Acute and chronic effects of cannabinoids on human brain: gene-environment interactions related to psychiatric disorders
Year: 2014
Type: dissertation
Study design: Observational Study
Abstract: 1)\tIntroduction \n \nCannabis use has been associated to mental health problems and worsened outcome of established psychiatric disorders. Disturbances of the endocannabinoid system may be responsible for long-lasting effects, such as neuropsychological deficits and morphological brain alterations. As not all the exposed individuals are equally affected, proneness to cannabis induced impairment may rely on key factors such as age of onset, cannabis use parameters and genetic background. \n \nThe aim of the present thesis is to expand current knowledge of the effects of cannabinoids, while assessing gene-environment interactions that are relevant for psychiatric disorders, based on the following hypothesis: \n \n-\tCannabis use in first-episode psychosis would be associated with worse outcome regarding readmission rates (Chapter 3). \n-\tAcute and chronic cannabis use would be associated with alterations on brain function and structure in key areas relevant for psychiatric disorders (Chapters 4-5). \n-\tEarly-onset chronic cannabis users would show morphological brain alterations compared to non-using controls, and variation in the dopamine-regulating genes would result in diverse liability to experience cannabis-related brain impairment (Chapters 6-7). \n \n2)\tMethods \n \nWe assessed a cohort of 58 first-episode psychosis patients. The main outcome was the time until first readmission. All subjects were interviewed using the Structured Clinical Interview SCIO-I, the Positive and Negative Syndrome Scale (PANSS) and the Dartmouth Assessment of Lifestyle Inventory (DALI) scale. The subjects also underwent blood and urine sampling for drug use (Chapter 3). \n \nIn addition, we conducted two systematic literature reviews in accordance with PRISMA guidelines. Chapter 4 included 43 neuroimaging studies of experimental administration of cannabinoids involving animals naive to cannabinoids and naive/occasional cannabis users. Chapter 5 considered 4S neuroimaging studies involving chronic cannabis users with a matched control group. \n \nFinally, we performed a case-control study in male Caucasians, 30 early-onset chronic cannabis users and 29 age-, education- and intelligence-matched non-using controls. All subjects were assessed by a structured interview (PRISM). Catechol-a-methyltransferase (COMT Val(158)Met] and dopamine transporter (DATI-VNTR) genotyping were performed. MRI data was analysed by VBM (Chapter 6) and manual tracing of the hippocampus via well-validated methods (Chapter 7). \n \n3)\tResults \n \nCannabis was the most common drug found in the first-episode psychosis cohort, either in urinalysis (38%) or self-reported (50%). Both the DALI cannabis/cocaine subscale (p=0.002) and urinalysis for cannabis (p=0.02) were associated with increased readmission risk in survival curves. The DALI cannabis/cocaine subscale at baseline was a significant predictor of readmission over the study period (HR = 4.5: 95% CI = 1.1 to 18.7; p=0.036) after controlling for potential confounders (Chapter 3). \n \nStudies included in Chapter 4 showed that acute administration of cannabinoids modulate resting state activity and alter neural activity during performance of several cognitive tasks in areas related with reward and psychiatric disorders. Chapter 5 indicated that chronic cannabis use is associated with alterations in brain function and structure, particularly in medial temporal regions. \n \nIn the case-control study, chronic cannabis users showed morphologic brain alterations that were differently influenced by the COMT and DATI genotypes compared to controls. Variation in the COMT genotype affected the bilateral ventral caudate nucleus and left amygdala in both groups in an opposite direction (Chapter 6). Chapter 7 expanded these results by showing that COMT and DATI genes interacted with each other moderating individual differences also in the hippocampal volume. \n \n4)\tConclusion \n \nTogether, these results proVide support for endocannabinoid Involvement in the outcome of psychiatric disorders, as well as in the control of different cognitive functions, dopamine release and brain volume. Findings also provide evidence that dopamine-regulating genes may playa particular role in the sensitivity to the effects of cannabis on brain morphology, providing further insights into the mechanisms of cannabis-related brain impairment and genetic vulnerability.
Author: Albert Batalla Cases
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Generalitat de Catalunya, Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Centro de Investigación Biomédica en Red de Salud Mental, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Plan Nacional sobre Drogas, Medical Research Council, National Health and Medical Research Council, Instituto de Salud Carlos III
OpenAlex ID: W641540520