Conversion of ultra-high Risk state (prodromal) to psychosis: How does cannabis play a role? Amresh Srivastava Megan Johnston 1. Abstract Cannabis abuse causes a number of acute and chronic health problems. Links between cannabis abuse, psychosis and cognitive dysfunction are not yet clearly investigated. This pilot project proposes: a) to study the pattern of cannabis usage in relation to development of psychosis and its risk factors. b) To investigate the neuro-cognitive status of people abusing cannabis. And its relationship to development of psychosis, if any. 2. Background 2.1. Prevalence, Health Effects and Misconceptions Regarding Cannabis Use Cannabis is one of the most commonly used illicit drugs. Its active compound ‘cannabidols’ has 64 active isomers, each having different effects on human health and behaviour. Effects of cannabis have traditionally been seen as less harmful than alcohol abuse, drugs and other illicit substances. Consequently, less attention has been focused on developing and evaluating interventions related to cannabis use [1, 2]. There is a strong link between cannabis and the exacerbation of psychosis as well as other mental health conditions such as anxiety and depression. However, further research is needed to determine the underlying neurochemical processes of cannabis exposure as a possible causative and/or exacerbating factor in the development and progression of psychosis in young adults. HBSC data over the past 12 years suggest that experimentation with marijuana has continued to rise for Grade 10 boys (50 percent) but has leveled off for girls (40 percent) (Figure 6.18). Earlier regional studies in Canada indicate that approximately 40 percent of adolescents have tried marijuana by the age of 15 (The McCreary Centre Society, 1999). Some authors suggest that the popularity of marijuana as a social drug among adults is contributing to the availability and acceptance of its use as a safe recreational activity by adolescents (Tonkin, 2002). However, data on the impact of long-term marijuana use on adolescent health are not yet available. Data derived from clinical reports has demonstrated an association between marijuana use and declining performance in school, decreased motivation, and increased absenteeism (Tonkin, 2002). Figures 6.19 and 6.20 show increasing use of marijuana by grade. One-third of boys and one-quarter of girls in Grade 10 had used marijuana three or more times in the past year. (Public health agency of Canada (http://www.phac-aspc.gc.ca/dca-dea/publications/hbsc-2004/chapter_6_e.html) Grade 10 students who ever tried marijuana, by year of survey (%) A recent study conducted over 27 years (between 1976 and 2002) reported that approximately 50% of 12th grade students had been exposed to cannabis in the United States . These statistics are likely reflective of the Canadian population and have serious health implications for our youth. Substance abuse disorders have high co morbidity with various psychiatric disorders and are associated with substantial functional impairments . For instance, there is growing evidence that early and regular use of cannabis is associated with subsequent increases in depression, suicidal behavior, psychotic illness, and may also accelerate the onset of schizophrenia. It is important to note that the vast majority of recent studies reject the view that marijuana is used to self-medicate psychotic or depressive symptoms and that; in fact, cannabis appears to be causative and/or exacerbating of mental illness. To date, research on cannabis exposure and its associated psychiatric disorders remains limited as does research regarding treatments and rehabilitation for cannabis users and co morbid mental illnesses [4, 5, 6]. 2.2. The Effects of Cannabis on Neurocognition and Neurophysiology There is little information on the neurocognitive and neurophysiological effects of cannabis. Preliminary neuro-imaging studies (in mainly nonpsychotic populations) show that cannabis does not affect gross brain anatomy. But cannabis does acutely increase cerebral blood flow and long-term exposure causes an overall reduction of cerebral blood flow. In terms of cognition, acute cannabis administration induces memory impairments, which can persist for weeks and months following abstinence, though there is little evidence of residual effects following years of abstinence. Animal studies using an active cannabidol (delta9- tetrahydrocannabinol) demonstrate enhanced dopaminergic neurotransmission in brain regions known to be implicated in psychosis. In humans, delta9-tetrahydrocannabinol induces psychotic like states and memory impairments in healthy volunteers . Overall, the current body of research literature does not provide evidence of significant, long-term effects due to cannabis use. However, several acute effects are noted and some are suggestive of negative mental health consequences. For these reasons, the proposed study aims to look at acute mental health patients with and without cannabis use. In addition, the acute and long-term effects of cannabis are unknown in individuals that may be genetically or biochemically predisposed to mental illness. The proposed study will also examine linkages between serum biochemical markers and mental health status (with and without cannabis exposure). This is an important line of investigation as studies in humans show that genetic vulnerability may add to increased risk of developing psychosis and cognitive impairments following cannabis consumption. For instance, continued cannabis use by persons with schizophrenia causes a small increase in psychotic symptom severity but not vice versa . Cognitive dysfunction associated with long-term or heavy cannabis use is similar in many respects to the cognitive endophenotypes that have been proposed as vulnerability markers of schizophrenia . Closer examination of the cognitive deficits associated with specific parameters of cannabis use and interactions with neurodevelopmental stages and neural substrates will better inform our understanding of the nature of the association between cannabis use and psychosis. Further research in this field will enhance our understanding of underlying pathophysiology and improving treatments for substance abuse and mental illness . 2.3. Cannabis and Psychosis Many studies now show a robust and consistent association between cannabis consumption and the development of psychosis. Furthermore, our understanding of cannabis biology allows the proposal of a plausible hypothetical model, based notably on possible interactions between cannabis and dopaminergic neurotransmission . Cannabis use can induce and exacerbate psychotic symptoms and accelerate the disease process. In one such study of first- episode schizophrenia, it was observed that patients with long-term cannabis consumption were significantly younger at disease-onset, mostly male, and suffered more often from paranoid schizophrenia (with a better prognosis) than those without cannabis consumption. The significance of higher serum neurotrophin levels in cannabis consuming schizophrenics as compared to those without cannabis consumption remains equivocal so far. The cognitive functions of this patient group are at least not worse than in those with schizophrenia alone. Hence, the proposed study has been planned to understand the complex interaction of cannabis and psychiatric disorders via cognition and other behavioural components. 3. Hypothesis Cannabis use is a potential risk factor for development of Psychosis Cognitive dysfunctions occurs in early and prodromal psychosis, which remains fairly stable, a dconsistent thoughout the course. It is hypothesized that cannabis abusers who have cognitive deficits are the candidates who go on to develop psychosis. . In further studies, it is intended to explore whether cognitive challenge pre-exist Cannabis abuse or occur later. Future Directions The data and findings derived from this pilot study will be presented and disseminated via mental health research conferences (e.g. Canadian Psychiatric Association, American Psychiatric Association and World Psychiatric Association conferences) and in clinical journals such as Addiction and British Journal of Psychiatry. This project contributes to overall program of research that seeks to address two major themes: 1) to study the interrelationship of addictive behaviours (including substance abuse), cognitive status and underlying psychiatric disorders, 2) to examine the changes in brain functions/mechanisms of cannabis users and the relationship to mental illness. This is an important area of research as information available regarding the health effects of cannabis abuse is not currently sufficient to manage and treat cannabis abusers. We expect that this project will reveal the interrelationship of addictive behaviour, cognitive status and underlying psychiatric disorders in cannabis abusers. This work will also establish an expertise at the University of Western Ontario for targeted approaches to mental health research and services in rural areas. Furthermore, as students will be collecting and analyzing the data, they will be gaining valuable experience which will serve them well as their careers progress as scientists and clinicians. In addition, this grant money will serve as an invaluable stepping stone to establish collaborations within London’s medical research community and to collect preliminary data which will, in turn, assist in competing for external grants at provincial, national and international levels. 9. References 1. 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