Pathways to psychosis among cannabis users

Epidemiological and experimental evidence implicates cannabis use as a risk factor for psychotic disorder, which in England has an annual cost of £12 billion. My work has demonstrated a) that the greatest risk is from daily use of potent cannabis, high in Tetrahydrocannabinol (THC) and low in Cannabidiol (CBD). I have also shown that differences in cannabis use across Europe contribute to striking variations in the occurrence of psychosis; 30% of new cases in London are attributable to cannabis use. However, only a minority of cannabis users develop psychotic disorder, and it is unclear what makes some particularly susceptible. This is a question of global importance given that 200 million people use cannabis daily, and the spread of laws legalising cannabis for medicinal or recreational use. I work one day per week as a Consultant Psychiatrist treating young people suffering their first episode of psychosis, and have established a specialized Psychosis Clinic for cessation/reduction of cannabis use. This presents an ideal setting for research. I propose to study psychotic disorder and in particular paranoia which is one of the most frequent symptoms in psychotic disorder; it is especially prominent in patients who use cannabis, and in volunteers administered THC. I will ascertain 1)the impact of heavy cannabis use on mental health in a non-clinical population and 2)genetic and epigenetic markers that explain differences in individual susceptibility to develop paranoia among heavy cannabis users, with or without a diagnosis of psychotic disorder. I will recruit two samples of non-clinical young adults: a)daily current cannabis users and b)never users/past users as well as c)a sample of cannabis using first episode psychosis patients. I shall invite subsets of the non-clinical samples and all the first episode psychosis patients to provide 1)details on their patterns of drug use 2)blood for DNA and levels of THC and CBD as biological indicators of cannabis exposure 3)complete an assessment of psychotic symptoms especially paranoia, and of memory and 4)take part in a Virtual Reality (VR) experiment measuring propensity to develop paranoid ideas in response to social situations. The VR study will establish if current daily cannabis users, even those that do not develop psychotic disorder, are more likely to experience socially disabling paranoia. Then I shall 1) generate for each person genetic pathway scores and examine if they explain susceptibility to develop cannabis use disorders with/without psychotic disorder and 2) build epigenetic profiles that show the signature that cannabis use leaves on DNA. The genetic and epigenetic data will be used to identify, among the daily users, those susceptible to experience paranoia and to understand why some heavy cannabis users remain symptomless, others develop only paranoia, and others a full psychotic disorder. Moreover, by studying the first episode psychosis patients before and after they stop/reduce their cannabis use,I will test if biological markers a)predict response to the intervention and b)change with change in cannabis use. Finally,I will build on a mouse experiment of exposure to THC and CBD, already funded by the MRC, run by my collaborators. I will have access to blood DNA samples from the mice pre and post exposure to THC and CBD, plus the post exposure behavioral data and DNA from brain. My addition to this study will examine overlap in the effect of cannabis compounds on the epigenome in mouse brains with their effect in mouse and human blood. The Schizophrenia Commission pointed out that cannabis use is the most preventable cause of psychotic disorder. My proposal will facilitate understanding the neurobiology of psychosis and paranoia in the context of daily cannabis use, advance knowledge on the effects of the latter on mental health short of formal psychotic disorder, and identify young adults for whom recreational/medicinal cannabis use carries special risk.