Prevalence of stimulant use and the role of opioid agonist treatment among people who inject drugs in France: Results from the COSINUS cohort study.

INTRODUCTION: The co-use of stimulants and opioids, including opioid agonist treatment (OAT), is very prevalent worldwide. A large body of data exists on the association between stimulant use and its health complications, and on OAT effectiveness among people with opioid use disorder. However, few data exist on stimulant-opioid co-use among people receiving OAT. Using data from the COSINUS cohort study, we investigated the association between the type of OAT and problematic stimulant use among persons who inject drugs (PWID). METHODS: COSINUS is a 12-month French cohort study of 665 PWID. Data were collected in face-to-face interviews at enrolment, at 6 and 12 months. We defined problematic stimulant use as daily use of and/or injecting stimulants. We used Bayesian model averaging (BMA) to identify factors associated with problematic stimulant use. RESULTS: At baseline, 76% (n = 505) of the participants reported problematic stimulant use. The optimal model from the BMA estimation showed that, after adjusting on social precarity and daily injection, participants on prescribed morphine sulfate as an OAT (compared with methadone) and those who use daily unprescribed buprenorphine were less likely to report problematic stimulant use. DISCUSSION AND CONCLUSIONS: Our work highlights the high prevalence of problematic stimulant use among PWID in France but also the potential association between the type of OAT taken and stimulant use, by suggesting a protective effect of morphine sulfate on stimulant use. Since it has a higher intrinsic activity than other opioids, PWID on this OAT may be less interested in stimulants. Our findings warrant further investigation in clinical studies.

Housing instability increases for stimulant-involved overdose deaths after linking surveillance data to electronic health records in Kentucky.

BACKGROUND: According to the U.S. Centers for Disease Control and Prevention, approximately 10.2 % of fatal overdoses in 2022 were among people experiencing homelessness or housing instability. In the United States, the majority of all drug overdoses now involve stimulants. METHODS: We linked stimulant-involved fatal overdose records occurring between 2017 and 2021 from Kentucky's Drug Overdose Fatality Surveillance System to the electronic health records (EHR) of the state's largest safety-net hospital network. We used State Unintentional Drug Overdose Reporting System (SUDORS) definitions of homelessness or housing instability to establish baseline estimates before linking decedents to medical records. After linkage, we augmented SUDORS data with structured administrative billing codes, semi-structured address data, and unstructured clinical notes identifying homelessness from the EHR. RESULTS: There were 313 individuals with stimulant-involved fatal overdoses linked to at least one medical encounter in the EHR (2017-2021). Thirty-three individuals (10.5 %) were identified as having unstable housing according to SUDORS. After linkage, 130 individuals (41.5 %) had evidence of housing instability. For this period, these 313 individuals represent 8.0 % of stimulant-involved overdoses in KY or 38.5 % of stimulant-involved overdoses from residents of the primary and secondary catchment area of our healthcare network. CONCLUSIONS: The single-site increase in observed housing instability in stimulant-involved fatal overdoses suggests that increased data linkage between state medicolegal death investigation system and EHRs would significantly improve the public health surveillance of overdoses.

Heavy burden of non-fatal overdose among people who inject drugs in San Francisco, 2022.

BACKGROUND: Drug overdose deaths increased by 50 % between 2017 and 2021 in San Francisco. Little is known about non-fatal overdose, which heralds future risk for morbidity and overdose death. We assessed non-fatal overdose, access to drug treatment, and overdose prevention service utilization among people who inject drugs (PWID) in San Francisco in 2022. METHODS: Data were from the National HIV Behavioral Surveillance (NHBS), a cross-sectional survey among PWID recruited by respondent-driven sampling from June-December 2022. Participants self-reported their experience of overall overdose. Logistic regression analysis identified factors associated with non-fatal overdose. RESULTS: Of 521 PWID, 120 (23.0 %) experienced non-fatal overdose; 207 (39.7 %) frequently injected methamphetamine and 175 (33.6 %) frequently injected heroin in the past 12 months. PWID who experienced non-fatal overdose were more likely to reside in the low-income neighborhoods (25.9 % vs. other neighborhoods 16.8 %, p = 0.022) in the past 12 months. Less than half (43.7 %) of PWID who experienced non-fatal overdose received overdose treatment. Compared to those who did not try to access treatment, adjusted odds of non-fatal overdose was 1.89 times higher among PWID who attempted to access drug treatment but were unable to (p = 0.035, 95 % CI 1.05-3.43); and 1.86 times higher among PWID who attempted to obtain medications to treat drug use but were unable to in the past 12 months (p = 0.049, 95 % CI: 1.00-3.43). CONCLUSIONS: Non-fatal overdose was highly prevalent among PWID, including those who frequently inject stimulants. Public health surveillance will need to be vigilant in monitoring stimulant use and tracking fentanyl contamination in non-opioid drugs. PWID who were most engaged in harm reduction practices were also the most likely to experience non-fatal overdose. Expansion of substance use and overdose treatment, naloxone, fentanyl test strips, and safe drug use education are needed to reduce risk of overdose deaths among PWID.

Detection and Characterization of Online Substance Use Discussions Among Gamers: Qualitative Retrospective Analysis of Reddit r/StopGaming Data.

BACKGROUND: Video games have rapidly become mainstream in recent decades, with over half of the US population involved in some form of digital gaming. However, concerns regarding the potential harms of excessive, disordered gaming have also risen. Internet gaming disorder (IGD) has been proposed as a tentative psychiatric disorder that requires further study by the American Psychological Association (APA) and is recognized as a behavioral addiction by the World Health Organization. Substance use among gamers has also become a concern, with caffeinated or energy drinks and prescription stimulants commonly used for performance enhancement. OBJECTIVE: This study aimed to identify substance use patterns and health-related concerns among gamers among a population of Reddit users. METHODS: We used the public streaming Reddit application programming interface to collect and analyze all posts from the popular subreddit, r/StopGaming. From this corpus of posts, we filtered the dataset for keywords associated with common substances that may be used to enhance gaming performance. We then applied an inductive coding approach to characterize substance use behaviors, gaming genres, and physical and mental health concerns. Potential disordered gaming behavior was also identified using the tentative IGD guidelines proposed by the APA. A chi-square test of independence was used to assess the association between gaming disorder and substance use characteristics, and multivariable logistic regression was used to analyze whether mental health discussion or the mention of any substance with sufficient sample size was significantly associated with IGD. RESULTS: In total, 10,551 posts were collected from Reddit from June 2017 to December 2022. After filtering the dataset for substance-related keywords, 1057 were included for further analysis, of which 286 mentioned both gaming and the use of ≥1 substances. Among the 286 posts that discussed both gaming and substance use, the most mentioned substances were alcohol (n=132), cannabis (n=104), and nicotine (n=48), while the most mentioned genres were role-playing games (n=120), shooters (n=90), and multiplayer online battle arenas (n=43). Self-reported behavior that aligned with the tentative guidelines for IGD was identified in 66.8% (191/286) posts. More than half, 62.9% (180/286) of the posts, discussed a health issue, with the majority (n=144) cited mental health concerns. Common mental health concerns discussed were depression and anxiety. There was a significant association between IGD and substance use (P<.001; chi-square test), and there were significantly increased odds of IGD among those who self-reported substance use (odds ratio 2.29, P<.001) and those who discussed mental health (odds ratio 1.64, P<.03). CONCLUSIONS: As gaming increasingly becomes highly prevalent among various age groups and demographics, a better understanding of the interplay and convergence among disordered gaming, substance use, and negative health impacts can inform the development of interventions to mitigate risks and promote healthier gaming habits.

"Everything's a Challenge": An Interview Study of ADHD Individuals in the Midst of the Prescription Stimulant Shortage.

BACKGROUND: The shortage of prescription stimulants is an ongoing issue that is impacting the ability of individuals with ADHD to access their medication. Amidst concerns that this shortage may have a substantial impact on individuals' ability to manage their symptoms effectively, this research seeks to understand the experiences and consequences for those affected. METHODS: In this study, we interviewed individuals with ADHD who have been directly impacted by the stimulant shortage. Thematic analysis focused on identifying common themes related to challenges with medication access and the resulting effects on daily living. RESULTS: The study uncovered significant difficulties in accessing ADHD medication due to current shortages, leading to disruptions in the management of ADHD symptoms and subsequent detriments to individuals' professional, educational, and personal lives. Systematic controls aimed at reducing non-medical use were found to exacerbate these access issues, inadvertently compounding the challenges faced by those using medication for legitimate medical needs. Individuals also described ways they coped with the shortage, with some seeking ADHD medication via unofficial channels. CONCLUSION: Our findings highlight the urgency of addressing stimulant shortages to safeguard the wellbeing of individuals with ADHD. This study also calls for a critical review of policy measures regulating stimulant medication access, and their effectiveness at reducing non-medical use given the unintended consequences these regulations appear to have on individuals prescribed these medications for therapeutic purposes.

Understanding the effect of recreational drug use on bone health and musculoskeletal disease in the establishment of pain regimens.

BACKGROUND: The widespread use of recreational drugs has raised concerns regarding their effects on various organ systems. The use of cannabis and opioids in chronic pain management increases their prevalence among patients with musculoskeletal conditions whose bone health may already be compromised. This article aims to review the pathophysiology and toxic effects of recreational drug use on musculoskeletal health to establish appropriate pain regimens for patients with substance use. METHODS: Medical literature published from 1970 until 2022 was identified utilizing MEDLINE/PubMed and the Cochrane Library. In addition to the databases, references were obtained through the use of reference lists of published articles identified by the aforementioned databases. The initial search terms included opioids, inhalants, hallucinogens, cannabis, stimulants, and bone health. There were no methodological limitations in relation to the initial acquisition and analysis of data. RESULTS: A total of 55 research articles were included in this review. Cannabis, stimulants, opioids, and inhalants impact bone maintenance, specifically osteoblast and osteoclast activity, as well as impede hormone production. These substances inhibit bone remodeling and development, manifesting as lower bone mineral density and increased fracture risk in chronic users. CONCLUSION: Although the current literature suggests a deleterious effect of recreational drugs on bone health and musculoskeletal disease, further research is warranted to evaluate the clinical effects of long-term substance use. The evaluation of such effects will aid in establishing appropriate pain regimens, as well as appropriate screening and treatment plans for recreational drug users.

Social homeostasis and psychoactive drugs: What can we learn from opioid and amphetamine drug challenge studies in humans?

BACKGROUND: Social disequilibrium, or disrupted social homeostasis, underlies many behavioral disorders, including problematic drug use. One way to study the relationship between drug use and social homeostasis is to determine whether single doses of psychoactive drugs relieve some of the discomfort of social isolation and promote social connection. METHODS: In this narrative review, we discuss challenges and opportunities in studying the relationship between psychoactive drugs and social homeostasis. Using the examples of opioids and amphetamines, we discuss the evidence that drugs alleviate dysphoria related to lack of social connection or produce pro-social effects that improve connection. RESULTS: With regard to opioid drugs, we report that mu opioid agonists and kappa opioid antagonists reduce distress from social isolation, and mu opioid agonists enhance social reward. Amphetamine-like stimulant drugs, including MDMA, do not seem to act by reducing the distress of social isolation, but they have notable prosocial effects that increase both motivation for social contact and the pleasure derived from interacting socially. CONCLUSIONS: Many questions remain in understanding interactions between drugs and social equilibrium, including whether these effects contribute to problematic drug use. We identify gaps in knowledge, including the effects of drug withdrawal or dependence on social function, or the responses of individuals with psychiatric symptomatology. Understanding these actions on social processes will help to develop novel pharmacologic treatments for clinical problems related to social disequilibrium.

Evaluation of Minimum Reporting Limits to Determine In-Competition Use of Stimulants.

The applicability of urinary minimum reporting limits (MRLs) to determine in-competition use of prohibited substances is an evolving topic. Most stimulants are subject to a universal MRL, despite the wide range of commercially available dosages for commonly used stimulants. Further, it is unknown whether the urinary MRL is reflective of a pharmacological dose ingested after the start of the in-competition period. To evaluate whether urinary MRLs can distinguish between in-competition and out-of-competition use, a controlled administration study was performed with three commonly used stimulants-amphetamine, methylphenidate, and modafinil at relatively low but therapeutically relevant dosages. Four to six volunteers were administered a particular drug once per day for five consecutive days. Urine, serum, dried blood spots (DBS), and oral fluid (OF) were collected during the active administration period and for 48 h after cessation of use. For all participants, urinary concentrations for all target analytes exceeded the MRL even 48 h after cessation of use. In serum and DBS, most volunteers showed detectable amounts at 48 h post use. Peak concentrations were variable between target compounds even with similar administered dosages. Further, there was a reproducible difference between serum and DBS concentrations. Interpretation of results from OF measurements was challenging due to the inability to normalize for hydration status and OF viscosity. Analyte concentrations decreased steadily over the washout period but did not correlate across matrices for all target analytes. The study reiterates the challenges associated with determining in-competition use by relying on urinary concentrations.

Naloxone Administration and Survival in Overdoses Involving Opioids and Stimulants: An Analysis of Law Enforcement Data from 63 Pennsylvania Counties.

Background: In consideration of rising deaths from opioid-stimulant-involved overdoses in the United States, this study explored rates of naloxone administration and survival in opioid overdoses with versus without stimulants co-involved. Methods: The study used data from the Pennsylvania Overdose Information Network, focusing on 26,635 suspected opioid-involved overdose events recorded by law enforcement and other first responders in 63 Pennsylvania counties from January 2018 to July 2024. Relative frequencies and chi-square tests were first used to compare suspected opioid overdoses with, versus without, stimulants (cocaine or methamphetamine) co-involved. Next, mediation analyses tested naloxone administration as a mediator of the association between stimulant co-involvement (in opioid overdoses) and survival. Results: Naloxone was reportedly administered in 72.2% of the opioid-no-cocaine overdoses, compared to 55.1% of the opioid-cocaine-involved overdoses, and 72.1% of the opioid-no-methamphetamine overdoses vs. 52.4% of the opioid-methamphetamine-involved overdoses. With respect to survival rates, 18.0% of the opioid-no-cocaine overdoses ended in death, compared to 41.3% of the opioid-cocaine overdoses; 18.1% of the opioid-no-methamphetamine overdoses ended in death, versus 42.9% of the opioid-methamphetamine overdoses. In mediation analyses (adjusted for demographics, county, year, and other drug co-involvement), naloxone administration mediated 38.7% (95% Confidence Interval [CI], 31.3%-46.0%) of the association between cocaine co-involvement and survival and 39.2% (95% CI, 31.3%-47.1%) of the association between methamphetamine co-involvement and survival. Conclusions: Among suspected opioid overdose events recorded in the Pennsylvania Overdose Information Network, stimulant co-involvement was associated with lower naloxone administration and higher fatality, with naloxone partially mediating the association between stimulant co-involvement and death.

Association between exposure to antidepressants and stimulants and age at onset of mania or psychosis: A retrospective population-based cohort study.

This study investigated the impact of prior antidepressant and stimulant exposure on the age at onset (AAO) of first episode mania (FEM) or psychosis (FEP). Patients with FEP and FEM born after 1985 in Olmsted County, Minnesota, were identified using the Rochester Epidemiology Project. Duration and peak dose of antidepressant and stimulant exposure were quantified by review of the electronic health record. Peak doses were converted to defined daily dose (DDD), and cumulative exposure was calculated as DDD multiplied by treatment duration. Linear models were used to assess relationships between AAO with any exposures, and cumulative antidepressant and stimulant exposures. A total of 190 FEM/FEP patients (mean AAO=20.8 ± 3.7 years) were included. There was no significant difference in AAO with vs. without exposure to antidepressants or stimulants. Cumulative antidepressant exposure correlated with a later AAO in overall sample (r = 0.28, p < 0.001), and in FEP (r = 0.33, p < 0.001). No significant correlation emerged between cumulative stimulant exposure and AAO. Multivariable modeling confirmed that cumulative antidepressant exposure (Estimate=2.42, 95 %CI=1.66-3.18, p < 0.001), but not cumulative stimulant exposure (Estimate=-0.04, 95 %CI=-1.10-1.02, p = 0.94), was associated with later AAO. Antidepressant and stimulant exposures were not associated with earlier AAO. However, cumulative antidepressant exposure was associated with later AAO. Limitations include retrospective design and relatively small sample size. Our findings may inform adolescent treatment recommendations when assessing risk for psychotropic-related adverse events. Further risk modeling investigations of antidepressants and stimulants with larger sample sizes are needed to explore the role of antidepressant and stimulant exposure in the trajectory leading to FEM/FEP.

Unraveling how hydrogen-bonding networks affect the capture of amphetamine-type stimulants by polymerized deep eutectic solvent modified magnetic biochar: Coupling quantum chemical calculations with experiment.

The abuse of amphetamine-type stimulants (ATSs) has caused irreversible harm to public safety and ecosystems. A novel polymerized deep eutectic solvent modified magnetic pomelo peel biochar (PMBC) was prepared, and the differences in adsorption of four abused amphetamine-type stimulants (ATSs: AMP, MAMP, MDA and MDMA) were due to varying hydrogen bonds quantities and strengths. PMBC showed excellent chemical reactivity to MDMA, with a maximum adsorption capacity of 926.13 µg g-1, which was 3.25, 2.52 and 1.15 times higher than that of AMP, MAMP and MDA, respectively. Modern spectral analysis showed that there were a series of active centers (-COOH, -NH2 and -OH) on the PMBC, which could form hydrogen bond networks with the nitrogen and oxygen functional groups of ATSs. In various chemical environments: pH level (4-11), inorganic ion and organic matter (humic acid), PMBC maintained high activity towards four ATSs. Additionally, the quantum chemical calculations revealed that the methylenedioxy bridge of ATSs can increase the active sites, and the -NH- and -NH2 groups had different hydrogen bond formation capabilities, which together resulted in the adsorption order of PMBC on the four ATSs: MDMA > MDA > MAMP > AMP. Moreover, the hydrogen-bonding binding energies of several common hydrogen-bonding types were compared, including O-H····O, N-H····O/O-H····N and N-H···N. This study laid an empirical and theoretical foundation for the efficient capture of ATSs in water and contributed to the innovative design of materials.

Risk of Incident Psychosis and Mania With Prescription Amphetamines.

OBJECTIVE: Amphetamine prescribing has increased in the United States in recent years. Previous research identified an increased risk of incident psychosis with prescription amphetamines. The purpose of this study was to examine the impact of dose levels of prescription amphetamines on the risk of this rare but serious adverse outcome. METHODS: A case-control study using electronic health records was conducted to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients ages 16-35 hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and/or anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use. RESULTS: Among 1,374 case subjects and 2,748 control subjects, the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio=2.68, 95% CI=1.90-3.77). A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania. Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio=0.91, 95% CI=0.54-1.55). CONCLUSIONS: Although use of hospitalized control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania.

Factor VIII stimulants and other novel therapies for the treatment of von Willebrand disease: what's new on the horizon?

INTRODUCTION: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting about 0.6% to 1.3% of the population, and is characterized primarily by mucocutaneous bleeding secondary to defective platelet adhesion and aggregation. Current therapeutic options for those with severe disease are limited and require frequent intravenous infusions. AREAS COVERED: This review discusses the current and recently completed clinical trials involving pathways to FVIII augmentation for the treatment of VWD. Clinical trials registered on clinicaltrials.gov and published data via PubMed searches through June 2024 were included. EXPERT OPINION: Available treatment options to those with VWD are limited in part due to limited clinical trials, the complexity of VWD types, and the pharmacokinetics of current treatment options. The development of therapeutic options that reduce treatment burden is necessary to improve quality of life and reduce bleeding complications and in recent years there has been an increased interest from industry to apply novel therapeutics for VWD. The FVIII mimetic, emicizumab, has demonstrated early success in patients with severe VWD and is a promising treatment option for those who require prophylaxis. Furthermore, products like efanesoctocog alfa (Altuviiio®) and BT200 have achieved enhanced VWF/FVIII half-life extension could expand the current treatment landscape while concurrently minimizing treatment burden.

Trends in toxicological findings in unintentional opioid or stimulant toxicity deaths in Québec, Canada, 2012-2021: Has Québec entered a new era of drug-related deaths?

INTRODUCTION: We aimed to describe rates and toxicological findings of unintentional opioid and stimulant toxicity deaths, 2012-2021. METHODS: The dataset included accidental deaths determined by the Coroner to be due to opioids or stimulants. We calculated annual crude mortality rates and described combinations of drugs identified in toxicological examinations of these deaths. We described temporal trends in the detection of specific opioids, stimulants, benzodiazepines (including novel benzodiazepines), gabapentinoids and z-drugs in deaths due to opioids and stimulants. RESULTS: Mortality rates increased over time, reaching their peak in 2020 and remaining high in 2021. In deaths due to opioids, there was a decline in the proportion of deaths involving pharmaceutical opioids after 2019, and a corresponding increase in the proportion of deaths with fentanyl detected. Benzodiazepines were often present in deaths due to opioids, with novel benzodiazepines increasing rapidly from 2019 onwards. Cocaine was the most frequently detected drug in deaths due to stimulants, but amphetamine/methamphetamine was detected in around half of all stimulant deaths from 2016 onwards. DISCUSSION AND CONCLUSIONS: Despite availability of a multitude of overdose prevention interventions, mortality rates due to drug toxicity have increased in Québec. Toxicological findings of these deaths suggest concerning shifts in the illicit drug market, with Québec potentially having entered a new era of elevated overdose mortality. Intervention scale-up is essential, but unlikely to be sufficient, to reduce drug-related mortality. Policy reform to address the root causes of drug toxicity deaths, including an unpredictable drug supply, strained health systems and socio-economic precarity, is essential.

Stimulant medications in the management of bulimia nervosa and anorexia nervosa in patients with and without comorbid attention deficit hyperactivity disorder: A systematic review.

OBJECTIVE: People with attentional problems are at increased risk of eating disorders. This paper aimed to systematically review and synthesize the existing evidence on stimulant medication in the management of patients with bulimia nervosa (BN) or anorexia nervosa (AN) with or without comorbid attention deficit hyperactivity disorder (ADHD). METHOD: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A protocol for the review was registered with Open Science Framework (OSF) Registry and critical appraisal of the literature was conducted using Joanna Briggs Institute (JBI) Critical Appraisal Tools. RESULTS: Thirteen articles met inclusion criteria including two quasi-experimental studies, one randomized controlled trial, four case series, and six case reports. 26 cases were included from studies and 32 from case series/reports. Only two cases from a single case report had a diagnosis of AN, while the remainder had BN. Stimulants included methylamphetamine, lisdexamfetamine, methylphenidate, dextroamphetamine sulphate and mixed amphetamine salt. In nearly all cases of BN there were reported reductions in eating disorder symptoms. The rates of adverse effects were high and included weight loss, decreased appetite, tachycardia, dry mouth, fatigue, insomnia, restlessness, nausea, bruxism, headache, palpitations, blood pressure changes, irritability, anxiety, depressed mood, and diaphoresis. CONCLUSION: There is currently insufficient evidence to support the use of stimulant medications to treat symptoms of BN or AN. The authors recommend considering screening patients with BN for ADHD.

Preventing overdoses involving stimulants: the POINTS study protocol.

BACKGROUND: In recent years, overdoses involving illicit cocaine, methamphetamine, and other stimulants have increased in the U.S. The unintentional consumption of stimulants containing illicit fentanyl is a major risk factor for overdoses, particularly in Massachusetts and Rhode Island. Understanding the drug use patterns and strategies used by people who use stimulants (PWUS) to prevent overdose is necessary to identify risk and protective factors for stimulant and opioid-involved overdoses. Mixed-methods research with people who distribute drugs (PWDD) can also provide critical information into the mechanisms through which fentanyl may enter the stimulant supply, and the testing of drug samples can further triangulate PWUS and PWDD perspectives regarding the potency and adulteration of the drug supply. These epidemiological methods can inform collaborative intervention development efforts with community leaders to identify feasible, acceptable, and scalable strategies to prevent fatal and non-fatal overdoses in high-risk communities. METHODS: Our overall objective is to reduce stimulant and opioid-involved overdoses in regions disproportionately affected by the overdose epidemic. To meet this long-term objective, we employ a multi-pronged approach to identify risk and protective factors for unintentional stimulant and opioid-involved overdoses among PWUS and use these findings to develop a package of locally tailored intervention strategies that can be swiftly implemented to prevent overdoses. Specifically, this study aims to [1] Carry out mixed-methods research with incarcerated and non-incarcerated people who use or distribute illicit stimulants to identify risk and protective factors for stimulant and opioid-involved overdoses; [2] Conduct drug checking to examine the presence and relative quantity of fentanyl and other adulterants in the stimulant supply; and [3] Convene a series of working groups with community stakeholders involved in primary and secondary overdose prevention in Massachusetts and Rhode Island to contextualize our mixed-methods findings and identify multilevel intervention strategies to prevent stimulant-involved overdoses. DISCUSSION: Completion of this study will yield a rich understanding of the social epidemiology of stimulant and opioid-involved overdoses in addition to community-derived intervention strategies that can be readily implemented and scaled to prevent such overdoses in two states disproportionately impacted by the opioid and overdose crises: Massachusetts and Rhode Island.

Gabapentinoids increase the potency of fentanyl and heroin and decrease the potency of naloxone to antagonize fentanyl and heroin in rats discriminating fentanyl.

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperadine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine discrimination dose-effect function to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures. Significance Statement The number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically with gabapentinoids commonly detected in opioid overdose victims. This study reports that in rats gabapentinoids increase the potency of fentanyl and heroin to produce discriminative stimulus effects while decreasing the potency of naloxone to antagonize those effects of fentanyl and heroin. These results can help guide policies for regulating gabapentinoids and treating opioid misuse and overdose.

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.

Placebo-related improvement with methylphenidate treatment in children with ADHD.

Non-specific effects of methylphenidate treatment, including expectancy and regression to the mean effects, contribute to the overall effect of methylphenidate on attention-deficit/hyperactivity disorder (ADHD) symptoms. Knowledge on the extent to which non-specific effects contribute to the overall effect and whether regression to the mean explains part of the non-specific effects, is currently lacking. A double-blind, randomized, placebo-controlled, cross-over trial was used to compare parent and teacher ratings of child ADHD symptoms at baseline and during treatment with placebo and 5, 10, 15 and 20 mg of methylphenidate, twice daily. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). The extent to which non-specific effects contributed to the effects of methylphenidate was determined by ADHD symptom reductions observed with placebo versus reductions observed with active doses of methylphenidate. The influence of regression to the mean was examined by estimating the contribution of baseline ADHD symptom severity to the effects observed with placebo treatment. Data were analyzed using multilevel analyses. We observed significant non-specific effects of methylphenidate for parent-rated ADHD symptoms, but not for teacher-rated symptoms. For parent reported hyperactive/impulsive symptoms, higher baseline symptoms predicted larger effects with placebo, indicating regression to the mean effects. For parent-reports, a significant part of the overall effect of methylphenidate treatment is explained by non-specific effects. Our findings stress the importance of taking non-specific effects into account when evaluating methylphenidate treatment, by including teacher-reports and using a double baseline assessment during titration. Comparing active medication with a placebo in the titration trial has the potential to identify non-specific effects.