A Study of Tolerability and Efficacy of Cannabidiol on Motor Symptoms in Parkinson's Disease

Persons with PD have progressive disabling tremor, slowness, stiffness, balance impairment,
cognitive deficits, psychiatric symptoms, autonomic dysfunction, fatigue and insomnia. Tremor
may interfere with necessary daily and work functions. The disorder affects approximately
seven million people globally. The total economic cost in the US is around 23 billion
dollars. In addition to economic costs, PD reduces quality of life of those affected and
their caregivers.

Cognitive impairment is a common feature and ranges from delayed recall in early stages to
global dementia in up to 80% at end stage. PD with dementia has been associated with reduced
quality of life, shortened survival, and increased caregiver distress. Community-based
studies have estimated the point prevalence for dementia in PD to be 28% and 44%.

Depression, anxiety and psychosis are also common and are particularly disabling in PD, even
at the earliest stages. These symptoms have important consequences for quality of life and
daily functioning, are associated with increased carer burden and risk for nursing home
admission. Anxiety affects up to 40% of patients with PD, and may predate motor symptoms by
several years. The most common anxiety disorders in PD are panic attacks (often during
off-periods), generalized anxiety disorder, and simple and social phobias. Psychotic symptoms
vary in frequency according to the definition used. If mild forms are included, these affect
up to 50% of patients. Visual hallucinations are the most common type. However,
hallucinations occur in all sensory domains and delusions of various types are also
relatively common. The impact of psychosis is substantial in that it is associated with
dementia, depression, earlier mortality, greater caregiver strain, and nursing home
placement. Thus, it is crucial to treat these symptoms in order to optimize the management of
PD patients.

Generally, however, current therapies are inadequate. Medications have improved the prognosis
of PD, but also have problematic adverse effects.

Since treatment of PD is often unsatisfactory and since cannabis has recently become legal
and readily available in Colorado, persons with PD have been trying it. Patients have heard
from the internet, support groups and other sources that marijuana is helpful. Most are doing
so on their own, without the supervision or even knowledge of their neurologist. In a survey
conducted in the spring of 2014 in University of Colorado Hospital Movement Disorders clinic
about 5% of 207 PD patients, average age 69, reported using cannabis. In another study
Katerina Venderova and colleagues reported that 25% of PD patients had taken cannabis in the
General University Hospital in Prague. In the investigators clinics, about 30% of the PD
patients have asked doctors during their clinic visits over the past 6 months about cannabis.
In an anonymous web-based survey, 72% PD patients reported current or past using medical
cannabis, and 48% reducing prescription medication since beginning cannabis use.

PD mostly affects the elderly, and affected persons often have cognitive, psychiatric and
motor problems, such as being prone to falling. Cannabis is well documented to cause
psychosis, anxiety, slowness and incoordination. Studies have also shown that chronic users
have structural and functional Central Nervous System (CNS) alterations. Thus cannabis is
expected to be risky in persons with PD. Further, there are many components of cannabis, and
the cannabis preparations being sold in Colorado vary widely in composition. There are no
definitive data regarding the benefits and risks in of these various preparations in PD.
Studies on safety and efficacy are greatly needed to protect this fragile Colorado
population.

Human trials report that CBD decreases anxiety and causes sedation in healthy individuals,
decreases psychotic symptoms in schizophrenia and PD, and improves motor and non-motor
symptoms and alleviates levodopa-induced dyskinesia in PD. Given the current literature
regarding CBD: possible neuroprotective effect, good tolerability, anxiolytic and
antipsychotic effects and general lack of information in PD, including its effect on tremor,
the investigators feel that it is important to study its use in PD further. The investigators
hypothesized that it would reduce tremor, anxiety and psychosis, and would be well tolerated
in PD.

The Specific Aims are:

Primary Specific Aim: To evaluate the efficacy of CBD on motor symptoms in PD, specifically
on the motor section of the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS).

Secondary Specific Aim: To assess the safety and tolerability of CBD in PD, and to examine
the effect of CBD on severity & duration of intractable tremor, night-time sleep, rigidity,
emotional dyscontrol, anxiety and pain in PD.

Exploratory Analyses:

To study the efficacy of CBD on cognition, psychosis, sleep, daytime sleepiness, mood,
fatigue, impulsivity, bladder function, other motor and non-motor PD signs, restless legs
syndrome and Rapid Eye Movement (REM) sleep behavior disorder and quality of life.

The study is a randomized, placebo controlled, double-blind parallel design with two
treatment arms, each of approximately 2-3 weeks duration. In the 2-3 week treatment phase
participants will start study drug and titrate up to the maximum tolerated or targeted dose
(2.5 mg/kg/day of CBD). Each participant will have a screening visit, baseline visit within 3
weeks, 1 liver function monitoring visits on 3rd to 5th day of 2.5 mg/kg/day, 2 dose
assessment visit (1.25 mg/kg/day and 2.5 mg/kg/day), and a safety visit (6 visits total).
Participants will be evaluated on the 3rd to 5th day at each dose level for monitoring liver
function and adverse events, as well as changes in medical history and concomitant
medications. Participants are called 3 days and 1 week after stopping the study drug to check
for signs of withdrawal.

Inclusion criteria:

- Male or female participants 40 - 85 years of age.

- Willing and able to give informed consent (including through use of a legally
authorized representative (LAR), if necessary).

- Idiopathic PD, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical
Diagnostic Criteria

- ON motor MDS UPDRS >20.

- Anti-parkinsonian medication is fixed for at least one month prior to the day the
participant starts study drug treatment.

- If MoCA<22 participant must have a designated caregiver that agrees to ensure study
protocols followed. This includes accompanying patient to study visits and being
available for study phone calls.

- Must have a driver or available transportation (including provided Uber vouchers) to
drive them to and from study visits and for other transportation needs during the
treatment period.

- Has a significant other (someone who knows the participant well) that is appropriate
for doing the NPI assessment, and agrees to do so

- Agrees to not take more than 1 gram per day of acetaminophen, due to a possible
interaction with study drug that could increase risk of hepatotoxicity.

Exclusion criteria:

- Known or suspected allergy to cannabinoids or excipients used in the study drug
formulation.

- Cannabis is detectable at the screening visit by blood testing or at the baseline
visit by urine testing. If cannabis is detected at either the screening or baseline
visit, then the participant is a screen fail and may return >14 days later for a
repeat screening visit. If cannabis is again detected at either the screening or
baseline visit, then the participant is excluded and not allowed to rescreen.

- History of drug or alcohol dependence; defined by prior inpatient stay(s) for this or
that patient states s/he has a history of this.

- Use of dopamine blockers within 180 days and amphetamine, cocaine, and MAO-A
inhibitors within 90 days of baseline.

- Currently taking tolcapone, valproic acid, felbamate, niacin (nicotinic acid) at ≥2000
mg/day or nicotinamide (nicotinic acid amide or nicotinamide) at ≥3000 mg/day,
isoniazid and ketoconazole due to risk of liver injury and clobazam and ketoconazole
because of risk of toxic interactions with the study drug. These medications need to
be stopped 90 days before the baseline visit.

- Unstable medical condition.

- Any of the following laboratory test results at screening:

Hemoglobin < 10 g/dL WBC <3.0 x 109/L Neutrophils <1.5 x 109/L Lymphocytes < 0.5 x 109/L
Platelets <100 x 109/L Hemoglobin A1C > 9%

- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the
upper limit of normal. Persons with stable liver disease of known etiology can be
included, unless total bilirubin or prothrombin time/INR is abnormal.

- Is pregnant or lactating, or has a positive pregnancy test result pre-dose.

- If a sexually active female, is not surgically sterile or at least two years
post-menopausal, or does not agree to utilize an effective method of contraception
from screening through at least four weeks after the completion of study treatment,
using one of the following: barrier methods (diaphragm or partner using condoms plus
use of spermicidal jelly or foam, preferably double-barrier methods); oral or
implanted hormonal contraceptive; intrauterine device (IUD); or vasectomized male
partner.

- Planned elective surgery during study participation.