Clinical trial NCT02460692
Conditions: Cannabis Low Back Pain Neuropathic Pain
Sponsor: University of California, San Diego
Start date: 2016-12-01; Completion date: 2020-03-25
Enrollment: 131 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will involve treating low back pain associated with nerve injury with oral delta-9-tetrahydrocannabinol (Δ9-THC) or whole plant cannabis for eight weeks. Research subjects will consume either oral Δ9-THC (dronabinol), vaporized 3.7% Δ9-THC/5.6% CBD, or placebo. An analysis will then be determined to assess the risk--benefit ratio of dronabinol and vaporized 3.7% Δ9-THC/5.6% CBD .

Detailed description:
The present study is designed to assess whether treatment with vaporized cannabis or dronabinol (oral Δ9-THC) reduces spontaneous and evoked pain more than placebo, and whether there are any differences between the two active treatments in terms of interference with activities of daily living. This study also aims to examine the effects of vaporized whole plant cannabis and dronabinol on mood, neuropsychological function, and psychomimetic side-effects (high, stoned, etc.) compared to placebo and to each other. In addition, we plan to examine the acute effects (after receiving stable treatment for 4 weeks) of vaporized cannabis and dronabinol compared to placebo and each other on driving skills.

Arms: arm 1: The present study is designed to evaluate whether or not a medium dose of cannabis (3.7% delta-9-THC/5.6% CBD) can maintain an analgesic response over an eight week period compared to placebo. arm 2: A direct comparison of cannabis and dronabinol has not been performed in a clinical population. The present study will fill this void by performing a randomized, controlled 8 week trial comparing the effectiveness of oral versus vaporized cannabis in patients with neuropathic low back pain. arm 3: The eight week outpatient study will compare the efficacy and side effect profile of cannabis (3.7%THC/5.6%CBD) and dronabinol. We will also perform a human laboratory experiment evaluating driving using the same study medications that subjects received during their 8 week outpatient treatment.
Interventions: intervention 1: Placebos intervention 2: dronabinol intervention 3: Vaporized Cannabis 3.7% THC/5.6% CBD
Intervention descriptions: intervention 1: Administration of vaporized cannabis plus either dronabinol or placebo pill intervention 2: Administration of vaporized cannabis plus either dronabinol or placebo pill intervention 3: Administration of vaporized cannabis plus either dronabinol or placebo pill

Protocol documents:
Prot_000.pdf: 
 
 
 
 
UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN  
10/10/2016 
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 Randomized Controlled Trial of Dronabinol and Vaporized Cannabis in Chronic Low Back Pain 
2. 
PRINCIPAL INVESTIGATOR  
Thomas D. Marcotte, PhD., Professor, Department of Psychiatry 
3. 
FACILITIES 
We plan on conducting the study at the following locations: 
1. HIV Neurobehavioral Research Center/Center for Medicinal Cannabis Research (CMCR), 220 
Dickinson Street, Suite B, MC8231 
San Diego, CA 92103-8231 
4. 
ESTIMATED DURATION OF THE STUDY 
We estimate that the study will take 4 years. 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
This study will involve treating low back pain associated with nerve injury with two types of medicinal 
cannabis for eight weeks. Research subjects will consume either oral Δ9-THC (dronabinol), vaporized 
4.0% Δ9-THC/6.5% CBD (estimated percentages), or placebo. An analysis will then be performed to 
assess the risk-benefit ratio of dronabinol and vaporized 4.0% Δ9-THC/6.5%. In addition, subjects will 
undergo driving simulation to determine how long it takes for them to recover from these medications.  
6. 
SPECIFIC AIMS 
AIM #1 To assess whether treatment with vaporized whole plant cannabis or oral ∆9-THC reduces 
spontaneous and evoked pain more than placebo, and whether there are differences between the 
two active treatments. 
AIM #2 To examine the effects of vaporized whole plant cannabis and oral Δ9-THC (dronabinol) on 
mood, neuropsychological function, and psychomimetic side-effects (high, stoned, etc.) compared to 
placebo and to each other. 
AIM #3 To examine the acute effects (after receiving stable treatment for 4 weeks) of vaporized 
whole plant cannabis and oral Δ9-THC compared to placebo and each other on driving skills. 
7. 
BACKGROUND AND SIGNIFICANCE 
             The present proposal builds upon previous work funded by the University of California Center 
for Medicinal Cannabis Research (CMCR) 1. In our first study, thirty-eight patients with a 
heterogeneous collection of neuropathic pain conditions (e.g., spinal cord injury pain, central post-
stroke pain, peripheral neuropathy, post-herpetic neuralgia, and complex regional pain syndrome) 
resistant to standard pharmacologic treatments were recruited.2 Subjects underwent a standardized 
procedure for smoking high dose (7% Δ9-THC), medium dose (3.5% Δ9-THC), or placebo Δ9-THC 
while continuing to use their regularly prescribed treatments. 2 A mixed linear model demonstrated an 
equivalent analgesic response to smoking cannabis with both the high and medium doses. 
Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly 
with memory, at the high dose (7% Δ9-THC).  
 
Our second study involved subjects with similar neuropathic pain diagnoses.3 Smoking was 
discarded as a delivery technique in favor of vaporization to reduce exposure to harmful pyrolytic 
compounds.4, 5 In addition, low dose (1.3%) Δ9-THC was substituted for high dose (7%) Δ9-THC. We 
did this to evaluate a further reduction of the concentration of this psychoactive constituent of 


 
 
Biomedical IRB Application Instructions 
Page 2 
cannabis on cognitive and psychoactive side-effects. In this second study, both the low (1.3%) and 
medium dose (3.5%) Δ9-THC proved to be equivalent analgesics. In general, the effect sizes on 
cognitive testing were consistent with the minimal doses of Δ9-THC employed; the effect of the low 
dose (1.3%) was often less than that of the medium dose (3.5%) Δ9-THC.  
            Both of the above studies were 6-hour human laboratory experiments. The present study is 
designed to evaluate whether or not the medium dose of cannabis (3.5%) can maintain an analgesic 
response over an eight-week period. In addition, a direct comparison of this vaporized preparation will 
be made with dronabinol and placebo. The medium dose of cannabis (3.5%) has been selected as it 
was utilized in a human experimental laboratory experiment that compared inhaled Δ9-THC and 
dronabinol.6 Using the cold-pressor test, participants immersed their hand in cold water (4 degrees 
C), and the time to report pain (pain sensitivity) and withdraw the hand from the water (pain 
tolerance) was recorded. Compared with placebo, marijuana and dronabinol decreased pain 
sensitivity, increased pain tolerance, and decreased subjective ratings of pain intensity. The 
magnitude of peak change in pain sensitivity and tolerance did not differ between marijuana and 
dronabinol, although dronabinol produced analgesia that was of a longer duration. Marijuana and 
dronabinol also increased abuse-related subjective ratings relative to placebo; these ratings were 
greater with marijuana. These data indicate that under controlled conditions, marijuana and 
dronabinol decreased pain, with dronabinol producing longer-lasting decreases in pain sensitivity and 
lower ratings of abuse-related subjective effects than marijuana.  
              A direct comparison of cannabis and dronabinol has not been performed in a clinical 
population. The present study will fill this void by performing a randomized, double-blind placebo 
controlled 8-week trial comparing the effectiveness of oral versus vaporized cannabis in patients with 
chronic low back pain. In addition to studying efficacy, we will also perform a driving simulation study 
to determine the real-world impact of cannabinoid treatments. 
9. 
RESEARCH DESIGN AND METHODS 
           All procedures will be experimental, investigational and/or are carried out solely for research 
purposes. There will be no standard treatment or therapy (i.e., procedures that participants would 
receive even if not participating in research) performed in the two arms of this study that are 
described below: 
.  
ARM #1. Eight-Week Randomized Controlled Study Of 4% THC/6.5% CBD Cannabis Versus 
Oral Δ9-THC:  
 
An 8 week randomized, controlled phase 2/3 clinical trial of cannabinoid preparations will be 
performed utilizing three treatment regimens: 
 
(1) vaporized Δ9-THC (4.0% Δ9-THC/6.5% CBD) plus placebo oral pills 
 
(2) vaporized Δ9-THC (placebo) plus dronabinol  
 
(3) vaporized Δ9-THC (placebo) plus placebo oral pills 
 
 
Screening Potential Research Subjects:  
 
Subjects will be recruited through letters provided patients by practitioners in the UCSD Center 
for Pain Medicine, Perlman Medical Office, 9350 Campus Point Drive, Suite 2C 
La Jolla, CA (Appendix 1), newspaper advertisements (Appendix 2), and Research Match, a 
volunteer online registry funded by the National Institutes of Health (Appendix 3). In addition, ICD-9 
code 724.2 will be used to identify pertinent potential subjects. The following PHI will be requested: 
patient name, mailing address, date of birth. A request (along with documentation of UCSD IRB 
approval) will be forwarded to database managers at the Clinical Data Warehouse for Research 
(CDWR) who will be asked to pull a subset of the data from the Electronic Health Record system to 
query patient information in a HIPAA-compliant manner. Volunteers will be screened via telephone 
 


 
 
Biomedical IRB Application Instructions 
Page 3 
interview and, as appropriate, via face-to-face assessment. Telephone screening (respondents blind 
to selection criteria) will assure volunteers meet general age and medical criteria.  
 
If already using cannabis, participants will be asked to slowly taper cannabis use over a one-week 
period (Baseline Week - Figure 1) so that they are only using study medications during the remaining 
10 weeks of the clinical trial. If unable to abide by this, subjects will not be allowed to participate in the 
study. Participants will be asked to abstain from cannabis 7 days prior to study entry. In order to 
ensure abstinence, we will use the Draeger 5000 saliva screening test for tetrahydrocannabinol at 
their first experimental visit to ensure that they have adhered to this period of abstinence before the 
study. A level above 5 ng/ml will indicate recent use and the appointment will be rescheduled. 
 
Baseline Period:  
If eligibility criteria (see below) are met, subjects will be instructed on completing a paper diary 
(Appendix 4). Provided their VAS pain intensity remains above 3/10 during the Baseline Week, they 
will be given oral and herbal study medication (and a Volcano Vaporizer) at the next study visit one 
week later. 
 
At the baseline visit, participants will be given the Beck Depression Inventory (BDI-II) in order to 
screen for depression and suicidality. They will also be given the AUDIT and DAST to screen for 
substance use problems. The PSQ and Mood Disorder Questionnaire will also be administered to 
screen for Schizophrenia and Bipolar Type I, respectively. The painDETECT Questionnaire will be 
administered to distinguish neuropathic low back pain from non-neuropathic low back pain. The 
Survey of Cannabis Use will be administered during this period to obtain information on the cannabis 
use habits of the participant.  
 
Should the participant choose to participate the in the driving simulation portion of the study, the 
Driving History and Habits Questionnaire will be administered to obtain information on participant 
driving history, should they decide to participate in the driving simulation study portion.  
 
Telephone Interview:  
To determine eligibility, each prospective participant will be asked the following questions from the 
NIH Chronic Low Back Pain Definition: 
1. Do you have low back pain? 
No ………………………………STOP……………............................  
0 
Yes ……………………………………………………..........................  
1 
2. How long has low back pain been an ongoing problem for you? 
Less than 1 month     …………………………………………………… 
0 
1-3 months …………………………………………………… 
1 
3-6 months …………………………………………………… 
2 
6 months -1 year …………………………………………………… 
3 
1-5 years …………………………………………………… 
4 
More than 5 years …………………………………………………… 
5 


 
 
Biomedical IRB Application Instructions 
Page 4 
3. How often has low back pain been an ongoing problem for you over the past 6 months? 
Every day or nearly every day in the past 6 months    ……………… 
0 
At least half the days in the past 6 months                  ……………… 
1 
Less than half the days in the past 6 months               ……………… 
2 
4. In the past 7 days, how would you rate your low back pain on average?” (with an accompanying 
description of the following numerical pain intensity scale: 
No pain 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst 
imaginable 
pain 
 
Titration, Treatment and Tapering Periods Beginning with Week 1, patients will receive study 
medication for eight weeks after which they will be tapered off of investigational treatments (Figure 1). 
Study visits will take place at the UCSD Center for Medicinal Cannabis Research.  
 
 
Figure 1 Study Visits 
 
 
 
 
 
 
   
   
 
 
 
     Subjects will be randomly assigned to receive either one active study medication (e.g., medium-
strength vaporized cannabis, or dronabinol) plus one placebo study medication, or double-placebo. 
Within the limits of safety and tolerability, patients will undergo titration of both vaporized and oral 
study medication during Weeks 1-4. The oral medication will be titrated from a minimum of 5 mg qd 
up to a maximum of 10 mg tid. The vaporized cannabis will be titrated from a minimum of 4 puffs to a 
maximum of 18 puffs per day. The aforementioned falls within the parameters of consumption of 
cannabis as depicted in a survey of medicinal cannabis patients. 8 The dosing, in terms of the 
maximum number of puffs at each vaporization session, will also be consistent with the amount 
utilized in our previous human laboratory experiment. 3 Subjects not able to tolerate the minimum 
amounts described above by the end of Week 4 will be dropped from the study and replaced by 
another volunteer. Subjects will be informed that concurrent medications should be administered on a 
continuing basis during the study at a constant amount and frequency.  
     During treatment at home, patients will maintain a paper daily diary to record their intake of 
vaporized cannabis (i.e., number of vaporization sessions, puffs), oral study medications, and 
breakthrough pain medications, as well as pain relief measurements. In order that an effect from 
study medication will be evident, subjects will be asked to enter data into paper diary within a one-to-
two hour window following dosing of study and breakthrough medications. In between visits, patients 
Outcome measures will be collected during the six study visits, represented above as red vertical arrows. 
Driving simulation will be performed on the Hillcrest Campus at times denoted by the blue X’s 
Titration 
Treatment  
Tapering  
 
  
  
 
  


 
 
Biomedical IRB Application Instructions 
Page 5 
will be contacted by telephone every 7 days so that the investigative team can discuss compliance 
and answer any questions (Appendix 5). 
 
Study Visits:  
           Subjects will come in for 2-hour study visits at the intervals designated by the vertical arrows in 
Figure 1. A review of the paper daily diary, and, after the baseline week, the completion of the 
assessments described below under Outcome Measures will also be reviewed. 
           Study Δ9-THC will be packaged in separate prescription vials for each vaporization session to 
be performed at the subject’s residence. The vial will be marked with the date, directions for timing of 
vaporization session(s), and the maximum number of puffs from that vial. The collection vial will also 
be labeled for return of vaporized cannabis. All study medication will be packaged in a security 
container for purposes of preventing diversion with instructions to keep the locked strong box in a 
secure location. At the time of the subsequent visit, the vaporized and unused cannabis will be 
weighed by the research pharmacist who will report any suspected lapse of safekeeping of cannabis 
to the PI. Table 1 below outlines the amount of vaporized and oral study medication participants will 
be administered throughout the study. 
 
 
 
Table 1 Schedule of Administration of Vaporized and Oral Study Medication 
week 
maximum 
dronabinol 5 
mg or 
placebo 
tablets 
maximum 
dronabinol 5 
mg or 
placebo 
tablets per 
week 
number of 
vaporization 
sessions per 
day 
maximum 
number of 
puffs per day 
number of 
400 mg vials 
per 
week         
(8 puffs per 
vial ) 
Screening 
  
  
 
 
 
Baseline 
  
  
1 
1 po qd 
7 
1 
4 
4 
2 
1 po bid 
14 
2 
8 
7 
3 
   1-2 po tid 
28 
3 
12 
11 
4 
2 po tid 
42 
3 
18 
16 
5 
2 po tid 
42 
3 
18 
16 
6 
2 po tid 
42 
3 
18 
16 
7 
2 po tid 
42 
3 
18 
16 
8 
2 po tid 
42 
3 
18 
16 
Taper Week 1 
1 po tid 
21 
2 (average) 
9 
10 
Taper Week 2 
1 po qd 
7 
1 (average) 
4 
4 
 
Subjects will be instructed on the use of a vaporizer at the visit prior to Week 1. The manufacturer’s 
instructional brochure (Appendix 6) will be reviewed. In order to ensure consistency of dosing 
throughout the study, they will also be instructed on the use of the Foltin puff procedure at the visit 
prior to Week 1 (Appendix 7). A copy of both of these documents will be provided for review at home. 
 
On completion of eight weeks of treatment or at the time of withdrawal from the study, patients 
will completely taper their cannabis over a period of one to two weeks to avoid withdrawal symptoms. 
Cannabis withdrawal symptoms will be measured via a phone call after Taper weeks 1 and 2 
(Appendix 8). Questions (Appendix 26) will be added to access subject’s beliefs of what they received 
(e.g., THC or placebo) after the first week and again after the eighth week. This will enable us to 
assess the effectiveness of blinding and thus report on the assay sensitivity of the study. The optimal 


 
 
Biomedical IRB Application Instructions 
Page 6 
timing and frequency of blinding assessments has not been established. Thus, we will use a strategy 
to collect blinding data two times from participants: shortly after randomization and at the end of the 
trial. This will permit a comparison of blinding at the two stages. 
           If a subject does not participate in the driving simulation or the microbiome substudy, we will 
test their oral fluid for the presence of THC using the Draeger 5000. This will be done to exclude 
participants who use their own cannabis seeking pain relief because they were given placebo. 
 
An online questionnaire will be deployed (Appendix 27). Potential participants will complete this using 
HIPAA compliant software, the Platinum Edition of Survey Monkey. Please see 
https://www.surveymonkey.com/pricing/details/ for verification of the HIPAA compliance of this 
survey. 
 
Outcome Measures:  
 
DAILY TESTING IN SUBJECT’S RESIDENCE USING PAPER DIARY 
Medication intake: The timing and number of puffs of vaporized cannabis or placebo THC), oral 
medication (dronabinol or placebo), and breakthrough pain medication will be chronicled. (5 minutes) 
 
REPEATED TESTING AT STUDY VISITS 
 
Center for Medicinal Cannabis Research Forms 
• Neurobehavioral Medical Screen: The clinician will fill this out to record any events that may 
have occurred between visits to confound results from the Neuropsychological testing such as 
an any trauma to the head or any open head wounds.  
• Behavior Notes Instrument: The clinician will fill this out during Neuropsychological testing to 
note confound variables associated with participant during the appointment.  
• Adverse Events Form: A form to be filled out by the clinician that records any adverse events 
that have occurred since the last appointment due to study medication. 
 
NIH Task Force on CLBP Impact Score  
The impact score is a novel combination of 3 constructs; pain intensity, interference, and function. It 
is assembled in the Repeated Measures Recommended Minimal Dataset (Appendix 9).9 
 
Pain Relief 
Neuropathic Pain Scale: This instrument has an ordinal scoring of one to ten for 
several characteristics of neuropathic pain.10, 11 Specifically, the responses measure pain 
characteristics such as intensity, sharpness ("like a knife"), burning ("on fire"), aching ("like a bruise"), 
cold ("freezing"), sensitivity ("like raw skin"), itching ("like poison oak"), unpleasantness ("intolerable"), 
and the amount of deep versus superficial pain. (5 minutes) 
 
Mood Evaluation 
Profile of Mood States (POMS): The POMS measures six identifiable mood or affective states: 1) 
Tension-Anxiety 2) Vigor-Activity 3) Depression-Dejection 4) Fatigue-Inertia 5) Anger-Hostility 6) 
Confusion-Bewilderment. The POMS can be re-administered on a weekly basis, which is long 
enough to detect the respondent’s mood responses to his or her current life situation, but short 
enough to assess acute treatment effects. Sixty five items rated from 0 to 4 and scored in terms of 
total mood disturbance. 12 (10 minutes) 


 
 
Biomedical IRB Application Instructions 
Page 7 
Beck Depression Inventory-II (BDI-II): The BDI-II is a twenty-one item depression scale in which 
participants can rate depressive symptoms and attitudes from 0 to 3 in terms of intensity.13 We will 
measure clinical depression using the BDI-II and will include this measurement in analyses to provide 
an adjusted view of analgesia and side-effects. (3 minutes) 
 
Neuropsychological Testing 
WAIS-III Digit Symbol test: a test of concentration, psychomotor speed, and graphomotor abilities. 
This pen and paper test involves having subjects substitute a series of symbols with numbers as 
quickly and accurately as possible during a 120 second period. The results are expressed as the 
number of correct substitutions.14 (10 minutes). 
Hopkins Verbal Learning Test (HVLT): The HVLT provides information on the ability to learn and 
immediately recall verbal information across trials, as well at the ability to retain, reproduce, and 
recognize this information after a delay.15 A list of 12 words (four words from each of three semantic 
categories) is presented to the subject over three trials.  After each trial, the subject is to recall as 
many items as possible from the list in any desired order.  A 20-minute delay follows the 
administration of the three trials, after which the subject is asked to recall the list.  Subjects are then 
read a list of 24 words, one at a time, and are asked if the word appeared in the original list.  The 
items presented during the recognition phase contain the originally presented words, words in the 
same semantic class, and unrelated words. In order to minimize practice effects that may result from 
repeated administrations, six alternate forms of the test are available. (10 minutes) 
Grooved Pegboard Test: This is a test of fine motor coordination and speed.16 In this test, subjects 
are required to place 25 small metal pegs into holes on a 3" x 3" metal board. All pegs are alike and 
have a ridge on one side, which corresponds to a notch in each hole on the board.  First the dominant 
hand is tested, and subjects are asked to place the pegs in the holes as fast as they can.  This is then 
repeated with the non-dominant hand, and the total time for each hand is recorded. (5 minutes) 
Psychomimetic Effects of Cannabis 
Marijuana subscale (M-scale) of the Addiction Research Center Inventory: The M-scale consists 
of 12 true or false questions corresponding to symptoms of cannabis intoxication; the maximum 
possible score is 12.21 The questions will be rephrased to evaluate the experience from the past week 
rather than an acute response to cannabis. (3 minutes) 
 
Sensory Testing 
Cold-Pressor Test (CPT): The cold-pressor apparatus will consist of two water coolers, fitted with a 
wire cradle and an aquarium pump for water circulation. One cooler will be filled with warm water (37 
°C) and the other with cold water (4 °C). Participants will remove jewelry from the hand and forearm 
at the beginning of the session; during the test, participants will be instructed to rest a hand with 
fingers spread apart on the wire cradle. Each CPT will begin with an immersion of the left hand into 
the warm water bath for 3 min. During this time, blood pressure and heart rate will be measured. After 
removal of the hand from the warm water, skin temperature of the thumbpad will be recorded and 
participants will listen to a standardized script describing the procedures (Appendix 11). Participants 
will then immerse the left hand into the cold water bath and will be instructed to report the first painful 
sensation after immersion. They will then be asked to tolerate the stimulus as long as possible, but 
will be permitted to withdraw their hand from the cold water at any point. Maximum immersion time 
will be 2 min. Latency to first feel pain (pain sensitivity) and latency to withdraw the hand from the 
water (pain tolerance) will be recorded. Blood pressure and heart rate will be measured before and 
after each immersion using the arm that was not immersed in the water bath. 
 


 
 
Biomedical IRB Application Instructions 
Page 8 
Microbiome Assays: 
Stool Sample: Participants will be asked to provide a stool sample, a saliva sample, and a blood 
sample at their first, second, and sixth experimental visit. Participants will provide up to 20 milliliters of 
blood and 10 milliliters of saliva per sample. The overall objective of collecting the blood sample is to 
investigate inflammatory markers or other biomarkers that relate to changes in the microbiome. The 
overall objective of collecting the saliva and stool samples is to assess the effects of oral administration 
vs. inhalation of exogenous cannabinoids on the gut microbiota, as well as downstream effects on gut and 
systemic inflammation and neurocognition. CB1 and CB2 ligands that increase gut barrier function 
(“gatekeepers”) are expected to result in reduced inflammation. Programmed death 1 (PD-1) and its 
ligand PD-L1 are expressed in inflammatory environments such as the intestinal epithelium in 
inflammatory bowel disease Untargeted metabolomics applied to stool samples and blood is a powerful 
approach to identify compounds produced by gut microbes that gain access to the host bloodstream 
where it may exert systemic and CNS effects. We hypothesize that the composition of the gut microbiota 
may be altered (measured by 16S rDNA profiling) by cannabinoids, in turn influencing inflammatory 
states, or alternatively, reduced inflammatory states may result in an alteration of the gut microbiota.  This 
will be a longitudinal substudy of an ongoing randomized clinical trial. Stool, saliva, and blood samples for 
microbiome analysis will be collected before participants receive study treatment 1 week after participants 
receive study treatment, and 8 weeks after participants receive study treatment (dronabinol, vaporized 
cannabis, or placebo). Pre- and post-neurocognitive assessments will be done in all participants. The gut 
microbiota and relevant microbial metabolome will be assessed using a metabolite extraction and 
reconstitution protocol followed by untargeted HILIC/MS profiling in ESI negative mode. We will measure 
markers of gut inflammation (PBMC PD-1/PDL-1), systemic inflammation (IL-6), microbial translocation 
(sCD14) and neurocognitive function. Oral THC is expected to have the greatest impact on the gut 
microbiota due to higher local concentrations with this route of administration compared to vaporized 
cannabis. 
 
TESTING VIA TELEPHONE CALL AFTER TAPER PERIOD 
Cannabis Withdrawal Scale: The Cannabis Withdrawal Scale can be used as a diagnostic 
instrument in clinical and research settings where monitoring of withdrawal symptoms is required.22 
This will be performed after the 2-week tapering period has concluded. (10 minutes) If there was a 
previous adverse event or events (AE(s)), the Cannabis Solicited Adverse Events instrument will 
again be administered to ensure that the AE(s) have resolved. Participants will continue to be 
followed until there is resolution of the AE(s). 
 
ARM #2. Driving Simulation: 
Subjects with drivers’ licenses will be scheduled for two experimental visits; one before they begin the 
randomized controlled trial, and a second visit after finishing their 8th week treatment. The initial visit 
will involve a 20-minute session to garner baseline values for driving skills. This visit will coincide 
temporally with the first session for the randomized controlled trial prior to Week 1 (Appendix 12). 
 
At the time of the second driving simulation visit, subjects will be assigned the same 
medication that they have been using during the randomized controlled trial. Using a Volcano 
Vaporizer, subjects will inhale the average number of puffs they had consumed per session 
throughout the four previous weeks of the randomized controlled trial. They will use the Vaporizer 
before Hour 2 and again before Hour 6 (Table 3). They will also take the same oral medication that 
was provided during the randomized controlled trial. In addition to examining the effects on driving 
simulation, acute effects of study medications on spontaneous pain and vital signs will be determined 
(Appendix 13). We will administer the simulator sickness assessment during the first 2 hours of the 
appointment to ensure that the participant is physically able to perform the driving simulation tasks.  


 
 
Biomedical IRB Application Instructions 
Page 9 
At the beginning of driving simulation appointments, participants will be given a urine toxicology and a 
breathalyzer test to test for any illicit substances that is not prescribed by a physician. Should the 
participant screen positive for an illicit substance, they will either be asked to reschedule or be 
discontinued from the study at the Principal Investigator’s discretion. If this happens, participants will 
be compensated $10 for arriving to the scheduled appointment. 
 
During the Driving Simulation study visit, the participants will be given paper and pencil forms that 
measure the following:  
• Psychoactive Effects (including Drug Liking): A total of 15 separate VAS ratings will be 
presented at the time of driving simulation as a 100-mm horizontal line, anchored on the left 
with `not at all' and on the right with `extremely' (Appendix 10). Participants will pencil in a 
vertical line along the horizontal line that represents their current feeling (questions usually 
phrased, `During the past week, did you feel ___after consuming the vaporized cannabis?'). 
Ratings will be: any drug effect, a good drug effect, a bad drug effect, high, drunk, impaired, 
stoned, as if you liked the drug effect, sedated, confused, nauseous, like you desired more of 
the drug, anxious, down, and very hungry. Similar VAS questions have been shown to be 
sensitive and reliable subjective measures of cannabis intoxication.17-20 (5 minutes) 
• Pain Relief: The degree of pain relief after taking the study medication will be assessed by 
asking the participate to rate if their pain is (1) very much improved (2) much improved (3) 
minimally improved (4) no change (5) minimally worse (6) much worse (7) very much worse. 
• Pain Score: Participants will be asked to rate their pain before and after vaporizing marijuana 
between 0 = no pain and 10=worst possible pain.  
• Driving Simulation Self-Assessment: This comprises of a total of two questions to be asked 
hourly. They ask participants to rate how well they did on a VAS scale how well they believe 
they performed on the driving simulator and how much they believe their ability to perform on 
the driving simulator was affected by study drug.   
• Driving Test Questionnaire: This will be administered to evaluate for possible confounding 
variables on the day of the driving simulation. We will ask the participant how much they slept 
the previous night and about their experience with computer games. 
 
Sensory Testing 
The Cold Pressor Test administered at all study visits will also be administered during driving 
simulation 3 times at hours 1, 3, and 7 to measure acute effects of pain relief.  
 
By conducting repeat assessments for four hours following the first vaporization, we will be able to 
determine at what point participants no longer exhibit acute effects for each of the study medications. 
Participants will then complete a second vaporization and ingestion of oral medication before hour 6. 
We will then assess them for three hours in order to determine whether the acute effects are similar 
to those seen after the first vaporization, or perhaps greater (due to cumulative/residual effects). 
To minimize the novelty of the driving simulations, participants will complete a pretest training session 
to re-familiarize themselves with the hardware and the tasks that they are to encounter during the 
simulations. Four separate tasks will be embedded within the simulation. 
 
Table 3 Assessments of Acute Effects One Day following 2 and 8 Weeks of Cannabis 
Treatment  
 


 
 
Biomedical IRB Application Instructions 
Page 10 
 
Hour 
1 
 
2 
3 
4 
5 
 
 
6 
7 
8 
Vital Signs 
X 
Vaporization/Oral Medication 
X 
X 
X 
X 
Vaporization/Oral Medication 
 
X 
X 
X 
Numerical Pain Intensity 
Score 
X 
X 
X 
X 
X 
X 
X 
X 
Cold Pressor Test 
X 
 
X 
 
 
 
X 
 
Pain Relief 
 
X 
X 
X 
X 
X 
X 
X 
Psychoactive Effects 
 
X 
X 
X 
X 
X 
X 
X 
Driving Simulation 
X 
X 
X 
 
X 
X 
X 
X 
iPad Performance Testing 
X 
X 
X 
 
X 
X 
X 
X 
Blood Draw (Δ9-THC  levels) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Driving simulations: Simulation hardware will consist of a 3-screen, wide field-of-view 
monitor setup, steering wheel, and accelerator and brake pedals. The fully interactive simulations will 
assess lane tracking (standard deviation of lateral position [SDLP], or “weaving”), response to divided 
attention stimuli (accuracy, response time), car following, and performance during scenarios 
simulating routine driving as well as crash avoidance situations.  
 
Participants in the simulator study will also be assessed for far visual acuity (Snellen Visual Acuity 
eye chart; need to have acuity of 20/40 or better, with or without correction), color vision, and contrast 
sensitivity (Vistech Contrast Sensitivity (Pelli-Robson Chart)). Participants will complete an orientation 
and practice drive prior to the initial simulation, in order to familiarize them with the controls and 
roadways. 
 
• Task 1: Lane Tracking/Divided attention: Participants will be instructed to maintain their 
lane position and speed, and respond to divided attention stimuli in the two corners of the 
monitor. The primary outcomes are standard deviation of lateral deviation (SDLP), latency and 
accuracy on the divided attention tasks, and speed deviation. SDLP is a measure of how well 
subjects maintain their lane position, providing an index for each subject’s road tracking error 
and ability to control the lateral motion of the car. It is primarily controlled by automatic 
information processing and outside of conscious control. SDLP has been shown to be 
sensitive to the effects of medications in both on-road and simulator studies (23-27). It has 
been examined in individuals under the influence of alcohol, marijuana, and MDMA, as well as 
with neurologic populations (28-32). SDLP has also demonstrated good test-retest reliability 
over short and long-term follow-ups (33-36).  (7 minutes) 
• Task 2: Car Following: The primary outcomes are (1) coherence between the participant and 
lead cars (a general correlation [0–1] of the participant’s ability to accurately track the speed 
variations of the lead car); (2) time delay (or the reaction time to changes in the lead car’s 
speed); and 3) distance from the lead car (7 minutes) 
• Task 3: Multi-tasking (Surrogate Reference Task [SuRT]): The primary outcomes are 
response latency and accuracy on the SuRT tasks. In addition, we will examine SDLP and 
speed deviation during this more challenging divided attention task. The SuRT is a visual 


 
 
Biomedical IRB Application Instructions 
Page 11 
perceptual task which presents subjects with an approximately 8" touch screen filled with 
circles and requires participants to point to a target circle.  
 
 
 
 
 
 
 
 
 
The level of difficulty is varied by changing the ratio of the size of the distractor circles and 
target circles. The equipment will be to the side of the monitor. Task conditions will include 
no search, easy, medium and hard searches (based upon the standard SuRT protocol). 
The SuRT is a measure of performance under high cognitive load and controlled 
processing, in that participants must divide their attention among three stimuli (roadway, 
speedometer, and events in the periphery), and is reflective of the workload generated by a 
real task (e.g., a GPS system). Face valid tasks such as navigation destination entry draw 
attention away from the road in highly variable ways (i.e. there tend to be large differences 
in how people attack problems associated with complex interactions). On the other hand, 
surrogate or structured tasks allow us to look at changes in attention in a more controlled 
fashion. This will enable us to address how participants under the influence of cannabis 
vary allocation strategies with workload. (5 minutes). 
• Task 4: Crash avoidance/decision-making: In order to assess treatment effects during 
routine and non-routine events we will include scenarios addressing 1) the “yellow light 
dilemma”, wherein individuals need to respond to a yellow light onset by abruptly braking 
(risking a rear-end collision), or go through the intersection (risking running a red light), and 2) 
crash avoidance. Participants will be instructed to drive 45mph, and will encounter 8 green 
traffic lights, 4 of which will switch to yellow. These will be randomized within each drive. 
Consistent with California law (37), the yellow light phase (time before the yellow light turns 
red) will be 4.3s. The time available to perceive and respond to the yellow light will be held 
constant for all participants by controlling initiation of the yellow light by using the vehicle’s 
velocity to determine the time-to-location (start of intersection). This will be set at 3.4, 3.0, 2.7 
and 2.2s, settings which in previous studies have shown to elicit a range of responses (running 
the yellow light, stopping) (38, 39). The primary outcomes will be stop/go percent and 
perception-reaction time (PRT; time of yellow onset to start braking or accelerating through the 
intersection), although a number of additional behavioral outcomes will be of interest. The 
simulation will also include a crash avoidance scenario in which the participant drives down a 
visually complex roadway (moving cars, pedestrians) and encounters the sudden appearance 
of a pedestrian, or car pulling out, in the roadway. Primary outcomes are the PRT to the 
incursion, and whether a collision occurs. Since an important aspect of this task is the 
unexpected nature of the event, the incursion point and object (vehicle, pedestrian) will vary 
across assessments (but be consistent across all participants).  (5 minutes) 
 
 
Performance-based tablet assessments: The following will be performed using an iPad with software 
designed by Digital Artefacts LLC (119 Oakdale Campus Iowa City, IA  52242 (319) 335-4985 
http://www.digitalartefacts.com):  
 
 
Figure 1. Surrogate Reference Task (SuRT) 


 
 
Biomedical IRB Application Instructions 
Page 12 
§ Critical Tracking: This test assesses the participant’s ability to adapt to an 
error signal in a first-order compensatory task, and has been shown to be 
sensitive to the effects of Δ9-THC. Participants use their finger to overcome 
built-in error in horizontal deviation from a midpoint by returning the cursor 
to the midpoint. However, the frequency, and velocity, of the deviations 
increases as a function of time. The primary outcome is the average lambda-
c across 5 trials. (5 minutes) 
§ Time estimation. Cannabis can affect time perception and estimation. 
Deficits in temporal processing could have significant implications for driving, 
for example in estimating the amount of time available to pass through a 
yellow light, or anticipating cross-traffic. We will thus administer a brief 
measure of time estimation. As recommended by Sewell et al., we will use 
an approach that minimizes the use of subvocal counting, which may 
artificially decrease variation that might occur during real-world multi-tasking. 
Five trials, with randomly generated durations ranging from 5 to 30s (e.g., 7, 
11, 29, 14, 23 seconds), will be generated. During each assessment, 
participants will complete the five trials. The participant will sit at a computer, 
and once the test starts will be presented with random letters in random parts 
of the screen. The participant is then to count the number of “M”s that appear 
until a second flash on the screen, at which point he/she is to announce the 
number of “M”s and the amount of time that has elapsed. The primary 
outcome is the ratio of estimated time to actual time. (3 minutes) 
§ Balance. Individuals may exhibit increased body sway when taking 
cannabis. To assess balance, participants will hold the iPad to their chest 
with their arms crossed, and their postural sway will be assessed while: 1) 
standing on both feet with eyes closed and 2) on a single foot and raising 
the other leg with the knee bent at 45 degrees, with eyes closed. Sway will 
be calculated using the iPad triaxial accelerometer. 
§ Visual Spatial Memory Learning Test Cannabis can affect memory 
acutely. Variation in some aspects of cognitive performance has been found 
to be moderately and positively correlated with some individual aspects of 
the SFST; particularly among tasks which assess reaction time. Impairment 
of these cognitive processes can also contribute to the completion of 
complex tasks such as driving or the SFST. We will assess short term 
memory using a visual-spatial learning test (VSLT). This test is modeled after 
other tests of visuospatial memory (e.g., the Brief Visuospatial Memory Test-
Revised, Visual Spatial Learning Test). The test requires the subject to a) 
memorize 5 designs that are difficult to verbally encode, b) recognize them 
among a group of 15 designs (8 foils) and c) recall the correct placement of 
these designs on a 6 X 4 matrix. Participants will complete one trial. The 
score is the number of figures correctly identified and placed. (2 minutes). 
 
 
Assays for Δ9-THC  in Plasma  
     For purposes of correlation with the above findings, serum levels of THC will be determined 
hourly. Blood will be collected in grey top (NaF) tubes tubes and then the tubes inverted 8-10 times to 
mix. EDTA plasma will be processed as soon as possible after collection. The tubes will be 
centrifuged at 400xg for 10 minutes to separate plasma and cells and then, using a transfer pipette, 


 
 
Biomedical IRB Application Instructions 
Page 13 
plasma will be removed carefully to avoid disturbing the cell layer. The plasma will be transferred to 
1.8 ml cryovials and stored as plasma aliquots at –70C. 
     
     Δ9-THC and metabolites will be quantified using isotope dilution ultra-performance liquid 
chromatography (UPLC) and tandem mass spectrometry (MS/MS) using methodologies similar 
to what have been published. Briefly, deuterium labeled internal standards will be added and 
proteins will be precipitated using acetonitrile. Δ9-THC and CBD will be isolated using solid phase 
extraction and analyzed using electrospray ionization. Δ9-THC will be analyzed using positive ion 
electrospray while negative ion ESI will be used for CBD using Waters Xevo TQS equipped with 
Waters Acquity UPLC. The limit of quantification (LOQ) will be 0.5 ng/mL of each of the 
components in whole blood. Our laboratory at UCSD has been using similar methodologies to 
accurately quantify small molecules for many years (39). 
 
 
 
10. 
HUMAN SUBJECTS 
Total number of participants to be enrolled:  This will be a single site study with 120 participants 
enrolled at UCSD.  
Age: Because of the problems inherent in the use of cannabis in children and adolescents, we will not 
enroll individuals below the age of nineteen. Frequent use can affect school performance and 
relationships with family members in younger individuals 42, 43. Earlier and greater involvement with 
marijuana has also been associated with increased risk of poor mental health 44, 45.  
Gender: Both male and female populations develop chronic low back pain (CLBP); however, there is a 
tendency towards a higher incidence in males.  
Ethnic background: CLBP is ubiquitous. Global studies have shown that low back pain is one of the 
most common complaints that patients bring to their physicians 46, 47. Given the diverse ethnic 
background of San Diego, we should be able to recruit subjects from multiple ethnic backgrounds. 
A neuropathic component has been found in approximately 37% of patients with CLBP 48; given the 
relative frequency of the latter, we should not encounter difficulty recruiting 120 participants. 
Health status: Individuals with significant cardiovascular, hepatic or renal disease, uncontrolled 
hypertension, and chronic pulmonary disease (eg, asthma, COPD), will be excluded. This will be 
operationalized using criteria from the literature on adverse effects of medicinal cannabis 49, 50. 
 
Inclusion criteria 
• Age greater than 18  
• Presence of chronic low back pain (CLBP) defined as the response to two questions 1) How 
long has back pain been an ongoing problem for you? 2) How often has low back pain been an 
ongoing problem for you over the past 6 months? A response of greater than 3 months to 
question 1 and a response of “at least half the days in the past 6 months” to question 2 will 
define CLBP according to the NIH Task Force on Research Standards for Chronic Low Back 
Pain (Appendix 15). 9. 
• Visual average numerical pain intensity greater than 3/10 during one-week observation period 
• To avoid confounding by concurrent medications and/or prior cannabis exposure, participants 
will have had a stable analgesic regimen that they will continue throughout the study and not 
having used cannabis for more than 7 days prior to study entry. The latter criteria will be 
verified by the use of the Draeger test at the first experimental visit.   
 


 
 
Biomedical IRB Application Instructions 
Page 14 
Exclusion criteria 
• Presence of another painful condition of greater severity than the back pain condition which is 
being studied.   
• History of traumatic brain injury. 
• Clinically significant or unstable medical condition. Individuals with significant cardiovascular, 
hepatic or renal disease, uncontrolled hypertension, and chronic pulmonary disease (eg, 
asthma, COPD), will be excluded. With respect to cardiovascular and pulmonary status, a 
clinician will screen participants with a tool developed for detection of congestive heart failure, 
coronary artery disease, obstructive and/or restrictive lung disease (Appendix 28 
Cardiopulmonary Screen). Hepatic and renal disease will be evaluated with liver and renal 
function laboratory tests. If warranted clinically, subjects will undergo further evaluation 
(urinalysis, electrocardiogram, and/or chest X-ray).  
• A positive result on toxicity screening will exclude individuals from participation.  A urine drug 
test that screens for 5 categories of drugs: marijuana (Δ9-THC), cocaine, 
amphetamines/methamphetamines, opiates, benzodiazepines and phencyclidine (PCP) will be 
employed. A positive result for opioids and/or THC will not be exclusionary if the patient is 
receiving a prescription for an opioid and/or THC.  
• Allergy to sesame oil, lactose, or gelatin   
• Vascular disease, especially Raynauld’s syndrome, systolic blood pressure > 170 mm, 
diastolic blood pressure > 100 mm 
• Recent injuries to the upper extremity  
• Cognitive impairment, such as Dementia or Alzheimer’s Disease  
• Substance Abuse History: individuals with current substance use disorders55 as assessed 
using the Drug Abus65e Screening Test (DAST-10) (a score greater than or equal to 3) and 
the Alcohol Use Disorders Identification Test (AUDIT) (a score greater than or equal to 8 or a 
score greater than or equal to 7 if over 65 years old) (Appendix 31). 
• Pregnancy as ascertained by a mandatory commercial pregnancy test  
• Women who are lactating 
• History of schizophrenia, bipolar depression with mania, current suicidal ideation or past 
history of suicide attempt. Cannabis can exacerbate pre-existing schizophrenia, and has been 
linked to an increase in the risk of suicide in such patients.56 In patients with bipolar disorder, 
cannabis use has been associated with worsening of manic and psychotic symptoms.57 Such 
findings suggest that cannabis is contraindicated in individuals with serious mental health 
issues, a line of reasoning that will be observed in the present study by excluding patients in 
the bipolar/schizoaffective/schizophrenic spectrum.  
• Suicidality. Exposure to cannabis does not lead to depression but it may be associated with 
suicidal thoughts and attempts58. Therefore, the BDI-II will be used to measure suicidal 
ideation.  
• Unwillingness to abstain from dronabinol for the rest of the study if taking dronabinol before 
study participation.   
 
11. RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
     Four methods will be used for patient recruitment. First, a UCSD clinician may ask patients directly 
if they are interested in the study. For example, a UCSD Center for Pain Medicine clinician can 
provide interested patients with an information sheet about the study, including research staff contact 
information (Appendix 1). Second, we will use ResearchMatch to send a recruitment message to 
potential participants who meet the criteria specified. (Appendix 3). Third, newspaper advertisements 


 
 
Biomedical IRB Application Instructions 
Page 15 
will be utilized (Appendix 2). Fourth, ICD-9 code 724.2 will be used to identify pertinent potential 
subjects. The following PHI will be requested: patient name, mailing address, date of birth. This 
request (along with documentation of UCSD IRB approval) will be forwarded to database managers 
at the Clinical Data Warehouse for Research (CDWR) who will be asked to pull a subset of the data 
from the Electronic Health Record system to query patient information in a HIPAA-compliant manner. 
All recruitment methods will rely on potential subjects voluntarily initiating contact with study research 
staff. 
 
Data Mining  
HIPAA Access to personal health information (PHI) will be requested through a waiver of consent and 
partial waiver of HIPAA Authorization for recruitment purposes. In order for a partial waiver of HIPAA 
authorization to be granted, we present the following options: 
 
 1 A plan to protect identifiers from improper use and disclosure 
Multiple procedures for protecting against or minimizing risks will be put in place. All research staff 
will complete training for HIPAA and human subjects’ protections regulations and procedures. 
Confidentiality of participant data will be maintained through several mechanisms. All participants will 
be assigned identification numbers, and a list linking names and ID number will be stored separate 
from participant data in a locked file cabinet and electronically on a secure server. Access to this list 
will be restricted to the principal investigator, project manager and research assistant. Blood 
specimens will be stored in a -70 degree freezer using the ID number. 
 
Paper documents will be kept in a locked cabinet in the CMCR office on Dickinson Street. Electronic 
information will be stored in a password-protected account.  
 
2. Justification as to why these procedures could not a) practicably be done without the waiver, and 
b) be done without access to, use, or disclosure of the PHI;  
The proposed study cannot be done without the specified information because PHI is required in 
order to contact potential participants and screen for eligibility for the study. We will only collect 
minimal PHI necessary to distinguish patients who have chronic lower back pain who may qualify for 
the study. Once they have been identified, patients who agree to participate in the study will be 
consented and authorization will be obtained.   
 
3. Justification that the privacy risk to individuals whose PHI will be used or disclosed is minimal and 
reasonable in relation to the anticipated benefit, if any, to the individuals;  
PHI acquired for the purposes of recruitment will not be disclosed to any other agency, party or 
individual (other than the sponsor (NIDA), FDA and UCSD research compliance personnel). Evidence 
of UCSD IRB approval will be required to obtain this document from NIDA. 
 
4. What PHI will be used and who will access, use or disclose the PHI.  ICD-9 code 724.2 will be 
used to identify pertinent potential subjects. The following PHI will be requested: patient name, 
mailing address, date of birth. This request (along with documentation of UCSD IRB approval) will be 
forwarded to database managers at the Clinical Data Warehouse for Research (CDWR) who will be 
asked to pull a subset of the data from the Electronic Health Record system to query patient 
information in a HIPAA-compliant manner.  
 
 


 
 
Biomedical IRB Application Instructions 
Page 16 
 
  History and Physical Exam 
  Progress Notes 
  Operative Report(s)        
  Discharge Summary(ies) 
  Diagnoses 
 
 
 
  Medications 
  Radiology Images 
 
      
  Radiology Reports 
  Pathology Reports 
 
 
  Laboratory Reports 
  EKG Reports 
  
 
      
  Consult Reports 
  Alcoholism or Alcohol Use 
 
  Drug Abuse Information 
 
Only authorized members of the research team will have access to PHI, specifically the principal 
investigator, project manager, and research associate/assistant. 
 
12. 
INFORMED CONSENT 
Process To Be Followed For Obtaining Consent/Assent/Permission And HIPAA Authorization. 
     We request a waiver of documented consent for conducting the phone screening. This part of the 
research, i.e., the telephone interview, presents no more that minimal risk of harm to subjects and 
involves no procedures for which written consent is normally required outside of the research context. 
If a subject qualifies for the study and decides to participate, the screening information will be kept 
with their research record. If they not qualify for the study, the screening information will be 
destroyed.  
  
1. Potentials volunteers will be screened via telephone interview (Appendix 16) and, as 
appropriate, via face-to-face assessment. Telephone screening (respondents blind to selection 
criteria) will assure volunteers meet general age and medical criteria. For those subjects 
interested in proceeding to a face-to-face assessment, a consent form will be mailed with 
instructions to peruse the document. The intent of this is to allow sufficient time for the 
prospective participant to consider whether to participate; a step to be taken to minimize the 
possibility of coercion or undue influence. 
2. The Research Associate will obtain consent /authorization. The person in this position will 
undergo CITI training to gain requisite knowledge to perform the consent /authorization 
process. S/he will have sufficient knowledge of the study to answer any questions regarding 
the study. S/he will explain the research activity, how it is experimental (e.g., a new drug, extra 
tests, separate research records, or nonstandard means of management, such as flipping a 
coin for random assignment or other design issues). S/he will inform the human subjects of the 
reasonably foreseeable harms, discomforts, inconvenience and risks that are associated with 
the research activity. Information communicated to the participant/parent or legally authorized 
representative during the consent/assent/permission process will not include exculpatory 
language through which the participant is made to waive or appear to waive any of the 
participant’s legal rights or release or appear to release the Researcher, Sponsor, the 
University or its agents from liability for negligence. 
3. The Investigator will retain the original consent form and HIPAA authorization in a master 
research file. An electronic copy of the signed informed consent and HIPAA authorization will 
also be inserted into the electronic Medical Record alerting other providers of the subject’s 
participation in this research protocol.  
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
     The therapeutic alternatives that are reasonably available that may be of benefit to a potential 
participant include standard of care measures; e.g., spinal manipulation, acupuncture, biofeedback, 
cognitive-behavioral therapy, massage and/or a comprehensive rehabilitation programs.  


 
 
Bi o m e di c al I R B A p pli c ati o n I n str u cti o n s  
P a g e 1 7  
     I n a st u d y s u c h a s t h e pr e s e nt o n e w h er e t h er e i s n o pr o s p e ct of di r e ct b e n efit t o t h e p arti ci p a nt, 
a n ot h er alt er n ati v e i s t o n ot e p arti ci p at e.    
1 4.  
P O T E N TI A L RI S K S  
Li k el y  
� diffi c ulti e s wit h b al a n c e  
� e y e irrit ati o n  
� t hr o at irrit ati o n  
� i n cr e a s e d h e art r at e  
� p o s si bl e l o w bl o o d pr e s s ur e  
� r e v er si bl e pr o bl e m s wit h y o ur a p p etit e, l et h ar g y 
 
L e s s Li k el y  
� s o m e c h a n g e i n y o ur m o o d ( g o o d or b a d)  
� l o s s of m e m or y  
� d e cr e a s e d a bilit y t o c o n c e ntr at e or t hi n k pr o p erl y  
 
R ar e B ut S eri o u s  
� di z zi n e s s  
� h e a d a n d c h e st pr e s s ur e  
� di s ori e nt ati o n  
� a git ati o n  
� c o m b ati v e n e s s  
� i n c o h er e n c e  
� vi s u al h all u ci n ati o n s  
 
P h y si c al h ar m: Ri s k s of i n h al e d c a n n a bi s pr o d u ct s m a y i n cl u d e p s y c h o m ot or c o or di n ati o n 
diffi c ulti e s, e y e irrit ati o n, t hr o at irrit ati o n, i n cr e a s e d h e art r at e, p o s si bl e h y p ot e n si o n, a n d r e v er si bl e 
a p p etit e/ m o o d/ m e m or y/ c o g niti o n eff e ct s.  
     T h er e m a y b e s o m e di s c o mf ort w h e n bl o o d s a m pl e s ar e t a k e n, a n d t h er e i s a s m all ri s k of 
br ui si n g, i nf e cti o n, or i nfl a m m ati o n at t h e sit e at w hi c h t h e n e e dl e i s i n s ert e d. W e will b e t a ki n g t w o 
t a bl e s p o o n s of bl o o d f or t h e p ur p o s e s of t hi s st u d y.  
     T h er e i s virt u all y n o ri s k a s s o ci at e d wit h p ai n t e sti n g i n c ol d  w at er u nl e s s t h er e i s a cir c ul at or y 
pr o bl e m. T h e s u bj e ct will b e fr e e t o wit h dr a w t h eir h a n d fr o m t h e w at er b at h at a n y ti m e. H o w e v er, 
t h er e i s al w a y s t h e p o s si bilit y of d a m a g e d e s pit e t h e s e pr e c a uti o n ar y m e a s ur e s.  
• P s y c h ol o gi c al h ar m: M e nt al a n d/ or e m oti o n al di str e s s m a y r e s ult fr o m q u e sti o n s a s k e d d uri n g 
a s s e s s m e nt or a s a r e s ult of t h e ti m e t a k e n i n t h e a s s e s s m e nt p r o c e s s. A d diti o n all y, s o m e 
n e ur o p s y c h ol o gi c al t e st s m a y r e q uir e c o n c e ntr at e d eff ort a n d m a y b e fr u str ati n g f or t h e s u bj e ct t o 
c o m pl et e.  
• L e g al h ar m: W e will b e a s ki n g s e n siti v e q u e sti o n s a b o ut u s e of m arij u a n a, a n d t e sti n g f or illi cit 
s u b st a n c e u s e . A c c e s s t o s u c h m at eri al f or l e giti m at e r e s e ar c h p ur p o s e s i s ge n er all y a c c e pt a bl e, 
a s l o n g a s t h e r e s e ar c h er pr ot e ct s t h e c o nfi d e nti alit y of t h at i nf or m ati o n.  
• S o ci al h ar m: I n v a si o n s of pri v a c y a n d br e a c h e s of c o nfi d e nti alit y m a y r e s ult i n e m b arr a s s m e nt 
wit hi n o n e' s b u si n e s s or s o ci al gr o u p. E v er y eff ort will b e m a d e t o m ai nt ai n c o nfi d e nti alit y of t h e 
s u bj e ct’ s p arti ci p ati o n t o l e s s e n t hi s t y p e of ri s k.  S u bj e ct s m a y h a v e s o m e di s c o mf ort or f e el 
e m b arr a s s e d w h e n t h e y pr o vi d e a st o ol s a m pl e. 


 
 
Biomedical IRB Application Instructions 
Page 18 
• Economic harm: Eligibility for insurance, political campaigns, and standing in the community are 
problems may result from loss of confidentiality. Vaporizing marijuana may hinder application for 
future employment, if drug screening is a condition of employment. It is likely that detectable 
traces of marijuana will remain in the subject’s hair or blood for a minimum of six weeks after 
vaporizing. If applicable, a letter will be written to the subject’s employer explaining their 
participation in this research study and the dates of participation.  Confidential information 
regarding your history, DNA information (genetic risk for certain diseases), substance use or 
health diagnosis may become known outside of the research setting. 
• Reproductive risks: The procedures in this research are known to hurt a pregnancy or fetus in 
the following ways: poor educational attainment. A participant should not become pregnant or 
father a baby while on this study because the drugs in this study can affect an unborn baby. 
Women should not breastfeed a baby while on this study. Subjects will need to use birth control 
while on this study. Acceptable methods of birth control are: oral contraceptive pills, diaphragm 
and condom with spermicide, progestin implant, intrauterine contraceptive device.  
• Unknown Risks: The experimental treatments may have side effects that no one knows about 
yet. The researchers will let subjects know if they learn anything that might make you change 
your mind about participating in the study.  
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
At every study visit, stopping criteria will include: 
Pulse: an irregular pulse or pulse rate > 110 beats per minute 
Blood Pressure: systolic blood pressure > 180 mmHg or diastolic  > 110 mmHg 
 
Respirations: respiratory rate > 20 breaths per minute 
Pulse: an irregular pulse or pulse rate greater than 110 beats per minute will result in 
cessation of participation and, if deemed advisable by a study clinician, transfer to the 
emergency department (across the street from our research center). 
 
Blood Pressure: If the systolic blood pressure is ≥ 160 to < 180 mmHg  or the diastolic is  
≥ 100 to < 110 mmHg, a study clinician will conduct  an evaluation to see if the participant 
has symptoms that would mandate discontinuation. Examples would include 
severe headache, confusion, chest pain, dyspnea, irregular heartbeat, and/or palpitations. 
Final determination regarding possible discontinuation will be made by a study 
investigator. If discontinued from the study, the participant will be asked to have their 
blood pressure evaluated by their primary care physician as soon as possible. If the 
systolic blood pressure is > 180 mmHg or the diastolic is  > 110 mmHg, the participant 
will be discontinued from the study and either be transferred to the emergency 
department or be asked to visit their primary care physician as soon as possible. The end 
organ response to the blood pressure will guide the clinician’s decision (e.g., the 
development of angina pectoris or hemiplegia will mandate transfer to the emergency 
department). 
 
Respirations: shortness of breath will result in potential cessation of participation and 
possible transfer to the emergency department following evaluation by a study clinician, 
who will consult with the study investigator. 
 
A locally developed self-report instrument, the Cannabis Solicited Adverse Events (Appendix 
29) will be administered to assess distress from psychological effects of cannabis. This will be 
performed on a prn basis by the trained staff and routinely at the end of the acute 


 
 
Biomedical IRB Application Instructions 
Page 19 
administration session. The items on this instrument ask participants about experiencing 
anxiety, paranoia, and hallucinations. Excess intoxication will also be assessed using this 
instrument which asks participants about their having dizziness, drowsiness, confusion, 
emotional changes, and/or cognitive changes. Positive responses to these items, if Grade 2, 3 
or 4 (see below for definitions), will result in notification of a study clinician who will speak with 
the participant to see if discontinuation of participation in the study would be in her or his best 
interest. 
 
Using the Cannabis Solicited Adverse Events instrument mentioned above, an Adverse Events 
Form (Appendix 30) will be completed. Adverse events will be characterized as 1 = Mild, 2 = 
Moderate, 3 = Severe, and 4 = Life Threatening using the following definitions (consistent with 
those used by the National Cancer Institute): 
 
 
 
Inasmuch as the scoring of Grades 2, 3, and 4 mention that an intervention is indicated, AEs 
with Grades 2 or 3 will be brought to the attention of a study clinician so that s/he may interact 
with the participant to determine if discontinuation of study participation is warranted. This will 
be done in consultation with an investigator. Grade 4 AEs will be managed by reports tendered 
to the FDA and the IRB within the required time limits specified by each organization. There 
will also be a determination of whether the AE is related, possibly related or not related to the 
study by the investigator for Grades 1 to 4.  
 
Furthermore, the participant will be followed by the research team to insure that the AE(s) 
resolve. This might include recommending that the participant see their primary care physician 
(e.g., for a change in blood pressure medication).  
 
Risks will also be mitigated using the following measures: 
• Preventing children and adolescents from gaining access to medicinal cannabis because of 
potential harm to their well-being. Subjects will be required to store cannabis in an area of their 
home that would prevent anyone else from discovering its location. 
• Because some people cannot control their use of cannabis, we will not allow patients with 
recent substance abuse histories (less than 12 months) to participate.  
• We will exclude patients if they are pregnant or refuse to exercise birth control if engaging in 
sexual activities that could result in pregnancy, have a heart disease or heart rhythm problem 
or have a history of serious mental illness (e.g., schizophrenia, mania, or a history of 
hallucinations or delusions)  
• In order to avoid carcinogens, we will have subjects use a vaporizer rather than smoke joints or 
use a water pipe. 


 
 
Biomedical IRB Application Instructions 
Page 20 
• We will instruct subjects not to drive a car or operate heavy machinery for 3-4 hours after use 
of medicinal cannabis, or longer if larger doses are used or the effects of impairment persist. 
They will use a designated driver for automobile transportation if they have to go out sooner 
than 3-4 hours after taking this medicine.  
• As the response to cannabis varies widely, participants will titrate to effect and in essence use 
the minimum amount of medicinal cannabis needed to obtain relief from pain.  
• A cannabis withdrawal syndrome will be under surveillance for two weeks; difficulty with getting 
to sleep and angry outbursts might require that they withdraw from the cannabis more slowly. 
 
The UCSD Department of Psychiatry (Appendix 17) is committed to providing the resources and 
other supports (e.g., data management and information systems, statistical, and physical 
performance site) to ensure the timely implementation, conduct, and completion of this program. 
 
Data and Safety Monitoring Board (DSMB) 
     A DSMB will be selected utilizing a group of experts that will advise the study investigators, with 
the primary responsibility to monitor human subject safety. The members will be comprised of at least 
3 independent clinicians familiar with the conduct of clinical trials The DSMB will consider study-
specific data as well as relevant background information about the test agents and target population 
under study. The DSMB will review the protocol, including the safety monitoring plan, and identify any 
major concerns prior to implementation. During the trial the DSMB will review: 
 
1. Real-time and cumulative safety data for evidence of study-related adverse events,  
    unanticipated problems 
2. Factors that might affect the study outcome or compromise the trial data (such as protocol  
    violations, losses to follow-up) 
3. Staff performance for protection of privacy, confidentiality, and maintenance of secured  
    databases 
4. Progress of interventional trial, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention. 
 
     The DSMB should conclude each review with each member’s recommendation as to whether the 
study should continue or be modified. Recommendations for modification of the design and conduct 
of the study may include corrective action when performance is unsatisfactory. Confidentiality must 
always be maintained during all phases of DSMB review and deliberations. The DSMB report will 
include the participants' demographic characteristics, expected versus actual recruitment rates, 
treatment retention rates, any quality assurance or regulatory issues that occurred during the past 
year, a summary of all and serious adverse events, and any actions or changes with respect to the 
protocol.  
16.PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT  
     As stated above in Section 11, 3 methods will be used for patient recruitment. First, a clinician 
may ask patients directly if they are interested in the study. UCSD Center for Pain Medicine clinicians 
can provide interested patients with an informational sheet about the study, including research staff 
contact information (Appendix 1). Second, a list of patients meeting specific ‘International Statistical 
Classification of Diseases and Related Health Problems’ (ICD-9 724.2) criteria for chronic low back 
pain will be sent an informational letter informing them about the study and inviting them to contact 
research staff if interested in learning more information (Appendix 1). Third, newspaper 
advertisements may be used (Appendix 2). All recruitment methods will rely on potential subjects 
voluntarily initiating contact with study research staff, an “opt-in” approach. 


 
 
Biomedical IRB Application Instructions 
Page 21 
 
Once protected health information (PHI) is obtained, measures to protect privacy and confidentiality 
will be implemented. This will include coding, removal of identifying information, limiting access to 
data, and the use of a Certificates of Confidentiality that will be applied for from the National Institute 
of Drug Abuse following IRB approval. Physical safeguards for research data will include storage of 
paper records in locked files, separation of personal identifiable demographics data from study data 
referenced only to a unique study ID. Electronic records will be maintained on a HIPAA Compliant 
server using password protection.  
 
All laboratory specimens, evaluation forms, reports and other records will be identified only by a 
coded number in order to maintain confidentiality. All records will be kept in a locked file cabinet.  All 
computer entry and networking programs will be done with coded numbers only.  All stored samples 
are accessible only to the HNRP laboratory personnel and the appropriate study members. Samples 
are stored under the coded identifiers in freezers equipped with locks, behind locked doors requiring 
ID scan entry.  
      
     The consent process will be performed under conditions to insure privacy and confidentiality. It will 
take place in a private exam room in the Department of Psychiatry, 220 Dickinson St. San Diego, CA. 
Should interviewee disclose suicidal ideation (Appendix 18), further evaluation will take place. 
Important elements of the history that permit appraisal of the seriousness of suicidal ideation include 
the intent, plan, and means; the availability of social support; previous suicide attempts; and the 
presence of comorbid psychiatric illness or substance abuse. After intent has been established, 
outpatient management will be sought. 
17. POTENTIAL BENEFITS 
     There is no direct benefit to subjects. 
18. RISK/BENEFIT RATIO 
    There is a substantial disconnect between the therapeutic use of cannabis and research on the 
risks and benefits of this practice. Although edible marijuana merchandise has become widely 
available at medical dispensaries, there is little information in the literature on the medical efficacy of 
these products 62. Pharmacologic oral preparations, which like the edible products, avoid deleterious 
effects upon the respiratory system, have had more attention from the scientific community 63-69. 
However, some experts have opined that whole plant cannabis is superior to the FDA approved oral 
cannabinoid preparations, e.g., synthetic tetrahydrocannabinol (dronabinol, Marinol®) and/or the 
synthetic analog of Δ9-THC (nabilone,Cesamet®). As testament to this belief, oral cannabinoids have 
been on the market in the United States for many years and are not widely used 70. Peak plasma 
concentrations occur 1 to 6 hours after ingestion, with a magnitude approximately 10% of that 
achieved with smoking 71. As a result of the pharmacokinetics of oral preparations, it has been 
postulated that the preference expressed by patients for herbal cannabis is a result of the faster onset 
and shorter duration of action allowing titration of dose to the desired effect 72. The present study will 
compare the risk benefit ratio of herbal cannabis to an oral preparation (dronabinol).  We know that 
cannabinoids appear to have some benefit in alleviating a heterogeneous collection of neuropathic 
pain conditions 2, 3. Preliminary recommendations have been issued from the College of Family 
Physicians in Canada to help guide clinicians in prescribing cannabis for the treatment of for chronic 
noncancer pain 73. But we do not know if chronic low back pain will respond to cannabis (or 
dronabinol). 
19. EXPENSE TO PARTICIPANT 
     There will no expense for participants other that the cost of travel/parking. 
20. COMPENSATION FOR PARTICIPATION 


 
 
Biomedical IRB Application Instructions 
Page 22 
     Subject payments are requested in order to compensate subjects for their participation. Total 
compensation could equal $960. 
 
Participants will be asked to arrange for transportation to and from the research site. For the 
screening appointment, participants will receive $40. For the baseline visit, participants will be given 
$10 for their arrival. Participants will receive $20 for each microbiome stool and saliva sample. If 
participants provide stool and saliva samples for the first, second, and sixth experimental visits, they 
will receive $60. Participants will receive $20 for each microbriome blood sample. If participants 
provide blood samples for the first, second, and sixth experimental visits, they will receive $60. We 
will budget $20 per week x10 weeks equals $200 and $65 per visit x6 visits equals $390. The total 
per subject payment will be $760 for visits. Compensation will be pro-rated if the subjects does not 
complete by weeks of participation and study visits attended.  
 
    For the baseline driving visit, participants will receive $20. In addition, we will pay subjects for one 
other driving session. In this driving session, we are budgeting $20 per hour for 9 hours equals $180 
per subject. While the experiment will last 8 hours, the time for preparation and lunch will have the 
participant stay at our center for a total of 9 hours. Compensation will be pro-rated if the subject does 
not complete driving simulation at $20 per hour. The total compensation for both driving visits will be 
$200. 
 
Inasmuch as participants will be given a vaporizer worth $600 to take home and use, they will not be 
compensated for their visits and weekly journals until study completion and after they return the 
vaporizer. Should they withdraw from the study prematurely, they will be compensated for completed 
visits but still be required to return the vaporizer they were given in order to be compensated.  
 
21. BIBLIOGRAPHY 
 
1. Grant I. Center for Medicinal Cannabis Research.  http://www.cmcr.ucsd.edu/. 
2. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of 
cannabis cigarettes in neuropathic pain. J Pain. Jun 2008;9(6):506-521. 
3. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized 
cannabis significantly improves neuropathic pain. J Pain. Feb 2013;14(2):136-148. 
4. Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL. Vaporization as a 
smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. Nov 2007;82(5):572-
578. 
5. Gieringer D, St. Laurent J, Goodrich S. Cannabis Vaporizer Combines Efficient Delivery of 
THC with Effective Suppression of Pyrolytic Compounds Journal of Cannabis Therapeutics 
2004;Vol. 4. 
6. Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and 
smoked marijuana in daily marijuana smokers. Neuropsychopharmacology. Sep 
2013;38(10):1984-1992. 
7. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data 
capture (REDCap)--a metadata-driven methodology and workflow process for providing 
translational research informatics support. J Biomed Inform. Apr 2009;42(2):377-381. 
8. Reinarman C, Nunberg H, Lanthier F, Heddleston T. Who are medical marijuana patients? 
Population characteristics from nine California assessment clinics. J Psychoactive Drugs. Apr-
Jun 2011;43(2):128-135. 


 
 
Biomedical IRB Application Instructions 
Page 23 
9. Deyo RA, Dworkin SF, Amtmann D, et al. Report of the NIH Task Force on Research 
Standards for Chronic Low Back Pain. Pain Med. Aug 2014;15(8):1249-1267. 
10. Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to 
neuropathic pain: the Neuropathic Pain Scale. Neurology. Feb 1997;48(2):332-338. 
11. Jensen MP, Dworkin RH, Gammaitoni AR, Olaleye DO, Oleka N, Galer BS. Assessment of 
pain quality in chronic neuropathic and nociceptive pain clinical trials with the Neuropathic Pain 
Scale. J Pain. Feb 2005;6(2):98-106. 
12. McNair D, Lorr M, Droppleman L. Revised manual for the profile of mood states. San Diego, 
CA Educational and Industrial Testing Services; 1992. 
13. Beck, AT, Steer, RA, Garbin, MG. Psychometric Properties of the Beck Depression Inventory: 
Twenty-Five Years of Evaluation. Clinical Psychology Review. 1988;8(1);77-100. 
14. Wechsler D. Wechsler Adult Intelligence Scale, Third Edition, Administration and Scoring 
Manual. San Antonio, TX,: The Psychological Corporation, Harcourt Brace & Co; 1997. 
15. Benedict R, Schretlen D, Groninger L, J B. Hopkins Verbal Learning Test-Revised: Normative 
data and analysis of inter-form and test-retest reliability. The Clinical Neuropsychologist. 
1998;12:43-55. 
16. Heaton R, Grant I, Matthews C. Comprehensive Norms for an Expanded Halstead-Reitan 
Battery: Demographic Corrections, Research Findings, and Clinical Applications. Odessa, FL; 
1981. 
17. Azorlosa JL, Heishman SJ, Stitzer ML, Mahaffey JM. Marijuana smoking: effect of varying 
delta 9-tetrahydrocannabinol content and number of puffs. J Pharmacol Exp Ther. Apr 
1992;261(1):114-122. 
18. Heishman SJ, Arasteh K, Stitzer ML. Comparative effects of alcohol and marijuana on mood, 
memory, and performance. Pharmacol Biochem Behav. Sep 1997;58(1):93-101. 
19. Heishman SJ, Stitzer ML, Bigelow GE. Alcohol and marijuana: comparative dose effect profiles 
in humans. Pharmacol Biochem Behav. Nov 1988;31(3):649-655. 
20. Kelly TH, Foltin RW, Fischman MW. Effects of smoked marijuana on heart rate, drug ratings 
and task performance by humans. Behav Pharmacol. Apr 1993;4(2):167-178. 
21. Haertzen  C, Hickey J. Addiction Research Center Inventory (ARCI): Measurement of euphoria 
and other drug effects. . In: Bozarth ME, ed. Methods of assessing the reinforcing properties of 
abused drugs. New York Springer-Verlag. ; 1987:pp. 489-524. 
22. Allsop DJ, Norberg MM, Copeland J, Fu S, Budney AJ. The Cannabis Withdrawal Scale 
development: patterns and predictors of cannabis withdrawal and distress. Drug Alcohol 
Depend. Dec 1 2011;119(1-2):123-129. 
23. Rosenthal T. STISIM Drive User’s Manual Hawthorne, CA: Systems Technology, Inc; 1999. 
24. Brookhuis KA, Volkerts ER, O'Hanlon JF. Repeated dose effects of lormetazepam and 
flurazepam upon driving performance. Eur J Clin Pharmacol. 1990;39(1):83-87. 
25. Ramaekers JG, O'Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects on driving 
performance as a function of dose and time after dosing. Eur J Clin Pharmacol. 
1994;47(3):261-266. 
26. Theunissen EL, Vermeeren A, van Oers AC, van Maris I, Ramaekers JG. A dose-ranging 
study of the effects of mequitazine on actual driving, memory and psychomotor performance 
as compared to dexchlorpheniramine, cetirizine and placebo. Clin Exp Allergy. Feb 
2004;34(2):250-258. 
27. Weiler JM, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine, diphenhydramine, 
and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving 
simulator. Ann Intern Med. Mar 7 2000;132(5):354-363. 


 
 
Biomedical IRB Application Instructions 
Page 24 
28. Lenne MG, Dietze P, Rumbold GR, Redman JR, Triggs TJ. The effects of the opioid 
pharmacotherapies methadone, LAAM and buprenorphine, alone and in combination with 
alcohol, on simulated driving. Drug Alcohol Depend. Dec 11 2003;72(3):271-278. 
29. Arnedt JT, Wilde GJ, Munt PW, MacLean AW. How do prolonged wakefulness and alcohol 
compare in the decrements they produce on a simulated driving task? Accid Anal Prev. May 
2001;33(3):337-344. 
30. Ramaekers JG, Robbe HW, O'Hanlon JF. Marijuana, alcohol and actual driving performance. 
Hum Psychopharmacol. Oct 2000;15(7):551-558. 
31. Brookhuis KA, de Waard D, Samyn N. Effects of MDMA (ecstasy), and multiple drugs use on 
(simulated) driving performance and traffic safety. Psychopharmacology (Berl). May 
2004;173(3-4):440-445. 
32. Marcotte TD, Heaton RK, Wolfson T, et al. The impact of HIV-related neuropsychological 
dysfunction on driving behavior. The HNRC Group. J Int Neuropsychol Soc. Nov 
1999;5(7):579-592. 
33. Marcotte TD, Rosenthal TJ, Roberts E, et al. The contribution of cognition and spasticity to 
driving performance in multiple sclerosis. Arch Phys Med Rehabil. Sep 2008;89(9):1753-1758. 
34. O'Hanlon JF. Driving performance under the influence of drugs: rationale for, and application 
of, a new test. Br J Clin Pharmacol. 1984;18 Suppl 1:121S-129S. 
35. O'Hanlon JF, Volkerts ER. Hypnotics and actual driving performance. Acta Psychiatr Scand 
Suppl. 1986;332:95-104. 
36. Vermeeren A, O'Hanlon JF. Fexofenadine's effects, alone and with alcohol, on actual driving 
and psychomotor performance. J Allergy Clin Immunol. Mar 1998;101(3):306-311. 
37. Marcotte TD, Wolfson T, Rosenthal TJ, et al. A multimodal assessment of driving performance 
in HIV infection. Neurology. Oct 26 2004;63(8):1417-1422. 
38. Fiorentino D, Parseghian Z. Time-To-Collision: A sensitive measure of driver interaction with 
traffic. . Paper presented at: Proceedings of the 41st Annual Human Factors and Ergonomics 
Society. Santa Monica, CA 1997  
39. Chindarkar NS, Park HD, Stone JA, Fitzgerald RL: Comparison of Different Time of Flight-  
Mass Spectrometry Modes for Small Molecule Quantitative Analysis. J Anal Toxicol. 2015, 
39:675-685 
42. Butters JE. Family stressors and adolescent cannabis use: a pathway to problem use. J 
Adolesc. Dec 2002;25(6):645-654. 
43. Fergusson DM, Horwood LJ, Swain-Campbell N. Cannabis use and psychosocial adjustment 
in adolescence and young adulthood. Addiction. Sep 2002;97(9):1123-1135. 
44. Hall W. The Mental Health Risks of Adolescent Cannabis Use. PLoS Med. 2006 Feb; 3(2): 
e39. 2006. 
45. Hall W. Cannabis use and the Mental Health of Young People. Aust N Z J Psychiatry February  
2006;vol. 40 no. 2 105-113. 
46. Hoy D, Bain C, Williams G, et al. A systematic review of the global prevalence of low back 
pain. Arthritis Rheum. Jun;64(6):2028-2037. 
47. Hoy D, March L, Brooks P, et al. The global burden of low back pain: estimates from the Global 
Burden of Disease 2010 study. Ann Rheum Dis. Jun;73(6):968-974. 
48. Fishbain DA, Cole B, Lewis JE, Gao J. What is the evidence that neuropathic pain is present in 
chronic low back pain and soft tissue syndromes? An evidence-based structured review. Pain 
Med. Jan 2014;15(1):4-15. 
49. Grant I, Atkinson JH, Gouaux B, Wilsey B. Medical marijuana: clearing away the smoke. Open 
Neurol J. 2012;6:18-25. 


 
 
Biomedical IRB Application Instructions 
Page 25 
50. Wilsey B, Atkinson JH, Marcotte TD, Grant I. The Medicinal Cannabis Treatment Agreement: 
Providing Information to Chronic Pain Patients via a Written Document. Clin J Pain. Nov 3 
2014. 
51. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to 
identify neuropathic components in patients with back pain. Curr Med Res Opin. Oct 
2006;22(10):1911-1920. 
52. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with 
nervous or somatic lesions and development of a new neuropathic pain diagnostic 
questionnaire (DN4). Pain. Mar 2005;114(1-2):29-36. 
53. Bennett MI, Smith BH, Torrance N, Potter J. The S-LANSS score for identifying pain of 
predominantly neuropathic origin: validation for use in clinical and postal research. J Pain. Mar 
2005;6(3):149-158. 
54. Krause SJ, Backonja MM. Development of a neuropathic pain questionnaire. Clin J Pain. Sep-
Oct 2003;19(5):306-314. 
55. Robins LN, Helzer JE, Croughan J, Ratcliff KS. National Institute of Mental Health Diagnostic 
Interview Schedule. Its history, characteristics, and validity. Arch Gen Psychiatry. Apr 
1981;38(4):381-389. 
56. Davison K, Wilson CH. Psychosis associated with cannabis smoking. Br J Addict Alcohol Other 
Drugs. Sep 1972;67(3):225-228. 
57. van Rossum I, Boomsma M, Tenback D, Reed C, van Os J. Does cannabis use affect 
treatment outcome in bipolar disorder? A longitudinal analysis. J Nerv Ment Dis. Jan 
2009;197(1):35-40. 
58. Pedersen W. Does cannabis use lead to depression and suicidal behaviours? A population-
based longitudinal study. Acta Psychiatr Scand. Nov 2008;118(5):395-403. 
59. Garrison CZ, Addy CL, Jackson KL, McKeown RE, Waller JL. A longitudinal study of suicidal 
ideation in young adolescents. J Am Acad Child Adolesc Psychiatry. Jul 1991;30(4):597-603. 
60. Garrison CZ, Jackson KL, Addy CL, McKeown RE, Waller JL. Suicidal behaviors in young 
adolescents. Am J Epidemiol. May 15 1991;133(10):1005-1014. 
61. Chabrol H, Choquet M. Relationship between depressive symptoms, hopelessness and 
suicidal ideation among 1547 high school students. Encephale. Oct 2009;35(5):443-447. 
62. Walsh Z, Callaway R, Belle-Isle L, et al. Cannabis for therapeutic purposes: patient 
characteristics, access, and reasons for use. Int J Drug Policy. Nov 2013;24(6):511-516. 
63. de Vries M, van Rijckevorsel DC, Wilder-Smith OH, van Goor H. Dronabinol and chronic pain: 
importance of mechanistic considerations. Expert Opin Pharmacother. Aug 2014 15(11):1525-
1534. 
64. Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D. Comparison of analgesic effects and 
patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, 
crossover, double blind study. Bmj. Jan 26 2008;336(7637):199-201. 
65. Grotenhermen F, Muller-Vahl K. The therapeutic potential of cannabis and cannabinoids. 
Dtsch Arztebl Int. Jul 2012;109(29-30):495-501. 
66. Issa MA, Narang S, Jamison RN, et al. The subjective psychoactive effects of oral dronabinol 
studied in a randomized, controlled crossover clinical trial for pain. Clin J Pain. Jun 
2014;30(6):472-478. 
67. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for 
chronic pain patients on opioid therapy. J Pain. Mar 2008;9(3):254-264. 
68. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. 
J Pain. Feb 2008;9(2):164-173. 


 
 
Biomedical IRB Application Instructions 
Page 26 
69. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in 
multiple sclerosis? Randomised double blind placebo controlled crossover trial. Bmj. Jul 31 
2004;329(7460):253. 
70. Mechoulam R, Parker L. Towards a better cannabis drug. Br J Pharmacol. Dec 
2013;170(7):1363-1364. 
71. Huestis MA. Pharmacokinetics and metabolism of the plant cannabinoids, delta9-
tetrahydrocannabinol, cannabidiol and cannabinol. Handb Exp Pharmacol. 2005(168):657-690. 
72. Gowing LR, Ali RL, Christie P, White JM. Therapeutic use of cannabis: clarifying the debate. 
Drug Alcohol Rev. Dec 1998;17(4):445-452. 
73. Kahan M, Srivastava A, Spithoff S, Bromley L. Prescribing smoked cannabis for chronic 
noncancer pain: preliminary recommendations. Can Fam Physician. Dec 2014;60(12):1083-
1090. 
74. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: 
a randomized placebo-controlled trial. Neurology. Feb 13 2007;68(7):515-521. 
75. Corey-Bloom J, Wolfson T, Gamst A, et al. Smoked cannabis for spasticity in multiple 
sclerosis: a randomized, placebo-controlled trial. Cmaj. Jul 10 2012;184(10):1143-1150. 
76. Marcotte TD. Cognitive impact of medicinal cannabis. Presented at the 42nd annual meeting of 
the International Neuropsychological Society. Seattle, WA., 2014. 
77. Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on 
capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. Nov 
2007;107(5):785-796. 
78. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a 
randomized, crossover clinical trial. Neuropsychopharmacology. Feb 2009;34(3):672-680. 
79. Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of Inhaled Cannabis on 
Painful Diabetic Neuropathy. J Pain. Jul 2015;16(7):616-627. 
 
 
22. FUNDING SUPPORT FOR THIS STUDY 
This study will be funded by the National Institute of Drug Abuse as 1R01DA038634-01A1 "A 
Randomized, Cross-Over Controlled Trial of Dronabinol and Vaporized Cannabis in Neuropathic Low 
Back Pain" 
23. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
N/A 
 
24. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
IND 102847 Vaporized Cannabis 
     This study involves an FDA-regulated investigation product for vaporized cannabis. Barth Wilsey 
MD is the IND holder (subsequently transferred to Dr. Marcotte). The IND Acknowledgement and 
Form 1572 from 2008 are attached (Appendices 20 and 21). An email from the FDA official is 
attached stating that the IND is may be used for the present study (Appendix 22). 
     The investigational drug will be handled by the UCSD Investigational Pharmacy. Accountability 
records will be maintained according to policies and procedures (Appendix 23). This has been 
discussed with the UCSD Investigational Pharmacy. Sign out logs will be kept as dictated by NIDA 
and DEA officials. At the end of each experimental session and/or study visit, all unused materials will 
be collected and stored in a sealed container that will be returned to the UCSD Investigational 
Pharmacy, with the exact amount noted and dated in the log (e.g., “bulk cannabis weighing x mg”). All 
records will be made available to the DEA and the Research Advisory Panel of California, which 
supervises all controlled substance research in California. At the end of the study, all unused plant 


 
 
Biomedical IRB Application Instructions 
Page 27 
material (i.e., cannabis not vaporized or the debris from vaporization) from each subject’s 8 week 
treatment period and, if applicable, driving simulation session will be collected and placed in a 
container, which will disposed at the facility used to incinerate unwanted medical or containment 
materials. 
25. OTHER APPROVALS/REGULATED MATERIALS 
     No other UCSD review committees have reviewed and approved/authorized this study or are 
currently reviewing the study. However, we have multiple federal and state reviews that are being 
conducted.  Marijuana is currently classified at the highest (most restrictive) level as a Schedule I 
drug (no accepted medical use, high potential for abuse). U.S. investigators are subject to specific 
Food and Drug Administration (FDA) and Drug Enforcement Agency (DEA) regulations concerning 
research with controlled substances. These reviews are described below: 
 
DEA: Under the Controlled Substances Act (21 USC 822 (a)(1)) and implementing DEA 
regulations, persons conducting clinical research with any controlled substance must register 
with the DEA, keep specific types of records, provide evidence of safety precautions to prevent 
diversion, and periodically report to the DEA. The PI, Barth Wilsey, has maintained a Schedule I 
license to study marijuana for over a decade. The DEA in Washington is awaiting UCSD IRB 
approval and will then have the San Diego Branch inspect the UCSD Investigational Pharmacy to 
insure that the facility meets their guidelines for secure handling of cannabis.  
 
FDA: Barth Wilsey, has an IND to study vaporized cannabis. A document was made to them earlier 
this year providing the background on the present proposal.  
 
NIDA: The source of marijuana will be the National Institute on Drug Abuse (NIDA); they will not 
release the marijuana until DEA and FDA approvals are granted. As we have documentation that the 
FDA will allow us to proceed (Appendix 21), the only remaining regulatory approval is that from the 
DEA.  
 
A Certificate of Confidentiality has been obtained from NIDA.  
 
 Research Advisory Panel of California: Some States may have their own registration requirements 
for Schedule I substances above and beyond the Federal requirements. California requires 
registration with the Regulatory Advisory Panel of California (RAPC). We have received approval 
from this agency (Appendices 24 and 25). 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
 
N/A 
 
 
 
 
 

SAP_001.pdf: 
Dronabinol and Vaporized Cannabis in Chronic Low Back Pain 
 
Statistical analysis plan 
 
 
Principal investigators: 
Thomas D. Marcotte, Ph.D. 
Barth Wilsey, M.D. (retired) 
 
Protocol Statisticians: 
Bin Tang, Ph.D. 
Florin Vaida, Ph.D. 
 
 
 
 
 
 
 
 
April 24, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
1. Summary of Study Design 
 
This study is a prospective, randomized, placebo controlled, double blind, phase 
2/3 clinical trial of dronabinol and vaporized cannabis for the treatment of chronic 
low back pain. A total of 120 (n = 120) subjects with chronic low back pain, aged 
between 19-70 years will be randomized in a ratio of 1:1:1 to the three treatment 
arms (40 participants per arm): 1) vaporized 3.7% Δ9-THC /5.6% cannabidiol 
plus placebo oral pills, 2) oral Δ9-THC (dronabinol) plus vaporized placebo, and 
3) double placebo. The three arms are shortly called 1) vaporized cannabis; 2) 
dronabinol; 3) placebo. After randomization, each patient will receive study 
medication at home for 8 weeks after which they will be tapered off of 
investigational treatments over two weeks.  The three study periods include: i) 
Titration (weeks 0-4); ii) Treatment (weeks 5-8); iii) Tapering (Weeks 9-10). 
During the titration period, patients will undergo titration of vaporized medication 
from 4 puffs to 18 puffs, or oral medication from 5 mg qd to 10 mg tid per day. 
Subjects will be dropped from the study by the end of Week 4 if they are unable 
to tolerate the minimum amounts of medication described above, and replaced by 
another volunteer. During the treatment period, subjects will be expected to 
consume the amount of study medication that they titrated themselves up to by the 
end of week 4. During the tapering period, patients will slowly withdraw from 
medication over two weeks. During treatment at home (weeks 1-8), patients will 
maintain a paper daily diary to record their intake of study medications, and 
breakthrough pain medications, as well as pain relief measurements. Outcome 
measure (such as self-report forms and neuropsychological testing) will be 
collected during the six study visits. If participating in Driving Simulation, 
subjects with driver licenses will be scheduled for two experimental visits.  
 
The variables being assessed include vital signs, pain evaluation (cold pressor 
test), driving simulation, iPad performance testing, blood draws, 
neuropsychological tests, self-reports (BDI-II, Neuropathic Pain Scale, side 
effects). The primary outcome will be measured using self-reported average 
numerical pain intensity during the past 24 hours. A secondary outcome measure 
will be the level of use of breakthrough pain medication, mood, attention, verbal 
learning, fine motor coordination, psychomimetic side-effects, and driving 
performances. 
 
The three main objectives of this study are to 1) assess whether treatment with 
vaporized whole plant cannabis or oral ∆9-THC reduces spontaneous and evoked 
pain more than placebo, and whether there are differences between the two active 
treatments. 2) examine the effects of vaporized whole plant cannabis and oral Δ9-
THC (dronabinol) on mood, neuropsychological function, and psychomimetic 
side-effects (high, stoned, etc.) compared to placebo and to each other. 3) examine 
the acute effects (after receiving stable treatment for 4 weeks) of vaporized whole 


plant cannabis and oral Δ9-THC compared to placebo and each other on driving 
skills. 
 
 
2. Baseline characteristics, treatment, and study enrollment summaries 
 
2.1 Demographic and medical and laboratory characteristics 
 
These measures will be tabulated and summarized by treatment arm using 
Mean (SD), N (%), and Median (IQR), as appropriate. Fisher’s exact test for 
categorical variables and analysis of variance (ANOVA) for numeric 
variables will be used to test the overall differences between the three 
treatment arms. 
 
2.2 Study enrollment, Randomization, and dropout 
 
The 120 eligible participants will be randomized to Arm A (vaporized Δ9-
THC (3.5%)/placebo oral pill, n=40), to Arm B (dronabinol/vaporized 
placebo THC, n=40), or Arm C (double placebo, n=40). With a 16% dropout 
rate, we expect 33 subjects completing the 8-week visit for each arm. The 
completers who have a valid driver’s license will implement driving 
simulation. The number (%) of subjects randomized, number (%) of subjects 
completing the 8-week-treatment, and number (%) of patients lost to follow-
up will be summarized overall and by treatment arm. Fisher’s exact test will 
be used to compare the arms in the proportions of lost to follow-up. Reasons 
(if known) for lost to follow-up will also be recorded. The comparisons are 
following an order of importance: arm A vs. arm B; arm A vs. arm C; arm B 
vs. arm C. Since the three comparisons have different levels of importance, 
no correction will be done for multiple comparisons. 
 
The dropouts and completers will be compared, overall and stratified by 
treatment arm, with respect to their baseline demographics, medical 
characteristics, and the prevalence and timing of adverse events. The 
statistical analysis will use Fisher’s exact test for binary and nominal 
variables, Student’s t test or Wilcoxon rank-sum test for continuous variables, 
and log-rank test for time-to-event analysis, censored at the time of dropout. 
 
2.3 Treatment Adherence and Discontinuation 
 
The number (%) of subjects who discontinue assigned study treatment 
permanently, dates and reasons for treatment discontinuation will be 
summarized overall and by treatment arm, and will be compared between 
arms using Fisher’s exact test with the strategy of the comparison described 
in 2.2. 
 
 


3. Safety and treatment toxicity 
 
3.1 Adverse events 
 
The number (%) of subjects with adverse events will be tabulated and 
summarized overall and by treatment arm, with the grade of the adverse event 
(1-4) included. The study week and reasons for adverse events will be 
included. Using the Kruskal-Wallis rank sum test, the number of adverse 
events per individual and maximal grade for each individual were compared 
among the three treatment arms. The proportion of participants with severe 
adverse events (leading to permanent treatment determination) will be 
compared between treatment arms with Fisher’s exact test using the strategy 
of the comparison described in 2.2. 
 
4. Endpoints 
 
4.1 Primary endpoint 
 
The primary outcome will be self-reported daily average numerical pain 
intensity during the past 24 hours. The comparisons are following as 
following: 1) primary comparison: arm A vs. arm B; 2) secondary 
comparison: arm A vs. arm C; exploratory comparison: arm B vs. arm C. 
Since the three comparisons have different levels of importance, no 
correction will be done for multiple comparisons. 
 
4.1.1 Primary analysis 
 
The primary analysis will be the comparison of self-reported pain 
intensity between arm A and arm B. An intent-to-treat analysis will be 
performed on data from participants who complete baseline. Data 
transformation (e.g., log10, square root) may be performed to improve 
distribution normality as appropriate. Response profiles analysis will 
be performed if the trend of pain intensity over time is not linear. We 
will compare different covariance pattern models (e.g., unstructured, 
compound symmetry) based on AIC and identify a covariance model 
with the best fit to our data. This is a randomized controlled trial so 
that we can remove main group effect with assumptions about equal 
mean responses (i.e., pain scores) at baseline for the three treatment 
arms. Weekly or biweekly average of pain intensity from the daily 
diary will be calculated as a primary outcome. Time will be treated as 
a factor with 6 levels (i.e., baseline, weeks 1, 3, 5, 7, 8), and the mean 
response profiles will be compared between the arms. The treatment 
effect over time will be assessed by the significance of the treatment 
arm x time interaction using Wald test. Also, average change at the 
treatment period (weeks 5-8) from baseline will be compared between 
the groups. (Aim 1) 


 
4.1.2 Secondary analysis of primary endpoint 
 
The secondary and exploratory comparisons of pain intensity will be 
performed for arm A vs. arm C, and arm B vs. arm C respectively. The 
same statistical analyses will be performed as described above in the 
primary analysis. (Aim 1) 
 
4.2 Secondary endpoints 
 
The secondary outcomes include the level of use of breakthrough pain 
medication, pain tolerance and sensitivity, chronic low back pain (CLBP) 
impact score, neuropathic pain scale (NPS, a sum of 10 pain descriptors), 
profile of mood states (total mood disturbance scores), Beck Depression 
Inventory II, ability to learn and recall measured using Hopkins Verbal 
Learning Test (HVLT), measures of concentration, psychomotor speed, and 
graphomotor abilities by Wechsler Adult Intelligence Scale -III (WAIS-III)  
digit symbol test, marijuana subscale (M-scale), motor coordination and 
speed evaluated by grooved pegboard test. In addition, subjective and 
psychoactive side effects (e.g., good drug effect, drug high) and measures 
(e.g., lane tracking, car following) in driving simulation will be examined as 
secondary outcomes in a substudy, where completers with a valid driver’s 
license will receive acute administration of treatment at the driving 
simulation visit.  
 
All comparisons of secondary outcomes between arms will be with an order 
of importance as described above for the primary endpoint:  1) primary 
comparison: arm A vs. arm B; 2) secondary comparison: arm A vs. arm C; 
exploratory comparison: arm B vs. arm C. No correction will be done for 
multiple comparisons.  
 
4.2.1 Comparison of outcomes measured at 6 visits between treatment arms 
 
The similar analysis strategies as described above for primary endpoint 
will be used for the secondary outcomes measured at 6 visits. Briefly, 
the interaction effect of treatment arm and time (6 visits) on outcome 
will be tested using a covariance pattern model (e.g., unstructured 
model). Average change at the treatment period (weeks 5-8) from 
baseline will be compared between the groups. Non-significant 
interaction terms will be removed from the models (Aim 2). 
 
4.2.2 Comparison of cannabis withdrawal scale between treatment arms 
 
Cannabis withdrawal intensity and negative impact of withdrawal will 
be assessed via telephone calls at week 8 and week 10. Linear 
regression will be used to compare changes in intensity and negative 


impact of withdrawal symptoms from week 8 to week 10 between the 
arms. 
 
4.2.3 Comparison of subjective and psychoactive side effects between 
treatment arms 
 
Psychoactive effects will be assessed at 1, 2, 3, 4, 5, and 6 hours after 
the first acute administration of treatment at the driving simulation 
visit in a substudy. Area under the time concentration curve (AUC) 
will be used as a measure for the aggregate effect of response over a 
period of time (during 1-6 hours after the 1st dose). AUC will be 
compared between the arms using linear regression (Aim 2). 
 
4.2.4 Comparison of driving performance between treatment arms 
 
The driving simulation assessments will be conducted in the substudy. 
(1) Driving measurements (standard deviation of lateral deviation 
(SDLP) for lane tracking and coherence for car following) following 8 
weeks of study medication administration will be compared between 
treatment arms using ANOVA, to determine whether driving skills 
will be different after stable cannabis treatment. Acute cannabis effects 
will be then tested using a covariance pattern model (e.g., unstructured 
model) including fixed effects of treatment arm, time (minutes), and 
their interaction. (2) We will also include terms for pain (separately 
using intensity and relief), its interaction with treatment, and time too, 
the latter to test for recovery of the cannabis effect back to the Hour 1 
baseline level. (3) The correlation (Pearson or Spearman, as 
appropriate) between blood Δ9-THC and each of SDLP and coherence 
will be estimated at each hour using a 95% confidence interval applied 
to the Fisher Z-transformation, then back-transformed. Secondary 
analyses will use independent t-tests or Wilcoxon rank sum tests to 
compare differences between the means of each of coherence and 
SDLP for high and low blood Δ9-THC levels split at 7 ng/ml. (Aim 3) 
 
 
4.3 Exploratory analysis: 
 
4.3.1 We will assess the association of daily pain intensity and the dose of 
treatment (mean daily number of puffs or pills) using a mixed-effects 
model including fixed effects of dose, treatment regimen, time (i.e., 
day or week), and dose x treatment regimen interaction, and subject-
specific random effect. A significant interaction indicates the 
association of the dose and pain intensity differs in the three treatment 
arms. Use of breakthrough pain medication will be then included in the 
model to remove its confounding effect if it’s present. A Non-
significant interaction will be removed from the models.  


4.3.2 Cumulative distributions of maximal pain reduction from baseline 
among treatment groups will be compared using Kolmogorov-Smirnov 
tests. This test (nonparametric) will indicate if a given treatment is 
likely to produce more overall pain reduction than another treatment 
regimen and takes into account an expected delay in effects of 
dronabinol compared to whole plant cannabis. 
4.3.3 To test if a treatment effect on pain may be linked to mood and 
neuropsychological side effects of treatment, a mechanistic analysis 
using the mediation model methods of Preacher and Hayes {Preacher 
KJ and Hayes AF: SPSS and SAS procedures for estimating indirect 
effects in simple mediation models, 2004, Behavior Research 
Methods, 36:717-731} will be used, allowing for multiple mediators 
to be tested simultaneously. 
  
5. Sample Size and Accrual 
 
5.1 Power Estimation 
 
Power estimates for each outcome assumed a 5% significance level. Totally, 
N=120 subjects will be randomized in 1:1:1 ratio to the three treatment arms, 
that is, 40 subjects to each arm. Using the same 16% drop-out rate 
experienced in our previous study and that 87% of the completers possess a 
valid driver’s license, a national average published by the Department of 
Transportation, power was calculated for 33 subjects per treatment arm (total 
N=99) for Aims 1 and 2, and 29 subjects per treatment arm (total N=87) for 
Aim 3. We have 80% power to detect effect sizes equivalent to Cohen’s 
d=0.54 and d=0.58 for sample sizes 33 and 29 respectively.  This effect size 
is based on differences between groups of changes from baseline at the end 
of the study (week 8). The power is calculated using specific formulas for a 
time-by-treatment interaction in a longitudinal linear mixed-effects model 
{Diggle PJ, Heagarty P, Liang KY, Zeger SL: Analysis of Longitudinal Data, 
2nd edition, 2002, Oxford University Press, Oxford, p.29}.  Power is expected 
to be higher for larger effect sizes and fewer dropouts.  
 
6. Data and Safety Monitoring Committee (DSMC) 
 
Progress reports will be presented to the DSMC every 6 months. Two reports (open 
and closed reports) will be generated and presented in two sessions.  
 
Key study personnel and all DSMC members will attend the open session; the open 
report will present data in aggregate form (not by arm). Open session attendees will 
review presented summarized data for data completeness and accuracy (e.g., review 
ranges for numeric variables to catch any outliers/unusual observations). 
 
The closed session will include only the study statistician and members of the 
DSMC; the closed report will present data by treatment arm, but in blinded fashion, 


i.e., arms will be presented as arm X, arm Y, arm Z. Treatment labels can be 
revealed to the DSMC members upon their request if major concerns arise. 
Statistical comparison of relevant characteristics between the arms will be done. 
No interim analysis comparing primary outcomes between the arms will be 
performed in order to preserve the power of the primary analysis and the overall 
Type I error at 0.05 level till the end of the study, unless requested by the DSMC. 
Members of the DSMC will be asked to maintain confidentiality related to the 
interim data presented in the closed report until the end of the trial.  
 
Number of available observations (N) will be given for each variable to give a sense 
of data collection completeness. The reasons of data entry lagging, leading to a 
large portion of missing values, will be provided. 
 
 
6.1 The information included in open report 
 
The data will be presented in aggregate form, but not by arm. The measures 
will be tabulated and summarized using Mean (SD), N (%), and Median 
(IQR), as appropriate.  
 
A. Outline of the study design:  1) aims, 2) design summary, 3) database 
freezing date, 4) confidentiality statement 
 
B. Enrollment and study status: the number of 1) screened subjects; 2) 
exclusion and the reasons; 3) enrolled subjects and projected enrollment 
(graph of enrollment by month); 4) subjects completing the entire study; 
5) withdrawal from the study and the reasons; 6) missing visit(s) and the 
reasons. 
 
C. Demographic characteristics of the cohort: 1) age, 2) sex, 3) education, 
4) Race 
 
D. Baseline study relevant characteristics of the cohort: 1) baseline of pain 
intensity; 2) baseline levels of the driving performance 
 
E. Baseline lab characteristics: vital signs, e.g. heart rate and blood pressure 
 
F. Safety data and study-related adverse events: 1) type and severity (grade) 
of adverse events; 2) number of adverse events; 3) number of subjects 
with adverse events; 4) number of deaths related to adverse events; 5) 
unanticipated problems. 
 
G. Protocol deviations 
 
 
6.2 The information included in closed report 


 
The data will be presented by blinded arms (arm X, arm Y, and arm Z), 
except for a notice of aggregate. The measures will be tabulated and 
summarized in aggregate form or by treatment arm using Mean (SD), N (%), 
and Median (IQR), as appropriate. The items with an asterisk (*) will be 
compared between arms. Kruskal-Wallis test and Fisher’s Exact test will be 
used to compare numeric and categorical variables, respectively. 
 
A. Outline of the study design:  1) aims, 2) design summary, 3) database 
freezing date, 4) confidentiality statement 
 
B. Enrollment and study status: the number of 1) screened subjects 
(aggregate); 2) exclusion and the reasons (aggregate); 3) enrolled subjects 
and projected enrollment (graph of enrollment by month) (aggregate); 4) 
subjects completing the entire study; 5) *withdrawal from the study and 
the reasons; 6) missing visit(s) and the reasons. 
 
C. Demographic characteristics of the cohort: 1) age, 2) sex, 3) education, 
4) Race 
 
D. Baseline study relevant characteristics of the cohort*: 1) baseline of pain 
intensity; 2) baseline levels of the driving performance 
 
E. Baseline lab characteristics: vital signs, e.g. heart rate and blood pressure 
 
F. Safety data and study-related adverse events: 1) type and severity (grade) 
of adverse events*; 2) number of adverse events; 3) number of subjects 
with adverse events*; 4) number of deaths related to adverse events*; 5) 
unanticipated problems. 
 
G. Protocol deviations 
 
H. Summary of the overall study status (closed report only)