Background: Opioid overdoses have killed almost 20,000 Canadians since 2016. To address this, Canada has established supervised consumption sites where people can use drugs in the presence of trained staff and get access to pharmacological treatments such as methadone. However, there is very little research on whether supervised consumption clients use methadone, or whether their use of methadone prevents opioid overdose. Methods: A secondary data analysis of information collected from one supervised consumption site was undertaken in order to explore relationships between client self-reported methadone dosage and subsequent observed same-day opioid overdose. Results: Statistical analysis showed no correlation between methadone usage and reduced chance of opioid overdose. However, the most common dosage of methadone reported (30mg/day) was far below the minimum therapeutic dose of methadone. Conclusion: Clients of supervised consumption sites often report being prescribed methadone, but not at a dose high enough to reduce opioid overdose.

Indiana University-Purdue University Indianapolis (IUPUI) / Aromatase is the cytochrome P450 enzyme that converts androgens to estrogens. Aromatase is the target of the aromatase inhibitor class of drugs widely used to treat estrogen-mediated conditions including breast cancer. Little is known about the role of this enzyme in drug metabolism or in drug interactions. Since this lack of knowledge has been an impediment to optimal therapy, it is important to understand these roles of aromatase. Therefore, a comprehensive series of studies was carried out to characterize its ability to metabolize drugs and its susceptibility to inhibition by xenobiotics. The overall objective of this work was to better understand the interactions of small molecules with aromatase and to use this new knowledge to predict aromatase-mediated drug interactions and anticipate novel molecular structures that interact with the enzyme. Aromatase was shown to be a drug metabolizing enzyme able to metabolize methadone both in vitro (Km of 314 μM) and in vivo (22% of methadone clearance). A number of novel aromatase inhibitors that employ diverse kinetic mechanisms were identified. These include a potent competitive inhibitor: norendoxifen (Ki of 35 nM), two non-competitive inhibitors: endoxifen (Ki of 4.0 μM) and N-desmethyl-tamoxifen (Ki of 15.9 μM), a mechanism-based inhibitor: methadone (KI of 40.6 ± 2.8 μM; kinact of 0.061 ± 0.001 min-1), and a stereoselective inhibitor: naringenin (IC50s of 2.8 μM for (R)-enatiomer and 1.4 μM for (S)-enatiomer). Through investigation of the structure-potency relationships so discovered, a series of new biochemical structures to be exploited as aromatase inhibitors were identified. These studies have identified new roles for aromatase as a catalyst for methadone metabolism and as a mediator of the effects of tamoxifen by demonstrating that a number of its metabolites can act as aromatase inhibitors. This work also provides a new mechanistic framework for the design of novel aromatase inhibitors that can be used in breast cancer. Overall, the data suggest ways to more consistently treat breast cancer with current medications, to better anticipate drug interactions, and therefore to improve the quality of life of patients in ways that minimize side effects, while optimizing therapeutic benefits, in each person treated.

Objective: Cocaine use is prevalent among patients in methadone maintenance and a risk factor for poor treatment outcomes. Contingency management (CM) decreases cocaine use in this population, but little is known about its efficacy when marijuana use is present prior to or during treatment. Method: Data from five randomized CM trials (N = 557) were used to evaluate whether: (a) marijuana frequency (none, low, or high) prior to or during treatment impacts cocaine use outcomes and (b) marijuana use differentially impacts cocaine outcomes with standard care (SC) + CM versus SC alone. Results: Relative to no marijuana use, low (β = .28, p < .01) and high marijuana use (β = .32, p < .05) during treatment were associated with roughly 1 week shorter duration of cocaine abstinence on average. Low marijuana use (β = .71, p < .05) during treatment was associated with a lower proportion of negative cocaine samples during treatment relative to no marijuana use. Treatment group by marijuana use (before or during treatment) interactions on duration and proportion of cocaine abstinence during treatment were not significant. For longer term outcomes, in SC + CM, marijuana use during treatment did not impact cocaine abstinence 6 months post-baseline. In SC, low (OR = .44, p < .05) and high (OR = .26, p < .001) marijuana use during treatment decreased odds of cocaine abstinence at 6 months post-baseline relative to no use. Conclusions: Findings highlight the benefits of SC + CM and abstaining from marijuana use during active treatment. At 6 months postbaseline, SC + CM evidenced similar cocaine abstinence regardless of marijuana use levels during treatment, while those with low and high marijuana use showed decreased abstinence rates in SC only. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Indiana University-Purdue University Indianapolis (IUPUI) / Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide spectrum of biological processes including apoptosis, immune response and inflammation. S1P receptor (S1PR) ligands have been utilized as an effective immunosuppressant, treatment in multiple sclerosis and studied as a treatment for pain. The primary cellular response to S1P is thought to be elicited through S1PR type 1 (S1PR1). My first goal was to understand how S1PR1 signaling affects neuronal excitability in the central amygdala (CeA), a supraspinal node of the descending pain pathway. The CeA is made up of a heterogenous population of neurons which form complex local and long-range circuits. The central lateral amygdala (CeL) consists of two major populations of inhibitory neurons identified by expression of the peptides somatostatin (Sst) and protein kinase Cδ (PKCδ). Sst neurons have been shown to maintain control over local circuits within the CeL and play a critical role in pain modulation. I utilized transgenic breeding strategies to fluorescently label Sst-expressing CeL neurons for whole-cell electrophysiology in acute brain slice. This strategy allowed me to study the effects of S1PR1 agonist SEW2871 and S1PR1 antagonist NIBR on the cellular physiology of CeL Sst neurons. My findings reveal intrinsically distinct subtypes of CeL Sst neurons that are uniquely affected by S1PR1 activation, which may have implications for how S1P alters supraspinal pain pathways. My second goal was to assess the physiology of motor cortex neurons in mice exposed to prenatal methadone. Methadone is a synthetic μ-opioid agonist used for opioid maintenance therapy and chronic pain management. Methadone treatment for opioid use disorder in pregnant women can result in structural changes within the brain of their offspring causing and developmental delays to their children, including poorer motor performance. Using a mouse model of prenatal methadone exposure (PME), whole-cell electrophysiology, and analyses of cellular morphology, I elucidated the effects of PME on primary motor cortex (M1) output layer 5 (L5) neurons, which encompass the major cortical output pathway for motor control. My findings provide the first evidence that PME disrupts neuronal firing, subthreshold properties, and strength of local inputs onto M1 L5 neurons in prepubescent mice. / 2023-05-05

Opioid use disorder (OUD) is a chronic relapsing condition associated with significant patient morbidity and mortality. Patients suffering from OUD have an increased risk of death from suicide, HIV, infectious disease, and trauma, among other causes. Patients suffering from OUD often manage various comorbid psychiatric illnesses and homelessness. From 1999 to 2017, an estimated 400,000 people died from prescription opioid related overdoses. In 2014, there were 28,647 opioid related overdose deaths in the United States. The current standard of care for treatment of OUD is an opioid receptor agonist methadone or buprenorphine combined with a psychosocial intervention, like cognitive behavioral therapy (CBT), contingency management (CM), or motivational interviewing (MI). MI has proven to be effective in treating OUD when combined with methadone and buprenorphine. Other studies have found increased rates of opioid abstinence when study subjects were provided recovery housing contingent on urine that was free of opioids and other substances (CM). Among patients with a history of incarceration and co-morbid OUD, stable housing in some form -- private residence or living with a friend or family -- has been found to be effective in reducing opioid use when compared to homelessness as a control, suggesting homelessness confers a higher risk of opioid use. This prospective observational study aims to evaluate the effect of stable housing on opioid use disorder treatment and recovery. Study subjects will be Boston area residents who are prescribed methadone. Investigators will follow study subjects over six months while they attend weekly motivational interviewing sessions as part of their treatment regime and attend methadone clinics as usual. Once per week, study subjects will submit urine samples to study affiliated Medical Assistants (MA). Urine samples will be sent to LabCorp for toxicology analysis. At the conclusion of the study, investigators will examine which patients had longer time to relapse based on their housing status. We hypothesize that subjects with stable housing will have longer abstinence, as measured by urine toxicology, than subjects without stable housing. Positive findings could be used to help influence policy makers and federal and state legislation to promote stable housing for patients recovering from OUD.

The primary purpose of this study is to determine the occurrence of drug therapy adjustment in people with substance use disorder receiving medication-assisted treatment when admitted to an acute care facility for a comorbid condition. The secondary purpose is to understand the correlation between the presence of adjustment of therapy for substance use disorder and influence on recovery from comorbid conditions. A literature review exploring drug therapy for addicted individuals during hospitalization was performed using various databases, search terms included *substance use disorder or *substance abuse or *illicit drug use or *drug abuse or *MAT or *maintenance therapy, combined with *inpatient or *hospital or *acute care or *admission. The data was conformed into tables that synthesized the relationship between drug therapy adjustment for individuals with substance use disorder during an acute care admission. Initial review of the articles revealed 78 articles relative to the topic, 16 of those articles met inclusion criteria and were selected for a detailed analysis. Studies suggest the need for provider education and guidelines for treating individuals receiving MAT in an acute care facility. While individuals with substance use disorder often use acute care services, their medication-assisted treatment is rarely acknowledged or adjusted. Many studies focus on individuals with substance use disorder, yet, addressing medication-assisted therapy is still inconsistent, and lacks official guidelines.

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.

No description available.

The thesis focuses on the subjectively perceived changes in the lives of persons in the methadone maintenance treatment program, on their experiencing of the changes and subjective judgment of the treatment. The topic is treated according to the Bio-Psycho-Socio-Spiritual Model of Addiction. The theoretical part deals with the quality of life and the subjectively perceived well-being and defines six dimensions of well-being on which the practical part of the thesis is based. It also elaborates on the Bio-Psycho-Socio-Spiritual Model of Addiction in the context of the methadone maintenance treatment. Moreover, it describes the factors in life change and the motivation to change. The last theoretical chapter focuses on the opioid substitution treatment as such and more specifically on the methadone maintenance treatment. The practical part presents the results of the research. The aim of the thesis is to analyse how the persons in the methadone maintenance treatment program in České Budějovice perceive life changes. A qualitative research was chosen for that purpose. The data were obtained through the technique of narrative interview. The research group consisted of four respondents who were on the methadone maintenance treatment program. The results show that the subjectively perceived changes in the lives of the persons in the methadone maintenance treatment program relate to five out of six dimensions of well-being. No changes were recorded in the dimension concerning the sense of life, in other words, even after a several month methadone maintenance treatment these persons perceive no goal of their lives. Important consequences for work with these persons can be drawn from that, especially for therapists in opioid substitution centres, who should develop spirituality aspects of persons.

The Medical Examiner of Virginia (ME) dataset and the Virginia Department of Forensic Science Driving Under the Influence of Drugs (DUI) datasets were used to determine whether people have the potential to develop tolerances to diphenhydramine, cocaine, oxycodone, hydrocodone, methadone, and morphine. These datasets included the years 2000-2004 and were used to compare the concentrations of these six drugs between people who died from a drug-related cause of death (of the drug of interest) and people who were pulled over for driving under the influence. Three drug pattern groups were created to divide each of the six drug-specific datasets in order to compare concentrations between individuals with the drug alone, the drug and ethanol, or a poly pharmacy of drugs (multiple drugs). An ANOVA model was used to determine if there was an interaction effect between the source dataset (ME or DUI) and the drug pattern groups. For diphenhydramine and cocaine, an interaction was statistically significant, but for the other drugs, it was not significant. The other four drug-specific datasets showed that the DUI and ME were statistically significantly different from each other, and all of those datasets except for methadone showed that there was a statistically significant difference between at least two drug pattern groups. Showing that all of these datasets showed differences between the ME and DUI datasets did not provide sufficient evidence to suggest the development of tolerances to each of the six drugs. One exception was with methadone because there were 14 individuals that had what is defined as a "clinical 'lethal' blood concentration". These individuals provide some evidence for the possibility of developing tolerances.The main outcomes of this study include suggesting changes to make to the ME datasets and the DUI datasets with regard to the way data is kept and collected. Several problems with the fields of these datasets arose before beginning the analysis and had to be corrected. Some of the changes suggested are currently being considered at the Virginia Office of the Chief Medical Examiner as they are beginning to restructure their database.