The role of the endocannabinoid system and cannabis use in the expression of psychosis
Lead Research Organisation:
King's College London
Department Name: Social Genetic and Dev Psychiatry Centre
Abstract
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 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.
Technical Summary
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.
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.
Publications

Corsi-Zuelli F
(2024)
Transdiagnostic dimensions of symptoms and experiences associated with immune proteins in the continuity of psychosis.
in Psychological medicine

D'Andrea G
(2024)
Variation of subclinical psychosis across 16 sites in Europe and Brazil: findings from the multi-national EU-GEI study.
in Psychological medicine

Hatoum AS
(2023)
Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders.
in Nature. Mental health

Sideli L
(2023)
The relationship between genetic liability, childhood maltreatment, and IQ: findings from the EU-GEI multicentric case-control study.
in Social psychiatry and psychiatric epidemiology

Spinazzola E
(2023)
The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study.
in Psychological medicine

Spinazzola E
(2023)
The effect of the COVID-19 pandemic on the treated incidence of psychotic disorders in South London.
in Psychiatry research
Description | Cannabis Clinic for Psychosis - Education Portal |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Feedback from the launch of the portal suggests this type of educational approach is well received to improve public health education. |
URL | https://leap.slam.nhs.uk/course/view.php?id=771 |
Description | 2023 European Psychiatric Association (EPA) Early Career Psychiatrists (ECP) Scholarship |
Amount | € 1,000 (EUR) |
Organisation | European Psychiatric Association (EPA) |
Sector | Charity/Non Profit |
Country | France |
Start | 03/2023 |
End | 03/2023 |
Title | Clinical Record Interactive Search (CRIS) studies: Change in the incidence of Psychosis in South London and Predictors of long-term outcome in the GAP/EU-GEI FEP cohort |
Description | These two databases include 1) incidence data of the first episode of psychosis over several years and 2) long-term follow-up data after the first episode of psychosis, based on the linkage of CRIS data, which therefore include biological, socioenvironmental, and clinical variables. The first database allowed the publication of the paper showing the changes in the incidence of psychosis during the COVID-19 pandemic. A second paper is in preparation, focusing on the incidence of first-episode psychosis patients who required intensive care admission and how cannabis misuse is associated with this negative outcome. |
Type Of Material | Database/Collection of data |
Year Produced | 2024 |
Provided To Others? | No |
Impact | Papers in preparation |
URL | https://projects.slam.nhs.uk/research/cris/cris_projectsdetails?ID=1906 |
Title | Clinical Record Interactive Search (CRIS) study: 'Factors associated with violence and aggression in Psychiatric Intensive Care Unit' |
Description | I have completed data collection for the project 'Factors associated with violence and aggression in Psychiatric Intensive Care Unit' using the Clinical Record Interactive Search (CRIS), including 1,263 unique admissions over five years, for which an extensive assessment of clinical and socioenvironmental determinants has been done. |
Type Of Material | Database/Collection of data |
Year Produced | 2024 |
Provided To Others? | Yes |
Impact | I have completed the data collection and analysis and am writing the first draft of the core paper. MSc and PhD students will use the database for additional projects and dissertations. The database is available and ready to use in the secure environment of BRC CRIS. |
URL | https://projects.slam.nhs.uk/research/cris/cris_projectsdetails?ID=1672 |
Title | Genetic data - UK Biobank - EU-GEI - GAP studies |
Description | I have built an endocannabinoid polygenic score in these three datasets and merged it with the relevant sociodemographic, environmental, and clinical variables. I have also generated dimensions of psychotic symptoms and experiences. The datasets are secured and ready for analysis in the CREATE High-Performance Computing cluster of King's College London. |
Type Of Material | Database/Collection of data |
Year Produced | 2023 |
Provided To Others? | No |
Impact | I have completed the first draft of the core paper |
Description | Psychiatric Genomic Consortium - Educational Committee member |
Organisation | Psychiatric Genomics Consortium (PGC) |
Country | Global |
Sector | Learned Society |
PI Contribution | I have contributed to the group's activities and co-authored two papers on psychiatric genetic education (one published and another in submission). |
Collaborator Contribution | We collaborated to group's activities including writing educational papers. |
Impact | Peer-reviewed publications |
Start Year | 2023 |
Description | Research Collaboration on genetics |
Organisation | Cardiff University |
Country | United Kingdom |
PI Contribution | I have been collaborating with the MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) at Cardiff University, where I was granted a visiting position in 2023. I have participated in their weekly research project discussions. I provided feedback on their work on polygenic risk scores, symptom dimensions, and cannabis use, and factor analyses. Moreover, I co-authored a paper on symptom dimensions in twin and clinical samples with this group, currently under peer review revision. |
Collaborator Contribution | I presented to the research team in Cardiff my data on the additive effect of the endocannabinoid polygenic risk score and cannabis use in increasing 1) the risk of psychosis in the EU-GEI study and 2) the risk of psychosis and the severity of subclinical psychosis experience in the UK Biobank. I received positive and valuable feedback from the Cardiff group, including suggestions on further improving and expanding my work (for example, replicating results together in another sample). I also received critical feedback on better considering linkage disequilibrium when building the endocannabinoid polygenic risk score. |
Impact | 1) I built a new and more reliable endocannabinoid polygenic score, which now better accounts for linkage disequilibrium and considers the genes in my endocannabinoid pathway's downstream and upstream regions; 2) I repeated this procedure in the different datasets I am using; 3) My data presentation/talk in Cardiff increased awareness of the effects of cannabis use at the first episode of psychosis; 4) Cardiff post-docs and I plan to collaborate on a symposium submission, for example, at the World Conference of Psychiatric Genetics (WCPG) congress. |
Start Year | 2023 |
Description | Teaching and Research Collaboration |
Organisation | Shenzhen KangNing Hospital |
Country | China |
Sector | Hospitals |
PI Contribution | I was invited to visit the Shenzhen Kangning Hospital for clinical teaching and academic purposes as part of the Sanming Project of Medicine, which is conducted in collaboration with King's College London. I had the opportunity to give talks to more than 4,000 psychiatrists on psychotic disorders, the endocannabinoid system, cannabis use, and how to run a psychiatric intensive care unit and reduce restrictive practices. I provided expert supervision to local clinical and academic work. |
Collaborator Contribution | Shenzhen Kangning Hospital contributed to my understanding of the different and transcultural expressions of psychotic disorders and the importance of personalised medicine in the management of mental health. This was important for generating new ideas to implement in clinical practice, which may be part of a future grant application. |
Impact | We planned further visits from King's College academics to Shenzhen Kangning Hospital and vice versa. |
Start Year | 2023 |
Description | Teaching and Research Collaboration |
Organisation | University of Chieti-Pescara |
Country | Italy |
Sector | Academic/University |
PI Contribution | I was invited to visit the University of Chieti-Pescara, Italy, for teaching and research purposes. The teaching was centred on biological, environmental, and clinical determinants of psychotic disorders. I presented my research work on the endocannabinoid system and my clinical work at the Maudsley NHS Foundation Trust on identifying predictors of violence and aggression and reducing restrictive practices. I also presented the current understanding and research directions of refining the classification of the spectrum of psychosis, identifying dimensions of symptoms by presumed aetiology such as cannabis use and polygenic scores, and mapping their trajectories over time. I have started to supervise local trainees, supporting them in obtaining an international perspective on their research interests and developing their clinical academic ambitions. |
Collaborator Contribution | We planned to collaborate on a study to expand clinical data collection of endocannabinoid and cannabinoid profiles in psychosis in inpatient settings. |
Impact | 1) Three psychiatric trainees from the Univerisity of Chieti-Pescara visited my Institution in London and are collaborating on research projects on cannabis, violence and psychosis. 2) I organised and chaired a symposium at the 2023 Schizophrenia International Research Society (SIRS) Congress, Toronto, Canada (https://schizophreniaresearchsociety.org) addressing the 'Validity and Utility of a Dimensional Model of Psychosis over the Lifespan' bringing together junior and senior researchers at the forefront of the transdiagnostic approach in Psychiatry from King's College London in the UK, University of Chieti-Pescara in Italy, Stony Brook University in the USA, University of São Paulo in Brasil, and University of Heidelberg in Germany. |
Start Year | 2023 |
Description | Camberwell Green community safety |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I have participated in activities of the local community to enhance awareness of mental health and the risks of using cannabis, and actively contributing to a project to improve the safety of the area collaborating with the Council. |
Year(s) Of Engagement Activity | 2023,2024 |
Description | Difficult clinical cases discussion |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I chaired the session "Difficult clinical cases" during the WPA 2023 Congress for educational purposes. In this innovative format, early career psychiatrists presented their case histories in the presence of well-known experts with extensive knowledge in psychiatry. |
Year(s) Of Engagement Activity | 2023 |
Description | Interview for television |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | I was interviewed by a local Italian television on violence and mental health, focusing on the role of cannabis use as one of the risk factors leading to violence. |
Year(s) Of Engagement Activity | 2024 |
Description | Medical School Visit |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Undergraduate students |
Results and Impact | I have run a seminar focusing on the disruptive impact of cannabis misuse on mental health, directed to the medical students of the University of Chieti-Pescara, Italy. |
Year(s) Of Engagement Activity | 2023 |
Description | Mediterranean Maudsley Forum organization |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I have been an International Committee member of the annual Mediterranean Maudsley Forum (MMF) since 2016. Junior and senior colleagues and individuals with lived experience of psychosis, as testified by their feedback, consider the MMF to be an excellent educational opportunity for improving knowledge of psychiatric research, clinical care, and networking. Since 2023, I have led the workshop on 'The high and low of running a Psychiatric Intensive Care'. This is an opportunity to present my clinical and research work on the role of cannabis use and the endocannabinoid system in increasing the risk of psychosis, violence, and aggression. The MMF participants highly rated this workshop. |
Year(s) Of Engagement Activity | 2016,2017,2018,2019,2023,2024 |
URL | https://www.mediterranean-maudsley-forum.co.uk |
Description | Patients peer group |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I have been co-leading the Cannabis Clinic for Psychosis weekly peer group since 2020, which allows me to interact with people with lived experience of psychosis associated with cannabis use. We have been observing a positive change in the views of both patients and mental health professionals. This great opportunity is still inspiring and driving my current investigation on the link between cannabis, psychosis, violence and aggression. |
Year(s) Of Engagement Activity | 2019,2020,2021,2022,2023,2024 |
Description | Psychiatry training school visit |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | I have run a seminar on the role of the endocannabinoid system and cannabis use in the onset and the expression of psychosis. |
Year(s) Of Engagement Activity | 2023 |