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

Persons with Parkinson's disease (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.

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.

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
marijuana 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 Movement Disorders Center (UCMDC) clinic about 5% of 207 PD patients, average age
69, reported using marijuana. In the same clinic, about 30% of the PD patients have asked
doctors during their visits over the past 6 months about marijuana. In another study Katerina
Venderova and colleagues reported that 25% of PD patients had taken cannabis in the General
University Hospital in Prague.

PD mostly affects the elderly, and with the cognitive, psychiatric and motor problems,
subjects are prone to falls. Cannabis is well documented to cause psychosis, slowness, and
incoordination. Studies have also shown that chronic users have structural and functional 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 of these
various preparations in PD. Studies on safety and efficacy are greatly needed to protect this
fragile Colorado population.

Cannabidiol (CBD) is a cannabinoid that is present to a lesser extent in street marijuana,
and limits delta-9-tetrahydrocannabinol (THC)'s psychoactive effect. CBD acts in some
experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic,
anxiolytic and antipsychotic agent, and therefore has potential beneficial medical uses.
Further, animal studies suggest that CBD is neuroprotective, perhaps due to reported
anti-oxidative and anti-inflammatory actions.

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. The ratio of THC to CBD plays a
role in the preparation's therapeutic outcome: strains of cannabis with higher concentrations
of CBD did not produce short-term memory impairment vs. strains with higher concentrations of
THC and lower concentrations of CBD.

Many clinicians who suspect cannabis may have a positive effective upon a particular patient
group have no idea of the cannabinoid profile that is being used. Without knowing the
composition, it is impossible to draw any conclusions simply because of the huge variety of
strains utilised.

Given the current literature regarding CBD: possible neuroprotective effect, good
tolerability, anxiolytic and antipsychotic effects and general lack of be well tolerated in
PD, including its effect on tremor, the investigators hypothesize that CBD would be well
tolerated and would reduce tremor, anxiety and psychosis, and would stabilize cognitive
decline in PD. First the investigators will perform an open label study to determine a
reasonable dose, and then a randomized, double-blind, placebo-controlled crossover study to
evaluate the efficacy and tolerability of oral CBD on tremor and other important aspects of
PD. A strength of the study is that it uses well defined form or CBD.

Stage 1: Open Label Dose Escalation Tolerability Study

Primary Specific Aim: To confirm that the dosage regimen of CBD, in the form of GWP42003-P
recommended by the study drug manufacturer is safe and tolerated in 10 subjects with PD.
GWP42003-P is started at 5 mg/kg/day and is increased by 5 mg/kg at 3 day intervals to a
target dose of 25 mg/kg/day.

Secondary Specific Aim: To examine the effect of CBD on severity & duration of tremor and
other conditions that are problematic in PD.

The dose escalation tolerability study will be conducted in 10 subjects (the investigators
will be recruiting up to 15 subjects to end up with 10) as an open label study lasting
approximately 3 weeks followed by a 2-week safety follow up. Subjects are closely monitored
as the dose is titrated. Subjects will have a screening visit, a baseline visit within the
next three weeks, a visit when subjects are on 20 mg/kg/day, a final assessment visit when
subjects have been on the maximal tolerated or the targeted dose for 10-15 days, and a safety
visit 2 weeks later. The subject is to be on the maximal tolerated or targeted dose for 10-15
days. Subjects will be called on the 3rd day of each dose. During phone calls subjects are
monitored for adverse events, especially excessive daytime sleepiness, symptoms of
hepatotoxicity, as well as changes in medical history and concomitant medications. Subjects
are also called 3 days after stopping the study drug to check for signs of withdrawal.

Stage 1:

Inclusion criteria:

- Male or female subjects between 45 and 78 years of age inclusive.

- Willing and able to give informed consent.

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

- Rest tremor amplitude score of ≥2 in any limb on question 3.17 of the MDS-UPDRS (ON
state).

- Anti-parkinsonian medication is fixed for at least 1 month prior to study entry

- If MoCA<22 subject must have a legally authorized representative (LAR) sign the
consent, and 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 to drive them to and from study visits

- Has a significant other (someone who knows the subject well) that is appropriate for
doing the NPI assessment, can accompany patient to study visits, 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.

- Cannabinoids taken currently or in the previous 30 days.

- History of drug or alcohol dependence; defined by prior inpatient stay(s) for this or
that patient stats 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, 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: