A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation.

Human Vγ9Vδ2 T cells respond to microbial infections and malignancy by sensing diphosphate-containing metabolites called phosphoantigens, which bind to the intracellular domain of butyrophilin 3A1, triggering extracellular interactions with the Vγ9Vδ2 T cell receptor (TCR). Here, we examined the molecular basis of this "inside-out" triggering mechanism. Crystal structures of intracellular butyrophilin 3A proteins alone or in complex with the potent microbial phosphoantigen HMBPP or a synthetic analog revealed key features of phosphoantigens and butyrophilins required for γδ T cell activation. Analyses with chemical probes and molecular dynamic simulations demonstrated that dimerized intracellular proteins cooperate in sensing HMBPP to enhance the efficiency of γδ T cell activation. HMBPP binding to butyrophilin doubled the binding force between a γδ T cell and a target cell during "outside" signaling, as measured by single-cell force microscopy. Our findings provide insight into the "inside-out" triggering of Vγ9Vδ2 T cell activation by phosphoantigen-bound butyrophilin, facilitating immunotherapeutic drug design.

Withdrawal from 3-Fluoroethamphetamine induces hyperactivity and depression-like behaviors in male mice.

3-Fluoroethamphetamine (3-FEA) belongs to the amphetamine class of stimulant drugs and functions as a releasing agent for the monoamine neurotransmitters norepinephrine, dopamine, and serotonin. 3-FEA acts on the central nervous system and elicits physical and mental side effects, such as euphoria, increased heart rate, and excitement. However, little is known about the withdrawal symptoms and behavioral changes induced by 3-FEA administration. This study aimed to evaluate the short-term consequences of 3-FEA administration (twice a day, 7 days, i.p.; 1 and 10 mg/kg) in C57BL/6J mice (male, 7 weeks old) at three behavioral levels following 1-4 days of withdrawal. The evaluation included (1) withdrawal score, (2) hyperactivity (open field [OF], elevated plus maze [EPM], and cliff avoidance [CA] test), and (3) depression-like behavior (forced-swim test). In the withdrawal score test, withdrawal behavior increased in all 3-FEA groups at 16 and 40 h after withdrawal. In the OF, EPM, and CA tests, the 3-FEA administration group showed significant changes in terms of hyperactivity. In addition, in the forced-swim test, both the 1 mg/kg and 10 mg/kg 3-FEA groups showed increased immobility time. These findings indicate that 3-FEA administration may lead to physical dependence, demonstrated by the withdrawal score increase and significant changes in hyperactivity and depression-like behavior following repeated administration and drug cessation. In conclusion, this study reveals the adverse consequences of 3-FEA administration and highlights the need for awareness raising and regulatory action to control the use of this new psychoactive substance.

Tumor-targeting bacteria as immune stimulants - the future of cancer immunotherapy?

Cancer immunotherapies have been widely hailed as a breakthrough for cancer treatment in the last decade, epitomized by the unprecedented results observed with checkpoint blockade. Even so, only a minority of patients currently achieve durable remissions. In general, responsive patients appear to have either a high number of tumor neoantigens, a preexisting immune cell infiltrate in the tumor microenvironment, or an 'immune-active' transcriptional profile, determined in part by the presence of a type I interferon gene signature. These observations suggest that the therapeutic efficacy of immunotherapy can be enhanced through strategies that release tumor neoantigens and/or produce a pro-inflammatory tumor microenvironment. In principle, exogenous tumor-targeting bacteria offer a unique solution for improving responsiveness to immunotherapy. This review discusses how tumor-selective bacterial infection can modulate the immunological microenvironment of the tumor and the potential for combination with cancer immunotherapy strategies to further increase therapeutic efficacy. In addition, we provide a perspective on the clinical translation of replicating bacterial therapies, with a focus on the challenges that must be resolved to ensure a successful outcome.

Translating the nuanced risk for substance use among adolescents treated for attention-deficit/hyperactivity disorder (ADHD) into clinical practice: a commentary on McCabe et al. (2023).

In their recent examination of the Monitoring the Future (MTF) data, McCabe et al. (Journal of Child Psychology and Psychiatry, 2023) address the complex, longstanding, and clinically valuable questions of whether and how stimulant medication treatment for adolescents with ADHD relates to their risk for substance use. Here, we expand on the authors' interpretations of their nuanced findings of increased risk for illicit stimulant use and non-prescribed stimulant medication use for youth with later age of medication treatment initiation and shorter treatment duration. We particularly focus on highlighting tangible clinical implications, and we recommend ways future research can build on the authors' findings to further clarify this important issue.

Is age of onset and duration of stimulant therapy for ADHD associated with cocaine, methamphetamine, and prescription stimulant misuse?

BACKGROUND: To assess whether age of onset and duration of stimulant therapy for attention-deficit/hyperactivity disorder (ADHD) are associated with cocaine, methamphetamine, and prescription stimulant misuse during adolescence. METHODS: Nationally representative samples of US 10th and 12th grade students (N = 150,395) from the Monitoring the Future study were surveyed via self-administered questionnaires from 16 annual surveys (2005-2020). RESULTS: An estimated 8.2% of youth received stimulant therapy for ADHD during their lifetime (n = 10,937). More than one in 10 of all youth reported past-year prescription stimulant misuse (10.4%)-past-year cocaine (4.4%) and methamphetamine (2.0%) use were less prevalent. Youth who initiated early stimulant therapy for ADHD (≤9 years old) and for long duration (≥6 years) did not have significantly increased adjusted odds of cocaine or methamphetamine use relative to population controls (ie, non-ADHD and unmedicated ADHD youth). Youth who initiated late stimulant therapy for ADHD (≥10 years old) and for short duration (<1 year) had significantly higher odds of past-year cocaine or prescription stimulant misuse in adolescence than those initiating early stimulant therapy for ADHD (≤9 years old) and for long duration (≥6 years). Youth who initiated late stimulant therapy for ADHD (≥10 years) for short duration (<1 year) had significantly higher odds of past-year cocaine, methamphetamine, and prescription stimulant misuse versus population controls during adolescence. No differences in past-year cocaine, methamphetamine, and prescription stimulant misuse were found between individuals who only used non-stimulant therapy for ADHD relative to youth who initiated early stimulant therapy (≤9 years old) and for long duration (≥6 years). CONCLUSIONS: An inverse relationship was found between years of stimulant therapy and illicit and prescription stimulant misuse. Adolescents with later initiation and/or shorter duration of stimulant treatment for ADHD should be monitored for potential illicit and prescription stimulant misuse.

Strict regulations on energy drinks to protect Minors' health in Europe - It is never too late to set things right at home.

The consumption of energy drinks poses significant risks to minors' health, and strict regulations are urgently needed to protect them. The high caffeine, high sugar, and high caloric content of energy drinks have drawn concern from health professionals. The consumption of energy drinks has been linked to unhealthy dietary behaviors, obesity, and mental health problems in adolescents. The psychoactive and stimulant effects of energy drinks are particularly worrisome, and the marketing of these drinks on social media platforms is also a cause for alarm. In light of these concerns, we strongly recommend policy measures, such as restrictions on the sale of energy drinks to minors, to prevent their health risks. The evidence clearly suggests that energy drinks pose significant risks to minors' health and well-being, and regulatory standards must be implemented without further delay.

Structural Determinants of Health and Markers of Immune Activation and Systemic Inflammation in Sexual Minority Men With and Without HIV.

Among sexual minority men (SMM), HIV and use of stimulants such as methamphetamine are linked with immune activation and systemic inflammation. Throughout the COVID-19 pandemic, SMM encountered financial challenges and structural obstacles that might have uniquely contributed to immune dysregulation and systemic inflammation, beyond the impacts of HIV and stimulant use. Between August 2020 and February 2022, 72 SMM with and without HIV residing in South Florida enrolled in a COVID-19 prospective cohort study. Multiple linear regression analyses examined unemployment, homelessness, and history of arrest as structural correlates of soluble markers of immune activation (i.e., sCD14 and sCD163) and inflammation (i.e., sTNF-α receptors I and II) at baseline after adjusting for HIV status, stimulant use, and recent SARS-CoV-2 infection. Enrolled participants were predominantly Latino (59%), gay-identified (85%), and with a mean age of 38 (SD, 12) years with approximately one-third (38%) of participants living with HIV. After adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use, unemployment independently predicted higher levels of sCD163 (ß = 0.24, p = 0.04) and sTNF-α receptor I (ß = 0.26, p = 0.02). Homelessness (ß = 0.25, p = 0.02) and history of arrest (ß = 0.24, p = 0.04) independently predicted higher levels of sCD14 after adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use. Independent associations exist between structural barriers and immune activation and systemic inflammation in SMM with and without HIV. Future longitudinal research should further elucidate complex bio-behavioral mechanisms linking structural factors with immune activation and inflammation.

Overdose from Unintentional Fentanyl Use when Intending to Use a Non-opioid Substance: An Analysis of Medically Attended Opioid Overdose Events.

Fentanyl-mixed and substituted heroin is well-documented, but less is known about unintentional fentanyl use among people using stimulants. To determine the prevalence of and racial and ethnic disparities in unintentional fentanyl use among people experiencing a medically attended opioid overdose, we reviewed 448 suspected non-fatal overdose cases attended by a community paramedic overdose response team in San Francisco from June to September 2022. We applied a case definition for opioid overdose to paramedic records and abstracted data on intended substance use prior to overdose. Among events meeting case criteria with data on intended substance use, intentional opioid use was reported by 57.3%, 98.0% of whom intended to use fentanyl. No intentional opioid use was reported by 42.7%, with most intending to use stimulants (72.6%), including methamphetamine and cocaine. No intentional opioid use was reported by 58.5% of Black, 52.4% of Latinx, and 28.8% of White individuals (p = 0.021), and by 57.6% of women and 39.5% of men (p = 0.061). These findings suggest that unintentional fentanyl use among people without opioid tolerance may cause a significant proportion of opioid overdoses in San Francisco. While intentional fentanyl use might be underreported, the magnitude of self-reported unintentional use merits further investigation to confirm this phenomenon, explore mechanisms of use and disparities by race and ethnicity, and deploy targeted overdose prevention interventions.

Simultaneous identification of three emergent stimulant laxative adulterants in slimming foods using only one antibody.

Stimulant laxatives were recently found to be abused in slimming foods, resulting in harmful effects on consumers. To ensure the safety of relative products, sensitive yet multiplex immunoassays are crucial in rapid screening of stimulant laxatives. However, there are few immunoassays for these substances, and even less for broad-specific recognition. Thus, in this work, four theoretically promising haptens of emerging stimulant laxative bisacodyl were rationally designed using molecular modeling and synthesized to immune animals, whose feasibility was confirmed by the obtained broad-specific antibody. Based on this unique antibody, a highly sensitive multiplex competitive indirect enzyme-linked immunosorbent assay (ciELISA) was established with low limits of detection for bisacodyl, sodium picosulfate, and BHPM (0.23, 13.68, and 0.11 ng/mL). In spiked sample recovery test and real sample detection, this ciELISA exhibited acceptable consistency with the validation method, demonstrating high accuracy and applicability of our method. This reliable multiplex ciELISA proceeds the rapid screening of stimulant laxatives in slimming foods.

Common and distinct fronto-striatal volumetric changes in heroin and cocaine use disorders.

Different drugs of abuse impact the morphology of fronto-striatal dopaminergic targets in both common and unique ways. While dorsal striatal volume tracks with addiction severity across drug classes, opiates impact ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAcc) neuroplasticity in preclinical models, and psychostimulants alter inhibitory control, rooted in cortical regions such as the inferior frontal gyrus (IFG). We hypothesized parallel grey matter volume changes associated with human heroin or cocaine use disorder: lower grey matter volume of vmPFC/NAcc in heroin use disorder and IFG in cocaine use disorder, and putamen grey matter volume to be associated with addiction severity measures (including craving) across both. In this cross-sectional study, we quantified grey matter volume (P < 0.05-corrected) in age/sex/IQ-matched individuals with heroin use disorder (n = 32, seven females), cocaine use disorder (n = 32, six females) and healthy controls (n = 32, six females) and compared fronto-striatal volume between groups using voxel-wise general linear models and non-parametric permutation-based tests. Overall, individuals with heroin use disorder had smaller vmPFC and NAcc/putamen volumes than healthy controls. Bilateral lower IFG grey matter volume patterns were specifically evident in cocaine versus heroin use disorders. Correlations between addiction severity measures and putamen grey matter volume did not reach nominal significance level in this sample. These results indicate alterations in dopamine-innervated regions (in the vmPFC and NAcc) in heroin addiction. For the first time we demonstrate lower IFG grey matter volume specifically in cocaine compared with heroin use disorder, suggesting a signature of reduced inhibitory control, which remains to be tested directly using select behavioural measures. Overall, results suggest substance-specific volumetric changes in human psychostimulant or opiate addiction, with implications for fine-tuning biomarker and treatment identification by primary drug of abuse.

Childhood abuse and craving in methamphetamine-dependent individuals: the mediating role of alexithymia.

Individuals with a history of childhood abuse (CA, including neglect and abuse by caregivers before the age of 18 years) have more severe substance dependence problems than those without a history of childhood abuse. However, whether a history of CA exacerbates craving and the mechanism of this effect remain largely unknown. The aim of this study was to explore the role of alexithymia in the effects of CA on craving in a large sample of methamphetamine-dependent individuals based on latent vulnerability theory. A total of 324 methamphetamine-dependent individuals who met DSM-5 criteria for substance use disorder were recruited. CA, alexithymia, and craving data were collected from the Childhood Trauma Questionnaire, the Toronto Alexithymia Scale-20, and the Obsessive Compulsive Drug Use Scale, respectively. t tests and ANCOVA were conducted to compare variables between the CA and non-CA groups, while partial correlation and mediation analyses were conducted to examine the potential mediating role of alexithymia in the relationship between CA and craving. Abused methamphetamine-dependent individuals reported higher levels of craving and higher levels of alexithymia than those of non-abused methamphetamine-dependent individuals. Alexithymia partially mediated the link between CA and craving, especially the effect of CA on craving frequency was fully mediated by alexithymia. Our findings reveal that a history of childhood abuse has a lasting effect on craving in stimulant-dependent individuals, and alexithymia contributes to some extent to the severity of substance abuse problems in abused methamphetamine-dependent individuals.

Stimulant-like subjective effects of alcohol are not related to resting-state connectivity in healthy men.

Individual differences in subjective, stimulant-like effects of alcohol are associated with the risk of developing alcohol use disorder. Specifically, individuals who experience more pronounced stimulant-like effects from alcohol are more likely to continue and escalate their usage. The neural basis for these individual differences in subjective response is not yet known. Using a within-subject design, 27 healthy male social drinkers completed three fMRI scans after ingesting a placebo, 0.4 and 0.8 g/kg alcohol, in a randomized order under double-blind conditions. Subjective stimulant effects of alcohol were assessed at regular intervals during each session. Seed-based and regional homogeneity analyses were conducted to evaluate changes in resting-state functional connectivity in relation to the stimulant effect of alcohol. Results indicated that 0.4 g/kg alcohol increased the connectivity to thalamus, and 0.8 g/kg alcohol decreased the connectivity to ventral anterior insula, primarily from the superior parietal lobule. Both doses reduced regional homogeneity in the superior parietal lobule but without an exact overlap with clusters showing connectivity changes in the seed-based analyses. The self-reported stimulant effect of alcohol was not significantly related to changes in seed-based connectivity or regional homogeneity. These findings suggest that alcohol-induced stimulation effects are not related to these indices of neural activity.

Social setting interacts with hyper dopamine to boost the stimulant effect of ethanol.

Alcohol consumption occurring in a social or solitary setting often yields different behavioural responses in human subjects. For example, social drinking is associated with positive effects while solitary drinking is linked to negative effects. However, the neurobiological mechanism by which the social environment during alcohol intake impacts on behavioural responses remains poorly understood. We investigated whether distinct social environments affect behavioural responses to ethanol and the role of the dopamine system in this phenomenon in the fruit fly Drosophila melanogaster. The wild-type Canton-S (CS) flies showed higher locomotor response when exposed to ethanol in a group setting than a solitary setting, and there was no difference in females and males. Dopamine signalling is crucial for the locomotor stimulating effect of ethanol. When subjected to ethanol exposure alone, the dopamine transport mutant flies fumin (fmn) with hyper dopamine displayed the locomotor response similar to CS. When subjected to ethanol in a group setting, however, the fmn's response to the locomotor stimulating effect was substantially augmented compared with CS, indicating synergistic interaction of dopamine signalling and social setting. To identify the dopamine signalling pathway important for the social effect, we examined the flies defective in individual dopamine receptors and found that the D1 receptor dDA1/Dop1R1 is the major receptor mediating the social effect. Taken together, this study underscores the influence of social context on the neural and behavioural responses to ethanol.

Efficacy and Safety of Modafinil for Treatment of Amphetamine-Type Stimulant Use Disorder: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials: Efficacité et innocuité du modafinil pour le traitement des troubles liés à l'usage de stimulants de type amphétamine : revue systématique et méta-analyse d'essais randomisés contrôlés par placebo.

INTRODUCTION: Amphetamine-type stimulants (ATSs) are related to significant harm worldwide, with limited effective pharmacological treatments for ATS use disorder (ATSUD). Modafinil has been explored as a potential treatment for ATSUD. This systematic review and meta-analysis (PROSPERO ID: CRD42023388487) aimed to evaluate the efficacy and safety of modafinil for the treatment of ATSUD. METHODS: A comprehensive search of major indexing sources and trial registries, from inception to search date, was conducted on February 15, 2023, and updated on October 31, 2023. Eligible studies were randomized placebo-controlled trials (RCTs) of modafinil in individuals meeting the criteria for the Diagnostic and Statistical Manual of Mental Disorders, fourth and fifth editions, diagnoses of ATSUD. Eligible studies were assessed for risk of bias, using the Cochrane Risk of Bias tool. The primary outcome included the effect of modafinil on ATS use. Secondary outcomes included retention in treatment, ATS craving, treatment discontinuation due to adverse events (AEs), and serious AEs. Subgroup analysis by modafinil dose was conducted where appropriate. Risk ratio (RR) or Peto's odds ratio (OR) was calculated for the meta-analysis of dichotomous variables and standardized mean difference (SMD) was calculated for the random-effect meta-analysis of continuous variables. RESULTS: Five RCTs (N = 451 participants) were included. Modafinil did not significantly impact ATS use (RR = 0.99; 95% CI, 0.97 to 1.02; p = 0.655), retention in treatment (RR = 1.02; 95% CI, 0.91 to 1.14; p = 0.799), ATS craving (SMD = -0.36; 95% CI, -1.19 to 0.47; p = 0.398), or treatment discontinuation due to AEs (Peto's OR = 0.48; 95% CI, 0.20 to 1.14; p = 0.100). These results were consistent across subgroup analyses. More episodes of serious AEs were reported in the modafinil group than in the placebo group, at higher doses (Peto's OR = 4.80; 95% CI, 1.18 to 19.56, p = 0.029). CONCLUSION: There is currently no evidence suggesting that modafinil has a statistically significant effect on efficacy outcomes in populations with ATSUD. Continued research into effective treatments and harm reduction strategies for ATSUD is essential.

Gender identity, stimulant drug use, and criminal justice history on internalized stigma among a nationally representative sample of adults who misuse opioids.

PURPOSE: The rise of fatal stimulant use among adults who use opioids is a public health problem. Internalized stigma is a barrier to substance use treatment, which is greater for women and populations with criminal justice involvement. METHODS: Using a nationally representative sample of adults in the United States from a probability-based survey on household opinions in 2021, we examined characteristics of women (n = 289) and men (n = 416) who misuse opioids. In gender-stratified multivariable linear regression, we investigated factors associated with internalized stigma, and tested for the interaction of stimulant use and criminal justice involvement. RESULTS: Compared to men, women reported greater mental health symptom severity (3.2 vs. 2.7 on a 1 to 6 scale, p < 0.001). Internalized stigma was similar between women (2.3 ± 1.1) and men (2.2 ± 0.1). Among women and not men, however, stimulant use was positively associated with internalized stigma (0.36, 95% CI [0.07, 0.65]; p = 0.02). Interaction between stimulant use and criminal justice involvement was negatively associated with internalized stigma among women (- 0.60, 95% CI [- 1.16, -0.04]; p = 0.04); among men, the interaction was not significant. Predictive margins illustrate among women, stimulant use eliminated the gap in internalized stigma such that women with no criminal justice involvement had a similar level of internalized stigma as women with criminal justice involvement. CONCLUSION: Internalized stigma between women and men who misuse opioids differed based on stimulant use and criminal justice involvement. Future research should assess whether internalized stigma influences treatment utilization among women with criminal justice involvement.

Loneliness, Methamphetamine Use, and Cardiovascular Risk Factors Among Sexual Minority Men in the COVID-19 Era.

BACKGROUND: Important gaps exist in our understanding of loneliness and biobehavioral outcomes among sexual minority men (SMM), such as faster HIV disease progression. At the same time, SMM who use methamphetamine are approximately one-third more likely than non-users to develop cardiovascular disease. This study examined associations of loneliness, stimulant use, and cardiovascular risk in SMM with and without HIV. METHOD: Participants were enrolled from August 2020 to February 2022 in a 6-month prospective cohort study. The study leveraged self-report baseline data from 103 SMM, with a subset of 56 SMM that provided a blood sample to measure markers of cardiovascular risk. RESULTS: Loneliness showed negative bivariate associations with total cholesterol and LDL cholesterol in the cardiometabolic subsample (n = 56). SMM with methamphetamine use (t(101) = 2.03, p < .05; d = .42) and those that screened positive for a stimulant use disorder (t(101) = 2.07, p < .05; d = .46) had significantly higher mean loneliness scores. In linear regression analyses, negative associations of loneliness with LDL and total cholesterol were observed only among SMM who used methamphetamine. CONCLUSION: We observed lower cholesterol in SMM reporting loneliness and methamphetamine use. Thus, in addition to the observed associations of loneliness with cholesterol, there are important medical consequences of methamphetamine use including cardiovascular risk, higher HIV acquisition risk and progression, as well as stimulant overdose death. This cross-sectional study underscores the need for clinical research to develop and test interventions targeting loneliness among SMM with stimulant use disorders.

Identifying the challenges of policy content related to high-risk sexual behaviors, stimulant drugs, and alcohol consumption in adolescents.

BACKGROUND: This study aims to identify policy content challenges related to high-risk sexual behaviors, stimulant drugs, and alcohol consumption in Iranian adolescents. METHODS: This qualitative study analyzed high-level and national documents pertaining to adolescent health, high-risk sexual behaviors, stimulant, and alcohol consumption in adolescents. The documents, which were published by public organizations between January 1979 and February 2023 and publicly available, were complemented by interviews with policymakers and executives. The study involved reviewing 51 papers and conducting interviews with 49 policymakers and executives at the national, provincial, and local levels who were involved in addressing adolescent behaviors related to high-risk sexual behaviors, stimulant, and alcohol consumption. The data collected was analyzed using conventional content analysis. RESULTS: The study's results involved examining policy content and identifying challenges related to policy content. The analysis revealed that from the beginning of the Iranian revolution in 1979 until the late 1990s, the dominant approach in Iran was to deny the existence of high-risk behaviors among adolescents. However, in the early 2000s, the country began to adopt a new approach that acknowledged the social harms and ineffectiveness of previous strategies. As a result, a new policy framework was introduced to address high-risk behaviors among adolescents. The study's interviews with policymakers and executives identified 12 challenges related to policy content, including parallel programs, lack of institutional mapping, lack of evidence-based policymaking, lack of integrated approach regarding training, late parent training, lack of consideration of all occurrence reasons in adolescents' high-risk behaviors policymaking, and the existence of many abstinence policies regarding high-risk behaviors. CONCLUSIONS: The study's findings suggest that high-risk behaviors among adolescents in Iran are primarily a health issue, rather than a social or ideological one. Unfortunately, ideological approaches, stigma, and policymaking based on anecdotes rather than evidence have had a significant impact on this area. To improve policymaking in this domain, it is crucial to address these challenges by tackling stigma, adopting an integrated and holistic approach, and implementing evidence-based policies that consider all relevant aspects, including adolescents' subcultures and policy audiences. Such an approach can also be useful for other countries facing similar conditions.

Motivation and context of concurrent stimulant and opioid use among persons who use drugs in the rural United States: a multi-site qualitative inquiry.

BACKGROUND: In recent years, stimulant use has increased among persons who use opioids in the rural U.S., leading to high rates of overdose and death. We sought to understand motivations and contexts for stimulant use among persons who use opioids in a large, geographically diverse sample of persons who use drugs (PWUD) in the rural settings. METHODS: We conducted semi-structured individual interviews with PWUD at 8 U.S. sites spanning 10 states and 65 counties. Content areas included general substance use, injection drug use, changes in drug use, and harm reduction practices. We used an iterative open-coding process to comprehensively itemize and categorize content shared by participants related to concurrent use. RESULTS: We interviewed 349 PWUD (64% male, mean age 36). Of those discussing current use of stimulants in the context of opioid use (n = 137, 39%), the stimulant most used was methamphetamine (78%) followed by cocaine/crack (26%). Motivations for co-use included: 1) change in drug markets and cost considerations; 2) recreational goals, e.g., seeking stronger effects after heightened opioid tolerance; 3) practical goals, such as a desire to balance or alleviate the effects of the other drug, including the use of stimulants to avoid/reverse opioid overdose, and/or control symptoms of opioid withdrawal; and 4) functional goals, such as being simultaneously energized and pain-free in order to remain productive for employment. CONCLUSION: In a rural U.S. cohort of PWUD, use of both stimulants and opioids was highly prevalent. Reasons for dual use found in the rural context compared to urban studies included changes in drug availability, functional/productivity goals, and the use of methamphetamine to offset opioid overdose. Education efforts and harm reduction services and treatment, such as access to naloxone, fentanyl test strips, and accessible drug treatment for combined opioid and stimulant use, are urgently needed in the rural U.S. to reduce overdose and other adverse outcomes.

Feasibility, acceptability, and perceived usefulness of a community-evidence-based harm reduction intervention for sexualized stimulant use among Mexican gay, bisexual, and other men who have sex with men.

BACKGROUND: The use of stimulants and other substances with the purpose of enhancing, maintaining, and prolonging sexual activity is known as sexualized substance use. Also known as chemsex, this pattern of use has been mainly explored in high-income countries. The aim of this article was to assess the feasibility, acceptability, and usefulness of a community- evidence-based harm reduction intervention among Mexican gay, bisexual, and other men who have sex with men (gbMSM) adults who reported sexualized stimulant use in the past 6 months and who were not enrolled in any psychosocial treatment. METHODS: The in-person intervention was designed in partnership with gbMSM who used substances. It consisted of 39 harm reduction strategies before, during, and after episodes of use. The components of the intervention were health and self-care, safety, and psychopharmacology. The intervention was delivered at a university campus, a public recreational space, and an HIV public clinic. Feasibility to deliver the intervention was assessed based on enrolment and completion rates; acceptability through a 28-item, 5-point Likert scale (140 max.) constructed and validated for the Mexican population with good reliability coefficients; usefulness through a 5-point Likert scale ("not useful"-"very useful") for each of the 39 strategies; and potential behavioral change by subtracting the likelihood of implementing each strategy minus the frequency of use of the technique before the intervention. RESULTS: Participants (n = 19; recruitment rate = 35.2%; completion rate = 84.2%) rated the intervention as acceptable with a mean score of 121.6 (SD = 7.5). The highest potential for behavioral change was regarding the use of information about the half-life of stimulants, polysubstance use, and overdose prevention. CONCLUSIONS: This intervention is feasible when provided within public health services where potential participants are already in contact. Harm reduction strategies need to surpass sexually transmitted infections prevention and HIV care and focus on substance use and mental health strategies.

Erythrocytic metabolism of ATLX-0199: An agent that increases minute ventilation.

Both L- and D-isomers of S-nitrosocysteine (CSNO) can bind to the intracellular domain of voltage-gated potassium channels in vitro. CSNO binding inhibits these channels in the carotid body, leading to increased minute ventilation in vivo. However, only the l-isomer is active in vivo because it requires the l-amino acid transporter (LAT) for transmembrane transport. In rodents and dogs, the esterified D-CSNO precursor-d-cystine dimethyl ester (ATLX-0199)-overcomes opioid- and benzodiazepine-induced respiratory depression while maintaining analgesia. Although ATLX-0199 can enter cells independently of LAT because it is an ester, its stability in plasma is limited by the presence of esterases. Here, we hypothesized that the drug could be sequestered in erythrocytes to avoid de-esterification in circulation. We developed a liquid chromatography-mass spectrometry method for detecting ATLX-0199 and characterized a new metabolite, S-nitroso-d-cysteine monomethyl ester (DNOCE), which is also a D-CSNO precursor. We found that both ATLX-0199 and DNOCE readily enter erythrocytes and neurons and remain stable over 20 min; thus ATLX-0199 can enter cells where the ester is stable, but the thiol is reduced. Depending on hemoglobin conformation, the reduced ester can be S-nitrosylated and enter carotid body neurons, where it then increases minute ventilation. These data may help explain the paradox that ATLX-0199, a dimethyl ester, can avoid de-esterification in plasma and exert its effects at the level of the carotid body.