Title: CANnabidiol as a Treatment fOr Psychosis clinical high-risk state- a Randomised Clinical Trial (CANTOP-RCT)
Funder: Department of Health and Social Care

Abstract: There are no licensed pharmacological treatments for patients who are at clinical high-risk of developing psychosis (CHR), and although psychological interventions are well tolerated, they do not appear to reduce the risk of later transition to psychosis. CHR patients commonly experience low-grade anxiety and psychotic symptoms. We have recently completed proof-of-concept studies aimed to inform a go/ no-go decision regarding an efficacy trial with Cannabidiol, a non - intoxicating cannabinoid found in cannabis. Collectively these results provide a strong case for a fully powered clinical trial to investigate its efficacy. We now propose to conduct a multi-site, double-blind, randomised controlled trial to evaluate the efficacy and tolerability of Cannabidiol when added to 'treatment as usual' (TAU), compared to TAU plus placebo, in 300 CHR patients (n=150 per treatment arm). Patients will be given a single daily dose of 600 mg cannabidiol or placebo for 6 months. We will primarily compare the effect of the two treatment conditions on change in attenuated psychotic symptom severity at 6 months compared to baseline as measured using standardized criteria (comprehensive assessment of at risk mental state; CAARMS). We will also compare their effect on side-effects, other symptoms (anxiety); and global functioning. Evidence suggests that the onset of psychosis in CHR patients critically dependent on alterations in medial temporal cortex and the striatum. Thus, the modification of neurobiological abnormalities in these two regions represents a potentially useful biomarker for the evaluation of interventions for patients in the CHR state. Our proof-of-concept data gives preliminary evidence that Cannabidiol may affect the function of these regions. Hence, in a subsample of participants (total n=100; n=50 per treatment arm), we will formally test this. We will use magnetic resonance spectroscopy to measure hippocampal glutamate levels, functional MRI (while patients perform verbal memory and emotional processing tasks), and arterial spin labelling (to measure blood flow) to measure the function of the medial temporal cortex and basal ganglia. We will investigate the mechanisms underlying the effects of Cannabidiol, which are currently unclear, by comparing the effect of Cannabidiol treatment on change in these measures over 28 days of treatment compared to placebo treatment. These participants will be studied twice using these three imaging approaches, once before treatment initiation and again after 4 weeks of treatment. We will compare changes in hippocampal glutamate and medial temporal cortex and basal ganglia activation and blood flow at 4 weeks compared to baseline. The clinical trial data will be analysed using an intention-to-treat analytic approach. Imaging data will be analysed using non-parametric analytic methods and focus on brain activation or blood flow changes within the medial temporal lobe and basal ganglia regions of interest and on hippocampal glutamate levels.

Lay abstract: Psychotic disorders such as schizophrenia typically affect young people and rank as one of the most disabling conditions worldwide. They pose an enormous burden on those affected and their families. They also cost society a great deal. In England alone, the total cost to society for services caring for people with schizophrenia and from lost employment is estimated to be £11.8 billion per year. Estimates suggest that in England alone, around 15,763 people present every year with early symptoms of psychosis. Around a third of such people who are clinically at high risk (CHR) of developing psychosis will do so over the next 3 years. CHR patients commonly experience low level anxiety and psychotic symptoms such as delusions (e.g. false beliefs) and hallucinations (e.g. hearing voices that are not there). Typically these experiences are short-lasting or less severe compared to when they develop frank psychosis. We would like to prevent young people from developing psychotic illnesses. However, this is not easy, as it is not possible to accurately predict which CHR person will later develop psychosis. Also, current treatments do not always work. The medications (such as antipsychotic drugs) that we have available were originally developed for those with frank psychosis. They have only a modest benefit and are not tolerated very well. As treatments have to be offered to all CHR patients and not just those who will later develop frank psychosis, this also raises ethical concerns. Hence, at the moment, most CHR patients presenting to the NHS typically receive practical help and support (e.g. for housing or vocational support) and help from clinicians to address current issues. Cannabidiol (CBD), a naturally available chemical found in the extract of cannabis plant, has emerged as a promising candidate as it displays anti-anxiety and anti-psychotic like properties in animal models and in man. It has also been tolerated very well in human studies. We have recently tested this in a small number of CHR patients by giving them a 600 mg capsule of CBD daily for a short period (3 weeks) and comparing it with a group of CHR patients who were given an inactive drug. Results from these small studies suggest that CBD may be useful in treating symptoms in CHR patients. CBD was also safe and tolerated well by CHR patients. However, we do not know whether CBD treatment will actually be useful in providing symptom relief in CHR patients. A large clinical trial comparing CBD to placebo is needed to test this. We plan to do this in our proposed study. We propose to study 300 CHR patients. Half of them will receive the same dose of CBD (600 mg once a day) that we have used before and the other half will receive a placebo capsule. They will receive the treatment for 6 months. Neither the researchers nor patients will know what they have been treated with during the study. At the end of treatment, we will compare whether those who received CBD were significantly better off in terms of the symptoms that they were experiencing before they started treatment compared to those who received placebo. We will also study a sub-group of people (50 of those receiving CBD and 50 of those receiving placebo) with to study brain chemistry and function using brain scanning to understand how CBD may work. These results will help inform whether CBD can be used to treat symptoms of CHR in the clinic.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH