treatment strategies in intact tumors with high sensitivity, resolution, and contrast, opening the possibility of noninvasive deep-tissue calcium imaging for assessing treatment efficacy longitudinally.

Development and validation of a rapid LC-MS/MS method for methylphenidate, atomoxetine, and their metabolites with application to pediatric pharmacokinetics.

Attention-Deficit/Hyperactivity Disorder Treatment Patterns and Association With Clinical Outcomes in Adolescents and Young Adults with Co-occurring Attention-Deficit/Hyperactivity Disorder and Substance Use Disorder: A Retrospective Analysis.

Attention Deficit/Hyperactivity Disorder (ADHD) is a chronic neurodevelopmental condition characterized by inattention, hyperactivity, and impulsivity, affecting both children and adults. While stimulant medications remain the first-line treatment due to their rapid and robust symptom control, they often fall short in addressing functional impairments related to executive functioning, emotional regulation, and social skills. This review explores a comprehensive spectrum of interventions for ADHD management, encompassing pharmacological, formulation-based, psychosocial, neurocognitive, digital, and lifestyle approaches. Pharmacological therapies, including both stimulants and nonstimulants, have strong short-term efficacy, and advances in drug formulations such as extended-release, transdermal, and prodrug preparations have improved adherence, reduced abuse potential, and enabled time-specific symptom control. Psychosocial and behavioral therapies, such as Cognitive Behavioural Therapy (CBT), parent training, and mindfulness-based interventions, address emotional and executive challenges and enhance overall functioning. Neurocognitive and digital interventions, including neurofeedback, cognitive training, and FDA-approved digital therapeutics like EndeavorRx, offer scalable and engaging options targeting attention and cognitive control. Lifestyle strategies such as aerobic exercise, diet quality, micronutrient supplementation, and gut microbiome modulation serve as supportive or adjunctive tools with growing empirical support. The integration of these strategies into personalized, multimodal treatment plans has shown superior outcomes compared to monotherapies. This review underscores the importance of tailoring interventions based on individual needs, preferences, and developmental context, and highlights the need for ongoing research to optimize long-term care in ADHD.

Methamphetamine is a highly addictive psychostimulant drug derived from amphetamine. It can produce euphoria and stimulant effects like those caused by other stimulants such as cocaine. This case report describes a 22-year-old female who was brought to the hospital emergency department with agitation, tachycardia, hyperthermia, altered mental status, profuse perspiration, and vomiting. The symptoms observed in cases of polydrug toxicity fall into multiple toxidromes, making it a diagnostic dilemma. In this case, the patient was diagnosed with methamphetamine and cocaine toxicity and developed acute liver and kidney injury. She required haemodialysis with specialised filters and prolonged intensive care unit (ICU) stay, but eventually recovered to full strength. This case emphasises the importance of early extracorporeal therapy for multi-organ support and multi-disciplinary approach involving various specialties along with the critical care team, to enhance recovery in toxicity cases.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurological disorder characterized by persistent patterns of hyperactivity, impulsive behavior, and difficulty maintaining attention. Stimulant drugs are effective in improving ADHD. Objectives: This study sought to assess the impact of probiotic supplementation on managing symptoms of ADHD in children during the 2023 - 2024 period. Methods: In this randomized double-blind placebo-controlled clinical trial, 168 children aged 6 - 12 years diagnosed with ADHD were recruited from child and adolescent psychiatry centers in Isfahan (2023 - 2024). Participants were randomly assigned to receive either probiotics or a placebo for 8 weeks. Data were collected using the ADHD Rating Scale-IV, the Parent Conners Questionnaire, the Pediatric Quality of Life Inventory (PedsQOL, parent version), the Children’s Depression Inventory (CDI, completed by the child), and the Hamilton Anxiety Rating Scale (HAM-A, completed by the parents). Parenting education sessions were conducted for all participants before the intervention phase. Results: No significant differences were observed between the probiotic and placebo groups regarding ADHD symptoms or in physical, emotional, social, psychological, or educational dimensions (all P &gt; 0.05, indicating a lack of statistically significant between-group differences). Both groups demonstrated significant improvement over time in ADHD symptom scores and quality-of-life measures (P &lt; 0.001 for the time effect within groups), likely reflecting the effects of standard treatment and parental training rather than probiotic supplementation. Therefore, the addition of probiotics did not provide statistically significant benefits compared with placebo across any outcome measure (i.e., there was no evidence of a treatment effect beyond the placebo response). Conclusions: Contrary to expectations, probiotic supplementation did not produce measurable advantages over placebo in improving ADHD symptoms or related psychosocial outcomes. Given that the Hamilton Anxiety Questionnaire only measures parental anxiety rather than comprehensive mental health, future studies should include broader parental psychological assessments.

Attention-deficit/hyperactivity Disorder (ADHD) is the most common neurobehavioral condition of childhood and can be controlled with stimulant medication. Evidence-based guidelines endorse use of standardized ADHD symptom reports to facilitate medication titration to therapeutic dosage. Children living in under-resourced areas experience barriers to receiving this recommended evidence-based care. The Remote ADHD Monitoring Program (RAMP) uses a text-based platform to relay symptom reports from caregivers and teachers to healthcare providers. This pilot study is a feasibility study examining intervention uptake. It compares the submission of structured symptom reports in those children enrolled in RAMP compared to usual care as well as utilization of the RAMP platform by providers. This paper describes the protocol to evaluate the feasibility of deploying RAMP in practices serving rural or underserved children. We will recruit 36 dyads from 4 practices in 2 separate states. Each dyad will include a caregiver and their child aged 5-11 years with a diagnosis of ADHD who is starting or reinitiating stimulants. Dyads will be randomized 1:1 to receive the RAMP intervention or usual care with attention controls. Our primary outcome is number of symptom reports (paper assessments in control arm and RAMP reports in intervention arm) per participant that are completed by caregivers and teachers and returned to providers. Our secondary outcome is proportion of submitted RAMP reports that are reviewed by providers. As telehealth use increases, it is critical that we improve access to high quality care for children with chronic conditions. Leveraging technology may be a meaningful approach to improve efficiency in optimizing medication management. This pilot study tests a text-based platform designed to improve communication between the caregivers and teachers of children with ADHD and health care providers. If successful, a future trial will examine the effectiveness of the RAMP intervention on improvement in symptoms. ClinicalTrials.gov NCT06743425.

BackgroundAttention-deficit/hyperactivity Disorder (ADHD) is the most common neurobehavioral condition of childhood and can be controlled with stimulant medication. Evidence-based guidelines endorse use of standardized ADHD symptom reports to facilitate medication titration to therapeutic dosage. Children living in under-resourced areas experience barriers to receiving this recommended evidence-based care. The Remote ADHD Monitoring Program (RAMP) uses a text-based platform to relay symptom reports from caregivers and teachers to healthcare providers. This pilot study is a feasibility study examining intervention uptake. It compares the submission of structured symptom reports in those children enrolled in RAMP compared to usual care as well as utilization of the RAMP platform by providers.MethodsThis paper describes the protocol to evaluate the feasibility of deploying RAMP in practices serving rural or underserved children. We will recruit 36 dyads from 4 practices in 2 separate states. Each dyad will include a caregiver and their child aged 5–11 years with a diagnosis of ADHD who is starting or reinitiating stimulants. Dyads will be randomized 1:1 to receive the RAMP intervention or usual care with attention controls. Our primary outcome is number of symptom reports (paper assessments in control arm and RAMP reports in intervention arm) per participant that are completed by caregivers and teachers and returned to providers. Our secondary outcome is proportion of submitted RAMP reports that are reviewed by providers.DiscussionAs telehealth use increases, it is critical that we improve access to high quality care for children with chronic conditions. Leveraging technology may be a meaningful approach to improve efficiency in optimizing medication management. This pilot study tests a text-based platform designed to improve communication between the caregivers and teachers of children with ADHD and health care providers. If successful, a future trial will examine the effectiveness of the RAMP intervention on improvement in symptoms.Trial registrationClinicalTrials.gov NCT06743425.

Chemical profile of synthetic drugs seized in Paraná State (Brazil): Possible decline of new psychoactive substances.

The present study explores, for the first time, the physicochemical and molecular interaction behaviour of tetramethylammonium hydroxide (TMAH)-caffeine (CAF) mixtures in aqueous medium. Caffeine (CAF) is a widely consumed central nervous system stimulant, and tetramethylammonium hydroxide (TMAH) is an industrially significant compound with known toxicological implications. Combination of these two solutes represents a novel system where ionic, hydrophobic, and hydrogen-bonding interactions coexist, providing unique insight into mixed solute behaviour and solvation dynamics in aqueous media. This work focuses on the physicochemical, acoustic and thermodynamic properties of aqueous TMAH solutions in the presence of varying concentrations of CAF over a range of temperatures (293.15-313.15K). Acoustic measurements, including ultrasonic velocity, and density were utilized to compute key thermodynamic parameters such as compressibility, relaxation strength, specific heat capacity, acoustic impedance, internal pressure, and isobaric expansion coefficient. The results reveal complex ion-solvent and ion-cosolute interactions, highlighting significant structural reorganization within the solution matrix. Observations such as decreasing compressibility and relaxation strength with concentration and temperature suggest stronger intermolecular forces, while variations in partial molar compressibility and transfer parameters indicate hydration shell modification due to CAF's presence. The findings offer valuable insights into hydration dynamics and solvation behaviour, with practical relevance to drug delivery, material design, and toxicity evaluation. This work advances understanding of solute-cosolute interactions, supporting applications in pharmaceutical formulations and chemical process development.