MOLECULAR MECHANISMS OF CANNABIS EXPOSURE RISK IN PATIENTS WITH PSYCHOSIS.

Cannabis use is observed more frequently in patients suffering from psychosis than in the general population. In patients that use cannabis, psychosis tends to begin earlier, be more severe and more persistent. Currently, we have little understanding of what causes this relation. Several hypotheses have been proposed: cannabis could be a risk factor on its own that regardless of existing risks could trigger the psychosis, or cannabis may interact with existing predispositions thus precipitating the appearance of the disorder, or cannabis could be seen as self medication that patients come across and which relieves some of their symptoms. Many drugs act on cells by inducing chemical modifications of their DNA. This is referred to as epigenetic modifications and result in changes of the expression of the genes . With this project we gained better understanding of the effects cannabis has on the DNA in neurons. In our first study, we have characterised changes in the methylation of DNA that are associated with the current use of cannabis in patients. We have also shown that some of these modifications are reversed, but not all, in patients that have stopped using cannabis. These results are relevant for the users, ie both for patients and for the health care. In our second study, we have exposed neurons to THC and cannabidiol and identified genes differentially expressed and differentially methylated during exposure. These results are currently under publication and validation.

We have identified effects of cannabis in the DNA methylation in patients that are using versus non users of cannabis. Our results are highly relevant for the users (patients and health care workers) since it supports clinical observation and clinical practice. We identified differences in response to THC and cannabidiol between cells derived from patients and cells derived from controls. That might reflect biological differences in exposure response and we are further characterising these differences. We are in the process of publishing the results from the study in the blood of patients and have already communicated preliminary results in congress and to patients forum. At the publication of these results, we will ensure that our results be communicated to user groups. The results from our blood study will also be integrated in a larger study from a consortium of three groups that have been generated similar data.

Cannabis is the most illicit drug used worldwide. In recent years, since it has been shown to have benefits in the treatment of some diseases that induce pain, there is increasing pressure from patients and users groups to legalise its use, worldwide but also in Norway. However, it is very well documented that cannabis is the strongest environmental factor associated with psychosis. Psychotic disorders are arguably the most serious of mental illnesses, that affect more than 1% of the population, causing major burden on the patients, their environment and the society. Although a large part of their etiology is attributable to genetic factors, environment factors, such as cannabis, are considerable risk factors. The aim of our project is to understand how cannabis increases the risk of developing psychosis at the molecular level, and how it interacts with genetic risk. We will employ a translational approach utilizing expertise in clinical studies with samples of patients, in combination with molecular genetics and functional genomics expertise. We will develop a cellular model from human induced pluripotent stem cells from patients and controls that will be derived into frontal cortical induced neurons and exposed to THC and cannabidiol (the main active compounds of cannabis). We will employ detailed transcriptomics, epigenetics and phenotypic profiling to characterise those induced neurons. We will integrate the results with the characterisation of the same markers in blood from patients exposed to cannabis, and put a special emphasis on understanding the interaction between genetic profile and cannabis exposure. With this project we expect to achieve a deeper understanding of 1) the effect of cannabis exposure in induced neurons, 2) the interplay between cannabis use and genetic factors in the etiology of psychosis and 3) the potential to develop treatment adapted to the effect of cannabis on neurons in patients.