An Observational Study of the Effects of Edible Cannabis and Its Constituent Cannabinoids on Pain, Inflammation, and Cognition
Conditions: Chronic Pain, Chronic Low Back Pain, Cannabis Use
Sponsor: University of Colorado, Boulder

 
 
 
 
 
 
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TITLE:  Observational Study of Cannabis and Pain  
 
PROTOCOL VERSION DATE:  24 January 2023 
VERSION: 28 
NCT NUMBER: NCT03522324 
PRINCIPAL INVESTIGATOR (PI): 
Name: L. Cinnamon Bidwell, Ph.D. 
Address: Institute of Cognitive Science, 344 UCB 
Telephone: 303-735-5383  
Email: lcb@colorado.edu 
KEY PERSONNEL 
Name: Kent Hutchison, Ph.D.   
Role in project: Co-PI  
 
Name: Angela Bryan, Ph.D.   
Role in project: Co-PI  
 
Name: Gregory Giordano, B.S. Ed., M.S. 
Role in project: Research Coordinator 
 
Name: Nicholas Gonyea, B.S. 
Role in project: Research Assistant 
 
Name: Elicia Azua, B.A. 
Role in project: Research Coordinator 
 
Name: Jonathon Lisano, Ph.D 
Role in project: Research Coordinator 
 
Name: Paige Phillips, B.A. 
Role in project: Research Assistant 
Name: William Carpenter III, B.A. 
Role in project: Research Assistant  
 
Name: Evangelique Lopez, B.A. 
Role in project: Research Coordinator 
 
Name: Austin Drake 
Role in project: Research Coordinator 
 
Name: Nora Elkerton  
Role in project: Research Assistant 
 
Name: Luiza Rosa, B.A, B.S. 
Role in project: Research Assistant 
 
Name: Shelly Dey 
Role in project: Research Assistant 
 
 
 
 
 
 
 
In addition to the co-investigators listed above, undergraduate and professional research assistants will 
play an active role in the recruiting and data collection phase of this study. These persons have completed 

 
 
 
 
 
 
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CITI training, and have been trained by the lead Professional Research Assistant and project manager 
regarding responsible conduct in research and study specific procedures/guidelines. 
I. 
OBJECTIVES 
Please note that the grant proposal supporting this project has now received funding by the National 
Center for Complementary and Integrative Health (NCCIH). The grant and protocol follow many of the 
same procedures as two IRB-approved studies: “Anxiety, Inflammation, and Cannabis” (protocol 
number 16-0767); and “An Observational Study of Cannabidiol, Neurocognition, and Mood” (protocol 
number 14-0087).   
The National Center for Health Statistics reports that approximately 76 million Americans suffer from 
chronic pain, affecting the lives of more Americans than cancer, diabetes, and heart disease combined1. 
Perhaps because of its ubiquity and the challenge to its treatment, relief from chronic pain is by far the 
most commonly cited condition by patients for use of marijuana, with 87%-94% of medical marijuana 
users reporting using for relief of a pain condition2,3.  Although the mechanisms are still unclear, 
marijuana and its constituent cannabinoids, including 9-delta-tetrahydrocannabinol (THC), are thought to 
be involved in reducing pain and associated inflammation.  However, THC is also associated with harm in 
the form of cognitive dysfunction. Synergistic interactions of cannabinoids are believed to produce 
different effects on both pain relief and cognitive function as compared to THC alone.  For example, 
cannabidiol (CBD) is another primary cannabinoid that may work synergistically with THC in a multi-
target analgesic approach [a strategy embodied in the pharmaceutical Sativex (aka nabiximols), a 
CBD/THC based oral spray for pain available in Europe].  CBD does not have psychoactive properties 
and may modulate the negative cognitive effects of THC.  Further, both THC and CBD have anti-
inflammatory properties that likely mediate their role in pain relief.  However, the anti-inflammatory 
profiles differ across the two cannabinoids and these differences may impact the mechanistic effects of 
marijuana on chronic pain.  The marijuana products available for pain treatment across dispensaries 
throughout the US contain a vast array of cannabinoid potencies and ratios.  Notably, data from Colorado 
and other states with legal marijuana suggest that medical users are more likely than recreational users to 
use edible marijuana, which is a form of marijuana which remains psychoactive much longer than smoked 
marijuana4.  The most recent data from Colorado suggest that over 650,000 edible products were sold per 
month in Colorado dispensaries in 2015.  Importantly, there have been no reported studies of the 
mechanistic effects of edible marijuana products on pain, inflammatory, and cognitive processes, despite 
the fact that consumption of edible marijuana is prevalent and rapidly increasing in individuals with 
chronic pain.  
We propose to examine the effects of cannabinoids in edible form on pain relief, inflammation, and 
cognitive dysfunction in chronic low back pain patients who choose to use marijuana in the context of a 
short-term (2 weeks) mechanistic study using a patient-oriented, observational design and a Mobile 
pharmacology and phlebotomy lab that solves many of the logistical problems with marijuana research.  
Our global hypothesis is that our observations of self-report and objective measures of the effects of 
marijuana edible products by pain patients who choose to use these products will vary as a function 
of the levels of THC to CBD in their blood. Further, we hypothesize that cognitive impacts observed 
will differ by the THC/CBD levels in blood. To that end, we will measure the association of pain, 
inflammation, and cognitive impairment with the levels of THC and CBD in the blood of pain patients 
who wish to use edible cannabis to treat their pain. This approach is ecologically valid and timely given 
that edibles of various cannabinoid ratios are widely used by patients in state legalized markets, yet 
absolutely no research has been done on these products. Edibles generally have either THC-only, CBD-
only, or include both THC and CBD. Recent data, including our pilot work, suggest that THC and CBD 
together produce unique effects on pain, inflammation, and cognition. We will use a patient-oriented, 
observational design, in which chronic low back pain patients who self-initiate the use of a marijuana 
edible to manage their pain are observed over their 2-Week study period while using a product of their 
choosing. THC and CBD blood levels will be tested in relation to all outcomes. 

 
 
 
 
 
 
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Aim 1. To investigate the mechanisms that may underlie the widespread use of marijuana among pain 
patients in a 2-week observational study of ad-libitum use, we will observe whether there is an association 
between cannabinoid levels in blood and measures of self-reported pain. 
Hypothesis 1. Based on numerous studies that suggest CBD and THC may work together to produce 
the analgesic effects of marijuana, we hypothesize that higher blood levels of both THC and CBD will 
have the strongest association with lower levels of pain interference after 2 weeks. 
Hypothesis 2. Given the role of elevated inflammatory markers as an underlying mechanism 
involved in chronic pain, we predict that THC and CBD blood levels will additively be most strongly 
associated with lower levels of four circulating cytokines (TNFα, IL-6, IL-8, IL-1B) after 2 weeks. 
Aim 2. To understand the relationship of self-directed edible cannabis-use to cognitive function in 
individuals with chronic low back pain, we will observe the association between cannabinoid levels in 
blood and measures of cognitive function.   
Hypothesis 3. Based on prior research and our preliminary data, we predict an interactive relationship 
of blood levels of THC and CBD to cognitive impairment, such that at lower levels of CBD in blood, 
THC blood levels will be dose-dependently associated with poorer verbal recall and selective attention 
after 2 weeks of ad libitum use, whereas at higher levels of CBD in blood, the relationship of THC in 
blood to cognitive impairment will be attenuated.  
II. 
BACKGROUND AND SIGNIFICANCE  
Use of cannabis for chronic pain  
The National Center for Health Statistics reports that approximately 76 million Americans suffer from 
chronic pain; thus, chronic pain (pain lasting more than 12 weeks) affects the lives of more Americans 
than cancer, diabetes, and heart disease combined1. Perhaps because of its ubiquity and the challenge to 
its treatment, relief from chronic pain is by far the most common condition cited by patients for use of 
medical marijuana now available in more than half of U.S. states; 87%-94% of self-reported medical 
marijuana users report using marijuana for relief of a pain condition2,3. In addition, there is some evidence 
that individuals are replacing the use of traditional pain medications with marijuana. For example, one 
recent study reported survey data suggesting that medical marijuana use in pain patients was associated 
with a 64% decrease in opiate use5.  Similarly, recent analyses of prescription data in states with medical 
access to marijuana suggest a significant reduction in the prescription of traditional pain medications6. 
Finally, a study recently observed significantly lower opiate overdose deaths in states with medical access 
to marijuana7.  Combined with the survey data suggesting that pain is one of the primary reasons cited for 
the use of medical cannabis, these recent reports suggest that a large number of pain patients are replacing 
the use of opiates with marijuana, despite the fact that cannabis is not an FDA approved medicine for 
chronic pain. This increased use via medical and recreational marijuana laws suggests there is a strong 
need for research into the mechanisms that may underlie the effects of marijuana on pain.   
Synergistic effects of multiple cannabinoids and pain  
Marijuana and its constituent cannabinoids are directly involved in reducing pain and inflammation, 
including 9-delta-tetrahydrocannabinol (THC) which has well-known analgesic effects. Across five high 
quality reviews conducted in the past four years, results were largely consistent in suggesting that 
cannabinoids demonstrate a modest effect on pain8-12.  For example, a rigorous, systematic review by 
Whiting et al11 covered 28 chronic pain studies (2454 participants) primarily conducted in Canada or 
Europe.  Twenty-two of these studies evaluated plant-derived cannabinoids (cannabis extract mouth spray 
or nabiximols n=13, plant flower that was smoked or vaporized n=5, oral mucosal spray n=3, oral THC 
n=1) while 5 studies evaluated synthetic THC (i.e., nabilone). All of the selected studies included either 
an active comparator or placebo control. Analyses across studies that evaluated nabiximols and a single 
study that evaluated the effects of inhaled cannabis suggested a statistically significant effect of plant-
derived cannabinoids on the odds of a 30% or greater improvement in pain (OR=1.41).  Nabiximols were 

 
 
 
 
 
 
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also associated with significant reductions in numerical pain ratings across six additional studies. The 
largest single effect size presented across the reviews was observed with inhaled cannabis on pain (e.g. 
OR=3.4313). Consistent with this, an average OR of 3.22 (CI: 1.59 to 7.24) was found across 9 doses of 
inhaled THC tested across 5 studies8.  
While the analgesic properties of THC are the most widely studied, pharmacological and clinical data 
suggest that cannabidiol (CBD) is another primary cannabinoid that may work synergistically with THC 
in a multi-target analgesic approach to pain relief. For example, reviews cited above, consistently support 
that administration of nabiximols, a plant-based mixture of THC and CBD via mouth or nasal spray, 
provide pain relief. Overall, there is compelling clinical evidence that the synergistic interactions of 
naturally derived cannabinoids may be effective for pain relief. However, very little is known about the 
efficacy, dose, routes of administration, or side effects of commonly used cannabis products in the U.S 
that come in a variety of potencies and cannabinoid contents. Most importantly, it is not clear how the 
combination of THC and CBD may differ from THC or CBD alone. 
Marijuana has anti-inflammatory properties  
Cannabinoids have profound effects on immune system function and inflammation, both peripherally 
and centrally, that indirectly impact their analgesic properties(for review see 14).  A number of studies support 
the notion that the cannabinoids THC and CBD, when considered in isolation, are importation modulators 
of pro-inflammatory cytokines, including TNF, IL-2, IL-6, IL-12, IL-1b(see 14). Importantly, although both 
THC and CBD exert inhibitory effects on the production of inflammatory cytokines, their activities seem 
to involve distinct intracellular pathways which remain somewhat elusive and appear to at least partially 
involve non-CB1 or CB2 related mechanisms15. In addition, pharmacological data suggest that CBD may 
interact with or alter the effects of THC, suggesting that THC and CBD synergistically may produce 
different and/or stronger anti-inflammatory effects16.  Consistent with this, pre-clinical animal studies 
demonstrate that CBD expands THC’s therapeutic window and may enhance the efficacy of THC across a 
variety of inflammatory conditions, including pain relief 17. 
A unique role for THC and CBD in pain through inflammatory pathways  
These data, consistent with our pilot data, suggest that THC and CBD have profound anti-
inflammatory effects on peripheral and neuro-inflammatory markers(see review 18), which play a pivotal role 
in pain related therapeutic processes19,20.  While THC and CBD have anti-inflammatory properties 
individually, the totality of data, including our own pilot work, suggest that THC and CBD have differing 
inflammatory profiles21 which may result in differing effects on pain relief and/or create a synergy 
whereby a balance of these cannabinoids have the strongest anti-inflammatory and analgesic effects. 
These exact questions are ideally answered by our proposed design, to examine the range of THC and 
CBD (both individually and in combination) in edible products chosen by patients. Given that pro-
inflammatory shifts are thought to underlie chronic pain, the anti-inflammatory effects of THC and CBD 
may be key players in explaining associations among marijuana use and relief from chronic pain.   
THC and cognitive impairment 
In addition to reducing pain and inflammation, studies also indicate that marijuana produces acute 
cognitive impairment, especially relating to memory and attention during intoxication and possibly for 
hours to days after use (see reviews 22,23). For example, studies that were published as early as the 1970’s 
suggest that marijuana disrupts immediate and delayed free recall of information(e.g., 24,25). Recall of words 
from a list is one of the most common approaches to demonstrating the effect of THC on recall 
performance(e.g., 26).  Studies have also suggested that acute marijuana use may interfere with working 
memory, as evidenced by the effect of marijuana on the digit symbol substitution task (DSST), which 
some studies suggest may be the working memory measure most sensitive to the acute effects of 
marijuana(see 27). Among the studies that included two THC concentrations, higher doses mostly yielded 
greater cognitive impairment22,28-30. In neuroimaging work, cannabis users showed differential brain 
response to an associative memory task while under the influence of THC compared with a placebo. 
Specifically, THC attenuated brain activity in the insula, right inferior frontal gyrus (IFG) and left middle 

 
 
 
 
 
 
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occipitals gyrus during encoding, and increased network-wide activity during recall. Taken together, these 
results suggest that THC has a negative effect on the neurocognitive processes involved with encoding, 
and neural activation changes during recall likely reflect a compensatory mechanism for the affected 
encoding. That is, the memory system as a whole must work harder in order to account for the cognitive 
deficits induced by THC.  
In sum, the literature suggests that acute administration of marijuana impairs the encoding and 
retrieval of information, albeit to a modest degree, and these effects may be dose-dependent on THC 
level. Further, this cannabis-induced cognitive impairment can last from hours to days after use22 and 
potentially longer in heavy chronic users.  Thus, the potential cognitive side effects of regular use of 
current medical marijuana products are highly relevant to pain patients, who may use marijuana on a 
regular basis to treat their pain and still wish to function well in their daily lives.   
Does CBD mitigate the harmful cognitive effects of THC? 
Clearly, the evidence suggests that acute marijuana use is associated with at least modest cognitive 
impairment. However, almost all of this research was conducted with low potency marijuana provided by 
the government and almost all of this research was focused on the effect of one particular cannabinoid, 
namely THC. The effects of other primary cannabinoids, such as CBD, are important to consider when 
interpreting the harmful effects of marijuana use, especially given that marijuana includes more than 80 
additional phytocannabinoids31,32. Strains commonly available in states like Colorado differ dramatically 
on the potency of these cannabinoids. As a concrete example regarding the importance of cannabinoids 
other than THC, several studies have demonstrated that THC and CBD have very different effects on 
cognition. As noted previously, results from both imaging and non-imaging studies suggest that THC is 
associated with memory and other cognitive impairment(see review 22). Conversely, analyses suggest that 
CBD may attenuate the negative effects of THC on cognition and other measures33-42. Most of the work 
on CBD has involved the administration of THC and CBD in synthetic pill form. Much less is known 
about the combined effects of THC and CBD when using marijuana in the forms commonly available in 
dispensaries across the U.S. Given that CBD mitigates some effects of THC, this is a high priority area of 
research in terms of understanding how to reduce the potentially harmful effects of marijuana use in 
chronic pain patients.   
 Limitations of existing literature 
The majority of studies on cannabinoids and pain11 evaluated nabiximols (cannabis based oral spray) 
outside the U.S.  Only a handful of studies have evaluated the use of cannabis in the U.S. and all of them 
evaluated cannabis in flower form provided by NIDA that was either vaporized or smoked. In contrast, 
most of the cannabis products that are sold in state regulated markets bear little resemblance to the 
products that are available for research from NIDA at the federal level in the U.S. For example, in 
Colorado alone >600,000 edible units of cannabis were sold across medical and recreational dispensaries 
each month of 2015, nearly a 50% increase from the monthly data reported for 2014, the first year of legal 
marijuana sales in our state43. Data also suggest that pain patients are more likely to use edible products 
than recreational users 43. Importantly, using marijuana in edible form represents a very different way to 
use marijuana, in part because in contrast to smoked forms of marijuana which produce acute effects that 
begin to diminish rapidly after consumption (blood levels dramatically decrease within 15 minutes of 
smoking), edible marijuana produces prolonged effects that last at least 4 hours post-consumption44,45.  
This in part explains their increased use in pain patients who seek sustained relief. However, no data are 
available to understand the mechanisms or effects of edibles of various potencies and cannabinoid ratios. 
Thus, while the use of particular forms of cannabis for the treatment of pain is supported by well-
controlled clinical trials as reviewed above, very little is known about the efficacy, dose, routes of 
administration, or side effects of commonly available and increasingly used edible cannabis products. 
More research is desperately needed on the various forms, routes of administration, and 
combination of cannabinoids, given the ubiquitous availability of cannabis products in much of the 
nation and the complete lack of any research in the U.S. on the beneficial or harmful effects of 
edible marijuana.   

 
 
 
 
 
 
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III. 
PRELIMINARY STUDIES 
Prior experience and expertise of the team 
 
The PI (Bidwell) takes a transdisciplinary approach to the risks and determinants of marijuana and 
other substance use. She and her team have conducted complicated randomized controlled intervention 
trials with laboratory assessments and longitudinal follow-up. The PI and Co-Is Bryan and Hutchison 
have extensive experience in the integration of neurocognitive and biological assessments into 
longitudinal behavioral research (e.g. R01 DA025074, PI Hutchison; site PI Bidwell; Co-I Bryan; 
R01AA024632: PI Hutchison; Co-I’s Bidwell and Bryan; R01DA039707: PI Hutchison; Co-I’s Bidwell 
and Bryan), and Co-I Hutchison is also an expert on the testing of neurocognitive and inflammation 
biomarkers.  
Previous and Current Marijuana Studies 
Our lab has been conducting behavioral and imaging research on marijuana46,47 as well as 
observational research on the relationship of marijuana use to broader health behavior48-50 for many years.  
More recently, the lab has focused on the development of cutting edge observational designs to examine 
the effects of various types of marijuana. One current pilot study utilizes an experimental design 
compared to the observational one proposed in this application but with many of the same outcome 
measures. In the pilot study, regular marijuana users (n=22) were asked to switch strains for three days 
after a washout period. Participants used either +THC/-CBD (~14% THC, <1% CBD) or a +THC/+CBD 
(7% THC, 14% CBD) smoked strain that is acquired from a local dispensary. Both the researchers and 
participants are blinded to strain condition, and the blind is maintained by the dispensary and one senior 
member of the lab. After a washout period of no marijuana use, participants use the assigned marijuana 
strain daily for three days, including the last use on the third day. Blood draws and assessment of 
cognitive responses are collected before the 3-Day use period at the Baseline Appointment (i.e., after 
washout), immediately after and 1 after the last self-administration use, at the 3-Day Appointment 
(participants come to the lab by taxi within 15 minutes of last marijuana use). In our ongoing studies, 
participants’ complete similar measures in our Mobile pharmacology and phlebotomy lab, as well as the 
currently proposed motor battery. 
This pilot work provides proof of concept and hypothesis-consistent data on several levels. 1) It 
confirms that we can work with our IRB, legal team, and local dispensaries to recruit participants and 
complete the proposed research. 2)  Our pilot data suggest that CBD blood levels are associated with 
mitigating THC-associated verbal recall deficits.  These effects further support our hypothesis that the 
harmful effects of marijuana vary by THC vs CBD composition across different strains. 3) It shows that 
we have measured peripheral inflammatory markers (e.g. TNF-a, IL-1B, IL-6) in our participants prior to 
strain assignment (Before 3-Day Self-Administration), immediately after last use (Immediately After 3-
Day Self-Administration), and 2-hours post use (2 Hours After last 3-Day Self-Administration), and that 
these markers vary based on cannabinoid blood levels.  The cytokine associations among marijuana 
strains are in the hypothesized direction (e.g., use of +THC/+CBD marijuana is associated with the lowest 
cytokine levels and the strongest anti-inflammatory responses, while the +THC/-CBD strain is associated 
with comparatively higher levels of inflammation Thus, effects on peripheral inflammatory markers 
suggest that strains that include both +THC and +CBD may have more positive effects on inflammatory 
responses than +THC alone. Given the limited scope of the pilot study, we were not able to test the range 
of edible products (i.e., CBD only) or collect measures of sleep and physical activity (subjective and 
objective) that potentially mediate inflammatory and cognitive effects, but will in the current proposal. 
IV. 
RESEARCH STUDY DESIGN  
Overview and Design of the Proposed Study 

 
 
 
 
 
 
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A sample of 289 patients who report chronic (at least 12 weeks) low back pain and the intention 
to try marijuana products for pain relief will be collected.  Although the origin of chronic pain is 
heterogeneous and diagnostically complex, with subjective, affective, and cognitive components, self-
report is the backbone of a medical diagnosis51.  Thus, we rely on self-report of pain intensity and 
duration for inclusion decisions for our study.  Participants need to have at least one instance of lifetime 
marijuana use, but must have less than weekly marijuana use for the prior six months.  Additionally, 
participants must not have used marijuana at any time for the treatment of their pain.  As such, 
participants will be naïve to the use of marijuana for pain, but not to marijuana consumption in general.  
Recruitment will be via a number of sources that have been used successfully by our research team 
(described below).  If the patient meets minimum eligibility criteria (also described below) and is 
interested in participating, they will set up an appointment to come to the CU Change Lab for their 
Baseline Appointment (1st Appointment) involving consent, extensive measures of health behavior (e.g., 
substance use, sleep quality, physical function, mood, health history, etc.), a blood draw to determine 
cannabinoid levels and biomarkers of inflammation, and baseline assessments of their low back pain and 
cognitive function.  
During this Baseline Appointment, a research assistant will provide information on three 
observational, at-home aspects of the study: 1) the range of edible cannabis products, prices, and nearby 
locations where participants may choose to purchase and 2) the ActiGraph wearable watch device that 
participants will be loaned to measure physical activity and sleep. Because the study is observational we 
will not assign individuals to a type of edible product. Instead, we are recruiting individuals who have 
indicated that they are unsure of what marijuana product to try and therefore want to try different 
marijuana products. We then inform them about available products and ask that they inform us of their 
subsequent choice. Participants will then self-administer the product as they see fit, without any 
instructions from study staff, for 2 weeks. As an exploratory endpoint, we will track participant’s self-
reported pain level, marijuana use, and sleep pattern with a daily follow-up message (online via email) 
over the course of these 2 weeks. This aspect will provide important data on patient choice, patient 
behavior, and edible impact on pain.  
After the initial 2-Week administration period, patients will be scheduled for their follow up 2-
Week Appointment (2nd Appointment) in our mobile pharmacology and phlebotomy lab to examine the 
acute and mechanistic effects of the product.  Following the 2-week edible self-administration period, this 
2nd Appointment will involve assessments from Baseline repeated at three time points: once immediately 
Before, 1 hour after, and 2 hours after the last edible use during the 2-week study period (i.e., Pre-
administration, Post 1-hour , &  2-hour administration). The details of each time point are provided 
below. While the main observational portion of the study will be complete after this 2-Week 
Appointment, we will continue to track participant’s self-reported pain level, sleep pattern, and marijuana 
use with a monthly follow-up survey (online via email, over the course of a six-month follow-up), in 
keeping with the observational and exploratory nature of the design. This aspect will provide important 
data on patient choice, patient behavior, and the effects of other marijuana products on pain. 
 The complete schedule of assessments taken at each Appointment are outlined in Table 1 and 
described in detail below. Additional details regarding sample ascertainment, marijuana edible selection 
procedures, power analyses, and the analytic plan follow. 
 
Table 1. Schedule of assessments. 
Assessment 
Includes 
Time to 
Complete 
1. Orientation Assessments: 
ASAP after screening  
[Part of Baseline Appointment] 
-  Description of study procedures and measures 
-  Informed consent; Eligibility re-screening 
-  Edible product selection 
~0.5 hour 

 
 
 
 
 
 
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Marijuana Administration at Home  
The proposed work will utilize a design that is observational and does not involve assignment by the 
research team. More specifically, patients who are already planning to try marijuana as a treatment for 
their pain will choose their own product at baseline and inform staff of their choice. The patient will then 
purchase the product at a dispensary. The patient will be observed before they purchase and begin using 
their product (Baseline Appointment), during use (Daily follow-up messages), and after 2-weeks (2-Week 
Appointment) of using their product ad libitum at home. After the 2-Week Appointment, we will 
complete Monthly follow-up surveys with the patient for 6 months to determine what additional products 
the patient may have tried and to collect self-report information on product use and current levels of pain.  
Specifically, at the end of the Baseline Appointment, individuals will be asked to select and purchase 
an edible marijuana product to use ad libitum for the next 2 weeks. Colorado requires all edibles to be 
tested by a state lab, which allows us to have a precise measure of potency after the participants purchase 
their products.  Importantly, the researchers who conduct the assessments as well as all the senior 
investigators will be blind to the participant’s product choice.  Participants will use their selected product 
at home consistent with the packaging directions, direction from their physician, or as they see fit, and 
will be asked not to use any other marijuana product during the 14 days before their 2-Week Appointment 
(with one Pre- and two Post-administration mobile assessments on the final day of the 2-week ad libitum 
study period).  Study staff will not provide any directions regarding dosing and administration. 
Rationale for Marijuana Administration Procedure  
With respect to the naturalistic aspects of the design, it is important to note that we carefully 
considered alternative designs. The federally sourced marijuana supplied through NIDA does not 
currently offer any edible marijuana products (www.drugabuse.gov), although these are widely available 
through Colorado dispensaries and used in great numbers by Colorado residents and patients to provide 
relief from chronic pain.  Thus, we are not able to acquire marijuana edibles via NIDA-supply and 
administer them directly to participants via a tightly controlled randomized clinical trial. Given the dearth 
of data available on why so many people are turning to marijuana as a treatment for pain and on the 
effects of marijuana edibles more broadly, we developed our design that naturalistically reflects common 
routes and methods of administration of marijuana in medical patients, particularly in states with legalized 
marijuana. Because the long-term goal of this work is to better understand the effect of different levels of 
2. Baseline Assessments: 
Same day as orientation 
[Part of Baseline Appointment] 
- Pregnancy test, Blood Alcohol Content, Toxicology 
drug screen 
- Self-report of pain intensity & interference 
- Questionnaires on health behavior, substance use, 
and psychological measures  
- Inflammation and cannabinoid blood draw 
- Motor and Cognitive battery 
- Wearable device distributed  
~1.5 hours 
3. Daily Follow-up Assessments: 
1x/day for 2 weeks of ad libitum edible use 
Between Baseline and 2-Week Appointment 
- Daily online message report on pain management, 
marijuana use (if used: amount, strain, method), and 
sleep; individually tailored links  
~2-5 mins/day 
4. 2-Week Mobile Assessments: 
Before, 1, and 2 hours after self-administration 
2-weeks after Baseline Appointment 
- All Baseline measures (wearable device collected) 
- Additional surveys on Impact of Marijuana  
~3 hours 
5. Monthly Follow-up Assessments: 
1x/month for six months 
After 2-Week Appointment 
-  Monthly online survey; individually tailored links 
~10-15 
mins/month 
Total time (6.5 months) 
Participants paid $220 
~6.5 hours 

 
 
 
 
 
 
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cannabinoids in edible marijuana in pain patients, as they are used real world, we decided that it was 
critically important to emphasize external validity. The disadvantage of our observational design is that 
we do not have direct control over the choice of product or the dosing and administration of the 
marijuana. To address this limitation, both in our pilot study and in this application, we rely on blood 
quantitation of cannabinoids to determine the level of THC and CBD in each subject.  Thus, regardless of 
which product the participant uses or how much of the edible is consumed, we have an objective measure 
of circulating THC and CBD for each subject, which is the sine qua non of pharmacological research. 
This aspect is also critical for our analytic approach, which is the analysis of THC and CBD levels in 
blood. 
Finally, it is worth noting that being a major research university in a community that was the first in 
the United States to legalize recreational marijuana use gives us the unprecedented opportunity to be at 
the forefront of innovative research to build the knowledge base on marijuana harm reduction. As such, 
we have worked very closely with the legal team at the University of Colorado to develop our 
methodological approach so that it does not violate any federal laws, such as the Controlled Substances 
Act and Drug Free Schools Act. 
Blood Analyses of Inflammation   
As noted in the background and in our description of our preliminary studies, we expect that CBD 
and THC will reduce biomarkers related to inflammation during the course of the study. Blood samples 
drawn at each assessment will be assayed for IFNg, IL-1a, IL-1b, IL-6, IL-2, IL-4, IL-8, IL-10, IL-12, and 
TNF. Previous studies in animals 52 and humans53, as well as our own preliminary data, suggest that 
cytokine activation is associated with the pathophysiology of pain. This is the same assay used in our 
preliminary studies.  To that end, 40 mL of whole blood will be drawn at each assessment point. We will 
collect 40 ml of blood at each blood draw. We will use 24 ml of blood to perform the inflammatory 
analysis, and 16 ml of blood for cannabinoid analysis. There will be four blood draws total, with one 
during the 1st Appointment (Baseline) and three (each separated by an hour) during the 2nd Appointment 
(2-Week Mobile Van). We will measure changes in cannabinoid and inflammatory levels after the long 
(2-week pre) and short/acute (1 and 2hour post) time course of edible consumption. 
Power Analysis and Sample Size Requirements 
Sample size was selected to permit analysis of the primary research questions at two-tailed alpha of 
.05 and power level of .80. Estimates of effect size follow Cohen54 and were conducted in G*Power 355.  
We will rely on cannabinoid blood levels (e.g. THC and CBD and their relevant metabolites) as 
continuous independent variables to predict study outcomes. Thus, we will be testing regression 
coefficients in the context of a multivariate model with, in the simplest case, three predictors (THC level, 
CBD level, and the THCXCBD interaction). With a sample of 246 participants, we will be able to detect 
effects as small as f2 = .04 with power = .88. This is critical particularly for hypotheses as in each case we 
predict interaction effects of THD and CBD in blood. It is well known that tests of interactions in non-
experimental, observational designs are notoriously small56, and thus it is critical that we are adequately 
powered to detect small effects.  
The impact of attrition 
It is anticipated that some attrition will occur.  Based on our current pilot study and previous 
marijuana studies, we anticipate a 10-15% attrition rate between the Baseline and the 2-Week 
Appointment. Though we have not experienced differential attrition by condition, and do not anticipate 
attrition by edible selection, we assume an approximate 85% retention rate over the course of the primary 
data collection. To adjust for this attrition rate, we will recruit n»289 participants.  
Statistical Analysis Plan 
 Analyses will be conducted primarily on the SAS system for Windows Version 9.457 which includes 
capabilities to test multilevel models that appropriately model both normally and non-normally 
distributed data as well as missing data.  The distributional properties of continuously scaled variables 

 
 
 
 
 
 
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will be examined for skewness and kurtosis to determine appropriate analytic techniques or normalizing 
transformations prior to the primary analyses. 
 
Specific Aim 1: 
Hypothesis 1 
Objective 1: We will observe levels of pain in individuals with chronic low back pain who engage in 
2 weeks of ad libitum use of marijuana edible product of their choice with various cannabinoid content. 
Hypothesis 1 predicts that observed THC and CBD blood levels will impact lower levels of low back pain 
interference after 2 weeks, compared to THC or CBD blood levels considered in isolation. 
Primary endpoint/analysis:  The Roland Morris Disability Questionnaire (RMDQ58,59) has been 
used in studies of low back pain and asks participants about how their experience of low back pain 
interfered with 24 daily activities in the past two weeks; total score ranges from 0-24. Using the total 
RMDQ score, we will test pain interference using two time points – Baseline (prior to taking any 
cannabis) and 2-Week Pre-administration (after 2 weeks of product use but immediately before last edible 
use in the 2-Week study period). We will test a ordinary least squares (OLS) regression model in which 
blood levels of CBD, THC, and the CBDxTHC interaction are used to predict 2-Week pre-administration 
pain interference controlling for Baseline pain interference. Note that our participants are naïve to recent 
cannabis use at Baseline (per our eligibility criteria) so it is not necessary to control for Baseline levels of 
cannabinoids. Thus we are testing the effect of blood levels of cannabinoids on experience of recent pain 
interference. We predict that higher levels of THC and CBD will be associated with less pain interference. 
Secondary endpoint/analysis: Using the “current pain” version of the Pain Intensity scale (i.e., 
“Rate your pain level right now.” on a scale from 0-10) we will test acute effects of cannabinoids on 
pain at the 2-Week Appointment, using three time points: a) Pre administration (before the last edible 
use), b) Post-1h administration (1 hour after the last edible use), and c) Post 2h administration (2 hours 
after the last edible use) of the 2-week ad libitum study period. We will test a RCR model in which 
changes in blood levels of CBD, THC, the CBD x THC interaction time (pre administration, 1-hour post-
administration, and 2 hours post administration) and all possible interactions are used to predict pain. All 
independent variables in this analysis are within-subjects as they occur over time. Thus, we are testing the 
effect of changes in blood levels of cannabinoids on changes in acute pain. We predict that greater 
increases in THC and CBD acutely will be associated with greater decreases in pain, and that there will be 
interactive effects such that those participants with the greatest increases in both THC and CBD will 
experience the greatest decreases in acute pain. 
Other secondary endpoints will be analyzed using the same modeling structure described above as 
appropriate and include: Pre-administration Pain intensity over the two weeks prior to the 2-Week 
Appointment (average of current, worst, and average back pain over the prior two weeks); Pre-
administration Depression, Anxiety, and Stress subscales of the Depression Anxiety Stress Scale 
(DASS60) over the prior two weeks; the Patient Global Impression of Change scale61 which asks 
participants to rate their improvement in pain over the prior two weeks on a 7-point scale (completely 
gone, much better, somewhat better, a little better, about the same, a little worse, and much worse). 
 
Hypothesis 2 
Objective 2: To observe levels of circulating cytokines in individuals with chronic low back pain 
who engage in 2 weeks of ad libitum use of marijuana edibles with various cannabinoid content. 
Hypothesis 2 predicts that THC and CBD blood levels will additively impact lower levels of circulating 
cytokines after 2 weeks and after a single use compared to THC or CBD blood levels considered in 
isolation. 
 
Primary endpoint/analysis: Using the levels of four individual circulating cytokines (TNFα, IL-6, 
IL-8, IL-1B) after two weeks, we will test level of recent inflammation using two time points: a) Baseline 

 
 
 
 
 
 
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(prior to taking any cannabis) and b) Pre-administration (after two weeks of product use but immediately 
before the last edible use in the 2-Week study period). We will test an OLS regression model model in 
which blood levels of CBD, THC, and the CBDxTHC interaction are used to predict pre-administration 
inflammation controlling for baseline inflammation. Note that our participants are naïve to recent 
cannabis use at baseline (per our eligibility criteria) so it is not necessary to control for baseline levels of 
cannabinoids. Thus we are testing the effect of blood levels of cannabinoids on recent inflammation. We 
predict that higher levels of THC and CBD will be associated with lower levels of inflammation, and that 
there will be interactive effects such that those participants with the highest levels of both THC and CBD 
will experience the lowest levels of inflammation. 
 
Secondary analysis/endpoint: Average Z-scored value for the panel of circulating inflammatory 
markers (IFNg, IL-1a, IL-1b, IL-6, IL-2, IL-4, IL-8, IL-10, IL-12, and TNFα). Using the average of our 
panel of inflammatory markers, we will test level of recent inflammation using two time points: a) 
Baseline (prior to taking any cannabis) and b) Pre-administration (after two weeks of product use but 
immediately before final edible use in the 2-Week study period). We will test an OLS regression model in 
which blood levels of CBD, THC, and the CBDxTHC interaction are used to predict pre-administration 
inflammation controlling for baseline inflammation. Note that our participants are naïve to recent 
cannabis use at baseline (per our eligibility criteria) so it is not necessary to control for baseline levels of 
cannabinoids. Thus we are testing the effect of blood levels of cannabinoids on recent inflammation. We 
predict that higher levels of THC and CBD will be associated with lower levels of inflammation, and that 
there will be interactive effects such that those participants with the highest levels of both THC and CBD 
will experience the lowest levels of inflammation. 
  
Specific Aim 2: 
Hypothesis 3 
Objective 3: To observe cognitive function in individuals with chronic low back pain who engage in 
2 weeks of ad libitum use of marijuana edibles with various cannabinoid content. Hypothesis 3 predicts 
that THC blood levels will dose-dependently impact poorer verbal recall and selective attention after 2 
weeks, whereas the CBD bloods will attenuate cognitive impairment. 
Primary endpoint/analysis: Age and sex-corrected scores from the Flanker Inhibitory Control and 
Attention task (FICA) and the NIH toolbox cognitive battery and delayed Verbal Recall Memory from the 
International Shopping List Task are our co-primary outcomes. We will test level of recent cognitive 
impairment using two time points – Baseline (prior to taking any cannabis) and Pre-administration (after 
2 Weeks of product use but immediately before the last edible use in the 2-Week study period). We will 
test an OLS regression model model in which blood levels of CBD, THC, and the CBDxTHC interaction 
are used to predict Pre-administration cognitive impairment controlling for Baseline cognitive 
impairment. Note that our participants are naïve to recent cannabis use at Baseline (per our eligibility 
criteria) so it is not necessary to control for Baseline levels of cannabinoids. Thus we are testing the effect 
of blood levels of cannabinoids on recent cognitive impairment. We predict that higher levels of THC and 
lower levels of CBD will be associated with higher levels of cognitive impairment, and that there will be 
interactive effects such that those participants with the highest levels of THC and the lowest levels of 
CBD will experience the highest levels of cognitive impairment. 
Secondary analysis/endpoint: Using our co-primary measures of cognitive impairment listed above, 
we will test acute effects of cannabinoids on cognitive impairment at the 2-Week Appointment, using 
three time points: a) Pre administration (before the last edible use), b) Post-1h administration (1 hour after 
the last edible use), and c) Post 2h administration (2 hours after the last edible use) of the 2-week ad 
libitum study period. We will test an OLS regression model in which changes in blood levels of CBD, 
THC, the CBDxTHC interaction, time (pre-administration, 1hour post administration and 2 hours post 
administration) and all possible interactions are used to predict acute changes in cognitive impairment. 
All independent variables in this analysis are within-subjects as they occur over time. Thus we are testing 

 
 
 
 
 
 
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the effect of changes in blood levels of cannabinoids on changes in acute cognitive impairment. We 
predict that greater increases in THC and smaller increases in CBD acutely will be associated with greater 
increases in cognitive impairment, and that there will be interactive effects such that those participants 
with the greatest increases in THC and the smallest increases in CBD will experience the greatest 
increases in acute cognitive impairment. 
Another secondary endpoint includes the total score from the self-reported subjective cognitive 
functioning from the Functional Assessment of Cancer Therapy – Cognitive Function (FACT-Cog62) 
scale, which assesses perceived cognitive impairments, abilities, and quality of life.   
 
Exploratory Analysis (Specific Aims 1 & 2): 
Daily: Follow-up online message data on marijuana use and pain during 2-week period of ad 
libitum use 
Multilevel modelling via random coefficient regression (PROC MIXED or PROC GLIMMIX in SAS 
Version 9.4) will be used to test between and within-participant relationships between marijuana use and 
pain in daily message data63. Conditional models will be specified with random and fixed effects of 
marijuana use (modelled as either yes/no for daily use or as quantity of use) predicting pain intensity or 
pain interference.  To account for repeated measures over time, an autoregressive covariance structure 
will be used for all models. For the continuous quantity of use measure, following Wang and Maxwell64, 
between- and within-participant effects will be disaggregated by person mean-centering the marijuana 
quantity variable (subtracting the average quantity of marijuana use for that individual), and including 
time (in days since baseline) as a covariate to detrend the outcome variable (pain intensity/pain 
interference) in case there are any linear trends in pain over time.  The test of the fixed effect of the 
person mean-centered marijuana quantity variable indicates whether on average there is a significant 
within-participant relationship between marijuana quantity of use and pain.  The test of the fixed effect of 
the person-mean marijuana quantity (each individual’s own average marijuana quantity) indicates 
whether there is a between-participant relationship of marijuana quantity of use to pain 
intensity/interference. Due to the intensive longitudinal nature of the design, we will have more than 
enough power with n=246 participants to estimate these models. In addition, the random coefficient 
regression procedures allow us the capability of using modern approaches to the handling of missing 
data65 including full information maximum likelihood estimation.  
 
Monthly: Follow-up online survey data on marijuana use and pain after 2-week period of ad libitum 
use 
The prospective data we are collecting on a monthly basis for six months after the 2-week ad libitum 
phase allows for the possibility of changes in marijuana use over time and tests of the extent to which 
those changes vary with changes in pain intensity or pain interference.  We do not have a priori 
hypotheses about what will occur during this six-month time frame so these analyses are exploratory in 
nature.  In order to explore these data, we envision that the primary version of this analysis would be 
parallel process latent growth modeling (LGM)66.  With this analytic strategy we can statistically test 
whether the change in frequency or quantity of marijuana use (slope) over time is positive or negative, 
whether the change in pain is positive or negative, and whether there is an association between the slope 
in change of marijuana use and pain over time.  Importantly, should edible groups arise in our data, it is 
also possible to conduct a cross-groups parallel process LGM in which the model is simultaneously 
estimated and the moderation of each path in the model can be examined to determine whether it differs 
in the groups.  For example, we could stratify the analyses by type of marijuana product chosen by the 
participant (high THC versus low THC), and then test the model of marijuana use and pain as a cross-
groups model by marijuana use characteristics.  These analyses, while exploratory, will provide important 
naturalistic data on marijuana use among chronic pain patients over time, and lay critical groundwork for 
future studies in this area.  We have estimated similar models with ~200 participants67, so we anticipate 
adequate power for these exploratory models in the current study.  Further, LGM incorporates full 

 
 
 
 
 
 
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information maximum likelihood of missing data, which allows us to maximize the sample size65. 
Because these analyses are exploratory, we will also examine graphical presentations of growth curves in 
addition to traditional null hypothesis significance tests. 
 
Interim Analyses 
       We do not plan to analyze any primary or secondary outcome data prior to reaching a sufficiently 
powered sample. We will examine descriptive data as appropriate throughout the study, e.g. to determine 
whether recruitment efforts need to target particular groups to increase diversity. But we will not conduct 
tests of any of our hypothesized primary endpoints until the dataset is locked. 
V. 
FUNDING 
This study is funded by a grant from the National Center for Complementary and Integrative Health 
(NCCIH). 
VI. 
ABOUT THE SUBJECTS  
Ethnic diversity of this sample is expected to be representative of the greater Boulder-Denver area at 
large, such that approximately 20-30% of the final sample will represent Latino and non-Caucasian 
individuals.  A trained research assistant will screen prospective participants who call, email, or complete 
an online survey, according to the inclusion/exclusion criteria below (Table 2).  In order to increase 
consistency between our observational study and published clinical trials in low back pain patients68, we 
will recruit individuals between 21 to 70 years of age with non-specific low back pain that has persisted at 
least 3 months. Given potential confounding influences on inflammatory markers (e.g., IL6, TNFa) and 
pain outcomes, we will exclude indviduals who report daily tobacco use, an immune-related disease (e.g., 
HIV), use of antivirals, steriods, psychotropic medications other than anti-depressant SSRIs and ADHD 
stimulant and non-stimulant medications, or maximal doses of NSAIDs. Use of opiates, anti-depressants, 
ADHD medications, menstrual cycles, and birth control will be tracked during the study.  Specific criteria 
for study participants are listed in Table 2 below.  
 
 
 
 
 
 
 
 
 
Table 2. Inclusion/Exclusion criteria. 
Inclusion 
Exclusion 
Self-reported low back pain 
≥ 3 months 
Low back pain with pain intensity rated at less than 4 and 
pain interference with activities rated at less than 3 (on 1-5-
point scales) 
At least one episode of lifetime marijuana use, but 
less than or equal to weekly marijuana use for prior 
six months  
More than weekly use of marijuana in prior six months, or 
use of marijuana to treat their low back pain at any time in 
their lives 
Intent to initiate use of marijuana to treat their low 
back pain   
Actively seeking or in treatment for any substance use 
disorder; Report of drug use in past 72 hours before Baseline 

 
 
 
 
 
 
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Self-reported information that determines eligibility will be exclusionary at Screening (online or on the 
phone) only (e.g., concomitant medications), not throughout study. 
 
Ineligible if any of these illnesses are present currently or occurred in the last month: Hemophilia, HIV, 
Concussion (Grade 3 – Loss of Consciousness), Pulmonary Embolism, Stroke, Myocardial infraction, 
Liver Disease (Cirrhosis or hepatitis), Leukemia or Lymphoma, Ablation Therapy for Arrhythmias or any 
treatment for heart Arrhythmias, Heart Murmurs or Heart Disease, Tuberculosis, Trauma with Internal 
bleeding (i.e. Abdominal Aortic Aneurysm) 
VII. 
VULNERABLE POPULATIONS 
This study does not include any vulnerable populations.  
VIII. 
RECRUITMENT METHODS 
Recruitment will be via a number of sources that have been used successfully by our research team.  
First, as in our pilot project, we will recruit using flyers posted in and ads on the webpages and social 
media pages of dispensaries in the Denver and Boulder areas. Second, with assistance from Dr. Rzasa-
Lynn, as well as local health care providers and physicians, we will advertise our study with flyers (see 
attached flyer) in and referrals from local pain clinics. Third, we will utilize targeted mailings, advertising 
the opportunity to participate in our observational study. We will obtain a list of names and addresses of 
individuals who fit our target demographics and geographical area. These names/addresses are obtained 
from publicly available records purchased from a marketing firm (see 
http://www.alescodata.com/reseller-programs.html). Recruitment materials are mailed to each address on 
the list. We can narrow the list based on age, gender, geographic location, and other criteria. Fourth, we 
will use the NIH-funded free ResearchMatch (see https://www.researchmatch.org/) tool to link health 
criteria from potential participants to our specific research criteria. ResearchMatch has a large population 
of volunteers who have consented to be contacted by researchers about health studies for which they may 
be eligible. In addition to ResearchMatch, we will be utilizing the free online clinical trial matching 
platform HealthMatch (see https://healthmatch.io). HealthMatch is a resource for persons interested in 
clinical trials. It is similar to ResearchMatch and also has a large population of volunteers who consent to 
be matched to health studies for which they may be eligible. We will also advertise on free platforms like 
online patient groups and pay for platforms (e.g. Facebook/Twitter advertising) that often allows for 
targeting advertisements based on age, geographic location, and interests (e.g., following or “liking” posts 
related to chronic pain).  
In summary, we will recruit subject locally and primarily through: target ads on pain groups in 
Facebook, mailing flyers w/purchased names & addresses from Alesco and NIH-based ResearchMatch 
Appointment (other than opiates) or failed urine screen (e.g., 
cocaine, methamphetamine, etc.).  
21-70 years of age  
Daily tobacco use (cigarette, E-cigs, and smokeless)  
Able to provide informed consent 
Current diagnosis of bipolar disorder or schziophrenia, use of 
psychotropic medications (other than SSRIs and ADHD 
meds), antivirals, steriods, or maximal doses of NSAIDs 
Health eligibility approved by study physician 
when applicable 
Acute illness other than low back pain or any immune-related 
disease (e.g., HIV; See excluded illness list below.) 
 
Females cannot be pregnant, or trying to become pregnant 

 
 
 
 
 
 
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tool, flyers and referrals from doctors’ offices (Orthopedic, Chiropractic, Rheumatologist, Physical 
Therapists, Occupational Therapists, Pain Specialists, etc.), recreational and alternative health centers 
(e.g., yoga studios, acupuncture and massage specialists, and gymnasiums, etc.), as well as in local 
restaurants and shops in Boulder. The combination of these varied recruitment methods should provide 
ample and steady potential participants, as in previous studies similar in size. All interested participants 
will be directed to complete an online screening survey (via RedCap) or to contact the CU Change Lab by 
phone or email (to be screened over the phone). 
IX. 
COMPENSATION  
Participants will receive $220 for completing all aspects of the study: $60 in cash and for the Baseline 
Appointment (1st in-person Appointment) and $100 for the 2-Week Appointment (2nd in-person 
appointment). Participants will receive $1/day for each of the daily follow-up messages that they 
complete during the two ad libitum period, with a possible bonus of $6 for completing at least 12 of the 
14 daily messages, for a maximum of $20 extra paid in cash at the 2-Week Appointment ($120 total). 
Participants will receive a $5 Amazon.com gift card for each of the 6 brief Monthly follow-up surveys 
completed, plus a bonus $10 Amazon.com gift card for the final assessment ($40 total, delivered online 
via email). If a participant does not complete the study, payment will be pro-rated for the 
Appointments/online follow-up assessments that they do complete, in person, and in cash.  Given the 
amount of time required in the study and the travel to and from the lab for the 1st Appointment, this is a 
reasonable amount of money to compensate participants for their time and effort. Thus, there is no 
question of coercion.   
X. 
CONSENT PROCESS  
When a participant arrives for their 1st Appointment at the Center for Innovation and Creativity 
(CINC), a member of the research team will greet them in the 1st -floor lobby. The research assistant will 
take the participant to a private room and provide the participant with a copy of the informed consent 
document. Prior to asking the participant to sign the consent form, the trained research assistant and the 
participant will have a discussion regarding the research study. Additionally, the research assistant will be 
available to answer any questions they may have about the study. We will also explain that participation 
includes a study appointment in our Mobile Van Pharmacology and Phlebotomy Laboratory, which will 
be seen outside their home, possibly by their neighbors, and that privacy may not be 
maintained. Participation will be clearly stated as voluntary, with the option to withdraw at any time. 
There will be no deception involved with this study. After discussing the study and all measures, and 
going over the consent form with the researcher, the participant will be included in the study if they 
choose to initial and sign the informed consent document.  
XI. 
PROCESS TO DOCUMENT CONSENT IN WRITING 
In accordance with 45 CFR 46.117, a printed copy of the written informed consent document will be 
signed by the participant after all of his/her questions have been answered and prior to the start of any 
experimental procedure.  Additionally, an unsigned copy of the form used to document consent will also 
be given to the study participant electronically.   
XII. 
PROCEDURES  

 
 
 
 
 
 
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Participants will contact the researchers with their interest by phone, e-mail, or through an online 
screening survey (RedCap, provided as a CCTSI resource).  In the case that a potential participant 
requests more information via e-mail or voicemail message, the research assistant responding to the 
message will ask the participant to call the lab phone number for more information (same phone number 
provided on all study advertisements), e-mail the study team a phone number at which the potential 
participant could be reached at and a desirable time for the research staff to call, or to complete the online 
survey.  The first page of the online screening survey will give a brief description and the estimated time 
involved in completing the screening process and the observational study (in the case that they are eligible 
and elect to participate) and instructed to click the Next Page button if they wish to be screened further. 
The online screening that follows will be identical to the phone screening. All subjects that complete the 
screening will be asked to leave their preferred contact information and the best time to contact them so 
that a research assistant can inform them of eligibility (according to the inclusion/exclusion criteria in 
Table 2 above) and answer any questions they may have. For participants that prefer to complete a phone 
screening, a trained research assistant will provide an overview of the study, answer any questions that the 
potential participant has, and then screen them for preliminary eligibility according to the 
inclusion/exclusion criteria in Table 2 above. This process will help to ensure participants have ample 
opportunity to be informed of the main study components and maintain their privacy as much as possible. 
If the participant meets the study criteria after the initial online screening survey or phone interview and 
the follow-up contact, they will be invited to come to the CU Change Laboratory at the CINC for their 
Baseline Appointment.  If any subject is questionable for inclusion, our PI and study physician team (Dr. 
Bidwell, a licensed clinical psychologist and Dr. Rzasa-Lynn, a licensed M.D.) will make the final 
determination of eligibility.  
 
COVID-19: Before interacting with research assistants, eligible participants will be asked additional 
questions related to COVID-19. These questions will be administered prior to any in-person appointment 
and by a research assistant over the phone (or at a distance of at least 6-feet if the participant is unable to 
complete the questions over the phone). These questions will be administered to protect staff and 
participants from the spread of COVID-19. The questions are a precaution based on current university and 
Centers for Disease Control and Prevention guidelines and may need to be updated as the understanding 
of COVID-19 evolves. These procedural questions are temporary in nature and will be lifted once 
university guidelines deem it unnecessary. 
 
Baseline Appointment Procedure and Assessments 
Subjects who meet inclusion criteria (see Table 2 above) will be scheduled for a Baseline 
Appointment and given instructions, including not consuming alcohol for 24 hours, tobbacco, caffeine, 
and any other drugs for 72 hours (excluding those needed for regular pain management) prior to the 
appointment.  Subjects will be reminded to eat a small meal and hydrate well before the baseline 
appointment. After arriving at the CUChange Laboratory, each subject will go through the consent 
process and after all questions have been answered and if participants consent, Baseline procedures will 
begin (see Table 3). A urine toxicology and a pregancy test (for females) will also be administered to 
verify if subjects have recently taken illicit drugs and to ensure that they are not pregnant. A blood draw 
will be taken to quantify current use of cannabinoids and inflammatory markers (1st of 4 total blood draws 
completed during the entire study). All blood draw procedures performed during this study will involve 
collecting venous blood (40 mL per draw) with venipuncture of a peripheral arm vein using standard, 
sterile phlebotomy techniques. Subjects will then complete current and historical health and substance use 
assessments (see section below and Table 3 for details), and a motor and cognitive testing battery.  
At the end of the Baseline Appointment, individuals will be asked to self-select an edible marijuana 
product based on their preference. Participants will then use their selected product at home, consistent 
with the packaging directions, direction from their physician, or as they see fit, and will be asked not to 
use any other marijuana product during the 2-Week study period, before their 2-Week Appointment 

 
 
 
 
 
 
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(Mobile Laboratory assessment).  Study staff will not provide any directions regarding dosing and self-
administration. While participants themselves will not be blind to their product choice, importantly, the 
researchers who conduct the assessments as well as most of the senior investigators will be blind to their 
selection.  At the Baseline Appointment, participants will be given instructions and allowed to practice 
responding to an online daily message prompt (described below), that will commence after they purchase 
an edible of choice.  
Participants will be given an ActiGraph wearable device (described below) to track their physical 
activity and sleep during the 2-Week observational period (http://actigraphcorp.com/). They will be 
instructed on how to wear and use the device at this Baseline Appointment. Participants will be instructed 
to wear the device as long as they feel comfortable during the 2-Week period and to return the device at 
the 2-Week Mobile Appointment (2nd Appointment). The importance of returning the device will be 
emphasized to participants and we expect the vast majority of Actigraph watches to be returned at the 2-
week Mobile lab Appointment, which takes place at the participant’s home.  In our prior studies that 
involved “take-home” devices, such as heart monitors, we had a 96% return rate.   For any wearable 
watch device that is not recovered (for any reason), up to three attempts will be made to contact the 
participant and collect any wearable watch device that is not recovered (for any reason). The research 
staff will not make further attempts to collect the device, and will consider the device forfeited and 
irretrievable after this point.  Details on the exploratory Actigraphy data analysis will be provided in a 
separate Actigraphy Data Analysis Plan. 
Research study staff will debrief participants and compensate them with $60 in cash for their time and 
effort during the Baseline Appointment. 
Daily (Online-based) Follow-up Assessments  
Assessment of marijuana use (online) has been shown to be feasible in a variety of studies69,70.  
Subjects will answer online survey assessments via email with individually tailored links hosted by our 
university’s licensed survey tool RedCap. During the 2-Week study period, participants will report daily 
on the Pain Intensity item from the NIH Toolbox, their edible marijuana use, other pain management 
strategies, and their sleep pattern. This brief message report will provide a daily repeated measure of our 
primary constructs (pain and marijuana use) and potential mediators or moderators over the course of the 
2-Week study. All subjects will be given extensive instructions on completing the daily message at the 
Baseline Appointment and will practice answering the questions in the lab using their cell phone or a lab 
computer to ensure they understand the process and time commitment. To enhance the response rate, 
participation on daily follow-ups will be monitored and participants will be contacted if they do not 
respond for two consecutive days of daily messages. Participants will then be compensated for their time 
and effort during the 2-Week Appointment, receiving a $1/day with a $6 bonus for completing 12 or 14 
online follow up message reports ($20 in total possible). 
2-Week Mobile Appointment Procedure and Assessments (Pre, Post 1hr, & Post 2hr time points) 
Because we wish to obtain our data while the participant is under the influence of their cannabis 
product, and because it is not safe to operative a vehicle while under the influence, we will bring our 
state-of-the-art Mobile Van pharmacology and phlebotomy laboratory to the patient’s location to 
complete all 2-Week Appointment procedures (see Table 3).  Prior to taking their last edible of the 2-
Week study period, participants will come out to the Mobile laboratory to complete their 2nd blood draw, 
heart rate, motor and cognitive battery and self-report assessments (including quantity of marijuana use 
and pain severity over the study period).  The blood draw will be a venipuncture of a peripheral arm vein 
using standard, sterile phlebotomy techniques, and 40 mL of blood will be collected.  Participants will 
then return to their home to take their edible. 
After taking their edible product, they will return to the Mobile Laboratory 1 hour later.  Because 60 
minutes is the average time that CBD and THC levels begin to peak in the blood after oral administration 
of cannabis extract44,45, assessment of the acute effects of marijuana (e.g., pain, cognition, and 
inflammation) will begin at exactly 1-hour post-edible consumption (Post 1-hour self-administration).  

 
 
 
 
 
 
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After peak, cannabinoid levels steadily decrease over the next 2-3 hours and by 4 hours post-ingestion 
begin to rapidly drop off in blood44,45_ENREF_82.  To account for individual differences in metabolism 
and sensitivity, patients will be assessed again at 2 hours (Post 2-hr self-administration).  Each assessment 
time point [Baseline & 2-Week (Pre, Post 1-hr & 2-hr) self-administrations] will include a 40 mL venous 
blood draw, heart rate, questionnaires, and motor & cognitive battery.  Thus, including the Baseline 
Appointment, a total of 160 mL of blood (40 ml x 4 time points) will be collected for the entire study. 
After completing the Post 2-hour consumption assessments, participants will hand in their ActiGraph 
device, they will be debriefed, and the RA will escort them back to their home.  Participants will then be 
compensated $100 in cash for their time and effort during the 2-Week Appointment.  
Monthly (Online-based) Follow-up Assessments  
 After the 2-Week ad libitum period of edible use with detailed online and in-person tracking, 
participants will be asked to provide monthly follow-up information on their pain and marijuana use. All 
subjects will be given extensive instructions on completing the daily message report at the Baseline 
Appointment and will practice answering the questions in the lab using their cell phone or a lab computer 
to ensure they understand the process and time commitment. They will answer online survey assessments 
with individually tailored links hosted by our university’s licensed survey tool RedCap. To track 
participant behavior and potential effects (e.g., marijuana use and pain levels) naturalistically, a monthly 
survey will assess self-reported marijuana use, sleep, pain ratings and management, and cognitive effects 
over the past month, for the six months. To enhance the response rate, participation on monthly follow-
ups will be monitored and participants will be contacted if they if they do not respond to one monthly 
survey. Participants will receive a $5 gift card by mail for every monthly online follow-up survey that 
they complete, plus a $10 bonus gift card for the final survey ($40 in total possible). 
 
Please see Table 3 for a detailed description of the procedures and measure by appointment and Table 
4 (page 26) for a Schedule of Evaluations.  
Table 3. Description of observational procedures by appointment. 
Name of Instrument/Procedure 
Data collected 
 
Eligibility Screening (ES) 
 
Phone Interview or Online Survey questionnaire used to 
determine subject eligibility (based on Table 2 
inclusion/exclusion criteria). 
 
Baseline Appointment (only) 
 
 
Informed Consent (IC) 
In-person discussion and review of consent document detailing 
all observational measures and any questions. 
 
Medical History (MH) 
General assessment of medical history for any major disease or 
illness, the neuropathic pain scale, and prescribed medication 
use. 
 
Toxicology Drug Screening (TDS) 
A urine sample will test for recent substance use (e.g., 
marijuana, cocaine, benzodiazepines, MDMA, sedatives, or 
methamphetamine) other than pain medications.  
 
Pregnancy Screening (PS) 
All female participants will take a urine pregnancy test and 
report their last menstrual cycle and any birth control methods. 
 
Demographics (D) 
Age, sex, marital status, race/ethnicity, education, birth date, 
and height. 
 
Alcohol Use History Questionnaire 
(AUH) 
Targets the frequency of lifetime and recent use for alcohol. 
 
Alcohol Use Disorders Identification 
Test (AUDIT) 
The AUDIT71,72_ENREF_82 will be used to examine the extent 
of co-morbid alcohol use and problems related to alcohol use.  
 

 
 
 
 
 
 
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The Beck Depression Inventory-II 
(BDI-II) 
Consists of 21 scaled statements designed to assess symptoms 
of depression over the past 2 weeks and will be administered to 
examine comorbid depression and covary baseline differences 
if necessary73. 
 
The Beck Anxiety Inventory (BAI) 
Consists of 21 items, each describing a common symptom of 
anxiety over the past week and will be administered to 
examine comorbid anxiety and covary baseline differences if 
necessary (BAI74). 
 
ADHD Self-Report Scale (ASRS) 
ADHD Self-Report Scale75_ENREF_87, will be used to assess 
ADHD symptoms in participants, given the high rates of 
ADHD among marijuana users. This measure consists of 18 
items that correspond to the DSM-V ADHD symptoms and are 
rated over the past six months on a 1 (never) to 5 (very often) 
scale.  
 
Baseline & 2-Week Appointment 
                  (Pre-administration only) 
 
 
Pain Intensity-7d (PIT7) 
Consists of two items asking about the participant’s level of 
pain on average and at its worst in the past 7 days.   
Participants are asked to rate their pain on a scale from 0 (no 
pain) to 10 (worst imaginable pain). 
 
Pain Interference-7d (PIF7) 
Participants are asked to rate their pain interference in the last 
7 days (1-item, PROMIS) on a scale from 1 (not at all) to 5 
(very much), as it refers to the degree to which pain limits or 
interferes with their physical, mental, and social activities.  
 
Marijuana Dependence Scale (MDS) The MDS based on DSM-V criteria that were converted to a 
self-report measure. Individuals respond 'yes' or 'no' to each 
dependence item (e.g., "When I smoked marijuana, I often 
smoked more or for longer periods of time than I intended"). 
The items are then summed to form the scale. This scale has 
been previously used in the cannabis literature. The internal 
consistency of the MDS (based on the DSM IV) was good in 
our pilot study (α=.73) and even better in previously published 
reports (α=.8576). 
 
Marijuana Purchase Task (MPT) 
The marijuana purchase task (MPT) is a valid measure of the 
relative economic value of marijuana is needed to characterize 
individual variation in the drug's reinforcing value. This asks 
participants to estimate the number of marijuana joints they 
would purchase at increasing prices and can be used to 
examine the associations between marijuana use and MPT 
demand indices. 
 
*Cannabis 
Questionnaire/Marijuana Users 
Health Cohort/ (MUHC) 
This modified version details the primary reasons, frequency, 
and type of cannabis use patterns in occasional and regular 
users. 
 
*Impact of Marijuana on Pain 
(IMP) 
This modified short self-report questionnaire on the impact of 
marijuana on pain and health compared to other types of pain 
management (e.g., drugs, opioids, exercise) and the expected 
and past risks and benefits (e.g., sleep, mood, anxiety). 
 
Health Related Quality of Life 
(HRQL) 
This is a Short Form 12 Health Survey, which consists of 12 
questions across eight health domains and is sensitive in 
 

 
 
 
 
 
 
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detecting changes in time (one month) in health-related quality 
of life. 
*Timeline Follow-Back (TLFB) 
TLFB is used to assess daily substance use (for the 2 weeks 
prior to the Baseline Appointment, and 2 weeks prior to the 
Mobile Appointment. Our modified TLFB procedure will 
estimate both frequency of marijuana use and amount used per 
day, using visual stimuli as well as the method of 
administration77,78. 
 
Blood Alcohol Content (BAC) 
Breathalyzer test for recent alcohol consumption. 
 
Physiological Weight Scale 
A digital scale will be used to collect subject weight at each in-
person appointment. 
 
Stadiometer 
A ruler with a sliding horizontal headpiece will be used to 
collect subject height at the Baseline Appointment. 
 
Pittsburg Sleep Quality Index 
(PSQI) 
Measurement of the quality and patterns of sleep from poor to 
good measuring seven domains (e.g., latency, duration, 
disturbances) over the last 2 weeks. 
 
*Roland Morris Disability 
Questionnaire (RMDQ) 
This asks participants about how their experience of low back 
pain interfered with or affected their enjoyment of various 
daily activities in the past 2-weeks (modified from today).  
This 24-item self-report asks participants to mark an item if 
they experienced each type of pain interference, each mark is 
scored as 1 point, with a total range from 0-24, higher scores 
demark higher interference. 
 
Depression Anxiety Stress Scale 
(DASS) 
The DASS is a 21-item short-form self-report instrument for 
measuring the three related negative emotional states of 
depression, anxiety, and tension/stress. 
 
Self-Rated Diet (SRD) 
Assesses self-rated quality of overall diet and amount of fruit 
and vegetables consumed daily, on average. Includes EATS 
(10 item questionnaire asking about fruit and vegetable 
consumption in past two weeks) and FVS (3-item measure 
asking about the health of their diets and daily fruit/vegetable 
consumption).   
 
Current Opioid Misuse Measure 
(COMM) 
Standardized measure of opiate misuse, characterizes opiate 
users in our sample and allows us to draw comparisons to other 
research samples using this measure. 
 
Stanford Leisure-Time Categorical 
Activity Item (L-Cat) 
The L-Cat is a single item measure asking about average level 
of exercise/activities. 
 
Perceived Stress Scale (PSS) 
The Perceived Stress Scale (PSS) is a self-reported scale 
asking about feelings and thoughts within the last 2 weeks. 
 
*Pain Interference-current (PIFc) 
Consists of 1-item asking about the participant’s level of pain 
interference currently (modified from the NIH PROMIS).  
Participants are asked to rate their pain on a scale from 1 (no 
pain) to 5 (worst imaginable pain). 
 
2-Week Appointment (only) 
(Pre, Post 1- & 2-hr administration) 
 
 

 
 
 
 
 
 
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The Drug Effects  
Questionnaire (DEQ) 
The Drug Effects Questionnaire (DEQ) is a 5 items visual 
analog scale used to measure the strength of marijuana as well 
as the desirable effects79. 
 
The Addiction Research Center 
Inventory (M-Scale) 
The Addiction Research Center Inventory80 (ARCI), including 
the ARCI—Marijuana (M) scale81 will be used to measure 
subjective effects of marijuana in addition to drug-induced 
euphoria, stimulant-like effects, intellectual efficiency and 
energy, sedation, dysphoria, and other somatic effects. 
 
Baseline & 2-Week Appointment 
(Pre, Post 1- & 2-hr administration) 
 
 
Heart Rate (HR) 
Heart rate will be collected using a basic fingertip pulse 
oximeter. 
 
Blood Pressure (BP) 
An automated, small, portable machine will be used to collect 
blood pressure. 
 
Venous Blood Draw (BD) 
A 21-23g needle and vacutainer will be used to obtain 40 mL 
of blood through a peripheral arm venipuncture using standard, 
sterile, phlebotomy techniques. 
 
Pain Intensity-current (PITc) 
Consists of 1-item asking about the participant’s level of pain 
currently.  Participants are asked to rate their pain on a scale 
from 0 (no pain) to 10 (worst imaginable pain). 
 
Motor/Movement Battery (MB) 
Physical function assessment of functional reach, dynamic 
sway (balance) sit-to-stand and finger tapping. A standard 
smartphone (iPod Touch) will be attached to participant’s 
hand, arm, leg, or waist with a simple elastic/Velcro strap. An 
App on the device will record their fine grained movements 
while they perform slow or fast movements with their hand, 
arm, or leg.  Also, they will be asked to stand as still as 
possible for 30-60 seconds, with eyes open or closed, while the 
iPod is attached to their hip, trunk, or leg. They will also be 
asked to tap the smartphone repeatedly for no more than 60 
seconds. 
 
International Shopping List Test 
(ISLT) 
The International Shopping List Task82 (ISLT) is a computer 
software program, consisting of a 12-item shopping list that 
is read out loud to the participant. The participant is asked to 
recall as many words as they remember. The list of words 
is presented again in the same order two additional times to 
facilitate memorization. After 30 minutes, a delayed recall trial 
is administered and participants are asked to recall the list 
again. At each session, participants are read a different 
shopping list. 
 
Neurocognitive Toolbox Battery 
(NCB) 
From the NIH toolbox, this cognitive battery will include the 
Flanker Inhibitory Control and Attention task, the Pattern 
Comparison Speed Test, the Picture Sequence Memory Test, , 
and the List Sorting Working Memory Test. The battery covers 
the domains found to be sensitive to the effects of marijuana83 
 
Marijuana Craving Questionnaire 
(MCQ) 
A Marijuana Craving Questionnaire will be used to assess 
craving at each time point during the experimental session. The 
MCQ was adapted from a valid tobacco craving 
questionnaire84 and has proven to be useful in cannabis studies 
 

 
 
 
 
 
 
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85. In our pilot study, internal consistency was very high (α= 
.90). 
Alcohol Craving Questionnaire 
(ACQ) 
Asks participants to rate their desire to consume an alcoholic 
beverage at the current moment, as a self-rated measure of co-
administration potential.  
 
*Profile of Mood 
States (POMS) 
The modified Profile of Mood States (POMS) will be used to 
collect baseline information on mood as well as information on 
mood changes throughout the study86-88. 
 
Functional Assessment  of Cancer 
Therapy-Cognitive Function 
(FACT-Cog) 
A subjective measure of perceived cognitive impairments, 
ability, as it impacts others, and quality or life. 
 
Patient Global Impression of 
Change (PGIC) 
The Patient Global Impression of Change (PGIC) scale is a 
subjective measure consisting of 1 question to ask participants 
any changes in their overall status of pain in the past two 
weeks.  
 
Baseline Appointment 
(CINC Lab) 
Informed consent & study orientation; BAC test; Urine 
toxicology and Pregnancy test; Heart rate; Pain Intensity & 
Interference ratings; 1st Blood draw; Questionnaires; Cognitive 
& Motor Battery; Wearable distributed; Appointment 2 
scheduling; Monetary Compensation. 
120 minutes 
Daily Follow-Up Messages 
Respond to brief questions (online) about marijuana use, sleep 
quality, and pain management once per day for 2 weeks after 
self-directed edible use. Each survey has a 24 hour window 
before the link expires. 
2-5 mins/day  
x 14 days 
(~30 mins total) 
2-Week Appointment 
(Mobile Lab) 
                    -Pre-administration      
Immediately before edible self-administration; Come out to 
Mobile laboratory; Heart rate; Pain Intensity & Interference 
ratings; 2nd Blood draw; Questionnaires; Cognitive & Motor 
Battery; Return home to self-administer edible. 
 
 
75 mins 
      -Post 1-hr administration  
 
1 hour after edible self-administration; Return to Mobile 
laboratory; Heart rate; Pain Intensity ratings; 3rd Blood draw; 
Questionnaires; Cognitive & Motor Battery; Return home. 
45 mins 
     -Post 2-hr administration 
 
2 hours after edible self-administration: Return to Mobile 
laboratory; Heart rate; Pain Intensity ratings; 4th Blood draw;  
Questionnaires; Cognitive & Motor Battery; Return wearable; 
Debriefing; Monetary Compensation; Return home.   
60 mins 
Monthly Follow-up Surveys 
Respond to brief questions (online) about marijuana use,  
sleep quality, and pain management once per month for 6 
months, Monetary compensation (each month). Each survey 
has a 2 week window before link expires. 
10-15 
mins/month 
x 6 months 
(~60 mins total) 
TOTAL STUDY DURATION 
(6.5 months) 
 
~6.5 hours 
 
Key: *=use of a modified measure 
 
Protocol Deviations: This study is observational in nature, entails multiple exploratory time points and 
analysis, and asks for a large amount of self-initiated and voluntary participation for each task, with no 

 
 
 
 
 
 
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previously defined or investigated expected norms or minimum standards for completion. Therefore, if 
participants decide to not complete a particular assessment(s) they will not be considered a protocol 
deviation (i.e., if they elect to not answer or complete parts of the Baseline or 2-Week appointment or 
any/all of the daily or monthly exploratory surveys). However, we will record and account for any 
missing data in our data analysis (as noted in Section IV Research Study Design – Statistical Analysis 
Plan). Importantly, our lab has had little difficulty completing all or nearly all of the proposed 
assessments in ongoing or previous longitudinal studies, scheduling and maintaining similar appointment 
criteria (i.e., scheduling follow-up visits within a set time window), and collecting multiple blood samples 
on different visits or within the same visit.  
While we do not anticipate deviations from the above procedures, to increased replicability and 
efficiency of future studies, we will define and record the following events as they may impact the 
primary outcomes of the study. Therefore, a protocol deviation will be noted (unless missed due only to 
participant refusal) if:  
1) A 2-Week Mobile Lab appointments is not completed within 2 weeks (14 days) ± 4 days from the 
Baseline appointment (i.e., 2-Week appointment should be ±4 days from the intended 14-day study 
period), and/or  
2) A blood sample collection is not obtained from the Baseline appointment, and/or 2 or more blood 
sample collections are not obtained from the 2-Week Mobile Lab appointment. 
3) An assessment is not administered to the subject due to unforeseeable events (i.e. REDCap system 
malfunction). 
XIII. 
SPECIMEN MANAGEMENT 
Blood samples collected in the mobile lab will be kept in an insulated biohazard transport bag.  All 
blood samples collected during the study will be stored in locked freezers within the PI’s laboratory 
designed specifically for storing biological specimens. Samples will be coded with a randomly generated 
participant ID number and all data collected will be stored on a password protected server and separate 
from the master list linking the ID numbers to participants’ contact information, also stored on a password 
protected server and only accessible by a research team member. At study closure, all links between 
participant name and number will be destroyed, at which point the blood specimens will be considered 
de-identified.  After all analyses are complete, these specimens will be destroyed.  
XIV. 
DATA MANAGEMENT 
Signed consent forms will be stored in a locked filing cabinet in the PI’s lab at the CINC. All data 
from self-report and interview measures will be stored on password protected computers and on the PI’s 
password protected server in the CINC, both of which are only accessible to research staff.  All stored 
data will be recorded from secure survey software. Any identifying information will be destroyed after the 
last appointment (on-line or in-person), and biological samples will be destroyed after all analyses are 
complete.  
XV. 
WITHDRAWAL OF PARTICIPANTS 
Situations in which the entire study may be terminated early include the following:  If the Principal 
Investigator or other governing official discovers serious concerns about subjects' safety, inadequate 
performance or rate of enrollment (this includes a missed study appointment); because study objectives 
have been obtained according to pre-established statistical guidelines; or in the unlikely event that the 
Principal Investigator retires and no other additional investigators are able to succeed his role within the 

 
 
 
 
 
 
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research project. Though highly unlikely, the circumstances under which a participant would be 
withdrawn without his or her consent include: obviously not following instructions or behavior that is 
verbally or physically abusive towards research staff. Those who experience early withdrawal will receive 
prorated payment based on the number of appointments that they completed.  
XVI. 
RISKS TO PARTICIPANTS 
Risks Pertaining to the Legality of Cannabis 
The possession and use of cannabis is legal at the state level, but illegal at the federal level. Any risk 
associated with this study is not greater than risks experienced by participants when they purchase 
cannabis outside of the study. We will comply with all NIH guidelines, and a Certificate of 
Confidentiality will be deemed applicable for our study, decreasing the risk for participants. 
Risks Associated with Venipuncture  
There is a small risk of local hematoma, infection, and syncope associated with phlebotomy. Any risk 
associated with undergoing four blood draws for a total of 120 ml over ~ five hours in two separate days 
will be minimized with certified and experienced venipuncture staff, collecting information on the 
subjects’ last meal and by offering a standard snack before the last blood draw. 
Psychological Risks and Discomforts 
While participants who use cannabis in the context of the research must already be experienced 
cannabis users in order to be in the study, it is still possible that some participants might experience some 
adverse effects from the cannabis such as changes in mood/affect, sleepiness, paranoia, and increased 
heart rate. There is a slight risk that the ingestion of cannabis may be associated with a psychotic episode.  
Participants will be monitored during study period by the PI Dr. Bidwell who is a licensed clinical 
psychologist (Colorado license #4116) to make sure that there are no clinically significant events that 
occur during the study period, including careful monitoring of suicidal ideation endorsement on the BDI. 
Levels of pain will be also monitored by study staff and should clinically severe pain be present (Pain 
intensity of >=8 or Pain interference of 5), the participants will be contacted by the study physician 
(Dr..Rzasa-Lynn) and referred to their primary care physician or other appropriate  treatment.  This 
practice has been used frequently by the PI in other IRB approved studies and the risks for clinically 
meaningful increases in pain are not expected to be greater than what would be experienced in daily 
living. Information regarding pain treatment resources and appropriate referrals will be made to each 
participant at the end of participation, if requested. 
 
Risks Pertaining to Loss of Confidentiality and Privacy  
Confidentiality of participants is a priority for research staff and must be maintained unless the 
investigator obtains the express permission of the participant to do otherwise. Risks from breach of 
confidentiality include invasion of privacy, as well as social and economic risks. Economic risks include 
alterations in relationships with others that are to the disadvantage of the subject, and may involve 
embarrassment, loss of respect of others, labeling with negative consequences, or diminishing the 
subject's opportunities and status in relation to others. These risks include payment by subjects for 
procedures, loss of wages or income, and/or damage to employability or insurability. 
Participants will be asked and tested for illegal activities that they may have been involved in (i.e., 
illicit drug use). Participants will also be warned that there are some things that they might tell us that we 
CANNOT promise to keep confidential, however all NIH funded research involving human subjects and 
identifiable data, bio-specimens or genomic data, will be issued a Certificate of Confidentiality for all 
research that is commenced or ongoing after December 1st 2017. Updates to our associated documents 
(e.g., consent form, see attached) and IRB approval is underway and will be followed and managed, as 
directed by NIH. Participants will be informed that we are required to report information like child abuse 

 
 
 
 
 
 
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or neglect, crimes that they tell us they or others plan to commit, or harm planned against themselves or 
others. 
Unanticipated risks 
Any experiment may involve risks that cannot be anticipated.  If unanticipated risks occur, the 
investigators will follow the IRB guidelines for adverse event reporting.  
XVII. MANAGEMENT OF RISKS 
Risks Pertaining to the Legality of Cannabis 
The risk is minimal given the legality of cannabis in Colorado. 
Protection against risks associated with Venipuncture 
The risks of hematoma and infection are minimized by having trained personnel perform the 
procedures using sterile techniques. Any additional risks are decreased by using the participants preferred 
arm for venipuncture (in case prior injury or surgery has decreased function) and by reminding 
participants to adequately hydrate prior to their appointment. In addition, we provide snacks and complete 
supervision in a seated and protected position to reduce any risk of dizziness or falling. 
Psychological Risks and Discomforts 
In the unlikely event that an edible cannabis user has an adverse reaction to the edible cannabis product 
that they have chosen to use at the mobile clinic visit and needs assistance, the research assistant will 
immediately notify Dr. Bidwell who will make herself immediately available to evaluate the condition of 
the participant and intervene if necessary. We do not anticipate adverse reactions or any greater risk to be 
induced by our study than during daily life, however, we have developed a plan should a cannabis or non-
cannabis related negative event occur.  First, we always have two trained members of the research staff in 
the Mobile Laboratory every time they are with a participant.  Should a concerning event arise, if it is an 
emergency, staff will be instructed to immediately call 911.  Second, or in a non-emergency case, staff 
will call Dr. Bidwell, Dr. Bryan, and/or Dr. Hutchison (who will be on call/reachable during all scheduled 
appointments) to resolve the situation.  First, it will be determined if the situation can be resolved over the 
phone.  If not, the PI or Co-I will immediately drive to the Mobile Laboratory for further assessment of 
the participant and situation.  The participant will be given the option of withdrawing from the study and 
medical or mental health referrals will be made as appropriate and as determined by the clinically 
trained Senior Investigators.  Importantly, Mobile lab staff are First Aid trained and the PI Bidwell and 
Co-I Hutchison are both licensed clinical psychologists. 
Another potential risk that the study team will be prepared to manage is participant endorsement of 
thoughts of suicide on the BDI. The BDI is a measure of depression symptomatology that will be 
included on the baseline surveys. Item number 9 from the BDI inquiries about “suicidal thoughts or 
wishes” that participants may or may not be experiencing. REDCap, the online survey system that we will 
use to administer our inventories for this project, has a feature that allows researchers to receive an email 
alert if a participant responds to particular items with a specific response. In order to ensure the safety of 
our participants, we will program the survey to alert the study coordinator, who will then immediately 
notify the PI or co-I Hutchison (both licensed clinical psychologists), if a participant responds to item 9 
from the BDI with any response other than, “I don’t have any thoughts about killing myself or “I have 
thoughts of killing myself, but I would not carry them out”. If a participant was to respond to item 9 from 
the BDI with a different response (i.e., “I would like to kill myself;” or “I would kill myself if I had the 
chance”), Drs. Bidwell or Hutchison would immediately assess the participant for imminent suicide risk 
and provide him/her with a list of psychological services referral contacts. After the participant has been 
assessed for risk, the study coordinator will use the CU CHANGE lab’s previously IRB approved 
‘Suicide Ideation Protocol’ to connect the participant with an appropriate referral resource (i.e., 911 if in 
imminent danger, Boulder County Mental Health Center (BCMHC) if the participant is a community 

 
 
 
 
 
 
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member, or Wardenburg Health Center and/or BCMHC if the participant is a CU Boulder student, staff, 
or faculty member). The study coordinator will immediately follow up with the PI to ensure that all of the 
necessary measures had been taken to protect the safety of the participant. During this meeting the PI and 
study coordinator, in consultation with Dr. Hutchison, will determine whether or not it is safe for the 
participant to continue his/her involvement in the study. If it is determined that the participant is at 
imminent risk and should not continue participating in the study, the study coordinator will contact the 
participant and explain that for his/her safety, the research team does not feel that it is safe for him/her to 
continue participating in the study. The study coordinator will also answer any questions that the 
participant may have about this decision. 
 
Risks Pertaining to Loss of Confidentiality and Privacy  
We intend to mitigate risks as much as possible by collecting the minimum amount of identifying 
information from participants necessary to conduct our study. Participants’ information will be coded 
with a randomly generated number, and the document linking their number with their contact information 
will be stored on a password protected server that is only accessible by members of the research staff.  
All study computers are password protected and housed in the PI’s lab space at the CINC, which are 
kept locked unless researchers or students are currently using the space. Further, there is no identifying 
information contained on the laptops. All identifying information (e.g., consent forms, contact 
information) is kept separate and secure from the data files and never on the same laptop.   
XVIII. POTENTIAL BENEFITS  
There is no direct benefit to participants for their participation; however, all participants will have 
the opportunity to examine their own cannabis use in the context of completing the measures. The 
minimal costs associated with participation in this research seem reasonable in relation to the scientific 
importance of gaining insight into the health-related implications of cannabis use, particularly given the 
timely nature of this study and the recent legislation regarding cannabis.  
XIX. 
PROVISIONS TO MONITOR THE DATA FOR THE SAFETY OF PARTICIPANTS 
The project manager will monitor and report to the PI on adherence to the protocol. He/she will assess 
adherence via periodic observation of the appointments, visual inspection of the completeness of data 
collection, and verification of follow-up information collected from participants (to ensure they have 
agreed to be contacted and there are no safety concerns that arise). He/she will give bi-weekly reports to 
the PI. The PI will be in daily contact with the research assistants running the study and will be informed 
immediately of any adverse event. Consistent with IRB policy, the project manager will use the 
Reportable Event eForm and/or the Deviation eForm in eRA to report all adverse events consistent with 
those listed under points 19.1 (adverse events) and 19.2 (deviations) in the CU Boulder IRB policy 
procedures document: http://www.colorado.edu/VCResearch/integrity/humanresearch/SOP_TOC.html.  
For any other problem or event requiring reporting to the IRB, the PI or designee will submit to the 
IRB a Reportable Event or Deviation in eRA as soon as possible, but no later than 10 working days from 
notification of event.  
XX. 
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS  
To ensure participants’ confidentiality, all data will be identified with a unique research subject 
identifier in a randomized, confidential manner. This system is operated by the research team member 
who can only access the program by using a login name and password. The list linking the numerical 

 
 
 
 
 
 
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identifier to the participant’s identifying information will be maintained separate and secure from the data 
and will be destroyed at study closure. The data files themselves will be maintained in the CINC at the 
University of Colorado, and will be identified only by the numeric identifier. Only staff cleared on a 
specific project can view data collected on that given project. 
Fully informed consent will be sought to ensure that participants are aware of any possible risks. 
Participation in the research is completely voluntary, as is answering each particular question in the 
screening and in all of the measures. 
XXI. 
MEDICAL CARE AND COMPENSATION FOR INJURY 
 Participants will be informed to contact Dr. Bidwell immediately by phone (303-735-5383) should 
they feel that they have been harmed while participating in this study. They will be told that the cost for 
any treatment will be billed to them or their medical or hospital insurance. Information regarding 
compensation for injury is included in the informed consent document.  
XXII. COST TO PARTICIPANTS 
Participants will be responsible for paying for the cannabis that they choose and purchase. We 
estimate the approximate cost of edibles for 2 weeks to be $90, depending in part on what type and how 
much each participant chooses to use. Parking is free at the CINC. 
XXIII. DRUG ADMINISTRATION 
Not Applicable.  
XXIV. INVESTIGATIONAL DEVICES 
Not applicable.  
XXV. MULTI-SITE STUDIES 
Not applicable. All drug use will be self-directed. 
 
XXVI. SHARING OF RESULTS WITH PARTICIPANTS 
There are no plans to share results of the study with participants. 
 
 

 
 
 
 
 
 
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Table 4. 
Schedule of Evaluations 
Assessment:                                    
Screen
ing: 
Baseline    
Visit 1: 
Daily: 
2-
Week                        
Visit 2: 
 Monthly: 
Phone/ 
Online 
Enrollment, 
Randomization, 
Observation 
Follow-up 
Surveys 
 
 
Observation 
Follow-up 
Surveys 
 
<Pre-2w SA> 
 
<Pre-0h 
SA> 
<Post-1h 
SA> 
<Post-2h 
SA> 
 
(d: -14) 
(d: 1) 
(d: 2-15) 
(d: 16) 
(d: 16) 
(d: 16) 
(d: 30+) 
(w: -2) 
(w: 1) 
(w: 1-2) 
(w: 2) 
(w: 2) 
(w: 2) 
(w: 4+) 
 
 
 
 
 
 
(m: 1-6) 
Time point 
 
In-Person (1d)    
1 time point 
Online (14d)    
14 time points 
In-Person (1d)                  
3 time points 
Online 
(6m)                
6 time 
points 
Eligibility Screening Form/Scheduling 
(Inclusion/Exclusion Criteria Table 2) 
X 
X 
  
  
  
  
  
Physician Review 
(If needed for eligibility or safety concerns) 
X 
  
  
  
  
  
  
Informed Consent Form/Enrollment 
 
X 
 
 
 
 
 
Breathalyzer/Alcohol Content Test   
 
X 
 
X 
 
 
 
Blood Pressure (BP) 
 
X 
 
X 
X 
X 
 
Physiological Weight Scale 
 
X 
 
X 
 
 
 
Stadiometer (Height) 
 
X 
 
 
 
 
 
Medical History & Prescribed Medication Use  
 
X 
  
X* 
 
 
X*  
Urine Analysis 
(Pregnancy & Toxicology) 
 
X 
 
 
 
 
 
Demographics (D)  
 
X 
 
 
 
 
 
Alcohol Use History (AUH) 
 
X 
 
 
 
 
 
Alcohol Use Disorder Identification test (AUDIT) 
 
X 
 
 
 
 
 
Marijuana Purchasing Task (MPT) 
 
X 
  
X  
  
  
  
Beck Depression Inventory-II (BDI-II)  
 
X 
 
 
 
 
 
Beck Anxiety Scale (BAI)  
 
X 
 
 
 
 
 

 
 
 
 
 
 
Page 29 of 34 
HRP-503: Protocol       
 
 
 
ADHD Self-Report Scale (ASRS) 
 
X 
 
 
 
 
 
Pain Intensity (PIT7) 
 
X 
 
X 
 
 
X 
Pain Interference (PIF7) 
 
X 
 
X 
 
 
X 
Marijuana Dependence Scale (MDS) 
 
X 
 
X 
 
 
X 
Marijuana users Cohort (MUHC) 
 
X* 
 
 
 
 
 
Impact of Marijuana on Pain (IMP) 
 
X 
 
X* 
 
 
X* 
Health Related Questionnaire (HRQL/SF-12) 
 
X 
 
X 
 
 
X 
*Time Line Follow Back (TLFB) 
 
X 
 
X 
 
 
X 
Pittsburg Sleep Quality Index (PSQI) 
 
X 
 
X 
 
 
X 
*Roland Morris Disability Questionnaire (RMDQ) 
 
X 
 
X 
 
 
X 
Depression Anxiety Stress Scale (DASS) 
 
X 
 
X 
 
 
X 
Self-Rated Diet  (SRD) 
 
X 
 
X 
 
 
X 
Functional Assessment of Cancer Therapy – Cognitive 
Function (FACT-Cog) 
 
X 
 
X 
 
 
X 
Current Opioid Misuse Measure (COMM) 
 
X 
 
X 
 
 
X 
The Drug Effects Questionnaire (DEQ) 
 
 
 
X 
X 
X 
 
The Addiction Research Center Inventory (M-Scale)  
 
 
 
X 
X 
X 
 
Heart Rate (HR) 
 
X 
 
X 
X 
X 
 
Venous Blood Draw (BD) 
 
X 
 
X 
X 
X 
 
Pain Intensity-current (PITc) 
  
X 
 
X 
X 
X 
X  
*Pain Interference-current (PIFc) 
  
X 
  
X 
 
 
X  
Motor/Movement Battery (MB) 
 
X 
  
X 
X 
X 
  
International Shopping List Test  (ISLT) 
 
X 
  
X 
X 
X 
 
Neurocognitive Toolbox Battery (NCB) 
 
X 
  
X 
X 
X 
  
Marijuana Craving Questionnaire (MCQ) 
 
X 
  
X 
X 
X 
  
Alcohol Craving Questionnaire (ACQ) 
 
X 
  
X 
X 
X 
  
*Profile of Mood States (POMS) 
 
X 
  
X 
X 
X 
 
Perceived Stress Scale (PSS) 
 
X 
  
X 
 
 
X 
Stanford Leisure-Time Activity Categorical Item (L-
Cat) 
 
X 
 
X 
 
 
X 
Patient Global Impression of Change (PGIC)  
 
 
 
X 
 
 
X 

 
 
 
 
 
 
Page 30 of 34 
HRP-503: Protocol       
 
 
 
Daily Questions Survey (DQS) 
(Daily report of cannabis use, pain, mood, and sleep) 
 
 
X 
 
 
 
 
Approximate Assessment Duration  
(includes 5-10 min breaks every 30 mins) 
10 min 
2 hour 
2 min 
75 min 
45 min 
60 min 
15 min 
Key: d=days; w=weeks; m=months; h=hour, min=minute; SA=Self-Administration, *=use of a modified measure 

 
 
 
 
 
 
Page 31 of 34 
HRP-503: Protocol       
 
 
 
References 
 
1. 
Medicine AAoP. Facts and Figures on Pain. http://wwwpainmedorg/files/facts-and-figures-on-painpdf. 2016. 
2. 
Light MK, Orens A, Lewandowski B, Pickton T. Market size and demand. . In: Revenue. RpftCDo, ed2014. 
3. 
Ilgen MA, Bohnert K, Kleinberg F, et al. Characteristics of adults seeking medical marijuana certification. Drug 
Alcohol Depend. 2013;132(3):654-659. 
4. 
Pacula RL, Jacobson M, Maksabedian EJ. In the weeds: a baseline view of cannabis use among legalizing states 
and their neighbours. Addiction. 2016;111(6):973-980. 
5. 
Boehnke KF, Litinas E, Clauw DJ. Medical Cannabis Use Is Associated With Decreased Opiate Medication Use 
in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain. J Pain. 2016;17(6):739-744. 
6. 
Bradford AC, Bradford WD. Medical Marijuana Laws Reduce Prescription Medication Use In Medicare Part D. 
Health Aff (Millwood). 2016;35(7):1230-1236. 
7. 
Bachhuber MA, Saloner B, Cunningham CO, Feingold J, Barry CL. Could Delaware's medical marijuana law 
reduce harms from opioid analgesics? Del Med J. 2014;86(11):341-343. 
8. 
Andreae MH, Carter GM, Shaparin N, et al. Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of 
Individual Patient Data. J Pain. 2015;16(12):1221-1232. 
9. 
Fitzcharles MA, Ste-Marie PA, Hauser W, et al. Efficacy, Tolerability, and Safety of Cannabinoid Treatments in 
the Rheumatic Diseases: A Systematic Review of Randomized Controlled Trials. Arthritis Care Res (Hoboken). 
2016;68(5):681-688. 
10. 
Richards BL, Whittle SL, Buchbinder R. Neuromodulators for pain management in rheumatoid arthritis. 
Cochrane Database Syst Rev. 2012;1:Cd008921. 
11. 
Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-
analysis. JAMA. 2015;313(24):2456-2473. 
12. 
Snedecor SJ, Sudharshan L, Cappelleri JC, et al. Systematic review and comparison of pharmacologic therapies 
for neuropathic pain associated with spinal cord injury. J Pain Res. 2013;6:539-547. 
13. 
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. 2007;82(5):572-578. 
14. 
Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005;5(5):400-411. 
15. 
Kozela E, Pietr M, Juknat A, Rimmerman N, Levy R, Vogel Z. Cannabinoids Delta(9)-tetrahydrocannabinol and 
cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT 
proinflammatory pathways in BV-2 microglial cells. J Biol Chem. 2010;285(3):1616-1626. 
16. 
Alexander SP, Benson HE, Faccenda E, et al. The Concise Guide to PHARMACOLOGY 2013/14: G protein-
coupled receptors. Br J Pharmacol. 2013;170(8):1459-1581. 
17. 
McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin 
negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172(3):737-
753. 
18. 
Burstein SH, Zurier RB. Cannabinoids, endocannabinoids, and related analogs in inflammation. AAPS J. 
2009;11(1):109-119. 
19. 
Kuner R. Central mechanisms of pathological pain. Nat Med. 2010;16(11):1258-1266. 
20. 
Stein C, Clark JD, Oh U, et al. Peripheral mechanisms of pain and analgesia. Brain Res Rev. 2009;60(1):90-113. 
21. 
de Mello Schier AR, de Oliveira Ribeiro NP, Coutinho DS, et al. Antidepressant-Like and Anxiolytic-Like 
Effects of Cannabidiol: A Chemical Compound of Cannabis sativa. CNS & Neurological Disorders - Drug 
Targets. 2014;13(6):953-960. 
22. 
Ranganathan M, D’souza DC. The acute effects of cannabinoids on memory in humans: a review. 
Psychopharmacology (Berl). 2006;188(4):425-444. 
23. 
Lundqvist T. Cognitive consequences of cannabis use: comparison with abuse of stimulants and heroin with 
regard to attention, memory and executive functions. Pharmacology Biochemistry and Behavior. 2005;81(2):319-
330. 
24. 
Abel EL. Marihuana and memory: acquisition or retrieval? Science. 1971;173(4001):1038-1040. 
25. 
Darley C, Tinklenberg J, Roth W, Atkinson R. The nature of storage deficits and state-dependent retrieval under 
marihuana. Psychopharmacologia. 1974;37(2):139-149. 

 
 
 
 
 
 
Page 32 of 34 
HRP-503: Protocol       
 
 
 
26. 
Heishman SJ, Stitzer ML, Yingling JE. Effects of tetrahydrocannabinol content on marijuana smoking behavior, 
subjective reports, and performance. Pharmacology Biochemistry and Behavior. 1989;34(1):173-179. 
27. 
Wilson WH, Ellinwood EH, Mathew RJ, Johnson K. Effects of marijuana on performance of a computerized 
cognitive-neuromotor test battery. Psychiatry Res. 1994;51(2):115-125. 
28. 
McDonald J, Schleifer L, Richards JB, de Wit H. Effects of THC on behavioral measures of impulsivity in 
humans. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 
2003;28:1356-1365. 
29. 
Ramaekers JG, Kauert G, van Ruitenbeek P, Theunissen EL, Schneider E, Moeller MR. High-potency marijuana 
impairs executive function and inhibitory motor control. Neuropsychopharmacology : official publication of the 
American College of Neuropsychopharmacology. 2006;31:2296-2303. 
30. 
Crean RD, Crane NA, Mason BJ. An evidence based review of acute and long-term effects of cannabis use on 
executive cognitive functions. J Addict Med. 2011;5:1-8. 
31. 
Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new 
therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009;30(10):515-527. 
32. 
Huestis MA, Smith ML. Human cannabinoid pharmacokinetics and interpretation of cannabinoid concentrations 
in biological fluids and tissues. In: Marijuana and the Cannabinoids. Humana Press; 2007:205-235. 
33. 
Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and 
hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19-27. 
34. 
Hermann D, Schneider M. Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis 
users and psychosis: a critical review. Curr Pharm Des. 2012;18(32):4897-4905. 
35. 
Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of Δ9-Tetrahydrocannabinol and cannabidiol 
on human brain function and psychopathology. Neuropsychopharmacology. 2010;35(3):764-774. 
36. 
Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Revista Brasileira 
de Psiquiatria. 2008;30(3):271-280. 
37. 
Morgan CJA, Freeman TP, Schafer GL, Curran HV. Cannabidiol Attenuates the Appetitive Effects of Δ9-
Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis. Neuropsychopharmacology. 
2010;35(9):1879-1885. 
38. 
Demirakca T, Sartorius A, Ende G, et al. Diminished gray matter in the hippocampus of cannabis users: possible 
protective effects of cannabidiol. Drug Alcohol Depend. 2011;114(2):242-245. 
39. 
Schubart CD, Sommer IEC, van Gastel WA, Goetgebuer RL, Kahn RS, Boks MPM. Cannabis with high 
cannabidiol content is associated with fewer psychotic experiences. Schizophr Res. 2011;130(1–3):216-221. 
40. 
Vann RE, Gamage TF, Warner JA, et al. Divergent effects of cannabidiol on the discriminative stimulus and place 
conditioning effects of Δ9-tetrahydrocannabinol. Drug Alcohol Depend. 2008;94(1–3):191-198. 
41. 
Ren Y, Whittard J, Higuera-Matas A, Morris CV, Hurd YL. Cannabidiol, a nonpsychotropic component of 
cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. The 
Journal of Neuroscience. 2009;29(47):14764-14769. 
42. 
Griffith-Lendering MFH, Huijbregts SCJ, Vollebergh WAM, Swaab H. Motivational and cognitive inhibitory 
control in recreational cannabis users. J Clin Exp Neuropsychol. 2012;34(7):688-697. 
43. 
Colorado Department of Revenue. Marijuana Enforcement. In: Division E, ed2016. 
44. 
Nadulski T, Sporkert F, Schnelle M, et al. Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-
COOH, CBD, and CBN by GC-MS in plasma after oral application of small doses of THC and cannabis extract. J 
Anal Toxicol. 2005;29(8):782-789. 
45. 
Ohlsson A, Lindgren J-E, Andersson S, Agurell S, Gillespie H, Hollister LE. Single-dose kinetics of deuterium-
labelled cannabidiol in man after smoking and intravenous administration. Biol Mass Spectrom. 1986;13(2):77-
83. 
46. 
Haughey HM, Marshall E, Schacht JP, Louis A, Hutchison KE. Marijuana withdrawal and craving: influence of 
the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes. Addiction. 2008;103(10):1678-
1686. 
47. 
Schacht JP, Selling RE, Hutchison KE. Intermediate cannabis dependence phenotypes and the FAAH C385A 
variant: an exploratory analysis. Psychopharmacology (Berl). 2009;203(3):511-517. 

 
 
 
 
 
 
Page 33 of 34 
HRP-503: Protocol       
 
 
 
48. 
Schmiege SJ, Bryan AD. Heterogeneity in the Relationship of Substance Use to Risky Sexual Behavior Among 
Justice-Involved Youth: A Regression Mixture Modeling Approach. AIDS Behav. 2016;20(4):821-832. 
49. 
Callahan TJ, Caldwell Hooper AE, Thayer RE, Magnan RE, Bryan AD. Relationships Between Marijuana 
Dependence and Condom Use Intentions and Behavior Among Justice-Involved Adolescents. AIDS Behav. 
2013;17(8):2715-2724. 
50. 
Bryan AD, Schmiege SJ, Magnan RE. Marijuana use and risky sexual behavior among high-risk adolescents: 
Trajectories, risk factors, and event-level relationships. Dev Psychol. 2012;48(5):1429-1442. 
51. 
Tait RC. Vulnerability in clinical research with patients in pain: a risk analysis. J Law Med Ethics. 2009;37(1):59-
72. 
52. 
Mayfield J, Ferguson L, Harris RA. Neuroimmune signaling: a key component of alcohol abuse. Curr Opin 
Neurobiol. 2013;23(4):513-520. 
53. 
Bala S, Marcos M, Gattu A, Catalano D, Szabo G. Acute binge drinking increases serum endotoxin and bacterial 
DNA levels in healthy individuals. PLoS One. 2014;9(5):e96864. 
54. 
Cohen J. Statistical power analysis for the behavioral sciences. . Routledge Academic; 2013. 
55. 
Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: A flexible statistical power analysis program for the 
social, behavioral, and biomedical sciences. Behavior Research Methods. 2007;39(2):175-191. 
56. 
McClelland GH, Judd CM. Statistical difficulties of detecting interactions and moderator effects. Psychol Bull. 
1993;114(2):376-390. 
57. 
SAS 9.4 [computer program]. Cary, NC2013. 
58. 
Mehling WE, Gopisetty V, Bartmess E, et al. The prognosis of acute low back pain in primary care in the United 
States: a 2-year prospective cohort study. Spine (Phila Pa 1976). 2012;37(8):678-684. 
59. 
Roland M, Morris R. A study of the natural history of back pain. Part I: development of a reliable and sensitive 
measure of disability in low-back pain. Spine (Phila Pa 1976). 1983;8(2):141-144. 
60. 
Henry JD, Crawford JR. The short-form version of the Depression Anxiety Stress Scales (DASS-21): construct 
validity and normative data in a large non-clinical sample. Br J Clin Psychol. 2005;44(Pt 2):227-239. 
61. 
Guy W. Psychopharmacology Research Branch, NIMH. In: ECDEU Assessment Manual for 
Psychopharmacology, revised. . In: Rockville, MD: National Institute of Mental Health1976. 
62. 
Wagner LI, Sweet JJ, Butt Z, Lai JS, Cella D. Measuring patient self-reported cognitive function: development of 
the functional assessment of cancer therapy-cognitive function instrument. The Journal of Supportive Oncology. 
2009;7(6):W32-W39. 
63. 
Cohen J, Cohen P, West SG, Aiken LS. Applied multiple regression/correlation analysis for the behavioral 
sciences. Routledge; 2013. 
64. 
Wang LP, Maxwell SE. On disaggregating between-person and within-person effects with longitudinal data using 
multilevel models. Psychol Methods. 2015;20(1):63-83. 
65. 
Schafer JL, Graham JW. Missing data: Our view of the state of the art. Psychol Methods. 2002;7(2):147-177. 
66. 
Curran PJ. A latent curve framework for the study of developmental trajectories in adolescent substance abuse. 
Mahwah, NJ: Lawrence Erlbaum Associates, Inc; 2000. 
67. 
Thayer RE, Montanaro E, Weiland BJ, Callahan TJ, Bryan AD. Exploring the relationship of functional network 
connectivity to latent trajectories of alcohol use and risky sex. Current HIV research. 2014;12(4):293-300. 
68. 
Cherkin DC, Sherman KJ, Balderson BH, et al. Effect of Mindfulness-Based Stress Reduction vs Cognitive 
Behavioral Therapy or Usual Care on Back Pain and Functional Limitations in Adults With Chronic Low Back 
Pain: A Randomized Clinical Trial. Jama. 2016;315(12):1240-1249. 
69. 
Schuster RM, Mermelstein RJ, Hedeker D. Ecological momentary assessment of working memory under 
conditions of simultaneous marijuana and tobacco use. Addiction. 2016:n/a-n/a. 
70. 
Phillips KT, Phillips MM, Lalonde TL, Tormohlen KN. Marijuana use, craving, and academic motivation and 
performance among college students: An in-the-moment study. Addict Behav. 2015;47:42-47. 
71. 
Collins RL, Vincent PC, Yu J, Liu L, Epstein LH. A behavioral economic approach to assessing demand for 
marijuana. Exp Clin Psychopharmacol. 2014;22(3):211-221. 
72. 
Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro MG. AUDIT. The Alcohol Use Disorders Identification 
Test (AUDIT): Guidelines for use in primary care (2nd edition). 2001:Department of Mental Health and 
Substance Dependence, World Health Organization (WHO). 

 
 
 
 
 
 
Page 34 of 34 
HRP-503: Protocol       
 
 
 
73. 
Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric 
outpatients. J Pers Assess. 1996;67(3):588-597. 
74. 
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J 
Consult Clin Psychol. 1988;56(6):893-897. 
75. 
Kessler RC, Adler L, Ames M, et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a 
short screening scale for use in the general population. Psychol Med. 2005;35(2):245-256. 
76. 
Stephens RS, Roffman RA, Curtin L. Comparison of extended versus brief treatments for marijuana use. J 
Consult Clin Psychol. 2000;68(5):898-908. 
77. 
Sobell MB, Sobell LC, VanderSpek R. Relationship between clinical judgment, self-report, and breath-analysis 
measures of intoxication in alcoholics. J Consult Clin Psychol. 1979;47(1):204-206. 
78. 
Sobell LC, Sobell MB. Timeline Follow-Back. In: Litten RZ, Allen JP, eds. Measuring Alcohol Consumption: 
Psychosocial and Biochemical Methods. Totowa, NJ: Humana Press; 1992:41-72. 
79. 
de Wit H, Phillips TJ. Do initial responses to drugs predict future use or abuse? Neurosci Biobehav Rev. 
2012;36(6):1565-1576. 
80. 
Martin WR, Sloan JW, Sapira JD, Jasinski DR. Physiologic, subjective, and behavioral effects of amphetamine, 
methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther. 
1971;12(2):245-258. 
81. 
Chait LD, Fischman MW, Schuster CR. 'Hangover' effects the morning after marijuana smoking. Drug Alcohol 
Depend. 1985;15(3):229-238. 
82. 
Thompson TA, Wilson PH, Snyder PJ, et al. Sensitivity and test-retest reliability of the international shopping list 
test in assessing verbal learning and memory in mild Alzheimer's disease. Arch Clin Neuropsychol. 
2011;26(5):412-424. 
83. 
Ranganathan M, D'Souza DC. The acute effects of cannabinoids on memory in humans: a review. 
Psychopharmacology (Berl). 2006;188(4):425-444. 
84. 
Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on smoking urges. Br J Addict. 
1991;86(11):1467-1476. 
85. 
Budney AJ, Moore BA, Vandrey RG, Hughes JR. The time course and significance of cannabis withdrawal. J 
Abnorm Psychol. 2003;112(3):393-402. 
86. 
McNair DM, Lorr M, Droppleman LF. Manual for the Profile of Mood States. . San Diego, CA: Educational and 
Industrial Testing Services.1971. 
87. 
Johanson CE, Uhlenhuth EH. Drug preference and mood in humans: diazepam. Psychopharmacology (Berl). 
1980;71(3):269-273. 
88. 
Johanson CE, Uhlenhuth EH. Drug preference and mood in humans: d-amphetamine. Psychopharmacology 
(Berl). 1980;71(3):275-279.