Mendelian randomisation studies have not yet clarified the direction of causality between heavy cannabis use and Schizophrenia. Thus, while cannabis use remains the most preventable risk factor for psychotic disorders, it is still unclear what makes some heavy users more susceptible to develop clinical psychosis. This is a question of global relevance with the spreading of laws legalising cannabis use for medicinal and/or recreational purposes.

Recently, epigenetic processes that regulate where our DNA is expressed, have been implicated in both psychotic disorder and substance use. Indeed, genome wide DNA methylation (DNAm) studies (EWAS), which measures where the DNA is switched on or off, have become a tool to look at the biological effects of environmental exposures.
This proposal, nested within a larger MRC Senior Fellowship project, focuses on the development of a genome wide DNAm score associated with regular cannabis use, taking into account both genetic factors and other environmental exposures. These analyses will run in parallel to mouse model experiment of exposure to both THC and CBD (cannabidiol), the most studied ingredient of cannabis. Finally, we plan to examine overlaps in the effect of cannabis compounds on the brain of mice with the effect in human blood tissue, to begin to understand a) the neurobiology of psychosis in the context of heavy cannabis use and b) to build epigenetic and genetic scores that might help distinguish those cannabis users that come to no harm from those who develop a) sub-clinical psychotic experiences paranoia and b) frank clinical psychosis.