Impact of Acute Cannabis Administration on Pain Symptomology and Inflammatory Markers Among Patients With Rheumatoid or Psoriatic Arthritis
Phase: PHASE2
Conditions: Rheumatoid Arthritis, Psoriatic Arthritis
Sponsor: Brown University

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Cover page 
Official Title of Study: Impact of Cannabis on Pain and Inflammation Among Patients with Rheumatoid or 
Psoriatic Arthritis 
ClinicalTrials.gov Identifier: NCT04269993 
Document Type: Protocol and Statistical Analysis Plan dated 4/7/2022 
Subtitle: N/A 
(The informed consent form document(s) uploaded in Portable Document Format Archival (PDF/A) format. It 
is strongly encouraged that the PDF/A file also be consistent with the PDF Universal Accessibility (PDF/UA) 
format, to optimize accessibility). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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RESEARCH PROTOCOL 
 
Principal Investigator: 
 
Elizabeth R. Aston, Ph.D. 
 
 
 
 
 
 
Brown University School of Public Health 
 
 
 
 
 
 
Center for Alcohol and Addiction Studies 
 
 
 
 
 
 
121 South Main Street, 5th Floor, Providence, RI 02912 
 
 
 
 
 
 
 
Primary Mentor/Co-Investigator: Jane Metrik, Ph.D., Brown University  
 
Project Title:  
 
 
Impact of Acute Cannabis Administration on Pain Symptomology  
 
 
 
 
 
and Inflammatory Markers among Patients with Rheumatoid or  
 
 
 
 
 
Psoriatic Arthritis 
 
NIGMS Grant #: 
 
 
P20GM130414 
Authority: 
 
 
 
This study has been approved by the Brown University Institutional  
Review Board  
 
 
 
 
 
 
 
____________ 
 
 
 
 
 
 
A. RATIONALE AND OVERVIEW 
Approximately 25 million adults in the United States report experiencing daily chronic pain 1. The majority of 
these patients use pharmacotherapies, including opioids, to alleviate negative physiological and psychological 
symptoms associated with pain. However, while analgesic pharmacotherapy has efficacy in pain treatment, 
some classes of medications (e.g., opioids) have significant abuse liability. Moreover, patients frequently report 
ongoing experience of chronic pain symptoms despite these treatments. For some conditions, patients have 
sought alternative therapies, including cannabis, to alleviate negative symptoms. Between 45% and 80% of 
those who use cannabis for medicinal purposes do so for pain management 2,3. Self-report surveys on use of 
cannabis for medical purposes suggest that it improves pain, sleep, and negative mood, with modest side effects 
4,5. Indeed, randomized controlled trials (RCTs) indicate that cannabis may be an effective pharmacotherapy for 
certain chronic pain diagnoses, including multiple sclerosis 6,7, neuropathic pain 8, and cancer-related pain 9. 
However, there is a dearth of well-controlled research on use of cannabis to treat symptoms associated with 
inflammatory conditions such as rheumatoid arthritis (RA) or Psoriatic Arthritis (PA). RA is a chronic 
inflammatory disease that affects approximately 1.3 million Americans, which is increasing as the US 
population ages 10. RA is characterized by joint destruction, stiffness, swelling and pain, leading to loss of 
function 11. In addition, key cytokines, or pro-inflammatory secreted proteins, are involved in joint injury 
associated with RA 12; specifically, TNF-α and IL-1. Pre-clinical studies indicate that cannabinoids demonstrate 
promising anti-arthritic properties in both human cells from RA patients and animal models of RA 13. 
Preclinical research has shown that cannabinoids are strong anti-inflammatory ligands and function via 
induction of apoptosis, inhibition of cell proliferation, and suppression of cytokine production 14. Only one 
clinical study has investigated the effect of a cannabis plant derivative comprised of an equal ratio of two 
cannabinoids (i.e., Δ⁹-tetrahydrocannabinol [THC] and cannabidiol [CBD]), in oromucosal form, on pain 
related to RA, and reported promising results 15. Therefore, more research in this area is critical. Whole plant 
cannabis may be more effective than synthetic and partial formulations to treat chronic pain conditions, 
purportedly due to its composition of hundreds of distinct cannabinoids that work in synergy to alleviate 
symptoms 16. In addition to THC, which has been shown to reduce several types of chronic pain, CBD may be 
particularly effective in reducing negative symptomology in RA patients due to its anti-inflammatory properties 
13,17.  
 
B.1. SPECIFIC AIMS 
This proposal will investigate the impact of whole plant cannabis on pain, affect, and inflammation among RA 
patients (n = 66). We will administer two cannabis formulations via vaporization (placebo and medium THC 
[3.6%]/medium CBD [5.4%]) across two experimental sessions using a counter-balanced, double-blind, 
crossover design. THC doses in the medium potency range will be tested in combination with CBD in the 

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medium potency range. With respect to inflammation outcomes, prior studies have demonstrated efficacy of 
cannabis with a 1:1 ratio of THC:CBD. Therefore, we hypothesize that cannabis in the medium THC potency 
range in combination with medium potency CBD will decrease inflammatory biomarkers relative to placebo.  
 
Aim 1. To determine whether cannabis acutely reduces pain and negative affect as compared to placebo.  
a. We hypothesize that, relative to placebo, cannabis (medium THC/medium CBD will decrease subjective 
reports of pain. 
b. We hypothesize that, relative to placebo, cannabis (medium THC/medium CBD) will decrease 
subjective reports of negative affect. 
c. We hypothesize that blood THC and CBD levels will be negatively correlated with subjective reports of 
pain and negative affect. 
Aim 2. To determine whether cannabis acutely reduces markers of inflammation (IL-1α, IL-1β, IL-6 and TNF-
α) as compared to placebo.  
a. We hypothesize that, relative to placebo, cannabis (medium THC/medium CBD) will decrease blood 
markers of inflammation. 
b. We hypothesize that inflammation marker levels will be positively correlated with subjective reports of 
pain and negative affect, and negatively correlated with blood THC and CBD levels.  
 
B.2. SAMPLE DESCRIPTION AND RECRUITMENT 
Human subject involvement is necessary to complete this research proposal (n = 66). This proposal will require 
patients with rheumatoid arthritis (RA) or psoriatic arthritis (PA) to participate in laboratory cannabis 
administration sessions. Patients will be initially screened by phone or at the clinic, followed by a rigorous 
medical and diagnostic screening at intake. We describe recruitment procedures, inclusion criteria for 
participation, rationale for the proposed population, and retention strategies below. 
 
Participants will be recruited from rheumatology clinics in Rhode Island (Brown University Physician 
outpatient clinic and the Chapman Street Outpatient Clinic of Rhode Island Hospital) and Massachusetts via 
initial contact by providers involved in the patient's care, flyers, advertisements, mailings, and referral. Potential 
subjects will be screened via phone, online screener, or at the clinic. Eligible subjects will be scheduled to meet 
briefly via videocall to provide consent, and then will be scheduled for an initial baseline laboratory visit.  
Participants may be asked to fill out a HIPAA Authorization Form to facilitate confirmation of RA/PA 
diagnosis. We will include subjects with a range of baseline pain levels to capitalize on variability, and baseline 
VAS pain score will be used as a covariate in all analyses. Participants will be enrolled in the study using the 
following inclusion criteria: 
 
Inclusion Criteria:  
a) current RA or PA diagnosis with active arthritis not adequately controlled by standard medication (i.e., 
self-report pain levels at or above 30/100 on a visual analog scale (VAS) pre-study enrollment) 
b) if taking prescribed steroid, non-steroidal anti-inflammatory (NSAID), and/or disease-modifying anti-
rheumatic drugs (DMARDS; e.g., tumor necrosis factor inhibitors), must be stable use for at least 1 
month prior to enrollment (all must be maintained throughout the study)  
c) English-speaking or Spanish-speaking 
d) negative urine toxicology screen for cannabis and other drugs (opiates with prescription allowed; may 
not be used the morning of the study) 
e) negative pregnancy test  
f) not nursing  
g) use of highly effective birth control during the study for both males and females  
h) prior history of vaping or smoking cannabis with similar to that being used in the current investigation 
(i.e. cannabis use via smoking or vaping at least once in lifetime) 
 
Exclusion Criteria: 

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i) greater than zero breath alcohol concentration 
j) presence of a DSM-5 diagnosis of psychosis or panic disorder as assessed by the Mini International 
Neuropsychiatric Interview (MINI) and not suicidal [past month ideation or intent] 
k) self-report of serious adverse reaction to cannabis in the past year 
l) smoking more than 20 tobacco cigarettes per day  
m) body mass index below 18.0 or above 33.0 kg/m2 range confirmed during medical exam (as extreme 
BMIs can influence drug blood levels and BMIs in the obese range are considered cardiovascular risk 
factors) 
n) all current asthma conditions (i.e., active symptomatic asthma within the last week) or current or past 
history of asthma triggered by smoking or vaping 
o) current diagnosis of dementia or Parkinson’s disease 
p) scores below 23 on the Folstein Mini-Mental Status Exam 
q) current diagnosis of moderate to severe traumatic brain injury 
r) current diagnosis of epilepsy 
s) individuals who are immunocompromised (i.e., post-organ transplant, those with an immune deficiency 
disorder such as HIV, individuals taking immunosuppressant steroids such as continuous prednisone 
use, and those with lupus) 
t) past kidney disease (e.g., glomerular nephritis, polycystic kidney disease) and/or presence of elevated 
creatinine (levels above 2.0)  
u) cardiac disease confirmed via clinically significant abnormal findings on an EKG (e.g., arrhythmia, 
conduction abnormalities, ischemia, or evidence of past myocardial infarction), as well as diagnoses of 
congestive heart failure or cardiomyopathy  
v) abnormal vital signs (heart rate will be required to be below 50 or above 110 BPM; blood pressure 
above 160/100 or below 90/60; blood oxygen levels below 90%) 
w) taking any medications on our List of Exclusionary Medications 
x) presence of any severe cardiovascular, renal, or hepatic disorder 
y) below 18 or above 65 years of age  
z) use of cannabis in the past 1 month before commencement of study participation and throughout the 
study as confirmed via urine toxicology screening  
aa) below minimum self-reported pain level of 30/100 on a visual analog scale (VAS) pre-study enrollment 
via telephone and at baseline due to potential variability in pain level 
 
B.3. RECRUITMENT METHODS 
We plan to recruit RA patients primarily from the Brown University Physician outpatient clinic and the 
Chapman Street Outpatient Clinic of Rhode Island Hospital. Approximately 9,000 patients with various 
rheumatic conditions and approximately >3,000 with rheumatoid arthritis visit these clinics annually. With the 
facilitation of our collaborators (please see letter of support), participants will be recruited via initial contact by 
providers involved in the patient's care, flyers, advertisements, mailings, and referral. Potential subjects will be 
screened via phone. 
 
Primarily, we will receive referrals from our collaborators at the Brown University Physician outpatient clinic. 
In addition, we will use internet advertisements on social media sites and flyers at local treatment clinics. The 
study PI and research assistant (both having completed all required CITI certifications) will be contacted by our 
collaborators in the instance of referrals, and by other interested patients with rheumatic disease (rheumatoid 
and psoriatic arthritis). Potential participants will be screened in person at the clinic, or via telephone or online 
screener. Potential participants will primarily be referred by our collaborators. Patients that meet eligibility 
criteria, are not well-controlled on current medications, and are deemed to potentially benefit from 
incorporating cannabis into their treatment regimen will be enrolled in the study.  
While use of cannabis to treat chronic pain associated with various conditions (e.g., inflammatory rheumatic 
diseases) is approved in Rhode Island and many other states, there is limited research in this area and it is not 

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the standard of care for such diseases. Of note, the cannabis that will be administered in the current 
investigation will be an adjunct to current approved treatment regimen.  
 
At baseline session conclusion, eligible participants will be scheduled for two 5-hour experimental CB 
administration sessions and randomized to either placebo or medium THC/medium CBD dose for Experimental 
Session 1 and will receive the other dose at the following session (Experimental Session 2). The study PI will 
randomize participants to the dose conditions but will not run experimental sessions. In order to maintain 
double-blind conditions, CB will be prepared by a pre-designated staff member with DEA clearance. 
Participants and other study staff working directly with participants will be blind to dose. To control for 
expectancy effects18,19, participants will be told they will vaporize CB varying in THC in the low to moderate 
potency range. CB appearance is identical across dose. 
 
Compensation/Reimbursement: Participants will be compensated $50 for the baseline session, $100 for each 
of two cannabis administration sessions, and will receive an additional $50 bonus for completion of all 
experimental sessions for a maximum total of $300. Ineligible subjects will be paid $10 and excluded from 
participation. Due to experimental sessions involving cannabis administration, participants will be transported 
home following each experimental session via taxi, Uber, or other rideshare service.  
 
B.4. METHODOLOGY 
Synopsis. This study will be the first to investigate the effect of vaporized CB on pain, affect, and markers of 
inflammation among patients with RA. This research will be conducted over two Aims. Aim 1: To determine 
whether CB acutely reduces RA-associated pain and negative affect as compared to placebo. Aim 2: To 
determine whether CB acutely reduces markers of inflammation (IL-1α, IL-1β, IL-6 and TNF-α) as compared to 
placebo. Using a randomized, placebo-controlled, crossover design, participants (n = 66) will vaporize CB 
(placebo and medium THC/medium CBD) over two experimental sessions. Blood will be collected during each 
session (pre-vaporization, 10 min post-vaporization, 60 min post vaporization). Self-reported pain and affect 
will be assessed at the same time points.     
 
Baseline Session: Following online/phone screening, potential subjects will meet remotely with research staff 
for a videocall to complete the study consent forms and discuss any questions. Participants will then attend an 
in-person baseline screening session at the laboratory to confirm eligibility and complete a physical exam. They 
will be asked to refrain from alcohol for 24 hours and caffeine for 2 hours prior to experimental sessions. 
Subjects will complete an alcohol breathanalysis for breath alcohol concentration (BrAC), and urine drug screen 
and pregnancy test (females). Subjects with a positive BrAC will be rescheduled. Tobacco smokers will be 
permitted to smoke a cigarette following the CO test to prevent nicotine withdrawal. Subjects will be 
administered a medical screening questionnaire to rule out history of adverse reaction to CB, and the MINI to 
make diagnostic exclusions of suicidality and key DSM-5 diagnoses (psychosis, panic disorder).  
 
Eligible subjects will complete baseline measures and a physical exam conducted by physician or nurse 
practitioner to determine medical clearance prior to the CB administration sessions. The physical exam will 
include assessment of heart rate, blood pressure, and blood oxygen levels. Vital signs will be assessed again at 
the beginning of each experimental session. During the physical exam, a medical history will be obtained, blood 
will be drawn, and an EKG will be performed. To assess severe renal disease, the nurse practitioner will ask 
about any past kidney disease (e.g., glomerular nephritis, polycystic kidney disease), and blood will be tested 
for presence of elevated creatinine. The physical exam will also include physical function testing pertaining to 
RA/PA: self-selected gait speed, 5-chair rise test, single leg stance test20,21.  
 
To confirm that participants are not currently experiencing cognitive impairment at the commencement of study 
participation, they will complete the Folstein Mini-Mental Status Exam (MMSE; Folstein et al., 1975) which 
includes 30 items to assess cognitive impairment on a scale from 30 (no impairment) to 0.  
 
Psychoactive and pain-relieving effects of CB are acute, thus experimental sessions will be separated by at least 

6 
 
two days. No subjective or behavioral effects will last past CB administration in the laboratory. Urine screens 
may test positive for CB at session 2 (if active dose was administered at session 1), however, we confirm no 
recent smoking via CO test, thus urine screens that are positive for THC are irrelevant.  
 
Experimental CB Administration Sessions (1-2): Information including medications and pain level will be 
reconfirmed the morning of experimental sessions to maintain study eligibility. At each experimental session, 
BrAC and carbon monoxide (CO) level will be tested to confirm no recent alcohol or CB use. CO level must be 
8ppm or below in order to proceed with the session; levels that are higher than 8ppm may be given some time 
to decrease to 8ppm (i.e. we will re-test) at the PI's discretion. Cigarette smokers will be given an opportunity 
for a smoking break after the test if they would like. Subjects will complete urine toxicology screening to 
confirm no other drug use. Females will be tested for pregnancy at each session. Vital signs will be obtained. 
Subjects will consume a calorie-controlled breakfast and complete pre-administration measures and 
questionnaires, an automatically inflating blood pressure (BP) cuff will be secured to continuously record heart 
rate and BP during the entire experimental session, and blood collection procedures will be implemented (see 
Figure 1). Participants will complete physical function testing20,21. Participants will then vaporize the assigned 
CB dose and complete post-administration subjective measures of pain, affect, and drug effects. CB 
vaporization procedures will begin at 11am in order to reduce variability in pain that may occur throughout the 
day. Subjects will vaporize CB using a Storz & Bickel MIGHTY Vaporizer apparatus. Approximately 250mg 
CB will be ground to maximize surface area and will be placed in the vaporizer. The vaporizer will be prepared 
exclusively by study staff or the PI. Using the step-by-step quick-start guide and manual, study staff will 
prepare the vaporizer and will give it to the participant. The vaporizer device will be used on a dry surface away 
from paper and other flammable substances. A cued-puff procedure22 will standardize CB administration. 
Participants will listen to an audio-recording that will signal them to “get ready” (5 seconds), “inhale” (5 
seconds), “hold vapor in lungs” (10 seconds), “exhale,” and to wait before repeating the inhalation cycle (40 
seconds). A research assistant and the study nurse will continuously monitor the subject during the vaporization 
session via two-way mirror. In our previous studies which employed the paced-puffing procedure for 
combustible CB cigarettes with similar THC levels, all participants were able to complete an entire cigarette in 
9 puffs in 8 mins on average18,19. All participants will be required to complete 9 inhalations according to 
standardized procedures. Following cannabis administration (peak effects at 20-min post vaporization), 
participants will complete assessments including pain and affect. Peak THC/CBD levels will be assessed. Pain 
and affect will continue to be assessed three times over the recovery period at 1-hour intervals. 
 
 
 
Blood Sampling Procedures: We will collect blood at 3 time-points during each experimental session for 
analysis of inflammatory biomarkers (i.e., IL-1α, IL-1β, IL-6, IL-10, IL-17A, TNF-α, INFɣ, MCP1, BDNF;  
sCD14); whole blood for future genetic analysis, if the participant consents to that portion; cannabinoid plasma 
levels (i.e., THC and CBD) pre-CB administration, at the termination of the CB administration procedure (10 
mins post-completion of CB administration), and 60 mins post-completion of CB administration. These time-
points were selected to characterize the impact of acute CB administration on pain and affect immediately 
following administration and at a delayed time-point (60-minutes post completion) to assess the duration of 
analgesia. Individual blood draws will be conducted in an antecubital vein at each pre-designated time point 
(see Figure 1). Blood samples will be collected in heparinized tubes (0.15 μl heparin) and placed on ice 
immediately after each blood draw. Within 15 minutes of collection, blood will be centrifuged and plasma will 
110 min 
105 min 
Controlled 
paced puff 
vaporization 
procedure 

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be transferred to a microtube and stored at -30ºC. Plasma will be analyzed for inflammatory biomarkers and 
cannabinoid levels using gas chromatography/mass spectrometry (GC-MS) techniques.  
 
Blood samples taken at the baseline/physical exam will be analyzed: i.e. IL-1α, IL-1β, IL-6, IL-10, IL-17A, 
TNF-α, INFɣ, MCP1, BDNF; sCD14; CRP; cannabinoid plasma levels (i.e., THC and CBD); creatinine, AST, 
ALT; whole blood for future genetic analysis (if the participant consents to that portion, as it is optional) 
 
Blood samples taken at the experimental sessions will be analyzed: i.e. THC, CBD, IL-1α, IL-1β, IL-6 and 
TNF-α, sCD14, CRP 
 
Sobriety Assessment: Subjects will remain in the laboratory for 3-hours following CB vaporization 
(psychotropic effects taper off within 2-3 hours24), during which time snacks and water will be provided. Vital 
signs will be monitored and resumption of normal vital signs will be required for discharge. Subjects will then 
be evaluated for motor signs of intoxication. To ensure there are no residual cannabis effects 3 hours post-
vaporization, participants will complete and pass a field sobriety test (i.e., heel-to-toe walking test, single leg 
raise balance test)25. Following successful completion of the field sobriety test, subjects will be transported 
home via train, taxi, rideshare, or with a responsible adult to avoid driving following CB use. In the event of a 
failed test, participants will remain in the laboratory 20 more minutes until repeat testing is completed and 
passed.  
 
Discharge Criteria: Participants will be permitted to leave the laboratory three hours following vaporization 
and only following a 75% reduction in their peak heart rate level during the experimental session. Blood 
pressure will be required to return to baseline ranges (below 160/100 and above 90/60).  To ensure there are no 
residual cannabis effects 3 hours post vaporization, participants will complete and pass a field sobriety test (i.e., 
heel-to-toe walking test, single leg raise balance test). In the event of a failed test, participants will remain in the 
laboratory 20 more minutes until repeat testing is completed and passed. 
 
Drug: Bulk CB (placebo, 3.6% THC/5.4% CBD) will be provided by the NIDA Drug Supply Program. Placebo 
CB is identical in appearance to active CB however THC and CBD have been extracted. Non-psychoactive 
plant material remains. Bulk CB will be stored in a freezer until the day before use. At least 12 hours before 
each session, CB will be thawed by staff and humidified in a closed humidifier with a saturated sodium chloride 
solution at room temperature (for security and storage aspects, see Security and Regulatory Aspects for 
Cannabis). These doses were selected based on previous chronic pain work suggesting that the pain-relieving 
effects of CB are experienced at lower THC doses. Previous work found that identical levels of analgesia were 
produced by both 7% and 3.5% THC concentrations26. Thus, THC in the 1-5% range was selected to avoid 
undesirable effects of CB administration (e.g., acute anxiety) that may occur in some subjects, particularly in 
individuals without recent exposure to CB. Previous research using similar samples suggests that such adverse 
effects are acceptable to patients with chronic pain4,27. 
 
Security and Regulatory Aspects for Cannabis: Cannabis is subject to regulatory control under Schedule I of 
the Controlled Substances Act and the Psychotropic Convention. Cannabis will be provided by the National 
Institute on Drug Abuse (NIDA) and will be stored frozen in an airtight container in a locked refrigerator safe 
located in a cement block room without windows and one door that is locked with code-protected card-key 
access at 121 South Main Street on the 3rd floor. Only DEA designated individuals will have access to this 
room (located in the same building and floor as the location of cannabis administration). Thus, cannabis will 
remain secure at all times. Cannabis will be prepared by a pre-designated staff member with DEA clearance. 
The staff member will retrieve cannabis prior to a scheduled experimental session, humidify it at room 
temperature for 24 hours before use (per NIDA’s instructions) in the same cement block room, and transfer it 
directly to the laboratory following the start of the session. Cannabis will be logged and monitored by the DEA; 
remainders will be incinerated as per compliance with the DEA regulations. Dr. Robert Swift, MD, PhD, 
Professor at CAAS, holds a Drug Enforcement Administration (DEA) license for Schedule I drugs with a 
specific approval for cannabis.  

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Statistical Analysis Plan: The sample size required for the proposed study is based on the primary outcome: 
pain assessment score. Using the results on SF-MPQ pain at present from Blake and colleagues to inform our 
parameters, we assume that participants will have a reduction in pain of 0.72 points following active cannabis 
compared to placebo cannabis with a standard deviation of the mean difference of 2.0715. We calculate the 
necessary sample size using a 2-period, 2-treatment, crossover design, comparing cannabis to placebo.  At a 
two-sided significance level of 0.05, a design encompassing 66 patients will have power equal to 0.79 to detect 
this difference with this standard deviation.  
 
The primary aim of this investigation is to assess current self-reported pain level (SF-MPQ) following cannabis 
administration (THC versus placebo). A one-sided t-test will be conducted to compare pain level following 
vaporization of each dose.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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