Clinical trial NCT03805750
Conditions: Essential Tremor
Sponsor: University of California, San Diego
Start date: 2019-01-22; Completion date: 2020-11-30
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a pilot trial to evaluate the safety and efficacy of a combined oral formulation of THC and CBD in patients with Essential Tremor.

Detailed description:
Essential tremor (ET) is the most common neurological movement disorder, affecting up to 1% of the population and up to 5% of individuals over the age of 65. ET is characterized by often disabling tremors that occur when an individual moves. The tremors most commonly affect the hands, head, voice, and legs in order of frequency, leading to impairment in activities of daily living and morbidity. No pharmacological agent has been developed for ET, though existing agents such as propranolol and primidone are used off-label to reduce tremor amplitude. Deep brain stimulation surgery is often reserved for only individuals with the most severe tremors. Patients with ET have long reported tremor benefits with the use of cannabis, though no controlled trials have been conducted. The investigators plan to conduct the first double-blind, placebo-control clinical trial of cannabis in an oral capsule. Various validated tremor rating methods will be used to quantify tremor severity, while looking at tolerability and safety.

Arms: arm 1: Treatment arm consisting of Tetrahydrocannabinol (5mg/capsule) and Cannabidiol (100mg/capsule). arm 2: Matched placebo capsule with no active ingredients.
Interventions: intervention 1: CBD/THC intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Oral formulation of combined Cannabidiol (CBD) and Tetrahydrocannabinol (THC). intervention 2: Matched Placebo

Protocol documents:
Prot_SAP_002.pdf: 
 
 
UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 9/30/2013 
1. 
PROJECT TITLE 
A Double-Blind, Cross-Over, Placebo- Controlled Efficacy and Tolerability Study of oral cannabidiol (CBD) 
and tetrahydrocannabinol (THC) for Essential Tremor (ET) 
2. 
PRINCIPAL INVESTIGATOR  
Fatta B. Nahab, M.D. 
 
3. 
FACILITIES 
UCSD Altman Clinical Translational Research Institute 
9452 Medical Center Drive 
La Jolla, CA 92037 
4. 
ESTIMATED DURATION OF THE STUDY 
24 months 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Essential tremor (ET) is the most common neurological movement disorder, affecting up to 1% of the 
population and up to 5% of individuals over the age of 65.  ET is characterized by often disabling tremors that 
occur when an individual moves.  The tremors most commonly affect the hands, head, voice, and legs in order 
of frequency, leading to impairment in activities of daily living and morbidity.  No pharmacological agent has 
been developed for ET, though existing agents such as propranolol and primidone are used off-label to reduce 
tremor amplitude.  Deep brain stimulation surgery is often reserved for only individuals with the most severe 
tremors.  Patients with ET have long reported tremor benefits with the use of cannabis, though no controlled 
trials have been conducted.  We plan to conduct the first double-blind, placebo-control clinical trial of cannabis 
in an oral capsule.  We will use various validated tremor rating methods to quantify tremor severity, while 
looking at tolerability and safety. 
6. 
SPECIFIC AIMS 
The present study seeks to assess the efficacy and tolerability of TILRAY TN-CT120LM (FDA IND#137400), a 
pharmaceutical-grade formulation containing THC and CBD, vs. placebo in an Essential Tremor patient 
population.  The study is intended to collect pilot data to determine whether larger studies are warranted and assist 
in their future design. 
 
Aim 1:  To determine if short-term exposure to orally administered THC/CBD improves tremor amplitude in ET 
patients.  Hypothesis 1:  ET patients receiving THC/CBD orally will have reduced peak tremor power (compared 
with their own baseline measures) by accelerometry and spirography vs. placebo. 
 
Aim 2:  To determine acute and short-term tolerability of orally administered THC/CBD.  Hypothesis 2:  ET 
patients receiving THC/CBD orally will be associated with more frequent ratings of sedation on the Common 
Toxicity Criteria compared with placebo. 
 
Aim 3:  To characterize the relationship between THC/CBD exposure with clinical response (i.e. tremor 
amplitude) to define a plausibly useful dose range for evaluation in future confirmatory clinical trials. 
7. 
BACKGROUND AND SIGNIFICANCE 
7.1 There is a great medical need for a more effective treatment for essential tremor. 
Essential tremor (ET) is traditionally defined as bilateral, generally symmetric postural and kinetic tremor of 
the upper extremities that is not attributable to identifiable causes, and has been present for at least 5 years. A 
meta-analysis of prevalence studies indicates that 0.4 to 0.9% of the general population has ET. The figure rises 


 
 
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to 4.6 to 6.3% among those 65 years or older (Louis and Ferreira, 2010). ET is a common cause of 
embarrassment, social withdrawal, disability, and loss of occupation. 
The most commonly utilized medications for ET are propranolol, primidone, topiramate, gabapentin, and 
benzodiazepines. Unfortunately, the long-term efficacy and tolerability of current medications leave much to be 
desired. If one surveys hundreds of ET patients, it is found that one-third have stopped all ET medications, even 
those with the most severe tremor. In other words, many of the most disabled ET patients have abandoned the 
search for a drug that can help them. Over half the patients who try primidone, propranolol, diazepam or 
topiramate end up stopping them, and the percentage is higher with other anti-ET medications (Louis et al., 
2010). 
 
This situation arises from lack of knowledge about the cause of ET, so that clinical trials on medications have 
been performed on the basis of guess-work or serendipity, with the majority ending with a negative result. The 
lack of any new positive recommendations by the 2011 Academy of Neurology evidence-based guideline 
update on the treatment of ET attests to the poor yield of present approaches to drug discovery (Zesiewicz et al., 
2011). 
 
The lack of knowledge about the etiology of ET is clearly a barrier to drug discovery. However drug discovery 
has proceeded for other neurological conditions in which the precise etiology is not clear, such as epilepsy, 
migraine and multiple sclerosis. We suspect that another barrier to drug discovery for tremor is the under-
appreciation by pharmaceuticals of the social, economic, and clinical significance of ET. 
Given that half of ET persons aged 65 and over take medication for tremor (Louis et al., 2000), and 2012 
demographic data that, among the 1,006.9 million persons living in the European Union, the United States, 
Japan, Canada, Australia and New Zealand, 163.7 million persons are aged 65 years and over, it can be 
estimated that 3.8 million persons in this age group in these countries are seeking or receiving medication for 
ET. If they are willing to pay $4 a day to treat their tremor, the market size would be $5.5 billion per year. 
Given that persons under age 65 are not included in this calculation, and another 2-3 billion persons in Asia, 
Latin America, Africa and the Middle East have joined or will soon join the middle class, the market size is 
likely much greater, at $10-15 billion per year world-wide. Any new ET medication that is highly effective and 
well tolerated will likely soon dominate a large market. 
 
In addition to neurologists empirically identifying potential treatments for tremor, ET patients themselves have 
empirically sought remedies. Numerous patients have identified low-dose alcohol as more effective than any 
prescribed ET medication for tremor suppression. Of particular interest, many ET patients have identified 
marijuana as more effective and well-tolerated for tremor than any prescribed ET medication, as discussed in 
the next section. 
 
7.2 Observations that cannabinoids suppress tremor in ET 
Dr. Nahab has clinically encountered a number of ET patients at the University of Miami and now at the 
University of California San Diego clinic who report that marijuana use alleviates tremor. He has carefully 
documented the tremor improvement in a case before and after initiation of marijuana (see Figure 1) and a 
separate individual before and after oral intake of CBD in hemp oil (see Figure 2).  
Case 1:  A 28-year old man had longstanding ET and had failed propranolol, primidone, topiramate and sodium 
oxybate due to adverse effects.  The case clearly demonstrates a striking reduction in ‘tremor power’ (severity) 
using objective spirography in the absence of other medication changes that could account for the tremor 
improvement with maintenance of tremor frequency that would be expected with any therapy.  See Figure 1 for 
change in tremor power by objective spirography. 


 
 
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Figure 1:   
Objective spirography of a patient with 
essential tremor at baseline and 
following inhaled cannabis.  A) Raw 
spirograms demonstrate reduced tremor 
amplitude, B) fast Fourier 
transformation of the spirography data 
shows a consistent tremor frequency for 
both right limbs (right=square, left-
diamond) with at least a 30-40% 
reduction in tremor power 
Case 2:  An 80-year old woman with longstanding bilateral ET underwent objective spirography of her tremors 
as she recreationally consumed increasing doses of CBD in hemp oil on subsequent days.  During the patient’s 
trial, she reported no adverse effects.  See Figure 2 for change in tremor power by objective spirography. 
  
Figure 2:   
Objective spirography of a 
patient with ET at baseline 
(day 0) with tremor severity 
in right (gray line) and left 
(orange line) hands.  
Reduction in tremor 
severity can then be seen on 
subsequent days 1-3 with 
measurements taken at 1-
hour post-CBD ingestion 
(termed peak) and prior to 
next day’s ingestion (termed 
trough).  
 
 
 
 
7.3 What is the mechanism by which cannabinoids may suppress tremor? 
Although the cause of ET is unknown, we do have some knowledge about the neural circuits that may be 
involved in tremor initiation and expression. It is therefore appropriate to consider these circuits and how 
cannabinoids may affect them.  
 
ET tremor does not disappear with anesthesia of the limb, or the frequency change with mechanical loading, 
indicating that it arises from a central generator. Magnetoencephalography during tremor in ET subjects reveals 
an oscillatory network involving the cerebellum, thalamus, motor cortex, and brainstem (Schnitzler et al., 
2009). In ET, PET scans show increased blood flow in the cerebellum even at rest (Boecker et al., 1996). ET 
patients have many anomalies of cerebellar function, including imbalance, irregular finger tapping, and subtle 
eye movement abnormalities, some of which improve with successful tremor treatment. The highly effective 
deep brain stimulation therapy acts by blocking outflow from the cerebellum to the motor thalamus. 
Transcranial magnetic stimulation of the cerebellum improves tremor (Popa et al., 2013).  
Our concept of the circuits involved in excessive cerebellar oscillatory activity underlying action tremor is 
displayed in Figure 3. A key concept is that these circuits form feedback loops, so that disease processes could 
occur at one or more of several sites within the loops to unleash and sustain the abnormal oscillations. 


 
 
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Likewise, interventions that dampen the oscillation could be applied at one or more points within these loops, 
and need not coincide with the site of disease.  
 
In considering the role of various components of the cerebellar system in tremor, we consider a ventral tier, 
likely involved in oscillation initiation, and a dorsal tier, involved in oscillation amplification. 
 
Inferior olive (IO) PET scans of ET patients have shown increased IO glucose utilization, and increased IO 
blood flow when patients are given alcohol (Boecker et al., 1996). Eyeblink conditioning, which depends on the 
olivo-deep cerebellar nuclei (DCN) projection, is impaired in ET patients, but improves after thalamic DBS. 
The IO is a natural pacemaker, and offers a mechanism for providing rhythmicity to cerebellar oscillatory 
activity. 
 
Deep cerebellar nuclei (DCN) The excitatory DCN neurons are the sole output neurons of the cerebellum, and 
in ET tremor an oscillatory loop involves DCN-motor thalamus-motor cortex-IO/pons-cerebellum. It is thus not 
surprising that strokes that severely damage the DCN, motor thalamus, frontal white matter or internal capsule 
can eliminate tremor in ET patients (Dupuis et al., 2010). The participation of DCN in tremor is demonstrated 
by PET imaging in ET and by c-fos imaging in rodents given the tremorigenic drug harmaline. Interestingly, 
partial lesions of the DCN produce action tremor in patients with head trauma and tremor in rats after chemical 
DCN lesions. An extensive literature has documented that action tremor ensues after lesions of DCN in 
monkeys (Gemba et al. 1980). Thus the DCN may be involved in both the initiation and propagation of the 
oscillations that underlie tremor. 
 
Cerebellar cortex Pcd mice that lose all Purkinje neurons still respond to harmaline with tremor, but the 
tremor is of lower amplitude and frequency compared to wild-type, indicating that Purkinje cells have a role in 
amplifying tremor. PET scans in ET patients demonstrate increased blood flow in the cerebellar cortex, present 
at rest, and increased with tremor. This increase is abolished by alcohol (Boecker et all, 1996). In the harmaline 
model, granule cells express c-fos early. Strokes involving the pons, which interrupt mossy fiber projections to 
granule cells, abolish tremor in ET (Dupuis et al., 2010). In summary, the components of the cerebellar cortex 
appear to be important for the amplification of hyperoscillations that underlie action tremor. 


 
 
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How might cannabinoids affect tremor in ET? Endocannabinoids are released by post-synaptic neurons to act 
retrogradely on pre-synaptic cannabinoid receptors to modulate the release of excitatory and inhibitory 
neurotransmitters.  The CB1R is intensely expressed on the 
terminals of parallel fibers derived from granule cells that 
contact Purkinje cells. CB1Rs are also expressed on 
terminals of basket and stellate interneurons, and on 
climbing fibers, all projecting to Purkinje cells. The 
Purkinje cells themselves do not express CB1Rs.  Aside 
from the rubro-olivary projection to inferior olive, there is 
little CB1R expression in the DCN or inferior olive. CB2Rs 
are also expressed in the terminals of parallel fibers and 
basket cells, but are also intensely expressed in the mossy 
fibers to the granule cell layer, neuropil of DCN, and in spinal cord terminals within the inferior olive (Suarez 
et al. 2008). Given this strong expression of cannabinoid receptors 
within all the components of the cerebellar system that have been 
implicated in tremor initiation and expression, it can be seen that 
endogenous or exogenous cannabinoids could be expected to 
influence the hyperoscillations that underlie tremor.  
 
An alternative mechanism could be the activation of glycine 
receptors. Glycine receptors are pentamers made of alpha and beta 
subunits. There are 4 isoforms of alpha, and one of beta. D9-
Tetrahydrocannabinol (THC) and cannabidiol (CBD) (see Figure 4) 
act as positive allosteric modulators of glycine receptors, including 
alpha1, alpha2 and alpha3 receptors (Ahrens et al., 2009; Hejazi et 
al., 2006). It has been suggested, for example, that CBD and related 
compounds exert analgesic effects against chronic pain via spinal 
alpha-3 glycine receptors, as these compounds suppress pain in CB1 
knockout mice, but not in alpha3 glycine receptor knockout mice 
(Xiong et al., 2012). In the cerebellum, Purkinje cells and deep 
cerebellar nucleus neurons strongly express messenger RNA for 
glycine receptors (Fujita et al., 1991). The deep cerebellar nuclei, 
from which all cerebellar outlow emanates, including tremor-associated oscillations, are composed of three 
types of neurons: (1) large, glutamatergic output neurons, (2) GABAergic neurons that project to the inferior 
olive, and (3) glycinergic or mixed glycinergic/GABAergic interneurons. All three types receive Purkinje 
afferents. The glycinergic interneurons project to the large DCN output neurons, and thus are positioned to play 
an important role in cerebellar output (Pedroarena and Kamphausen, 2007). 
 
These glycine receptors, composed of alpha1 and beta subunits, might be allosterically potentiated by 
cannabinoids, thereby suppressing tremor.  
Figure 3. Schematic of neural circuits involved by hyper-
oscillatory activity in action tremor. See text for discussion. 
Arrowheads connote excitation and bar endings connote 
inhibition. A  
 reciprocal loop involving stellate and Purkinje cells is omitted.  
CF: Climbing Fibers; DCN: Deep Cerebellar Nuclei; Go: Golgi 
interneurons; Gr: Granule cells: IO: Inferior Olive; MF: Mossy 
Fibers 
Thalamus
Pons
MF
CF
IO
Go
Gr
Purkinje
cells
DCN
Cerebral
Cortex
Thalamus
Pons
MF
CF
IO
Go
Gr
Purkinje
cells
DCN
Cerebral
Cortex
Figure 4.  Chemical structures of 
THC and CBD 


 
 
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7.4 Objective assessment of efficacy can be performed with a relatively small number of ET subjects 
Tremor is reliably elicited during posture and movement in persons with ET, thus permitting assessment of 
efficacy with relatively few subjects compared to other medical or neurological conditions that are 
characterized by intermittent events. Cross-over Phase 2 trials for ET that use rating scales typically employ 20 
to 60 subjects. Moreover, the use of digital spirography and accelerometry provide greater power at smaller 
sample sizes, as these measures appear to be more sensitive and reliable than the use of rating scales. 
In the ET field, the standard is to include placebo in the first reported trial of a treatment. The reason for this is 
that in the 1980's and 1990's numerous open-label positive results could not be replicated in controlled trials. 
Given the paucity of new treatments for ET in the past 10 years, knowledge of a positive result with even a 
small trial will rapidly become disseminated within the ET community. It may be noted that none of the 
medications currently prescribed for ET are FDA-approved for that condition.  A single positive Phase 2 study 
can result in a marketed drug gaining access to the $5-15 billion global ET market. 
8. 
PROGRESS REPORT 
Based on preliminary date from the first 5 subjects enrolled, we have learned a number of things to date that are 
being integrated into this protocol amendment: 
§ The dosing maximum that we have selected was poorly tolerated at 3 capsules administered 
concurrently, while it was tolerated by some subjects at the 2-capsule dose.  We are modifying the 
protocol to limit the maximum concurrent administration of study drug to 2 capsules QAM and 
providing the last capsule in the evening. 
§ The only adverse effect to date took place when a subject did not take the study drug after a meal.  This 
is already specified in both the protocol and consent, and we are simply emphasizing this and providing 
regular reminds to subjects. 
§ The frequent monitoring of vital signs, efficacy measures, and adverse effects within the first 3 hours of 
each study visit are excessive since the onset of effect in all subjects has been 2-3 hours post-dose.  We 
are modifying the protocol to reduce the number of initial assessments and extending the duration of 
each study visit to 4 hours to allow for an enhanced sensitivity in identifying adverse effects and 
efficacy. 
 
9. 
RESEARCH DESIGN AND METHODS 
9.1 Rationale for Study Design Selection 
The overall goal of this pilot trial is to determine whether TILRAY TN-CT120LM (FDA IND#137400), a 
pharmaceutical-grade formulation containing THC and CBD, is a viable therapeutic option for the management 
of ET.  The primary endpoints will include safety and efficacy.  Since the therapeutic dose of THC/CBD to 
manage ET is unknown, the study is designed to include a titration of the investigational drug to determine 
therapeutic doses.  The protocol allows for a maximum dose of 15mg of THC and 300mg of CBD. 
 
9.2 Strategies/Procedures for recruitment 
Subjects with a diagnosis of ET will be recruited from the UCSD Movement Disorder Center and the general 
community.  There will be an emphasis on obtaining a diverse sample composed of equal numbers of males and 
females, as well as an equal number of subjects above and below the age of 50.  
 
9.3 Description of Screening and Study Design  
SCREENING VISIT 
After being screened for inclusion/exclusion criteria and providing informed consent, subjects will undergo a 
complete neurological examination to confirm their diagnosis of ET and exclude other neurological disorders.   
Additional measures collected during this visit are listed in Appendix 1.  Note that subjects will need to have 
been on a stable dose of their medications for a minimum of 6 weeks prior to the screening visit and will be 


 
 
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encouraged to remain on these doses for the remainder of the study period.  Subjects will be asked about their 
other tremor medication doses at each follow-up visit to confirm stable doses. 
 
VIDEOTAPED TETRAS 
As part of each study visit (1-3), subjects will complete a TETRAS rating scale while being videotaped.  This is 
intended for rating purposes by two blinded raters at the completion of the study. 
 
RANDOMIZATION 
After completion of the screening visit, subjects will be assigned to one of two possible treatment arms based 
on a pre-set randomization matrix.  Only the research pharmacy who will be responsible for dispensing the 
doses will be aware of which of two treatment options will be provided, but not the identity of the particular 
agent. The equivalence of the THC/CBD and Placebo will be equally matched by the manufacturer, making it 
difficult for the subject to discriminate which arm they are on.  Subjects will be asked which arm they are 
receiving at each assessment visit and on telephone follow up to assess for potential unblinding. 
 
DOSE TITRATION AND TREATMENT 
On visit 1 and 5, subjects will receive 1 capsule of IMP every morning.  On visit 2 and/or 6, if the subject 
tolerated 1 capsule then they would receive 2 capsules every morning.  Alternatively, if 1 capsule was not 
tolerated, the timing of the administration would be changed to 1 capsule in the evening.  At visit 3 and/or 7, if 
the single nightly capsule was not tolerated, the subject would be dropped at this visit. If the 2 capsules every 
morning were tolerated, the subject would then receive 2 capsules in the morning and 1 capsule in the evening. 
If 2 capsules in the morning were not tolerated, the subject dosing would be changed to 1 capsule in the 
morning and 1 capsule nightly.  Subjects will remain on the highest tolerable dose for the duration of the period 
until visit 4 or 8 (See Appendix 2). 
 
The starting dose, titration schedule and target dose were selected based on safety, tolerability and efficacy data 
reported in previous studies using cannabinoids to treat pain (Langford et al., 2013; Portenoy et al., 2012; 
Johnson et al., 2010). Adverse effects will be inventoried at each study visit.  If the patient or investigator feel 
that the higher study drug dose is causing troublesome side effects, the dosage may be lowered.  Food intake 
can affect systemic exposure of cannabinoids (Zgair et al. 2016).  Subjects will be advised to schedule their 
dose at a similar time every morning after breakfast to maintain similar systemic exposure throughout the study.  
Regular reminders will be provided to subjects to ensure they are taking the study drug post-meals.  During 
study visits when drug is administered, subjects will be provided with a standardized FDA high-fat, high-
calorie meal prior to taking the study drug. 
 
DOSE TAPER AND WASHOUT 
After completing a 2-week course on 15/300 mg/day of THC/CBD or placebo, subjects will return on this dose 
for assessment and completion of the various measures detailed in Appendix 1.  After completion of this visit, 
subjects will taper from the treatment gradually over 1-week, in similar fashion to the dose titration up to the 
target dose.  Subjects will then complete a 3-week washout period prior to being crossed-over to the alternate 
arm.  This is to allow subjects to return to their baselines.  The duration selected is conservative and takes into 
consideration the known elimination half-life of THC/CBD. 
 
9.4 Assessment Measures 
DIGITAL SPIROGRAPHY 
This functional measure of kinetic tremor in subjects with ET has been validated by a group at NINDS, 
including Dr. Nahab. In this technique, the subject is asked to draw a spiral between the loops of a pre-printed 
spiral with an unsupported hand, proceeding from inside the figure to outside. This measure offers an objective 
measure of functional tremor, and may enable detection of efficacy with fewer subjects (Haubenberger et al., 


 
 
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2011).  As this methodology is recent, it has not yet found widespread application ET clinical trials. Subjects 
with severe tremor who have difficulty keeping the inking stylus in contact with the paper are not suited for this 
test. Based on our experience, we consider this scale to be appropriate as a primary outcome measure. 
 
ACCELEROMETRY 
This functional measure of tremor allows objective measurement of postural tremor.  During this task, subjects 
are asked to maintain each arm in an isometric posture with the arm in a ‘winged’ position in front of the chest.  
Tri-axial accelerometers are used to collect the tremor frequency and magnitude.  Tremor severity is derived 
from the time domain of a Fourier transformation.  This measure allows for standardization across time and 1-
minute of data is collected for each limb to minimize variability. 
 
TETRAS  
This scale evaluates tremor of various body parts during postures, kinesis and tasks. Items are scored from 0 to 
4, with 4 representing the highest degree of severity. The maximum score is 64 (Elble et al., 2012). Although 
this scale was recently published, it is a refinement of the long-used Fahn-Tolosa-Marin scale. Based on the 
authorship, this scale has clearly received widespread endorsement from the opinion leaders in the field of 
essential tremor. To achieve maximum credibility with any result from this clinical trial, it is appropriate to 
include this scale as a second primary measure. One difficulty with on-site blinded examiners is that they may 
be prone to placebo effects in their ratings, as they are aware which visit is baseline and which is the treatment 
visit, although the latter may be with placebo or active drug. To eliminate such order effects, we will videotape 
the subject undergoing this rating and provide the videos to a minimum of two blinded raters unfamiliar with 
which visits are baseline and treatment visits.  
 
GLOBAL IMPRESSION OF CHANGE 
This is a standardized and commonly used 7-point scale in which both the subject (PGI) and blinded clinician 
(CGI) rate the degree of change from baseline.  
 
PATIENT REPORTED OUTCOMES OF THE COMMON TERMINOLOGY CRITERIA 
All adverse events will be assessed and recorded using the Patient Reported Outcomes of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) version 1.0.  This is a standardized tool for 
identifying adverse events across all organ systems and includes severity classification.   
 
PHARMACOKINETIC ANALYSES 
Established nonlinear mixed-effects modeling methods will be used to evaluate the population pharmacokinetic 
and pharmacodynamic properties of CBD, THC, and 11-OH-THC.  The correlation between plasma 
concentrations and/or PK parameters with demographic factors (age, sex, body size, race) will be investigated, 
along with analysis of any relationship between exposure and the resulting efficacy and/or safety response.  
Different relationships (linear, log-linear, Emax and Sigmoidal Emax) will be explored to correlate exposure 
with pharmacodynamic metrics (assessment measures of tremor).  In addition, as prior studies have shown a 
hysteresis between THC plasma concentration and drug effect, we anticipate modeling the effect(s) using a 
hypothetical effect compartment, i.e. dCe/dt = ke0 ⋅ (Cp – Ce), where Cp is the plasma concentration, Ce is the 
concentration in the effect compartment, and ke0 is the a first-order rate constant describing transport into the 
effect compartment.   The final population pharmacokinetic model will be used to perform Monte Carlo 
simulations to determine the distribution of CBD, THC, and 11-OH-THC at various oral doses. 
 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
Suicidality will be assessed by trained study personnel using the C-SSRS (Posner et al. 2011). The C-SSRS is a 
standardized suicidal rating system conducted by a certified rater. The interview measures presence of 
suicidality and consists of four categories: suicide ideation, intensity of ideation, suicidal behavior and answer 


 
 
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for actual attempts only. This scale will be used for screening as well as to assess for the occurrence of any 
suicidal ideation and/or behavior during the study.  
 
9.5  Subject Monitoring 
Subjects will be monitored using PRO-CTCAE.  The principal investigator and sponsor will also select a 
committee of up to 4 qualified individuals to serve on a Data Safety and Monitoring Board.  The DSMB will 
receive regular updates on adverse events and will have access to unblinded data should they decide to explore 
whether a frequent or serious adverse event is associated with the study drug.  Assessment of suicidal ideation 
and/or behavior will be conducted using the Columbia-Suicide Severity Rating Scale (C-SSRS). 
 
9.6  Outcome Measures 
 
Primary Outcome Measures 
 
The primary outcome measures will be change from baseline of tremor power by digital spirography for drug 
vs. placebo. 
 
Secondary Outcome Measures 
 
The secondary outcome measures will include the TETRAS, CGI, PRO-CTCAE, plasma concentrations of 
CBD/THC, Common Toxicity Criteria for adverse effects, and Columbia-Suicide Severity Rating Scale. 
 
9.7 Sample Size Estimation 
A power analysis was performed to estimate the minimum number of subjects for enrollment.  We assumed the 
following:  Significance (p<0.01 or p<0.05, corrected), Power=0.80, minimum expected group difference of 
15%, and an estimated standard deviation of 10%.  Based on these assumptions, we will require a minimum of 
14 participants to complete the study.  For purposes of this study, 16 subjects will be enrolled and will complete 
all aspects of this study.  To account for drop-outs due to various causes, we plan to have an accrual ceiling of 
20 subjects. 
 
9.8 Data Analysis 
Data analysis will be performed by a consulting statistician who will also provide guidance in the final 
experimental design.  Each subject will serve as their own control.  We will collect baseline tremor severity 
using the various outcome measures described and will utilized paired-sample t-tests for evaluation of statistical 
significance between drug and placebo vs. baseline.  Descriptive statistics will also be performed in an 
exploratory fashion. 
 
10. 
HUMAN SUBJECTS 
10.1 Subjects 
Description of Study Population 
16 patients with Clinically Definite or Clinically Probable ET will complete the study.  We will have an accrual 
ceiling of 20 to allow for dropouts.  This will be a single site investigator-initiated trial with all aspects of the 
study taking place at UCSD.  Subject selection will be equitable among adult men and women.  We plan to 
enroll a wide selection of ages (≥21) and ethnicities to enhance our sample diversity and generalizability.  
Pregnant or lactating females will be excluded due to the unknown teratogenicity of THC/CBD.  Any women 
of childbearing potential will undergo a urine pregnancy test prior to receiving study medication and will be 
required to use some form of contraception during the course of the trial.  
 
10.2 Inclusion/Exclusion Criteria 


 
 
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Inclusion criteria 
• 
Subjects with ET diagnosed by a Movement Disorder Neurologist aged 21 and older 
• 
Subjects on a stable dose of tremor medication for a period of at least 6 weeks prior to screening 
• 
Subjects with upper limb tremors 
• 
Subjects with a minimum score of 2 on the TETRAS Question 2.4 (amplitude of at least 1-3cm) 
 
Exclusion criteria 
• 
Subjects with significant non-ET related abnormal findings on neurological exam. 
• 
Subjects with a tremor at rest. 
• 
Subjects with a diagnosis of mild cognitive impairment or dementia 
• 
Subjects who are pregnant or nursing, or suspect that they might be 
• 
Women of childbearing potential unable or unwilling to use a form of contraception during course of the 
trial  
• 
Subjects on medications known to interact with cannabinoid-type agents 
• 
Subjects with a history of alcohol use disorder (based on DSM-5 criteria) or substance abuse. 
• 
Subjects with exposure within the past 21 days to primidone or within the past 7 days to benzodiazepines, 
ketoconazole, ritonavir, clarithromycin, rifampin, carbamazepine, St. Johns Wort, digoxin or other agents 
known to be strong inducers or inhibitors of CYP3A, CYP2C19, and CYP2C9. 
• 
Subjects unwilling to abstain from consumption of grapefruits, grapefruit juice or grapefruiting-containing 
products that are known to strongly inhibit CYP3A4. 
• 
Subjects taking concomitant medications that are highly protein-bound with a narrow therapeutic index 
(e.g. warfarin, cyclosporine, and amphotericin B). 
• 
Subjects who do not wish to take a cannabis-derived agent 
• 
Subjects who an allergy or sensitivity to sorbitol, xylitol, stevia or other natural sweeteners 
• 
Subjects with an allergy or sensitivity to cannabis. 
• 
Subjects actively using cannabis or a cannabis-derived product (within 4 weeks of screening) or who are 
unwilling to discontinue its use during the course of the study. 
• 
Subject with a history of significant Axis I psychiatric disorder (e.g., mania, bipolar depressive disorder, 
schizophrenia, schizoaffective disorder, or other major psychiatric disorder) 
• 
Subject with active or prior history of suicidal ideation and/or behavior. 
• 
Subject with significant coagulopathy, immunologic, gastrointestinal, respiratory, cardiovascular (e.g., 
uncontrolled hypertension, myocardial infarction in the last 18 months, significant bundle branch block, 
congestive heart disease), or endocrine (e.g., uncontrolled diabetes, hyperthyroidism) disorder 
• 
Subject with current or chronic infection. 
• 
Subject with renal insufficiency (GFR <60) 
 
11. 
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
Subjects will be recruited primarily through print and online advertising (advertisement language is also 
attached for approval) with the assistance of the International Essential Tremor Foundation and the local UCSD 
Movement Disorders clinic.  In addition, we would request a partial waiver of individual authorization for use 
of Protected Health Information (PHI) by the IRB as this component meets the requirements outlined by the 
HIPAA Privacy Rule, 45 CFR 164 section 512(I).  Specifically, we would request a waiver pertaining to 
targeted EMR queries of UCSD Epic to identify individuals with Essential Tremor and collecting the following 
variables:  name, contact info, birthdate, diagnosis of essential tremor, presence of parkinson’s disease (as an 
exclusion variable), and use of primidone.  Data from the EMR query will be used to inform treating physicians 
that they may have eligible patients and to assist in making patients aware of the study.  We will not contact 
patients directly without having received prior consent to be contacted. 
 


 
 
Biomedical IRB Application Instructions 
Page 11 
12. 
INFORMED CONSENT 
Interested patients and their caregivers will be scheduled to meet with a qualified investigative staff member 
and receive an explanation of the study purpose and requirements in lay language.  If still interested in 
participating after receiving an explanation of the study, patients and their caregivers will be given an 
opportunity to review and inquire about the study-specific written informed consent form.  Patients and their 
caregivers will have ample time to think about the information in the written informed consent form and have a 
chance to discuss it with family members or other people.  Any patient and caregiver who has difficulty 
understanding the information contained in the written informed consent form will be asked to reread the 
misunderstood portion(s) of the consent and discuss it with a research staff member until s/he shows complete 
understanding of the information discussed in the informed consent form, and may thus give full consent.  
Research staff will work closely with patients and their caregivers in an effort to help them understand the 
requirements of study participation.  Patients’ and caregivers’ questions must be answered fully by trained and 
qualified staff.  Any patient or caregiver who is unable to demonstrate understanding of the information 
contained in the informed consent form will be excluded from study participation.  
Prior to a patient’s participation in the study, the written IRB approved informed consent form will be signed 
and personally dated by the patient) and by the person who conducted the informed consent discussion.  In 
addition, a statement to document the informed consenting process will be recorded in the patient’s source 
documents.   
The consent form and any other information provided to patients will be revised whenever important new 
information becomes available that is relevant to a patient’s consent and continued participation in the study. 
The revised consent form and information will receive IRB approval prior to use. The Investigator, or study 
coordinator should fully inform all patients of all pertinent aspects of the study and any new information 
relevant to the patients’ willingness to continue participation in the study.  This communication with the patient 
should be documented by the patient signing and personally dating the revised consent form and by written 
documentation of this discussion with the patient in the Investigator’s study files available to Sponsor for onsite 
review.   
Each patient who consents to participate in the study will receive a copy of the signed and dated written 
informed consent form and any other information provided to patients prior to the participation in the study. 
The original signed forms will be maintained in the Investigator’s study file.  After providing and documenting 
consent on the IRB approved written informed consent form, patients will be assigned their patient screening 
number and proceed to the Screening Period.  
A copy of the informed consent and HIPAA form has been uploaded for review and approval.   
The signed informed consent includes the following information:  
1. 
Who is conducting the study 
2. 
Procedures 
3. 
Potential risks and discomforts 
4. 
Benefits 
5. 
Expense to subjects 
6. 
Confidentiality 
7. 
Voluntary participation/withdrawal 
8. 
Emergency and study contact 
9. 
HIPAA discussion 


 
 
Biomedical IRB Application Instructions 
Page 12 
No study procedures will occur including screening until informed consent is obtained.  The patient may 
withdraw his/her consent to participate in the study at any time. A patient is considered as enrolled in the study 
when he/she has signed the informed consent form. The entire consenting process will take place in a private 
exam room to ensure the participant’s privacy and confidentiality is protected.  
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
The alternative to participation in this study is to not participate and continue with any prior clinical care.  
 
14. 
POTENTIAL RISKS 
GENERAL ADVERSE EFFECTS 
The risks and discomforts known to occur from the use of cannabis include but may not be limited to the 
following:  coordination difficulties, dizziness, lightheadedness, eye irritation, increased heart rate (rapid heart 
beat), decreased blood pressure (low pressure of blood within arteries), sedation (sleepiness), feeling high, 
reversible effects on your appetite, mood, memory (ability or recall) and judgment (capacity to form an 
opinion). Specific mood changes may include anxiety, paranoia, and unusual, disturbing thoughts. Individual 
response to cannabis varies widely.   
 
DEPENDENCE 
Few Cannabis users develop dependence. With prolonged use, individuals may experience withdrawal 
symptoms such as irritability, restlessness, mild agitation, cramping, nausea, vomiting, sleep disturbances, and 
loss of appetite.  Based on the dose of CBD and THC in TILRAY TN-CT120LM (FDA IND#137400), we do 
not anticipate symptoms of dependence or withdrawal, but will monitor for them nonetheless. 
 
SOCIAL 
Subjects are also informed that THC and CBD can be found in the body days or weeks after exposure, leading 
to a theoretical risk of a positive drug test should the subject be seeking employment, or undergoes testing as a 
part of their employment.  
 
CARDIOVASCULAR 
While the use of one of the cannabinoids (THC) found in the investigational drug is a rare trigger of 
cardiovascular events, there may be a significant increase in the rate of cardiovascular events (e.g. heart attack) 
for 1 hour following the use of cannabis. 
 
REPRODUCTIVE RISKS 
While THC and CBD are not known to cause birth defects, the investigators do not wish to expose the unborn 
child to any unnecessary medications, so subjects who are pregnant or unwilling to use a contraceptive during 
the course of the study will be excluded.  A urine pregnancy test will be performed and confirmed negative 
before women of childbearing potential may participate in the study.  
 
BLOOD SAMPLING 
Since a blood sample will be collected at required study visits, subjects are informed about the risks of  pain, 
discomfort, redness, bruising, infection and/or irritation at the needle insertion site, and rare risks of fainting, 
dizziness, and lightheadedness that may occur.  
 
QUESTIONNAIRES AND SCALES 
Subjects will need to complete questionnaires and scales during the study visits.  These ask about quality of life 
and ability to carry out certain daily activities.  Reviewing health related information might be stressful or make 
the subject feel uncomfortable.   


 
 
Biomedical IRB Application Instructions 
Page 13 
 
LOSS OF CONFIDENTIALITY 
Every effort will be made to keep all information including the results for substance abuse screening 
confidential; however there is slight risk of loss of confidentiality that may affect a subject’s employability, 
insurability, ability to adopt and possible criminal/civil liabilities.  These risks will be minimized to the extent 
possible. 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
Subject safety and tolerability will be monitored in this study across multiple dimensions by tracking clinical 
adverse events; vital signs (including orthostatic pulse and blood pressure); general and neurological physical 
examinations; standard clinical laboratory safety panels for complete blood counts, chemistry, coagulation, and 
urinalysis; standard 12-lead electrocardiograms; the Patient Reported Outcomes of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE), and Columbia Suicide Severity Rating Scale (C-SSRS).  Subjects 
answering “yes” to Suicidal Ideation item 4 or 5 on the C-SSRS during the study must be withdrawn from the 
study treatment. The PI will also withdraw subjects from treatment if, in the judgment of the Investigator, the 
subject develops other indicators of significant risk of suicide. In the event that suicidal ideation is observed in 
any study subject, the PI will manage the situation as he/she deems medically and psychiatrically appropriate. 
Further, In the event that a subject reports suicidal ideation, the subject will be withdrawn from the study and 
personally escorted by a study team member to the UCSD Emergency department for urgent psychiatric 
evaluation and management.  In the event that we are made aware of such suicidal ideation by telephone 
outside of routine study visits, subjects will be referred to a local ED for evaluation and we will conduct a 
telephone follow up to ensure the subject followed through with these recommendations. 
 
The specified inclusion/exclusion criteria have been carefully considered to avoid enrollment of subjects for 
whom exposure to the study drug might pose a hazard, particularly as it relates to individuals with a history of 
substance abuse. 
 
In order to provide independent oversight over patient safety, the PI will select of committee of up to 4 
qualified individuals to serve on a Data Safety and Monitoring Board (DSMB).  The DSMB will receive 
regular updates (minimum of quarterly) on adverse events and will have access to unblinded data should they 
decide to explore whether a frequent or serious adverse event is associated with the study drug.  All serious 
adverse events (SAEs) meeting criteria for expedited reporting to the US FDA will be reported to the FDA,  
IRB, and DSMB in accordance with regulatory timelines.  In the case of a fatal or life-threatening event, we 
will notify the FDA by telephone within 3 working days and stop further enrollment until the serious adverse 
event can be reviewed by the DSMB.  In addition, any event that is unexpected will be reported to the FDA and 
IRB within 7 working days. 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
Subjects will be given a Health Insurance Portability and Accountability Act (HIPPA) authorization form to 
sign. This separate consent will authorize the Investigator(s) and his/her/their staff to access medical records 
and associated information as may be necessary for purposes of this study.  The Investigator and his/her 
collaborators, staff will consider your records confidential to the extent permitted by law. The Sponsor, Food 
and Drug Administration (FDA) and Department of Health and Human Services (DHHS) may review these 
research records. Records may also be reviewed for audit purposes by authorized UCSD employees or other 
agents who will be bound by the same provisions of confidentiality. 
 
All study-related data will be maintained securely on UCSD computers based on UCSD Information Security 
policies outlined by the UCSD Administrative Computing and Telecommunications department (ACT).  
Subjects will receive a study identification number that will only be available to the principal investigator.  All 
other study databases will only include this anonymous study ID number.  This anonymous study data may be 


 
 
Biomedical IRB Application Instructions 
Page 14 
maintained indefinitely.  Authorized access will only be granted to study investigators or as otherwise defined 
by university policy.  The study site personnel may use this information to notify subjects of appointments, 
send appointment reminders, or schedule additional appointments.   
17. POTENTIAL BENEFITS 
Subjects may or may not directly benefit from participating in this study.  However, participation may be 
beneficial to others by providing information that is useful to our understanding of the study drug and its use in 
ET.  The study drug may or may not have any effect on ET. 
18. RISK/BENEFIT RATIO 
This research represents a more than minimal risk.  While there is the limited prospect of direct benefit to 
individual subjects who could experience a reduction in their tremors, it is more likely to yield generalizable 
knowledge.  All aspects of this research have been designed to limit risk to the extent possible and provides a 
favorable risk:benefit ratio. 
19. EXPENSE TO PARTICIPANT 
There will be no cost to subjects to be in this study.  Study drug will be provided to subjects free of charge.  The 
study visits, interviews, and examinations during participation will be provided at no cost to subjects.  Participants 
will not be required to pay for parking. Parking permits will be provided by study staff if necessary. The only 
expense to the participant will be transportation to UCSD.   
20. COMPENSATION FOR PARTICIPATION 
Subjects will not receive remuneration for participating in this study.   
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Fatta Nahab, MD is an Associate Professor of Neurosciences and Director of the Functional Imaging of 
Neurodegenerative Disorders Lab in the Movement Disorders Center at UC San Diego.  As PI, he will oversee 
and assist with the performance of all aspects of this study, including study design, implementation, data 
collection, data analysis, and reporting.   
 
Brenton Wright, MD is an Assistant Professor of Neurosciences in the Movement Disorders Center at UC San 
Diego.  He will serve as associate investigator and will assist with the performance of data collection, data 
analysis and reporting. 
 
Katherine Longardner is a Clinical Research Fellow in the Movement Disorders Center at UC San Diego.  She 
will serve as associate investigator will assist with the performance of data collection, data analysis and reporting. 
 
Leander Lazaro is a study coordinator and under the direction of the PI will be responsible for screening and 
recruiting participants, scheduling study visits, perform activities related to those visits, collecting data, 
maintaining regulatory documents, research records, and keeping the PI informed of all adverse events. 
22. BIBLIOGRAPHY 
Agurell S, Carlsson S, Lindgren JE, Ohlsson A, Gillespie H, Hollister L. Interactions of delta 1-tetrahydrocannabinol with cannabinol 
and cannabidiol following oral administration in man. Assay of cannabinol and cannabidiol by mass fragmentography. Experientia 
1981;37: 1090. [PubMed: 6273208]  
Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L. Pharmacokinetics and metabolism of delta 1-
tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol. Rev 1986;38: 21. [PubMed: 3012605]  
Ahrens J, Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, Haeseler G. The nonpsychotropic cannabinoid 
cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology 2009;83: 217-22.  
Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L. Cannabinoids control spasticity and tremor in 
multiple sclerosis model. Nature 2000;404: 84. [PubMed: 10716447]  


 
 
Biomedical IRB Application Instructions 
Page 15 
Benowitz NL, Nguyen TL, Jones RT, Herning RI, Bachman J. Metabolic and psychophysiologic studies of cannabidiol-hexobarbital 
interaction. Clin. Pharm. Ther 1980;28: 115.  
Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr 
Drug Saf 2011;6: 237-49. 
Boecker H, Wills AJ, Ceballos Baumann A, Samuel M, Thompson PD, Findley LJ, Brooks DJ. The effect of ethanol on alcohol 
responsive essential tremor: a positron emission tomography study. Ann Neurol 1996;39: 650 8. 
Dupuis MJ, Evrard FL, Jacquerye PG, Picard GR, Lermen OG. Disappearance of essential tremor after stroke. Mov Disord 2010;25: 
2884 7. 
Elble RJ, Biondi DM, Ascher S, Wiegand F, Hulihan J. Carisbamate in essential tremor: brief report of a proof of concept study. Mov 
Disord 2010;25: 634 638. 
Elble R, Comella C, Fahn S, Hallett M, Jankovic J, Juncos JL, Lewitt P, Lyons K, Ondo W, Pahwa R, Sethi K, Stover N, Tarsy D, 
Testa C, Tintner R, Watts R, Zesiewicz T. Reliability of a new scale for essential tremor. Mov Disord 2012;27: 1567-1569. 
Fujita M, Sato K, Sato M, Inoue T, Kozuka T, Tohyama M. Regional distribution of the cells expressing glycine receptor beta subunit 
mRNA in the rat brain. Brain Res 1991;560: 23-37.  
Gemba H, Sasaki K, Yoneda Y, Hashimoto S, Mizuno N. Tremor in the monkey with a cerebellar lesion. Exp Neurol 1980;69: 173 
82. 
Gironell A, Kulisevsky J, Barbanoj M, Lopez-Villegas D, Hernandez G, Pascual-Sedano B. A randomized placebo-controlled 
comparative trial of gabapentin and propranolol in essential tremor. Arch Neurol 1999;56: 475-480. 
Gorman WP, Cooper R, Pocock P, Campbell MJ. A comparison of primidone, propranolol, and placebo in essential tremor, using 
quantitative analysis. J Neurol Neurosurg Psychiatry 1986;49:64-68. 
Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. 
Proc. Natl. Acad. Sci. U.S.A 1998;95: 8268. [PubMed: 9653176]  
Harvey, DJ.; Martin, BR.; Paton, WDM. Marijuana: Biological Effects. Nahas, GG.; Paton, WDM., editors. Pergamon Press; Oxford: 
1979: 45. 
Harvey DJ, Mechoulam R. Metabolites and cannabidiol identified in human urine. Xenobiotica 1990;20: 303. [PubMed: 2336840]  
Haubenberger D, Kalowitz D, Nahab FB, Toro C, Ippolito D, Luckenbaugh DA, Wittevrongel L, Hallett M. Validation of digital 
spiral analysis as outcome parameter for clinical trials in essential tremor. Mov Disord 2011;26: 2073-80. 
Heuberger JA, Guan Z, Oyetayo OO, Klumpers L, Morrison PD, Beumer TL, van Gerven JM, Cohen AF, Freijer J.  Population 
pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term 
pharmacokinetics.  Clin Pharmacokinet. 2015 Feb;54(2):209-19. doi: 10.1007/s40262-014-0195-5. 
Hejazi N, Zhou C, Oz M, Sun H, Ye JH, Zhang L. Delta9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly 
potentiate the function of glycine receptors. Mol Pharmacol 2006; 69:991-7. 
Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, Double-Blind, Randomized, 
Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety and Tolerability of THC:CBD Extract and THC Extract in Patients 
with Intractable Cancer-Related Pain. Journal of Pain and Symptom Management 2010; 39: 167-179 
Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U.  Analgesic effect of the synthetic cannabinoid CT-3 on chronic 
neuropathic pain: a randomized controlled trial. J. Am. Med. Assoc 2003;290: 1757.  


 
 
Biomedical IRB Application Instructions 
Page 16 
Koller WC, Royse VL. Time-course of a single oral dose of propranolol in essential tremor. Neurology 1985;35: 1494-1498. 
Louis ED, Barnes LF, Ford B, Pullman SL, Yu Q. Ethnic  differences in essential tremor. Arch Neurol 2000;57: 723 727. 
Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential 
tremor. Mov Disord 2010;25: 534 541. 
Louis ED, Rios E, Henchcliffe C. How are we doing with the treatment of essential tremor (ET)?: Persistence of patients with ET on 
medication: data from 528 patients in three settings. Eur J Neurol 2010;17: 882 4. 
Malfait AM, Galllily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M. The nonpsychoactive cannabis 
constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. U.S.A 2000;97: 
9561. [PubMed: 10920191]  
Mechoulam R, Gaoni Y. Recent advances in the chemistry of hash- ish. Fortschritte der Chemie organischer Naturstoffe Progress in 
the chemistry of organic natural products. 1967;25:175–213.   
Melamede, R. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Grotenhermen, F.; Russo, E., 
editors. The Haworth Integrative Healing Press; New York: 1984: 111. 
Nadulski T, Sporkert F, Schnelle M, Stadelmann AM, Roser P, Schefter T, Pragst F. 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 2005;29: 782. [PubMed: 16356335]  
Peat, MA. Advances in Analytical Toxicology II. Baselt, RC., editor. Year Book Medical Publishers; Chicago: 1989: 186.  
Pedroarena CM, Kamphausen S. Glycinergic synaptic currents in the deep cerebellar nuclei. Neuropharmacology 2008;54: 784-95. 
Perez-Reyes M, Timmons MC, Davis KH, Wall EM. A comparison of the pharmacological activity in man of intravenously 
administered delta9-tetrahydrocannabinol, cannabinol, and cannabidiol. Experientia 1973;29: 1368. [PubMed: 4761242]  
Plasse, T. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Grotenhermen, F.; Russo, E., editors. 
The Haworth Integrative Healing Press; New York: 1984: 165.  
Popa T, Russo M, Vidailhet M, Roze E, Lehericy S, Bonnet C, Apartis E, Legrand AP, Marais L, Meunier S, Gallea C. Cerebellar 
rTMS stimulation may induce prolonged clinical benefits in essential tremor, and subjacent changes in functional connectivity: An 
open label trial. Brain Stimul 2013;6: 175 9. 
Schnitzler A, Monks C, Butz M, Timmermann L, Gross J. Synchronized brain network ssociated with essential tremor as revealed by 
magnetoencephalography. Mov Disord 2009;24: 1629 35. 
Suárez J, Bermúdez-Silva FJ, Mackie K, Ledent C, Zimmer A, Cravatt BF, de Fonseca FR. Immunohistochemical description of the 
endogenous cannabinoid system in the rat cerebellum and functionally related nuclei. J Comp Neurol 2008;509: 400-21. 
Troster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor Questionnaire (QUEST): development 
and initial validation. Parkinsonism Relat Disord 2005;11: 367 373. 
Wall, ME.; Brine, DR.; Perez-Reyes, M. The Pharmacology of Marihuana. Braude, MC.; Szara, S., editors. Raven Press; New York: 
1976: 93.  
Xiong W, Cui T, Cheng K, Yang F, Chen SR, Willenbring D, Guan Y, Pan HL, Ren K, Xu Y, Zhang L. Cannabinoids suppress 
inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med 2012;209: 1121-34.  


 
 
Biomedical IRB Application Instructions 
Page 17 
Zesiewicz TA, Elble RJ, Louis ED, Gronseth GS, Ondo WG, Dewey RB Jr, Okun MS, Sullivan KL, Weiner WJ. Evidence based 
guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of 
Neurology. Neurology 2011;77: 1752 1755. 
Zhornitsky S, Potvin S.  Cannabidiol in Humans—The Quest for Therapeutic Targets. Pharmaceuticals 2012, 5: 529-552.  
doi:10.3390/ph5050529  
Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC 
in normal subjects. Psychopharmacology 1982;76: 245. [PubMed: 6285406]  
23. FUNDING SUPPORT FOR THIS STUDY 
Funding is provided by a grant from the International Essential Tremor Foundation.  A contract between Tilray 
and UCSD will provide study drug and funding for the PK portion of this study. 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
N/A 
 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
See attached FDA IND 137400 Permission to Proceed Letter and Investigator’s Brochure. 
 
26. IMPACT ON STAFF 
This study will utilize existing resources to conduct this study, including the services of the ACTRI clinic. 
 
27. CONFLICT OF INTEREST 
The principal investigator and research have report no conflicts of interest with regard to this study. 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
N/A 
 
29. OTHER APPROVALS/REGULATED MATERIALS 
N/A 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Biomedical IRB Application Instructions 
Page 18 
APPENDIX 1:  STUDY OVERVIEW 
EVENT 
VISIT 0: 
SCREENING 
VISIT 1: DOSE 
TITRATION 
VISIT 2: PK 
VISIT 3: PK 
TREATMENT 
PHASE 
VISIT 4:  
ASSESSMENT 
TAPER 
WASHOUT 
VISIT 5: DOSE 
TITRATION 
VISIT 6: PK  
VISIT 7: PK 
TREATMENT 
PHASE 
VISIT 8: 
ASSESSMENT 
TAPER 
TELEPHONE 
FOLLOW-UP 
TOTAL 
DAYS 
TOTAL DAYS  
0 
5 
1 
16 
1 
5 
22 
5 
1 
16 
1 
5 
1 
77 
DAY 
NUMBER (±3) 
0 
1 
3 
6 
 
22 
23 
28 
50 
52 
55 
 
71 
72 
77 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
Exam 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
 
 
TETRAS 
(video) 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Spirography 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Accelerometry 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
CGI/PGI 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
PRO-CTCAE 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
C-SSRS 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Lab Testing -
pregnancy, 
CBC, CMP, 
Drug screen 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
EKG* 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
 
 
PK Sample(s) 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
* EKG at screening, then post-dose at each subsequent visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Biomedical IRB Application Instructions 
Page 19 
9.16.2 APPENDIX 2:  DOSE TITRATION AND TREATMENT PLAN (THC/CBD*** or PLACEBO) 
 
***Note:  THC/CBD formulation will consist of 5mg of THC and 100mg of CBD per capsule. 
 
 
 
 
9.16.3 APPENDIX 3:  PHARMACOKINETIC SAMPLING TIMES** 
DAY # 
TIME 
3 
Trough 
6 
Trough 
22 
Trough + Pseudorandom (1,2,3, 
or 4 hrs/post-dose) sample 
**NOTE:  Samples will be collected for drug and placebo to maintain blinding, but PK lab will be unblinded in order to 
process only drug samples.  If subject receive placebo first, PK days will be: #52, 55, and 71.