The role of the endocannabinoid system and cannabis use in the expression of psychosis

Psychotic illnesses are a major cause of mortality and cause a financial burden of £12 billion per annum in England. There is a pressing need to understand which individuals can be helped by simple targeted interventions. The most modifiable risk factor of psychotic outcomes is cannabis use, the most illicit substance used worldwide. Further, individuals with psychosis using cannabis are more likely to be involved in aggression and violence incidents, at times requiring detention in a psychiatric intensive care unit (PICU) under the Mental Health Act to contain the risks.

My previous work has shown that patients with psychosis who are heavy cannabis users have more severe symptoms than those who are non-cannabis users, which may potentially reflect different biological mechanisms. The main psychotropic element of cannabis, delta-9-tetrahydrocannabinol (THC), elicits its effects through interacting with the endocannabinoid system (ECS). The ECS is the most widespread receptor system in our brain. It serves to respond to internal and external stimuli, which includes regulating brain development, memory formation, stress, pain, energy metabolism, and the immune system. These responses are mediated by endocannabinoids (eCBs) produced on demand, such as anandamide (AEA).

Blood levels of eCBs have been therefore used as biological markers of the activity in the ECS. A growing body of studies indicates a disruption in the ECS in patients with psychosis, but whether its functioning is particularly disrupted in individuals with psychosis using cannabis is yet to be resolved. In fact, it is thought that AEA levels are low in the acute phase of psychosis and subsequently increase to regulate the recovery process. However, no study has measured eCB levels throughout the most acute phase of a psychotic episode. Moreover, eCB levels have never been examined in relation to violence and aggression outcomes.
Finally, no study has investigated the genetics of the entire ECS, which includes several biological components. I recently provided preliminary findings on a substantial genetic variation in the ECS at a population level, that may make some individuals at a higher risk of developing a psychotic disorder. This genetic risk can be summarised into an endocannabinoid polygenic risk score (ECS-PRS).

The proposed study will first test whether, in the two large non-clinical samples, individuals with high ECS-PRS and using cannabis are more likely to present with subclinical psychotic experiences and propensity to aggression/violence.
Second, it will utilise two sites for data collection, providing access to individuals with an acute psychotic episode and individuals with psychosis living in the community. I aim to collect blood samples to generate an individual ECS-PRS and measure eCB blood levels.

These data would allow me to address three objectives. Firstly, do ECS-PRS and cannabis use have a relationship with psychopathology and violence and aggression at a population level. Second, do eCB blood levels in the newly recruited clinical sample differ throughout the different phases of the psychosis presentation and between patients using and not using cannabis. Finally, do ECS-PRS and cannabis use explains differences in the normalization of eCB levels across the sample.

The common use of cannabis and current social attitudes toward legalization makes it is imperative examining the relationship between the neurobiology of the ECS and psychopathological outcomes.

The present research proposal may inform the public, scientific and clinical community. In addition, this project will potentially identify blood biomarkers of psychosis exacerbations, which could lead to better management of violence in PICU and prevent detention in the hospital and its distressing consequences.

My research project focuses on examining the endocannabinoid system to identify peripheral biomarkers associated with the expression of psychosis, and violence and aggression, in cannabis users compared to non-users.
First, using two large independent non-clinical samples, I will work at identifying whether genetic variations of the endocannabinoid system, summarised in a genetic score, explain differences in subclinical psychotic experiences and violence and aggression outcomes between individuals who use and do not use cannabis.
Second, I will examine if the newly developed endocannabinoid genetic score and peripheral plasma levels of endocannabinoids differ between patients with a psychotic disorder who use cannabis compared with their non-user counterparts. I will recruit a) a clinical sample of patients in the acute phase of psychosis and admitted to psychiatric intensive care unit (N=150), and b) patients living in the community with a psychotic disorder and undergoing a cannabis discontinuation intervention (N=100). I shall collect clinical data, psychopathology scores, violent and aggressive behaviour data, blood samples for DNA extraction, and plasma levels of endocannabinoids and cannabinoid metabolites. I will analyse these newly collected data, and the endocannabinoid genetic score developed from the independent dataset to predict: a) those cannabis users susceptible to psychosis and violence and aggression outcomes; b) differences between individuals who develop psychosis using and not-using cannabis and their clinical correlates.
This research covers an important topic at a time of increasing cannabis consumption in the general population and the case of legalising its recreational use. It makes a significant contribution to research into the endocannabinoid system and how cannabis use impacts on its functioning. Finally, this research addresses both psychosis and violence and aggression outcomes and may inform primary and secondary prevention.