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.

My research focuses on the effect of cannabis use on the mental health of young adults, an important topic at a time of global trends towards legalising cannabis, and increasing availability of potent cannabis with high tetrahydrocannabinol (THC) and low cannabidiol (CBD). I seek to establish biological and psychological mechanisms,which determine why some heavy cannabis users develop clinical psychotic disorder, or intermediate phenotypes such as paranoia in the non-clinical population. I will assess the genetic and epigenetic factors that underlie this susceptibility by examining a) a non-clinical sample of daily cannabis users (n=400), b) never/past users (n=200) and c) 70 first episode psychosis patients using cannabis daily. I shall collect clinical data, paranoia scores, blood samples for DNA methylation and plasma cannabinoids, and carry out a virtual reality (VR) experiment measuring propensity to develop paranoid ideas in social situations. I will analyse the above, and data from large GWAS samples to generate genetic pathways and epigenetic profiles to predict: a) those daily cannabis users susceptible to disabling paranoia and b) why some users develop only paranoia and others frank psychotic disorder. In the patients, I will test if these biological markers predict cannabis cessation/reduction and improvement in paranoia and VR social response. Finally, I shall expand a mouse experiment run by my collaborators by collecting a) blood DNA pre and post THC and CBD juvenile exposure, b) post exposure behavioral data and c) brain epigenome data. I will compare the epigenetic changes associated with exposure to cannabinoids in mouse brain and blood to those measured in human blood. This program will clarify the mechanisms underlying the effects of cannabis use in inducing paranoia and other psychotic symptoms within, and beyond, frank clinical disorder, why some users are susceptible, and provide guidance for treating psychosis in the context of cannabis use.

Firstly, my analyses will clarify the effect of heavy cannabis use on the mental health of young adults who do not have a clinical diagnosis of psychotic disorder but experience paranoia with adverse effects on their social functioning. A Virtual Reality(VR) test, like the one in my proposal which takes 5 minutes, could together with a brief paranoia questionnaire, become a screening tool available in walk-in clinics, university/college counselling services as well as mental health services; young people reporting daily cannabis use could be screened with the VR social scenario and if they show a paranoid response, be offered help to decrease/stop their cannabis use, thus decreasing their risk of developing psychosis. A similar approach could be used in the care of people receiving medicinal cannabis under medical supervision. Data from the VR part of the study could also be used to develop more engaging public health campaigns to inform the public of the impact of heavy cannabis use on paranoia; in collaboration with Public Health England as well as Science Media Centre, KCL and the MRC, we could, for instance, develop social media platforms with interactive dissemination to adolescents and adults. Furthermore, a central aim of my work is to improve the care of young adults suffering from psychotic disorder following heavy cannabis use, of their carers and the support needed by the services involved in their journey to recovery. The Schizophrenia Commission recommended that efforts similar to those used to inform patients and the public about the risks of tobacco smoking should be invested in education about the risks associated with heavy cannabis use and its impact in. precipitating onset of psychosis and adversely affecting the illness outcome. Sadly, to date patients with psychosis have no access to services or interventions specifically set to promote cannabis use cessation/reduction. This is significant for the clinical outcome of this patient group, as clear evidence indicates that continuing to use cannabis after the illness onset is associated with greater relapses with great cost to their families and Mental Health services. Sadly the care of these young adults falls unsatisfactorily between adult psychiatry and addiction services, and patients rarely received optimum treatment for both aspects of their illness. My ambition is to integrate the scientific findings generate by this proposal into the clinical work of my Cannabis Clinic for Psychotic Patients to contribute a) further knowledge b)provide training for psychiatrists/mental health workers, alongside an active collaboration with addiction clinicians and academics and c) extend my collaboration to other physicians, prescribing cannabis for medicinal purposes to inform each other practise and safe prescribing. Indeed, my work on the genetic pathways and epigenetic scores associated with current daily cannabis use and their potential application as peripheral markers of cannabis associated psychosis-proness could be used to identify individuals at risk among those prescribed medicinal cannabis use, allowing them to receive closer monitoring. 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 facilitate 1) 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 the above impacts are likely to become more important at a time of changes in cannabis legislation across the world.