Title: Towards a harm reduction approach to problematic cannabis use in schizophrenia
Funder: Department of Health and Social Care

Abstract: Research Question Does cannabis containing a 'safe' ratio of CBD:THC (3:1) have fewer harmful effects than THC alone in people with schizophrenia while continuing to be acceptable to users? Background The THC content of street-bought cannabis has increased considerably over recent years. At the same time, the CBD content has fallen. These changes are believed to have increased the harms associated with cannabis use. In patients with schizophrenia, where cannabis use is widespread, they may have further increased patients' risk of relapse and hospital admission, the single largest source of costs in NHS mental health care, as well as exacerbating symptoms and worsening quality of life. At present, there are no effective evidence-based medical or psychological treatments for reducing cannabis use in schizophrenia. Objectives To assess the extent to which, in individuals with schizophrenia, the presence of CBD attenuates the effects of THC on: Psychotic symptoms and anxiety symptoms Cognitive performance The intoxicating and the pleasurable effects of cannabis To explore the feasibility of a harm reduction approach to cannabis use in patients with schizophrenia To collect data on genetic factors that may alter the response to cannabisHypotheses Compared to THC alone, cannabis with a 'safe' CBD:THC ratio will lead to: Fewer psychotic symptoms and anxiety symptoms Less cognitive impairment A 'high' that is comparably pleasurable Patients will be willing to replace their own high-potency illicit cannabis with a 'safe' form of cannabisMethods The study will have a randomised, double-blind, 2-arm, cross-over, within-subjects design. It will recruit 30 female and male volunteers with a clinical diagnosis of schizophrenia who use cannabis regularly. At each experimental visit, participants will be administered a vaporised cannabis preparation containing either THC 10mg or THC 10mg + CBD 30mg. Participants will be assessed for psychosis, anxiety and mood symptoms and complete a comprehensive cognitive test battery. Blood samples will be collected post-inhalation to analyse plasma endocannabinoid levels as well as levels of THC and CBD and their relevant metabolites. Blood samples for genetic data will also be collected. To ensure safety, the study will only recruit participants who use cannabis at least weekly and will be performed in a state of the art research facility with staff who have extensive experience in working with patients with schizophrenia and in the administration of inhaled cannabinoid compounds. Impact If the study demonstrates that CBD/THC is significantly less harmful than THC alone it will sanction the development of a cannabis harm reduction treatment for patients with schizophrenia and persistent cannabis use. If an alternative outcome is demonstrated the results will continue to have major implications for our understanding of the role of cannabis and the endocannabinoid system in schizophrenia.

Lay abstract: Background to the research Schizophrenia is a mental disorder which is characterised by disordered thoughts and beliefs, reduced motivation, poor memory, and hallucinations. Many patients with schizophrenia use illicit drugs, of which cannabis is the most popular. Cannabis use exacerbates symptoms and doubles the risk of relapse and hospital admission, the single largest source of NHS costs and a considerable personal burden for patients. At present, there are no evidence-based medical or psychological treatments for problematic cannabis use in patients with schizophrenia. In recent years, the level of delta-9-tetrahydrocannabinol (THC) found in UK cannabis has increased dramatically. THC produces the 'high' associated with cannabis but can also cause psychotic symptoms, memory impairment, and anxiety. Over this period, the content of cannabidiol (CBD) found in illicit cannabis has fallen to low or near-absent levels. CBD is believed to ameliorate the negative effects of THC without reducing its acceptability to users. High-potency cannabis, with high levels of THC and low levels of CBD, is believed to have particularly negative effects on users' mental health and may lead to even higher rates of relapse in patients with schizophrenia. Aims of the research This fellowship aims to answer the following question: does a 'safe' form of cannabis (with a higher CBD content) minimise the unwanted effects of cannabis (psychotic symptoms, memory impairment, and anxiety) while still providing an acceptable 'high' for patients with schizophrenia? Answering this question will enable the development of a novel harm reduction treatment for patients with schizophrenia in whom persistent cannabis use worsens symptoms or triggers relapse. Design and Methods Used The study will be carried out at the NIHR-Wellcome Trust Clinical Research Facility at King's College Hospital by researchers with clinical experience in working with patients with schizophrenia and in the administration of cannabis in a research setting. It will recruit patients with a diagnosis of schizophrenia who are clinically stable, use cannabis regularly, and have no major medical illnesses which would place the participant at risk of harm. Participants who use cannabis extremely frequently, are dependent on other illicit drugs or alcohol, or who are unable to refrain from alcohol and illicit drug use during the study will be excluded. Participants will attend on three occasions: an initial baseline visit, followed by two testing days at least one week apart. On testing days, participants will inhale, via a vaporiser, one of two types of cannabis (THC only or CBD+THC) in a randomised order. Participants and researchers will not know the type of cannabis being administered. After inhaling the cannabis vapour, participants will complete cognitive tests, be interviewed about psychotic symptoms, and answer questionnaires on their experience of the drug's effects. In the weeks after the study, participants will be closely monitored for any adverse effects. Patient and public involvement A number of patients with a diagnosis of schizophrenia who use cannabis regularly were interviewed to discuss the proposed fellowship. Feedback was overwhelmingly positive with no criticisms of its design. 86% of patients interviewed were keen to participate in the study and agreed to be contacted in the future by our research team. With regards to the development of a harm reduction treatment, 86% of patients believed it was a good idea and were open to trialling a 'safer' cannabis themselves.Dissemination The results of the fellowship will be presented at international academic conferences and published in peer-reviewed scientific journals. They will be discussed with the study's participants, local patient groups, and relevant charities and public bodies such as Mind, Rethink Mental Illness, Hearing Voices Network, DrugScience and the Advisory Council on the Misuse of Drugs.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH