B4002 - Pathway to psychosis among cannabis users - 28/02/2022

B number: 
Principal applicant name: 
Marta Di Forti | SGDP, KCL IoPPN (UK)
Robin M Murray, Isabelle Austin-Zimmerman, Diego Quattrone , Giulia Trotta, Edoardo Spinazzola, Chloe Chung Yi Wong, Emma Dempster , Luis Alameda
Title of project: 
Pathway to psychosis among cannabis users
Proposal summary: 

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.

Impact of research: 
Our ambition is to develop, from the work on the genetic pathways and epigenetic scores associated with cannabis use, potential peripheral markers of cannabis associated psychosis-risk. These peripheral biomarkers could be integrated into screening tools to identify individuals at risk of developing psychosis outcome not only among recreational cannabis users but also among those prescribed medicinal cannabis use; the latter would allow them to receive closer monitoring and might increase confidence in the prescription of cannabis-based medication when indicated. The novelty of the comparative analyses of genetic-epigenetic data in the context of cannabis exposure from the human studies and from the mouse model experiment will 1) facilitate closer collaborations between the psychosis and neuroscience research communities and beyond to replicate and build on my findings; 2) inform Pharma companies of potential new drug targets and better understanding of how cannabidiol (CBD) and other potentially cannabinoids could be used in the treatment of cannabis-associated psychosis. All of these impacts are likely to become more important at a time of changes in cannabis legislation across the world.
Date proposal received: 
Monday, 14 February, 2022
Date proposal approved: 
Monday, 21 February, 2022
Mental health - Psychology, Psychiatry, Cognition, Mental health, DNAm longitudinal profiling Genetics Pathway analyses, Statistical methods