Novel Approaches to Understanding the Role of Cannabinoids and Inflammation in Anxiety
Conditions: Anxiety, Anxiety Disorders, Anxiety Generalized, Anxiety Chronic, Inflammation, Inflammatory Response
Sponsor: University of Colorado, Boulder

 
 
 
 
 
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TITLE:  Anxiety, Inflammation, and Cannabis  
PROTOCOL VERSION DATE:  June 1, 2023 
VERSION: 21 
PRINCIPAL INVESTIGATOR (PI):  
Name: L. Cinnamon Bidwell, PhD 
Address: Institute of Cognitive Science, 344 UCB 
Telephone: 781-608-3711  
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: Nicholas Gonyea, B.S.  
Role in project: Research Assistant 
 
Name: Gregory Giordano, B.S. Ed., M.S. 
Role in project: Research Coordinator 
 
Name: Paige Phillips, B.A. 
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: Evangelique Lopez, B.A. 
Role in project: Research Coordinator 
 
Name: Austin Drake 
Role in project: Research Coordinator 
 
Name: Luiza Rosa, B.S., B.A. 
Role in project: Research Assistant 
 
Name: Shelly Dey 
Role in project: Research Assistant 
 
 
 
 
In addition to the co-investigators and research coordinators listed above, undergraduate 
and professional research assistants play an active role in the recruiting and data collection phase 
of this study. These persons have completed CITI training, and have been trained by the lead 

 
 
 
 
 
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Professional Research Assistant and project manager regarding responsible conduct in research 
and study specific procedures/guidelines. 
I. 
OBJECTIVES 
Please note that the grant supporting this project was recently funded through NIDA. The 
grant and protocol follow many of the same procedures as four IRB-approved studies: 1) our 
pilot study that has been approved for almost three years, “An Observational Study of 
Cannabidiol, Neurocognition, and Mood," (protocol 14-0087),  where participants purchase a 
cannabis strain from a local dispensary with a range of very common THC and CBD ratios 
assigned our two follow up studies, 2) “Cognition, Mood, and Cannabis” (protocol 15-0797) and 
3) “Acute Effects of Dabbing Concentrated Marijuana Products” (protocol 16-0768), where 
participants purchase a similar range of products (as in this study), or a very high THC products 
with no CBD, and 4) our more recent study in a pain population “Observational Study of 
Cannabis and Pain” (protocol 17-0268), where participants choose their edible cannabis product 
of choice. The current protocol overlaps heavily with the 1st, 2nd, and 4th studies above, so that 
our overall research endpoints can inform future medical and recreational questions regarding 
common current and real-world cannabis use. 
Marijuana is approved for medical use in over half the states and is gaining traction for use as 
an “off-label” add-on therapy for treatment-resistant anxiety and stress-related disorders. 
Paradoxically, however, while data suggest that marijuana, in particular ∆9-tetrahydrocannabinol 
(THC), increases anxiety acutely, cross sectional and longitudinal data suggest associations 
between marijuana use and lower risk for anxiety disorders.  Such findings imply biological 
and/or behavioral changes in the post-intoxicated state that impact anxiety related processes.  In 
light of considerable evidence that inflammation plays a pivotal role in the etiology of anxiety 
disorders and the putative anti-inflammatory properties of marijuana, we propose that the anti-
inflammatory properties of marijuana are linked with its anxiolytic effects. Importantly, prior 
work has not considered that the anxiolytic effects of marijuana are the compound action of 
different cannabinoids, which vary in their pharmacology and effects. Specifically, cannabidiol 
(CBD), a non-psychotomimetic component of marijuana (doesn’t produce a “high”), is thought 
to have anxiolytic properties and may mitigate some of the harmful effects of THC. Further, 
preliminary data, including our own, suggest that THC and CBD render differential effects on 
anxiety-related processes, such as effects on inflammatory and stress responses. Differences in 
inflammation likely impact processes such as the degree of stress-reactivity and acute and/or 
chronic variability in anxiety. Therefore, the degree to which different types of marijuana 
influence stress-response and inflammation may have a large and clinically-relevant impact on 
the effects of marijuana on anxiety. We propose to systematically examine the effects of 
cannabinoids on anxiety, inflammation, and stress reactivity in mild to moderately anxious 
(Generalized Anxiety Disorder (GAD-7) ≥ 5) marijuana users.         
Our global hypothesis is that the anxiolytic and inflammatory effects of marijuana vary 
as a function of the ratio of THC to CBD, and that these effects may shed light on the 
marijuana use/anxiety paradox. The goal of this study is to test the effects of real-world, 
commercially-available, common marijuana products, that differ markedly in their ratio of THC 
to CBD [3 flower THC:CBD ratios (1:0, 1:1, or 0:1) and 3 edible THC:CBD ratios (1:0, 1:1, or 
0:1) currently available]. To that end, we will test the effects of the following marijuana ratios: 
1) +THC/-CBD (1:0), 2) +THC/+CBD (1:1), or 3) -THC/+CBD (0:1) on anxiolytic, 

 
 
 
 
 
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inflammatory, and stress-reactivity processes. The first and last strains test the effects of THC 
and CBD in isolation, respectively, while the middle strain (+THC/+CBD) provide additional 
data on the effects of THC when CBD is also in blood, a critical comparison given our pilot data, 
suggesting that CBD mitigates the effects of THC.  
We will employ a design with marijuana users assigned to one of three (flower users) or 
one of three (edible users) marijuana strains (differing by ratio) for 4 weeks of ad-libitum 
cannabis use. We will compare marijuana users to non-users (a matched control group), who are 
not assigned and do not use marijuana, and who do not have a desire to use marijuana to cope 
with their anxiety. Users, with a desire to self-administer marijuana to cope with their anxiety, 
will have the option to self-administer a flower (one of three ratios) or an edible (one of three 
ratios) cannabis product, however, each subject (regardless of their type of administration 
chosen) will be assigned to a product with +THC alone (1:0), a combinations of +THC and 
+CBD (1:1), or  +CBD alone (0:1), and will use their assigned product ad libitum (using as much 
or as little cannabis as they would like). 
Aim 1: To assess anxiety in mild to moderately anxious marijuana users exposed to one of three 
marijuana strains: 1) +THC/-CBD, 2)+THC/+CBD, or 3)-THC/+CBD compared to matched 
(non-using) controls. 
Hypothesis 1. Based on numerous studies, including our own pilot data, that suggest CBD may 
be anxiolytic and mitigate the harmful effects of THC, we hypothesize a step wise effect of strain 
such that the –THC/+CBD group will demonstrate the lowest anxiety, as compared to the 
+THC/+CBD group(s), which will have lower anxiety levels than the +THC/-CBD and non-
using control groups. In addition to strain assignment, CBD and THC blood levels will also be 
tested in relation to anxiety, with greater CBD levels associated with lower levels of anxiety. 
Aim 2: Based on the notion that CBD decreases inflammation and acute stress, the study will 
examine: 1) circulating inflammatory markers and 2) behavioral and biological markers of 
stress reactivity in mild to moderately anxious marijuana users exposed to one of three 
marijuana strains:  1) +THC/-CBD, 2) +THC/+CBD, or 3) -THC/+CBD versus a matched (non-
using) group. 
Hypothesis 2A. There will be a main effect of strain such that the –THC/+CBD group will have 
the lowest levels of circulating peripheral inflammatory markers, as compared to the 
+THC/+CBD group(s), which will have lower levels than the +THC/-CBD and non-using 
control groups. In addition to strain assignment, CBD and THC blood levels will also be tested 
in relation to inflammation, with CBD levels associated with lower levels of inflammation. 
Hypothesis 2B. There will be a main effect of strain such that the –THC/+CBD strain group will 
have the lowest levels of stress-reactivity to a laboratory stressor (measured via self-report, 
physiological, and inflammatory stress responses), as compared to the +THC/+CBD group(s), 
which will have lower levels of reactivity than the +THC/-CBD and non-using control groups. In 
addition to strain assignment, CBD and THC blood levels will also be tested in relation to stress-
reactivity outcomes, with CBD levels associated with less stress-reactivity. 
Aim 3: Based on the notion that the effects of CBD on inflammation or stress may mediate the 
effects of marijuana on anxiety, the study will examine the mechanisms by which CBD 
influences anxiety. 

 
 
 
 
 
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Hypothesis 3. We will estimate a mediational model that tests whether the effect of marijuana 
strain on anxiety is mediated by changes in circulating inflammatory markers, stress-reactivity, 
or both.  
II. 
BACKGROUND AND SIGNIFICANCE  
Marijuana use is on the rise with the number of adults reporting medical and recreational use 
doubling in the past decade1. Among adult medical marijuana users, 39% report using marijuana 
for the purposes of self-treating or coping with anxiety2.  Despite limited scientific data on the 
effects of marijuana on anxiety, public perception is growing regarding a role for marijuana in 
anxiety treatment.  
Mixed data on marijuana and anxiety. There is some evidence demonstrating that marijuana 
use is associated with increases in acute anxiety and anxiety disorders3. However, other data 
(including our own recent, prospective work in Colorado where various marijuana strains are 
widely available) suggests that marijuana use may be protective for adolescents at-risk for 
anxiety and decrease the chances of developing an anxiety disorder during college4. This finding 
is consistent with a growing body of evidence from animal models suggesting that marijuana has 
anxiolytic and anti-inflammatory properties5. Clarifying the anxiolytic effects of specific strains 
that differ in their cannabinoid composition may explain these discrepant findings. Thus, 
regardless of whether our results support or refute the anxiolytic properties of marijuana, 
findings from this study fill a critical void and can inform public perception.  
Marijuana contains different cannabinoids that may have differential effects on anxiety. 
Advertising materials provided by marijuana organizations go so far as to recommend particular 
marijuana strains to treat specific anxiety conditions. The data the scientific community has 
provided thus far is strikingly limited and disconnected from public perceptions and industry 
messages. Overall, research studies have largely ignored the fact that marijuana exists in 
different forms and have not characterized the effects of marijuana as the compound action of 
different cannabinoids that vary in terms of their pharmacological effects. Two of the primary 
cannabinoids, ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have opposing effects, 
and the ratio of THC to CBD varies dramatically among different strains of marijuana, with 
some strains in Colorado testing at greater than 20 to 1 CBD to THC, while many strains have a 
1:1 THC to CBD ratio or have negligible CBD. Importantly, THC is thought to be acutely 
anxiogenic6, while treatment with CBD, a non-psychotomimetic cannabinoid, induces anxiolytic 
effects without the experience of a “high” and may mitigate some of the harmful effects of 
THC7. However, the impact of CBD level and its ratio to THC on the anxiolytic effects of 
marijuana is largely unknown. Here, we propose to test the hypothesis that the anxiolytic effects 
of marijuana vary as a function of the ratio of CBD to THC in order to address this major gap in 
understanding of the effects of cannabinoids on anxiety.  
Does CBD alter the effects of THC on anxiety? In addition to epidemiological data, one of the 
primary methods used to understand the effects of marijuana on anxiety in humans has been 
standardized smoking of marijuana in a laboratory setting. With respect to self-report measures, 
a number of studies have found that marijuana acutely increases positive affect as well as 
anxiety8-10_ENREF_8. These effects also appear to follow a dose dependent function based on the 
THC content of the marijuana (e.g.,11). Studies have also compared the effects of smoked 
marijuana to the effects of THC in pill form, suggesting that both forms produce similar effects 

 
 
 
 
 
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on subjective mood ratings (e.g.,12,13). 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.  More recent analyses suggest that 
CBD may have very different effects on mood and attenuate the anxiogenic effects of THC14-17.  
Importantly, there are no current data that can speak to the longer term effects of either THC or 
CBD, or their combination, on anxiety processes. Clearly, the evidence suggests that acute 
marijuana use is associated with mood alterations and that marijuana use is likely related to long-
term anxiety outcomes, although the data are mixed as to the direction of the effect.  Thus, a key 
issue and a focal point of the present proposal is that the anxiolytic effects of CBD differ 
considerably from those of THC, an issue critical to understanding the spectrum of post-
intoxication effects of marijuana strains on anxiety. Given that CBD is thought to be anxiolytic 
and non-psychotomimetic (doesn’t produce a “high”), and mitigates some effects of THC, the 
use of strains containing CBD will likely result in different anxiety outcomes. Importantly, our 
design includes tests of the effects of a THC based strain (1:0), a CBD based strain (0:1), or a 
+THC/+CBD combination strain (1:1). All three are critical comparisons given emerging data 
supporting potentially differential effects of each of these cannabinoids on their own, and when 
tested in different combinations (See Preliminary Studies). 
The role of inflammation in anxiety.  Rodent and human studies support the role of 
inflammatory processes in the development of anxiety and stress-related disorders. Several 
laboratories have shown that neural IL-1β and the subsequent pro-inflammatory cascade is both 
necessary and sufficient to induce anxiety-like behaviors in rodents18,19 _ENREF_1920.   Although 
the data is more equivocal, human studies also suggest that pro-inflammatory cytokines are 
involved in the generation of anxiety-related symptoms, such as anxiety, fear, and rumination, 
putatively via interactions with the stress system21. Research suggests that acute stress such as 
rumination on traumatic experiences or exposure to emotional visual images (e.g. during the 
Rumination Induction or Dot Probe task) triggers cytokine signaling (e.g. IL-6, TNF- α, IL-2, IL-
1, CRP, etc.) and oxidative stress, which have downstream effects on inflammatory responses 
(Boyle et al 2017, Cooper et al 2017, Rood et al 2012, Hannibal et al 2014).  Importantly, 
inflammation is associated with a number of negative consequences including risk for anxiety 
and stress-related disorders, immune-suppression, and deleterious neurocognitive effects, and has 
important implications for overall health and well-being 24,25.  Several studies have reported 
significantly higher concentrations of various pro-inflammatory cytokines in serum in 
cerebrospinal fluid (CSF) of individuals with anxiety and stress-related disorders26,27. Further a 
considerable number of studies have shown that acute psychological stress in human subjects 
also increases pro-inflammatory cytokines (IL-1β) in serum18.  
Marijuana has anti-inflammatory properties. Cannabinoids have profound effects on immune 
system function and inflammation, both peripherally and centrally (for review see Klein28). A 
number of studies have suggested that cannabinoids, both THC and CBD, modulate pro-
inflammatory cytokines, including TNF, IL-2, IL-6, IL-12, IL-1b (see review Klein28). 
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 involve non-CB1 or CB2 related mechanisms29. Rodent 
models suggest that this may be particularly true for CBD30,31, where treatment with CBD or a 
synthetic derivative blocked the LPS-induced increase in serum TNF and other cytokine immune 
responses32. Martin-Moreno et al.33 found that CBD treatment in mice reduced the 

 
 
 
 
 
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neuroinflammatory effects of amyloid beta, specifically cortical levels of the pro-inflammatory 
cytokine IL-6. In a similar set of studies, CBD attenuated several facets of the 
neuroinflammatory response to amyloid beta in the hippocampus including IL-1 and GFAP 
expression34_ENREF_32 and inducible nitric oxide synthase, NF-kB activation and astrocytic 
reactive gliosis35. Anti-inflammatory effects of CBD in brain were also observed in models of 
multiple sclerosis (e.g. decreased IL-1)36 and meningitis37. 
A unique role for CBD in anxiety through inflammatory pathways. These data, consistent 
with our pilot data, suggest that CBD has profound anti-inflammatory effects on peripheral and 
neuro- inflammatory markers (for review see 38), which play a pivotal role in the etiology of 
psychiatric disorders including anxiety disorders, PTSD, and depression39.  These are exactly the 
questions our proposed design is ideal to answer. Given that pro-inflammatory shifts are thought 
to underlie stress-responses and anxiety behaviors, marijuana’s anti-inflammatory effects may be 
key players in explaining associations among marijuana use and anxiety disorders. While THC 
also has some anti-inflammatory properties, possibly via its effects on CB2 receptors, the totality 
of data (including our own pilot work) suggest that CBD may be a highly potent anti-
inflammatory component of marijuana40 that could potentially mitigate harmful effects of THC 
or create a synergy whereby a balance of these cannabinoids have the strongest anxiolytic 
effects.    
Significance. In order to unpack associations among marijuana use and the biological and 
behavioral processes underlying anxiety, studies that consider multiple cannabinoids and then 
quantitatively measure cannabinoid levels in blood are critically needed. This is becoming 
increasingly important, because the types of marijuana commercially available have increasingly 
high levels of THC (typical products widely commercially available in Colorado dispensaries are 
18% to 25% THC) and there is huge variation in the ratio of THC to CBD in these products. 
While some products have a near 1:1 ratio of THC to CBD (e.g., Jamaica Lion), others are closer 
to a 1:2 ratio of THC to CBD (e.g., Gumbi). On the other hand, many have almost no CBD at all 
(e.g., a 1:0 ratio with Starfighter is 27% THC, 0% CBD) and others have virtually no THC and 
are entirely CBD (e.g., a ratio of 0:1 with Charlotte’s Web). It is difficult to describe the 
enormous variation in the products that are currently available in dispensaries throughout 
Colorado and other states that have legalized marijuana (see http://thefarmco.com/ marijuana-
strains-descriptions-all/ for an example). In contrast, the human laboratory work on the effects of 
marijuana use on mood, health behavior, etc. have nearly all been conducted with marijuana 
grown by a single government source in Mississippi, with a THC potency of approximately 3-
6% and 0% CBD. This is no fault of investigators, as to date this was the only legal avenue for 
pursuing this work. The critical point from a scientific perspective is that as a result of the 
constraints on prior research, we know virtually nothing about the effects of different ratios of 
cannabinoids in marijuana on biological and behavioral processes relevant to anxiety. This is 
critical information from a public health perspective, and we simply cannot gather relevant data 
without conducting externally valid research with everyday users of these products. 
THC is well known for having immediate negative effects both acutely and potentially even 
over the longer term on anxiety, suggesting that higher potency THC strains could have negative 
consequences that exacerbate anxiety. CBD, on the other hand, is non-psychoactive, has high 
tolerability in humans, and may counteract some of the negative cognitive effects of THC, at 
least in the short term (see Preliminary Studies). Further, protective effects of CBD have been 
widely shown in preclinical models of inflammation and anxiety40. In order to determine: 1) 
whether marijuana has effects on anxiolytic and inflammatory processes, 2) whether these effects 

 
 
 
 
 
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are more likely to be due to THC, CBD, or some combination of the two, and 3) to provide data 
on the minimization of harm due to marijuana use with respect to anxiety symptoms, the current 
study will quantitatively assess THC and CBD blood levels in mildly to moderately anxious 
marijuana users who have a desire to use cannabis to cope with their anxiety and will use one of 
three different strains of marijuana (that vary in their levels of THC and CBD). These 
participants (marijuana users) will be compared to a matched control group that does not 
currently use or have a desire to use marijuana to cope with their anxiety. We propose that the 
opposing pharmacology effects of THC and CBD may result in differing inflammation and 
stress-reactivity profiles in anxious marijuana users as compared to anxious non-users. 
Limitations of the Extant Literature. All—or nearly all—published data linking marijuana use 
to anxiety are taken from either: 1) large surveys or 2) from studies of acute effects on mood that 
rely on low potency THC marijuana. Thus, it is not possible to know whether there is any causal 
(direct or indirect) effects of marijuana use on biological or behavioral mechanisms relevant to 
anxiety. Legal impediments have to date prevented human laboratory human studies from 
examining the effects of marijuana on anxiety processes using strains that are currently available 
and widely used. Further, studies have largely not characterized the effects of marijuana as the 
compound action of different cannabinoids that vary in terms of their medical and 
pharmacological effects. Two of the primary cannabinoids, THC and CBD, although both 
classified as partial agonists and antagonists, appear to have opposing effects. However as 
discussed, the ratio of THC to CBD varies dramatically among different strains of marijuana. 
Thus, studies that examine marijuana strains, as they are commercially available and used in the 
real world, are critically needed in order to understand the potential health impact of increasing 
marijuana use. 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 marijuana (Pacula et al 2016).  
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 anxiety, inflammatory, and cognitive 
processes, despite the fact that consumption of edible marijuana is prevalent and rapidly 
increasing in individuals with anxiety. Therefore, we will observe our participants self-dosed 
cannabis use (flower or edible) and measure neurocognitive and inflammatory mechanisms 
underlying potential changes in anxiety. 
Summary. Our goal is to understand the anxiolytic effects of cannabinoids, in particular the 
effects of THC-based strains vs. CBD-based strains vs a combination of THC to CBD (1:1) 
strains on inflammation, stress-reactivity, and anxiety. This design (including some experimental 
elements) will capitalize on the novel opportunity to examine the effects of real world marijuana 
strains (selected for their THC and CBD ratios) on anxiety, stress-reactivity, and peripheral 
inflammation.  Thus, the proposed set of studies directly characterize the effects of specific 
cannabinoids on anxiety, stress-reactivity, and inflammatory pathways, and have the capacity to 
identify the potentially less harmful components of marijuana. These studies will provide the 
public, physicians, policy makers, and the scientific community valuable data regarding the 
effects of marijuana strains at commonly commercially available potencies and ratios in 
individuals with anxiety. 

 
 
 
 
 
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III. 
PRELIMINARY STUDIES 
Prior experience and expertise of the team. The CU Change lab has been conducting 
behavioral and imaging research on marijuana41,42 as well as research on the relationship of 
marijuana use to broader health and risk behavior43-45 for many years. For example, the PI 
Bidwell conducted a longitudinal study of adolescent and young adult marijuana use and found 
that higher levels of marijuana use were protective against anxiety for at-risk adolescents and 
decreased the chances of developing an anxiety disorder during college, even after controlling 
for baseline levels of psychopathology and the use of other substances4. More broadly, her 
research focused on the overlap of substance use and mental health outcomes. Co-I Hutchison 
has conducted prior research on the acute effects of cannabis (Schacht, Selly, & Hutchison, 
2009) as well as research on cannabis withdrawal and cue-elicited craving for cannabis 
(Haughey et al., 2008; Filbey et al., 2009; 2010) and the association between brain structure and 
cannabis use (Schacht et al, 2011; Weiland et al., 2015). More broadly, his research focuses on 
the study of neurocognitive and genetic factors underlying response to interventions to decrease 
substance-use and related risk behavior, and increase health behaviors. The co-PI (Dr. Bryan) has 
also studied the association of cannabis use and risk behavior (Bryan et al., 2012) and has 
extensive experience in research related to health behaviors and interventions. Thus, they are 
uniquely qualified to head this research project. 
Previous and Current Marijuana Studies. More recently, the lab has focused on the 
development of cutting edge study designs to examine the effects of various types of marijuana. 
One current pilot study utilizes an extensive experimental design compared to the 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, such as the currently proposed motor battery, the 
at-home microbiome collection kit, and use cannabis ratios identical to the ones in this proposal 
(i.e., all THC with no CBD (+THC/-CBD, 1:0, equal THC to CBD (+THC/+CBD, 1:1), or all 
CBD (-THC/+CBD, 0:1).    
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 

 
 
 
 
 
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based on cannabinoid blood levels. We have successfully been collecting and storing gut flora 
from the at-home microbiome kit (fecal sample) for subsequent analysis but are still in the early 
stages of analyzing these pilot samples. However, 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 and we suspect that diversity of gut 
flora may be altered based on drug use and immune function (Lowry et al 2016, Skosnik & 
Briones 2016, Mu et al 2016, DiPatrizio 2016, Cani et al 2016). Given the limited scope of the 
pilot study, we were not able to test a longer duration of cannabis use, the range of products (i.e., 
CBD only), complete a microbiome analysis on gut flora, 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. Consistent with our preliminary study, we will 
recruit (from the Denver and Boulder areas): 450 participants who report a desire to use 
marijuana to cope with their anxiety, have had previous experience with marijuana, and report a 
Generalized Anxiety Disorder-7 (GAD-7) score of ≥ 5 (at least mild to moderate anxiety) and 75 
non-using cannabis controls (matched for anxiety via GAD-7 ≥ 5) who do not report an intention 
to use marijuana to cope with their anxiety nor any marijuana use over the prior six months. A 
summary of the Assessment schedule and the additional inclusion/exclusion criteria are detailed 
below in Table 1 and Section VI (respectively).  
All participants will come to the CUChange Lab for a Baseline Appointment (Session 1) 
involving extensive measures of anxiety (e.g., Depression, anxiety, and stress scale, a rumination 
induction task, a dot probe task, rumination self-report scale, etc.) and other psychiatric 
symptoms, health behavior (e.g., stress, quality of life, sleep, alcohol use), the cognitive testing 
battery utilized in our preliminary studies, a blood draw for biomarkers of inflammation, and a 
motor battery (Baseline Appointment, Session 1). During this Baseline Appointment, a research 
assistant will provide information on three at-home aspects of the study: 1) the range of assigned 
cannabis products (e.g., differing THC to CBD ratios possible) and potential prices, 2) the 
ActiGraph wearable watch device that participants will be loaned to measure physical activity 
and sleep (during the final 2 weeks of the four week study), and 3) a microbiome collection kit 
that they will be given to complete (once before and once after 4 weeks of ad libitum use of their 
cannabis product). The experimental aspect of this study will be the assigned cannabis ratio, 
while the other aspects of this study are ad libitum based, with regard to the dosing schedule and 
choice of product type (flower or edible), by participants that would already like to use cannabis 
to cope with their anxiety.  
We are recruiting individuals who have indicated that they are unsure of what marijuana 
product to try and therefore want to try any of the ratios assigned in the study, would like to 
continue their typical strain use, or would like to change their strain to one of the ratios assigned 
in this study. We will ask that all subject inform of us of their subsequent strain purchased 
(assigned either strain C, D, or E), and the amount of cannabis purchased (not assigned) via an 
online short daily message (RedCap, provided as a CCTSI resource). Participants will then self-

 
 
 
 
 
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administer the product as they see fit, without any instructions from study staff, for 4 weeks. 
Marijuana users (who according to our preliminary data, typically use marijuana with a THC 
potency of ~18%) will be assigned to use one of three strains with differing levels of THC and 
CBD. Considering the wide range of potencies, ratios, and types of cannabis products used, we 
will assign one of three common flower cannabis ratios [(THC:CBD = 1:0 (18/0%), 1:1 
(12/12%), and 0:1 (0/18%)] and one of three common edible cannabis ratios [THC:CBD = 1:0 
(10 mg), 1:1 (10/10 mg), or 0:1 (0/10 mg)]. Therefore, both flower and edible users will be 
identically assigned to +THC alone (1:0), a combination of +THC and +CBD (1:1), or +CBD 
alone (0:1), and will use their assigned product ad libitum (using as much or as little cannabis as 
they would like). Users will be advised to use their assigned cannabis product as they choose 
(i.e., their typical behavior), while non-users (control group) will be advised not to change their 
behavior and all groups will be instructed to report any change to us.  
For cannabis user groups, we must recruit participants that have previously or currently used 
marijuana products and have a desire to continue or begin using any of the ratios and potencies 
potentially assigned during the study period. Thus, assignment to the all THC strain (+THC/-
CBD, 1:0) serves as a naturalistic control group and our primary hypotheses surround effects of 
switching anxious marijuana users to either a strain with THC and CBD (e.g., +THC/+CBD, 1:1) 
or to a CBD-based strain without THC (i.e., -THC/+CBD, 0:1,), which are both likely to reduce 
anxiety symptoms over 4 weeks of use. Assessments occur at 2 and 4 weeks of ad libitum use, 
the typical time frame that symptom change would be detected from pharmacological treatment 
(e.g. SSRI). Details regarding marijuana strain assignment procedures, sample ascertainment, 
timing of assessments, power analyses, and the analytic plan follow.  
As an exploratory endpoint, we will track participant’s self-reported anxiety level, marijuana 
use, and sleep pattern with daily follow-up messages (online via email and the RedCap tool) over 
the course of the 4-week study period. This aspect will provide important data on patient choice, 
patient behavior, and edible impact on anxiety.  
After the first two weeks (of four), all participants will return to the CINC (Creativity for 
Innovation & Creativity) laboratory (2-Week Appointment, Session 2) to complete the full set 
of biological measures and nearly all of the self-report measures and exercises with the 
elimination of one acute stressor (Rumination Induction) and the addition of one short survey on 
symptom change (Patient Global Impression of Change). After two more weeks (four weeks 
after the beginning of the study period), a final set of measures will be collected in our Mobile 
Van Pharmacology and Phlebotomy Laboratory (4-Week Mobile Appointment: Pre & Post 
self-administration, Sessions 3 & 4), to assess the longer/chronic (4-week, pre-administration, 
Session 3) and shorter/acute (0-1 hour, post-administration, Session 4) effects of cannabis use on 
all measures. Two additional measures will be added at this point to report the participant’s 
current feelings after cannabis self-administration (Addiction Research Center Inventory (ARCI) 
and Drugs Effects Questionnaire (DEQ)). 
While the main portion of the study will be complete after this 4-Week Appointment, we will 
continue to track participant’s self-reported anxiety level, sleep pattern, and marijuana use with a 
monthly follow-up survey (online via email and the RedCap tool), over the course of a five-
month follow-up, in keeping with the exploratory nature of the design. This aspect will provide 
important data on patient choice, patient behavior, and the effects of other marijuana products on 
anxiety. 
In sum, the study will involve a 4 (marijuana-user groups: +THC/-CBD, , +THC/+CBD,, -
THC/+CBD, and non-users) x 4 (Session: 1, 2, 3, and 4) mixed factorial design. The complete 

 
 
 
 
 
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schedule of assessments and measures taken at each assessment are outlined in Table 1 and 
described below. 
 
Marijuana Administration at Home. Unlike other studies done in the United States to date, the 
proposed work will utilize a design that allows participants to choose their type of administration 
and ad libitum dosing schedule, but contains an experimental element (i.e., strain assignment). 
Specifically, at the end of the baseline session, participants will be given instructions to purchase 
assigned strain, differing by THC to CBD ratio (n=75/flower strain; n=50/edible strain): 1) a 
THC-based strain akin to a typically used strain with normal levels of THC and little to no CBD 
(+THC/-CBD), 2) a 1:1 strain with equivalent THC and CBD levels (+THC/+CBD), or 3) a 
CBD-enriched strain with little to no THC (-THC/+CBD) at a good clinical practice dispensary 
in Boulder or Denver, Colorado.  
 
The market for flower versus edible cannabis products are similar, but differ slightly in their 
servings, typical doses, and labeling system (potency listed by percent with flower products 
rather than by mg with edibles) making it currently impossible to assign identical flower and 
Table 1. Schedule of Assessments. 
Visit 
Duration 
Includes 
1. Orientation @ CINC Lab (Session 1) 
ASAP after phone screen 
[Part of Baseline Appointment] 
0.5 
hrs 
-  Description of study procedures and measures 
-  Informed consent; Eligibility re-screening 
-  Strain assignment for marijuana users. 
2. Baseline Assessment @ CINC Lab (Session 1 
continued) 
ASAP after phone screen  
[Part of Baseline Appointment] 
1.5 
hrs 
- Pregnancy test, Blood Alcohol Content, 
Toxicology drug screen 
- Self-report of anxiety, stress and depression (e.g., 
GAD-7, BAI, DASS) 
- Rumination Induction & Dot Probe Task 
- Questionnaires on health behavior, substance use, 
Psychiatric interview, and psychological 
measures  
- Inflammation & cannabinoid blood draw 
- Motor & Cognitive battery 
3. Daily follow-up assessment for all participants  
1x/day for 4 weeks (~31 days) 
[Between Baseline, 2-, & 4-Week Appointments] 
 
~2 mins 
/day 
-  Daily online message report on  anxiety/stress 
management, ad libitum marijuana use (if used: 
amount, strain, method), and sleep; individually 
tailored links 
4. 2-Week Assessment @ CINC Lab (Session 2) 
2-weeks after Baseline Appointment 
1hr 
-  All Baseline measures (exception: rumination 
induction task removed and participant global 
change index added)  
-   Microbiome kit & Actigraph distributed 
5. 4-Week Assessment @ Mobile Lab (Sessions 3 & 4) 
Pre (Immediately) & Post (Immediately for flower or 1 
hour for edible) self-administration 
[4-Weeks after Baseline Appointment]  
2 
hrs 
-  All Baseline measures/tasks  
-  Microbiome kit & Actigraph wearable collected 
3. Monthly follow-up assessment for all participants  
1x/month for 5 additional months 
[After 4-Week Appointment] 
~12 mins  
/month 
-   Monthly online survey; individually tailored 
links 
Total time (6 months) 
8 hrs 
Participants paid $335 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
edible potency groups, or ratios. However, Colorado requires all strains to be tested by a state 
licensed lab, which allows us to have a precise measure of potency to operationalize our strain 
assignments. Therefore, the flower groups will be assigned either the +THC/-CBD strain 
(containing 18% THC and <1% CBD), a combination of THC and CBD strain (a 1:1 ratio 
+THC/+CBD containing 12% THC and 12% CBD), or the -THC/+CBD strain (containing <1% 
THC and 18% CBD). Like the flower group, the edible groups will be assigned to one of the 
same ratios (an all THC strain, a combination of THC to CBD strain with a 1:1 ratio, or an all 
CBD strain) and they will choose when and how much they would like to use this assigned 
edible over the next four weeks. However, the participants that choose to be in the edible group 
(rather than the flower group), will be assigned an edible product with 10 mg of THC, CBD, or a 
combination of THC and CBD per edible piece (comparable to the flower products with 6, 12, or 
18% THC, CBD, or a combination of THC and CBD).  
The dispensary will set aside a specific lot of each flower (to be smoked or vaporized) and 
edible form of the assigned strain, which will be packaged in childproof bottles and labeled as 
“Strain C”, “Strain D” or “Strain E”, such that participants and dispensary staff will be blind to 
the ratio assignment until the product is purchased (THC and CBD content will be printed on the 
label, as required by state law) , and the research staff will remain blind to which strain was 
assigned until after data analysis. Dr. Hutchison (co-investigator) will maintain the blind during 
the study period. The instruction to purchase “C”, “D” or “E” will be randomized across 
participants such that equal numbers of male and female participants are included across the ratio 
conditions. The design involves the instruction that participants can use as little or as much of the 
marijuana as they wish over the course of the four weeks of the study, and are asked not to use 
any other strain during that time (but if so, to just report what was used). Therefore, a research 
assistant will give participants that are marijuana users, a card with directions to a local 
dispensary.  The card will have instructions to purchase a particular strain of cannabis (e.g., 
“strain C”) but participants will choose the amount of cannabis that they expect to use during the 
study (i.e., we will not assign a specific amount for them to purchase or to use during the 4-week 
study period). While the potency may vary slightly by the strain assignment and the amount used 
may vary by each person, we expect approximately one gram of flower cannabis to cost $12 and 
approximately 75mg of edible cannabis to cost $15 (comparable across typical serving amount). 
However, this will depend in part on what cannabis type and how much cannabis each 
participant chooses to use. Study staff will not provide any directions regarding dosing and 
administration.  
Marijuana-using subjects are prompted by email to report how much was used each day 
using an online reporting system (RedCap). We will also provide patients with safety 
information that will contain warnings regarding driving or operation of machinery, consistent 
with the warnings used with other over the counter and prescription drugs that may impact 
cognitive and motor functions (e.g., Benadryl, robitussin, benzodiazepines, narcotics, etc.). The 
important marijuana safety warnings will include: Do not drive, operate machinery, or perform 
other hazardous activities while using cannabis. It may cause dizziness, drowsiness, and 
impaired judgment.  Do not drink alcohol while using cannabis. Alcohol will increase dizziness, 
drowsiness, and impaired judgment. Cannabis may increase the effects of other drugs that cause 
drowsiness, including antidepressants, alcohol, antihistamines, sedatives (used to treat insomnia), 
pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. More information can 
be found on the National Institute of Health (NIH) DrugFacts page “What is marijuana?” 
(https://www.drugabuse.gov/publications/drugfacts/marijuana). 

 
 
 
 
 
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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. For example, 
we previously conducted a study that involved a highly controlled laboratory administration of 
low THC and zero CBD marijuana obtained from the NIDA supplier in Mississippi42. However, 
external validity of the study was compromised because participants informed research staff that 
the marijuana was of significantly poorer quality than they had ever experienced. Further, 
although NIDA currently supplies a greater variety of marijuana strains that include some 
quantity of CBD, the NIDA-supplied marijuana does not reflect the levels of THC and CBD 
available through Colorado dispensaries and used by Colorado residents and patients 
(www.drugabuse.gov). Thus, those procedures simply did not, and cannot reflect the strains and 
administration of marijuana in our and other states. In addition, 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 anxiety.  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 anxiety 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 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 cannabinoids in anxiety patients, as they are used real world, we decided that it was critically 
important to emphasize external validity in both the flower and edible forms of cannabis use. The 
disadvantage of our design is that we have little control over how the participants use the 
marijuana or how much they use. To address this limitation, both in our pilot study and in this 
application, we rely on blood quantitation of cannabinoids (from both flower and edible users) to 
determine the level of THC and CBD in each subject. Thus, regardless of how the participant 
uses the marijuana, we have an objective measure of the dose received for both 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 allows for the analysis of THC and CBD blood levels as 
continuous measures. In this way, we also capitalize on the greater variability in blood levels 
expected in the design by analyzing overall levels of CBD and THC as well as by strain, which 
by design (in flower and edible forms) will have different THC/CBD ratios. This further allows 
for a direct test of whether any differences in outcomes for participants randomly assigned to the 
–THC/+CBD strain are due to an increase in CBD or a decrease in THC as compared to their 
Baseline. This strain is a critical comparison as there are data to suggest that the effects of THC 
differ when CBD is also in the blood.  
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 Cohen46 and were conducted in G*Power 347. The primary analyses in Aims 1-3 
broadly is the test of the group X time interaction effects across repeated assessments of THC/CBD 
and anxiety, inflammatory markers, and stress reactivity. For the current data analysis plan, we 
will only focus on the ratios and time points that we currently have supporting preliminary data 
for and hypothesize to have the greatest impact on anxiety. Hence, in this data analysis plan we 
will focus on the 3 main time points (out of 4) for a chronic use endpoint [Baseline, 2 Week, and 
4-Week Pre-administration (Sessions 1-3)] and the 3 main cannabis product so that there will be 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
an all THC, all CBD, and a combination of THC to CBD group [(+THC/-CBD, +THC/+CBD, and 
-THC/+CBD, ratios: 1:0, 1:1, and 0:1)]. 
To be conservative, we thus estimated an ICC of .50. Using a mixed model ANOVA design, 
with four groups, three assessment points, and an average ICC = .5 between assessment points, a 
total n=450 (75 per flower group and the control, and 50 per edible group) will allow us to detect 
a groupXtime interaction effect as small as f=.09. In Aim 2B, the test of the effects of group on 
stress-reactivity will again involve four groups ( 3 cannabis and 1 control) but only one assessment 
point.. Note that our power analysis is conservative, as our actual analysis will involve more 
powerful tests (e.g., focused interaction contrasts as opposed to overall F tests). For Aim 3, the 
estimation of the mediational model via path analysis (Hypothesis 3; see Figures 3a and 3b below), 
Monte Carlo simulation strategies formed the basis of our power analysis48. Given that the model 
in Figure 3b is the more complex of the two, we utilized the model structure with the three planned 
contrasts as exogenous variables in our simulations. The key test of Hypothesis 3 will involve the 
use of structural equation modeling techniques49. Because we have almost no empirical data on 
which to base estimates of effect size, we conservatively utilized small to moderate effect sizes 
depending upon hypothesized relationships. For example, we expect small coefficients (.20) from 
each contrast to stress reactivity, whereas we expect a slightly larger path (.40) between the 
contrast comparing the –THC/+CBD strain to control and inflammation. Power analyses were 
conducted in Mplus and then in SAS following procedures for estimating the power of the 
likelihood ratio test of the significance of parameters in structural equation models48. We utilized 
Monte Carlo simulation to generate a population covariance matrix based on the hypothesized 
parameters in the model. For the smallest path in the model (which requires the most power to 
test), assuming two-tailed alpha of .05, our estimates of power at various sample sizes appear in 
Table 3. To assure .80 power or better to detect small associations between all groups, we thus 
require data from 450  participants (75 in the control and each flower group as well as 50 in each 
edible group) for our mediational analyses.  
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 session and the final four-week follow up session, though we have not experienced and 
do not anticipate differential attrition by condition. Thus, to allow for attrition, we assume an 
approximate 85% retention rate over the course of data collection. To adjust for this attrition rate 
in all groups, we will recruit n»520 participants (n=86/flower or control group as well as 
58/edible group). Our approach to power analysis and accounting for attrition is also quite 
conservative, in that the techniques we will utilize in data analysis use state of the art 
recommendations for the handling of missing data in longitudinal studies50,51.  
Statistical Analysis Plan. Analyses will be conducted primarily on the SAS system for 
Windows Version 9.452 and Mplus Version 7.353, which include capabilities to test multilevel 
models that appropriately model both normally and non-normally distributed data as well as 
missing data. To test the success of random assignment across the marijuana strain groups the 
equivalence of the three marijuana user and control groups across all pretest measures will be 
assessed via t-tests on continuous items (e.g., BAI) and c2 tests of categorical items (e.g., race). 
The Bonferroni approach 54 will be used to correct for alpha inflation (familywise alpha of .05). 
The distributional properties of continuous variables will be examined to determine appropriate 
analytic techniques or normalizing transformations prior any analyses. 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
Specific Aim 1 – To compare changes in anxiety in mild to moderately anxious marijuana users 
exposed to 4 weeks of use of one of three different marijuana strains (+THC/-CBD vs. 
+THC/+CBD vs. -THC/+CBD) to a group of non-using controls matched on anxiety. Hypothesis 
1 predicts a main effect of strain such that –THC/+CBD marijuana users will have lower levels 
of anxiety (BAI) compared to other marijuana groups and to non-using controls. To examine the 
main effects of group on these outcomes, we will estimate a random coefficient regression 
(RCR) models in SAS Proc Mixed wherein the change in BAI scores will be regressed on 
marijuana user group, time, and the groupXtime interaction.  Hypothesis 1 also predicts that 
higher CBD levels in blood among marijuana users will be associated with lower BAI. The 
analysis for this hypothesis will again be a RCR model, but instead of group membership, the 
independent variables in these models will be level of CBD in blood, time, and the CBDxtime 
interaction. We will conduct additional models to explore whether there may also be main effects 
of THC in blood or a THCXCBD interaction effect on BAI. Secondary models will test the 
effects of strain and /or cannabinoid blood levels on the daily and monthly assessments of 
anxiety using a multi-level modeling approach. These additional analyses will appropriately 
control for Type I error, depending upon the number of tests run. Co-I Bryan has used such 
models extensively in prior work.55,56 
Specific Aim 2 - To assess inflammation and stress reactivity [biological and behavioral stress 
change scores during a stress induction (TSST)] in mild to moderately anxious marijuana users 
exposed to 4 weeks of use of one of three different marijuana strains compared to a group of 
non-using controls matched on anxiety. Hypothesis 2A predicts a main effect of strain such that –
THC/+CBD marijuana users will have lower levels of circulating peripheral inflammatory 
markers compared to other marijuana groups and to non-using controls. To examine the main 
effects of group on these outcomes, we will estimate a random coefficient regression (RCR) 
models in SAS Proc Mixed wherein the summary values of the panel of inflammatory markers 
utilized in our preliminary study will be regressed on marijuana user group, time, and the 
groupXtime interaction. Hypothesis 2A also predicts that higher CBD levels in blood among 
marijuana users will be associated with lower levels of circulating peripheral inflammatory 
markers. The analysis for this hypothesis will again be a RCR model, but instead of group 
membership, the independent variables in these models will be level of CBD in blood, time, and 
the CBDxtime interaction. We will conduct additional models to explore whether there may also 
be main effects of THC in blood or a THCXCBD interaction effect on inflammatory markers.  
Hypothesis 2B predicts a main effect of strain on reduced stress reactivity. RCR models in SAS 
will again be utilized, wherein stress reactivity (pre-rumination induction–post rumination 
induction change scores of self-report, state anxiety, and inflammatory markers) will be 
regressed on marijuana user group. Hypothesis 2B also predicts that higher CBD levels in blood 
among marijuana users will be associated with even lower stress reactivity. As in the test of 
Hypothesis 2A, we use RCR wherein the independent variables in these models will be level of 
CBD in blood. As with Aim 1, we will conduct additional models to explore whether there may 
also be main effects of THC in blood or a THCXCBD interaction effect on stress reactivity, with 
appropriate Type 1 error corrections.    
 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specific Aim 3 - To test indirect effects of marijuana use on anxiety (BAI) via inflammatory 
markers and stress reactivity in anxious marijuana users exposed to 4 weeks of use of one of 
three different marijuana strains compared to a group of non-using controls matched on anxiety. 
Hypothesis 3 will test mediational models that ask whether the effect of marijuana use and strain 
on anxiety is mediated by changes in inflammation, stress reactivity, or both. To this end, we will 
estimate the mediational models in Figures 3a and 3b via structural equation modeling57. To test 
the overall effect of use of marijuana versus non use, we will estimate model 3a wherein the sole 
exogenous variable is marijuana users (coded as 1) versus non-users (coded as 0).The mediators 
will be change in inflammation from Session 1 to Session 3 and stress reactivity at Session 3. 
The outcome variable is change in anxiety from Session 1 to Session 3. This model will be 
estimated and both the fit of the model and the significance of the path coefficients will be 
examined. Importantly, we will compare the path coefficients from user status to inflammation 
versus stress reactivity to determine whether use is associated with changes in inflammation, 
stress reactivity, or both. Assuming that the paths from inflammation and stress reactivity to 
anxiety are significant, we can test whether there are indirect effects of user status on anxiety that 
are mediated by inflammation, stress reactivity, or both. A test for completeness of mediation is 
employed through a 1 degree of freedom c2 test where a path directly from user status to anxiety 
is added to the model. A nonsignificant direct path and a nonsignificant change in c2 suggest that 
user group effects on the anxiety were mediated through the theoretical mediational constructs. A 
secondary test of mediation will utilize bootstrap methods to test the significance of, and 
confidence limits around, the mediated effect58,59. Similar mediational analyses have been widely 
used by Co-I Bryan56,60,61. The model depicted in Figure 3b will test the more focused hypothesis 
that the ratio of cannabinoids is critical for the biological and behavioral changes that drive 
anxiety. The analysis will follow identical procedures to those described to test Model 3a. 
Finally, it is also possible to use continuous values of THC and CBD in blood as the exogenous 
predictors in the model. 
Amendment update Spring 2023 - We are reaching out to participants who have completed the 
study and have usable data in order to collect a) updated sexual orientation and gender identitiy 
(SO/GI) demographics including sex assigned at birth, and b) the Perceived Discrimination Scale 
(PDS). The rationale for this change is that the PDS was added late in the study and thus not all 
participations had the opportunity to complete the measure, and the current SO/GI-related items 
are not aligned with our current approach to collecting these data, which was also finalized very 
late in this study’s course. 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
V. 
FUNDING 
This study is expected to be funded by a grant from NIDA. 
VI. 
ABOUT THE SUBJECTS  
Ethnic diversity of this sample is expected to be representative of the greater Boulder-Denver 
area at large. A trained research assistant will screen prospective participants who call, email, or 
complete an online survey, according to the inclusion/exclusion criteria listed below. Given 
established associations with inflammatory markers (e.g. IL6, TNFa), we will exclude indviduals 
who report an immune-related disease (e.g. HIV), use of maximal doses of steriods, or use of 
psychotropic medications (other than anti-depressants or ADHD medications). Use of opiates for 
pain, anti-depressants, ADHD medications, menstrual cycles, and birth control medications will 
be tracked during the study.  Specific criteria for study participants are listed below.  
Criteria for inclusion in the study are:   
1. Must be between the ages of 21 and 70 and provide informed consent; 
2. Must report at least moderate anxiety (≥5 on GAD-7); 
3. Users (cannabis group) must have used marijuana at least once; 
4. Users (cannabis group) must have a desire to use marijuana to cope with anxiety; 
5. Non-users (non-cannabis, control group) must not have used marijuana for prior 6 
months; 
6. Non-users (non-cannabis, control group) must not have a desire to use marijuana to cope 
with anxiety; 
7. Must report not using other drugs (cocaine, methamphetamine) in the past 72 hours and 
must not test positive on a urine toxicology test for drugs of abuse at the Baseline 
Appointment; 
8. Must not be using psychotropic, steroid-based medications, or maximal doses of non-
steroidal anti-inflammatories (NSAIDs), however anti-depressants and ADHD 
medications are ok; 
9. Must not have immune-relevant disease (e.g. HIV) or be using anti-viral medications; 
10. Must not be a regular tobacco user (≤4 days per week; cigarette, E-cigs, or smokeless); 
11. Must have a breath alcohol level of 0 at screening (to sign consent form); 
12. Must not be actively seeking or in treatment for any substance use disorder (drug use 
levels will be carefully monitored via Timeline Follow Back (TLFB) throughout the 
study to assess any confounding influences of drug or alcohol use; 
13. Female subjects must not be or trying to become pregnant (as indicated by a Pregnancy 
test & Screening form administered at Baseline) 
14. Must not be in treatment for psychotic disorder, bipolar disorder, or major depression 
disorder with suicidal ideation; or a history with these disorders. 
VII. 
VULNERABLE POPULATIONS 
This study does not include any vulnerable populations.  

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
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 local health care providers and physicians, we will advertise our study with flyers (see 
attached flyer) in and referrals from local mental health clinics. Third, we will utilize targeted 
mailings, advertising the opportunity to participate in our 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. We 
will also advertise on free platforms like online patient groups and pay for platforms (e.g., 
Facebook/Twitter advertising) that often allow for targeting advertisements based on age, 
geographic location, and interests (e.g., following or “liking” posts related to anxiety).  
In summary, we will recruit subjects locally and primarily through: target ads on anxiety 
groups in Facebook/Twitter, mailing flyers w/purchased names & addresses from Alesco and 
NIH-based ResearchMatch tool, flyers and referrals from providers’ offices (e.g., Clinical 
Psychologists), 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).  
All of these advertisements will describe the opportunity to contribute to research regarding 
cannabis use. Specifically, the posts on social media will include the following wording “The 
University of Colorado is conducting research on how levels of CBD and THC are related to 
anxiety and stress.” All social media pages will provide additional information about the study 
(see attached word flyer). The wording used on the social media page may also be used in flyers 
or other advertisements.  
IX. 
COMPENSATION  
Participants will receive $335 at the end of the study.  Given the amount of time required in 
the study and the travel to and from the lab for the first and second session, this is a reasonable 
amount of money to compensate participants for their time and effort. Thus, there is no question 
of coercion. Participants will receive $80 in cash and for the Baseline Appointment (1st in-person 
Appointment at CINC), $60 for the 2-Week Appointment (2nd in-person appointment at CINC), 
and $80 for the 4-Week Appointment (mobile in-person appointment). Participants will also 
receive $1/day for each of the daily follow-up messages that they complete during the ad libitum 
4-Week period, with a possible bonus of $10 for completing at least 26 of the 30 daily messages, 
for a maximum of $40 extra paid in cash. This will be split between the 2-Week Appointment 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
($20 for daily messages 1-15, $60 for Session 2, totaling $80) and 4-Week Appointment ($20 for 
daily messages 16-30, $80 for Sessions 3 & 4, totaling $100). Participants will receive a $6 
Grocery Store/Amazon.com gift card for the 1st part (questionnaires) of the 5 subsequent and 
brief Monthly follow-up surveys completed and a $5 Grocery Store/Amazon.com gift card for the 
2nd part (TLFB), with a bonus $20 Grocery Store/Amazon.com gift card if the 1st 
(questionnaires) and 2nd part (TLFB) of all 5 Monthly follow-up surveys are completed ($75 total, 
delivered online via email). If the 1st and 2nd part of only 4 out of 5 Monthly follow-up surveys 
are completed the participant will receive a $15 bonus gift card instead. 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. At request, participants may also 
receive complementary RTD/Bus transit passes to help with transportation to and from our 
facilities.  
 
X. 
CONSENT PROCESS 
 
When a participant arrives for their Baseline Appointment (Session 1) at the Center for 
Innovation and Creativity (CINC), a member of the research team will greet him or her in the 
first-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 he or she may have about the study. We will also explain that participation includes an 
appointment in our Mobile Van Pharmacology and Phlebotomy Laboratory (4-Week 
Appointment), 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 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, and an unsigned copy of the form used to document consent 
will also be given to the study participant electronically.  
XII. 
PROCEDURES  
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 

 
 
 
 
 
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survey will give a brief description and the estimated time involved in completing the screening 
process and the 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 list in 
Section VI 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 list in Section IV 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 (Dr. Bidwell, a licensed clinical psychologist) and 
Co-I team 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 (Session 1) Procedures. Subjects who meet inclusion criteria will be 
scheduled for a Baseline Appointment and given instructions for the assessments, including not 
consuming alcohol or marijuana for 24 hours,  or caffeine for 4 hours prior to coming into the lab 
for their sessions. After arriving at the CUChange Lab, each subject will go through the consent 
process and be breathalyzed to ensure a breath alcohol concentration of zero. A urine toxicology 
screen (and a pregancy test for females) will also be administered to insure that subjects have not 
recently taken illicit drugs (and are not pregnant). Menstral cycles and birth control use will be 
reported. A baseline blood draw (see details below) will be taken to quantify inflammatory 
biomarkers and cannabinoids. A member of our research team who has completed a certified 
training in phlebotomy will collect a blood sample. All blood draw procedures performed during 
this study will involve collecting venous blood (40 ml total/session) venipuncture of a peripheral 
arm vein using standard, sterile phlebotomy techniques. Subjects will then be administered the 
Beck Anxiety Inventory (BAI), the State Trait Anxiety Inventory (STAI), the Depression, 
Anxiety, and Stress Scale (DASS), and complete measures related to alcohol/drug use history, 
mood, stress, and quality of life  and will complete cognitive testing (see Table 2 below for 
measures to be completed).  
After completing the final blood draw, subjects will receive training in the use of online daily 
assessments (see details below) and the three user groups will then be assigned a marijuana strain 
to use for the next four weeks instead of their typical strain. Marijuana using participants will be 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
randomly assigned to one of three marijuana strains (a THC-based strain akin to a typically used 
strain with normal levels of THC and little to no CBD, a THC and CBD strain in combination, 
with a 1:1 ratio between THC and CBD levels, or a CBD-enriched strain with little to no THC, 
and then given instructions to purchase their assigned strain (labeled either C, D, or E) at a good 
clinical practice local dispensary. Marijuana users will be asked to use their assigned strain (and 
only that strain) as they wish over the course of  the next four weeks. Non-users will be asked to 
continue to abstain from marijuana use over the next four weeks. After completing the measures 
and procedures, research study staff will answer any questions subjects have on their daily 
messages (see details below), debrief participants, and compensate them with $80 in cash for 
their time and effort during the Baseline Appointment. Lastly, each participant will be scheduled 
for their 2-Week (Session 2) Apppintment at the CINC for two-weeks later.    
Blood Levels 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 Session 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 (Mayfield et al., 2013) and humans (Bala et al., 2014), as well as our own preliminary 
data, suggest that cytokine activation is associated with the pathophysiology of anxiety disorders. 
This is the same assay used in our preliminary studies. We also expect CBD and THC to impact 
the responses of blood monocyte cells to a lipopolysaccharide (LPS) challenge (see details 
below). This may represent a more accurate test of the effects of the CBD and THC, since LPS 
stimulation of peripheral blood mononuclear cells (PBMCs) simulates the inflammation cascade 
that putatively mediates the neuroinflammatory effects of pain. To that end, 40 mL of whole 
blood will be drawn at each session (1-4). We will use 22 ml of blood to perform the 
inflammatory analysis, 10 ml of that blood for DNA extraction, and 8 ml of blood for 
cannabinoid analysis. There will be four blood draws total, with one during the Baseline 
Appointment (Session 1), one during the 2-Week Appointment (Session 2) and two during the 4-
Week Appointment (Session 3 & 4 in the Mobile Van), separated by ~15 min (flower users) to 
one hour (edible users) for appropriate absorption. We will measure changes in cannabinoid and 
inflammatory levels after the long (2- and 4-week pre) and short/acute (4-week post) time course 
of cannabis consumption. 
DNA collection. DNA will be extracted from 10 ml of blood (out of the total 40 ml collected) at 
each visit. After extraction, DNA will be quantified and stored at -80° for future analysis. DNA 
will be collected to look at differences in epigenetic and single nucleotide polymorphisms 
(SNPs) in participants with varying levels of cannabinoid content after choosing to use cannabis 
with high versus low THC and CBD content. The blood DNA samples collected in this study are 
primarily for bio-banking purposes at this time, as the analysis of these samples are expected to 
be performed at a future date and therefore may contribute to the current study and/or future 
studies.  
Lipopolysaccharide (LPS)-PBMC challenge. Cannabis has been shown to mediate the pro-
inflammatory effects of LPS, therefore, this LPS challenge may represent an accurate test of the 
effects of the CBD and THC, as LPS stimulation of peripheral blood mononuclear cells 
(PBMCs) simulates the inflammation cascade that putatively mediates the neuroinflammatory 
effects of anxiety. To that end, PBMCs will be separated using density gradient centrifugation. 
Cells will be counted and viability assessed using trypan blue exclusion. PBMCs will be exposed 
to LPS (0, 0.1, 1, 10 and 100 ng/ml) for 20h in a 96 well v-bottom plate. Protein levels of 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
cytokines and chemokines (IFNg, IL-1a, IL-1b, IL-6, IL-2, IL-4, IL-8, IL-10, IL-12, and 
TNF) will be measured in supernatant using a multiplex ELISA assay (Aushon Biosystems, 
Billerica MA). Messenger RNA (mRNA) levels of the same cytokines and chemokines will be 
measured in cell lysates using real-time PCR. We have successfully performed the PMBC 
isolation and LPS challenge in other projects. 
Gut Microbiome Sample Collection. Participants will be instructed on how to collect and 
return microbiome samples at the Baseline Appointment. Gut flora (from fecal samples) will be 
collected from participants using at-home kits and then stored at -80°. Subjects will be given one 
kit during their 2-Week Appointment and will return the kit  to research staff at their 4-Week 
Mobile Lab Appointment (in the Mobile Van). A short dietary survey (EATS) will be conducted 
at the 2-Week and 4-Week Pre-administration Appointment to complement the microbiome kit 
and blood data collected. The microbial DNA collected in this study are primarily for bio-
banking purposes at this time, as the analysis of these samples are expected to be performed at a 
future date and therefore may contribute to the current study and/or future studies.  
We expect to see changes in abundance and diversity of microbiota populations found in the 
gut as a result of cannabis use. Because substance use, inflammation, and the gut microbiome, as 
well as pain and anxiety, and inflammation and the gut microbiome are all heavily intertwined 
(Fung et al 2017, Gorky & Schwaber 2016, Leclerq et al 2014, Mayer et al 2015, Peterson et al 
2017), we will examine the relationship between changes in the gut microbiome with changes in 
anxiety and inflammatory biomarkers in the blood (cytokines and blood monocyte cell response 
to LPS challenge) as a result of cannabis use. Microbial DNA will be extracted from fecal 
samples and then analyzed to determine how many and which bacterial species are present in the 
gut. Gut microbiome data will be collected at two time-points during this study, once before and 
one after study cannabis use (i.e., with assigned cannabis ratios).  
Daily (Online-based message) follow-up Assessments. Ecological momentary assessment of 
marijuana use via messaging has been shown to be feasible in a variety of marijuana users62,63. 
During the 4 week study, marijuana users will answer online survey assessments via email with 
individually tailored links hosted by our university’s licensed survey tool RedCap. During the 4-
Week study period, participants will report daily on the anxiety, their marijuana use, other stress 
management strategies, and their sleep pattern. This brief message report will provide a daily 
repeated measure of our primary constructs (anxiety and marijuana use) and potential mediators 
or moderators over the course of the 4-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 message 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 and 4-Week Appointments, receiving a $1/day with a $5 
bonus for completing 13 of 15 online follow up message reports for each two-week period ($40 
in total possible).  
2-Week Appointment (Session 2) & 4-Week Appointment (Sessions 3 & 4). All procedures in 
the baseline assessment (blood draws for cannabinoids and inflammation markers, anxiety and 
health self-report measures, cognitive testing, as well as past two week measures of health 
behavior and substance use will be completed two weeks after the baseline session (Session 2) 
and finally at four weeks after the baseline session (Sessions 3 & 4). 

 
 
 
 
 
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The 2-Week Appointment (Session 2) will take place at our lab in the CINC and includes all 
session 1 measures; peripheral inflammation, and cannabinoid levels. However, we will not 
conduct the Rumination Induction task, but will add the Patient Global Impression of Change 
scale (Guy, 1976), which asks participants to rate their improvement over the prior two weeks on 
a 7-point scale. Subjects will also be given one at-home micriobiome collecton kit at this visit 
with instuctions on completing and returning the completed kit as near as possible to their 4-
Week Appointment (after using their product). Participants will be given an ActiGraph wearable 
device as well on this Appointment, to use to track their physical activity and sleep during the 
final 2-Week study period (http://actigraphcorp.com/). They will be instructed on how to wear 
and use the device at this 2-Week Appointment. Participants will be instructed to wear the device 
as long as they feel comfortable during the last 2-4 Week period and to return the device at the 4-
Week Mobile Appointment (3rd Appointment). 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. At the end of the 2-Week Appointment, research study 
staff will debrief participants and compensate them with up to $80 ($60 for the 2-Week visit and 
an additional $20 for the first 15 or 30 daily message reports) in cash. 
For the 4-Week Appointment (Sessions 3 & 4), we will travel to the participant in our Mobile 
lab in order to ease subject burden and to get a more accurate measurement of acute cannabis 
effects. We will collect the microbiome kit. We will also complete the Rumination Induction 
Exercise for the 2nd and 3rd time (pre and post-cannabis use), and measure stress induction (via 
the Visual Analog Scale 1-100) both before and after Rumination Induction. We will also 
complete two new surveys (Drugs Effect Questionnaire and Addiction Research Center 
Inventory) to document the current effects and feelings that the subject has before and after 
cannabis use. After completing the acute Post-administration (Immediate or 1-hour) 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 up to $100 ($80 for the 4-Week 
visit and an additional $20 for the last 15 of 30 daily message reports) in cash. See additional 
details for each measure in Table 2.   
Monthly (Online-based survey) Follow-up Assessments. After the 4-Week ad libitum period 
of cannabis use with detailed online and in-person tracking, participants will be asked to provide 
monthly follow-up information. This will help track participant behavior and potential effects 
naturalistically, with a monthly self-report of marijuana use, sleep, anxiety ratings/stress 
management, and cognitive effects over each month, for the five additional months. All subjects 
will be given extensive instructions on completing the monthly 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 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 $6 gift card by email for every questionnaire that they 
complete (1st part of Monthly follow-up survey) a $5 gift card by email for every TLFB that they 
complete (2nd part of Monthly follow-up survey), plus a bonus gift card of $20 or $15 for 5/5 or 
4/5 months (1st and 2nd part) completed ($75 or $70 in total possible, respectively). 
 
Table 2. Description of procedures by appointment. 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
Name of Instrument/Procedure 
Data collected 
 
Eligibility Screening (ES) 
 
Phone Interview or Online Survey questionnaire used to 
determine subject eligibility (based on inclusion/exclusion 
criteria, listed above). 
 
Baseline Appointment (only) 
 
 
Informed Consent (IC) 
In-person discussion and review of consent document detailing 
all measures and any questions. 
 
Medical History (MH) 
General assessment of medical history for any major disease or 
illness (11-items). 
 
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, sexual orientation, marital status, race/ethnicity, 
SES, occupation, income, education, and religious affiliation. 
 
Neuropathic Pain Survey 
3-item self-report rating (0 no pain to 100 unimaginable pain) 
of any neuropathic pain. 
 
Alcohol Use History Questionnaire 
(AUH) 
Targets the frequency of lifetime and recent use for alcohol. 
 
Childhood/Recent Trauma Scale 
(C/RTS) 
A self-report questionnaire identifying potential traumatic 
events experienced, specifying the intensity of the trauma (1 = 
not at all traumatic, 7 = extremely traumatic) and the 
approximate age that it occurred. 
Alcohol Use Disorders Identification 
Test (AUDIT) 
The AUDIT (Babor et al., 2001) will be used to examine the 
extent of co-morbid alcohol use and problems related to 
alcohol use.  
 
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 necessary (Beck, Steer, Ball, & Ranieri, 1996). 
 
Marijuana Withdrawal Checklist 
(MWC) 
A 16-item scale used to collect information on withdrawal 
symptoms that one may have experienced the last time they 
stopped smoking marijuana (Budney et al., 2003). 
 
Cannabis Questionnaire/Marijuana 
Users Health Cohort/ (MUHC) 
Details the primary reasons, frequency, and type of cannabis 
use patterns in occasional and regular users. 
 
Marijuana Consumption 
Questionnaire (MCQ) 
Ask participants to reflect on the frequency and quantity of 
their cannabis use, age of first use, and perceived availability 
of cannabis (Heishman, Singleton, & Liguori, 2001). 
 
Self-Trait Anxiety Inventory (STAI) The Speilberger Description Inventory, (State-Trait Anxiety 
Inventory, STAI; (Spielberger 1983), a commonly used 
measure of trait and state anxiety, for presence and severity of 
distress symptoms and anxiety based on participants feelings at 
the current moment. Participants respond to statements of 
current feelings on a 1 to 4 scale. 
 
ADHD Self-Report Scale (ASRS) 
ADHD Self-Report Scale (ASRS; Kessler et al., 2005), will be 
used to assess ADHD symptoms in participants, given the high 
rates of ADHD among marijuana users. This measure consists 
 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
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- & 4-Week (Pre-
administration) Appointments 
 
 
Perceived Stress Scale (PSS) 
The PSS (Cohen, Kamarck, & Mermelstein, 1983) is a 
14-item scale that measures the degree to which situations 
in someone’s life are perceived as stressful. Stress is a 
known correlate of substance use and anxiety and it will 
be crucial for us to obtain a measure of our participants’ 
perceived stress levels while they are in the study.  
 
Rumination Self-Report Scale 
(RSRS) 
A brief self-report/assessment of typical rumination behavior 
(two sub-sets: brooding and reflection) and change in 
rumination  (Nolen-Hoeksema & Morrow, 1993). 
 
Generalized Anxiety Disorder-7 
Scale (GAD-7) 
Self-report, 7-item measure to assess generalized anxiety 
disorder, a diagnostic tool commonly used to assess symptoms 
in the primary care setting (Spitzer et al 2006, Kroenke et al 
2010). 
 
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. (BAI; Beck, Epstein, Brown, & Steer, 1988). 
 
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 used marijuana, I often used 
more 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=.85; see Stephens, Roffman, 
& Curtin, 2000). 
 
Impact of Marijuana (IMP) 
Short self-report questionnaire on the impact and expected 
impact of marijuana (e.g. negative effects or benefits on sleep, 
mood, health, and anxiety) compared to other types of pain and 
anxiety management strategies (e.g., drugs, opioids, exercise). 
 
Health Related Quality of Life 
(HRQL, SF-12) 
This is a Short Form 12 Health Survey, which consists of 12 
questions across eight health domains and is sensitive in 
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, 2-Week Appointment, and 
the 4-Week Mobile Appointment. Our modified TLFB 
procedure will estimate both frequency of marijuana (and other 
drug) use and amount used per day, using visual stimuli as well 
as the method of administration. (Sobell & Sobell, 1992) 
(Sobell, Sobell, & VanderSpek, 1979). 
 
Blood Alcohol Content (BAC) 
Breathalyzer test for recent alcohol consumption. 
 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
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. 
 
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) 
1-item self-rated assessment of overall diet quality and amount 
of fruit and vegetables consumed daily, on average. 
 
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. 
 
Marijuana Purchase Task (MPT) 
The marijuana purchase task (MPT, Collins et al., 2014) 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. 
 
Stanford Leisure Time Activity 
Categorical item (L-CAT) 
Single-item question on exercise/physical activity, comprised 
of six descriptive categories ranging from inactive to very 
active (Kiernan et al 2013). 
 
2- & 4-Week (Pre & Post-
Administration) Appointments 
 
 
Patient Global Impression of 
Change (PGIC) Scale 
Ask participants to rate their level of improvement on a 1-7 
scale (e.g., from completely gone to much worse) scale over 
the course of the 4-week study period. 
 
4-Week (Pre & Post-
Administration) Appointments 
 
 
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 effects (de Wit & Phillips, 2012). 
 
The Addiction Research Center 
Inventory (ARCI/M-Scale) 
The Addiction Research Center Inventory (ARCI; Martin, 
Sloan, Sapira, & Jasinski, 1971), including the ARCI—
Marijuana (M) scale (Chait, Fischman, & Schuster, 1985) 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- & 4-Week (Pre & Post-
Administration) Appointments 
 
 
Dot Probe Task 
Measure of attention bias to threatening and negative valance 
stimuli (MacLeod et al 2007). 
 
Physiological Measures 
Heart Rate, Blood Pressure, and Weight/Height (baseline only) 
will be measured using a basic fingertip pulse oximeter, 
automatic blood pressure wrist cuff, and scale/stadiometer. 
 
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. 
 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
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). 
 
Neurocognitive Toolbox Battery 
(NCB) 
From the NIH toolbox, this cognitive battery will include the 
Flanker Inhibitory Control and Attention task, and the List 
Sorting Working Memory Test. The battery covers the 
domains found to be sensitive to the effects of marijuana (for 
review see Ranganathan & D’Souza, 2006). 
 
International Shopping List 
Test  (ISLT) 
The International Shopping List Task (ISLT; Thompson et al 
2011) 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. 
 
Marijuana Craving Questionnaire 
(MCQ) 
A Marijuana Craving Questionnaire will be used to assess 
craving at each time point during the Mobile session. The 
MCQ was adapted from a valid tobacco craving questionnaire 
(Tiffany & Drobes, 1991) and has proven to be useful in 
cannabis studies (Budney et al., 2003). In our pilot study, 
internal consistency was very high (α= 0.90). 
 
Alcohol Craving Question (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.  
 
Motor/Movement Battery (MB) 
Physical function assessment of dynamic sway (balance) and 
finger tapping. A standard smartphone (iPod Touch) will be 
attached to participant with a simple elastic/Velcro strap. An 
App on the device will record their fine-grained movements 
while they are asked to stand as still as possible for 30-60 
seconds, with eyes open or closed, while the iPod is attached to 
their hip. They will also be asked to tap the smartphone 
repeatedly for no more than 60 seconds. 
 
Baseline & 4-Week (Pre-
Administration) Appointments 
 
 
Eating at Americas Table (EATS) 
Extensive self-report of typical fruits and vegetables eaten 
daily over the last month (Subar et al 2001). 
 
Baseline & 4-Week (Pre- & Post-
Administration) Appointments 
 
 
Rumination Induction (RI) Task 
Focused breathing and rumination induction exercise to 
experimentally examine the active occurrence of rumination 
thought and how it affects stress and cognitive function,, 
intermixed with a visual analog scale of perceived anxiety and 
stress used to measure changes in  intensity of negative 
emotional responses (0-10; Rood et al 2012, Arch & Craske 
2006). 
 

 
 
 
 
 
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HRP-503: Protocol       
 
 
 
Perceived Discrimination Scale 
(PDS) 
A 20-item scale to measure how often people feel that others 
treat them badly or unfairly based race, ethnicity, gender, age, 
religion, physical appearance, sexual orientation, or other 
characteristics separated into two subscales: The Lifetime 
Discrimination Scale and Daily Discrimination Scale.  
 
Positive and Negative Affect 
Schedule (PANAS) 
Self-rated measurement of positive and negative affect with 
two 10-item scales from 1 (not at all) to 5 (very much; Watson 
1988). 
 
Profile of Mood 
States (POMS) 
The Profile of Mood States (POMS) will be used to collect 
baseline information on mood as well as information on mood 
changes throughout the study. (Johanson & Uhlenhuth, 1980; 
McNair, Lorr, & Droppleman, 1971). 
 
4-Week (Post-Administration) 
Appointment 
 
 
Assessment of Marijuana Potency 
At the end of the experimental session, participants will be 
asked to report which product they received including the ratio 
and potency of THC and CBD in that strain. 
 
Appointments/Time points 
Instruments/Procedures 
Time to 
complete 
Baseline Appointment 
(CINC Lab)  
 
 
Session 1 
Informed consent & study orientation; BAC test; Urine 
toxicology & Pregnancy test; Physiological measures; Anxiety 
& Stress ratings;  1st Blood draw; Questionnaires; Cognitive & 
Motor Battery; Microbiome distributed; Appointment 2 
scheduling; Monetary Compensation. 
120 minutes 
Daily Follow-Up Messages 
 
(Days 1-15) 
Respond to brief questions (online) about marijuana use, sleep 
quality, and anxiety/stress management 1x/per day for 2 
weeks.  
~2 mins/day  
x 15 days 
(~30 mins total) 
2-Week Appointment 
(CINC Lab) 
 
Session 2 
BAC test; Physiological measures; Anxiety/Stress ratings; 2nd 
Blood draw; Questionnaires; Cognitive  & Motor Battery; 
Microbiome & Wearable distributed; Appointment 3 
scheduling; Monetary Compensation. 
60 minutes 
Daily Follow-Up Messages 
 
(Days 16-30) 
Respond to brief questions (online) about cannabis use, sleep 
quality, and anxiety/stress management 1x/per day for 2 weeks 
after self-dosed cannabis use. 
~2 mins/day  
x 15 days 
(~30 mins total) 
4-Week Appointments 
(Mobile Lab) 
 
                            -Pre-administration 
Session 3  
Immediately before cannabis use (type and dose self-selected); 
Participant comes out to Mobile laboratory; Return completed 
microbiome kit, Physiological measures; Anxiety & Stress 
ratings; 3rd Blood draw; Questionnaires; Cognitive & Motor 
Battery; Return home to self-administer edible. 
 
 
60 mins 
  
 
 
 
-Post-administration 
Session 4 
Immediately (flower) or 1-hour (edible) after self-dosing 
cannabis (time rage based on type of product chosen and 
similar drug onset time); Return to Mobile laboratory; 
Physiological measures; Anxiety & Stress ratings; 4th Blood 
draw; Questionnaires; Cognitive & Motor Battery; Return 
wearable; Debriefing; Monetary Compensation; Return home.  
60 mins 
Monthly Follow-up Surveys 
 
 
(Months 2-6) 
Respond to brief questions (online) about major behavioral 
changes (e.g., marijuana use, sleep quality, and anxiety/stress 
management) 1x/month for 5 months, Monetary compensation 
(each month). 
~12 mins/month 
x 5 months 
(~60 mins total) 

 
 
 
 
 
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TOTAL TIME (6 months) 
 
~8 hours 
XIII. SPECIMEN MANAGEMENT 
Blood and microbiome samples collected in the mobile lab will be kept in an insulated 
biohazard transport bag.  All blood and microbiome 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 specimen 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 and biological samples will be destroyed after all analyses are complete.  
After this, there will be no way to connect participant’s names with participant data, at which 
point they will be considered de-identified.  
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 session); 
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 her role within the 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 displaying behavior that is verbally or physically abusive 
towards research staff. Those who experience early withdrawal will receive prorated payment 
based on the number of sessions 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 normally, since a participant in the cannabis groups must 
be regular cannabis users to be in the study. We will comply with all NIH guidelines, and a 

 
 
 
 
 
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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 160 ml over ~ five hours in three 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 
using cannabis may be associated with a psychotic episode. However, participants will be 
monitored during the 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. 
Increases in anxiety or discomfort will be monitored and should clinically severe or impairing 
anxiety be present, the participants will be removed from the study and referred to appropriate 
mental health treatment.  This practice has been used frequently by the PI in other IRB approved 
studies and the risks for clinically meaningful increases in anxiety are not expected to be greater 
than what would be experienced in daily living. Information regarding anxiety 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 about 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 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 

 
 
 
 
 
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Risks Pertaining to the Legality of Cannabis. As mentioned previously, the risk is minimal 
given the legality of cannabis in Colorado and does not represent a significant increase in risk for 
non-cannabis or cannabis participants (individuals who are already planning to be or are regular 
cannabis users). 
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 
(with two trained research assistants) in a seated and protected position to reduce any risk of 
dizziness or falling. 
Psychological Risks and Discomforts. In the unlikely event that a cannabis user has an adverse 
reaction to any cannabis or any participant has a negative experience 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. Dr. Bidwell 
(clinical psychologist), Dr. Bryan (social psychologist), and/or Dr. Hutchison (clinical psychologist) 
will be on call/reachable during all scheduled session. Although we do not anticipate adverse 
reactions or any greater risk then daily life, 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 any 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 the PI or Co-Is Bryan or Hutchison (one of them will be on 
call) to resolved the situation.  First, it will be determined if the situation can be resolved over the 
phone.  If not, the PI or Co-I will drive out to the mobile laboratory for further assessment of the 
participants 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. 
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 cannabis user 
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 

 
 
 
 
 
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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 sessions, 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). He/she will give bi-weekly reports to the PI. 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 CUB IRB policy procedures document: 
(http://www.colorado.edu/VCResearch/integrity/humanresearch/SOP_TOC.html). Consistent 
with IRB policy, the reporting will occur: Immediately (within 24 hours) upon learning of a 
study-related death, study personnel will notify the IRB via e-mail by providing a brief summary 
of the event. Then, within ten business days, the PI or designee will submit a Reportable Event in 
eRA. 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. The PI will be in daily contact with the research 
assistants running the study and will be informed immediately of any adverse 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 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 all of the measures and providing each physiological measure. 
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.  

 
 
 
 
 
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XXII. COST TO PARTICIPANTS 
Participants will be responsible for paying for the cannabis that they choose to buy. We 
estimate the cost of 1 grams of flower cannabis to be approximately $12 and 75mg of edible 
cannabis to be approximately $15 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. All drug use will be self-directed. 
XXIV. INVESTIGATIONAL DEVICES 
Not applicable.  
XXV. MULTI-SITE STUDIES 
Not applicable.  
 
XXVI. SHARING OF RESULTS WITH PARTICIPANTS 
 There are no plans to share results of the study with participants.  
 

 
 
 
 
 
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