Background: Canada continues to face an opioid epidemic with 5,368 opioid apparent related deaths occurring between January and September of 2021. Methadone Maintenance Treatment (MMT), a form of Medication Assisted Treatment used to treat Opioid Use Disorder (OUD), has been reported to decrease opioid cravings and opioid use, however, individual differences exist in the effective dose of methadone. Further, individuals living with an OUD have higher rates of substance use including cannabis. A genetic component has been suggested to exist for both cannabis use and MMT outcomes, however inconsistent findings have been reported. Methods: Knowledge synthesis and primary genetic association studies were conducted. A protocol was prepared for the planning of a systematic review for Genome-Wide Association Studies (GWASs) of cannabis use. The full systematic review was then conducted, providing an assessment of the literature and a description of studies quality. A GWAS and Polygenic Risk Score (PRS) was then conducted for cannabis use and MMT outcomes, separately, in Europeans only. The top Single Nucleotide Polymorphisms (SNPs) were then analyzed separately by sex and sex interactions were conducted. Results: The systematic review included 6 studies, identifying 96 genetic variants associated with cannabis use. The GWASs for both cannabis use and MMT outcomes did not identify any significant results. A significant PRS was found for regular cannabis use and methadone dose. No sex-specific results were identified. Discussion: This thesis summarised the evidence on the genetics of cannabis use as well as employed GWASs and PRSs to investigate cannabis use and MMT outcomes within a European population. We were able to highlight gaps within the genetic literature of cannabis and MMT outcomes as well as identify areas of interest for future research. / Dissertation / Doctor of Philosophy (PhD) / Cannabis use rates in Canada are increasing, with Opioid Use Disorder (OUD) patients having high rates of cannabis use despite inconsistent findings on the impacts. To combat the opioid crisis, Methadone Maintenance Treatment (MMT) is utilized to reduce opioid cravings and use. However, individuals on MMT are likely to use other substances, including cannabis. This thesis explores the genetic literature on cannabis use and conducts a Genome-Wide Association Study (GWAS) and a Polygenetic Risk Score (PRS). The GWAS investigates genetic variants throughout the whole genome associated with a trait, while the PRS creates a genetic weight risk score. GWAS and PRS methods were used to investigate cannabis use and MMT outcomes within Europeans with OUD. While no significant GWAS results were found, a statistically significant PRS was found for regular cannabis use and methadone dose, suggesting each respective score can estimate an individual’s risk of that trait.

Background: Opioid use disorder (OUD), prescription opioid misuse, and increased heroin use are major public health crises in the US. Excessive non-medical use of prescription opioids and illicit drugs can alter the brain, disrupt mental health, and increase the risk of blood-borne illnesses and bacterial infections. The CDC reported that opioids caused nearly 70% of the 67,367 overdose deaths in 2018. Rural areas have high prescription and illicit drug use rates, limited resources, and unique challenges. There is an emerging need to understand rural residents' perspectives on OUD and substance use disorder (SUD) in their community in order to implement efforts. A community-based participatory research (CBPR) approach addresses the need for a systematic participatory solutions, and reduces community opposition and promotes sustainable, culturally appropriate interventions that can reduce the health-related harms caused by substance abuse. Methods: Two studies were conducted using CBPR principles to address the opioid crisis in a rural Southern Virginia community. Study I aimed to provide insight into community members' perceptions, knowledge, and experiences with OUD/SUD to inform community-led strategies. Study II assessed whether a virtual community platform with a Nominal Group Technique (NGT) can build consensus around Comprehensive Harm Reduction (CHR) in the same rural Southern Virginia community. Study II used the Community Readiness Model (CRM) and assessment tool. Stakeholder focus groups were conducted by a participatory research team, EM, as part of a larger project using the Stakeholder Engagement in quEstion Development (SEED) method. To assess the community's readiness to implement CHR using the CRM, Study II used semi-structured qualitative interviews with key stakeholders. The results of the readiness assessment were then used to inform a virtual community forum with members of a drug-free coalition. On the basis of CRM interview themes and findings, the forum used the NGT consensus-building technique. Results: The primary themes identified in the analysis of the community stakeholder focus groups conducted for Study I included the importance of family dynamics and social networks as risk and resiliency factors, addressing hopelessness as a preventive strategy, the need for holistic approaches to treatment, childhood exposure resulting in intergenerational substance use, the needs of overburdened healthcare providers, the expansion of long-term rehabilitation programs, and the need for judicial reform towards those with OUD. Comprehensive methods to address OUD's complexity require specific and well-defined strategies. Understanding the factors that contribute to OUD in rural communities should be the first step in developing actions. The overall community readiness score for Study II was 4.07, indicating the community is still in the pre-planning stage for bring CHR to the community. The majority of key informants believe that leaders and community members recognize the problem of SUD/OUD harms and that something should be done to improve and integrate harm reduction efforts. The forum had 12 attendees. The community forum produced 13 topics and a list of action priorities that at least 80% of participants agreed on. The two areas of high priority included: (1) raising awareness of secondary harms of SUD/OUD and available resources to assist the community, and (2) reducing the stigma associated with CHR and appeal to people's sense of humanity in order to create an environment conducive to understanding and increase buy-in around CHR. Implications: Both studies show rural stakeholders can help curb the drug epidemic. Their knowledge of internal community dynamics and needs allows them to prioritize actions to improve health outcomes. In addition, Study II demonstrated the effectiveness of the CR Model in determining community readiness to adopt CHR and the value of a virtual community forum in conjunction with an NGT process in fostering stakeholder consensus. / Doctor of Philosophy / Background: Opioid use disorder (OUD), prescription opioid misuse, and rising heroin use are major public health crises in the US. Taking too many prescription opioids or illegal drugs can be harmful. This can alter the brain, cause stress, and increase the risk of blood-borne illnesses and infections. Opioids caused nearly 70% of the 67,367 overdose deaths in 2018, according to the Centers for Disease Control and Prevention. Rural areas have high prescription and illicit drug use rates, limited resources, and unique issues. There is an emerging need to understand rural residents' perspectives on OUD and substance use disorder (SUD) in their community in order to implement efforts. Thus, this research which is based on the principles of Community-Based Participatory Research (CBPR) was conducted to help address this need. To reduce the health-related harms caused by substance abuse, CBPR promotes sustainable, culturally applicable interventions. Methods: Two studies used CBPR to address the opioid crisis in rural Southern Virginia. The goal of Study I was to gain insight into community members' perspectives, knowledge, and experiences to inform community-led action. For the first study, a community-research team, EM, conducted group discussions with community members as part of a larger project that used a participatory approach to unite the community in actions to address OUD in their community. Study II used the Community Readiness Model (CRM) and an assessment tool to determine community readiness for comprehensive harm reduction (CHR). The study also wanted to see how a virtual community platform with a consensus building process could help build agreement around CHR. In Study II, key stakeholders were interviewed to assess the community's readiness for CHR. Then a virtual community forum with members of a drug-free coalition was held. The forum got responses and put them in order based on themes and results from CRM interviews. Results: We learned from the first study, family dynamics, social networks, hopelessness, intergenerational substance use, and healthcare provider needs all influence risk and resilience. Long-term rehab programs should be expanded, and the justice system should treat OUD differently. Detailed methods to address OUD's complexity require specific and well-defined strategies. Understanding what causes OUD in rural communities should be the first step in finding solutions. Study II found that the community is still in the pre-planning stage, with a score of 4.07 out of 9, indicating that leaders and community members recognize that the harms associated with OUD are a problem and something should be done to improve and incorporate harm reduction efforts. The results of the community forum also show a list of important topics on which at least 80% of participants agreed. The two areas of high importance were: (1) raising awareness of secondary harms and available resources to help the community, and (2) lowering the stigma associated with CHR to make it easier for people to understand, but be deliberate in appealing to people's sense of humanity to get them to buy into CHR. Conclusions: Both studies show that people who live in rural areas can help solve the local drug problem. Their understanding of how needs change within a community gives us a unique way to improve health outcomes. Study II found that using CRM and a virtual consensus-building process can aid stakeholders in reaching an agreement on how to address issues. Study II also showed how useful it is to use a virtual community forum and an NGT process to figure out if a community is ready for CHR.

This study examines participant perspectives of medically assisted treatment (MAT) for opioid use disorder (OUD) in relation to critical factors such as overdose risk, stigma, housing, access, mental health, and criminal behavior. Nineteen participants were recruited from a residential treatment center for SUDs (substance use disorders) and asked about how MAT impacts these factors and their recovery. Findings indicate that MAT has positive impacts on perceptions of the ability to recover, overdose risk, mental health, and criminal behavior. However, there are significant flaws in the current system, including barriers to access and housing opportunities. These issues illustrate the need for changes in the current infrastructure of MAT and SUDs treatment that enable the many benefits of MAT.

Background: Outcomes are integral to psychiatry research for evaluating intervention effectiveness in randomized controlled trials (RCTs) and understanding disease progression in observational research. Carefully defined, measured, and consistently used outcomes guide clinical decision-making and enhance research applicability. Bridging methodological gaps through rigorous assessment is essential for minimizing variability and mitigating research waste. Objectives: This dissertation aims to assess: (i) outcome selection in geriatric depression RCTs, (ii) primary outcome reporting in these trials, and (iii) measurement of multimorbidity patterns in observational research on people with opioid use disorder (OUD). Methods: Three studies were conducted: (i) a systematic survey examining outcome selection heterogeneity in geriatric depression RCTs (2011-2021), (ii) an assessment of primary outcome reporting comprehensiveness in these trials, and (iii) an observational study using hierarchical cluster analysis (HCA) and K-means clustering to compare statistical techniques for measuring multimorbidity patterns among people with OUD. Results: Findings suggest variability in outcome selection, reporting, and measurement in psychiatry research. (i) The systematic survey revealed significant heterogeneity in outcomes and outcome measurement instruments (OMIs) in geriatric depression RCTs, impeding cross-study comparisons. (ii) The assessment of primary outcome reporting highlighted variability and insufficiency in reporting the rationale for outcome selection, measurement properties of OMIs, and criteria for clinically meaningful change, limiting the interpretability of trial findings. (iii) The observational study on multimorbidity patterns among people with OUD identified significant variations in chronic condition clusters using HCA and K-means clustering, indicating the need for careful consideration of statistical techniques in outcome measurement to inform clinical care accurately. Conclusion: These findings highlight the need for standardized practices in outcome selection, reporting, and measurement in psychiatry research. Addressing these issues through developing core outcome sets, improving adherence to reporting guidelines, and refining measurement methodologies will enhance research reliability and applicability, ultimately improving clinical decision-making and patient care in psychiatry. / Dissertation / Doctor of Philosophy (PhD) / When studying mental health, researchers examine outcomes to determine whether treatments are effective and how to measure co-occurring chronic conditions. These outcomes must be defined clearly, measured accurately, and used in the same way across research to help clinicians make treatment decisions and be able to use research in clinical practice. This project focussed on three main issues related to outcomes: how researchers select outcomes for studies on depression among older adults, how well they report these outcomes, and how they measure the outcome of multiple chronic diseases in people with opioid use disorder. The findings revealed significant differences in how outcomes are selected, reported, and measured, making it challenging for researchers to compare studies and for clinicians to use research results. By implementing standardized practices in outcomes and improving their selection, reporting, and measurement, research can become more useful, leading to better care for people with mental illness.

Opioid use disorder (OUD) is chronic relapse neurological disorder, best characterized by profound drug-induced neuroadaptations which drive drug-seeking phenotypes and persist in the absence of drug. In this dissertation we will examine circular RNA (circRNA) dysregulation following a rodent model of heroin self-administration and characterize a novel circRNA pathway regulating opioid induced neuroadaptations. We identified 76 circRNAs regulated by heroin self-administration, of these we selected circGrin2b_011731 (circGrin2b) for further characterization. circGrin2b is derived from exon 3 of linear Grin2b, which encodes the regulatory subunit of the NMDA receptor, GluN2b, a protein essential for opioid learning and memory paradigms. First, using a custom small-interfering RNA (siRNA) targeting the backsplice junction of circGrin2b, we show that knock-down of orbitofrontal cortex (OFC) circGrin2b significantly reduces heroin intake during self-administration, while only non-significantly reducing heroin-seeking phenotypes. This suggests that OFC circGrin2b is functionally relevant to heroin self-administration phenotypes. Next, we utilized an in vitro primary cortical culture morphine exposure model to interrogate putative upstream biogenesis mechanisms and examine expression of potential circGrin2b microRNA (miRNA)-sponge targets. We validated circGrin2b interactions with miR-26b-3p and miR-100-3p utilizing a luciferase binding assay. Sponging of these 2 miRNA targets can have extensive impact of translation of miRNA-repressed genes, as both miRNAs are involved in regulation of messenger RNAs involved in opioid signaling. Taken together, this dissertation characterized the behavioral and molecular role of a novel circRNA species in mediating opioid-induced neuroadaptations and expands upon the current understanding of the role of circRNAs in regulating synaptic plasticity. / Biomedical Sciences

The opioid epidemic has reached critical levels in American society. By affecting all demographics and socioeconomic levels, it has led to unprecedented numbers of overdoses and deaths while simultaneously burdening our healthcare system. Current policy towards opioid use disorder centers on medication and rehabilitation with the ultimate goal of long-term recovery and abstinence. However, as more studies have emerged over the past few years regarding substance use disorders, the idea of harm reduction as a potential method to mitigate the negative effects of opioid use disorder has grown from the public health sector and addiction advocates. Harm reduction policies encompass many avenues that include syringe exchange programs, widely available naloxone prescriptions, and more recently, the creation of safe injection facilities (SIFs). SIFs are a place for supervised and sterile injection use under the supervision of medical professionals. They have been growing in number in the international community and have shown promise in the United States as a means of providing healthcare to people with substance use disorders. This paper will demonstrate the efficacy and need for SIFs in the opioid use community of America. / Urban Bioethics

No description available.

Aims: Untreated opioid use disorder (OUD) is associated with overdose, premature death and infectious disease, including human immunodeficiency virus (HIV) and Hepatitis C (HCV). While prior studies have shown that educational interventions are associated with improvements in HIV and HCV knowledge and reductions in risk behaviors, those examined to date have typically been time- and resource-intensive. We recently developed an HIV+HCV Education intervention which aims to improve HIV and HCV knowledge in a single visit using an automated iPad platform. In this project, we examined its ability, using a within-subject evaluation, to improve knowledge of HIV and HCV transmission and risks among adults with OUD. Methods: Participants were 25 adults with OUD who were enrolled in a 12-week randomized trial evaluating the efficacy of an Interim Buprenorphine Treatment (IBT) for reducing illicit opioid use while awaiting entry into community-based opioid treatment. Participants completed a baseline HIV+HCV knowledge assessment (Pre-Test) followed by corrective feedback, both administered via iPad. They then completed an interactive HIV flipbook and animated HCV video, also on iPad, followed by a second administration of the knowledge assessment (Post-Test). Finally, to evaluate whether any changes in knowledge persisted over time, the HIV+HCV assessment was administered again at 4 and 12 weeks following study intake. Results: At baseline (Pre-Test), participants answered 69% and 65% of items correctly on the HIV and HCV assessments, respectively. After completing the educational intervention, participants answered 86% of items correctly on both the HIV and HCV assessments (p’s<.001). These improvements in knowledge also persisted throughout the three-month study, with scores at Week 4 and 12 timepoints significantly greater than baseline (p’s<.001). Conclusion: An HIV+Hepatitis Education intervention delivered via a portable, automated iPad platform may produce significant and persistent improvements in HIV and HCV knowledge among adults with OUD. These data provide additional support for the use of mobile educational interventions for enhancing HIV and HCV knowledge in individuals at elevated risk for infectious disease. Support: This trial was supported by NIDA R34 DA3730385 (Sigmon) with additional support by NIDA T32 DA007242 (Higgins).

No description available.

Aims: Opioid use disorder (OUD) is associated with significant morbidity and mortality, and opioid agonist treatment (OAT) with methadone or buprenorphine represents the most efficacious treatment. However, data suggest that chronic administration of opioids may be associated with significant weight gain, possibly by altering an organism’s perception of and preference for sweet foods. The primary aim of this laboratory study was to rigorously examine sucrose subjective response among adults receiving OAT and a comparison sample without OUD. As secondary outcomes, we also sought to compare the groups on additional baseline characteristics that may influence subjective sucrose response and weight gain during treatment. Methods: Participants were 40 adults receiving treatment for OUD (OUD+) and a comparison sample of 40 adults without OUD (OUD-). All participants completed an initial screening visit that included questionnaires on eating behaviors, diet and nutrition, recent substance use, and measurement of body mass index. Eligible participants completed two, same-day outpatient laboratory sessions during which they sampled six experimenter-administered concentrations of sucrose solution (0, 0.1, 0.25, 0.5, 0.75, and 1.0M in distilled water) each three times under double-blind counterbalanced conditions. Following each exposure, participants rated the pleasantness and intensity of each sample using 100-point visual analog scales. Results: OUD+ participants rated sucrose solutions as less pleasant than OUD- participants (p<0.001). However, this effect was limited to the three lowest sucrose concentrations (0, 0.1, 0.25M), and at higher concentrations there were no group differences. There were no between-group differences on ratings of intensity (p=0.35). Given these baseline group differences in placebo (0M) responding, sucrose response was also examined in terms of change from baseline. In this analysis, there was a significant group effect, with a higher magnitude of change in pleasantness ratings and a lower magnitude of change in intensity ratings from 0M in OUD+ vs. OUD- participants (p’s<0.05). With regard to baseline characteristics that may influence sucrose response and eating behavior more generally, the OUD+ group had a higher prevalence of obesity, food insecurity, unhealthy eating behaviors, high sugar consumption, and nutrition knowledge deficits compared to the OUD- group (p’s<0.05). Conclusion: Data from preclinical and clinical research have suggested that opioid agonist medications may enhance subjective response to sweet flavors. In the present study, OUD+ participants exhibited a higher magnitude of change in pleasantness ratings from placebo compared to OUD- participants. However, this effect was largely driven by pronounced group differences in perceived pleasantness of essentially unsweet solutions. On the outcome of sucrose intensity, findings were more mixed with no consistent differences between OUD+ and OUD- participants. In contrast, group differences were far more pronounced in participants’ daily eating behaviors and nutrition knowledge, with OUD+ participants presenting with a consistently more severe profile. These data highlight the significant risk factors experienced by OUD+ individuals that extend beyond drug-related risks and may inform future scientific and clinical efforts to improve health outcomes in this vulnerable population.