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Inquiry : a Journal of Medical Care... 2024Use of heroin, prescription painkillers, methamphetamines, and fentanyl led to a national health crisis in 2017, resulting in 1852 overdose deaths in Indiana. Governor...
Use of heroin, prescription painkillers, methamphetamines, and fentanyl led to a national health crisis in 2017, resulting in 1852 overdose deaths in Indiana. Governor Eric J. Holcomb made tackling substance use in the state one of his highest priorities, calling on all Hoosiers to collaborate. In October 2017, Indiana University (IU) President Michael A. McRobbie responded, announcing that the University would be initiating the Responding to the Addictions Crisis Grand Challenge (AGC). Partners included Governor Holcomb, IU Health, and Eskenazi Health. Leveraging the university's research strengths and partnering with more than 160 community organizations across the state, the AGC sought to address substance use facing Indiana and beyond. Fifty interdisciplinary research projects were created through the AGC, focusing on IU's greatest strength in five areas: (1) education, training, and certification; (2) data science and analysis; (3) policy analysis, economics, and law; (4) basic, applied, and translational research; (5) community engagement and workforce development. Diversity, equity, and inclusion implications were often considered. This supplement describes the IU approach to address the health of the people of the State, investigator initiated projects and research conducted to inform practice, strategy and policy.
Topics: Indiana; Humans; Universities; Substance-Related Disorders; Health Policy
PubMed: 38881186
DOI: 10.1177/00469580241254993 -
Molecular & Cellular Proteomics : MCP Jun 2024Substance use disorder is a major concern, with few therapeutic options. Heparan sulfate (HS) and chondroitin sulfate (CS) interact with a plethora of growth factors and...
Substance use disorder is a major concern, with few therapeutic options. Heparan sulfate (HS) and chondroitin sulfate (CS) interact with a plethora of growth factors and their receptors and have profound effects on cellular signaling. Thus, targeting these dynamic interactions might represent a potential novel therapeutic modality. In the present study, we performed mass spectrometry-based glycomic and proteomic analysis to understand the effects of cocaine and methamphetamine (METH) on HS, CS, and the proteome of two brain regions critically involved in drug addiction: the lateral hypothalamus (LH) and the striatum (ST). We observed that cocaine and METH significantly alter HS and CS abundances as well as sulfate contents and composition. In particular, repeated METH or cocaine treatments reduced CS 4-O-sulfation and increased CS 6-O-sulfation. Since C4S and C6S exercise differential effects on axon growth, regeneration and plasticity, these changes likely contribute to drug-induced neural plasticity in these brain regions. Notably, we observed that restoring these alterations by increasing CS 4-0 levels in the LH by adeno-associated virus (AAV) delivery of an shRNA to Arylsulfatase B (N-acetylgalactosamine-4-sulfatase, ARSB) ameliorated anxiety and prevented the expression of preference for cocaine in a novelty induced conditioned place preference test during cocaine withdrawal. Finally, proteomics analyses revealed a number of aberrant proteins in METH- and cocaine-treated vs. saline-treated mice, including MYPR, KCC2A, SYN2, TENR, CALX, ANXA7, HDGF, NCAN, and CSPG5, and oxidative phosphorylation among the top perturbed pathway. Taken together, these data support the role of HS, CS, and associated proteins in stimulants abuse and suggest that manipulation of HSPGs can represent a novel therapeutic strategy.
PubMed: 38880242
DOI: 10.1016/j.mcpro.2024.100803 -
Biochemical and Biophysical Research... Jun 2024This study introduces an innovative brain-targeted drug delivery system, RVG-Exo/CBD, utilizing rabies virus glycoprotein (RVG)-engineered exosomes for encapsulating...
This study introduces an innovative brain-targeted drug delivery system, RVG-Exo/CBD, utilizing rabies virus glycoprotein (RVG)-engineered exosomes for encapsulating cannabidiol (CBD). The novel delivery system was meticulously characterized, confirming the maintenance of exosomal integrity, size, and successful drug encapsulation with a high drug loading rate of 83.0 %. Evaluation of the RVG-Exo/CBD's brain-targeting capability demonstrated superior distribution and retention in brain tissue compared to unmodified exosomes, primarily validated through in vivo fluorescence imaging. The efficacy of this delivery system was assessed using a behavioral sensitization model in mice, where RVG-Exo/CBD notably suppressed methamphetamine-induced hyperactivity more effectively than CBD alone, indicating a reduction in effective dose and enhanced bioavailability. Overall, the RVG-Exo/CBD system emerges as a promising strategy for enhancing the therapeutic efficacy and safety of CBD, particularly for neurological applications, highlighting its potential for addressing the limitations associated with traditional CBD administration in clinical settings.
PubMed: 38878760
DOI: 10.1016/j.bbrc.2024.150260 -
The American Journal on Addictions Jun 2024Although concurrent stimulant use is common among people with opioid use disorder (OUD), there is little evidence on its impacts on opioid agonist therapy (OAT)...
Impact of baseline methamphetamine/amphetamine use on discontinuation of methadone and buprenorphine/naloxone among people with prescription-type opioid use disorder in Canada.
BACKGROUND AND OBJECTIVES
Although concurrent stimulant use is common among people with opioid use disorder (OUD), there is little evidence on its impacts on opioid agonist therapy (OAT) outcomes. This study sought to determine the impact of baseline methamphetamine/amphetamine use on discontinuation of OAT among individuals with prescription-type OUD (POUD) initiating methadone or buprenorphine/naloxone as part of a pragmatic randomized trial in Canada.
METHODS
Secondary analysis of a pan-Canadian pragmatic trial conducted between 2017 and 2020 comparing supervised methadone versus flexible take-home dosing buprenorphine/naloxone models of care. Cox proportional hazard models were used to evaluate the effect of baseline methamphetamine/amphetamine use (measured by urine drug test [UDT]) on two discontinuation outcomes (i.e., assigned OAT discontinuation, any OAT discontinuation).
RESULTS
Two hundred nine (n = 209) participants initiated OAT, of which 96 (45.9%) had positive baseline methamphetamine/amphetamine UDT. Baseline methamphetamine/amphetamine use was associated with shorter median times in assigned OAT (21 vs. 168 days, hazard ratio [aHR] = 2.45, 95% confidence interval [CI] = 1.60-3.76) and any OAT (25 days vs. 168 days, aHR = 2.06, CI = 1.32-3.24). No interaction between methamphetamine/amphetamine and assigned OAT was observed for either outcome (p > .05).
CONCLUSION AND SCIENTIFIC SIGNIFICANCE
This study offers novel insights on the impact of methamphetamine/amphetamine use on OAT outcomes among people with POUD. Methamphetamine/amphetamine use was common and was associated with increased risk of OAT discontinuation. Supplementary interventions, including treatment for stimulant use, are needed to improve retention in OAT and optimize treatment outcomes in this population.
PubMed: 38877969
DOI: 10.1111/ajad.13619 -
Journal of Pharmaceutical and... Jun 2024Surveillance testing is an essential component to ensuring safe, effective, and high-quality drug products are available in the commercially marketed US supply chain....
Surveillance testing is an essential component to ensuring safe, effective, and high-quality drug products are available in the commercially marketed US supply chain. Surveillance allows the agency to assess product quality and monitor for potential adulteration of drug products being used by consumers. Opioid drug products can be adulterated to enhance the effect of the intended active ingredient. Numerous accounts have been reported where fentanyl has been used as an adulterant in illicit street drugs such as heroin, cocaine, or methamphetamine. To efficiently surveil the legitimate opioid supply chain, an analytical method with the ability to simultaneously detect, identify and quantify opioid molecules is desired. In this study, a multi-opioid protocol (MOP) using liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) technology was developed and validated for the detection and quantification of 27 opioid drugs. The MOP analytical procedure was applied to the analysis of drug substance and finished dosage forms. MOP was used to identify and quantify active pharmaceutical ingredients (API) listed on the label claim, and in the case of suspected economically motivated adulteration could identify and quantify undeclared opioid APIs. The analytical method analysis time was 16 minutes and the LOD and LOQ in full MS mode were (average) 0.3 and 0.8 ng/mL, respectively. The validation criteria parameters were satisfactory based on international guidelines (ICH). The MOP was successfully applied to the analysis of over 160 drug substances and finished products. For all samples tested in the study, their identities were confirmed, and assays met specifications. Overall, there was no evidence of illegal substitution or adulteration in any of the ingredients and products tested from the legitimate commercial marketed US supply chain.
PubMed: 38876038
DOI: 10.1016/j.jpba.2024.116298 -
Traffic Injury Prevention Jun 2024This study examines the results of toxicological tests performed on blood and urine samples collected from suspected drug-impaired drivers in Ontario from 2008 to 2019....
OBJECTIVE
This study examines the results of toxicological tests performed on blood and urine samples collected from suspected drug-impaired drivers in Ontario from 2008 to 2019. The report examines the results of toxicological analysis of the samples submitted, the characteristics of those drivers from whom samples were collected, and the temporal and situational circumstances that led to police investigations and sample collection to better understand drug-impaired driving behavior and to assist in the development and implementation of countermeasure strategies and programs.
METHODS
Blood and urine samples were sent to the Center of Forensic Sciences where they were analyzed using standardized comprehensive toxicological analysis to test for a wide variety of potentially impairing drugs. Demographic and temporal information for each case from which a sample was collected were also examined to describe the circumstances and characteristics of these driving incidents.
RESULTS
During the 12-year period examined, 5,388 samples collected from suspected drug-impaired drivers were analyzed. The number of samples collected increased substantially following the implementation of the Drug Evaluation and Classification Program (DECP) in July 2008, the enactment of legislation facilitating the collection of blood samples from suspects, and the legalization of cannabis for nonmedical purposes in 2018. The number of samples submitted shows temporal correlation with the number of police officers certified as Drug Recognition Experts (DRE) in the province. Over the 12-year period of this study, cannabis was the most frequently detected substance in drivers (52.8% of cases), followed by cocaine (44.3%) and methamphetamine (24.8%). In 80% of cases, more than one substance was detected.
CONCLUSIONS
Examining the characteristics of suspected drug-impaired drivers, the temporal circumstances, and the drug findings throughout the large geographic area of Ontario and over the extended period of this study enhances our understanding of drug-impaired driving behavior. These characteristics can assist in the development and/or evaluation of enforcement strategies and enhanced countermeasure activities.
PubMed: 38875458
DOI: 10.1080/15389588.2024.2355593 -
Diabetes Jun 2024Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor...
Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2 (D2R) and D3 (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.
PubMed: 38869519
DOI: 10.2337/db24-0175 -
Journal of Addiction Medicine Jun 2024Addressing the methamphetamine epidemic will require a more complete understanding of its effect on healthcare systems and of the populations at risk. The objective of...
OBJECTIVES
Addressing the methamphetamine epidemic will require a more complete understanding of its effect on healthcare systems and of the populations at risk. The objective of the study was to assess the impact of methamphetamine use on psychiatric emergency services outcomes and on Asian American (AA) and Pacific Islander (PI) populations, a historically overlooked population in substance use research.
METHODS
A retrospective chart review was performed for all visits to a large level I trauma center in urban Hawaii from 2007 to 2019 that required psychiatric emergency services and in which urine drug screening was completed (N = 44,658). Demographic characteristics and emergency room courses were compared between amphetamine-positive and amphetamine-negative visits.
RESULTS
The proportion of amphetamine-positive visits approximately doubled from 13.3% in 2007 to 25.5% in 2019. Amphetamine-positive visits were more likely to involve arrival by law enforcement (38.3% vs 27.2.%, P < 0.001), require intramuscular psychotropic medications (17.3% vs 12.3%, P < 0.001), and have longer emergency department lengths of stay (median, 420 vs 372 minutes, P < 0.001). Visits by Native Hawaiian and Hispanic/Latino patients had the highest rate of amphetamine positivity, while visits by Chinese and Korean patients had the lowest.
CONCLUSIONS
The findings reveal a concerning rise in amphetamine positivity that is associated with increased resource utilization. There was also significant variability in the rate of amphetamine positivity within the AA and PI population, a group of ethnicities often analyzed as a single entity in previous studies. Culturally sensitive interventions may curb the methamphetamine epidemic's effect on healthcare systems and vulnerable populations.
PubMed: 38869174
DOI: 10.1097/ADM.0000000000001335 -
Der Nervenarzt Jun 2024Consumption of stimulant drugs, a heterogeneous group of addictive substances, has significantly increased in recent years with rising numbers of stimulant-associated... (Review)
Review
BACKGROUND
Consumption of stimulant drugs, a heterogeneous group of addictive substances, has significantly increased in recent years with rising numbers of stimulant-associated intoxication and deaths.
OBJECTIVE
To provide an overview of recent scientific evidence of the diagnosis and treatment of stimulant use disorders.
MATERIAL AND METHODS
A literature review of the neuropathology, clinical presentation, diagnostic criteria and evidence-based treatment for stimulant use disorders.
RESULTS
The chronic use of stimulant drugs is associated with significant physical (e.g., hypertension, tachycardia and dyspnoea) and psychological harm (e.g., dependence, psychotic disorders and affective disorders). Despite major advances in the research of the neuropathology of stimulant use disorder and the refinement of diagnostic criteria, the disorder still presents a challenge, not least because of the lack of effective treatments. There are currently no approved pharmacotherapeutic interventions for stimulant use disorder and meta-analyses show that the efficacy of behavioural interventions is low to moderate, similar to cognitive behavioural treatment.
CONCLUSION
Despite growing insights into the neuropathology associated with stimulant use disorder, treatment remains a challenge. The lack of effective interventions makes it difficult to give clear recommendations for the clinical practice. Further scientific research is thus warranted.
PubMed: 38867056
DOI: 10.1007/s00115-024-01687-5 -
The Journal of Neuroscience : the... Jun 2024We investigated sex differences in dopamine (DA) release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) using a chronic 16-channel carbon fiber electrode...
Sex Differences in Dopamine Release in Nucleus Accumbens and Dorsal Striatum Determined by Chronic Fast Scan Cyclic Voltammetry: Effects of social housing and repeated stimulation.
We investigated sex differences in dopamine (DA) release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) using a chronic 16-channel carbon fiber electrode and fast-scan cyclic voltammetry (FSCV). Electrical stimulation (ES; 60 Hz) induced DA release was recorded in the NAc of single or pair-housed male and female rats. When core (NAcC) and shell (NAcS) were recorded simultaneously, there was greater ES DA release in NAcC of pair-housed females compared with single females and males. Housing did not affect ES NAc DA release in males. In contrast, there was significantly more ES DA release from the DLS of female rats than male rats. This was true prior to and after treatment with methamphetamine. Furthermore, in castrated (CAST) males and ovariectomized (OVX) females, there were no sex differences in ES DA release from the DLS, demonstrating the hormone dependence of this sex difference. However, in the DLS of both intact and gonadectomized rats, DA reuptake was slower in females than in males. Finally, DA release following ES of the medial forebrain bundle at 60 Hz was studied over four weeks. ES DA release increased over time for both CAST males and OVX females, demonstrating sensitization. Using this novel 16-channel chronic FSCV electrode, we found sex differences in the effects of social housing in the NAcS, sex differences in DA release from intact rats in DLS, sex differences in DA reuptake in DLS of intake and gonadectomized rats, and we report sensitization of ES-induced DA release in DLS in vivo. Dopamine release is not uniform or fixed. In the nucleus accumbens, pair housing, compared with individual housing, is shown to differentially affect dopamine responsiveness to stimulation in a sex-dependent and region-specific way. There are also sex differences in stimulated dopamine release in the dorsolateral striatum of intact rats, which are not seen in gonadectomized rats, indicating the hormone dependence of this sex difference. However, reuptake of dopamine was slower in females than in males, independent of gonadal hormones. Importantly, the electrical stimulation-induced dopamine release in the dorsolateral striatum of gonadectomized rats demonstrated sensitization of dopamine release in vivo within animals for the first time. Thus, stimulated dopamine release exhibits sex-specific neuroplasticity that is modified in females by the housing conditions.
PubMed: 38866486
DOI: 10.1523/JNEUROSCI.1527-23.2024