Magister Artium (Psychology) - MA(Psych) / The aim of this study was to explore school learners' perceptions of the factors that influence methamphetamine use in Manenberg. To meet this aim, three objectives were proposed namely, to explore school learners' knowledge and understandings of methamphetamine use; to explore school learners' perceptions of methamphetamine and its uses and; to explore school learners' perceptions of the factors that influence methamphetamine use. Methamphetamine use amongst adolescents has become an increasing concern internationally and globally, with Cape Town's level of methamphetamine users being substantially higher compared to other parts of South Africa. The study was thus important as it firstly, permitted the understanding of adolescents knowledge of methamphetamine and its uses in a lower socioeconomic status community, secondly, permitted the understanding of adolescents perceptions of the contributing factors of meth use, and thirdly, by knowing and understanding their viewpoints, key focus areas were recommended for intervention and prevention programs in an attempt to decrease the high drug rate in South Africa. / South Africa

Magister Psychologiae - MPsych / The aims of this study were therefore to describe the personal experiences of a methamphetamine addict as well as the effects of this addiction on the family’s communication and problem-solving abilities.

US Foster Care is already known to be an under researched and complex topic, and the literature that is done tends to focus on the need for more investigation to improve this ineffective system. Foster care has even been described as “one huge experiment that has been conducted on children”, at a “cost of untold billions of dollars” (Courtney, 2000). This comment doesn’t seem too far off—there is a consensus that more work needs to be done in the realm of child welfare services, and some studies have even questioned whether removals and placements by foster care are beneficial at all (Doyle, 2006). In order to improve foster care and decisions in treatment (as these decisions have significant impact on children’s safety and well-being), we need to be more effective in using our resources and understanding the needs of the population, and the trends that might be influencing foster care. On that note, research by the US Department of Health and Human Services has shown a clear relationship between parental substance abuse and child abuse, and a study reported by Economic Inquiry (Cunningham, 2013), investigates this in terms of foster care. Cunningham’s study investigates the impact of methamphetamine abuse on admissions in foster care, and reports a significant causal relationship. This interesting report motivated me to investigate this further, and in terms of the recent opioid epidemic in the US. In this study, I adapt Cunningham’s strategies to investigate the effect of the opioid epidemic on US Foster Care, at a more recent time period. Surprisingly, I find different results for the opioid epidemic than the meth shocks, despite many variations of the model to proxy opioid use. My results show a negative relationship from opioid use on foster care admissions, while also confirming Cunningham’s study with a positive relationship with methamphetamine use and foster care at a more recent time period. This study will explain the methods that attain these results, as well as the reasons driving the results in the discussion. While contributing to Cunningham’s study, this study also contributes new research to a topic (the opioid epidemic) frequently mentioned in recent news. This study also considers the impact of this epidemic on individuals it might impact most, and addresses the gap in literature that exists regarding US Foster Care.

Magister Artium (Child and Family Studies) - MA(CFS) / Substance abuse among adolescents is a global problem and South Africa is no exception. In the Western Cape there is an alarming popularity and increased use of an illicit highly addictive substance, locally known as 'tik-tik'/methamphetamine. Adolescents are particularly vulnerable to the neurotoxic effects of this substance and there is an urgent need to address the 'tik-tik' problem in the Westen Cape. Tik/methamphetamine has thus become a great concern to educators, social workers and health practitioners in the province. The goal of this study was to explore the life-world of the adolescent methamphetamine/'tik-abusers' in order to describe their experiences of personal, social and environmental issues in the process of tik-addiction. / South Africa

Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs. This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine.

Personality pathology, especially antisocial personality disorder (ASPD), often occurs in patients with methamphetamine use disorder (MAUD). However, little is known about potential risk factors for this dual diagnosis, and the impact of this comorbidity on both the severity of MAUD and levels of functional impairment. Casting light on such phenomena may aid in early identification of treatment targets, assist in the management of patients in this particular population, and contribute to development of treatment strategies. This crosssectional study described and compared sociodemographic, clinical and childhood trauma correlates in patients with a dual diagnosis of MAUD and ASPD (MAUD+ASPD) and those with MAUD without ASPD (MAUD-ASPD). The contribution of sociodemographic and childhood trauma variables in predicting membership of the MAUD+ASPD group was also investigated. A sample of 62 adult patients with a primary diagnosis of MAUD took part in the study. A sociodemographic questionnaire was completed and well established diagnostic measures of ASPD (The Mini-International Neuropsychiatric Interview; MINI) and MAUD (Structured Clinical Interview; SCID - 5) were used to determine diagnostic status. Illness severity was evaluated with the Yale-Brown Obsessive Compulsive scale (adapted for MAUD) (Y-BOCS-du) and functional impairment was assessed with the Sheehan Disability Scale (SDS). Histories of exposure and severity of childhood trauma (CT) were measured using the CTQ-SF. Of the 62 participants, 14 (23%) had MAUD and had MAUD+ASPD whereas 48 (77%) had MAUD without ASPD (MAUD-ASPD). Bivariate analyses found significant group differences in terms of gender (df =1) = 8.05; p =< 0.01), language (df = 2) = 7.12; p = 0.03), and level of physical neglect (F(1, 60) = 2.33; M = 9.85; SD = 4.23; p = 0.04). The MAUD+ASPD group members were mostly male (N = 9; 64%), English-speaking and with histories of increased physical neglect. Logistic regression suggested that male gender (beta = 1.08; OR = 8.65; p = 0.01) and English language (beta = 1.55; OR = 11.38; p = 0.03) significantly predicted ASPD comorbidity. There were no significant differences in clinical severity or functional impairment between the MAUD+ASPD and MAUD-ASPD groups. In conclusion, this study indicated that male gender and having English as a first language are associated with MAUD+ASPD but other sociodemographic variables, CT histories and clinical severity and impairment were not. Men who use MA are thus more prone to antisocial behaviour, which complicates their substance use condition. Treatment approaches for MAUD may benefit from developing adaptations that cater for challenges specific to comorbid ASPD. Additionally, the finding regarding first language warrants further investigation. Recommendations for future research are suggested.

Substance use disorders are a prominent issue within the United States that must be addressed given the high prevalence, economic cost, and negative health consequences of these medical conditions. Current treatments are inadequate due to the limited success of behavioral therapies and the lack of pharmacological interventions geared towards preventing the neuroplastic changes initiated by substances of abuse that lead to addiction. Sigma-1 receptors represent promising pharmacological targets for treatment of substance use disorders involving cocaine and methamphetamine use. A review of recent studies suggests that sigma-1 receptors contribute to the underlying mechanisms of action utilized by cocaine. Yet the use of sigma-1 receptor antagonists shows promising results of mitigating the physiological effects induced by cocaine. In contrast to cocaine, sigma-1 receptors have yet to be linked to the underlying mechanisms of action utilized by methamphetamine. However studies indicate that the use of sigma-1 receptors agonists creates a neuroprotective effect against the physiological effects induced by methamphetamine. Currently the pharmacological targeting of sigma-1 receptors is not utilized to treat substance use disorders. A review of literature was conducted in order to elucidate the mechanistic role that sigma-1 receptors play in mediating the physiological effects induced by cocaine and methamphetamine that lead to addiction. Using this information, the potential use of sigma-1 receptors as therapeutic targets was discussed in order to provide insight about the benefits and limitations of utilizing such an intervention as treatment for substance use disorders involving cocaine and methamphetamine use.

As a part of the overall program in the Grandy laboratory at Oregon Health & Science University (OHSU), studying the underlying chemical biology of methamphetamine (Meth) addiction, this dissertation reports on the development of six new thyronamine analogs which were synthesized and assayed against trace amine associated receptor 1 (TAAR1), giving preliminary results consistent with the analogs being inverse agonists. Due to highly variable TAAR1 expression levels in the assays, based on inter-assay response to control Meth stimulation as well as other possible factors, kinetic models were developed to qualitatively explain the assay results. The models set approximate limits on the analogs' binding and disassociation rates relative to those of Meth. Analysis of the assays also provides more evidence of TAAR1's basal activity. Based on the models, the conversion rate of ligand-free inactive TAAR1 to ligand-free active TAAR1 is less than 6% of the binding rate of Meth to TAAR1. The models also suggest that the inverse agonists bind to the inactive ligand-free form of TAAR1 between 10 and 100 times faster than Meth binds to the inactive ligand-free form of TAAR1. Three of the new analogs, G5-110s8, G5-112s5, and G5-114s5, bind to the ligand-free active form of TAAR1 faster than they bind to the inactive ligand-free form of TAAR1. The models do not suggest an upper limit on the binding rate of those 3 analogs to the ligand-free active form of TAAR1. A control assay lacking TAAR1 revealed an electrophysiological off-target effect caused by G5-109s8. Also, a novel synthetic route was developed for ET-92, the lead compound for this project, which reduced the number of synthetic steps from 14 to 5 and improved the overall yield from 15.3% to 18.3% (77.4 mg) with the hope that further improvements in yield are possible.

Indiana University-Purdue University Indianapolis (IUPUI) / Thermoregulation system in mammal keeps their body temperature in a vital and yet narrow range of temperature by adjusting two main activities, heat generation, and heat loss. Also, these activities get triggered by other causes such as exercise or certain drugs. As a result, thermoregulation system will respond and try to bring back the body temperature to the normal range. Although these responses are very well experimentally explored, they often can be unpredictable and clinically deadly. Therefore, this thesis aims to analytically characterize the neural circuitry components of the system that control the heat generation and heat loss. This modeling approach can help us to analyze the relationship between different components of the thermoregulation system without directly measuring them and explain its complex responses in mathematical form. The first chapter of the thesis is dedicated to introducing a mathematical modeling approach of the circuitry components of the thermoregulation system in response to Methamphetamine which was first published in [1]. Later, in other chapters, we will expand this mathematical framework to study the other components of this system under different conditions such as different circadian phases, various pharmacological interventions, and exercise. This thesis is composed by materials from the following papers. ‎CHAPTER 1 uses the main idea, model, and figures from References [1]. Meanwhile, ‎CHAPTER 2 is based on [2] coauthored with me and is reformatted according to Purdue University Thesis guidelines. Also, ‎CHAPTER 3 interpolates materials from reference [3] coauthored and is reformatted to comply with Purdue University Thesis guidelines. ‎CHAPTER 4 is inserted from the reference [4] and is reformatted according to Purdue University Thesis guidelines. Finally, ‎CHAPTER 5 is based on Reference [5] and is reformatted according to Purdue University Thesis guidelines. Some materials from each of these references have been used in the introduction Chapter.

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