Transition to psychosis in Cannabis abusersSchizophrenia is a debilitating disease of major public health importance, the incidence of which shows prominent worldwide variation (up to fivefold) and is about 40% greater in men than in women. Furthermore, epidemiological studies have shown that the incidence is higher among those who grow up in urban areas and among migrants. Recent evidence indicates that, although the neurochemical origins of schizophrenia do not necessarily lie in dopamine dysregulation, this operates as the final common pathway underlying positive psychotic symptoms and may also play a role in negative and cognitive symptoms. The last few years have seen the development of a plausible model in which schizophrenia is seen as the consequence of the actions of a number of component causes, such as genes or early environmental hazards that subtly alter subsequent neurodevelopment. [1] Besides pre and peri-natal infection, obstetric events, childhood infection and a family history, cannabis is one such factor, which has been found to be a risk beyond doubt. Cannabis is the most widely used substance and cannabis psychosis has been known for a long time [2.] There is an alarming increase in its usage all across the world. [3The epidemic severely impacts healthcare yielding poor treatment outcomes and prognoses for afflicted patients. Health related issues due to cannabis are now the forefront in mental health services as well as in primary care. Because substance abuse can exacerbate or trigger psychosis and mood disorders, it is important to keep these issues in mind when evaluating patients. [4] The co-existence of psychosis and cannabis has been a matter of great interest to clinicians and basic science researchers. The main question, which is the focus of investigation, is to find out pathways of neurobiological changes occurring in psychosis. The hope is that if these changes are reversible possible risk of severity may be minimized and treatment outcome in psychotic disorders may be improved. What need to be clear to clinicians and researchers are the factors, sequence of biological events and a valid model of neurobiological mechanisms responsible for the conversion to a psychotic state due to cannabis in both vulnerable and non-vulnerable subjects. Further from public health and clinical perspective there is a need to know the predictive as well as protective factors for psychosis and schizophrenia related to cannabis. In this review we will discuss some of the neurobiological factors involved in the connection of cannabis and psychosis. Converging evidence suggests that cannabinoids can produce a full range of transient schizophrenia-like positive, negative and cognitive symptoms. Cannabinoids also produce some psychophysiological deficits also known to be present in schizophrenia. [5] It is clear that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Increasing evidence suggests that early and heavy cannabis exposure may increase the risk of developing a psychotic disorder such as schizophrenia. [6,7,8] Recently it has been found that cannabis can give rise to mood and anxiety disorders. Cannabis consumption is quite high in the population of patients suffering from schizophrenia. In general, almost half of these patients are known to consume cannabis in the western countries. This Comorbidity poses challenges in management and causes additional demands on the services. [9]It is interesting to note that there are therapeutic molecules as well, which are derivatives of cannabis. [10] These are being investigated in disorders such as multiple sclerosis, spasticity, pain disorders and in a range of neuropsychiatric conditions. [11] Basic research is discovering interesting members of this family of compounds that have previously unknown qualities, the most notable of which is the capacity for neuroprotection. One of the derivatives is also having properties of antipsychotic medication. In terms of its effects on brain, there is little information on the neurocognitive and neurophysiological effects of cannabis. [12] Similarly preliminary neuro-imaging studies show that cannabis does not affect gross brain anatomy. However cannabis does alter neurophysiological functioning such as increased cerebral blood flow in acute administration. [13.14] Neurobiology of cannabis related psyhcosis is complex. Attempts have been made to explore neurocognitive, neuroimaging and neurochemical pathways besides genetic predisposition. It is expected that such information would facilitate clearer understanding of the connection between cannabis and psychosis. Clinically there are few possibilities of co-occurrence of cannabis and psychosis. These are¡ 1.A common neurobiological basis to both, cannabis and psychosis; ¡ 2. Cannabis can alleviate some of the symptoms or the side effects ¡ 3. It may precipitate mental illnesses or lead to biological changes that have common elements with mental illnesses. The clinical and epidemiological evidence of coexistence only explains ‘whether or not cannabis is a risk factor for schizophrenia’. It does not however throw light on the possible mechanism for causation of psychosis or schizophrenia. I.e. it does not address the question: why cannabis is a risk factor for schizophrenia?’ Exploring neurobiological basis is extremely important in order to find out discrete therapeutetic options. Recent work in this has given some indication to the possible mechanism [15] The possible causes of cannabis-induced changes in the brain could be: [16,17,18,19] 1. A direct toxic effect of its metabolite 2. A gene-environment interaction precipitated particularly in vulnerable subjects 3. Setting up brain changes necessary for development of psychosis, which can be manifested due to life events or psychosocial stress. Cannabis use also has an independent impact on the course and outcomes in patients with schizophrenia and bipolar disorder, which in turn makes the illness treatment resistant and worsens the quality of life. [20,21,22] Cannabis is also of particular interest in the population of First Episode Psychosis (FEP) [23,24] and Ultra High Risk (UHR) subjects. These subjects are more susceptible to cannabis abuse [24,25] and have more neuropsychological changes. Cannabis is responsible for poor adherence, which leads to frequent relapse and increases severity of illness. Amongst FEP patients it equally affects those who go on to develop schizophrenia and those who do not. In this review, we try to summarize neurobiological changes for development of psychosis. 1. 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