CANNABIDIOL AS A NOVEL THERAPEUTIC AGENT FOR PATIENTS AT ULTRA HIGH-RISK OF PSYCHOSIS: AN EXPERIMENTAL MEDICINE APPROACH

Worldwide, there is increasing focus on intervening before the onset of frank psychosis in order to prevent much of the disability associated with the disorder. However, safe, effective and well-tolerated treatments for individuals who are at high-risk of developing psychosis (UHR) are currently unavailable. Further, as some of the UHR individuals will never go on to develop frank psychosis, it is critical to develop medications that are not only safe but also tolerated well. UHR individuals commonly experience anxiety and psychotic symptoms that are short-lasting and/ or less severe compared to when they develop frank psychosis. Cannabidiol (CBD), a naturally available chemical found in the extract of cannabis, has emerged as a promising candidate as it displays anti-anxiety and anti-psychotic like properties in animal models and in man and has also been tolerated very well in human studies. However, whether it may have beneficial effects in treating anxiety and psychotic symptoms that are commonly present in UHR individuals has never been tested. We propose to investigate whether CBD may be useful as a treatment in UHR individuals by employing an experimental approach where we test the effects of CBD on anxiety and psychotic symptoms and their underlying neural substrate both acutely and in the short-term following three weeks of treatment. UHR individuals who satisfy standard diagnostic criteria and have never received any antipsychotic treatment will be randomly allocated to a CBD treatment group or a placebo treatment group. On day 1 of the study, UHR individuals in the CBD treatment group will be asked to take one 600 mg capsule of CBD orally, while those in the placebo treatment group will take an identical placebo capsule. Anxiety and psychotic symptoms will be measured using standard rating scales both before and after drug administration on day 1. On the same day they will also undergo brain scanning and complete two psychological tasks outside the scanner. These tasks have been used by researchers before, and are meant to temporarily trigger feelings of anxiety and paranoia. In one of the tasks they will be asked to prepare and deliver a short speech. They will be told that this will be filmed and analysed by psychologists, to trigger anxiety. The second task will involve a virtual-reality journey on a busy London tube train, which will recreate the sights, sounds, and sense of immersion in a real-world 3D environment. This task has been shown to induce brief-lasting paranoia in UHR individuals. Only those UHR individuals who tolerate all aspects of the experiment on day 1 of the study will be asked to continue on the same drug, once a day, for 3 weeks. Otherwise, they will be withdrawn from the study. On the final day (day 21) of the study, all the experimental procedures, including clinical measures, brain scanning and off-line symptom-induction tasks, will be repeated as on day 1. By comparing the anxiety and psychotic symptoms with and without the symptom-induction tasks and the brain activity measures between the placebo and CBD treatment groups across the two experimental sessions, we will be able to establish whether CBD has a beneficial effect on symptoms both acutely and following short-term treatment and also establish the neural mechanisms underlying these effects. Both doctors and researchers involved in carrying out the study and the UHR individuals who participate will be blind to the treatment that the participants will be receiving. Safety of the participants will be monitored throughout the study by repeating routine blood investigations, ECG, clinical interviews and physical examination at regular intervals. The study will be carried out following regulatory guidelines after obtaining ethical and other regulatory approvals. This study will help provide important early information regarding the potential of CBD as a safe, effective and well-tolerated treatment that will guide future clinical trials.

Safe and effective treatments for patients who are at ultra high-risk of developing psychosis (UHR) are currently unavailable. UHR individuals commonly experience short-lasting and mild anxiety and psychotic symptoms. We propose to investigate whether Cannabidiol (CBD), a naturally available cannabinoid, can be a potential treatment for UHR individuals as it displays anti-anxiety and anti-psychotic like properties in animal models and in man and has also been tolerated very well in human studies. Employing a parallel-group, randomized, double-blind design we plan to examine the effects of CBD or placebo on anxiety and psychotic symptoms and their underlying neural substrate by employing functional MRI, both acutely and in the short-term following three weeks of treatment. Antipsychotic drug naïve UHR individuals satisfying standard diagnostic criteria will be randomly allocated to CBD or placebo treatment groups. On day 1 of the study, they will be asked to take either one 600 mg capsule of CBD or an identical placebo capsule orally. Anxiety and psychotic symptoms will be measured using standard rating scales both before and after drug administration on day 1. On the same day they will also undergo brain scanning while they perform a learning, salience processing and emotional (fear) processing tasks that have been previously employed in conjunction with CBD. Outside the scanner, they will complete two psychological tasks that are meant to temporarily trigger feelings of anxiety and paranoia: a public speaking task and virtual reality task. Only those UHR individuals who tolerate all aspects of the experiment on day 1 of the study will be asked to continue on the same drug, once a day, for 3 weeks. Otherwise, they will be withdrawn from the study. All the experimental procedures carried out on day 1 will be repeated on day 21. By comparing the two treatment groups this study will provide proof-of-concept for the beneficial effect of CBD in UHR individuals.

The results of the present proposal are likely to benefit a range of non-academic beneficiaries:
Patients: The most important group of users to benefit from the proposed research is the wider group of ultra high-risk for psychosis (UHR) patients, in whom this research will be carried out. Currently, no there are no safe, well-tolerated and effective treatments that are acceptable to UHR patients and their treating clinicians. If Cannabidiol (CBD) is found to be effective in treating anxiety and psychotic symptoms in this proof-of-concept study, then it can be moved to the next developmental stage including phase III clinical trials, with a potential for a novel treatment for UHR patients being available in the clinic within the next decade. Positive results in the present study will also mean greater impetus and support for exploring and developing other potential clinical applications of CBD such as in frank psychosis (where there is already some phase II data available), psychotic and anxiety symptoms in neurodegenerative conditions like dementia and parkinson's disease as well as anxiety disorders. Similarly, favourable tolerability data from the proposed study will support clinical applications in other medical conditions where CBD is thought to be potentially beneficial. Thus, there is a wider patient population beyond UHR patients who could potentially benefit from the proposed study in terms of a new treatment.

Commercial beneficiaries: The next stage of development, if this proposal were to yield positive results, would be properly powered Phase II multi-centre clinical trial after discussion of precise indication definition with the European Medicines Agency regulators. KCL has the experience and history of coordinating several multi-centre trials (via the Joint Clinical Trials Office and Clinical Trials Unit) and with the agreement and participation of GW pharmaceuticals would be able to lead this. Funding for this would have to be provided by GW or jointly sought as per our intellectual property (IP) exploitation agreements. If the Phase II study were to be positive, it would then require pharmaceutical scale Phase III pivotal trials and related marketing and regulatory developments.
Other pharmaceutical companies (including GW pharmaceuticals, a collaborator on this application) that are interested in developing cannabinoid-based medications for a number of therapeutic areas are also likely to benefit greatly from the proposed research in terms of helping make 'Go/ No Go' decisions that may potentially have significant financial consequences. The results of present study especially related to the mechanistic aspects of the effects of CBD on the brain may also provide important leads for future research to pharmaceutical companies.

Policy-makers: Currently there are no acceptable standard medication treatments for UHR patients, despite there being early detection services across UK and elsewhere in the world. If safe and effective treatment becomes available for the 15,763 UHR patients who present annually in England, there would be significant saving for health services in the UK. Economic modeling based on a 15% reduction in the transition rate to psychosis in the 35% of UHR individuals who go on to develop psychosis has been estimated to result in annual savings of about £47.6 million (Knapp, McDaid & Parsonage, DoH 2011). Similar economic impact would be evident worldwide if the present proposal were to yield positive results.