Investigating the association between regular cannabis use and human brain structure

© 2012 Dr. Valentina LorenzettiRegular cannabis exposure is related to significant adverse mental health outcomes that constitute a major burden on addiction treatment services. Converging evidence suggests that these adverse outcomes are persistent in nature and are mediated by persistent neurobiological alterations occurring in brain regions that are high in cannabinoid receptors (CB1). These brain regions are involved in mediating psychopathology and impaired neurocognition, both of which are observed in regular cannabis users (CB). Structural brain imaging techniques have proven useful in providing preliminary evidence for persistent brain alterations in regular CB users. However, the literature to date is limited by numerous methodological factors that prevent characterisation of structural brain abnormalities in CB users, including small sample sizes, limited investigation on the role of sex on the obtained findings, psychiatric and substance use comorbidity, poor sample characterisation and lack of analyses exploring the impacts of differing cannabis use patterns and psychopathology/neurocognitive measures on brain regional volumes in CB users. This thesis aimed to overcome the methodological limitations of the structural imaging literature to date, to provide an improved characterisation of the association between regular cannabis exposure and human brain morphology. To this end, high-resolution structural Magnetic Resonance Imaging (sMRI) was utilised to cross-sectionally compare regular CB users to age and sex-matched non-cannabis using controls (HC) in the largest sample examined to date. Regular CB users with a high inter-individual variability in levels of cannabis exposure with respect to dosage, frequency and duration of cannabis use were recruited. All participants were screened for significant psychopathology and exposure to substances other than cannabis, and were comprehensively characterised with respect to cannabis use patterns, psychopathology symptoms and neurocognitive measures. Key cannabis use patterns and measures of psychopathology, neurocognitive performance and global functioning were ascertained. The association between these variables and regional brain volumes was then examined in brain structures high in CB1 receptors and involved in mediating psychopathology and altered neurocognition observed in regular CB users. These regions included: - The hippocampus, which is involved in mediating memory and learning, psychopathology symptoms, stress regulation and reward processing; - The amygdala, which mediates emotional and reward processes, and is involved in the neurobiology of a range of psychiatric disorders and in the regulation of the stress response; - The pituitary gland that, being a core part of the stress regulation system, is involved in the neurobiology of a variety of psychiatric disorders and in cannabis-related craving and withdrawal states. These regions were manually delineated via application of previously validated manual tracing protocols to high-resolution sMRI images. This rigorous approach enabled sensitivity to identify potentially subtle effects of regular cannabis exposure on regional brain volumes using highly reliable and anatomically valid segmentation techniques. The analyses conducted in this work aimed to achieve a number of objectives, which included examining whether: 1. Regular cannabis exposure is associated with structural alteration of brain regions high in CB1 receptors and involved in mediating psychopathology and altered neurocognition in regular CB users; 2. Cannabis use patterns mediate the association between regular cannabis exposure and brain structural alterations, and which cannabis use patterns best predict structural brain alterations in regular CB users; 3. ‘Clinical’ variables including psychopathology symptoms, key neurocognitive measures and global functioning are associated with regional brain volumes in regular CB users independently from the impact of cannabis use patterns. The findings emerging from this thesis lead to three key results in relation to the presented research objectives. First, the association between regular cannabis exposure and brain morphology brain was regionally dependent, with CB users showing volumetric reductions in the hippocampus and the amygdala, but not the pituitary gland, with more marked alterations being observed in hippocampal, as opposed to amygdala, volumes. Second, the association between cannabis use patterns and brain volumes was also regionally dependent, being apparent for hippocampal volumes, subtle for on amygdala volumes, and not observable for pituitary volumes. The key cannabis use patterns that affected brain volumes in CB users were age of onset of regular cannabis use and cannabis dosage, affecting hippocampal and amygdala volumes, respectively. Sex, laterality and recency of cannabis use also played a key role in these associations. Third, ‘clinical’ variables did not exert a confounding influence on the association between cannabis use patterns and regional brain volumes, and there was preliminary evidence for positive psychotic symptoms to be associated with the volumes of the pituitary gland, but not those of the hippocampus and the amygdala, and in male, as opposed to female, CB users. The results emerging from this dissertation support the notion that the association between cannabis exposure, cannabis use patterns, psychopathology symptoms and brain volumes occur in a region-dependent manner. A number of factors including laterality, sex and recency of cannabis use also mediate the nature of structural brain alterations in regular CB users. These results demonstrate that the association between regular cannabis exposure and regional brain volumes is mediated by complex factors and provide useful insight for future studies investigating structural brain measures in regular CB users. Nevertheless, a number of limitations prevent from drawing firm conclusions regarding the nature of the observed structural brain alterations. The role of confounding factors associated with regular cannabis use, including comorbid substance use and heightened psychiatric symptoms, needs to be carefully accounted for in future studies. Further, longitudinal investigations are warranted to determine whether regional brain alterations pre-exist cannabis use onset and recover after prolonged abstinence