Clinical trial NCT03582137
Conditions: Parkinson Disease
Keywords: Parkinson's Disease Motor symptoms Tremor tolerability safety cognition anxiety psychosis mood dyskinesia sleep cannabidiol cannabis efficacy non-motor symptoms quality of life seborrhea
Sponsor: University of Colorado, Denver
Start date: 2018-09-05; Completion date: 2022-01-04
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The major purpose of this study is to assess the efficacy of CBD on motor symptoms of Parkinson's Disease (PD), and secondarily to study the safety and tolerability of CBD and other efficacy, particularly regarding tremor in PD. The study has been powered to detect a clinically significant reduction in Movement Disorder Society (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) Part III motor scores. This is a 1:1 parallel, double-blind, randomized controlled trial (RCT) with 60 participants. The investigators will be recruiting up to 75 participants; the goal is to have 60 participants (30 in CBD group and 30 in placebo group) complete the study. The study drug is obtained from the National Institute on Drug Abuse (NIDA).

Detailed description:
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 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. To explore the effect of CBD on plasma levels in PD.

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.

Arms: arm 1: Cannabidiol (CBD) Cannabis extract oral solution arm 2: Placebo oral solution
Interventions: intervention 1: Cannabidiol intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects randomized to this arm will receive Cannabidiol Cannabis extract oral solution intervention 2: Subjects randomized to this arm will receive Placebo

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #:17-2318 
Project Title: A randomized, double blind, placebo-controlled parallel study of tolerability and 
efficacy of Cannabidiol (CBD) on motor symptoms in Parkinson’s disease 
 
 
 
 
 
 
 
 
Principal Investigator: Maureen Anne Leehey, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version Date: June 9, 2020 
 
 


2 
 
 
TABLE OF CONTENTS 
Section 
Heading 
Page 
 
Face Page 
1 
Section I 
Hypotheses and Specific Aims.…………………………………................... 
3 
Section II 
Background and Significance………………………………….................... 
4 
Section III 
Preliminary Studies/Progress Report……………………………………… 
7 
Section IV 
Research Methods…………………………………………………………… 
15 
 
A. Outcome Measures………………………………………………………. 
15 
 
B. Description of Population to be Enrolled……………………………….. 
24 
 
C. Study Design and Research Methods…………………………………… 
24 
 
C.1. Study Design……………………………………………………….. 
24 
 
C.2. Study Drug: CBD………………………………………………….. 
31 
 
C.3. Randomization and Drug Dispensation………………………….. 
34 
 
C.4. Blinding Assessment and Un-blinding procedures………………. 
34 
 
C.5. Stopping Rules……………………………………………………... 
35 
 
C.6. Adverse Events Assessments……………………………………… 
36 
 
C.7. Risks of Study Drug……………………………………………….. 
38 
 
D. Description, Risks and Justification of Procedures and Data Collection 
Tools……………………………………………………………… 
40 
 
E. Potential Scientific Problems……………………………………………. 
42 
 
F. Data Analysis Plan……………………………………………………….. 
42 
 
G. Summarize Knowledge to be Gained…………………………………… 
44 
 
H. References………………………………………………………………... 
44 
Appendix  
1. Schedule of Events…………………………………………………………. 
50 
 
2. Myo Tremor Measurement Guide………………………………………. 
56 
 
3. Dermatology Photography Protocol…………………………………….. 
62 
 
4. CBD Cannabis Extract Certification of Analysis………………………. 
63 
 
5. Drugs interactions with CBD…………………………………………….. 
64 
 
6. Clinic Visits Procedures and Duration………………………………… 
66 
 
7. Chemotherapeutic, antihistaminic and Anti-inflammatory 
medications………………………………………………………………....... 
75 
 
8. Inflammatory and atopic diseases……………………………………….. 
76 


3 
 
 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #:17-2318 
Project Title: A randomized, double blind, placebo-controlled parallel study of tolerability and 
efficacy of Cannabidiol (CBD) on motor symptoms in Parkinson’s disease 
Principal Investigator: Maureen Anne Leehey, MD 
 
Version Date: December 17, 2019  
 
 
 
 
  
 
 
I. Hypotheses and Specific Aims:  
 
Parkinson disease (PD) is a relatively common, progressive, disabling disorder that responds 
partially to symptomatic treatments. Since cannabis has become legal in Colorado, many persons 
with PD have been trying it to see if it relieves any of their symptoms. Cannabis is composed of 
many cannabinoids, with delta-9-tetrahydrocannabinol (THC) the major constituent. THC has been 
shown to induce a “high,” psychosis, cognitive dysfunction and anxiety – all of which would be 
problematic in PD. Cannabidiol (CBD) is also a component of cannabis, and, according to published 
reports, has potential beneficial medical uses in PD. However, the literature regarding the use of 
cannabis in PD is minimal and inconclusive.  
 
There are many forms of cannabis being marketed, which range in potencies of THC and CBD. 
Since CBD is likely to be safer and more beneficial than THC, our study drug is primarily CBD, i.e., 
CBD:THC is 30:1. The dose used will deliver an amount of THC too low to cause a “high.” 
 
The major purpose is to assess the effect of CBD on motor symptoms in PD, and secondarily to study 
its safety, tolerability, and effect on other motor and non-motor symptoms that occur frequently in 
PD. This is a parallel, double-blind, randomized controlled trial (RCT) with 60 participants.   
Our Hypotheses are:  
1. CBD has a significant treatment effect on PD motor symptoms. 
2. CBD is safe and tolerated in PD. 
3. CBD has some beneficial effect on other conditions that occur in PD, including tremor, night-
time sleep, rigidity, emotional control, anxiety, pain, cognition, psychosis, and other motor and 
non-motor related PD signs. 
4. Plasma cytokine levels (Tumor Necrosis Factor TNF-alpha, interleukin (IL)-2,4,6) elevate in PD 
and are neurotoxic during the progress of PD. CBD has some beneficial effect on reducing 
cytokine levels in PD. 
Our 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). 


4 
 
Secondary Specific Aim: To assess the safety and tolerability of CBD in PD and to examine the 
effect of CBD on severity and 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 
REM sleep behavior disorder and quality of life.  
To explore the effect of CBD on plasma levels of cytokines in PD. 
 
II. Background and Significance:  
Parkinson 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 [Yao, S.C, et al. 2013; de Lau LM, et al. 2006]. The total economic cost in the US is 
around 23 billion dollars [Findley LJ. 2007]. 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 [Schrag A, et al. 2000], shortened survival [Nussbaum M, et al. 1998], and increased caregiver 
distress [Aarsland D, et al. 1999]. Community-based studies have estimated the point prevalence for 
dementia in PD to be 28% and 44% [Mayeux R, et al. 1992; Aarsland D, et al. 1996; Hobson P, et al. 
2004; Marttila RJ, et al. 1976]. 
 
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, and are associated with increased career burden and risk for nursing home admission. 
Anxiety affects up to 40% of patients with PD [Menza MA, et al. 1993; Richard IH. 2005; Leentjens 
AF, et al. 2008; Stein MB, et al. 1990; Nuti A, et al. 2004; Lauterbach EC, et al. 2004; Aarsland D, et 
al. 2009], 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 [Aarsland D, et al. 2009, Soulas T, et al. 2008]. 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.  
 
In PD the levels of various cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-
2, IL-4, IL-6, epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, TGF-beta1) 
were found significantly increased in the striatum of the postmortem brain and in ventricular or 
spinal cerebrospinal fluid [Nagatsu T, et al. 2000]. Cytokines may be initially neuroprotective, but 
may later become neurotoxic during the progress of PD [Sawada M, et al. 2006].  
 


5 
 
Generally, however, current therapies are inadequate. Medications have improved the prognosis of 
PD, but also have problematic adverse effects [Poewe W. 2006].  
 
Cannabis use in PD 
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 [Finseth TA. et al. 2015]. In another study Katerina 
Venderova and colleagues reported that 25% of PD patients had taken cannabis in the General 
University Hospital in Prague [Venderova K, et al. 2004]. In our clinics, about 30% of the PD 
patients have asked doctors during their clinic visits over the past six months about cannabis. In an 
anonymous web-based survey, 72% PD patients reported current or past use of medical cannabis, 
and 48% reported reducing prescription medication since beginning cannabis use [Kindred, et al. 
2017].   
 
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 CNS alterations [Sneider JT., et al. 2013; Matochik JA., et al. 2005; Jager G., et al. 2010; 
James A, et al. 2011; Battistella G., et al. 2014; Gruber SA., et al. 2005; Stone JM., et al. 2012]. 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. 
 
THC vs. CBD  
Many clinicians who suspect cannabis may have a positive effect upon a particular patient group do 
not know 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 utilized. CBD is 
present to a lesser extent in street marijuana, and has been shown to limit THC’s so called 
“psychoactive” effect [Bhattacharryya S et al, 2010; Hayakawa K, et al. 2008; Atakan Z. 2012], 
meaning the “high.”   
 
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 
[Zhornitsky S, et al. 2012; Crippa JA, et al. 2011; Iuvone T, et al. 2009; Vuolo F, et al. 2015]. 
Further, animal studies suggest that CBD is neuroprotective, perhaps due to reported anti-oxidative 
[Lastres-Becker I, et al. 2005; García-Arencibia M et al. 2007; Hayakawa K, et al. 2007] and anti-
inflammatory actions [Mecha M, et al. 2013]. 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 similar concentrations of THC, but lower 
concentrations of CBD [Englund A et al. 2013]. THC is associated with psychosis, cognitive 
impairment, anxiety, and psychomotor slowing [Hall W., et al. 1998, Hindocha C., et al. 2017]. 
Thus, CBD has likely beneficial effects in PD, but THC may have harmful effects. 


6 
 
 
CBD undergoes a significant first-pass effect leading to the formation of a number of metabolites, 
most notably, 7-hydroxy-CBD and CBD-7-oic acid [Agurell, S. et al. 1986; Harvey, D.J. 1990]. The 
half-life of CBD in humans was found to be between 2–5 days following oral administration. 
Bioavailability of oral CBD in humans was found to be around 6%, [Agurell, S. et al. 1986; Consroe, 
P. et al. 1991; Ohlsson, A. et al. 1986; Guy, GW. et al. 2004]. Oral administration of CBD (~700 mg) 
over six weeks to 14 Huntington’s disease patients resulted in a low, narrow plasma range of 5.9–
11.2 ng/mL [Consroe, P. et al. 1991].  
 
Literature review of studies of cannabis in neurological disorders, especially PD 
The American Academy of Neurology (AAN) Guideline Development Subcommittee performed a 
systematic review of medical marijuana to address treatment of symptoms of multiple sclerosis 
(MS), epilepsy, and movement disorders [Koppel BS, et al. 2014]. In patients with MS, oral cannabis 
extract is effective, and nabiximols (Sativex, GW Pharmaceuticals, 1:1 ratio of CBD to THC, with a 
fixed dose of 2.7 mg THC and 2.5 mg CBD) and THC are probably effective for spasticity, central 
pain, or painful spasms; nabiximols is probably effective for reducing bladder voids/day. Oral 
cannabis extract is probably ineffective for treating levodopa-induced dyskinesia in patients with PD. 
Oral forms of cannabis are of unknown efficacy in non-chorea-related symptoms of Huntington 
disease, Tourette syndrome, cervical dystonia, and epilepsy.  
 
A few studies have been reported that tested varied cannabis compositions in PD. A Class I double-
blind crossover study examined the effectiveness of an extract of cannabis sativa standardized to 2.5 
mg of Δ9 -THC and 1.25 mg of cannabidiol per capsule in the treatment of levodopa-induced 
dyskinesias in 19 patients [Carroll CB, et al. 2004] and concluded that cannabis is probably 
ineffective. Note that the CBD dose used was very low. In an open-label observational study, 22 
patients with PD were evaluated at baseline and 30 minutes after smoking cannabis to assess the 
clinical effect of cannabis on motor and non-motor symptoms of PD. There was significant 
improvement of sleep and pain scores. No significant adverse effects of the drug were observed 
[Lotan I, et al. 2014]. An anonymous questionnaire sent to all PD patients attending the Prague 
Movement Disorder Centre revealed that 85 (25%) out of 339 respondents had taken cannabis and 39 
patients (45.9%) described mild or substantial alleviation of their PD symptoms in general, 26 
(30.6%) improvement of rest tremor, 38 (44.7%) alleviation of bradykinesia, 32 (37.7%) alleviation 
of muscle rigidity, and 12 (14.1%) improvement of L-dopa-induced dyskinesias. Only 4 patients 
(4.7%) reported that cannabis actually worsened their symptoms [Venderová K, et al. 2004]. In 
another study, five patients with PD and severe tremor were given marijuana smoked as a cigarette in 
addition to other medications, including diazepam, levodopa/carbidopa and apomorphine. None of 
the patients experienced relief or demonstrated improvement of tremor following marijuana [Frankel 
J.P., et al. 1990]. 
 
Also, a few studies have been reported that tested CBD in PD. In a double-blind trial [Chagas MH, et 
al. 2014], 21 PD patients without dementia or comorbid psychiatric conditions were assigned to three 
groups of seven participants each who were treated with placebo, CBD 75 mg/day or CBD 300 
mg/day for six weeks. The study found significant improvements in measures of functioning and 
well-being of PD patients treated with CBD 300 mg/day compared to a group that received placebo, 
with no psychiatric comorbidities. In another study, six PD patients with psychosis symptoms for at 
least three months were recruited in an open-label pilot study to evaluate the efficacy, tolerability, 


7 
 
and safety of CBD on PD patients who had psychosis. All patients received CBD in flexible doses 
(starting with an oral dose of 150 mg/day) for four weeks, in addition to their usual therapy. The 
psychotic symptoms showed a significant decrease under CBD treatment. CBD did not worsen the 
motor function and decreased the total scores of the UPDRS. No adverse effect was observed during 
the treatment [Zuardi A.W., et al. 2009].  
 
Literature review of safety and tolerability of CBD 
There are more than 30 reported human trials testing CBD, but doses, cannabinoid compositions, and 
results vary widely. Generally, the studies find CBD is well tolerated. Several studies suggest that 
CBD does not affect food intake, affect physiological parameters (heart rate, blood pressure and 
body temperature), affect gastrointestinal transit, or alter psychomotor or psychological functions 
[Zuardi AW, et al. 2009; Riedel G, et al. 2009; Scopinho AA, et al. 2011; Gomes FV, et al. 2013; 
Bergamaschi MM, et al. 2011; Bhattacharyya S, et al. 2010]. Also, chronic use and high doses up to 
1,500 mg/day of CBD are reportedly well tolerated in humans [Zuardi AW, et al. 1995]. Conversely, 
some studies reported that this cannabinoid has adverse effects, including inhibition of hepatic drug 
metabolism, alterations of in vitro cell viability, and decreased fertilization capacity [Bergamaschi 
MM, et al. 2011; Bornheim LM, et al. 1994; Narimatsu S, et al. 1990], 
 
Extensive reports of CBD administration across a wide range of concentrations did not detect 
important adverse or toxic effects [Bergamaschi MM, et al. 2011]. With a median Lethal Dose 
(LD50) of 212 mg/kg in rhesus monkeys, CBD has a low toxicity [Rosenkrantz H, et al. 1981]. Some 
studies investigated mutagenic or teratogenic effects and describe no such events [Matsuyama SS, Fu 
TK. 1981; Dalterio S, et al. 1984]. We reviewed the tolerability of CBD doses used in human studies 
to date – one study suggested over 300 mg per day may exacerbate bradykinesia [Consroe P, et al. 
1986], but other studies used 7.5 to 1500 mg per day without significant adverse effects 
[Bergamaschi MM, et al. 2011; Zuardi AW, et al. 1995]. Most studies used doses in the range of 200 
- 600 mg/day.  
 
Summary 
Human trials report that CBD decreases anxiety and causes sedation in healthy individuals, decreases 
psychotic symptoms in schizophrenia [Zuardi AW, et al, 2006; Leweke FM et al. 2012] and PD 
[Zuardi AW, et al. 2009], and improves motor and non-motor symptoms and alleviates levodopa-
induced dyskinesia in PD [Venderova K., et al. 2004; Lotan I, et al. 2014; Chaqas MH, et al. 2014; 
Zuardi AW, et al. 2009]. Given the current literature regarding CBD’s possible neuroprotective 
effect, good tolerability, anxiolytic and antipsychotic effects and general lack of information in PD, 
including its effect on tremor, we feel that it is important to study its use in PD further. We 
hypothesized that it would reduce tremor, anxiety, and psychosis, and would be well tolerated in PD.  
 
III. Preliminary Studies/Progress Report:  
 
Rationale of study design 
With the long term goal of determining the safety and effects of CBD in PD, we designed our 
study to be conducted in two stages: an open label dose escalation study, to be followed by the 
current parallel, randomized, double-blind, placebo-controlled study (RCT). Here we provide 
a progress report that describes result of the open label study, and how the findings shape the 
design of the randomized, controlled parallel study. 


8 
 
 
First a study drug was needed: 
• We wanted a pure CBD product (as pure as possible) so that the results of the study could be 
assumed to be strictly from the CBD - not from THC, not from other cannabis components, and 
not from the “entourage’ effect. Also, we did not want to expose patients to the presumed risks of 
THC, described in the Background and Significance, THC vs. CBD section.  
• Since we would need to get an IND from the FDA the study drug would need to be of consistent 
good quality, made with good manufacturing processes (GMP).  
• We wanted an oral preparation, since smoking was not healthy and vaporization would be 
challenging for PD patients. Also it would be harder to give precise doses via smoking and 
vaporization compared to oral. Further the oral route has longer a half-life so we could achieve a 
steady state with twice daily administration for a number of days that is feasible for this study.  
 
The usual source of cannabis for study in the US is the National Institute of Drug Abuse (NIDA), but 
only material with THC and with a CBD:THC ratio that was too low was available. Also, only plant 
material was available, which would need to be taken via smoking or vaporization. 
 
GW Pharmaceuticals was conducting Phase III trials with Epidiolex®, a 99% pure CBD preparation, 
in pediatric epilepsy. Epidiolex® was a good choice for our study because it had <0.1% THC, and the 
FDA already had the data it would require for an IND for use in our PD study. Further, it was an oil 
based solution that could be readily taken by our PD cohort, and there existed reasonable data on 
dosing. GW was finding Epidiolex® to be tolerated and beneficial in pediatric epilepsy at doses 
titrated up to 20-25 mg/kg/day. GW agreed to supply Epidiolex® at no cost. 
 
We based our titration schedule and dosage on the dose that GW was finding to be effective in 
reducing seizures in pediatric epilepsy. Here we present the design and findings of the first stage 
study. 
 
Overview of open label dose-escalation study goals and methodology 
We conducted a Phase IIa, open label dose-escalation tolerability study (NCT02818777) in 13 PD 
patients at the University of Colorado between October 2016 and June 2017, using Epidiolex®. The 
primary outcome was safety and tolerability, measured by adverse events, changes in examinations, 
labs, EKGs and percentage of participants that discontinued study drug due to intolerability. The 
major secondary outcome measure was change in the total of two items on rest tremor in the MDS-
UPDRS, and others were measures of most motor and non-motor symptoms that occur in PD. 
Participants had a screening visit, a baseline visit within the next three weeks, a final dose 
assessment visit when they have been on the maximal tolerated or the targeted study dose for 10-15 
days, and a safety visit 2 weeks later. From the baseline visit, qualified participants took Epidiolex® 
in a 100 mg per mL sesame oil-based solution orally twice daily. Since somnolence was a reported 
adverse effect in the pediatric epilepsy population, and Epidiolex® had not been used in persons over 
age 50, we elected to be cautious and instructed participants not to drive while on study drug. 
 
CBD was started at 5 mg/kg/day and the dose could be increased or decreased by up to 2.5 to 5 
mg/kg/day until the study participants reached a maximum targeted dose (20-25 mg/kg/day) or 
experienced intolerable adverse events (AEs), in which case the dose would be dropped to the last 


9 
 
tolerated dose. Tolerability was assessed via collection of AEs during administration of the 
standardized phone script by study staff on the third or fifth day of each dose, and the participants 
were instructed whether or not to change the dose at the end of phone call. Participants filled out 
home diaries to increase and monitor compliance.  
 
Participants were called at the end of each dose level. During phone calls participants were 
monitored for AEs, especially excessive daytime sleepiness, symptoms of hepatotoxicity, as well as 
changes in medical history and concomitant medications. Participants were also called three days 
after stopping CBD to check for signs of withdrawal. The primary outcome was safety and 
tolerability of CBD and the secondary and exploratory outcomes examined the effect of CBD on 
severity and duration of tremor and other conditions that occur in PD. 
 
Results 
Figure 1 shows the trial profile. Data from all participants that took the study drug were analyzed for 
safety and tolerability, while only data from those that completed a final dose assessment were 
analyzed for efficacy. Table 1 shows the baseline clinical and demographic characteristics of safety 
and efficacy analysis groups. 
 
Figure 1. Open label study profile 
 
 
 
Table 1. Baseline demographics of the safety and efficacy analysis groups 
 
Safety analysis group 
(n=13) 
Efficacy analysis group 
(n=10) 
Age (years) (mean, SD) 
68.1 (6.05) 
68.7 (6.65) 
Male (n, %) 
10 (77%) 
8 (80%) 


10 
 
Total MDS UPDRS score  
(mean, SD) 
39.23 (13.32) 
43.20 (12.21) 
Motor MDS UPDRS score 
(mean, SD) 
22.92 (9.30) 
24.70 (8.93) 
Disease duration, years  
(mean, SD) 
6.08 (3.99) 
6.30 (4.52) 
Hoehn & Yahr Scale  
(mean, SD) 
1.73 (0.56) 
1.75 (0.59) 
MoCA (mean, SD) 
28.1 (1.63) 
27.9 (1.60) 
Levodopa Daily Dose 
Equivocation (LDDE)  
(mean, SD) 
 
398.3 (331.00) 
 
443.8 (348.97) 
 
The demographics show that, in general, the participants had an age of onset consistent with the 
general population of persons with PD and they had early to early-middle stage PD. Generally they 
had mild bilateral motor symptoms, walked without assistance, had disease for six years, and 
required a relatively low dose of medication for their motor symptoms. An entry criteria required 
them to have a relatively significant tremor, but it would be a resting tremor and thus as a general 
group these participants likely had very little disability. These participants had scored in the normal 
range on the entry cognitive screening test.  
  
The original protocol was that participants start at 5 mg/kg/day and titrate up to 25 mg/kg/day. 
Participants were to remain on each dose for three days, until the maximal tolerated dose was 
reached, and they were to be on that dose for 10-15 days, during which time they came in for an 
assessment visit.   
 
Due to AEs experienced by our first five enrolled participants and the recommendations of the two 
PharmDs in our study, the protocol was changed to a slower titration and the maximal targeted dose 
was reduced from 25 to 20 mg/kg/day, since December 2016. There had been increased AEs and no 
evidence of additional benefit in the five participants beyond 20 mg/kg/day. Therefore, participants 
started at 5 mg/kg/day and increased every three to five days by 2.5 to 5 mg/kg/day until reaching a 
maximal targeted dose (20 mg/kg/day) or experiencing intolerable adverse effects.  
 
The mean maximum CBD dose was 19.23 mg/kg/day (SD 5.44) in the safety analysis group and 
20.25 mg/kg/day (SD 3.43) in the efficacy analysis group. The average length of time (SD) on study 
drug was 26.8 (8.0) days in safety group and 28.5 (3.4) days in efficacy group. 
 
AEs were reported in 13 (100%) of participants, and are shown in Table 2.  
 
Table 2. Adverse effects reported among the safety analysis group (n=13) 
Adverse Effects* 
Frequency n (%) 
Diarrhea 
11 (84.6) 
Somnolence 
9 (69.2) 
Fatigue 
8 (61.5) 
Weight gain 
4 (30.8) 


11 
 
Abdominal pain 
3 (23.8) 
Dizziness 
3 (23.1) 
Weight loss, nausea, anorexia, increased appetite, 
headache 
2 (15.4) 
Vomiting, flatulence, gastroesophageal reflux 
disease, allergic reaction, spasm, fever, weakness 
1 (7.7) 
*Adverse effects terminology and severity is per the Common Terminology Criteria for Adverse 
Events (CTCAE) 
AEs were transient, and mild on average. Diarrhea, which increased with increasing doses: 1/13 (8%) 
at 5 mg/kg/day, 5/10 (50%) at 20 mg/kg/day, and 3/3 (100%) at 25 mg/kg/day, may be related to the 
increasing amount of sesame oil consumed at higher doses. There were no serious adverse events. 
 
Elevated liver enzymes occurred in five (38.5%) participants, one symptomatic and four 
asymptomatic, were all on 20-25 mg/kg/day, were transient, and resolved after discontinuation of the 
study drug. None were associated with elevated bilirubin or INR, thus suggesting no change in liver 
function. CBD002, the one symptomatic participant, also had a liver ultrasound, which was normal. 
The DSMB and a Hepatology consultant reviewed the findings as they occurred and recommended 
continuing the study with close monitoring. 
 
There were no clinically significant changes in vital signs, electrocardiogram, or physical and 
neurological exams or labs (complete blood count, renal function and liver function) other than the 
one symptomatic participant with elevated liver enzymes.  
 
Three participants (23%) stopped study drug due to intolerability, one due to rash at 5 mg/kg/day, 
one to abdominal pain and gas at 17.5 mg/kg/day and one to fatigue, diarrhea, and elevated liver 
enzymes at 25 mg/kg/day.  
 
The efficacy analysis found no change in the designated major secondary outcome, total of two 
items on rest tremor in the MDS-UPDRS, at the final maximal targeted dose compared with 
baseline. However, there were improvements in some motor signs, Table 3, and some non-motor 
signs, Table 4.  
 
Table 3. Change in motor scores among efficacy analysis group (n=10) 
 
Baseline 
Mean (SD) 
Final 
Mean (SD) 
Change 
Mean (SD) 
P Value* 
Total MDS 
UPDRS** 
43.20 (12.21) 
35.50 (14.31) 
-7.70 (9.39) 
0.0115 
Motor MDS 
UPDRS** 
24.70 (8.93) 
18.60 (9.66) 
-6.10 (6.64) 
0.0041 
*paired T-test, permutation distribution 
**Higher scores reflect more severe symptoms; reduction in scores from baseline means 
improvement 
 
Table 4. Change in non-motor scores among efficacy analysis group (n=10) 
 
Baseline 
Final 
Change 
P Value* 


12 
 
Mean (SD) 
Mean (SD) 
Mean (SD) 
SCOPA Sleep 
Night-time** 
5.70 (2.95) 
2.90 (2.60) 
-2.80 (3.91) 
0.0401 
Emotional 
behavioral 
dyscontrol short 
form** 
44.39 (7.91) 
39.70 (6.75) 
-4.69 (6.14) 
0.0474 
*paired T-test, permutation distribution 
**Higher scores reflect more severe symptoms; reduction in scores from baseline means 
improvement 
 
The other motor and non-motor assessments were not changed – however, participants had very little 
daytime sleepiness, fatigue, pain, cognitive dysfunction, psychosis, impulsivity, depressed mood, 
anxiety, levodopa induced dyskinesia, REM sleep behavior disorder, or restless legs syndrome, 
which often occur in PD. Thus our testing of these symptoms was not meaningful. Interestingly, 
although participants frequently reported daytime somnolence and fatigue, there was no change on 
the formal assessments tools. 
 
Upon completion of the study each participant and their study partner was interviewed regarding 
driving. Responses were obtained from 12/13 participants and their study partners. Eleven in each 
group thought that the participant would have been safe to drive while on the study drug. The one 
other participant and their study partner thought that the participant should not drive during the first 
couple of days when he started a new higher dose, due to somnolence. No participants reported 
feeling “high.” No study partners thought the participant got “high” from the study drug. 
 
Discussion 
The primary outcome was safety and tolerability. Generally, the study drug, Epidiolex®, was well 
tolerated. While adverse effects, mainly somnolence, fatigue, and diarrhea, were frequent, they were 
generally mild, and there was a relatively low percent of participants, i.e., 23%, that stopped study 
drug due to intolerability, and no clinically significant abnormalities in testing except for elevated 
liver enzymes.  
 
Regarding the elevated liver enzymes, GW had seen elevations in their pediatric group, but the 
pattern was hepatocellular, not cholestatic as in our population. Perhaps age contributed to the 
difference, since GW had not used Epidiolex® in persons over age 50. In our study liver enzymes 
were only checked on the highest dose and most of the affected participants were asymptomatic, so 
it is not clear at what dose the liver enzymes became elevated. Lisa Forman, MD, Hepatologist, 
reviewed detailed information on these participants and of all the liver function results in all 
participants, commented that the changes may represent early liver injury and felt that with 
close monitoring it was reasonable to move on with the next study. She will be a consultant on 
the randomized controlled parallel study. The DSMB also reviewed all the data and noted that all 
changes resolved with cessation of treatment and discussed the possibility the elevations may be 
related to medication vehicle, i.e., sesame oil. Most participants were talking 10-20 ml per day on 
the final maximal dose when the testing occurred. The DSMB agreed with continuation of the 
study with the monitoring plan in this protocol. 
 


13 
 
Solid conclusions regarding efficacy are not possible from an open label trial, but this study 
suggested benefit in motor symptoms, night-time sleep, and emotional dyscontrol. 
In summary, findings from the open label study suggest that CBD may be efficacious in PD, and that 
a lower dose may offer the best benefit to risk ratio, compared to the higher dose that GW reports is 
useful in pediatric epilepsy. Therefore, a lower dose will be used in the randomized controlled 
parallel study. 
GW declined to provide Epidiolex® for the randomized controlled parallel study, as they are focused 
on getting FDA approval for it in pediatric epilepsy. We therefore searched for other study drug 
options. We want to give a dose that provides a reasonable dose of CBD, per the PI’s judgement, and 
that provides a low enough THC dose so that participants will not get “high.”   
 
The PI (Dr. Leehey) considers the following to judge what would be a reasonable dose of  
CBD:  
• That is <1/2 of what we were giving on the open label study, i.e., <12.5 mg/kg/day 
• That is at least the minimal amount that persons are likely getting from dispensaries, e.g., 
estimate that a minimal dose some persons see some benefit from would be 1.67 mg/kg/day mg 
pure CBD (if they could get pure CBD); this is based on my experience with what patients tell 
me they feel when they take specific products 
• that is in the range of 100-200 mg/day, since this is the range that Professor Raphael Mechoulam 
has found to be effective based on his experience in a variety of medical illnesses [personal 
communication] 
 
Several factors need to be considered when determining the minimal dose of THC that will cause a 
person to feel “high,” including route of delivery, peak and half-life of THC, active metabolite (11-
OH-THC), co-existing CBD content, participant’s prior cannabis exposure, etc. The maximal oral 
dose of THC one would want to give that would not cause a person to feel high is approximately <5 
mg, and varies depending on these many factors. Also the timing of repeated dosing should be ≤ 6 
hours, given the pharmacodynamics and pharmacokinetics of THC [Raphael Mechoulam, personal 
communication, 2017; Colorado Department of Revenue, 2015; L.E. Hollister, et al. 1981; 
Grotenhermen F et al. 2003; Oviedo A et al. 1993]. 
 
Another consideration regarding selecting the study drug for the randomized controlled parallel 
study is that we have to use a study drug that is either from the only approved federal source, i.e., 
NIDA, or that the FDA has already evaluated and approved for use in clinical trials. Given that we 
have to complete this study before funding ends, June 2019, our timeframe does not allow the time 
the FDA would probably needed to ensure any drug that has not yet been evaluated meets its 
requirements. Further, the DEA has restrictions on what cannabis products can be studied under a 
given, e.g., Dr. Leehey’s, Schedule 1 license.   
 
We considered other factors while choosing a study drug to use in the randomized controlled parallel  
study. While Epidiolex® was the best option for our open label dose-escalation study, we recognized 
that a disadvantage of using a pure CBD preparation and such a high dose is that it is different from 
what persons with PD obtain from local dispensaries. While local dispensaries sell cannabis that is 


14 
 
high in CBD, their products are not pure CBD and markedly lower doses are used, so our findings 
would not be very applicable to the products our PD patients are taking. The study drug and dosage 
to be used in the randomized controlled parallel study will be more similar to what persons with PD 
are obtaining from local dispensaries. Another consideration is that THC, CBD, and the other 
components of the cannabis plant interact, e.g., the “entourage” effect, and this interaction may have 
a meaningful effect, which would not be occurring in Epidiolex® since it is such a pure CBD product. 
 
Therefore, we will use a cannabis extract with 59.3% CBD and 1.96% THC (30:1 CBD:THC) from 
NIDA. We will give 1.25 mg/kg twice daily of CBD and 0.041 mg/kg twice daily of THC. This 
equals 2.11 mg/kg twice daily (4.22 mg/kg/day) of the NIDA extract. For our average sized PD 
participant (84 kg) in our prior trial this will be approximately 100 mg CBD and 3.3 mg THC twice 
daily (morning and evening - > 6 hours apart). Therefore, the THC dose is below the threshold, 
~5mg, that is expected to cause a person to feel “high.” The interval of >6 hours is to minimize the 
possibility of the THC effect to overlap/build up. The extract solution will be in a sesame oil 
formulation, 100 mg/ml of CBD, so the participant would ingest 1 ml (100 mg CBD) twice daily. 
This much smaller amount of CBD and of oil is expected to be better tolerated, including less likely 
to cause liver enzyme elevations, than the study drug in the open label study. 
 
In comparison to the open label study, the amount of CBD in this study is less than 15% (19.23/2.5). 
This dose and the fact that there is a small amount of THC is in the product makes this study drug 
more similar to what persons are receiving from local dispensaries, although it may generally have a 
higher in CBD content. Therefore, the results of the study using this product will be more 
generalizable to the Colorado PD population. 
 
Whether participants should be allowed to drive has been carefully considered: 
• Medical problems (motor and/or cognitive issues) can affect the ability of older adults to drive 
safely. Persons with PD are permitted to drive until they develop significant motor and/or 
cognitive issues, and this is monitored by their treating physician.  
• Colorado law prohibits driving while intoxicated with cannabis - because of the “high” produced 
by THC component. CBD does not produce the high that occurs from THC [Niesink RJ, 2013].  
• The amount of THC in this randomized controlled parallel study is very unlikely to cause any 
“high” effect.  
• In the open label study participants and their study partners felt participants would have been 
safe to drive, and that study involved doses of CBD >7 times higher than participants in this 
randomized controlled parallel study will be taking. The only concern was from one participant 
regarding having somnolence with increases in the dosing. In the randomized controlled parallel 
study the dose will be started and increased only once, and, again, the dosage will be markedly 
lower.  
• Generally, medications that may cause somnolence or CNS adverse effects have warnings 
provided on the packaging. For example, patients who take opioid products are instructed that 
opioids may impair the mental or physical abilities needed to perform potentially hazardous 
activities such as driving a car or operating machinery. Persons are warned not to drive or 
operate dangerous machinery unless they know they are tolerating the effects of the medication 
and know how they will react to it. Patients who take clonazepam, a medication related to 


15 
 
diazepam (Valium), are also told not to drive, operate heavy machinery, or do other dangerous 
activities until they know how the clonazepam affects them. This labeling was directed by the 
FDA.  
Our study DSMB met October 29, 2017, considered the points above, and suggested that the study 
should include a clear statement that the effects of CBD on driving are not well known, that some 
users experience significant sedation but the effects vary among individuals, and that participants 
should not drive until they know how the drug will affect them. The DSMB also asked that the PI 
consider a systematic assessment of sedation after administration of the first dose of study drug. 
Therefore, our protocol includes: 
• To help the participant understand how the study drug affects them we will monitor them in 
clinic. A validated Alertness Scale will be administered before the dose and again when the 
blood level is expected to reach peak – in three hours.   
• We will have the following language in the consent form and will emphasize it verbally: 
“Whether or not the study drug affects driving ability is not known. You should not drive or 
operate heavy machinery while taking study drug.” 
IV. Research Methods 
A. Outcome Measure(s):  
Primary Specific Aim: To evaluate the efficacy of CBD on motor symptoms in PD. 
Primary Outcome Measures: Change of MDS-UPDRS Part III (motor examination) from baseline 
to the end of 2.5 mg/kg/day of CBD. MDS-UPDRS Part III assesses the motor signs of PD. 
Secondary Specific Aim: To examine safety and tolerability of CBD and the effect of CBD on 
severity and duration of tremor, night-time sleep, rigidity, emotional dyscontrol, anxiety, and pain in 
PD. 
Secondary Outcome Measures:  
1. To evaluate the safety and tolerability of CBD in PD: 
1.1 By examining the frequency of study-related adverse events at each dose level between the 
two groups (treatment vs. placebo). Adverse events are measured at study visits, starting with 
an open ended question (Do you notice any effects, good or bad, of the study drug?) and 
followed by a series of yes/no questions regarding adverse effects (including previously 
reported adverse effects of CBD and general common adverse effects of medications and the 
hepatotoxicity), and all the effects we hypothesize in the study. For each adverse and 
beneficial reported effect, further questions will be asked, such as when did the effect start 
and how is it progressing, etc. In addition, since a major dose limiting effect is somnolence, 
the daytime sleepiness part of the SCOPA-sleep is included. 
 
Tolerability is judged and supervised by PI and sub-I (who are MDs), based on their clinical 
expertise. 
Abuse-related AEs will also be collected at screening, each dose assessment visit, liver 
function monitoring visit, and safety follow up visit. The abuse-related AEs is provided by 
MedDRA Preferred Terms (PTs), including: 
Euphoria-related terms: Euphoric mood, elevated mood, feeling abnormal, feeling drunk, 
feeling of relaxation, dizziness, thinking abnormal, hallucination, inappropriate affect. 
Terms indicative of impaired attention, cognition, and mood: Somnolence, mood disorders, 
and disturbances. 


16 
 
Dissociative/psychotic terms: Psychosis, aggression, confusion, and disorientation. 
Related terms not captured elsewhere: Drug tolerance, habituation, drug withdrawal 
syndrome, substance-related disorders. 
The Abuse-related AEs will be collected and recorded on a CRF that includes timing of the 
event, duration, severity, indication if more than one event was observed simultaneously, if 
other drugs were taken by subjects at the time of the event, correlation between the onset of 
the event, and the use of study drug. 
Well trained investigators will capture and report cases of abuse, misuse, or addiction and 
monitor for drug accountability discrepancies before starting trials. 
1.2 Liver monitoring plan: Liver function tests (including Alk Phos, ALT, AST, GGT, Total Bili) 
will be tested at each dose during treatment phase. Study participants will be asked to check 
for symptoms of hepatotoxicity when on study drug. A Hepatology consultant, Lisa Forman, 
MD., has agreed advise on liver function aspects of the study.   
1.3 By monitoring and comparing vital signs, orthostatic blood pressures, physical exam, EKG, 
and labs (hematology, complete metabolic profile, and urinalysis) between the two groups. 
These are collected during study visits. 
1.4 By conducting standardized assessment tools on cognition, anxiety, psychosis, sleep, daytime 
sleepiness, alertness, mood, fatigue, pain, impulsivity, suicidality, and motor and non-motor 
PD signs, restless legs syndrome, REM sleep behavior disorder, and quality of life during 
study visits. The change from baseline to each dose is compared. The assessment tools are: 
Cognition: 
• MoCA - is designed as a rapid screening instrument for mild cognitive dysfunction. It 
assesses different cognitive domains: attention and concentration, executive functions, 
memory, language, visual-constructional skills, conceptual thinking, calculations, and 
orientation. [Freitas S, et al. 2013]. 
• Cognitive assessment battery: 
Intellectual Functioning Estimate 
1) Wechsler Test of Adult Reading (WTAR) - Word reading tests are an established 
method of establishing a premorbid estimate of verbal intellectual functioning, which will 
serve as an estimate of premorbid cognitive reserve. 
Attention/Processing Speed/Executive Functioning 
2) Grooved Pegboard Test: Manipulative dexterity, including finger speed, is assessed.  
3) Symbol Digit Modalities Test (SDMT) - The SDMT is a measure of processing speed 
and working memory that has proven to be sensitive to cognitive impairment in MS that 
has both oral and written trials (only the oral trial will be administered given the 
anticipated difficulty patients will have with tremor). Participants are presented with a key 
at the top of a page pairing unique symbols with single digits. Participants are required to 
provide the correct digit with symbols that are presented on the rest of the page. The 
number of correct responses provided in 90 seconds on the oral and written trials, 
respectively, is recorded. 
4) Paced Auditory Serial Addition Test (PASAT) - The PASAT is a more complex 
measure of processing speed and working memory in which a series of digits is presented 
to participants at varying intervals (i.e., 2 seconds, 3 seconds). Participants must add each 


17 
 
digit to the immediately preceding digit for the duration of each trial. The number of 
correct responses for each trial is recorded. 
5) Controlled Oral Word Association Test (COWAT) - The COWAT is a measure of 
speeded verbal fluency and word retrieval in which participants are asked to say as many 
words as they can that begin with each of three letters for 60 seconds. The total number of 
words generated across all three trials is recorded. 
Memory Functioning 
6) Hopkins Verbal Learning Test-Revised (HVLT-R) - The HVLT-R is a measure of 
verbal learning and memory in which participants are asked to learn a 12-item word list 
over three trials (total immediate learning). A delayed free recall trial is administered after 
20 minutes, followed by a yes/no recognition trial. 
Visuospatial construction 
7) Judgment of Line Orientation (JOLO) - The JOLO is test of visuospatial functioning 
which measures a person's ability to match the angle and orientation of lines in space. 
Patients are asked to match two angled lines to a set of 11 lines that are arranged in a 
semicircle and separated 18 degrees from each other. 
Language Functioning 
8) Semantic Verbal Fluency – Semantic Verbal fluency is a measure of speeded verbal 
fluency and word retrieval in which participants are asked to say as many animal 
names/fruits and vegetables for 60 seconds. The total number of words generated across 
all three trials is recorded. 
 
Anxiety: 
• Anxiety short form - is component of the Neurol-QOL (Quality of Life in Neurological 
Disorders) Measurement System, which is a collaborative effort of the National Institute 
of Neurological Disorders and Stroke and a number of partnering institutions. This 
measurement system was designed to be responsive to the needs of researchers in a 
variety of neurological disorders and to facilitate comparisons of data across clinical trials 
in different diseases. The short form is comprised of eight items that were selected from 
the respective item bank. Items have five response options (e.g., 1=Never, 2=Rarely, 
3=Sometimes, 4=Often, 5=Always). Respondents generally can answer five questions per 
minute. 
Psychosis: 
• Neuropsychiatric Inventory (NPI) - is a valid and reliable scale. It was developed to 
provide a means of assessing neuropsychiatric symptoms and psychopathology of 
patients with Alzheimer’s disease and other neurodegenerative disorders. It has proven to 
be sensitive to change and has been employed to capture treatment related behavioral. 
The NPI is administered to a caregiver/significant other who has detailed knowledge of 
the participant’s behavior. 
Sleep and daytime sleepiness: 
• Scales for Outcomes in Parkinson’s disease (SCOPA)sleep - is a valid, reliable, short 
scale for assessing nighttime sleep (NS) and daytime sleepiness (DS) in patients with PD 
[Marinus J, et al. 2003]. The SCOPA-Sleep consists of two parts. The NS subscale 
addresses sleep problems and includes five items with four response options. Participants 


18 
 
have to indicate how much they were bothered by particular sleep problems, ranging 
from 0 (not at all) to 3 (a lot). The five items address sleep initiation, sleep fragmentation, 
sleep efficiency, sleep duration, and early wakening. The maximum score of this scale is 
15, with higher scores reflecting more severe sleep problems. One additional question 
evaluates overall sleep quality on a 7-point scale. The DS subscale evaluates daytime 
sleepiness and includes six items with four response options, ranging from 0 (never) to 3 
(often). Participants indicate how often they fell asleep unexpectedly, fell asleep in 
particular situations, how often they had difficulty staying awake, and whether falling 
asleep in the daytime was considered a problem. The maximum score is 18, with higher 
scores reflecting more severe sleepiness. The average score for PD is 5.2 ± 4 for DS and 
4.9 ± 4 for NS. 
• Stanford Sleepiness Scale (SSS): The Stanford Sleepiness Scale is a quick and easy way 
to assess how alert the participant is feeling. SSS is validated and probably the most 
widely used instrument for the assessment of participant’s sleepiness [Maclean AW, et al. 
1992, Hoddes et al, 1972].  
Mood: 
• Depression short form - is a component of the Neurol-QOL (Quality of Life in 
Neurological Disorders) Measurement System, which is a collaborative effort of the 
National Institute of Neurological Disorders and Stroke and a number of partnering 
institutions. This measurement system was designed to be responsive to the needs of 
researchers in a variety of neurological disorders and to facilitate comparisons of data 
across clinical trials in different diseases. The short form is comprised of eight items that 
were selected from the respective item bank. Items have five response options (e.g., 
1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always). Respondents generally can 
answer five questions per minute. 
• Emotional and behavioral dyscontrol short form - is a component of the Neurol-QOL 
Measurement System, which is a collaborative effort of the National Institute of 
Neurological Disorders and Stroke and a number of partnering institutions. This 
measurement system was designed to be responsive to the needs of researchers in a 
variety of neurological disorders and to facilitate comparisons of data across clinical trials 
in different diseases. The short form is comprised of eight items that were selected from 
the respective item bank. Items have five response options (e.g., 1=Never, 2=Rarely, 
3=Sometimes, 4=Often, 5=Always). Respondents generally can answer five questions per 
minute. 
Fatigue: 
• Fatigue Severity Scale (FSS) - is a self-report nine-item questionnaire with questions 
related to how fatigue interferes with certain activities and rates its severity. The items 
are scored on a seven point scale with 1= strongly disagree and 7= strongly agree. The 
minimum score is 9 and maximum score possible is 63. The higher the score, the greater 
the fatigue severity. 
Pain: 
• Pain Intensity 3a short form and Pain Interference 4a short form - are components of the 
Patient Reported Outcome Measurement Information System (PROMIS), which was 


19 
 
developed by the NIH to provide a standardized metric for measuring physical, mental, 
and social health across chronic diseases. PROMIS instruments were developed using 
item response theory and have been tested in more than 20,000 individuals drawn from 
the general US population. The Pain Intensity instrument assesses how much a person 
hurts. The Pain Interference instrument measures the self-reported consequences of pain 
on relevant aspects of one’s life. This includes the extent to which pain hinders 
engagement with social, cognitive, emotional, physical, and recreational activities. Each 
question has five response options ranging in value from one to five.  
Impulsivity: 
• Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS) is a 
rating scale designed to measure severity of symptoms and support a diagnosis of 
impulse control disorders and related disorders in PD. QUIP-RS has four primary 
questions (pertaining to commonly reported thoughts, urges/desires, and behaviors 
associated with ICDs), each applied to the four ICDs (compulsive gambling, buying, 
eating, and sexual behavior) and three related disorders (medication use, punding, and 
hobbyism). It uses a five-point Likert scale (score 0-4 for each question) to gauge the 
frequency of behaviors, and instructs patients to answer questions based on behaviors that 
occurred in the preceding four weeks (or any four-week period in a designated time 
frame). Scores for each ICD and related disorder range from 0 to 16, with a higher score 
indicating greater severity (ie, frequency) of symptoms. The total QUIP-RS score for all 
ICDs and related disorders combined ranges from 0 to 112 [Weintraub D, et al. 2012]. 
Suicidality: 
• The Columbia-Suicide Severity Rating Scale (C-SSRS) is a suicidal ideation rating scale. 
It rates an individual’s degree of suicidal ideation on a scale, ranging from “wish to be 
dead” to “active suicidal ideation with specific plan and intent.” The scale identifies 
behaviors which may be indicative of an individual’s intent to commit suicide. The C-
SSRS has been found to be reliable and valid in the identification of suicide risk in 
several research studies. 
Motor and non-motor PD signs: 
• Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS)- 
The MDS UPDRS has four parts: Part I (non-motor experiences of daily living), Part II 
(motor experiences of daily living), Part III (motor examination) and Part IV (motor 
complications). Part I has two components: IA concerning a number of behaviors that are 
assessed by the investigator with all pertinent information from patients and caregivers 
and IB that is completed by the patient with or without the aid of the caregiver, but 
independently of the investigator. It can, however, be reviewed by the rater to ensure that 
all questions are answered clearly and the rater can help explain any perceived 
ambiguities. Part II is designed to be a self-administered questionnaire like Part IB, but 
can be reviewed by the investigator to ensure completeness and clarity. Part III has 
instructions for the rater to give or demonstrate to the patient; it is completed by the rater. 
Part IV has instructions for the rater and also instructions to be read to the patient. This 


20 
 
part integrates patient-derived information with the rater’s clinical observations and 
judgments and is completed by the rater.  
• Unified Dyskinesia Rating Scale (UDysRS) is developed to evaluate involuntary 
movements often associated with treated Parkinson’s disease. There are two primary 
sections: Historical [Part 1 (On-Dyskinesia) and Part 2 (Off-Dystonia)] and Objective 
[Part 3 (Impairment) and Part 4 (Disability)]. On-Dyskinesia refers to the choreic and 
dystonic movements described to the patient as “jerking or twisting movements that occur 
when your medicine is working.” Off-Dystonia should be described to the patient as 
“spasms or cramps that can be painful and occur when your Parkinson’s disease 
medications are not taken or are not working.” 
• Timed Up&Go (TUG) test: The TUG test is a validated, widely used test for evaluating 
balance and walking ability associated with advancing age, neurological (especially PD), 
or other disorders [Bohannon RW, et al. 2006].  
• Non-motor symptoms Scale for Parkinson’s disease (NMSS): NMSS is a validated 30-
item scale for the assessment of NMS in PD. NMSSS contains nine dimensions: 
cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, 
gastrointestinal, urinary, sexual function, and miscellany. 
Restless Legs Syndrome: 
• International Restless Legs Syndrome Study Group Rating Scale for restless legs 
syndrome (IRLS): IRLS is a ten-question instrument for measuring severity of restless 
legs syndrome (RLS). The scale reflects participants assessment of the primary features 
(reflected in questions 1 through 3 and 6 of the scale), intensity and frequency of the 
disorder (questions 7 and 8 of the scale) and associated sleep problems (reflected in 
questions 4 and 5 of the scale). The scale also includes questions which probe the impact 
of symptoms on the patients’ mood and daily functioning (question 9 and 10 of the scale). 
Each question has a set of five response options graded from no RLS or impact (score=0) 
to very severe RLS or impact (score=4). This produced a total scale whose overall score 
could range from 0 to 40. IRLS sum score and subscales (symptoms in questions 1, 2, 4, 
and 6 through 8; symptoms impact in questions 5, 9, and 10) at every time point will be 
recorded. Item 3 is used for the total score for overall RLS severity. 
REM Sleep Behavior Disorders: 
• REM sleep behavior disorder screening questionnaire (RBDSQ) – is a 10-item, patient 
self-rating instrument assessing the participant’s sleep behavior with short questions that 
have to be answered by either “yes” or “no”. Items 1 to 4 address the frequency and 
content of dreams and their relationship to nocturnal movements and behavior. Item 5 
asks about self-injuries and injuries of the bed partner. Item 6 consists of four sub items 
assessing nocturnal motor behavior more specifically, e.g., questions about nocturnal 
vocalization, sudden limb movements, complex movements, or bedding items that fell 
down. Items 7 and 8 deal with nocturnal awakenings. Item 9 focuses on disturbed sleep in 
general and item 10 on the presence of any neurological disorder. The maximum total 
score of the RBDSQ is 13 points. 
Bladder function: 


21 
 
• Overactive Bladder Symptom Score (OABSS) is a validated self-administered 
questionnaire consisting of seven questions on a five-point Likert scale. Five questions 
are related to urinary urgency and two are related to daytime and nighttime urinary 
frequency. 
Quality of Life 
• Parkinson’s Disease Questionnaire (PDQ-39): is a reliable, valid, responsive, acceptable, 
and feasible as the tool for the assessment of quality of life in Parkinson’s disease 
patients. There are 39 questions in the long form Parkinson’s Disease Questionnaire, with 
eight discrete scales: mobility (10 items), activities of daily living (six items), emotional 
well-being (six items), stigma (four items), social support (three items), cognitions (four 
items), communication (three items), and bodily discomfort (three items). Patients are 
asked to think about their health and general well-being and to consider how often in the 
last month they have experienced certain events. Patients are asked to indicate the 
frequency of each event by selecting one of five options (Likert Scale): 
never/occasionally/sometimes/often/always or cannot do at all. 
• EuroQoL-5 Dimension-5 level (EQ-5D-5L): consists of two pages-the EEQ-5D-5L 
descriptive system and the EQ Visual Analogue Scale (EQ VAS). The descriptive system 
comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has five levels: no problem, slight problems, 
moderate problems, severe problems, and extreme problems. This is a widely used well 
validated simple assessment that is comparable across disease populations. 
1.5 By assessing and comparing the proportion of participants that discontinue the study due to 
study drug intolerance in the two groups (treatment vs. placebo). 
2. Overall PD status - Change of total MDS UPDRS scores from baseline to the end of 2.5 
mg/kg/day visit. 
3. Tremor - Change of Severity and duration of tremor from baseline to the end of 2.5 mg/kg/day 
visit: Tremor is measured by the change from baseline to the end of 2.5 mg/kg/day between the 
two groups: 
3.1 Total of scores on items 3.17 and 3.18 in part III of the MDS-UPDRS in the ON state (when 
anti-PD medication is working). Item 3.17 is rest tremor amplitude. Extremity ratings range 
from 0: Normal, No tremor to 4: Severe, >10 cm in maximal amplitude. Lip/Jaw ratings are 
similar but smaller amplitudes. Item 3.18 is constancy of rest tremor: 0 (no tremor) to 4 
(present >75% of the exam). 
3.2 Item 2.10 in part II of the MDS-UPDRS in the ON state. Item 2.10 is patient’s tremor 
experience: 0 (Not at all. I have no shaking or tremor) to 4 (Shaking or tremor causes 
problems with most or all activities). 
3.3 Total of scores on items 3.15 and 3.16 in part III of the MDS-UPDRS in the ON state. Item 
3.15 is postural tremor of the hands: 0: Normal (No tremor) to 4: Severe (Tremor is at least 
10 cm in amplitude). Item 3.16 is kinetic tremor of the hands: 0: Normal (No tremor) to 4: 
Severe (Tremor is at least 10 cm in amplitude).  
3.4 Constancy and amplitude of tremor measured by Tremor GUI MATLAB package: Tremor 
will be measured at clinic and at home (twice a day, two hours after breakfast dose and two 
hours after dinner dose, for 2 consecutive days after screening visit, three consecutive days 
before baseline visit and each dose assessment visit). Each time tremor will be measured for 


22 
 
90 seconds. The constancy (percentage of tremor per minutes) and amplitude will be 
recorded using the package. See Appendix 2. Dr. John Thompson is collaborating on the 
tremor device. 
4. Motor sub-scores - Rigidity, bradykinesia, axial, and bulbar sub-scores will also be calculated – 
these are pulled from the motor MDS-UPDRS – the change from baseline to the end of 2.5 
mg/kg/day visit.  
5. Emotional control - Emotional and behavioral dyscontrol short form score change from baseline 
to the end of 2.5 mg/kg/day visit.  
6. Anxiety – Anxiety short form score change from baseline to the end of 2.5 mg/kg/day visit. 
7. Pain - Pain intensity short form score change from baseline to the end of 2.5 mg/kg/day visit. 
8. Sleep sub-study- The primary outcome is the change from baseline to the end of 2.5 mg/kg/day 
visit on wake after sleep onset (WASO, length of periods of wakefulness occurring after sleep 
onset), secondary outcomes are changes from baseline to the end of 2.5 mg/kg/day visit on: 
percentage of total sleep time spent in each sleep stage (N1, N2, N3, and REM), frequency of leg 
movements during REM, sleep efficiency (proportion of total time in bed spent asleep), total 
sleep time and the scales of SCOPA-night-time sleep, ISI, DBAS-16, and Pittsburgh Sleep 
Quality Index. 
8.1 Night-time sleep - SCOPA-night-time sleep score change from baseline to the end of 2.5 
mg/kg/day visit. 
8.2 Insomnia Severity Index (ISI): ISI is a verified seven-item self-report questionnaire assessing 
the nature, severity, and impact of insomnia. A five-point Likert scale is used to rate each 
item (e.g., 0=no problem; 4=very severe problem), yielding a total score ranging from 0 to 
28. The total score is interpreted as follows: absence of insomnia (0-7); sub-threshold 
insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28). 
8.3 Modified Dysfunctional Beliefs and Attitudes about Sleep Questionnaire (DBAS-16): A 
validated self-reported questionnaire designed to identify and assess various sleep/insomnia-
related cognitions (e.g., beliefs, attitudes, expectations, appraisals, attributions). 
8.4 Pittsburgh Sleep Quality Index: is an effective instrument used to measure the quality and 
patterns of sleep in adults. It differentiates “poor” from “good” sleep quality by measuring 
seven areas: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, 
sleep disturbances, use of sleeping medications, and daytime dysfunction over the last month. 
8.5 Home Sleep Monitoring: Polysomnography (PSG) will be performed using a Type II 
portable, unattended monitor in patients’ home. Study subjects will come to clinic to have 
electrodes and equipment attached by the study coordinator for electroencephalogram (EEG), 
electro-oculogram (EOG: bilateral), electrocardiogram (EKG), chin electromyogram (EMG), 
abdominal and thoracic effort belts, oxyhemoglobin saturation (SpO2; finger pulse oximetry; 
Nonin, Minneapolis, Minnesota), airflow (oral-nasal thermistor), and pressure transducer. 
Explicit instructions will be reviewed with each subject prior to leaving clinic: directions, 
timing for completing each questionnaire and initiating sleep recording. A registered 
polysomnographic technologist (PRSGT) will download and inspect the quality of the 
recorded signal of the PSG prior to scoring the data. Drs. Russell Bowler and Greg Kinney 
are collaborating on conduct of the polysomnograms.  
9. Skin evaluation for seborrheic dermatitis in collaboration with Drs. Robert Dellavalle and Andrea 
Steel: Dermatology Quality of Life Index (DLQI) and dermatology photography. DLQI is a 
dermatology-specific quality of life instrument. It is a simple 10-question validated questionnaire 
that has been used in over 40 different skin conditions. Dermatology photography (Appendix 3): 


23 
 
take a picture of the central face, as this is the most common area of seborrhea, and send it, with 
appropriate privacy safeguards, to dermatologists, Dr. Robert Dellavalle, MD., and Dr. Andrea 
Steel.  
10. Changes of outcome measures 1-7 and 8.1-8.4 from baseline to the end of 1.25 mg/kg/day will 
be compared between the two groups. 
 
Exploratory Analyses: 
To study the efficacy of CBD on the aspects of PD listed in Section IV, 1.4 and plasma levels of 
cytokine in PD.  
Exploratory Outcome Measures: The efficacy of CBD on these aspects of PD are measured by the 
same standardized tools used for safety and tolerability (listed in Section IV, 1.4). The effect of CBD 
is also measured by Clinical Global Impression (CGI) and Patient Global Impression-improvement 
(PGI-I) and Change (PGI-C). CGI is a three-item observer-rated scale that measures illness severity 
(CGIS), global improvement or change (CGIC) and therapeutic response. The CGI is rated on a 
seven-point scale, with the severity of illness scale using a range of responses from 1 (normal) 
through to 7 (amongst the more severely ill patients). CGI-C scores range from 1 (very much 
improved) through to 7 (very much worse). Treatment response ratings should take account of both 
therapeutic efficacy and treatment-related adverse events and range from 0 (marked improvement 
and no side-effects) and 4 (unchanged or worse and side-effects outweigh the therapeutic effects). 
Each component of the CGI is rated separately. PGI-I is a global index that may be used to rate the 
response of a condition to a therapy (transition scale). It is a simple, direct, easy to use scale that is 
intuitively understandable to patients. PGI-C is rated on a seven-point scale, evaluating all aspects of 
patient’ health and determining if there has been an improvement or not. The change from baseline 
to the end of 2.5 mg/kg/day is compared between the two groups. 
Change of plasma levels of cytokine from baseline to the end of 2.5 mg/kg/day will be compared 
between the two groups. 
 
Table 5. Measurement tools performed in current study.  
 
Assessments 
Primary 
(efficacy) 
Secondary  
(safety +tolerability) 
Exploratory 
(efficacy) 
MDS UPDRS Part III motor score 
X 
 
 
MoCA 
 
X 
X 
Detailed cognitive battery 
 
X 
X 
Anxiety short form 
 
X 
X 
NPI 
 
X 
X 
SCOPA-Sleep 
 
X 
X 
Sleep sub-study 
 
X 
X 
Stanford Sleepiness Scale (SSS) 
“Alertness Test” 
 
X 
 
Depression short form 
 
X 
X 
Emotional and Behavioral 
dyscontrol short form 
 
X 
X 
Fatigue Severity Scale 
 
X 
X 
Pain Intensity 3a and Interference 
4a short forms 
 
X 
X 


24 
 
 
 
B. Description of Population to be Enrolled:   
Parkinson 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 [Yao, S.C, et al. 2013; de Lau LM, et al. 2006]. PD usually begins 
around age 60, but it can start earlier. Treatment, typically medications such as levodopa and 
dopamine agonists, improve early stage symptoms. As the disease progresses and dopaminergic 
neurons continue to be lost, these drugs become less effective, and levodopa produces disabling 
motor fluctuations in most patients. PD invariably progresses with time. Untreated individuals are 
expected to lose independent ambulation after an average of eight years and be bedridden after ten 
years [Poewe W. 2006]. In people taking levodopa the progression of symptoms to a stage of high 
dependency from caregivers is on average 15 years.  
 
C. Study Design and Research Methods   
C.1 Study design 
The major purpose of this study is to assess the efficacy of CBD on motor symptoms of PD, and 
secondarily to study the safety and tolerability of CBD and other efficacy, particularly regarding 
tremor in PD. The study has been powered to detect a clinically significant reduction in MDS 
UPDRS Part III motor scores. This is a 1:1 parallel, double-blind, randomized controlled trial (RCT) 
with 60 participants. We will be recruiting up to 75 participants; the goal is to have 60 participants 
(30 in CBD group and 30 in placebo group) complete the study.   
QUIP-RS 
 
X 
X 
MDS UPDRS total and sub-scores 
 
X 
X 
Unified Dyskinesia Rating Scale 
(UDysRS) 
 
X 
X 
NMSS 
 
X 
X 
OABSS 
 
X 
X 
      TUG 
 
X 
X 
REM Sleep Behavior Disorder 
Screening Questionnaire 
(RBDSQ) 
 
X 
X 
The Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
 
X 
 
International Restless Legs 
Syndrome Study Group Rating 
Scale (IRLS) 
 
X 
X 
PDQ-39 
 
X 
X 
EQ-5D 
 
X 
X 
CGI 
 
 
X 
PGI 
 
 
X 
Tremor measure 
 
 
X 
Skin tests 
 
X 
X 
Plasma levels of cytokine 
 
 
X 


25 
 
See Appendix 1 Schedule of Events for more detail on study design. 
The study drug is obtained from NIDA. How the dose is started and escalated and what target dose is 
chosen is based on human literature and our open label study, as discussed in Section III under 
Discussion.  
 
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 four weeks, 2 dose assessment visits 
(1.25 mg/kg/day and 2.5 mg/kg/day), and a safety visit (5 visits total). Participants will be evaluated 
at each dose level for monitoring adverse events, as well as changes in medical history and 
concomitant medications. Further, in case CBD alters the reliability of self - report, repeated 
measures will be taken on the third to fifth day at each dose during the clinic visits or at home. The 
assessments include the assessment of tolerability and symptoms of hepatotoxicity, SCOPA-sleep, 
Anxiety short form, Depression short form, Emotional and behavioral dyscontrol short form, and 
EQ-5D-5L. Participants are called 3 and 7 days after stopping the study drug to check for signs of 
withdrawal. At dose assessment visits, urinary CBD and metabolites will be tested. To maximize 
compliance the coordinator calls the participant to remind them the next day’s clinical visit. To 
increase compliance with taking study drug, participants will be asked to fill out a diary at home. The 
diary will be a record of the date and time participants take study drug, dose of the study drug, and 
adverse and beneficial events. Study drug is dispensed at the baseline visit. Participants will measure 
their tremor using Tremor GUI MATLAB twice a day (two hours after breakfast dose and two hours 
after dinner dose) for two consecutive days after screening visit, three consecutive days prior to 
baseline and each dose assessment visit, as well as during the clinic visits. To evaluate the possible 
somnolence effect of CBD, participants will be evaluated their alertness before and three hours after 
they take the study drug at baseline visit.  
 
Inclusion and Exclusion criteria:  
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.  


2 6  
 
 
* * N ote: t he L A R ( if re q uire d f or i nf or m e d c o nse nt), care gi ver (re q uire d f or t h ose wit h M O C A < 2 2), 
a n d si g nifica nt ot her (re q uire d f or all partici pa nts) ma y be t he sa me p ers o n i n s o me cases. I n ot h er 
cases, t hese m a y be diff ere nt pe o ple.  
 
E xcl usi o n criteria:  
•  K n o w n or s us pect e d aller g y t o ca n na bi n oi ds or e x ci pie nts use d i n t he st u d y dr u g f or m ulati o n. 
•  Ca n na bis is detecta ble at t he scree ni n g visit b y bl o o d testi n g or at t he baseli ne visit b y uri ne 
testi n g. If ca n na bis is det ecte d at eit her t he scree ni n g or baseli ne visit, t he n t he partici pa nt is a 
scree n fail a n d ma y ret ur n > 1 4 da ys later f or a re p eat scree ni n g visit. If ca n na bis is a gai n 
detecte d at eit her t he scree ni n g or baseli ne visit, t he n t he partici pa nt is e x cl u de d a n d n ot all o we d 
t o rescree n.  
•  Hist or y of dr u g or al c o h ol de pe n de nce; defi ne d b y pri or i n patie nt sta y(s) f or t his or t hat patie nt 
states s/ he has a hist or y of t his. 
•  Use of d o pa mi ne bl oc k ers wit hi n 1 8 0 da ys a n d c o cai ne, a n d M A O- A i n hi bit ors wit hi n 9 0 da ys of 
baseli ne.  
•  C urre ntl y ta ki n g t olca p o ne, val pr oic aci d, fel ba m ate, niaci n ( nic oti nic aci d) at ≥2 0 0 0 m g/ da y or 
nic oti na mi de ( nic oti nic aci d a mi de or nic oti na mi d e) at ≥3 0 0 0 m g/ da y,  is o niazi d a n d 
ket oc o naz ol e d ue t o ris k of li ver i nj ur y a n d cl o baza m a n d ket oc o n az ole b eca use of ris k of t o xic 
i nteracti o ns wit h t he st u d y dr u g. T hese me dicati o ns nee d t o be st o p pe d 9 0 d a ys bef ore t he 
baseli ne visit.  
•  U nsta ble me dical c o n diti o n. 
•  A n y of t he f oll o wi n g la b orat or y test res ults at scree ni n g: 
� He m o gl o bi n < 1 0 g/ d L 
� W B C < 3. 0 x 1 09/ L 
� Ne utr o p hils < 1. 5 x 1 09/ L 
� L y m p h oc ytes < 0. 5 x 1 09/ L 
� Platelets < 1 0 0 x 1 09/ L 
� He m o gl o bi n A 1 C > 9 % 
•  As partate a mi n otra nsferase ( A S T) a n d/ or ala ni ne a mi n otra nsferase ( A L T) > 3 ti mes t he u p per 
li mit of n or mal. Pers o ns wit h sta ble li ver disease of k n o w n eti ol o g y ca n be i ncl u de d, u nless t otal 
bilir u bi n or pr ot hr o m bi n ti me/I N R is a b n or mal.  
•  Is pre g na nt or l actati n g, or has a p ositi ve pre g n a n c y test res ult pre- d os e. 
•  If a se x u all y acti ve f e mal e, is n ot s ur gicall y sterile or at least t w o years p ost- me n o pa usal, or d o es 
n ot a gree t o utilize a n eff ecti ve met h o d of c o ntrace pti o n fr o m scree ni n g t hr o u g h at least f o ur 
wee ks after t he c o m pleti o n of st u d y treat me nt, usi n g o ne of t he f oll o wi n g: barrier m et h o ds 
( dia p hra g m or p art ner usi n g c o n d o ms pl us use of s per mici dal jell y or f oa m, prefera bl y d o u ble-
barrier m et h o ds); ora l or i m pla nte d h or m o nal c o ntrace pti ve; i ntra ut eri ne d e vice (I U D); or 
vasect o mize d mal e part n er.  
•  Pla n ne d electi ve s ur g er y d uri n g st u d y partici pati o n. 
 
C yt o ki nes testi n g: E nr olle d s u bjects w h o meet  t he f oll o wi n g criteria will ha ve bl o o d c ollecte d f or 
c yt o ki nes test, al o n g wit h ot her bl o o d t u bes bei n g c ollecte d, at scree ni n g a n d at 2. 5 m g/ k g/ da y d ose 
assess me nt visit. If t hes e criteria are n ot met at scree ni n g b ut are m et at bas eli ne visit, t he dra w f or 
c yt o ki nes testi n g ma y be d o ne at t he baseli ne visi t i nstea d. 


27 
 
 
• Not currently taking or has not taken in the past 10 days chemotherapeutic or anti-inflammatory 
medications. A sample of such medications is listed in Appendix A, but it is not possible to list 
all medications in these broad classes. Thus, the PI will evaluate each subject’s medications and 
decide if any meet this exclusion criteria.  
• Does not have currently active cancer or is not currently being treated for cancer or inflammatory 
or atopic disease, listed in Appendix 8. It is not possible to list all such disorders, so the PI will 
evaluate each subject’s medical status and decide if they have any meet that this exclusion 
criteria. 
• No current kidney failure or renal dialysis, chronic respiratory disease requiring daily oxygen, 
active or treated seizures, and hyperthyroidism.  
• No current or in the past seven days any infection, for example common cold or urinary tract 
infection, again to be at discretion of the PI. 
 
Participants will be consented that the effects of CBD on driving are not known, that some users 
experience significant sedation but the effects vary among individuals and that participants should 
not drive while taking the study drug. A limited amount of Uber vouchers will be provided to 
subjects to assist with transportation needs during the treatment period. Alertness test will be done 
before and three hours after the first dosing is administered at baseline visit to judge the alertness 
degree for driving. 
 
Dose escalation strategy: 
Study product (CBD or placebo) will be started at 1.25 mg/kg/day of CBD (once a day) for four days 
and then increase to 2.5 mg/kg/day of CBD (twice a day) for 10 (+4) days. Tolerability will be 
assessed at each dose during each clinic visit. Subjects may take a reduced dose for the duration of 
the study according to the investigator’s medical judgement.  
Regarding possible drug interactions, study pharmacists will be provided the calculated dose based 
on body weight, the list of the subject’s medications, and additional relevant clinical information. 
The final study drug dose will be that recommended by the study pharmacists.  
 
Assessment of tolerability of each dose level 
Tolerability will be assessed at each dose via collection of adverse events and administration of the 
standardized questionnaires by appropriate study staff during each clinic visit. Severity of adverse 
events will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), 
which is published by the National Cancer Institute (NCI) of the National Institutes of Health (NIH):  
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2:  Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADLs. Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.  
Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLs. Self-care ADLs refer to 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.  


28 
 
Grade 4:  Life-threatening consequences; urgent intervention indicated.  
Grade 5:  Death related to AE.  
The protocol for dose adjustments, maintenance, and discontinuation based on adverse effects is as 
follows: 
• For participants with a grade 1 adverse event the dose will be increased by up to 1.25 mg/kg/day, 
or if they are on the maximal targeted dose (2.5 mg/kg/day) it will be continued.  
• For participants with a grade 2 adverse event the dose will be reduced by 1.25 mg/kg/day or less.  
• For participants with a grade 3 or 4 adverse event that the Investigator determines is unrelated, 
the dose will be continued. When the adverse event is stabilized or resolved, e.g., participant is 
stable after a hip fracture repair, the dose will be increased unless they are already on the 
maximum targeted dose.  
• For participants with a grade 3 or 4 adverse event that the Investigator determines is related the 
study drug will be stopped and not restarted.  
The Investigator will determine relatedness as described in Section IV. C.6, and will consider the 
adverse event related if she determines there is at least a reasonable possibility. 
The major dose limiting effect, is somnolence. To monitor for this closely, the daytime sleepiness 
part to the SCOPA-sleep will be administered during each clinic visit, thus before each increase in 
dose. A score of >7 (note that the average score for PD is 5.2 ± 4), if greater than before and 
considered problematic by the appropriate clinical staff, would result in the participant being 
instructed to drop to the prior dose for five more days before increasing the dose.  
Liver function test is done at the study visit on the third to fifth day of each dose. Additional 
assessments of safety and tolerability is done at the study visit when the participant is on the 
maximum tolerated or targeted dose. The same protocol for dosing is applied for both adverse events 
found during study visits.  
The CTCAE criteria are used to determine dose level adjustments and for participant and study 
stopping rules (Section IV C.5). Adverse events will be collected and reported as discussed in 
Section IV C.6. 
 
Urine collection, storage and transfer for cannabis and metabolites test: The purpose of the urine 
cannabis and metabolites test is to develop a methodology to quantitate CBD metabolites. 
Participants will be given two urine cups, 100 mL each, at the baseline visit, 1.25 mg/kg/day dose 
assessment visit, and 2.5 mg/kg/day dose assessment visit. Urine cannabis and metabolites test will 
be done at dose assessment visits (1.25 and 2.5 mg/kg/day) and safety follow up visit. On the phone 
call before the day of dose assessment visits and safety follow up visit, participants will be reminded 
to collect urine in the morning of the study visit. They are asked to fill each up at least three-quarters 
full if possible, and to bring them to the visit (no refrigeration needed). Upon arrival of the visit the 
study coordinator will collect and store the urine cups in a -80°C freezer until shipment. For 
shipment, samples for each individual will be placed onto a sealable plastic bag together with an 
absorption pad. All the individual bags will be placed into a large sealable plastic bag with contains 
absorption material. Samples will be placed onto a Styrofoam box and will be shipped on dry ice. 
Urine samples will be labeled with the name of the study and the date and time of collection. Urine 
samples will be shipped for analysis to Dr. Jost Klawitter at iC42 Clinical Research and 
Development. Dr. Klawitter is in charge of analyzing the specimens as well as contributing to 
interpreting results and writing publications. He receives only coded specimens with no PHI. 
 


29 
 
The blood and urine samples will be stored in Dr. Klawitter’s lab for possible unspecified future 
research under the consent of study subjects.  
 
Procedures at each visit 
Visit 1-Screening visit: Decisional capacity to provide informed consent will be evaluated as much 
as possible during prescreening as well as at screening visit during informed consent discussion. 
Capacity will be assessed by asking questions such as: Why is the study being done? What is the 
study asking you to do? What are the risks of the study? Is the study voluntary? Etc. If in PI’s 
opinion the subject does not have cognitive capacity to provide informed consent, legally authorized 
representative (LAR)  will be required to provide informed consent prior to any study procedures 
being completed.  
Prior to onsite screening visit, the research coordinator sends the consent form to the study 
participant through email or mail and schedules a time to explain the study and discuss the consent 
form with the participant via phone Zoom, or other HIPAA-compliant platform. The study 
participant doesn’t need to print the consent or sign the consent. We will finish the consent at on site 
screening visit with the PI or Sub-I. If the participant is unable to discuss the consent form in 
advance, consent discussion and review can be done in clinic. 
On site screening visit: Consent, demographics, concomitant medications,  family medical history, 
medical history and physical examination (complete physical exam and detailed neurological exam), 
vital signs, orthostatic blood pressures, tremor evaluation, MDS-UPDRS III, H&Y rating, MOCA, 
Drug, alcohol and tobacco abuse screening test, safety assessments (as listed in section IV A, 
including, QUIP-RS, C-SSRS, NPI, Emotional and behavioral dyscontrol short form, Drug abuse-
related AEs), EKG and safety labs (including hematology, hemoglobin A1C, Complete metabolic 
profile and Liver Function Tests), blood cannabis analysis testing, plasma cytokine level tests, serum 
pregnancy test (for women childbearing potential), and inclusion/exclusion criteria are done. Study 
participants are instructed not to take cannabis from outside source throughout the study. Tremor 
constancy and amplitude measure device (Tremor GUI MATLAB package) is dispatched and 
participants are instructed to use the Tremor GUI MATLAB package to measure their tremors in the 
clinic and will perform it independently before they leave the clinic. They will measure the tremors 
at home twice a day (two hours after breakfast dose and two hours after dinner dose) for two days 
after screening visit and three days prior to the baseline visit.  
To reduce in-person clinic visit time, part of the above procedures can be done remotely after onsite 
screening visit, including: demographics, concomitant medications, family medical history, medical 
history, safety assessments (C-SSRS, NPI, emotional and behavioral dyscontrol short form, drug 
abuse related AEs).  
Visit 2- Baseline visit: Eligibility confirmation (including tremor evaluation), medical history, 
concomitant medications collection, formal drug interaction assessment, vital signs, orthostatic blood 
pressures, brief physical exam, MoCA, MDS-UPDRS, H&Y rating, UDysRS, NMSS, OABSS, 
tremor constancy and amplitude two hours after taking study drug, TUG test, cognitive assessment 
battery (including tests of verbal intellectual function, attention, processing speed, executive 
function, verbal learning and memory, visuospatial memory, speeded verbal fluency, and word 
retrieval), Anxiety short form, Depression short form, SCOPA-Sleep, ISI, DBAS-16, Pittsburgh 
Sleep Quality Index, Alertness test, RBDSQ, C-SSRS, IRLS, Fatigue severity scale, Pain intensity 
and interference short form, PDQ-39, EQ-5D, CGI, PGI, urine drug (THC) test (urine dipstick test), 
urine pregnancy test (women childbearing potential) and study drug dispensing is done and, if 
appropriate, randomization. Skin evaluation (Dermatology Intake Form, DLQI, and dermatology 


30 
 
photography) will be done. Alertness test (Stanford Sleepiness Scale) will be done before and three 
hours after the first dosing was administered at clinic. Tremor evaluations reviewed. Home diary is 
also dispensed. Participants will pick up PSG equipment and home sleep test instruction and do the 
home sleep test for up to 14 to three nights before the baseline visit. Participants will complete 
Morning Daytime Dysfunction questionnaire and sleep diary on the morning after the sleep test. PSG 
equipment and data collected before or at this visit. Participants take the first dose and are instructed 
on how to take the medication and how to fill out the diary at home. Participants will be monitored 
for 2 hours and vital signs and orthostatic blood pressures will be checked at one hour after taking 
the study drug. Participants are also told to bring in empty, partially used, and unused bottles of study 
drug at next clinical visit. Participants will be told not to take the study drug on the day of the next 
visit, as they will take it upon arrival under instruction by study staff. Participants will be given two 
urine cups, 100 mL each, and will be instructed to collect their urine the morning of the 1.25 
mg/kg/day assessment visit. They are asked to fill each cup at least three-quarters full, if possible, 
and to bring them to the visit (no refrigeration needed). Participants are instructed to measure their 
tremors at home for three days prior to each dose assessment visit.  
Part of the above procedures can be done remotely through Zoom or other HIPAA-compliant 
platform, between screening and onsite baseline visit: Eligibility confirmation, medical history, 
concomitant medications collection, NMSS, OABSS, Anxiety short form, Depression short form, 
SCOPA-Sleep, ISI, DBAS-16, Pittsburgh Sleep Quality Index, Dermatology Intake Form, DLQI, 
Alertness test, RBDSQ, C-SSRS, IRLS, Fatigue severity scale, Pain intensity and interference short 
form, PDQ-39, EQ-5D. 
 
Visit 3 (3-4 days, 1.25 mg/kg/day) and Visit 4 (14 (+4) days, 2.5 mg/kg/day), dose assessment visits: 
On the morning of the visits, participants will collect their urine and bring it to the visits. Study 
coordinator will collect and store the urine cups in a -80°C freezer until shipment for urinary CBD 
and metabolites test. Concomitant medications, change in medical history, vital signs, orthostatic 
blood pressures, complete physical exam, detailed neurological exam, MDS-UPDRS, UDysRS, 
H&Y rating, tremor constancy and amplitude, NMSS, TUG, Anxiety short form, Depression short 
form, Emotional and behavioral dyscontrol short form, Fatigue Severity Scale, Pain Intensity and 
Interference short form, MoCA,  RBDSQ, QUIP-RS, C-SSRS, NPI, SCOPA-sleep, ISI, DBAS-16, 
Pittsburgh Sleep Quality Index, IRLS, OABSS, EQ-5D, PDQ-39, CGI, PGI, blood draw for safety 
labs (hematology, Complete Metabolic Profile and Liver Function Tests) and blood cannabis 
analysis, urinalysis, ECG, and urine pregnancy test are done. Study drug compliance check, adverse 
event check and blinding assessment are done. Participants will take their study drug upon their 
arrival to the clinic and record the taking time. Blood is drawn for cannabis testing and safety labs 
three hours after the dose. Participants will be monitored and vital signs and orthostatic blood 
pressures will be checked at one and three hours (2.5 mg/kg/day dose assessment visit) after taking 
the study drug. Home diary is collected and reviewed. Urine cups dispensed. 
In addition to the procedures above, for Visit 3 (3-4 days, 1.25 mg/kg/day), participants are told to 
bring in empty, partially used, and unused bottles of study drug at next clinical visit. Participants will 
be told not to take the study drug on the day of the next visit, as they will take it upon arrival under 
instruction by study staff. Participants are instructed to measure their tremors at home for three days 
prior to 2.5 mg/kg/day dose assessment visit. Participants will be given the questionnaires of 
SCOPA-sleep, Anxiety short form, Depression short form, Emotional and behavioral dyscontrol 
short form, EQ-5D-5L, C-SSRS. Study staff will call the participants on the 3rd to 5th day on 2.5 
mg/kg/day to remind them to complete the questionnaires and bring it in at next clinic visit. 


31 
 
 
For 2.5 mg/kg/day dose assessment visit, participants will pick up PSG equipment and home sleep 
tests instructions, and perform PSG during the night after at least seven days on the 2.5 mg/kg/day or 
tolerated max dose, and until (and including) the third night before the visit. Participants will 
complete Morning Daytime Dysfunction questionnaire and sleep diary on the morning after the sleep 
test. PSG equipment and data are collected before or at this visit. Participants will also perform full 
cognitive assessment battery tests and skin evaluation (DLQI and dermatology photography) during 
this visit. Study drug participants returned are disposed per the SOP at 2.5 mg/kg/day dose 
assessment visit. Plasma cytokine levels test at 2.5 mg/kg/day visit.  
 
 
Visit 5-Safety follow up: Vital signs, orthostatic blood pressures, history and complete physical 
examination, concomitant medications collection, MDS-UPDRS, H&Y rating, UDysRS, NMSS, 
RBDSQ, QUIP-RS, C-SSRS, NPI, SCOPA-sleep, Anxiety short form, Depression short form, 
Emotional and behavioral dyscontrol short form, Fatigue Severity Scale, Pain Intensity and 
Interference short form, IRLS, OABSS, PDQ-39, EQ-5D-5L, adverse event check, urine pregnancy 
test, and cannabis lab testing are done. Hematology, complete metabolic profile, urinalysis, and EKG 
will be done if there was a clinically significant change at the high dose evaluation visit compared to 
baseline visit. The PI will evaluate the participant for signs of withdrawal. On the morning of the 
visit, participants will collect their urine and bring it to the visit. Study coordinator will collect and 
store the urine cups in a -80°C freezer until shipment for urinary CBD and metabolites test. 
 
Part of the above procedures can be done remotely 1-3 days prior to or after safety follow up visit: 
medical history, concomitant medications collection, NMSS, RBDSQ, C-SSRS, NPI, SCOPA-sleep, 
Anxiety short form, Depression short form, Emotional and behavioral dyscontrol short form, Fatigue 
Severity Scale, Pain Intensity and Interference short form, IRLS, OABSS, PDQ-39, EQ-5D-5L, 
adverse event check. 
 
C.2 Study Drug: CBD: 
The study drug is supplied by NIDA; see Appendix 4 for Certificate of Analysis (COA). The study 
drug (CBD) is provided in the form of a thick liquid and will be diluted into a 100 mg/ml formulation 
with sesame oil. This procedure will be done by the PharmDs (Jacci Bainbridge, PharmD, Matthew 
Makelky, PharmD, and Professor Tom Anchordoquy as a consultant) or PI, according to the protocol 
we develop with guidance from NIDA and the University of Mississippi researchers that produced 
the material. The placebo will be made by the study Pharm Ds from USP grade sesame oil and food 
coloring. Because the placebo may be slightly different in appearance or taste, two study 
modifications are being done to preserve the blind. First, the study drug will be put into brown 
opaque bottles and the only study personnel to see the actual study drug will be the unblinded 
PharmD and the blinded CTRC PA that instructs the subject on how to take study drug. Further, the 
study drug is administered in a closed, vented room in the CTRC that removes the odor of cannabis 
within four minutes. After the study drug is administered and the study drug bottle closed, the PA 
will stay with the subject in the closed room while it is being vented for at least 10 minutes. The 
study design of parallel groups is being used instead of the original crossover design that was 
planned.  
ElSohy Laboratories, Incorporated (ELI) will perform the stability testing. The laboratory is 
registered with the FDA and the DEA (Manufacturing and Analytical), all the planned analytical 


32 
 
procedures are validated, and the lab has extensive experience with the drug substance (CBD 
extract) and with a very similar drug product to ours. Controls for both CBD and THC content are 
used. The stability testing will be done in real time.  
The shelf life will be determined by the testing described below. The final drug product will be 
stored at room temperature, 25°C.  
The microbial testing for the final drug product will be carried out according to UPS 61 (total 
aerobic microbial count and total combined yeast/mold count) and USP 62 (for salmonella and E. 
coli), and the specification and acceptance criteria will be the same as recommended in USP <111> 
(microbiological examination of non-sterile products: Acceptance Criteria for Pharmaceutical 
Preparations and Substances for Pharmaceutical Use for non-sterile, non-aqueous products with oral 
administration). This will be the same for the product and placebo. 
Microbial Specifications:  
• 
Route of Administration: Nonaqueous preparations for oral use. 
• 
Total Aerobic Microbial Count:<103 cfu/mL 
• 
Total Combined Yeasts/Molds Count: <102 cfu/mL 
• 
Specified Microorganism(s): Absence of Escherichia coli (1 g or 1 mL) 
The CBD extract will be shipped and stored frozen. The final drug product will be prepared within 
24 hours of being given to the subject. Once prepared it will be kept at room temperature. The 
subject will take home the final drug product in 60 ml amber bottles and take it orally for up to 20 
days. The stability study will be carried out only at room temperature at the following time points: 0, 
1 week, 2 weeks, 3 weeks, 1 month, 2 months, and 3 months. Duplicate analyses will be performed 
at each time point. Microbial testing will be carried out at the 0 time point for both drug product and 
placebo and again at the end of one month to show that no change in bioburden occurred during the 
one month storage at room temperature. 
Three manufacturing batches will be prepared (validation lots). These will be subjected to analysis to 
show consistency of the manufacturing process. 
The analytical specification will be that the analytical value should be within 10% of the nominal 
concentration (i.e. 100 mg CBD/ml should analyze for 90-110 mg/ml). The analytical method is 
validated for Linearity, LOD, LOQ, accuracy and precision for both CBD and THC. 
The specification for the drug product will be: 
Appearance: Greenish-yellowish brown, oily solution 
Potency: CBD Concentration = 100mg/mL = 10% solution; ±10% variation in measured potency (90 
to 110 mg/mL) is allowed due to manufacturing and analytical variation.  
Other Cannabinoids: 
• 
THC not greater than 5 mg/mL (0.5% solution) 
• 
CBD:THC ratio not less than 20:1 
 
We will provide the FDA with a final report with statistical analysis. 
We will prepare oral solution of 100 mg/ml CBD (10% CBD) and 3.31 mg/ml THC (0.33% THC) in 
60 ml capacity amber glass bottles.  
Each bottle will have 30 or 40 mL depending on how much the subject weighs. 
• 
30 mL CBD Cannabis extract oral solution filled: Each bottle will have 5055 mg of extract 
placed in it (3000 mg CBD), filled to 30 mL mark with sesame oil. 
• 
40 mL CBD Cannabis extract oral solution filled: Each bottle will have 6740 mg of extract 
placed in it (4000 mg CBD), filled to 40 mL mark with sesame oil. 
Dosage Form and Strength 


33 
 
Pre-dilution dosage unit: CBD Cannabis Extract (depending on the subject’s weight it will contain 
either 3 or 4 gms CBD) 
Diluted Unit: CBD Cannabis Oral Solution (100mg/ml CBD) 
 
The FDA has approved our IND. The DEA has approved the PI’s amended DEA Schedule 1 license.  
Participants will be given bottles with 30/40 ml of study drug, at concentration of 100 mg/ml CBD or 
placebo and instructed how to take it. The study drug is best taken fasted, as food will increase Cmax 
and delay Tmax. The study drug could be taken with a small amount of food as needed if the 
participants experience nausea. The study drug will be taken orally, started at 1.25 mg/kg/day of 
CBD, once daily in the morning for four days, then increased to 2.5 mg/kg/day, twice daily at 
standard times, with a minimum of six hours apart (Figure 2 dosing plan). Participants are instructed 
to take it before breakfast (30 to 60 minutes) and the same before dinner. Participants are instructed 
not to drink grapefruit for seven days prior to the first dose of study medication and during the rest of 
the study. 
The study drug is taken as normal on the mornings of assessments. As far as practical, the same 
assessor carries out assessments at each visit. Assessment data are stored and not made available at 
subsequent visits. 
 
Figure 2: Dosing plan. 
 
 
Legend: V: Visit. D: Day. QD: once a day. BID: twice a day. PC: Phone call. 
V1: -28 to -1 day. Screening visit. 
V2: Day 1, Baseline visit: The first day of CBD 1.25 mg/kg/day. 4 weeks within screening visit. 
V3: Day 3/4, 1.25 mg/kg/day dose assessment visit: The third to fourth day of CBD 1.25 mg/kg/day. 
PC: Day 7-9, Questionnaire survey reminder phone call. The third to fifth day of CBD 2.5 
mg/kg/day. 
V4: Day 14, 2.5 mg/kg/day Dose Assessment Visit: The 10th day of CBD 2.5 mg/kg/day. 
V5: Day 28, Safety follow up visit, 2 weeks after stopping study drug. 
 
Participants take their routine anti-PD medication on the day of their clinical visit, and when ON (PD 
medications are working) the testing is done. 
CBD and metabolite levels will be measurements: Blood CBD and metabolite levels will be 
measured at screening visit, each dose assessment visit, and safety follow up visit. Urinary CBD and 
metabolites levels will be tested at dose assessment visits and safety follow up visit. 
Potential drug-drug interactions: 
The PI has worked with Jacci Bainbridge, PharmD, to study possible drug interactions. CBD 
concentrations and adverse events will be monitored in the presence of concomitant medications 
which are inhibitors of CYP3A4 and 2C19. 
There are many possible interactions, but some are more likely and clinically relevant. Thus, the 
PI will especially monitor for clinical symptoms that may be associated with these particular 
interactions. The following drugs may increase the level of CBD: fluoxetine, fluvoxamine, 
fluconazole, ticlopidine, and nefazodone. The following dugs may decrease the level of CBD: 
 
 
 
1day to 
4 weeks 
V1
1.25 
mg/kg/day 
QD 
D1-4 
V2
2.5 
mg/kg/day 
BID 
D5-9 
V3
 
2.5 
mg/kg/day 
BID 
D10-14 
PC 
 
 
0 mg/day 
2 weeks 
V4
V5


34 
 
carbamazine, phenytoin, phenobarbital, rifampin, and St. John’s Wort. The following drugs may 
interact with CBD to cause their levels to increase: alprazolam, clonazepam, lorazepam, 
oxazepam, temazepam, zolpidem, clopidigrel, narcotics (codeine, methadone, oxycodone, 
hydromorphone, morphine), cyclosporine A, tacrolimus, propranolol, and acetaminophen. 
Participants will be instructed not to take more than 1 gram per day of acetaminophen.  
 
CBD is a potent inhibitor of CYP2C19. The plasma level of clobazam, which is metabolized by 
CYP2C19, therefore is expected to increase if CBD is added. Clobazam, per Micromedix, causes 
somnolence (16-25%). In a recent study, Lancet Neurology 2016;15:270-278, using the a much 
higher dose of CBD study drug than as in our trial there was approximately twice as much 
somnolence AEs reported in participants on both CBD and clozabam than in participants on 
CBD and not clobazam. Thus clobazam will be exclusionary in this study. 
 
The following is additional information relevant to the population of this study, Parkinson disease 
(PD).  
CBD is metabolized by the hepatic CYP450 enzymes 2C19 and 3A4 and an inhibitor of these 
isoenzymes. Thus the expectation is that selegiline levels could increase. CBD may mildly induce 
the expression of 1A2, 2B6, and 3A4. Thus the expectation is that levels of rasagiline, ropinirole, 
and selegiline may decrease.  
CBD is a relatively potent inhibitor of UGT1A9 and UGT2B7 and has no significant effect on other 
UGT isoenzymes. The expectation is that the level of rotigotine may increase. 
 
CBD is highly protein bound, so rasagiline, selegiline, and rotigotine levels may increase transiently. 
Checking plasma concentration levels of these anti-PD medications is not a routine clinical practice. 
Thus the PI will monitor participants on these medications for clinical changes. The most important 
and likely adverse effects of a clinically significant increase in the level of selegiline is anxiety, 
dyskinesia, agitation, insomnia, and hallucinations. The most important and likely adverse effects of 
a clinically significant decrease in the levels of rasagiline, ropinirole, and selegiline is an increase in 
the motor symptoms of Parkinson disease, which are resting tremor, bradykinesia, rigidity, and 
postural instability. The most important and likely adverse effects of a clinically significant increase 
in rotigotine is low blood pressure, somnolence, and impulse control disorders. 
Instructions to Participants at the End of Each Stage: 
We will provide the following instructions about continued marijuana use at the end of the study to 
facilitate safety: 
Cannabis (marijuana) is composed of many substances. Street cannabis is high in 
tetrahydrocannabinol (THC), which causes the “high” feeling. Street cannabis has lower 
concentrations of cannabidiol (CBD). The cannabis preparations sold at dispensaries have various 
concentrations of THC and CBD. The ratio of THC to CBD plays a role in a preparation’s beneficial 
and adverse effects. Studies to date suggest that THC is especially risky in person with PD, because 
it may worsen thinking and coordination and cause psychiatric symptoms. The precise effects of all 
the substances in cannabis is unknown. Using marijuana should be under the supervision of your 
physician, with monitoring the symptoms of PD and other diseases, as well as the interactions of 
marijuana and other drugs you take. 
 
C.3 Randomization and drug dispensation: 


35 
 
Patients who consent will be stratified by age (40-60 and 61-80) and disease severity (H&Y 1-2.5, 3-
5) and divided into blocks of a few patients each, depending on order of recruitment. Equal numbers 
from each block will be assigned to CBD or placebo group in random order.  
Dr. Leehey, the PI, will obtain an amended DEA Schedule 1 license prior to the shipment of the 
study drug and all procedures of drug handling will be according to DEA specifications and protocol 
provided by University of Mississippi researchers. Briefly, designated study personnel will receive 
the study drug, do the formulation procedure, store it, measure and label it. The PI or PharmDs will 
dispense to the participant.  
 
C.4 Blinding assessment and Un-blinding procedures:  
Blinding assessment: 
Active drug and placebo will look and taste the same as much as possible. Participants and all study 
personnel except for Dr. Sillau, Dr. Bainbridge, and her fellow, are blinded. 
At the end of treatment phase visits, participants will be asked about the treatment allocation they 
think they were assigned. The answers are taken in forms with five responses of “strongly believe the 
treatment is drug,” “Somewhat believe the treatment is drug.” “Somewhat believe the treatment is 
placebo,” “Strongly believe the treatment is placebo,” and “Don’t know.”  
Un-blinding procedures: 
The identity of the treatment assigned to individual participants can be revealed in an emergency 
only. The PI is responsible for ensuring that the instructions on how to request un-blinding of 
treatment are stored safely, that their location is known, and that access is readily available to the 
relevant staff in case of an emergency. Dr. Sillau, the statistician will provide the information when 
un-blinding is requested by the PI. As a back-up, Dr. Sillau will provide a file of sealed envelopes to 
the PI, which is kept in a locked file in her office. The location is known to the PI, sub-I, and 
coordinator. A sealed envelope coded with each participant number is provided. In the event that Dr. 
Sillau is not available to provide break the blind the PI and designated staff can do so. 
A participant’s treatment assignment should only be un-blinded when knowledge of the treatment is 
essential for the safety of the participant. Un-blinding for any other reason will be considered a 
protocol deviation. 
 
C.5 Stopping rules: 
Note there are no interim analyses planned. 
Participant stopping rules: 
• If participant cannot tolerate the study drug at any dose level 
• if participant develops a CTCAE criteria grade 3 or 4 adverse event per that the Investigator 
determines is related the study drug 
• Pregnancy or breast-feeding  
• Requested by participant to terminate treatment 
• Failure by the participant to attend consecutive study visits 
• Participant is at significant risk of failing to comply with the provisions of the protocol as to 
cause harm to self or seriously interfere with the validity of the study results 
• At the discretion of the IRB, Food and Drug Administration (FDA) 
If a participant is withdrawn from the study, all efforts will be made to complete the early 
termination visit that includes efficacy assessments and safety follow-up. In addition, women of 
childbearing potential will have a post-study pregnancy test performed at the early termination visit.  


36 
 
Withdrawals and the reason for withdrawal will be tabulated by treatment group. The number and 
percentage of participants who complete the study will be summarized by treatment group. The 
number and percentage of participants who withdraw from the study will be tabulated by original 
treatment group and last treatment taken at time of withdrawal. Study medication discontinuations 
will be summarized in a similar fashion. 
 
Participants will be advised that they are free to withdraw from the study at any time. Reasons that 
participants may be withdrawn from the study include the following:  
Participant discontinued study medication and wishes to withdraw. 
Participant consent is withdrawn. 
Study stopping rules 
• Participants are unable to be recruited 
• Study drug becomes unavailable 
• Participants are unable to tolerate the study drug at any dose level  
• Discovery (from this or other studies) of an unexpected, serious, or unacceptable health 
hazard to participants, i.e., development of the same adverse event, CTCAE criteria grade ≥3, 
related to study drug in ≥2 participants 
• At the discretion of the IRB, Food and Drug Administration (FDA). 
 
C.6 Adverse events assessments: 
Adverse events will be classified according to the grades defined in the Common Terminology 
Criteria for Adverse Events (CTCAE). Any adverse event or abnormal laboratory test value that is 
serious  (see definition below) and occurs after administration of the investigational product will be 
documented by the Sponsor-Investigator within 24 hours of discovery of the event. 
Severity of Adverse Events  
The severity of each AE/SAE will be classified into one of five defined grades. The CTCAE displays 
Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general 
guideline:  
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2:  Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADLs. Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.  
Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLs. Self-care ADLs refer to 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.  
Grade 4:  Life-threatening consequences; urgent intervention indicated.  
Grade 5:  Death related to AE.  
The severity of the AE will be recorded in the appropriate section on the AE page of the CRF.  
Serious Adverse Events (SAEs) 
The evaluation of severity will be distinguished from the evaluation of “seriousness.” A severe event 
might not meet the criteria for seriousness and a serious event might be evaluated as mild or 
moderate. For example, a participant might have a severe headache that does not require 
hospitalization and is consequently not serious; or a participant might have a mild myocardial 
infarction that requires hospitalization and is therefore serious. 


37 
 
An SAE is any untoward medical occurrence at any dose that: 
• Results in death during the period of protocol-defined surveillance. Death due to PD will not be 
considered an SAE. However, if a patient requires hospitalization due to an AE related to PD, the 
specific sign or symptom leading to hospitalization will be reported as an SAE. If death due to 
PD occurs outside of hospitalization and is considered to be due solely to the patient’s PD, no 
SAE report is required. The death will be recorded as part of PD and patient disposition. 
• Is life-threatening (NOTE: The term “life-threatening” in the definition of “serious” refers to an 
event in which the participant, in the view of the Investigator, is at risk of death at the time of the 
event; it does not refer to an event that hypothetically might cause death if it was more severe). 
• Requires inpatient hospitalization or prolongation of existing hospitalization*. 
• Results in persistent or significant disability or incapacity. 
• Results in a congenital anomaly/birth defect. 
*Hospitalization: Outpatient treatment in an emergency room is not in itself an SAE, although 
the reasons for it might be (e.g., bronchospasm, laryngeal edema). Hospital admission and/or 
surgical operations planned before or during a study are not considered SAEs if the illness or 
disease existed before the participant was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study. It should be noted that for this study, 
participants with planned or anticipated surgery should not be enrolled into the study. 
Important Medical Events: Medical and scientific judgment will be exercised in deciding whether a 
case is serious in situations where important medical events may not be immediately life-threatening 
or result in death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical or surgical intervention to prevent one or more outcomes listed in the definition of 
serious. These should usually be considered as serious, and examples of such events are: 
• Angioedema not severe enough to require intubation but requiring intravenous hydrocortisone 
treatment 
• Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with N-
acetylcysteine 
• Intensive treatment in an emergency room or at home for allergic bronchospasm 
• Development of drug dependency or drug abuse. 
Unanticipated Adverse Events 
An unanticipated problem is any event or information that was unforeseen and indicates that the 
research procedures caused harm (including physical, psychological, economic, or social harm) to 
participants or others or indicates that participants or others are at increased risk of harm than was 
previously known or recognized. An “unexpected” adverse reaction is one in which the nature or 
severity of which is not consistent with information in the relevant source document(s). Until source 
documents are amended, expedited reporting is required for additional occurrences of the reaction.  
Relationship to Study Drug  
The relationship or association of the AE/SAE to study drug will be characterized as “related” or 
“not related.” An AE/SAE will be considered to be not related to the use of the study drug if any of 
the following criteria are met:   
• An unreasonable temporal relationship between administration of the product and the onset on 
the AE (e.g., the event occurred either before, or too long after administration of the product for it 
to be considered product-related);   


38 
 
• A causal relationship between the product and the AE is biologically implausible (e.g., death as a 
passenger in an automobile accident);   
• A clearly more likely alternative explanation for the AE is present (e.g., typical adverse reaction 
to a concomitant drug).  
Adverse events will be considered “related” to the use of the study drug if none of the “not related” 
criteria are met. The Investigator will use clinical judgment to determine the relationship of the 
AE/SAE to study drug. An AE/SAE may be related to the study drug, other concomitant 
medications, intercurrent illness, a procedure performed in the course of the study, or another reason. 
Among the potential etiologies, the Investigator will make a determination based on the most likely 
causal relationship. Alternative causes, such as the natural history of any underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the study drug 
will be considered. The Investigator will also take into account the Investigator’s Brochure in the 
causality assessment. There may be situations when an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Sponsor. However, the Investigator will 
make an assessment of causality prior to transmission of the SAE report to the Sponsor, as the 
causality assessment is one of the criteria used when determining regulatory reporting requirements. 
The Investigator may change the causality assessment in light of follow-up information by amending 
the SAE report accordingly. 
SAEs that are considered related (i.e., determined to be possibly, probably, or definitely related) to 
the investigational product by the Sponsor-Investigator will be followed until the event resolves or 
stabilizes. Any SAE that occurs after treatment completion, and is considered by the Sponsor-
Investigator to be related to the investigational product, will be documented and reported as 
appropriate. 
Reporting Serious Adverse Events to Regulatory Agencies 
Events meeting the following criteria will be submitted to the Food and Drug Administration (FDA) 
as expedited IND Safety Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report 
The Sponsor-Investigator will notify the appropriate review division at the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the Sponsor-Investigator to be possibly 
related to the use of the investigational product. An unexpected adverse event is one that is not 
already described in the investigational product’s Investigator Brochure. Such reports are to be 
telephoned or faxed to the appropriate review division at FDA and to the manufacturer of the 
investigational product within seven calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Sponsor-Investigator will notify the appropriate review division at the FDA, in a written IND 
Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related to the 
use of the investigational product.  
Written IND Safety reports will include an Analysis of Similar Events in accordance with regulation 
21 CFR § 312.32. All safety reports previously filed by the Sponsor-Investigator with the IND 
concerning similar events will be analyzed and the significance of the new report in light of the 
previous, similar reports commented on. 
Written IND safety reports with Analysis of Similar Events will be submitted to the appropriate 
review division at the FDA, and the manufacturer of the investigational product within 15 calendar 
days of first learning of the event, using FDA Form 3500A. 
Written IND Safety Reports will be submitted to the IRB(s) of record per IRB Guidelines. 
IND Annual Reports 


39 
 
The Sponsor-Investigator will provide annual reports to the appropriate review division at the FDA 
within 60 days of the IND’s anniversary date, until the IND is withdrawn or terminated. 
 
C.7 Risks of Study Drug: 
A review of 25 studies on the safety and efficacy of CBD did not identify significant side effects 
across a wide range of dosages, including acute and chronic dose regimens, using various modes of 
administration [Bergamaschi M.M., et al. 2011]. There are no rare but serious side effects reported. 
The most frequently occurring side effect was somnolence (i.e.drowsiness) (25%). Other side 
effects, in order of prevalence, include: diarrhea (19%), decreased appetite (19%), fatigue (13%), 
convulsion  (11%), increased appetite (9%), status epilepticus (8%), lethargy (7%), weight increased 
(7%), and weight loss (6%) [Devinsky O, et al. 2016]. Other side effects include extrapyramidal 
symptoms, increased prolactin levels, weight gain, increased serum concentrations of antiepileptic 
drugs, and elevated liver function tests.   
 
Table 6 and 7 show the adverse reactions of pure CBD, i.e., Epidiolex®.  
 
Table 6. Adverse events and treatment-emergent serious adverse events of purified CBD reported in 
pediatric treatment-resistant epilepsy (an open-label interventional trial, maximum dose 25-50 
mg/kg/day of CBD) [Devinsky O, et al. 2016] 
Adverse events (reported >5% of patients) 
N =162 
Somnolence 
41 (25%) 
Decreased appetite 
31 (19%) 
Diarrhoea 
31 (19%) 
Fatigue 
21 (13%) 
Convulsion  
18 (11%) 
Increased appetite 
14 (9%) 
Status epilepticus 
13 (8%) 
Lethargy 
12 (7%) 
Weight increased 
12 (7%) 
Weight decreased  
10 (6%) 
Drug concentration increased 
9 (6%) 
Treatment-emergent serious adverse events 
 
Status epilepticus 
9 (6%) 
Diarrhoea 
3 (2%) 
Weight decreased 
2 (%) 
Convulsion 
1 (<1%) 
Decreased appetite 
1 (<1%) 
Drug concentration increased 
1 (<1%) 
Hepatotoxicity 
1 (<1%) 
Hyperammonaemia 
1 (<1%) 
Lethargy 
1 (<1%) 
Unspecified pneumonia 
1 (<1%) 
Aspiration pneumonia 
1 (<1%) 
Bacterial pneumonia 
1 (<1%) 
Thrombocytopenia 
1 (<1%) 


40 
 
  
Table 7. Adverse events occurring with a frequency of greater than 10% in either trial group (RCT in 
120 children and young adults with the Dravet syndrome and drug-resistant seizures, 20 mg/kg/day 
of CBD) [Devinsky O, et al. 2017] 
System Organ Class and Preferred Term 
Cannabidiol (n=61) 
Placebo (n=59) 
Gastrointestinal 
 
 
    Diarrhea 
19 (31%) 
6 (10%) 
    Vomiting 
9 (15%) 
3 (5%) 
General 
 
 
    Fatigue 
12 (20%) 
2 (3%) 
    Pyrexia 
9 (15%) 
5 (8%) 
Infections: upper respiratory tract infection 
7 (11%) 
5 (8%) 
Metabolism: decreased appetite 
17 (28%) 
3 (5%) 
Nervous system 
 
 
   Convulsion 
7 (11%) 
3 (5%) 
   Lethargy 
8 (13%) 
3 (5%) 
   Somnolence 
22 (36%) 
6 (10%) 
 
D. Description, Risks and Justification of Procedures and Data Collection Tools: 
Patients could be uncomfortable about their survey of cannabis, drug, alcohol, and tobacco use that 
is administered during screening in both Stages. However, this information is essential for their 
safety, to check for history of addiction, and if this is found then the participant could be harmed by 
participating and thus would be excluded. In addition, this information is needed for scientific rigor. 
Federal funding sources are likely to want this information to understand the relevance and 
importance of future cannabis studies. The importance of having the information will be explained 
and the participant will be reminded that participation is voluntary.   
 
CBD’s effect on many aspects of PD are being studied, besides the primary and major secondary 
outcome measures. This makes the visits longer and may be tiring for some participants. To 
minimize discomfort participants will be offered sufficient breaks and maximal efforts for efficiency 
will be made to minimize visit time. The reason for the many assessments is twofold. First, PD is a 
complex disorder with many different disabling symptoms, and secondly, it is prudent to maximize 
the information from this study. Studies on cannabis are sorely needed, since many PD patients are 
taking this potentially dangerous drug as it becomes more available. Access is becoming more 
available throughout the US as more states are considering legalizing use of medical and recreational 
marijuana. Besides this lack of vital information, obtaining funding and getting through all the 
regulatory steps required for study of cannabis is very hard, thus we want to obtain maximal 
information when such a study (as this one) can be done. This information is vital to guide future 
studies. 
To minimize the risk in the study, the following procedures will be complied with: 
1. The study will be conducted in compliance with the COMIRB approved protocol, GCP, and the 
applicable regulatory requirements. 
2. The study will be overseen by COMIRB and a Data Safety Monitoring Board (DSMB) at 
University of Colorado. 
3. Each patient will be closely monitored by frequent clinic visits during study drug treatment 
phases and the 7th day following discontinuation of study drug as described in Section C to 


41 
 
monitor for adverse effects or withdrawal, as well as changes of medical history and concomitant 
medications.  
4. Adverse events and serious adverse events will be reported from the time of study drug 
administration until the last study visit or death, whichever occurs first, according to mandated 
guidelines. 
5. All adverse events and serious adverse events will be followed until resolution (or return to 
baseline status), or until the condition stabilizes or is otherwise explained, or until participant 
dies or is lost to follow-up. 
6. Safety assessments are comprehensive and include vital signs, history and physical examination, 
concomitant medications collection, EKGs, safety labs (Hematology, Hemoglobin A1C, 
Complete Metabolic Profile and Liver Function Tests), blood and urinary cannabis and 
metabolites analysis, MoCA, QUIP-RS, C-SSRS, NPI, SCOPA-sleep, Anxiety short form, 
Depression short form, Emotional and behavioral dyscontrol short form, Fatigue Severity Scale, 
Pain Intensity and Interference short form, study drug compliance check, adverse event check, 
and urine and blood pregnancy testing. 
 
We will follow the FDA’s Guidance for evaluating and monitoring potential drug-induced 
hepatotoxicity. Participants with stable liver disease can be included if they have a normal total 
bilirubin and prothrombin time/INR at baseline. Liver function tests (ALT, AST, ALP and bilirubin) 
will be drawn at baseline and at each visit while participants are on the study drug. In addition, if 
these labs are abnormal at the end of the study visit they will be repeated at the safety follow up visit 
two weeks later and repeated until back to baseline values. During each visit that assesses the effects 
of the study drug, nonspecific symptoms of Drug Induced Liver Injury (DILI) will be checked, e.g., 
anorexia, nausea, fatigue, right upper abdominal discomfort, and vomiting. If symptoms indicative 
of DILI occur, the participant will return to clinic immediately for measurement of laboratory signs 
of hepatic injury, regardless of when the next visit or monitoring interval is scheduled. At any time if 
aminotransferase enzymes are greater than three times the upper limit of normal (ULN), we will 
repeat ALT, AST, ALP, and bilirubin within 48-72 hours. If symptoms persist or repeat testing 
shows aminotransferase >3xULN for participants with normal baseline measures or twofold 
increases above baseline values for participants with elevated values before drug exposure, we will 
initiate close observation to determine whether the abnormalities are improving or worsening. Per 
the FDA, close observation includes:  
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the trial drug has been 
discontinued and the participant is asymptomatic.  
• Obtaining a more detailed history of symptoms and prior or concurrent diseases.  
• Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets.  
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
NASH; hypoxic/ischemic hepatopathy; and biliary tract disease.  
• Obtaining a history of exposure to environmental chemical agents.  
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin).  
• Considering gastroenterology or hepatology consultations.  
 


42 
 
We will gather further history as recommended. Unless we find that the repeat testing shows the 
aminotransferase levels decline to baseline, we will consult the UCH Hepatology team to determine 
further management. 
 
The FDA advises that since transient fluctuations of ALT or AST are common and progression to 
severe liver injury or failure is uncommon, automatic discontinuation of trial drug upon finding a 
greater than 3xULN elevation of ALT or AST may be unnecessary. The decision of whether to stop 
the study drug will be affected by information on related drugs, the accumulating clinical experience, 
the clinical status of the patient, and many other factors. We will consult the UCH hepatology 
service and keep the following FDA guidance in mind. The FDA states that discontinuation of 
treatment should be considered if:  
ALT or AST >8xULN  
ALT or AST >5xULN for more than two weeks  
ALT or AST >3xULN and (TBL >2xULN or INR >1.5)  
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)  
 
Data collection tools:  
To protect the privacy of patients, the data collected in the study is stored completely de-identified. 
A code will be linked to the information provided, and answers are entered into a computer database 
using this code. No personal identifiers will be linked to the participant’s information in the 
database. All of this information in the computer is password protected. The code will be linked to 
the participant’s University of Colorado Hospital medical record number in a separate computer 
database. The PI will keep the surveys completed on paper in a locked cabinet. 
 
 
E. Potential Scientific Problems:   
To maximize scientific integrity this study was peer reviewed by the Colorado Department of Health 
and Safety (CDPHE) before receiving funding. We do not expect problems with recruitment because 
of the high level of interest and publicity regarding cannabis research, especially the CDPHE funded 
studies. In addition, we have a large population of PD patients, since we see over 2000 PD patients 
in our Movement Disorders clinics annually, including UCH, VAMC, and Denver Health, and will 
have 14 movement disorders providers assisting recruitment.  
 
F. Data Analysis Plan:   
Intention to treat concept is followed. In order to minimize data entry errors a double data entry 
system will be used.  
If study participant agrees, the de-identified data would be shared within CDPHE Marijuana grantee 
consortium for future research.   
The analysis will be performed in accordance with the analysis plan devised prior to unblinding. 
Baseline variables will be examined for equality between the two sequence groups. The primary, 
secondary and exploratory outcomes will be analyzed as below from baseline to the end of 2.5 
mg/kg/day. 
 
Primary Specific Aim: To evaluate the efficacy of CBD on motor symptoms in PD. 
The data will be analyzed to compare two randomized independent samples, CBD and placebo. 
Means and confidence intervals will be presented for the pre and post outcome values by treatment, 


43 
 
and for the change scores between pre and post treatment within treatment group. A two independent 
sample T-test will compare the means of the change scores between the treatment groups. We will 
test the null hypothesis of no treatment effect. Longitudinal regression models will be fit for further 
analysis, including adjusting for covariates if necessary.   
Secondary Specific Aim is to examine safety and tolerability of CBD and the effect of CBD on 
severity and duration of intractable tremor and other symptoms in PD. 
 
Safety and tolerability and will be assessed in five ways: 
1.  Frequency of study-related adverse events at each dose level collected at study visits. 
Analysis (frequency of study-related adverse events at each dose level in the two groups, 
treatment vs. placebo) will be mostly descriptive and proportions and confidence intervals 
will be calculated. Contrasts involving repeated measures on the same participants can be 
tested with McNemar’s test (for two correlated proportions) or GEE models/GLMMs. 
Contrasts for independent data can be tested with standard two sample proportions test and 
with GLMs. Proportions, logistic regression, and relative risk regression can be applied to 
binary outcomes over a fixed period of time, and Poisson models can be applied to counts or 
events over time. 
2. Vital signs, orthostatic blood pressures, physical exam, EKG, and labs (hematology, 
complete metabolic profile, urinalysis) will be done during study visits. For vital signs and 
labs, data will be analyzed as a simple two-period trial. Means and confidence intervals will 
be presented pre and post treatment by treatment group, and for the change scores by 
treatment group. A two independent sample T-test will compare the means of the change 
scores between the treatment groups. More complex situations can be analyzed with 
longitudinal regression models. 
3. Standardized assessment tools (MoCA, Cognition assessment battery, Anxiety short form, 
NPI, SCOPA-Sleep, ISI, DBAS-16, Pittsburgh Sleep Quality Index, RBDSQ, QUIP-RS, C-
SSRS, Depression short form, Emotional Behavioral dyscontrol short form, Fatigue severity 
scale, MDS UPDRS, UDysRS, Pain Intensity 3a short form and Pain Intensity 4a short form, 
IRLS, PDQ-39 and EQ-5D-5L) and lab tests, the data will be analyzed as a simple two-
period trial. Means and confidence intervals will be presented pre and post treatment by 
treatment group and for the change scores by treatment. A two independent sample T-test 
will compare the means of the change scores between the treatment groups. More complex 
situations can be analyzed with longitudinal regression models.   
4. Proportion of participants who drop out of the study due to study drug intolerance. Analysis 
(proportions of participants who drop out of the study due to study drug intolerance in the 
two treatment groups) will be mostly descriptive, and proportions and confidence intervals 
will be calculated. Proportion differences between groups can be compared with the standard 
test. 
 
Exploratory Outcome Measures: The efficacy of CBD on cognition, psychosis, sleep, daytime 
sleepiness, mood, fatigue, pain, impulsivity, other motor and non-motor PD signs, restless legs 
syndrome, REM sleep behavior disorder, quality of life, and plasma levels of cytokine are evaluated 
using the aforementioned assessment tools. The change from baseline to end of 2.5 mg/kg/day is 
compared. 


44 
 
 
Exploratory analyses: To study the efficacy of CBD on cognition, anxiety, psychosis, sleep, daytime 
sleepiness, mood, fatigue, pain, impulsivity, other motor and non-motor PD signs, restless legs 
syndrome, REM sleep behavior disorder, plasma levels of cytokine, and seborrheic dermatitis.  
 
Exploratory outcomes include assessments of cognition, anxiety, psychosis, sleep, daytime 
sleepiness, mood, fatigue, pain, impulsivity, other motor and non-motor PD signs, restless legs 
syndrome, REM sleep behavior disorder, and plasma levels of cytokine. Continuous outcomes will 
be analyzed in the same way as tremor. Transforms or non-parametric methods will be applied as 
necessary. Non-continuous outcomes will be analyzed with generalized estimating equations models, 
generalized mixed models, and McNemar’s test for binary outcomes.   
 
Sample Size Justification 
Using preliminary data we estimate a standard deviation for the within treatment UPDRS Motor 
change scores, post treatment compared to baseline, of 6.72, and a correlation between the paired 
observations of the change score of 0.75. Consistent with the preliminary data we anticipate a mean 
baseline UPDRS Motor score of 23, so a 25% treatment effect would have a magnitude of 5.75, less 
than the within treatment mean change score of magnitude 6.10 observed in the preliminary data. 
The estimated standardized effect size is 0.856. Therefore, the two independent samples T-test, 
testing for a between treatment difference on the within treatment UPDRS Motor change scores, at 
alpha = 0.05, would require a total sample size of 46 patients for 80% power, and 60 patients for 
90% power. Compensating for the possibility of 20% drop out, we would need to recruit 58 patients 
for 80% power, and 75 patients for 90% power. Thus we plan to recruit 75 patients with a goal of 
having at least 60 patients complete the study. 
 
Since other outcomes are either descriptive and/or exploratory, and sample size is limited, 
adjustment for multiple testing adjustments are not planned across different outcome variables. 
 
G. Summarize Knowledge to be Gained:   
Marijuana is one of the most used alternative medications. Since it became legal and readily 
available in Colorado, Parkinson disease (PD) and other movement disorders patients have been 
trying it, usually without the knowledge of or supervision of their neurologist. This study will 
promote the safety of our patients and provide data useful in evaluating the effect and safety of CBD 
on tremor, cognition, anxiety, psychosis, and other symptoms, including sleep, impulsivity, 
suicidality, mood, fatigue, restless legs syndrome, pain, bradykinesia, rigidity, balance, and 
dyskinesia in PD patients. Data from this study are essential to aid in designing future marijuana 
research.   
 
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48 
 
Nadulski, T.; Sporkert, F.; Schnelle, M.; Stadelmann, A.M.; Roser, P.; Schefter, T.; Pragst, F. 2005b. 
Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS 
in plasma after oral application of small doses of THC and cannabis extract. J. Anal. Toxicol. 29: 
782–789. 
Nagatsu T, Mogi M, Ichinose H, Togari A. 2000. Cytokines in Parkinson’s disease. J Neural Transm 
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Narimatsu S, Watanabe K, Yamamoto I, Yoshimura H. 1990. Inhibition of hepatic microsomal 
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50 
 
Appendix 1: Schedule of Events 
schedule of events 
  
screening 
baselin
e  
Treatment Period 
Safety Followup 
week (number of days) 
  
  
1 
1-2 (14 days) 
3 
3 
3 to 4 
(10 
days) 
4 
Days 
< 
negativ
e 28 
negativ
e 14-3 
1 (s) 
1-
3(i) 
4 
5-
8(i
) 
9* 10
-
12  
13(i)(
s) 
14 
(+4) 
(l) 
15-
17 
18
-
21 
22-27 
(i) 
28 
(+/- 
4)  
Dosage of CBD or placebo 
mg/kg/day 
0 
  
1.25  
(take 
the 
first 
dose in 
clinic) 
1.2
5 
1.2
5 
2.5 2.
5 
2.
5 
2.5 
2.5 
(take 
the 
study 
drug 
upon 
arriv
al at 
clinic
)  
0 
0 
0 
0 
clinical visit 
1 
  
2 
  
3 
  
  
  
4 
  
  
  
5 
telephone call 
  
  
  
  
  
  
 1 
  
  
  
2 (j) 3 
(j) 
  
  
Informed consent 
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Criteria 
√  
  
√ (y) 
  
  
  
  
  
  
  
  
  
  
  
Demographics 
√ ( r) 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History (a) 
√( r) 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
  
  
√(y) 
√ 
 
  
  
√ 
√ 
√ 
  
√(z) 
Family medical history 
√ ( r) 
  
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
√ ( r) 
  
√(y) 
 
√ 
 
 
  
  
√ 
√ 
√ 
  
√(z) 
Randomization 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
  
Blinding assessment 
  
  
  
  
√ 
  
  
  
  
√ 
  
  
  
  


51 
 
Study drug compliance 
check 
  
  
  
  
√ 
  
  
  
  
√ 
  
  
  
  
Dispense study drug and 
instruction 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
  
Adverse Events (b) 
  
  
√ 
  
√ 
  
  
√ 
√ 
√ 
  
√(z) 
Abuse-related Aes 
√( r) 
  
  
  
√ 
  
  
√ 
√ 
√ 
  
√ 
Formal drug interaction 
assessment 
  
√ 
  
  
  
  
  
  
  
  
Vital Signs (c)  
√ 
  
√ (n) 
  
√ 
(n) 
  
  
  
√(p) 
  
  
  
√ 
Orthostatic Blood Pressures 
check 
√ 
  
√ (n) 
  
√ 
(n) 
  
  
  
√(p) 
  
  
  
√ 
Height and Weight 
√ 
  
√ 
  
√  
  
  
  
  
√  
  
  
  
  
Complete Physical Exam (d) 
√ 
  
  
  
√  
  
  
  
  
√ 
  
  
  
√ 
Neurological exam (e) 
√ 
  
  
  
√  
  
  
  
  
✓ 
  
  
  
  
Brief physical exam (heart 
and lung auscultation) 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
  
Hematology (f) 
√ 
  
  
  
√  
  
  
  
  
√  
  
  
  
√ 
(m) 
Hemoglobin A1C 
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
Complete metabolic profile + 
LFTs (g) 
√ 
  
  
  
√  
  
  
  
  
√  
  
  
  
√ 
(m) 
Plasma cytokines test 
√ 
  
  
  
  
  
  
  
  
√ 
  
  
  
  
Blood cannabis analysis 
√ 
  
  
  
√ 
(o) 
  
  
  
  
√ (o) 
  
  
  
√ 
Urinalysis (h) 
√ 
  
  
  
√ 
  
  
  
  
√ 
  
  
  
√ 
(m) 
Urine drug (THC) test 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
  
Urinary CBD and 
metabolites levels test (q) 
  
  
  
  
√ 
  
  
  
  
√ 
  
  
  
√ 
Urine cups dispense and 
urine collection instruction 
  
  
√ 
  
 √ 
  
  
  
√ 
  
  
  
  


52 
 
ECG (12-LEAD) 
√ 
  
  
  
√ 
  
  
  
  
√ 
  
  
  
√ 
(m) 
Serum Pregnancy Test (for 
women childbearing 
potential) 
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
Urine Pregnancy Test (for 
women childbearing 
potential) 
  
  
√ 
  
√ 
  
  
  
  
√ 
  
  
  
√ 
Assessment of past 
marijuana use 
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug, alcohol and tobacco 
abuse screening test 
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
MOCA  
√ 
  
  
  
√ 
  
  
  
  
√ 
  
  
  
Cognitive assessment battery 
  
  
√ 
  
  
  
  
  
  
√ 
  
  
  
  
Alertness test (Stanford 
Sleepiness Scale SSS) 
  
  
√(t) 
(y) 
  
  
  
  
  
  
  
  
  
  
  
MDS-UPDRS part III 
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
MDS-UPDRS (all 4 parts) 
  
  
√ 
  
√ 
  
  
  
  
√ 
  
  
  
√ 
H & Y rating  
√ 
  
√ 
  
√ 
  
  
  
  
√ 
  
  
  
√ 
Schwab & England Daily 
Activities Scale 
 √ 
  
√ 
  
√ 
  
  
  
  
√ 
  
  
  
 √ 
TUG 
 
 
√ 
 
√ 
 
 
 
 
√ 
 
 
 
 
QUIP-RS  
√ 
  
  
  
√ 
  
  
  
  
√ 
  
  
  
√ 
C-SSRS 
√( r) 
  
√(y) 
  
√ 
  
√ 
  
  
√ 
  
  
  
√(z) 
RBDSQ  
  
  
√(y) 
  
√ 
  
  
  
  
√ 
  
  
  
√(z) 
NPI 
√( r) 
  
  
  
√ 
  
  
  
  
√ 
  
  
  
√(z) 
Anxiety short form 
  
  
✓(y) 
  
√ 
  
√ 
  
  
√ 
 
 
  
√(z) 
Depression short form 
  
  
✓(y) 
  
√ 
  
√ 
  
  
√ 
 
 
  
√(z) 
Emotional and behavioral 
dyscontrol short form 
√( r) 
  
  
  
√ 
  
√ 
  
  
√ 
 
 
  
√(z) 
SCOPA-sleep  
  
  
✓(y) 
  
√ 
  
√ 
  
  
√ 
 
 
  
√(z) 
IRLS 
  
  
√(y) 
  
√ 
  
  
  
  
√ 
  
  
  
√(z) 


53 
 
Fatigue severity scale 
  
  
✓(y) 
  
√ 
  
  
  
  
√ 
  
  
  
√(z) 
Pain intensity and 
interference short form 
  
  
✓(y) 
  
√ 
  
  
  
  
√ 
  
  
  
√(z) 
Bladder function-OABSS 
  
  
√(y) 
  
√ 
  
  
  
  
√ 
  
  
  
√(z) 
PDQ-39 
  
  
√(y) 
  
√ 
  
  
  
  
√ 
  
  
  
√(z) 
EQ-5D 
  
  
√(y) 
√ 
√ 
  
  
√ 
 
 
  
√(z) 
CGI 
  
  
√ 
  
√ 
  
  
  
  
√ 
  
  
  
  
PGI-I 
  
  
√ 
  
√ 
  
  
  
  
√ 
  
  
  
  
PGI-C 
  
  
  
  
√ 
  
  
  
  
√ 
  
  
  
  
Unified Dyskinesia Rating 
Scale (UDysRS) 
  
  
√ 
  
√ 
  
  
  
  
√ 
  
  
  
√ 
NMSS 
  
  
√(y) 
  
√ 
  
  
  
  
√ 
  
  
  
√(z) 
Dermatology Intake Form 
  
  
√(y) 
  
  
  
  
  
  
  
  
  
  
  
DLQI 
  
  
√(y) 
  
  
  
  
  
  
√ 
  
  
  
  
Insomnia Severity Index 
(ISI) 
  
  
√(y) 
  
√ 
  
  
  
  
√ 
  
  
  
  
Modified Dysfunctional 
Beliefs and Attitudes about 
Sleep Questionnaire (DBAS-
16) 
  
  
√(y) 
  
√ 
  
  
  
  
√ 
  
  
  
  
Pittsburgh Sleep Quality 
Index 
  
  
√(y) 
  
√ 
  
  
  
  
√ 
  
  
  
  
Home diary dispense & 
instruction 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
  
Home diary collection & 
review 
  
  
  
  
√ 
  
  
  
  
√ 
  
  
  
  
Tremor constancy and 
amplitude measure (k) 
√ 
  
√ 
  
√ 
  
  
√ 
  
√ 
  
  
  
  
Tremor measure device 
dispatched and instruction 
√ 
  
√ 
  
  
  
  
  
  
  
  
  
  
  
PSG equipment set up and 
instruction 
  
√ (x) 
  
  
  
  
  
  
√ (u) 
  
  
  
  
  


54 
 
Patient Instruction sheet for 
At-Home Sleep Monitoring 
Test dispense 
 
√ (x) 
 
 
 
 
 
 
√ (u) 
 
 
 
 
 
Morning Daytime 
Dysfunction Questionnaire 
(v) 
 
√ 
 
 
 
 
 
 
√ 
 
 
 
 
 
Sleep Diary (v) 
 
√ 
 
 
 
 
 
 
√ 
 
 
 
 
 
PSG equipment and data 
collected (w) 
  
  
√ 
  
  
  
  
  
  
√ 
  
  
  
  
skin evaluation (photo of 
central face) 
  
  
√ 
  
  
  
  
  
  
√ 
  
  
  
  
* Questionnaire reminder phone call on the 3rd to 5th day of 1.25 mg/kg BID. 
Note: regarding the rows of days and weeks, it is variable, because of note  (l). 
a. A complete medical history (including PD history, mental health history, alcohol and drug use) will be obtained from the subject 
at the Screening Visit and recorded on the appropriate CRF. The medical history and other enrollment criteria will be reviewed and 
updated at the Baseline/Day 1 visit to determine continued eligibility for the study. 
b. Adverse events will be recorded from the time that the study subject signs the consent form. Any subject with an ongoing AE will 
be followed until the AE is resolved, returns to baseline or deemed stable by the investigator. 
c. Vital signs obtained after the subject has been sitting for at least 5 minutes.  
d. Complete PE to include: skin, head-neck, eyes-ears-nose-throat, lungs-chest, heart, abdomen, extremities, neurological. 
e. Neurological exam. 
f. Hematology consists of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration 
(MCHC), red blood cell count (RBC), white blood cell (WBC) count, WBC differential (absolute), and numerical platelet count. 
g. Serum chemistry (fasting not required) consists of alkaline phosphatase, albumin, blood urea nitrogen, calcium, carbon dioxide, 
chloride, creatinine (MDRD formula for eGFR, to be done by the central laboratory), glucose, potassium, alanine aminotransferase, 
aspartate aminotransferase, sodium, total bilirubin, and total protein, GGT. 
h. Urinalysis dipsticks including leukocytes, specific gravity, pH, protein, ketones, glucose, nitrite, blood, urobilinogen, and 
bilirubin. If nitrite, blood, or protein tests are positive, a microscopic examination will be performed at the central laboratory. 
i. Call patient to remind them the clinical visit next day 
j. Call patient to collect adverse events and information of signs of withdrawal 


55 
 
k. Tremor time percentage and amplitude will be measured by a portable device and laptop. Subject will measure it at home 2 days 
after screening visit, 3 days before baseline visit, 3 days prior to each dose assessment visit, twice a day (2 hours after breakfast 
dose and 2 hours after dinner dose), 90 seconds each measurement. Tremor will also be measured at clinic, twice at screening visit, 
2 hours after taking study drug at baseline and each dose assessment visit.  
l. Treatment assessment visit can occur on 10 (+4) days for each dose. 
m. Hematology, chemistry, urinalysis and EKG will be done if there was a clinically significant change at the high dose evaluation 
visit compared to baseline visit. 
n. Subject will be monitored and vital signs will be checked again at before and 1 hour after taking the study drug. 
o. Blood drawn will be performed 3 hours after taking the study drug of the clinical visit day. 
p. Subject will be monitored and vital signs will be checked at before and 1 and 3 hours after taking the study drug. 
q. Clean catch urine collection after taking the study drug. Urine is collected in a 500 mL container and stored in 3-4 small cups 
(120 mL, fill up to 3/4).  
r. Procedures can be done remotely after onsite screening visit  
s. Phone call to remind patient to measure tremors at home for consecutive 3 days before the next clinic visit. 
t. Alertness test will be done before and 3 hours after taking study drug. 
u. Home sleep test will be done after at least 7 days on the max dose and until (including) the 3rd night before 2.5 mg/kg/day dose 
assessment visit. 
v. Morning Daytime Dysfunction Questionnaire and Sleep diary will be done within the first 30 minutes of waking after home sleep 
test. 
w. PSG equipment and data collected on the next day of home sleep test or at baseline or 2.5 mg/kg/day dose assessment visit 
x. The sleep study before the baseline visit is to be done from 14 to 3 nights before baseline visit. 
y. Procedures can be done remotely , between screening and onsite baseline visit 
z. procedures can be done remotely 1-3 days prior to or after safety follow up visit 
 
 
 
 
 


56 
 
Appendix 2: Myo tremor measurement guide 
RESTING STATE TREMOR DETECTION 
Procedures: 
1. Plug the USB cable into laptop. 
2. Strap the device to your hand (tremor dominant), with device on top of hand and cable protruding from the front of the device. 
3. When it is connected, click the Icon “tremor” to run the program.  
5. Use the dropdown menus to specify the time of your last dose. Provide the hour, minute, and AM/PM. Then click “Okay” to accept 
this entry and move on to the main program. 
6. Click start to begin collecting data. 
7. You will be shown an example of the hand movement to mimic: 1) finger tapping, 2) supination/pronation, and 3) ‘screwing in a 
lightbulb’. For each sequence you be told to ‘START’ and ‘STOP’. When the last sequence has run the program will indicate 
‘COMPLETE’. 
8. Close the program (click the X button on the upper right corner) to finish. 
 
Integrator Guide 
Contents 
1 
Introduction 
2 
Prerequisites 
3 
Setup and Installation 
4 
Using the Package 
5 
Options File 
 
  
1 
Introduction 
This Integrator Guide is the main technical reference for the recipients of the TremorGUI MATLAB package. This guide will walk 
through the  


57 
 
2 
Prerequisites 
The recommended system configuration for this package is a computer that is no more than 2 years old running Windows 7/8/10. 
Older machines might work as well, but it’s possible that the hardware may not support some required features. This package will not 
work with operating systems that are not 64 bit Windows (e.g. Mac OS or Linux). 
3 
Setup and Installation 
Begin this setup locating the provided package archive named Tremor_YYYYMMDD_hhmm.zip. 
1. 
Move this ZIP archive to a convenient location in your user profile such as the Desktop: 
C:\Users\<username>\Desktop\ 
 
  
2. 
Extract the ZIP archive here. This is described in detail for the default Windows Explorer extractor in Windows 7. If you have 
a different archive manager program, the steps may differ slightly. 
First double click the desktop icon. Then click on “Extract all files” 
 
Next click “Extract” to extraxt the archive to the standard location and show the files when the operation completes. 


58 
 
 
Finally, you’ll see the resulting folder. 
 
 
Important: The Tremor directory contents and the Tremor shortcut place on the desktop are written without checking for existing files 
of the same name. Verify that conflicts do not exist before performing this step! 
Note: If the above steps [partially] fail, the user may need to perform them manually and/or request support to repair the installation. 
1. 
Launch \Tremor.exe by double clicking its shortcut icon on the Desktop 


59 
 
 
2. 
Use the dropdown menus to specify the time of your last dose. Provide the hour, minute, and time of day (AM/PM). Then click 
"Okay" to accept this entry and move on to the main program. 
 
3. 
Click start to begin collecting data 
 
Note: The current dataset can be discarded by clicking the same button again to "Restart" the current trial. 
Note: There is no option to cancel collection. If this is desired, then close the program and begin again. 
4. 
Perform the distraction task as instructed. 
Note: Upon completion of a trial, the program will automatically save the data in multiple CSV files within the \private\data directory. 
5. 
Export data by clicking the Export button. 


60 
 
 
The following occurs: 
• 
All individual CSV files from \private\data are added to a new ZIP archive stored at the same location. 
• 
The ZIP archive is named with time/date stamp range indicated the earliest and latest data files it contains. The application 
name and user tag from one of the data files is prepended to the ZIP archive name. 
• 
The ZIP archive is saved primarily in the \private\data direcrory 
• 
The user is then prompted to select a location on the computer where a copy of the ZIP is also saved. The default location is 
the user's Desktop directory. This can be reconfigured using TremorOpts.txt 
When prompted, select a location to save the exported data archive. The default location is the Desktop. Click Save to save the data. 
 
6. 
Close the program to finish. 
5 
Options File 


61 
 
Tremor test: 
Device: recording device, USB charging cable, USB hard lock, a connector allows you to transfer information from the device to the 
computer. 
 
 


62 
 
Appendix 3: Dermatology Photography Protocol 
1. Ensure the patient did not apply make-up prior to having their picture taken. If the patient is wearing make-up, please make a note of this 
and have the patient remove make-up from the nasolabial folds (eye make-up is ok). 
2. Have patient remove any jewelry including necklace, scarves, glasses, hat.  
3. If needed, place headband to pull hair away from forehead 
4. Position patient away from a direct light source and standing against a wall of neutral color 
5. Instruct patient to have a relaxed facial expression with closed eyes and neutral lips 
6. Stand approximately 1.5m from the patient with the camera in portrait position 
7. Confirm camera settings- flash on, portrait orientation, and position camera in the same plane as the participants face.  
8. Give instructions like, “slowly move your chin down” or “slowly turn your nose to the left” to achieve the desired pose.   
9. Take 3 photos. Photos of the left and right side of the patient’s face should span from the ear to nose in horizontal plane, and from the 
forehead to chin in the vertical plane. From center, include both patient’s ears, forehead and chin. (see figure below) 
10. Take additional photos of the ears and if one or more is out of focus 
11. Upload photos to drive 
 
Figure:  
 
 
        
 
 
(a) right side 
(b) center 
(c) left side- not shown 


63 
 
Appendix 4: CBD Cannabis Extract Certification of Analysis 
 
 
 


64 
 
Appendix 5
 
If subject is on this & CBD 
(which is metabolized by this 
enzyme) is added, the CBD 
level may be reduced
If subject is on this & CBD (which 
is metabloized by this enzyme) is 
added then the CBD level may be 
higher
If subject is on this & CBD (which 
is metabolized by this enzyme) is 
added, the CBD level may be 
reduced
If subject is on this & CBD 
(which is metabloized by this 
enzyme) is added then the CBD 
level may be higher
Add CBD (which inhibits this 
enzyme) and the drug level may 
be increased
Add CBD (which inhibits this 
enzyme) and the drug level may 
be increased
Add CBD (which inhibits 
this enzyme) and the 
drug level may be 
increased
Add CBD (which 
inhibits this enzyme) 
and the drug level may 
be increased
If subject is on this & 
CBD (which is 
glucurondated  by this 
enzyme) is added then 
the CBD level may be 
higher
If subject is on this & 
CBD (which is 
glucurondated by this 
enzyme) is added then 
the CBD level may be 
higher
If subject is on this & 
CBD (which is 
glucurondated by this 
enzyme) is added then 
the CBD level may be 
higher
If subject in on CBD 
and starts any of these 
medications, CBD 
levels may decrease 
(CBD is glucurondated 
by this enzyme)
If subject in on CBD 
and starts any of these 
medications, CBD 
levels may decrease 
(CBD is glucurondated 
by this enzyme)
Highly Protein Boud 
drugs (serum 
concentrations can 
fluctuate between 
both drugs)
CYP 3a4 inducers
CYP 3a4 inhibitors
CYP 2c19 inducers
CYP 2c19 inhibitors
CYP 3a4 substrates
CYP 2c19 substrates
UGT1A9 substrates
UGT2B7 substrates
UGT1A7 inhibitors
UGT1A9 inhibitor
UGT2B7 inhibitor
UGT1A9 Inducers
UGT2B7 Inducers
Highly Protein Bound 
Carbamazepine
Amiodarone
Aminoglutethimide
Chloramphenicol
Alfentanil (Alfenta)
Aripiprazole (abilify)
Acetaminophen
Azidothymidine
--
Cyclosporin A
ketoconazole
--
Gancyclovir
Phenobarbital
armodafinil
alprazolam
Artemisinin
amitriptyline
Alfuzosin (Uroxatral)
Carisoprodol (Soma)
diclofenac
clofibrate
Milk Thistle (Silymarin) valproic acid
Phenobarbital
Phenytoin
bosentan
amlodipine
phenobarbital
armodafinil
Almotriptan (Axert)
Citalopram (Celexa)
ethinyl estidol
clorampehnicol
Niflumic acid
spironaldactone
Rifampin
Rasagiline
cisplatin
amprenavir
Carbamazepine (eg. Tegretol)
carbamazine
Alprazolam (Xanax)
Clobazam (Onfi)
flavipirido
Codeine
Tacromlimus (Prograf) canreone
Tobacco Smoking
Rotigitine
cyclophosphamide
Anastrozole
Phenytoin (eg. Dilantin)
Cimetidine (Tagamet)
Amiodarone (Cordarone)
Clomipramine (Anafranil)
ibuprofen
Cyclosporin A
Amitryptline
Selegiline
Dexamethasone
aprepitant
Primidone
Clopidogrel (Plavix)
Amlodipine (Norvasc)
Clopidogrel (Plavix)
kampferol
Cyclosporin A
Ketoconazole
Valproic Acid
efavirenz
atanazanavir
Rifampin (eg. Rifadin)
Delavirdine (Rescriptor)
Aprepitant (Emend)
Clozapine (Clozaril)
ketoprofen
diclofenac (Voltaren)
chloramphenicol
Ethosuximide
atorvastatin
Rifapentine
Efavirenz (Sustiva)
Atazanavir (Reyataz)
Desipramine (Norpramin)
labetolol
Entacapone
clofibrate
etravirine
Azithromzcin
ST. John's wort
Esomeprazole (Nexium)
Atorvastatin (Lipitor)
Diazepam (Valium)
naproxen
Hydromorphone (Dilaudid)
codeine
felbamate
bicalutimde
prednisone
esomeprazole (Nexium)
Bepridil (Vascor)
Diphenhydramine (Benadryl)
Propranolol
ibuprofen
diazepam
Glucocorticoids
boceprevir
ritonavir
etravirine
Bexarotene (Targretin)
Doxepin (Sinequan)
Propofol 
ketoconazole?
dicofenac
Griseofulvin
bromocriptine
valproic acid
Felbamate (Felbatol)
Bosentan (Tracleer)
Escitalopram (Lexapro)
 phenylbutazone
ketoprofen
ibuprofen
ifsofamide
Cannabinoids
Fluconazole (Diflucan)
Bromocriptine (Parlodel)
Fluoxetine (Prozac)
quercetin
Lorazepam (Ativan)
fluconazole
lopinavir
chloroquine
Fluoxetime (Prozac)
Budesonide (Entocort)
Lansoprazole (Prevacid)
valproic acid
losartan
guanfacine
methadone
cilostazol
Fluvoxamine
Buprenorphine (Subutex)
Lmipramine (Tofranil)
morphine
ketoprofen
methlyprednisolone
Cimetidine
imipramine
Bupropion (Zyban, Wellbutrin, VoMephenytoin (Mesantoin)
morphine
methadone
Modafinil
ciprofloxin
indomethacin
Carbamazepine (eg, Tegretol)
Methadone
nalaxone
morphine
Nafcillin
ciprofloxin
Isoniazid
Cevimeline (Evoxac)
Moclobemide (Manerix)
nalorphin
naproxen
Nelfinavir
Clarithromycin
ketoconazole
Cilostazol (Pletal)
Nelfinavir (Viracept)
naltrexone
oxazepam
Nevirapine
Clotrimazole
lansoprazole
Cisapride (Propulsid)
Olanzapine (Zyprexa)
naproxen
probenacid
Oxcarbazepine
conavapin
Moclobemide (Manerix)
Clarithromycin (Biaxin)
Omeprazole (Prilosec)
Oxazepam
propofol
Phenobarbital
conivaptan
Modafinil (Provigil)
Clonazepam (Klonopin)
Pantoprazxole(Protonix)
Oxycodone 
ranitidine
Phenylbutazone
crizotinib
norfluoxetine
Clopidogrel (Plavix)
Pentamidine
Tacrolimus (Prograf)
temazepam
Phenytoin
crizotinib
Omeprazole (Prilosec)
Colchicine
Phenobarbital
temazepam
trimethoprim
pioglitazone
Cyclosporine
oral contraceptives
Cyclophosphamide (Cytoxan)
Phenytoin (eg. Dilantin)
Tolcopone
prednisone
Danazol
Oxcarbazepine (Trileptal)
Cyclosporine (Neoral)
Proguanil
zidovudine
prednisone
darunavir
paroxetine
Dapsone (Avlosulfon)
Propranolol (Inderal)
Primidone
Delavirdine
ranitidine
Darunavir (Prezista)
R-warfarin (less active isomer)
primidone
Dexamethasone
ritonavir
Dasatinib (Sprycel)
Rabeprazole (Aciphex)
Progesterone
Diethyldithiocarbamate
Ticlopidine (Ticlid)
Delavirdine (Rescriptor)
Sertraline (Zoloft)
our PD patients are more likely to be taking these 
Rifabutin
Diltiazem
topiramate
Dexamethasone (Decadron)
Thalidomide
Rifampin
Dirithyromycin
Voriconazole (Vfend)
Dihydroergotamine
Voriconazole (Vfend)
strong
rifapentine
Disulfiram
Diltiazem (Cardizem)
moderate 
ritonavir
efavarinz
Disopyramide (Norpace)
weak
ritonavir
Entacapone (high dose)
Docetaxel (Taxotere)
Rofecoxib (mild)
Erythromycin
Donepezil (Aricept)
St John’s wort
Ethinyl estradiol
Doxorubicin (Adriamycin)
Sulfadimidine
fasoamprinavir
Droperidol
Sulfinpyrazone
Fluconazole
Dutasteride (Avodart)
Troglitazone
Fluoxetine
Ebastine (Kestine)
Fluvoaxamine
Efavirenz (Sustiva)
Gestodene
Eletriptan (Relpax)
ginkgo
Eplerenone (Inspra)
goldenseal
Ergotamine (Ergomar)
Grapefruit juice
Erlotinib (Tarceva)
haloperidol
Erythromycin
imitinib
Estazolam (ProSom)
Indinavir
Eszopiclone (Lunesta)
Isoniazid
Ethinyl Estradiol
itraconazole
Ethosuximide (Zarontin)
itraconazole
Etoposide (Vepesid)
Ketoconazole
Exemestane (Aromasin)
lapatinib
Felodipine (Plendil)
lopinavir
Fentanyl (Sublimaze)
methadone
Finasteride (Proscar)
methlyprednisolone
Flurazepam (Dalmane)
Metronidazole
Fosamprenavir (Lexiva)
Mibefradil
Galantamine (Reminyl)
Miconazole
Gefitinib (Iressa)
most ***ivir meds
Granisetron (Kytril)
Nefazodone
Halofantrine (Halfan)
Nelfinavir
Ifosfamide (Ifex)
Nevirapine
Imatinib (Gleevec)
nifedipine
Indinavir (Crixivan)
nilobinib
Irinotecan (Camptosar)
Norfloxacin
Isradipine (DynaCirc)
Norfluoxetine
Itraconazole (Sporanox)
Omeprazole
Ixabepilone (Ixempra)
oral contraceptives
Ketoconazole (Nizoral)
Oxiconazole
Lapatinib (Tykerb)
Paroxetine (weak)
Levomethadyl (Orlaam)
pazopanib
Loperamide (Imodium)
phenobarbital
Lopinavir (Kaletra)
posaconazole
Loratadine (Claritin)
primaquine
Lovastatin (Mevacor)
Propoxyphene
Maraviroc (Selzentry)
prosaconazole
Mefloquine (Lariam)
Quinidine
Methylprednisolone
Quinine
Midazolam (Versed)
Quinupristine and dalfopristin
Mifepristone (Mifeprex)
Ranitidine
Modafinil (Provigil)
ranolazine
Nefazodone
riton
Nevirapine (Viramune)
Ritonavir
Nicardipine (Cardene)
ritonavir
Nifedipine (Adalat)


65 
 
 
 
 
Saquinavir
Nimodipine (Nimotop)
saquinavir
Nisoldipine (Sular)
Sertindole
Nitrendipine (Baypress)
Sertraline
Oxybutynin (Ditropan)
tacrolimus
Oxycodone (Percodan)
tamoxifen
Paclitaxel (Taxol)
telaprevir
Paricalcitol (Zemplar)
telithromycin
Pimozide (Orap)
ticagrelor
Pioglitazone
tipranavir
Praziquantel (Biltricide)
Troglitazone
Prednisolone
Troleandomycin
Prednisone
Valproic acid
Propoxyphene (Darvon)
verapamil
Quazepam (Doral)
voriconizole
Quetiapine (Seroquel)
zafirlukast
Quinacrine
zileuton
Quinidine
Quinine
Ranolazine (Ranexa)
Repaglinide (Prandin)
Rifabutin (Rimactane)
Ritonavir (Norvir)
Saquinavir (Invirase)
Sibutramine (Meridia)
Sildenafil (Viagra)
Simvastatin (Zocor)
Sirolimus (Rapamune)
Solifenacin (Vesicare)
Sufentanil (Sufenta)
Sunitinib (Sutent)
Tacrolimus (Prograf)
Tadalafil (Cialis)
Tamoxifen (Nolvadex)
Tamsulosin (Flomax)
Teniposide (Vumon)
Testosterone
Tiagabine (Gabitril)
Tinidazole (Tindamax)
Tipranavir (Aptivus)
Topiramate (Topamax)
Triazolam (Halcion)
Vardenafil (Levitra)
Verapamil (Calan)
Vinblastine (Velbane)
Vincristine (Oncovin)
Ziprasidone (Geodon)
Zolpidem (Ambien)
Zonisamide (Zonegran)
Zopiclone (Imovane)


66 
 
Appendix 6: Clinic visits procedures and duration 
During each clinic visit, participants will be given breaks every 1.5 hours and will be given lunch 
vouchers. 
1. Screening visit 
Screening visit 
Time (min) 
Note 
Informed consent 
45 
PRA, PI 
Eligibility Criteria 
2 
PRA, PI 
Demographics 
3 
PRA  
Medical History  
10 
PRA, PI 
Family medical history 
2 
PRA 
Concomitant Medications 
10 
PRA, PI 
Assessment of past marijuana use 
3 
PRA 
Drug, alcohol and tobacco abuse screening test 
3 
PRA 
Drug Abuse-related AEs collection 
2 
PRA 
MOCA  
7 
PRA 
C-SSRS 
2 
PRA 
Vital Signs , orthostatic BP, weight, height 
10 
PRA 
Formal drug interaction assessment 
3 
PI 
QUIP-RS  
5 
PI 
Complete Physical Exam 
10 
PI 
Neurological exam  
10 
PI 
MDS-UPDRS part III, H&Y staging, Schwab & England 
Activities of Daily Living Scale 
10 
PI 
Urinalysis  
5 
PRA 
Blood draw for Hematology, hemoglobin A1C, CMP, 
cannabis test, serum pregnancy test if applicable 
10 
CTRC 
ECG (12-LEAD) 
10 
CTRC 
NPI 
5 
 
Emotional and behavioral dyscontrol short form 
2 
Study subject 
Tremor constancy and amplitude measure  
5 
PRA 
Tremor measure device dispatched and instruction 
10 
PRA 
Total visiting 
184 
Estimated visiting 
time-3 hours 
  
 
 


67 
 
2. Baseline visit 
Baseline visit 
Time 
Note 
Eligibility Criteria 
1 
PRA, PI 
Medical History 
2 
PRA, PI 
Concomitant Medications 
2 
PRA, PI 
Randomization 
1 
PRA, PI 
Alertness test 
3 
Study subject, 
before taking 
study drug 
Vital Signs, orthostatic BP, height, weight 
10 
PRA, before taking 
study drug 
Taking study drug 
2 
Study subject  
Dispense study drug and instruction 
10 
PI 
Adverse Events (b) 
2 
PRA, PI 
Brief physcial exam (heart and lung ausculation) 
5 
PI 
CGI 
1 
PI 
MDS-UPDRS (all 4 parts), H&Y, Schwab & England 
Activities of Daily Living Scale 
30 
PI, Study subject 
Unified Dyskinesia Rating Scale (UDysRS) 
5 
PI, Study subject 
Vital Signs, orthostatic BP 
10 
PRA, one hour 
after taking study 
drug 
Cognitive assessment battery 
60 
PRA 
C-SSRS 
2 
PRA 
NMSS 
10 
PRA 
Home diary dispense and instruction 
3 
PRA 
Tremor measure device dispatched and instruction 
5 
PRA 
RBDSQ  
2 
Study subject 
Anxiety short form 
2 
Study subject 
Depression short form 
2 
Study subject 
SCOPA-sleep  
5 
Study subject 
Insomnia Severity Index (ISI) 
2 
Study subject 
Modified Dysfunctional Beliefs and Attitudes about 
Sleep Questionnaire (DBAS-16) 
3 
Study subject 
Pittsburgh Sleep Quality Index 
3 
Study subject 
IRLS 
2 
Study subject 
Fatigue severity scale 
3 
Study subject 
Pain intensity and interference short form 
2 
Study subject 
Bladder function-OABSS 
3 
Study subject 
PDQ-39 
7 
Study subject 
EQ-5D 
2 
Study subject 


68 
 
PGI-I 
1 
Study subject 
Take picture of central face  
5 
PRA, Study subject 
TUG 
5 
PRA, Study subject 
Urine drug (THC) test, urine pregnancy test if applicable 
5 
PRA 
Urine cups dispense and urine collection instruction 
2 
PRA 
Tremor constancy and amplitude measure 
5 
PRA, 2 hours after 
taking study drug 
Alertness test 
3 
Study subject, 3 
hours after taking 
study drug 
PSG equipment and data collected 
2 
PRA 
Total time 
230 
estimated visiting 
time-3.5 hours 
 
 


69 
 
3. 1.25 mg/kg/day dose assessment visit 
1.25 mg/kg/day Dose assessment visit 
Time 
 Note 
Vital Signs, orthostatic BP 
10 
PRA, Begore taking study drug 
Taking study drug in clinic 
2 
Study subject 
Vital Signs, orthostatic BP 
10 
PRA, one hours after taking study drug 
Medical History 
2 
PI, PRA 
Concomitant Medications 
2 
PI, PRA 
Adverse Events and drug abuse related AEs 
Withdrawal AEs, Liver function related AEs 
3 
PI, PRA 
Complete Physical Exam  
10 
PI 
Neurological exam  
10 
PI 
QUIP-RS  
5 
PI 
CGI 
1 
PI 
MDS-UPDRS (all 4 parts), H&Y, Schwab & 
England Activities of Daily Living Scale 
30 
PI, Study subject 
Unified Dyskinesia Rating Scale (UDysRS) 
5 
PI, Study subject 
MOCA  
10 
PRA 
TUG 
5 
PRA 
NMSS 
10 
PRA 
Home diary collection and review 
2 
PRA 
Tremor constancy and amplitude measure (k) 
5 
PRA, 2 hours after taking study drug 
Blinding assessment 
1 
PRA 
Study drug compliance check 
2 
PRA 
C-SSRS 
2 
PRA 
RBDSQ  
2 
PRA 
NPI 
5 
Signifant others 
Anxiety short form 
2 
Study subject 
Depression short form 
2 
Study subject 
Emotional and behavioral dyscontrol short form 
2 
Study subject 
SCOPA-sleep  
5 
Study subject 
Insomnia Severity Index (ISI) 
2 
Study subject 
Modified Dysfunctional Beliefs and Attitudes 
about Sleep Questionnaire (DBAS-16) 
3 
Study subject 
Pittsburgh Sleep Quality Index 
3 
Study subject 
IRLS 
2 
Study subject 
Fatigue severity scale 
3 
Study subject 
Pain intensity and interference short form 
2 
Study subject 
Bladder function-OABSS 
3 
Study subject 
PDQ-39 
5 
Study subject 
EQ-5D 
2 
Study subject 
PGI-I 
1 
Study subject 


70 
 
PGI-C 
1 
Study subject 
Urinalysis, pregnancy test if applicable 
5 
PRA 
Urinary  collected for CBD and metabolites 
levels test 
2 
PRA 
ECG (12-LEAD) 
10 
CTRC 
Blood draw for Hematology, CMP, cannabis test 
10 
CTRC, 3 hours after taking study drug 
Total visiting time 
200 
3.5 hours 
 
 
 


71 
 
4. Liver function monitoring visit 
Liver Function monitoring visit 
Time 
 Note 
Medical History 
2 
PRA 
Concomitant Medications 
2 
PRA 
Adverse Events (b) and drug abuse related AEs 
3 
PRA 
Anxiety short form 
2 
Study subject 
Depression short form 
2 
Study subject 
Emotional and behavioral dyscontrol short form 
2 
Study subject 
SCOPA-sleep  
4 
Study subject 
EQ-5D 
2 
Study subject 
C-SSRS 
2 
PRA 
Vitals 
5 
PRA 
Blood draw for liver function tests 
10 
CTRC 
Total visiting time 
36 
0.5 hours 
 
 
 


72 
 
5. 2.5 mg/kg/day Dose assessment visit 
2.5 mg/kg/day Dose assessment visit 
Time 
 Note 
Vital Signs, orthostatic BP 
10 
PRA, Begore taking 
study drug 
Taking study drug in clinic 
2 
Study subject 
Cognitive assessment battery 
60 
PRA 
Vital Signs, orthostatic BP 
10 
PRA, one hours 
after taking study 
drug 
Medical History 
2 
PI, PRA 
Concomitant Medications 
2 
PI, PRA 
Adverse Events and drug abuse related AEs 
Withdrawal AEs and liver function related AEs 
3 
PI, PRA 
Complete Physical Exam  
10 
PI 
Neurological exam  
10 
PI 
QUIP-RS  
5 
PI 
CGI 
1 
PI 
MDS-UPDRS (all 4 parts), H&Y, Schwab & England 
Activities of Daily Living Scale 
30 
PI, Study subject 
Unified Dyskinesia Rating Scale (UDysRS) 
5 
PI, Study subject 
MOCA  
10 
PRA 
TUG 
5 
PRA 
NMSS 
10 
PRA 
Home diary collection and review 
2 
PRA 
Tremor constancy and amplitude measure (k) 
5 
PRA, 2 hours after 
taking study drug 
PSG equipment and data collected (u) 
2 
PRA 
Blinding assessment 
1 
PRA 
Study drug compliance check 
2 
PRA 
C-SSRS 
2 
PRA 
RBDSQ  
2 
PRA 
NPI 
5 
 
Anxiety short form 
2 
Study subject 
Depression short form 
2 
Study subject 
Emotional and behavioral dyscontrol short form 
2 
Study subject 
SCOPA-sleep  
5 
Study subject 
Insomnia Severity Index (ISI) 
2 
Study subject 
Modified Dysfunctional Beliefs and Attitudes about 
Sleep Questionnaire (DBAS-16) 
3 
Study subject 
Pittsburgh Sleep Quality Index 
3 
Study subject 
IRLS 
2 
Study subject 
Fatigue severity scale 
3 
Study subject 


73 
 
Pain intensity and interference short form 
2 
Study subject 
Bladder function-OABSS 
3 
Study subject 
PDQ-39 
5 
Study subject 
EQ-5D 
2 
Study subject 
PGI-I 
1 
Study subject 
PGI-C 
1 
Study subject 
Urinalysis, pregnancy test if applicable 
5 
PRA 
Urinary  collected for CBD and metabolites levels test 
2 
PRA 
Take picture of central face 
5 
PRA, Study subject 
ECG (12-LEAD) 
10 
CTRC 
Blood draw for Hematology, CMP, cannabis test 
10 
CTRC, 3 hours after 
taking study drug 
Vital Signs, orthostatic BP 
10 
PRA, 3 hours after 
taking study drug 
Total visiting time 
275 
4 hours 
 
 
 


74 
 
6.Safety follow up visit 
Safety follow up visit 
Time 
Note 
Medical History 
2 
PI, PRA 
Concomitant Medications 
2 
PI, PRA 
Adverse Events and drug abuse related AEs 
Withdrawal AEs, and liver function related AEs 
3 
PI, PRA 
QUIP-RS  
10 
PI 
Complete Physical Exam  
10 
PI 
Unified Dyskinesia Rating Scale (UDysRS) 
5 
PI, Study subject 
MDS-UPDRS (all 4 parts), H&Y, Schwab & England 
Activities of Daily Living Scale  
30 
PI, Study subject 
Vital Signs, orthostatic BP 
10 
PRA 
Urinalysis if applicable 
5 
PRA 
Urinary CBD and metabolites levels test  
5 
PRA 
NMSS 
10 
PRA 
Urine Pregnancy Test (for women childbearing potential) 
5 
PRA 
MOCA  
7 
PRA 
C-SSRS 
2 
PRA 
RBDSQ  
2 
Study subject 
NPI 
5 
 
Anxiety short form 
2 
Study subject 
Depression short form 
2 
Study subject 
Emotional and behavioral dyscontrol short form 
2 
Study subject 
SCOPA-sleep  
5 
Study subject 
IRLS 
2 
Study subject 
Fatigue severity scale 
5 
Study subject 
Pain intensity and interference short form 
2 
Study subject 
Bladder function-OABSS 
3 
Study subject 
PDQ-39 
5 
Study subject 
EQ-5D 
2 
Study subject 
Blood draw for Hematology, CMP, Cannabis test 
10 
CTRC 
ECG (12-LEAD) 
10 
CTRC 
Total visiting time 
165 
3 hours 
 
 
 


75 
 
Appendix 7: Chemotherapeutic, antihistaminic and Anti0inflammatory medications, including, but not 
limited to: 
 
Alemtuzumab (Lemtrada) 
Aspirin 
Celecoxib (Celebrex) 
Daclizumab (Zinbryta) 
Diclofenac (Cambia, Cataflam, Voltaren-SR, Zipsor, Zorvolex) 
Diflunisal (Dolobid) 
Dimethyl fumarate (Tecfidera) 
Etodolac (Lodine) 
Fingolimod (Gilenya) 
Glatiramer acetate (Copaxone) 
Ibuprofen (Motrin, Advil) 
Indomethacin (Indocin) 
Interferon beta-1a (Avonex, Rebif) 
Interferon beta-1b (Betaseron, Extavia) 
Ketoprofen (Active-Ketoprofen) 
Ketorolac (Toradol) 
Mitoxantrone 
Nabumetone (Relafen) 
Naproxen (Aleve, Anaprox, Naprelan, Naprosyn) 
Natalizumab (Tysabril) 
Ocrelizumab 
Oxaprozin (Daypro) 
Peginterferon beta-1a (Plegridy) 
Piroxicam (Feldene) 
Rituximab (Rituxab) 
Salsalate (Disalsate) 
Sulindac (Clinoril) 
Teriflunomide (Aubagio) 
Tolmetin (Tolectin) 
Other chemotherapeutic, antihistaminic and anit-inflammatory medications per PI discretion 
 
 


76 
 
Appendix 8: Inflammatory and atopic disease, including, but not limited to:  
 
Inflammatory Diseases 
Cryoglobulinemia  
Gout 
Allergic asthma 
Lupus 
Anaphylaxis 
Asthma 
Angioedema 
Crohn’s disease 
Urticaria 
Eczema 
Latex allergies 
Ulcerative colitis 
Systemic lupus erythematosus 
Hepatitis 
Acute hypersensitivity pneumonitis  
Nephritis, Glomerulonephritis 
Leukocytoclastic vasculitis 
Psoriasis 
 
Vasculitis 
Other inflammatory and atopic disease per PI 
discretion 
Thyroiditis 
 
Sarcoidosis 
 
Multiple Sclerosis 
 
Rheumatoid and other inflammatory arthritides 
 
Seborrheic dermatitis 
 
Wegener’s granulomatosis 
 
 

ICF_001.pdf: 
Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 1 of 15
Principal Investigator:
Maureen Leehey, MD
COMIRB No:
17-2318
Version Date:
09Jun2020
Study Title:
A randomized, double blind, placebo-controlled paralleled study of tolerability and efficacy 
of Cannabidiol (CBD) on motor symptoms in Parkinson’s disease
Randomized controlled Study
Some people in this study may have a medical condition or a disability that does not allow them to 
make important decisions for themselves.  If you have been asked to decide for someone else whether 
they should be in this study, please read this consent form carefully.  
In this form, we use the words “you” and “your.”  If you are reading this form and deciding for someone 
else, the words ‘you’ and ‘your’ refer to that other person, not to you.
You are being asked to be in a research study.  This form provides you with information about the 
study. A member of the research team will describe this study to you and answer all of your 
questions. Please read the information below and ask questions about anything you don’t understand 
before deciding whether or not to take part. 
Why is this study being done?
Cannabis, which is marijuana, is composed of many substances.  Cannabidiol (CBD) is one of these 
substances.  CBD may be helpful in treating the symptoms of Parkinson’s Disease (PD). This study 
plans to learn more about how well CBD is tolerated and works to treat symptoms of PD.
You are being asked to be in this research study because you have Parkinson’s Disease and related 
motor symptoms.
Other people in this study
Up to 75 people from your area will participate in the study. 
What happens if I join this study?
In this study, a placebo or CBD cannabis extract oral solution with 59.3% CBD and 1.96% THC 
(~30:1 CBD:THC) from National Institute on Drug Abuse (NIDA) will be used.  The CBD cannabis 
extract oral solution is an investigational drug and has not been approved for use by the FDA, 
however it is currently being used in FDA-approved research studies.
The CBD cannabis extract oral solution will be in a sesame oil formulation, 100 mg/mL of CBD. The 
placebo is a liquid that looks and tastes like the CBD cannabis extract oral solution but does not 
COMIRB
APPROVED
For Use
07-Jan-2022
06-Jan-2023


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contain the active ingredient of CBD. You will ingest the liquid by mouth at a low dose over the course 
of about 2-3 weeks and participants will be closely monitored for side effects at office visits. In this 
form, the term “study drug” is used to refer to both CBD Cannabis extract oral solution and placebo.
This study will have 2 different groups (CBD cannabis extract oral solution group and placebo group) 
of research subjects like you. To decide which group you will be in, we will use a method of chance. 
This method is like flipping a coin or rolling dice. You will receive study drug (CBD cannabis extract 
oral solution or placebo) for 2-3 weeks treatment period. You will start to take study drug at a low 
dose (1.25 mg/kg/day) of CBD once a day on day 1 and keep this low dose for 3-4 days (day 1-4). On 
day 4 or 5, you will start to take a high dose (2.5 mg/kg/day) twice a day for 10 (up to 14) days. 
You will not know which treatment group you are in. Neither will your study doctor. This information 
needs to be kept secret so that the study is based on scientific results, not on peoples’ opinions. 
However, we can give this information out if you have an emergency. If you are in an emergency, 
make sure you tell the emergency staff about this study. They can contact us, and we will give them 
all relevant information.
If you join the study, you will come into the Clinical Translational Research Center at the University of 
Colorado Anschutz Medical Campus for 7 visits over the course of about 8 weeks. You will take study 
drug daily for about 2-3 weeks. The visits are a screening visit, baseline visit (study drug is 
started),two dose assessment visits, and a follow up safety visit.  Below is a detailed description of 
what will be done at each visit and between visits. 
If you join the study you are instructed to not take any form of cannabis other than the cannabis that 
is supplied as part of the study.  Your blood and urine is checked at the first two visits, before you are 
given study drug.  If the testing is positive for cannabis at one of these visits, you may return 14 days 
later for a repeat test.  If that test is positive then you will not be included in the study. 
Screening Visit
The purpose of this visit is to determine if you are eligible to participate in this study. This visit will 
take approximately 4 hours.  After you discuss the study with the doctor and sign this consent form, 
the following will be done:

Collection of medical history, medication and demographic information

Vital signs

Physical exam

Evaluation of your PD symptoms 

Tests/questionnaires about your thinking/memory skills, health, mood, and sleeping habits, 
compulsivity, mental health concerns (if any)

Questionnaires about drug, alcohol, and tobacco use

Blood draw for laboratory tests (and pregnancy test for females)

Blood draw for cannabis test

Urine collection for urinalysis

ECG (a recording of electrical activity of your heart)

Tremor measure device dispatched and instruction


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
You will need to measure your tremor with the dispatched device at home for 2 days after 
screening visit, and 3 days before baseline visit, twice a day (2 hours after breakfast dose and 2 
hours after dinner dose), 90 seconds each measurement.
If possible, some of the above procedures may be done remotely, through a Zoom call after on-site 
screening visit.
Baseline Visit 
If the study doctor determines that you qualify for the study based on the results from the screening 
visit, you will be asked to come in for a baseline visit within 4 weeks of the screening visit. You will 
also be reminded to measure your tremor for 3 consecutive days before baseline visit, twice a day (2 
hours after breakfast dose and 2 hours after dinner dose), 90 seconds each measurement. This visit 
will take approximately 3-4 hours. The following will be done:

Collection of medication information

Vital signs

Brief physical exam

Evaluation of your PD symptoms 

Tests/questionnaires about your health, cognitive function, alertness, sleeping habits, mood, 
fatigue, pain, bladder function, skin, and quality of life

Urine drug test

Urine pregnancy test (for females)

Blood draw for laboratory tests (only for some patients)

Study drug will be dispensed and you will receive instructions about how to take the drug at home. 
This includes a diary on which you will record information each day about taking the medication, 
talking with study staff and any good or bad effects you notice 

You will start with a low dose (1.25 mg/kg/day) of CBD which will be taken in the clinic after the 
cognitive function test and MDS-UPDRS evaluation. You will need to stay for two hours after this 
dose so that study staff can monitor you 

Urine cups will be provided with instructions

Tremor data collected and reviewed

Take a picture of your central face and the photo will be reviewed by dermatologists for seborrheic 
dermatitis evaluation
If possible, some of the above procedures may be done remotely, through a Zoom call
Days 1-14 (+4) Treatment Period: at home
For the next 14 days or so, you will take the study drug at home every day as instructed by the study 
doctor and record information in the diary.  You should take the study drug at about the same times 
every day: 30-60 minutes before breakfast, once a day for  the first 4 days, and twice a day, 30-60 
minutes before breakfast, and 30-60 minutes before dinner, minimum of six hours apart, for the rest 


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of the treatment period (10 /+4 days). You could take the study drug with a small amount of food as 
needed if you experience nausea.  You will take study drug at a low dose (1.25 mg/kg/day) once a 
day for the first 3-4 days, and on day 4 or 5, switch to a higher dose (2.5 mg/kg/day) twice a day for 
10 (up to 14) days. You will also be reminded to measure your tremor for 3 consecutive days before 
each dose assessment visit, twice a day (2 hours after breakfast dose and 2 hours after dinner dose), 
90 seconds each measurement. 
1.25 mg/kg/day dose assessment visit: in clinic
After you have taken the 1.25 mg/kg/day of study drug for 3-4 days you will return to the clinic. On the 
day of this visit you do not take the study drug until you arrive at clinic and the staff asks you to take 
it. You need to bring all used, partially used and not used study drug with you to the visit. This visit will 
take approximately 3.5 hours. The following will be done:

Take the study drug and you have vital signs checked 1 hour later. At 3 hours after taking the 
study drug tremors are checked and your blood drawn for laboratory tests and to check the level 
of study drug 

Collection of medication information

Collection of changes to medical history and side effects

Vital signs

Physical exam

Evaluation of your PD symptoms 

Tests/questionnaires about your thinking/memory skills, health, mood, bladder function, non-motor 
symptoms, quality of life, pain, fatigue, and sleeping habits

Tremor measured

Blood draw for laboratory tests 

ECG (a recording of electrical activity of your heart)

Urine pregnancy test (for females)

Collect urine in the morning and bring it to the clinic visit

Urine collection for urine analysis and laboratory tests
After you have taken 2.5 mg/kg/day of study drug for 3-5 days you will be reminded to complete 
questionnaires about your health, mood, quality of life, and sleeping habits at home.
2.5 mg/kg/day Dose Assessment visit, End of Treatment Period: in clinic
After you have taken the 2.5 mg/kg/day of study drug for 10 (+4) days you will return to the clinic.  On 
the day of this visit you do not take the study drug until you arrive at clinic and the staff asks you to 
take it.  You need to bring all used, partially used and not used study drug with you to this visit.  This 
visit will take approximately 4 hours.  The following will be done:

Take the study drug and you have vital signs checked 1 hour later. Tremors checked 2 hours 
later. At 3 hours after taking the study drug vital signs are checked again and your blood drawn for 
laboratory tests and to check the level of study drug 

Collection of medication information

Collection of changes to medical history and side effects

Collection of your leftover study drug


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
Vital signs

Physical exam

Evaluation of your PD symptoms 

Tests/questionnaires about your thinking/memory skills, health, mood, bladder function, non-motor 
symptoms, quality of life, pain, fatigue, and sleeping habits

Tremor measured

Blood draw for laboratory tests 

ECG (a recording of electrical activity of your heart)

Urine pregnancy test (for females)

Collect urine in the morning and bring it to the clinic visit

Urine collection for urine analysis and laboratory tests

Seborrheic dermatitis evaluation
Safety follow-up
About 3 and 7 days after the Final Dose Assessment Visit, study staff will call you on the phone and 
will ask you about your possible signs of withdrawal, your medications, and how you are doing.    
About 2 weeks after the Final Dose Assessment Visit, you will return to the clinic.  This visit will take 
approximately 2 hours. The following will be done:

Collection of medication information

Collection of changes to medical history and side effects

Vital signs

Physical exam

Evaluation of your PD symptoms 

Tests/questionnaires about your health, mood, and sleeping habits

Blood draw for laboratory tests (if your test results have changed significantly during the study)

Blood draw for cannabis test

ECG (if your ECG has changed during the study) 

Urine collection for urinalysis (if your test results have changed significantly during the study)

Urine pregnancy test (for females)

Collect urine in the morning and bring it to the clinic visit
If possible, some of the above procedures may be done remotely, through a Zoom call, before or after 
safety follow up visit.
Additional clinic visits may be necessary if you have abnormal lab results.
Regarding future CBD/marijuana use after you finish this study:
Cannabis (marijuana) is composed of many cannabinoid compounds and other substances, including 
Cannabidiol (CBD) and Tetrahydrocannabinol (THC). THC is the substance in cannabis that produces 
psychoactive effects. CBD limits THC’s psychoactive effects. There is more THC and less CBD in 
street marijuana than in the drug you took for this study.  Using marijuana is risky because the high 


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THC and low CBD may worsen current symptoms, such as cognitive, psychiatric and motor 
problems, including falling. 
There are many forms of CBD being marketed. Using marijuana should be under the supervision of 
your physician, with monitoring the symptoms of PD and other disease, as well as the interactions of 
marijuana and other drugs you take.
Sleep Study Portion
You will also be asked to use a sleep monitoring device to monitor 2 nights of sleep. For this part of 
the study, you will also need to come to the clinic for 2 additional visits prior to using the sleep monitor 
to have the device set up and to receive instructions. The following will be done:
3-14 days before the Baseline Visit
You will come to clinic to have the sleep monitoring equipment set up and be instructed how to use it 
during the night at home.  You will need to complete a sleep diary and a sleep questionnaires in the 
morning when you finish the sleep test. You will need to bring the equipment, sleep diary and the 
questionnaire to the clinic before or at baseline visit to have the data collected and reviewed.   
Between your 7th night on the maximum dose and the 3rd night prior to the 2.5 mg/kg/day Dose 
Assessment Visit
You will come to clinic to have the sleep monitoring equipment set up and be instructed how to use it 
during the night at home.  You will need to complete a sleep diary and a sleep questionnaires in the 
morning when you finish the sleep test. You will need to bring the equipment, sleep diary and the 
questionnaire to the clinic before or at the 2.5 mg/kg/day Dose Assessment Visit to have the data 
collected and reviewed.   
Optional Consent for Data and Specimen Banking for Future Research
Dr. Leehey would like to keep some of the data and blood that is taken during the study but is not 
used for other tests. If you agree, the samples and data will be kept and may be used in future 
research to learn more about Parkinson’s disease. The research that is done with your samples and 
data is not designed to specifically help you. It might help people who have PD and other diseases in 
the future. Reports about research done with your samples and data will not be given to you or your 
doctor. These reports will not be put in your health records. The research using your samples and 
data will not affect your care.
The choice to let Dr. Leehey keep the samples and data for future research is up to you. No matter 
what you decide to do, it will not affect the care that you will receive as part of the study. If you decide 
now that your samples and data can be kept for research, you can change your mind at any time and 
contact your study doctor to let him or her know that you do not want your samples and data to be 
used any longer, and they will no longer be used for research. Otherwise, they may be kept until they 
are used up, or until Dr. Leehey decides to destroy them. 


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When your samples and data are given to other researchers in the future, Dr. Leehey will not give 
them your name, address, phone number or any other information that will let the researchers know 
who you are.  One group that will potentially receive your de-identified data would be the CDPHE 
Marijuana Grantee Consortium. 
Sometimes samples and data are used for genetic research (about diseases that are passed on in 
families). Even if your data and samples are used for this kind of research, the results will not be told 
to you and will not be put in your health records. Your data and samples will only be used for 
research and will not be sold. The research done with your data and samples may help to develop 
new products in the future, but there is no plan for you to be paid.
The possible benefits of research from your data and samples include learning more about what 
causes PD and other diseases, how to prevent them and how to treat them. The greatest risk to you 
is the release of your private information. Dr. Leehey will protect your records so that your name, 
address and phone number will be kept private. The chance that this information will be given to 
someone else is very small. There will be no cost to you for any sample or data collection and storage 
by Dr. Leehey.
Please read the sentence below and think about your choice. After reading the sentence, circle “yes” 
or “no.” If you have questions, please talk to your doctor or nurse. Remember, no matter what you 
decide to do about the storage and future use of your samples, you may still take part in the study.
I give my permission for my blood and data to be stored in a central tissue and data bank at 
University of Colorado Denver for future use by the study investigators:
   Yes
   No
_________Initials


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Optional Consent for Sharing Data with Primary Care Provider
It is important that your primary care provider is aware of your participation in the study. We would 
like your permission to share your study data and lab results with your primary care physician so they 
are fully informed about your care. If you agree, we will send a letter to them after each study visit 
updating them on your participation
I give my permission for you to share my study data and information about my participation with my 
PCP:
   Yes
   No
_________Initials
If you agree, please provide the name, telephone number, and address of your primary care 
physician (if you do not have it right now, you can provide this to us at a later time):
____________________________________________________________
____________________________________________________________
____________________________________________________________
What are the possible discomforts or risks?
Risks of Study Drug
As with any drug, side effects are possible. You will need to report any unusual symptoms to your 
Study Doctor immediately. Possible side effects, which usually go away with time, include the 
following:
Most common (>20%): sleepiness, fatigue, decreased appetite, dizziness, and diarrhea. 
Common (6-20%): increased appetite, increased weight, lethargy, acid stomach, urgency to have a 
bowel movement, burping, frequent bowel movements, vomiting, disorder of sense of taste, frequent 
urination, irritability, headache and skin rash. 
Less common (5% or less): seizure/convulsion, decreased weight, trouble walking, increased serum 
concentrations of anti-seizure drugs, and elevated liver enzyme tests.
The study drug may interact negatively with a substance found in grapefruit. Therefore, you should 
not eat grapefruit or drink grapefruit juice for 7 days prior to the first dose of study drug, or 
throughout your participation in the study. 
The study drug may interact with acetaminophen to produce increased acetaminophen levels in your 
body. Therefore, you should not take more than 1000 mg of acetaminophen (such as Tylenol) 
per day while you are taking study drug.   
The study drug may interact with other drugs and supplements as well. You should notify the study 
doctor of all drugs and supplements that you are taking now and throughout the study.


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The study drug should always keep in the container it is provided in.
Keep the study drug away from children and anyone that shouldn’t use it. The study drug is to only be 
taken by you.
If you require medical care outside of the study while participating in this study, please show the other 
medical personnel this information.
Driving
Whether or not the study drug affects driving ability is not known. You should not drive or operate 
heavy machinery while taking study drug. You must have a driver or available transportation 
to drive you to and from clinic and for any other transportation needs while you are taking 
study drug.
Risk of Having Blood Taken
In this study we will need to get about 1-2 tablespoon of blood from you at each visit. We will get 
blood by putting a needle into one of your veins and letting the blood flow into a glass tube.  You may 
feel some pain when the needle goes into your vein.  A day or two later, you may have a small bruise 
where the needle went under the skin. 
Risk of Questionnaires
Some of the questions may seem personal and may make you feel uncomfortable. If you have any 
questions or concerns while completing these questionnaires, please talk to your study doctor.
Other
The study drug is mostly CBD, which has a different effect in the body than marijuana.  Studies 
suggest that CBD does not cause the “high” that people get from marijuana.  Persons should not 
drive when on marijuana because of the “high”.  The study drug may cause side effects such as 
dizziness, sleepiness or fatigue which may impair judgment and performance of skilled tasks.
The study drug has a tiny amount (<2%) of the part of marijuana that causes the “high” in it.  
Therefore, if you had blood testing for marijuana it could come back positive.  We will provide you 
with a card explaining this to carry with you.  
There is a risk that people outside of the research team will see your research information.  We will 
do all that we can to protect your information, but it can not be guaranteed.
It is possible that you may experience fatigue from long study visits. We will take breaks as often as 
necessary.
If you become pregnant, the particular treatment involved in the study may involve risks to the embryo 
or fetus which are currently unclear.  Therefore men and women of child bearing potential should take 


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reliable contraceptive precautions for the duration of the study and for 3 months after finishing the 
study.
 
The study may include risks that are unknown at this time. 
What are the possible benefits of the study?
This study is designed for the researcher to learn more about the study drug as a treatment in 
patients with PD.  However, there is no guarantee that your health will improve if you join this study.  
Also, there could be risks to being in this study.  If there are risks, these are described in the section 
describing the discomforts or risks.
Are there alternative treatments? 
There may be other ways of treating your PD. These other ways include other medications and surgical 
therapy.   You could also choose to get no treatment at all.
You should talk to your doctor about your choices.  Make sure you understand all of your choices 
before you decide to take part in this study.  You may leave this study and still have these other choices 
available to you. 
Who is paying for this study? 
This research is being sponsored by the Colorado Department of Public Health and Environment.
The study drug is being provided by National Institute on Drug Abuse (NIDA). 
Will I be paid for being in the study?  
You will be paid $25.00 for each in-clinic visit in this study. On these days you will also be offered a 
lunch voucher for yourself and one person that comes with you to the visit, if you bring someone.  
This will add up to a total of $175.00 if you complete all of the visits. If you leave the study early, or if 
we have to take you out of the study, you will be paid only for the visits you have completed.
It is important to know that payments for participation in a study is taxable income. 
If necessary, limited funds for use of transportation will be provided during the time you are taking 
study drug.
Will I have to pay for anything?
It will not cost you anything to be in the study.


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Is my participation voluntary?
Taking part in this study is voluntary.  You have the right to choose not to take part in this study.  If 
you choose to take part, you have the right to stop at any time.  If you refuse or decide to withdraw 
later, you will not lose any benefits or rights to which you are entitled. 
If you leave this study, you will still receive your normal medical care.  The only medical care that you 
will lose is the medical care you are getting as part of this study.  You might be able to get that same 
kind of medical care outside of the study.  Ask your study doctor. 
 
If there are any new findings during the study that may affect whether you want to continue to take 
part, you will be told about them.
Can I be removed from this study? 
The study doctor may decide to stop your participation without your permission if the study doctor 
thinks that being in the study may cause you harm, or for any other reason. Also, the sponsor may 
stop the study at any time. 
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should call Dr. Leehey immediately at 303-724-
8984 or contact Ying Liu at 720-921-4815 outside of regular work hours. 
We will arrange to get you medical care if you have an injury that is caused by this research.  
However, you or your insurance company will have to pay for that care. 
Who do I call if I have questions?
The researcher carrying out this study is Dr. Maureen Leehey. You may ask any questions you have 
now. If you have questions, concerns, or complaints later, you may call Dr. Leehey at 303-724-8984. 
You will be given a copy of this form to keep.  
You may have questions about your rights as someone in this study. You can call Dr. Leehey with 
questions.  You can also call the responsible Institutional Review Board (COMIRB).  You can call 
them at 303-724-1055. 
You may also contact a Subject Advocate at the Clinical and Translational Research Center (CTRC). 
The number there is 720-848-6662. 
A description of this clinical trial will be available on http://www.Clinical Trials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time.
Who will see my research information?


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The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to protect 
information about you.  Federal and state laws including the Health Insurance Portability and 
Accountability Act (HIPAA) also protect your privacy.   This part of the consent form tells you what 
information about you may be collected in this study and who might see or use it.  
The institutions involved in this study include 
University of Colorado Denver
University of Colorado Hospital
We cannot do this study without your permission to see, use and give out your information.  You do 
not have to give us this permission.  If you do not, then you may not join this study.  
We will see, use and disclose your information only as described in this form and in our Notice of 
Privacy Practices; however, people outside the UCD and its affiliate hospitals may not be covered by 
this obligation.
We will do everything we can to maintain the confidentiality of your personal information but 
confidentiality cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your permission to use 
and disclose your information at any time by writing to the study’s Principal Investigator (PI), at the 
name and address listed below.  If you do cancel your permission to use and disclose your 
information, your part in this study will end and no further information about you will be collected.  
Your cancellation would not affect information already collected in this study.  
Maureen Leehey, MD
12631 E. 17th Ave, mailstop B185
Aurora CO 80045
Both the research records that identify you and the consent form signed by you may be looked at by 
others who have a legal right to see that information, such as:  

Federal offices such as the Food and Drug Administration (FDA) and the Office of Human 
Research Protections (OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team.

Officials at the institution where the research is conducted and officials at other institutions 
involved in this study who are in charge of making sure that we follow all of the rules for 
research

People at the Colorado Department of Public Health and Environment
We might talk about this research study at meetings.  We might also print the results of this research 
study in relevant journals.  But we will always keep the names of the research subjects, like you, 
private. 


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You have the right to request access to your personal health information from the Investigator. 
Information about you that will be seen, collected, used and disclosed in this study:

Name and Demographic Information (age, sex, ethnicity, address, phone number, etc.

Portions of your previous and current Medical Records that are relevant to this study, including 
but not limited to Diagnosis(es), History and Physical, laboratory or tissue studies, radiology 
studies, procedure results

Research Visit and Research Test records

Psychological and mental health tests

Alcoholism, Alcohol or Drug abuse
What happens to Data, Blood, and Specimens that are collected in this study? 
Scientists at the University of Colorado Denver and the hospitals involved in this study work to find 
the causes and cures of disease.  The data, blood, and specimens collected from you during this 
study are important to this study and to future research.  If you join this study:

The data, blood or specimens given by you to the investigators for this research no longer 
belong to you.  

Both the investigators and any sponsor of this research may study your data, blood or 
specimens collected from you.

If data, blood, or specimens are in a form that identifies you, UCD or the hospitals involved in 
this study may use them for future research only with your consent or Institutional Review 
Board (IRB) approval.

Any product or idea created by the researchers working on this study will not belong to you.

There is no plan for you to receive any financial benefit from the creation, use or sale of such a 
product or idea. 
A Certificate of Confidentiality has been obtained from the Federal Government for this study to help 
insure your privacy.  This Certificate means that the researchers cannot be forced to disclose 
information that may identify you, even by a court subpoena, in any federal, state, or local civil, 
criminal, administrative, legislative or other proceedings.    But, if you request disclosure, we can 
release the information.
The Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of federally funded projects or for information that 
must be disclosed in order to meet the requirements of the federal Food and Drug Administration 
(FDA).
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, without 
your consent, information that would identify you as a participant in the research project if they find 
out that you have intent to harm yourself or others. This also applies to any information about past or 
present child abuse. 


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 14 of 15
You should also take measures to ensure your own privacy.
HIPAA Authorization for Optional Additional Study Procedures 
In this form, you were given the option to agree to have your samples stored for future research.  You 
must also give us your permission, under HIPAA rules, to use and disclose the information collected 
from these optional procedures, as described above.  
Some of these optional procedures may involve genetic testing or the use of your genetic information.  
Your genetic information will not be released to others
If you decline to give us permission to use and disclose your information, you cannot take part in 
these optional procedures, but you can still participate in the main study.  Please initial next to your 
choice:
_____ I give permission for my information, from the optional procedures I have agreed to above, 
to be used and disclosed as described in this section.
_____ I do not give permission for my information for any optional procedures to be used and 
disclosed; I understand that I will not participate in any optional procedures


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 9-29-15
Page 15 of 15
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me.  I understand the possible risks and 
benefits of this study.  I understand and authorize the access, use and disclosure of my information 
as stated in this form.  I know that being in this study is voluntary.  I choose to be in this study: I will 
get a signed and dated copy of this consent form.
Signature:
Date:
Print Name:
Consent form explained by:
Date:
Print Name:
Signature Line For LAR, if applicable                                                      N/A (LAR not required)
______________________________________________
  Date_________
Legally Authorized Representative
Print Name:
Signature Line for witness; required for consent of non-reading subjects     N/A (witness not required) 
Witness Signature:____________________________________
  Date_________
Witness Print Name:
Witness of Signature

Witness of consent process