MOLECULAR MECHANISMS OF CANNABIS EXPOSURE RISK IN PATIENTS WITH PSYCHOSIS.

Der er et større antall kannabisrøykere blant pasienter som lider av psykoser enn det vi ser i den generelle befolkningen. Pasienter som bruker kannabis opplever psykoser i lavere alder, psykosene er gjerne alvorligere og varer lengre. Vi vet på nåværende tidspunkt veldig lite om hva som forårsaker denne sammenhengen mellom kannabisbruk og psykoser. Flere hypoteser er foreslått: kannabis kan i seg selv være en risikofaktor som utløser psykoser uavhengig av andre risikofaktorer, eller kannabis kan samhandle med andre eksisterende risikofaktorer og på den måten fremskynde sykdommen, eller kannabis kan oppfattes som noe som hjelper mot noen av de tidlige symptomene pasienter opplever og dermed oppfattes som selvmedisinering. Mange stoffer (både medisiner og narkotika) påvirker genene ved å gjøre kjemiske endringer på DNAet. Dette kalles epigenetiske endringer. I dette prosjektet har vi lært om endringene som skjer på DNA nivå, og hvordan dette påvirker genuttrykket i hjerneceller. I vår første studie har vi sett på modifisering i DNA metylering i pasienter som bruker kannabis of hvordan disse modifikasjoner endrer seg eller ikke etter at pasienter har sluttet å brukke kannabis. Disse resultater har en relevans til brukerne både pasienter og helse tjeneste. I den andre studien vår har vi sett på modifisering av DNA på metylering og genuttrykt nivå i nevroner som ble eksponert til THC og cannabidiol. Vi har identifisert gener som er differensialt uttrykt og metylert under eksponering. Disse resultatene er for øyeblikket under publisering og validering.

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.