Correlates of fentanyl preference among people who use drugs in Rhode Island.

BACKGROUND: Fentanyl is increasingly pervasive in the unregulated drug supply and is a driver of drug overdose deaths in the United States. The aims of this study were to characterize and identify correlates of fentanyl preference among people who use drugs (PWUD) in Rhode Island (RI). METHODS: Using bivariate analysis, we examined associations between fentanyl preference and sociodemographic and psychosocial characteristics at baseline among participants enrolled in the RI Prescription Drug and Illicit Drug Study from August 2020-February 2023. Fentanyl preference was operationalized based on responses to a five-point Likert scale: "I prefer using fentanyl or drugs that have fentanyl in them." Participants who responded that they "strongly disagree," "disagree," or were "neutral" with respect to this statement were classified as not preferring fentanyl, whereas participants who responded that they "agree" or "strongly agree" were classified as preferring fentanyl. RESULTS: Among 506 PWUD eligible for inclusion in this analysis, 15% expressed a preference for fentanyl or drugs containing fentanyl as their drug of choice. In bivariate analyses, preference for fentanyl was positively associated with younger age, white race, lifetime history of overdose, history of injection drug use, past month enrollment in a substance use treatment program, past month treatment with medications for opioid use disorder, and preferences for heroin and crystal methamphetamine (all p < 0.05). Descriptive data yielded further insight into reasons for fentanyl preference, the predominant having to do with perceived effects of the drug and desire to avoid withdrawal symptoms. CONCLUSIONS: Only a relatively small subset of study participants preferred drugs containing fentanyl. Given the increased prevalence of fentanyl contamination across substances within the unregulated drug market, the result for PWUD is increasingly less agency with respect to choice of drug; for example, people may be forced to use fentanyl due to restricted supply and the need to mitigate withdrawal symptoms, or may be using fentanyl without intending to do so. Novel and more effective interventions for PWUD, including increased access to age-appropriate harm reduction programs such as fentanyl test strips and overdose prevention centers, are needed to mitigate fentanyl-related harms.

Post-COVID-19 Yearly Pattern Changes and Gender Variations in Attention Deficit Hyperactivity Disorder Patients at an Urban Mental Health Clinic in Alabama, USA.

Introduction The COVID-19 era has seen an increased trend in attention deficit hyperactivity disorder (ADHD) diagnoses. Historically, males have been diagnosed with ADHD more frequently than females during childhood. Studies have indicated a higher use of stimulant medications among male ADHD cases compared to females. This study examines ADHD cases from 2021 to 2023 to analyze yearly trends following the initial COVID-19 spike and explores gender and age differences between ADHD-positive and ADHD-negative cases. Methods This retrospective study was conducted using data from an urban outpatient mental health clinic in Alabama. Data were extracted from Electronic Health Records (EHR) for patients seen from January 1, 2021, to December 31, 2023. The Institutional Review Board (IRB) approved the study under the exempt research category. Data were analyzed using Microsoft Excel (Microsoft® Corp., Redmond, WA, USA) and the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 26.0, Armonk, NY). Diagnoses were based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and clinical diagnoses and medication information were obtained from the EHR. Results The study included 1,422 patients, of whom 881 (62%) were diagnosed with ADHD. Females with ADHD had significantly higher comorbid conditions, such as major depressive disorder, generalized anxiety disorder, panic disorder, and post-traumatic stress disorder, compared to males with ADHD. Gender differences in ADHD diagnoses were seen over the years, though no significant age differences were observed. Conclusions The study indicates a sustained high rate of ADHD diagnoses even after the initial COVID-19 spike. Females showed a higher ADHD diagnoses compared to males, but stimulant medication use remained consistent across genders. No significant age differences were observed between males and females with ADHD. Further research is needed to explore the reasons behind these gender differences and to evaluate their implications.

California's Recovery Incentives Program: Implementation strategies.

INTRODUCTION: Due to the increasing role of psychostimulants in the US drug poisoning crisis, there is an increasing need to effectively implement evidence-based treatment for individuals with stimulant use disorder (StimUD). Contingency management is a behavioral strategy with robust evidence of support for the treatment of StimUD. In 2023, California initiated a large-scale effort to implement CM as a treatment for individuals with a stimulant use disorder (cocaine, methamphetamine, amphetamine) called the Recovery Incentives Program: California's Contingency Management Benefit. METHODS: The Recovery Incentives Program is being systematically implemented using the Becker et al. Science to Service Lab (SSL) implementation approach with several augmentations for this project. The SSL features three core components: didactic training, performance feedback, and external facilitation. We have augmented this approach with a readiness assessment process for sites prior to CM service launch, and an ongoing fidelity monitoring and feedback component post-launch. RESULTS: The present paper is a preliminary report describing the use of this augmented SSL strategy for CM implementation in a large-scale implementation effort. Data are presented to describe the implementation activities during the first ten months of the Recovery Incentives Program. CONCLUSION: The California Recovery Incentives Program has been systematically implemented and appears to be receiving a positive response from treatment program staff and enrolled members. Future papers and evaluation reports will continue to document member response to the Program and report on the ongoing training and implementation process.

Brain mechanisms of temporal processing in impulsivity: Relevance to attention-deficit hyperactivity disorder.

In this article, we critique the hypothesis that different varieties of impulsivity, including impulsiveness present in attention-deficit hyperactivity disorder, encompass an accelerated perception of time. This conceptualisation provides insights into how individuals with attention-deficit hyperactivity disorder have the capacity to maximise cognitive capabilities by more closely aligning themselves with appropriate environmental contexts (e.g. fast paced tasks that prevent boredom). We discuss the evidence for altered time perception in attention-deficit hyperactivity disorder alongside putative underlying neurobiological substrates, including a distributed brain network mediating time perception over multiple timescales. In particular, we explore the importance of temporal representations across the brain for time perception and symptom manifestation in attention-deficit hyperactivity disorder, including a prominent role of the hippocampus and other temporal lobe regions. We also reflect on how abnormalities in the perception of time may be relevant for understanding the aetiology of attention-deficit hyperactivity disorder and mechanism of action of existing medications.

From neurons to brain networks, pharmacodynamics of stimulant medication for ADHD.

Stimulants represent the first line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) and are among the most prescribed psychopharmacological treatments. Their mechanism of action at synaptic level has been extensively studied. However, it is less clear how their mechanism of action determines clinically observed benefits. To help bridge this gap, we provide a comprehensive review of stimulant effects, with an emphasis on nuclear medicine and magnetic resonance imaging (MRI) findings. There is evidence that stimulant-induced modulation of dopamine and norepinephrine neurotransmission optimizes engagement of task-related brain networks, increases perceived saliency, and reduces interference from the default mode network. An acute administration of stimulants may reduce brain alterations observed in untreated individuals in fronto-striato-parieto-cerebellar networks during tasks or at rest. Potential effects of prolonged treatment remain controversial. Overall, neuroimaging has fostered understanding on stimulant mechanism of action. However, studies are often limited by small samples, short or no follow-up, and methodological heterogeneity. Future studies should address age-related and longer-term effects, potential differences among stimulants, and predictors of treatment response.

Brain mGlu5 Is Linked to Cognition and Cigarette Smoking but Does Not Differ From Control in Early Abstinence From Chronic Methamphetamine Use.

BACKGROUND: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance. METHODS: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested. RESULTS: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus. CONCLUSION: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.

Trends and adverse pregnancy and birth outcomes associated with stimulant-related disorder diagnosis.

BACKGROUND AND AIMS: Stimulant-related disorders (SRD), or the continued misuse of illicit or prescribed stimulants, during pregnancy can have adverse health effects for mothers and infants. This study aimed to measure prevalence and trends of SRD diagnosis in pregnancy, and associations between SRD diagnosis and adverse maternal and infant health outcomes, among pregnant individuals in California. DESIGN: Retrospective cohort study. SETTING: California, USA. PARTICIPANTS: Pregnant individuals from the Study of Outcomes in Mothers and Infants (SOMI) with singleton live births between 2012 and 2020 (n = 3 740 079). MEASUREMENTS: SRD diagnosis (excluding cocaine) and maternal (gestational diabetes, gestational hypertension [gHTN], severe maternal morbidity [SMM]) and infant (very preterm birth [gestational age <32 weeks], preterm birth [gestational age 32-37 weeks], neonatal intensive care unit [NICU] admission, small for gestational age [SGA]) outcomes were classified using International Classification of Disease (ICD) codes and vital statistics. Risk ratios were estimated with modified Poisson log linear regression that accounted for sibling pregnancies. Covariates included maternal sociodemographic characteristics, mental and physical health problems, nicotine use and co-occurrence of other diagnosed substance use disorders. Bias analyses were conducted to address unmeasured confounding and exposure misclassification. FINDINGS: SRD diagnosis among pregnant individuals increased from 2012 to 2020 (554 to 748 per 100 000 births). SRD diagnosis was associated with an increased risk of SMM (adjusted risk ratio [aRR] = 2.3; 95% confidence interval [CI] = 2.2-2.5), gHTN (aRR = 1.8; 95% CI = 1.7-1.9), very preterm birth (aRR = 2.2, 95% CI = 2.0-2.5), preterm birth (aRR = 2.1, 95% CI = 2.1-2.2) and NICU admission (aRR = 2.0, 95%CI = 1.9-2.0), and a decreased risk of gestational diabetes (aRR = 0.8; 95% CI = 0.8-0.9). SRD diagnosis was not associated with infants born SGA. Findings were generally robust to unmeasured confounding and misclassification of diagnosis. CONCLUSIONS: Stimulant-related disorder diagnosis during pregnancy appears to be associated with an increased risk for select adverse maternal and infant health outcomes including severe maternal morbidity, gestational hypertension, very preterm birth, preterm birth and neonatal intensive care unit admission.

Locomotion changes in methamphetamine and amphetamine withdrawal: a systematic review.

Despite extensive preclinical research over the years, a significant gap remains in our understanding of the specific effects of methamphetamine (METH) and amphetamine (AMPH) withdrawal. Understanding these differences could be pivotal to unveiling the unique pathophysiology underlying each stimulant. This may facilitate the development of targeted and effective treatment strategies tailored to the specific characteristics of each substance. Following PRISMA guidelines, this systematic review was conducted to examine alterations in spontaneous locomotor activity, specifically horizontal activity, in animals experiencing withdrawal from extended and repeated administration of AMPH or METH. Original articles were retrieved from four electronic databases, supplemented by a review of the references cited in the published papers. A total of thirty-one full-length articles (n = 31) were incorporated in the analysis. The results indicated that six studies documented a significant increase in horizontal activity among animals, seven studies reported decreased locomotion, and eighteen studies (8 AMPH; 10 METH) reported no significant alterations in the animals' locomotor activity. Studies reporting heightened locomotion mainly employed mice undergoing withdrawal from METH, studies reporting diminished locomotion predominantly involved rats undergoing withdrawal from AMPH, and studies reporting no significant changes in horizontal activity employed both rats and mice (12 rats; 6 mice). Drug characteristics, routes of administration, animal models, dosage regimens, duration, and assessment timing seem to influence the observed outcomes. Despite more than 50% of papers enlisted in this review indicate no significant changes in the locomotion during the stimulant withdrawal, the unique reactions of animals to withdrawal from METH and AMPH reported by some underscore the need for a more nuanced understanding of stimulant withdrawal.

Research progress on pretreatment technology for the analysis of amphetamine biological samples.

Sample pretreatment technology is crucial for drug analysis and detection, because the effect of sample pretreatment directly determinates the final analysis results. In recent years, with the continuous innovation of microextraction and other technologies like material preparation technologies and assistant technologies for extraction, the sample pretreatment techniques in the process of drug analysis have become more and more mature and diverse. This article takes amphetamine (AM) or methamphetamine as an example to review the recent development of pretreatment methods for AM-containing biological samples from the perspectives of extraction techniques, extraction media and auxiliary technologies. Extraction techniques are summarized with the categories of contact microextraction, separate microextraction and membrane-based microextraction for better guidance of application according to their features. Prevailing and innovative extraction media including carbon-based material, silicon-based material, metal organic framework, molecularly selective materials, supramolecular solvents and ionic liquids are reviewed. Auxiliary technologies like magnetic field, electric field, microwave, ultrasound and so on which can enhance extraction efficiency and accuracy are also reviewed. In the last, prospects of the future development of pretreatment technology for the analysis of AM biological samples are provided.

Supporting treatment adherence for resilience and thriving (START): protocol for a mHealth randomized controlled trial.

BACKGROUND: Although behavioral interventions show some promise for reducing stimulant use and achieving durable viral suppression in sexual minority men (SMM) with HIV, scalable mHealth applications are needed to optimize their reach and cost-effectiveness. METHODS: Supporting Treatment Adherence for Resilience and Thriving (START) is a randomized controlled trial (RCT) testing the efficacy and cost-effectiveness of a mHealth application that integrates evidence-based positive affect regulation skills with self-monitoring of adherence and mood. The primary outcome is detectable HIV viral load (i.e., > 300 copies/mL) from self-collected dried blood spot (DBS) specimens at 6 months. Secondary outcomes include detectable DBS viral load at 12 months, self-reported stimulant use severity, anti-retroviral therapy (ART) adherence, and positive affect over 12 months. A national sample of up to 250 SMM with HIV who screen positive for stimulant use disorder and reporting suboptimal ART adherence is being recruited via social networking applications through April of 2024. After providing informed consent, participants complete a run-in period (i.e., waiting period) including two baseline assessments with self-report measures and a self-collected DBS sample. Those who complete the run-in period are randomized to either the START mHealth application or access to a website with referrals to HIV care and substance use disorder treatment resources. Participants provide DBS samples at baseline, 6, and 12 months to measure HIV viral load as well as complete self-report measures for secondary outcomes at quarterly follow-up assessments over 12 months. DISCUSSION: To date, we have paid $117,500 to advertise START on social networking applications and reached 1,970 eligible participants ($59.77 per eligible participant). Although we identified this large national sample of potentially eligible SMM with HIV who screen positive for a stimulant use disorder and report suboptimal ART adherence, only one-in-four have enrolled in the RCT. The run-in period has proven to be crucial for maintaining scientific rigor and reproducibility of this RCT, such that only half of consented participants complete the required study enrollment activities and attended a randomization visit. Taken together, findings will guide adequate resource allocation to achieve randomization targets in future mHealth research SMM with HIV who use stimulants. TRIAL REGISTRATION: This protocol was registered on clinicaltrials.gov (NCT05140876) on December 2, 2021.

Examining the Myth of Prescribed Stimulant Misuse among Individuals with Attention-Deficit/Hyperactivity Disorder: A Systematic Review.

The literature emphasizes the importance of addressing the misuse of ADHD medications as a potential significant healthcare issue within the general population. Nevertheless, there are no systematic reviews that specifically examine whether the misuse of psychostimulant medication among clinical populations diagnosed with ADHD who are undergoing prescribed stimulant therapy is a rational concern or a false myth. This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement. We searched PubMed databases for articles indexed up to 12th July 2023, without language restrictions. Our systematic search generated 996 unique articles. After a full-text revision, 13 studies met the eligibility criteria and were included in the systematic review. In the 50% of the study on the adult population, the reported prevalence of stimulant misuse was 0%. In other studies, the range of stimulant misuse rates varied from 2% to 29%, with no available data specifically focusing on the youth population. It has been noted that misuse of prescribed stimulant treatment is linked with particular subject characteristics, such as older age, prior or more frequent use of ADHD medication, use of short-acting medication, and a history of alcohol/substance misuse diagnosis. Despite certain limitations, our study highlights that while a significant proportion of individuals undergoing psychostimulant treatment for ADHD follow their prescribed medication regimens without resorting to misuse behaviors, there is variability in adherence, with occurrences of misuse behaviors. The misuse of prescribed ADHD treatment appears to be associated with distinct subject characteristics, underscoring the importance for tailored interventions addressing the specific requirements of these individuals to attain optimal treatment outcomes while mitigating misuse risks.

Changes in Substance Use Diagnoses in the Great Plains during the COVID-19 Pandemic.

As drug overdose mortality rises in the United States, healthcare visits present critical opportunities to mitigate this trend. This study examines changes in healthcare visits for substance use disorders (SUDs) and remission prior to and during the COVID-19 pandemic in the Great Plains, with a focus on identifying the characteristics of those served. Data were analyzed from 109,671 patient visits (mode = one visit per patient), encompassing diverse demographics, including sex, age, race, ethnicity, and geographic location. Visits analyzed included those for Alcohol Use Disorder (AUD), Opioid Use Disorder (OUD), or Stimulant Use Disorder (StUD) and those in remission of these disorders between March 2019 and March 2021. Patient demographic information and geographic factors, like rurality and Medicaid expansion status, were considered, and logistic regression was utilized. Visits were primarily by White (70.83%) and Native American (21.39%) patients, non-Hispanic (91.70%) patients, and males (54.16%). Various demographic, geographic, and temporal trends were observed. Findings indicated that males were more likely to receive an AUD diagnosis, while females were more likely to receive an OUD or StUD diagnosis. Metropolitan-residing patients were more likely to receive an AUD diagnosis, while non-metropolitan patients were more likely to receive an OUD diagnosis. Remission odds increased for StUD during the pandemic but decreased for AUD and OUD. These findings illuminate the demographic and geographic patterns of SUD-related healthcare visits, suggesting critical touchpoints for intervention. The results emphasize the urgent need for targeted healthcare strategies, especially in rural and underserved areas, to address persistent health disparities.

Coffee and sleep: Benefits and risks.

Consuming coffee, a widely enjoyed beverage with caffeine, can impact the central nervous system and disturb sleep if taken too close to bedtime. Caffeine impacts sleep by slowing the onset, blocking adenosine receptors, lowering deep sleep levels, disrupting sleep patterns, and lessening rapid eye movement sleep. Although coffee can help with alertness in the morning, it may disturb sleep in the evening, particularly for individuals who are sensitive to caffeine. To enhance the quality of sleep, reduce the consumption of caffeine in the afternoon and evening, refrain from drinking caffeine before going to bed, and choose decaffeinated drinks instead. Variables such as personal reactions, ability to handle caffeine, and engagement with other compounds also influence the impact of coffee on sleep. Keeping track of how much caffeine you consume and your sleeping habits can assist in recognizing any disturbances and making needed changes. Furthermore, taking into account variables such as metabolism, age, and the timing of coffee consumption can assist in lessening the effects of coffee on sleep. In general, paying attention to the amount of caffeine consumed from different sources and consuming it at the right times can assist in preserving healthy sleep patterns even while enjoying coffee.

Mapping consumptions and market size of cocaine, amphetamine and MDMA through wastewater analysis: A Dutch case study.

BACKGROUND AND AIMS: Illicit drug consumption is associated with public health effects and criminal activities. This study aimed to estimate Illicit drug consumption and annual market in the Netherlands from wastewater analysis of drug residues. METHODS: Residues of cocaine, amphetamine and 3,4-methylene dioxymethamphetamine (MDMA) were measured between 2015 and 2022 in 30 Dutch wastewater treatment plants serving both rural and urban populations. These wastewater treatment plants covered 20% of the total Dutch population. The Dutch annual retail market was estimated by extrapolating consumption to the total Dutch population, back-calculating consumption volume, correcting for drug purity and street price collected in voluntary checking services, and accounting for the correlation of consumption and urbanity. RESULTS: The per capita MDMA and cocaine consumption correlated positively with the urbanity of the wastewater treatment plant catchments with r2 of 31% and 64%, respectively. Amphetamine did not show a significant correlation with urbanity. The three studied drugs were conservatively estimated to cover an average annual market value of 903 (95% prediction interval 829 to 987) million Euro for the studied period. Market estimations from prevalence figures and interceptions of international trade were similar. CONCLUSIONS: Illicit drug consumption in the Netherlands appears to correlate positively with urban (in contrast to rural) areas. Wastewater analysis can be used to estimate the volume and monetary value of illicit drug markets as a proof of concept.

Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine.

OBJECTIVE: To determine whether the psychostimulant lisdexamfetamine improves subjective and objective measures of cognitive functioning among women genetically at-risk for cancer who have undergone risk-reducing salpingo-oophorectomy and report new-onset executive functioning difficulties. METHODS: 69 participants were assigned to a randomized controlled crossover trial with 6-week trials of active medication (lisdexamfetamine) and placebo, separated by a minimum 2-week washout in an intent-to-treat framework (clinical trial registration number: NCT03187353). At trial baseline, midpoint, and endpoint, participants completed a self-report measure of executive functioning (Brown Attention Deficit Disorder Scale). At study baseline and trial endpoint, participants completed sustained attention, attention/working memory, and verbal learning/memory cognitive tasks. Side effects were assessed at 2, 3, 4, and 6 weeks for each trial. RESULTS: From trial baseline to trial endpoint, lisdexamfetamine - relative to placebo - significantly improved total scores on the self-report Brown Attention Deficit Disorder Scale (and scores on four of five subdomains) as well as attention and working memory performance. Significantly more participants endorsed side effects across the lisdexamfetamine trial versus placebo; however, trial completion rates were similar, indicating that lisdexamfetamine was nonetheless well-tolerated. CONCLUSIONS: Lisdexamfetamine improved both subjective and objective measures of attention and working memory and could offer women experiencing cognitive difficulties post-risk-reducing salpingo-oophorectomy an alternative therapeutic option.

REM sleep in narcolepsy.

Narcolepsy is mainly associated with excessive daytime sleepiness, but the characteristic feature is abnormal rapid eye movement (REM) sleep phenomena. REM sleep disturbances can manifest as cataplexy (in narcolepsy type 1), sleep paralysis, sleep-related hallucinations, REM sleep behavior disorder, abnormal dreams, polysomnographic evidence of REM sleep disruption with sleep-onset REM periods, and fragmented REM sleep. Characterization of REM sleep and related symptoms facilitates the differentiation of narcolepsy from other central hypersomnolence disorders and aids in distinguishing between narcolepsy types 1 and 2. A circuit comprising regions within the brainstem, forebrain, and hypothalamus is involved in generating and regulating REM sleep, which is influenced by changes in monoamines, acetylcholine, and neuropeptides. REM sleep is associated with brainstem functions, including autonomic control, and REM sleep disturbances may be associated with increased cardiovascular risk. Medications used to treat narcolepsy (and REM-related symptoms of narcolepsy) include stimulants/wake-promoting agents, pitolisant, oxybates, and antidepressants; hypocretin agonists are a potential new class of therapeutics. The role of REM sleep disturbances in narcolepsy remains an area of active research in pathophysiology, symptom management, and treatment. This review summarizes the current understanding of the role of REM sleep and its dysfunction in narcolepsy.

Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.

Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries.

Neural correlates of impulsivity in amphetamine use disorder.

Impulsivity is a trait associated with several psychiatric conditions, not least addictive disorders. While the neural mechanisms behind certain aspects of impulsivity have been studied extensively, there are few imaging studies examining this neurocircuitry in populations with substance use disorders. Therefore, we aimed to examine the functional connectivity of relevant neural networks, and their possible association with trait impulsivity, in a sample with severe amphetamine use disorder and a control group of healthy subjects. We used data collected in a randomized clinical trial studying the acute effects of oral naltrexone in amphetamine use disorder. Our final sample included 32 amphetamine users and 27 healthy controls. Trait impulsivity was rated with the Barratt Impulsiveness Scale-11, and functional connectivity was measured during resting-state fMRI, looking specifically at networks involving prefrontal regions previously implicated in studies of impulsivity. Amphetamine users had higher subjective ratings of impulsivity as compared to healthy controls, and these scores correlated positively with a wide-spread prefrontal hyperconnectivity that was found among the amphetamine users. These findings highlight the importance of aberrant prefrontal function in severe addiction.

Recent advances in treating constipation in children.

INTRODUCTION: Functional constipation (FC) is a common childhood condition, diagnosed via the Rome IV criteria. Standard therapy includes lifestyle and dietary modification followed by initiation of osmotic laxative therapy. About 30% of children continue to experience symptoms related to FC despite appropriate management. New pharmacologic, surgical, and neuromodulatory therapies for FC are now available for use in adult and pediatric populations. In 2023, the first pharmacologic agent, linaclotide, obtained FDA approval for treatment of FC in children 6-17 years old. AREAS COVERED: This article reviews current and emerging pharmacologic, surgical, and neuromodulation therapies for the management of FC in pediatric patients. Efficacy and safety data regarding each of these modalities was reviewed and discussed. EXPERT OPINION: Advancements in therapeutics available for the management of FC necessitate further investigation on safety and efficacy in pediatric populations. Careful consideration should be taken in choosing an available treatment with limited pediatric evidence as adult and pediatric FC have different underlying pathophysiology and require a different therapeutic approach. Standardization of methodology and pediatric endpoints are needed to optimize ability to compare efficacy of different treatments. We predict the future of pediatric FC management will include a personalized approach to care, resulting in improved outcomes.

Impact of opioid overdoses on US life expectancy and years of life lost, by demographic group and stimulant co-involvement: a mortality data analysis from 2019 to 2022.

Background: The United States' opioid crisis is worsening, with the number of deaths reaching 81,806 in 2022 after more than tripling over the past decade. This study aimed to comprehensively characterize changes in burden of opioid overdose mortality in terms of life expectancy reduction and years of life lost between 2019 and 2022, including differential burden across demographic groups and the contribution of polysubstance use. Methods: Using life tables and counts for all-cause and opioid overdose deaths from the National Center for Health Statistics, we constructed cause-eliminated life tables to estimate mortality by age in the absence of opioid-related deaths. We calculated the loss in life expectancy at birth (LLE) and total years of life lost (YLL) due to opioid overdose deaths by state of residency, sex, racial/ethnic group, and co-involvement of cocaine and psychostimulants. Findings: Opioid-related deaths in the US led to an estimated 3.1 million years of life lost in 2022 (38 years per death), compared to 2.0 million years lost in 2019. Relative to a scenario with no opioid mortality, we estimate that opioid-related deaths reduced life expectancy nationally by 0.67 years in 2022 vs 0.52 years in 2019. This LLE worsened in all racial/ethnic groups during the study period: 0.76 y-0.96 y for white men, 0.36 y-0.55 y for white women, 0.59 y-1.1 y for Black men, 0.27 y-0.53 y for Black women, 0.31 y-0.82 y for Hispanic men, 0.19 y-0.31 y for Hispanic women, 0.62 y-1.5 y for American Indian/Alaska Native (AI/AN) men, 0.43 y-1 y for AI/AN women, 0.09 y-0.2 y for Asian men, and 0.08 y-0.13 y for Asian women. Nearly all states experienced an increase in years of life lost (YLL) per capita from 2019 to 2022, with YLL more than doubling in 16 states. Cocaine or psychostimulants with abuse potential (incl. methamphetamines) were involved in half of all deaths and years of life lost in 2022, with substantial variation in the predominant drug class by state and racial/ethnic group. Interpretation: The burden of opioid-related mortality increased dramatically in the US between 2019 and 2022, coinciding with the period of the COVID-19 pandemic and the associated disruptions to social, economic, and health systems. Opioid overdose deaths are an important contributor to decreasing US life expectancy, and Black, Hispanic, and Native Americans now experience mortality burdens approaching or exceeding white Americans. Funding: None.