Multi-centre trial of cannabidiol (CBD) for the treatment of Parkinson's disease psychosis

INTERVENTION: The first phase is a multi‐centre, open‐label, safety, tolerability and dose‐finding study of cannabidiol (CBD). CBD will be given orally, once per day for 6 weeks in different doses as per dosing protocol in up to 24 participants. To identify the maximum tolerated dose (MTD) of orally administered CBD, the researchers will employ a variation of the traditional 3+3 design, with subjects assigned in groups of 3 to each dose. For the purposes of this study, MTD will be determined by toxicity and defined as the highest dose at which 2 or more out of 6 patients at a specified dose level experience a drug‐related dose‐limiting toxicity. The second phase is a multi‐centre, randomised, double‐blind, placebo‐controlled trial of CBD versus placebo. Up to 120 eligible patients will be randomly assigned at the baseline visit to receive CBD or matching placebo capsules for 12 weeks. Within the CBD arm, a single daily dose of CBD (dosage as identified from Phase I study) given in capsule form to be taken orally. For both phases of the study, CBD or placebo will be added as an adjunct to treatment as usual (TAU). TAU corresponds to the typical package of care offered to PDP patients and may include antiparkinsonian medications, quetiapine or cholinesterase inhibitors (rivastigmine/ donepezil) in line with existing clinical practice. CONDITION: Parkinson’s disease psychosis ; Mental and Behavioural Disorders ; Parkinson disease PRIMARY OUTCOME: ; Part I:; 1. Maximum tolerated dose of CBD determined by the number of dose‐limiting toxicities occurring throughout the study; 2. Safety and tolerability of CBD assessed by evaluating treatment‐emergent adverse events, UKU side effect rating scale for psychotropic drugs, physical examination (vital signs, ECG and neurological assessment) and laboratory tests at every visit; ; Part II:; Safety and tolerability of CBD assessed by evaluating treatment‐emergent adverse events, UKU side effect rating scale for psychotropic drugs, physical examination (vital signs, ECG and neurological assessment) and laboratory tests at every visit; SECONDARY OUTCOME: ; Part I:; 1. Drug‐drug interaction with any of the safe and tolerated doses of CBD, assessed by measuring the change in CBD and quetiapine and its metabolite and/ or donepezil levels in the blood at baseline (pre‐treatment) and weeks 2 and 6; 2. Evidence of neuropsychiatric drug activity (pharmacodynamic signal) measured using Parkinson’s disease‐adapted scale for assessment of positive symptoms of psychosis (SAPS‐PD) and Neuropsychiatric Inventory (NPI) at baseline (pre‐treatment) and week 6; 3. Non‐motor symptoms of Parkinson’s Disease measured using the non‐motor assessment scale for PD (NMSS) at baseline (pre‐treatment) and week 6; 4. Quality of life measured using the Parkinson’s disease questionnaire‐39 (PDQ‐39) at baseline (pre‐treatment) and week 6; 5. Sleep measured using SCOPA‐Sleep at baseline (pre‐treatment) and week 6; 6. Cognition measured using SCOPA‐COG and MoCA at baseline (pre‐treatment) and week 6; 7. Global improvement/change measured using the Clinical Global Impression of Change at baseline (pre‐treatment) and week 6; 8. Caregiver burden measured using the Zarit Burden Interview at baseline (pre‐treatment) and week 6; 9. Motor symptoms of Parkinson’s disease measured using the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) at baseline (pre‐treatment) and week 6.; ; Part II:; 1. Drug‐drug interaction with any of the safe and tolerated doses of CBD, assessed by measuring the change in CBD and quetiapine and its metabolite and/or donepezil levels in the blood at baseline (pre‐treatment) and weeks 2, 6 and 12; 2. Evidence of neuropsychiatric drug activity (pharmacodynamic signal) measured using Parkinson’s disease‐adapted scale for assessment of positive symptoms of psychosis (SAPS‐PD) and Neuropsychiatric Inventory (NPI) at baseline (pre‐treatment) and week 12; 3. Non‐motor symptoms of Parkinson’s Disease measured using the non‐motor assessment scale for PD (NMSS) at baseline (pre‐treatment) and week 12; 4. Quality of life measured using the Parkinson’s disease questionnaire‐39 (PDQ‐39) at baseline (pre‐treatment) and week 12; 5. Sleep measured using SCOPA‐Sleep at baseline (pre‐treatment) and week 12; 6. Cognition measured using SCOPA‐COG and MoCA at baseline (pre‐treatment) and week 12; 7. Global improvement/change measured using the Clinical Global Impression of Change at baseline (pre‐treatment) and week 12; 8. Caregiver burden measured using the Zarit Burden Interview at baseline (pre‐treatment) and week 12; 9. Motor symptoms of Parkinson’s disease measured using the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) at baseline (pre‐treatment) and week 12; ; Mechanistic sub‐study:; Neurophysiological mechanisms underlying the antipsychotic effects of CBD in PDP measured using:; 1. Within‐subject change in medial temporal, prefrontal, and striatal activation (as estimated from the blood oxygen level‐dependent haemodynamic response signal measured using fMRI; BOLD signal) in the MRI scanner at baseline (pre‐treatment) and week 12; 2. Within‐subject change in functional connectivity between the medial temporal, prefrontal, striatal and visual cortical regions of interest (as estimated from the BOLD signal) and between these regions and the rest of the brain using both resting state and task‐based fMRI data in the MRI scanner at baseline (pre‐treatment) and week 12; INCLUSION CRITERIA: 1. Satisfy established diagnostic criteria (NINDS‐NIMH criteria for the diagnosis of Parkinson’s disease psychosis) and UK Brian Bank criteria for idiopathic Parkinson’s disease 2. Age 40 or older 3. For psychotic symptoms, they should have developed after the PD diagnosis and should have been present for at least 1 month, occurring at least weekly over the month before screening and should have a combined score of at least 6 or an individual score of at least 4 on the neuropsychiatric inventory (NPI) A (delusions) and/or B (hallucinations) subscale in the month before screening 4. Parkinson’s disease dementia would not be an exclusion criterion 5. Participants with score greater than 18 on the Montreal Cognitive Assessment scale 6. Treatment as usual will include patients on quetiapine and/ or cholinesterase inhibitors (rivastigmine/ donepezil) as well