Florey Department of Neuroscience and Mental Health - Theses
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ItemTowards a biobehavioral understanding of methamphetamine use disorder: Investigating psychiatric, cognitive, and genetic factors( 2021)Methamphetamine use is a major health concern globally, with ever-expanding market and an increasing number of users worldwide. In Australia, the number of people with methamphetamine use disorder has increased over the past 10 years, specifically amongst adolescents and young adults. This is a particular concern, as the age of onset of substance use predicts the severity of substance use disorder later in life. In addition, young people are more resistant to treatment. While it is still poorly understood why methamphetamine dependence is increasing in adolescents, literature suggests that methamphetamine use is associated with other psychiatric disorders, deficits in cognition, and certain genes involved in the neurocircuitry of addiction. Therefore, the aim of this thesis was to explore psychiatric, cognitive, and genetic factors associated with early onset of methamphetamine use to gain a holistic understanding of methamphetamine use disorder. To investigate these factors, I conducted a cross-sectional two-group study, recruiting people with a current diagnosis of stimulant use disorder, methamphetamine-type, and controls with no history of substance use disorder. All participants were administered a clinical interview to collect demographic and drug use characteristics. Psychiatric comorbidities and psychotic symptoms were also assessed. Following the interview, participants completed a cognitive task battery assessing attention, speed of processing, cognitive flexibility, working memory, and inhibitory control. Inhibitory control was also assessed using a cue reactivity task that I specifically developed for this project. It consisted of the pseudorandomized presentation of methamphetamine-related cues counterbalanced with control, food-related cues. Upon completion of the study session, whole blood was collected for single nucleotide polymorphism analysis in genes of interest. Genes were selected based on robust preclinical data and results from the meta-analysis presented in this thesis. Poor inhibitory control was identified as an age-dependent risk factor in this thesis, with an earlier age of onset associated with greater deficits. In addition, poor inhibition was associated with an increase in craving upon exposure to methamphetamine-related cues. This is critical as cue-induced craving may lead to relapse after abstinence, and therefore poor treatment outcome. Results from this thesis therefore suggest that pre-existing reduced inhibitory control in adolescence is a risk factor for developing methamphetamine use disorder when methamphetamine is first taken early in life, potentially by perpetuating methamphetamine use and inducing repeated relapses. This thesis also identified comorbid antisocial personality disorder as a strong predictor for age of onset of methamphetamine use. This highlights the need to treat cooccurring mental disorders in young people who use drugs to prevent them from transitioning into problematic use. Lastly, a mutation in the neuregulin-1 gene was associated with early onset methamphetamine use, suggesting that people carrying the gene variant are more likely to develop methamphetamine use disorder when exposed to methamphetamine earlier in life. Taken together, this thesis identified a range of psychiatric, cognitive, and genetic factors associated with early onset methamphetamine use. Findings from this work will contribute to the development of larger studies and clinical trials investigating new early interventions to prevent young people who casually use methamphetamine transitioning into a formal methamphetamine use disorder, thus alleviating the rising burden of disease