Clinical trial NCT04982029
Conditions: Opioid-use Disorder
Sponsor: Brigham and Women's Hospital
Start date: 2022-04-14; Completion date: 2022-12-02
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine the impact of cannabidiol on reward- and stress-related neurocognitive processes among individuals with opioid use disorder on buprenorphine or methadone treatment.

Detailed description:
Individuals with opioid use disorder (OUD) demonstrate reward- and stress-related neurocognitive changes compared to individuals without OUD, including cravings for opioids in response to exposure to triggers, tendency to make impulsive and disadvantageous decisions, and a strong attentional bias towards drug-related cues. Together, these deficits are significant contributors to relapse and discontinuation of treatment. Cannabidiol (CBD) has been shown to impact some of these cognitive deficits but studies of CBD among individuals with OUD are mostly lacking. Therefore, this study aims to answer whether CBD has any impact on reward-related neurocognitive deficits in individuals with OUD. If successful, this line of research will lay the groundwork for future studies to evaluate CBD's impact on OUD treatment outcomes.

Arms: arm 1: All subjects will receive 600mg of oral cannabidiol in a double-blind fashion. Cannabidiol will be provided using Epidiolex™ oral solution 100mg/mL. Following administration, a battery of tests will be conducted to examine reward- and stress-related neurocognitive processes. arm 2: All subjects will receive a matching placebo in a double-blind fashion. Following administration, a battery of tests will be conducted to examine the impact on reward- and stress-related neurocognitive processes.
Interventions: intervention 1: Cannabidiol 100 MG/ML [Epidiolex] intervention 2: Placebo
Intervention descriptions: intervention 1: 600mg intervention 2: Matching placebo

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
 
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Cannabidiol on Reward- and Stress-related Neurocognitive Processes in Individuals With Opioid 
Use Disorder 
 
 
 
 
NCT04982029 
 
 
 
 
 
Document Date: 4/14/22 
 
 


 
 
 
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Subject Identification 
 
 
Institutional Review Board 
Intervention/Interaction Detailed Protocol 
 
 
Principal Investigator: 
Joji Suzuki 
 
Project Title: 
Cannabidiol on reward-and stress-related neurocognitive processes in 
individuals with opioid use disorder: A double-blind, placebo-controlled, cross-over trial 
 
Version Date: 
4/14/2022 
 
 
For Intervention/Interaction studies, submit a Detailed Protocol that includes the following sections.  If 
information in a particular section is not applicable, omit and include the other relevant information.   
 
 
1. 
 Background and Significance 
 
Opioid use disorder (OUD) remains a major public health crisis: Drug overdoses continue to contribute 
over 70,000 death annually, with opioids, in particular synthetic opioids, playing the largest role in this 
ongoing epidemic1. Individuals with opioid use disorder (OUD) therefore continue to die each year despite 
the availability of effective therapies.  
Medication treatment for OUD (MOUD) reduces overdose mortality: MOUDs (i.e. buprenorphine and 
methadone) are gold-standard treatments for OUD because they will reduce overdose mortality by as much 
as 70%2. Unfortunately, close to 50% will relapse and discontinue treatment within 6 months3.  
Neurocognitive deficits play a critical role in relapse to illicit opioids: Individuals with OUD have a 
strong attentional bias towards drug-related cues over neutral cues. This process is automatic, fast, and 
operates largely outside of conscious awareness. With greater attention paid to these cues, subjective 
cravings then emerge4. The resulting cravings in turn enhances the attentional bias even further, creating a 
self-sustaining cycle that can lead to relapse. Furthermore, individuals with OUD demonstrate poor decision 
making, preferring smaller immediate rewards over larger delayed rewards5. Finally, individuals with OUD 
demonstrate heightened reactivity to stressors6.  Together, these neurocognitive deficits contribute to the 
risk of relapse. A problematic feature of these deficits is their persistence long after abstinence is achieved, 
highlighting the difficulty in sustaining recovery in the long-term. As such, these deficits are important 
targets to improve treatment outcomes of individuals being treated with MOUD.  
There are no evidence-based psychosocial or pharmacologic adjuncts to existing medications to 
improve outcomes: Psychosocial interventions such as cognitive-behavioral therapy and drug counseling 
teach individuals to manage cravings, and have robust empirical support with other substance use disorders. 
However, in numerous clinical trials, these psychosocial treatments have been largely ineffective for those 


 
 
 
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with OUD8. There currently are no evidence-based pharmacologic adjuncts to medication treatment to 
improve outcomes. As such, there is a critical need to identify novel adjunct interventions for individuals 
with OUD currently engaged in medication treatment. 
CBD has emerged as a possible intervention: We will address this need by conducting a study of CBD 
which has promise as an adjunctive treatment to MOUD. In humans, CBD administration has been shown 
to reduce attentional bias for tobacco-related cues in individuals with tobacco use disorder, as well as for 
cannabis-related cues among individuals who are regular cannabis smokers. CBD also significantly reduced 
cue-induced cravings compared to placebo in those with OUD but not taking MOUD9,10. In both animal 
and human studies, CBD appears to target brain regions that mediate neural responses to drug-related cues, 
indicating the relevance of CBD in modulating the attentional and motivational saliency of drug-related 
cues, which contribute to the risk for relapse11. In addition, CBD appears to attenuate the reactivity to 
stressors among individuals with social anxiety disorder. Stress-reactivity is another important driver of 
relapse risk among OUD patients. However, no human studies have been conducted in individuals with 
OUD to examine the impact of CBD on neurocognitive deficits including stress reactivity. Therefore, the 
critical question this study aims to answer is whether CBD can reduce cue- and stress-reactivity, reduce 
attentional bias to drug-related cues, and improve decision making in individuals with OUD.  
 
 
2. 
Specific Aims and Objectives  
 
To evaluate the impact of CBD on cue- and stress-reactivity, decision making, and attentional bias in 
individuals with OUD currently in treatment with medications for OUD (MOUD).  
• 
Approach: In a double-blind, placebo-controlled, cross-over trial, reward-related neurocognitive 
processes will be assessed after administration of CBD 600mg or placebo 
• 
Primary Outcome: The primary outcomes is cue-induced cravings (Opioid Craving Scale). 
• 
Secondary Outcomes: The secondary outcomes are impulsive decision making (Iowa Gambling Task, 
Monetary Choice Questionnaire), attentional bias (Visual Probe Task), and physiologic and subjective 
stress-reactivity. 
• 
Hypothesis: Individuals with OUD in MOUD treatment taking CBD will demonstrate less cue-induced 
cravings, stress-reactivity, poor decision making, delayed discounting, attentional bias and stress 
reactivity than those receiving placebo 
 
 
 
3. 
General Description of Study Design 
 
 
Overall study design: Double-blind, placebo-controlled, cross-over trial 
 


 
 
 
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Study schema: Shown below. 
 


 
 
 
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4. 
Subject Selection 
 
The proposed study is a double-blind, placebo-controlled, cross-over trial. The study will enroll 10 adult 
subjects with OUD currently receiving MOUD treatment with sublingual buprenorphine or methadone.  
Recruitment will occur from the outpatient programs that treat OUD patient at Brigham and Women’s 
Hospital and Brigham and Women’s Faulkner Hospital in Boston, MA, and at the Rutland Regional 
Medical Center in Rutland, Vermont.  
 
Inclusion criteria: 
• 
Age 18 to 65 
• 
English speaking 
• 
Receiving either buprenorphine or methadone for treatment of opioid use disorder for at least 3 
consecutive months prior to enrollment 
• 
Agreeable to abstaining from using any cannabis or CBD products for the duration of the trial.  
 
Exclusion criteria: 
• 
Any self-reported use of cannabis or CBD products in the past 30 days 
• 
Current marijuana users 
• 
Baseline depression (PHQ9) or anxiety (GAD7) scores of greater than 10 
• 
Currently pregnant 
• 
Hepatic liver enzymes greater than 3x upper normal limit 
• 
Hypersensitivity to cannabinoids, sesame oil (CBD solution comes in sesame oil emulsion), or 
artificial strawberry flavoring. 
• 
Currently taking any medications with known significant pharmacokinetic interactions with CBD 
 
Subject recruitment procedures: 
• 
We will use a variety of approaches to recruit for this study. We will use posted flyers at BWH 
clinical sites where OUD patients are being treated, and advertisements posted on Rally website. 
We will also utilize the Patient Gateway messages sent directly to active patients by sending an 
IRB-approved letter for recruitment. Potential participants will be identified by RPDR by 
searching for any MGB patient being treated with buprenorphine or methadone in their 


 
 
 
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medication list and also with a diagnosis of an opioid use disorder.  In addition, research staff will 
approach clinical staff during the staff meetings.  
• 
The RA will be largely responsible for identifying and recruiting potential participants. 
• 
Individuals will be recruited as soon as IRB approval is obtained and will continue until target 
sample size (n=10) is reached or when project period ends on December 31, 2022.  
• 
Individuals will be recruited from the Boston area, and patients being treated for OUD at BWH 
affiliated clinical programs.  
• 
OUD is present in about 3% of Massachusetts residents, and we have over 500 active OUD 
patients across BWH affiliated clinical programs with OUD and therefore should be able to reach 
recruitment target.  
• 
At our clinical sites, Black and Latino patients are over-represented, and therefore our study will 
likely recruit an ethnically and racially diverse participant population.  
 
 
5. 
Subject Enrollment 
 
Adults with a DSM-5 diagnosis of OUD and who are currently in treatment with buprenorphine or 
methadone will be recruited. Patients with OUD at Brigham and Women’s Hospital (BWH) and Brigham 
and Women’s Faulkner (BWF) will be referred to study staff by their health care providers at these 
clinical sites for possible inclusion. Their health care providers, who will be known to the potential 
subject and will have first-hand knowledge of the patient’s medical history, will (1) first give approval for 
his/her patient to be contacted/approached for research purposes, (2) initially introduce the study to the 
patient, and (3) obtain the patient’s permission, verbally during the course of providing medical care, to 
be contacted by study staff. Subjects will also be recruited from the Partners Clinical Trials website, 
http://Rally.partners.org, as well as print advertisements and flyers posted at the clinics. Study visits will 
be conducted at the BWH Center for Clinical Investigation. Study staff will perform a preliminary screen 
on the telephone or virtually to establish suitability for the study. If suitable, a study staff will schedule 
the individual for a baseline visit which will be performed remotely or in-person.  Informed consent will 
be obtained at the baseline visit in-person or remotely, after which the full inclusion and exclusion criteria 
will be applied. For remote consenting, study staff will utilize the Mass General Brigham REDCap 
eConsent. Those who meet criteria will then be randomized to either CBD first or placebo first, and 
scheduled for the two study visits.  
 
 
 
6. 
STUDY PROCEDURES 
Overall approach: A total of 3 study visits are planned (Table 1) The first visit is the baseline visit, and 
the other two are double-blind placebo-controlled medication visits, where either CBD or placebo will be 
administered.  Participants will be randomized using a random-number generator in a 1:1 ratio of CBD to 
placebo. During the baseline visit, after obtaining informed consent, participants will complete the 
baseline assessments. The subject will then be scheduled for their study visits 2 and 3 during which they 
will receive CBD or placebo in random order in double-blind fashion. Visits 2 and 3 will be scheduled at 


 
 
 
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least 1 week apart to function as a washout. Baseline visit will take no longer than an hour, and the 
subsequent visits will take no more than 2 hours to complete.  
 
Visit 1: Baseline 
Participants will provide written informed consent, obtained by the PI or another study physician. The 
blood and urine samples collected during the Baseline Visit will be used for inclusion/exclusion purposes. 
Specifically, participants who are currently pregnant (as confirmed by the pregnancy test), or have hepatic 
liver enzymes greater than three times the upper normal limit (as confirmed by the liver function tests, or 
LFTs) will be excluded. Subjects will also complete baseline PHQ9, GAD7, BPI, TLFB, COWS, 
PANAS, and opioid cravings.  
 
Visit 2: CBD or placebo 
After arrival to the study site, the participant will receive either the CBD 600mg or placebo, immediately 
followed by obtaining baseline heart rate, blood pressure, PHQ9, GAD, BPI, TLFB, COWS, opioid 
cravings, and urine sample for toxicology testing. Heart rate and blood pressure will be monitored every 
30 minutes (vital signs: heart rate, blood pressure) following receipt of CBD or placebo. At 60 minutes 
following the CBD or placebo administration, the participant will then proceed to complete the cue-
reactivity test, visual probe task, Iowa gambling task, monetary choice questionnaire (MCQ), and the 
mirror tracing persistence task (MTPT).  Just prior to and after the MTPT task, subjects will provide 
salvia sample and complete the positive and negative affect scale (PANAS). An additional saliva sample 
will be collected 20 minutes after the MTPT task.  
 
Visit 3: CBD or placebo 
The same procedures for Visit 2 will be repeated during visit 3, scheduled at least 1 week after visit 2. 
The order in which CBD or placebo is administered will be randomized.  
 
Cannabidiol:  


 
 
 
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Subjects will receive 600mg of oral CBD or matching placebo. Cannabidiol will be provided using 
Epidiolex™ oral solution 100mg/mL. Drug will be procured by the BWH Investigational Drug Services 
(IDS) pharmacy and the pharmacy at Rutland Regional 
Medical Center. The CBD or matching placebo will be 
placed in in oral syringes for the subjects to self-administer 
at the study site. CBD will be stored at room temperature 
(68 to 77 F) in its original bottle and in an upright position. 
Once opened, CBD has a shelf life of 84 days. 
 
Primary Outcome: The primary outcomes is the change in 
cue-induced cravings (Opioid Craving Scale). 
Secondary Outcomes: The secondary outcomes are 
impulsive decision making (Iowa Gambling Task, Monetary 
Choice Questionnaire), attentional bias (Visual Probe Task), 
and physiologic and subjective stress-reactivity. 
 
Assessments: 
o Patient Health Questionnaire 9-item (PHQ9): 
Assessment of depressive symptoms 
o Generalized Anxiety Disorder 7-item (GAD7): 
Assessment of anxiety symptoms 
o Brief Pain Inventory (BPI): Pain severity and 
interference assessment.  
o Time-line follow back (TLFB): A method of 
assessing for recent substance use using a calendar. 
o Clinical Opioid Withdrawal Scale (COWS): Assessment of opioid withdrawal. 
o Opioid craving scale12: A 3-item tool to assess current cravings, cravings when exposed to triggers, 
and likelihood of using if placed in an environment that the individual previous used opioids.  
o Cue-induced craving13: Participants will be shown both illicit opioid-related and neutral images on 
a computer screen for one minute each using a standardized protocol. The order in which the cues 
will be presented will be randomized and counter balanced. Participants will rate their cravings on 
a visual analog scale. The cue exposure procedure will end with a standardized debriefing 
exercise.  It is important to note that cue-exposure is a safe paradigm for studying craving in this 
population when employing debriefing procedures.  
o Monetary Choice Questionnaire (MCQ)14: This is a 27-item self-report tool used to measure 
delayed discounting, or the degree to which individuals prefer smaller immediate rewards 
compared to larger delayed rewards. Participant are asked to choose between a smaller (in dollars) 
immediate reward and a larger delayed reward.  


 
 
 
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o Iowa Gambling Task (IGT)15: This is a task to measure decision making, which utilizes four decks 
of cards (A, B, C, D). Participants are instructed to maximize profits by selecting cards from any 
deck. Cards from decks A and B earn more profits but lead to even higher occasional losses leading 
to net long-term losses, while decks C and D yield low profits but only low occasional losses 
resulting in a net long-term profit.  
o Visual Probe Task16: Opioid-related and neutral images will be used. Each trial will begin with a 
fixation point lasting 500ms. A pair of images then will appear on the left and right of the screen 
for either a short (200ms) or long (500ms) stimulus duration to assess automatic orientating and 
controlled attention processing, respectively. Image pairs will be replaced by a probe in the location 
of either the opioid-related or neutral image. The probe will remain until the participant responds 
to identify the probe orientation by pressing the response keys as quickly as possible.  
o Mirror Tracing Persistence Task (MTPT)17,18: This task functions to elicit a stress response and 
measures distress tolerance. Participants are asked to trace a red dot along the lines of a geometric 
shape (e.g., star) using the computer’s mouse, but the mouse moves the red dot in the reverse 
direction. Each time the participant moves the mouse out of the lines or hesitates for more than 2 
seconds, a buzzer sounds, and the dot moves back to the beginning. Three progressively more 
difficult shapes are used. The first two rounds last 1 minute each. The third and final round tests 
for distress tolerance. Participants may terminate the task at any point during the third round by 
pressing on the space bar. In addition to measuring distress tolerance, prior studies have shown 
consistently that this method elicits a robust stress response in individuals with substance use 
disorders. 
o Positive and Negative Affect Schedule (PANAS): Subjective stress reactivity  will be measured 
using the Negative Affect subscale of the PANAS, a routinely used measure of both positive and 
negative emotions. This will be administered before and after stress induction with MTPT.  
o Salivary cortisol: Hypothalamic-pituitary-adrenal (HPA)-axis response will be measured by 
collecting saliva for analysis of salivary cortisol before, immediately after, and 20-minutes after 
the stressor task.  
 
Compensation: Participants will be reimbursed for travel/parking. In addition, subjects will be compensated 
$100 for completing the baseline visit, $50 for visit 2 and $100 for completing visit 3 ($250 total for 
completing all visits).  We will utilize the Advarra payment systems to provide the study compensation.  
 
Stopping rules:  The Principal Investigator will assess all patients with regard to stopping criteria. This 
study will be stopped prior to its completion if: (1) the intervention is associated with adverse effects that 
call into question the safety of the intervention; (2) difficulty in study recruitment or retention will 
significantly impact the ability to evaluate the study endpoints; (3) any new information becomes 
available during the trial that necessitates stopping the trial; or (4) other situations occur that might 
warrant stopping the trial. 
 


 
 
 
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Data sharing: Data collected will be shared by investigators at BWH as well as with investigators at 
Rutland Regional Medical Center using MGB Dropbox Business. Regarding sharing of data with the 
study sponsor, the principal investigator will be required to provide regular written progress reports. No 
identifiable information will be shared with the sponsor. Data collected at Rutland Regional Medical 
Center will only be kept for record-keeping requirements, and will not be used for future studies not 
described in this protocol. If the participant wished to withdraw their data from then we will withdraw the 
participant from the study as outlined in the protocol. Subjects who wish to withdrawal their data can ask 
the PI to do so.  We are concurrently seeking IRB approval from Rutland Regional Medical Center.  
 
 
7. 
Risks and Discomforts 
 
The well-being of the study participants is of utmost importance. The in-depth screening procedure has 
been designed to ensure that individuals with any underlying medical or psychiatric illness are identified 
that may place them at greater risk for experiencing adverse effects during the study. The protocol raises 
several areas of concerns: confidentiality, emotional distress, adverse reactions to study procedures, 
suicidal ideation, and cannabidiol medication. 
 
Confidentiality: Confidentiality is of utmost importance given the sensitive nature of the illness and data 
collected. During research there is always a possibility for a breach of confidentiality, which may 
potentially cause personal, social, occupational, legal, and other harm. Our research team is very aware of 
the importance of maintaining strict confidentiality and has prior experience dealing with sensitive 
information. The following precautions will be used to protect the privacy of participants and maintain 
confidentiality of research data: all staff will be trained in confidentiality and data security procedures; 
privacy will be maintained by conducting all study procedures in private hospital rooms or in close, 
sound-proof rooms; data will be de-identified and coded with unique ID numbers; data will be securely 
stored in locked filing cabinets in locked rooms; electronic data will be stored in password protected 
documents located on password protected computers and secure servers; the key linking participants 
names and ID numbers will be stored in a separate password protected document in a password protected 
computer; access to data storage areas will be restricted to authorized study personnel; and all analysis 
will be conducted on de-identified data. While breach of confidentiality is possible, these safeguards will 
ensure that such a breach will be highly unlikely.  
 
Emotional distress: Some patients may experience discomfort or embarrassment related to providing 
urine samples or answering questions about substance use and other personal behaviors. They could also 
experience unexpected encounters with friends or associates while in the study. However, based on prior 
studies with this population, we expect the degree of distress to be very limited. All research personnel 
will be extensively trained on study procedures, including the conduct of the interviews that elicit 
personal information, and the importance of being sensitive to and respectful of all participants. In cases 
where emotional distress does occur, research personnel will be trained on how to identify and address it, 
and when to terminate an interview. Multiple levels of back-up support for research personnel will be 


 
 
 
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developed. The candidate is a board certified psychiatrist, and will be able to ensure that appropriate 
services are received.  
 
Adverse reactions to study procedures: The study procedures will end with a standardized relaxation 
and debriefing exercise. Before participants are discharged from each study session, their well-being will 
be assessed by the study staff and a standardized safety and adverse events questionnaire will be used to 
assess any adverse events. If needed, participants will be referred for further clinical evaluation and 
assistance. It is important to note that cue-exposure and stress-exposure are safe paradigms for studying 
this patient population when employing debriefing procedures.  
 
Suicidal ideation: Patients with OUD frequently have psychiatric co-morbidities, namely depression. 
Participants who disclose any suicidal ideation during the study (either through spontaneous expression of 
suicidal ideation, or self-reported on the PHQ-9) will result in emergent evaluation by a licensed clinician 
member of the study staff for appropriate assessment and triage. Any disclosures will be handled within 
existing legal mandates, clinical practice, and social norms. Consistent with standard clinical practice, 
when possible, disclosures will be discussed with the participant to determine the best management 
options. This may include notifying the outpatient providers or family members, referring to medical 
treatment, calling emergency services, or escorting the participant to the Emergency Room at Brigham 
and Women’s Hospital. When required by law, the police department will be notified. The candidate is a 
board certified psychiatrist and has extensive experience managing acutely distressed patients with mental 
or substance use disorders.  
 
Cannabidiol medication safety: All subjects in this trial will receive a single dose of 600mg of 
cannabidiol. Cannabidiol (Epidiolex) is approved by the U.S. Food and Drug Administration (FDA) for 
the treatment of seizures associated with two rare and severe forms of epilepsy. However, cannabidiol is 
not approved by the FDA for treatment of opioid use disorder. The PI has conducted a previous pilot trial 
of CBD 600mg administered to OUD patients for 3 consecutive days in a single-arm open-label design.  
That protocol was reviewed by the Center for Drug Evaluation and Research at the Food and Drug 
Administration and determined it met the regulatory criteria for an exemption from the requirement for 
the Investigational New Drug (IND) submission, and we therefore received the FDA IND exemption 
letter November 13, 2019. This protocol uses the same medication (Epidiolex), at the same dose (600mg), 
for the same patient population (OUD on buprenorphine or methadone), and will administer for only one 
dose instead of three consecutive days.  As such, we feel an additional FDA IND is not required to 
conduct this trial. Although this proposed clinical evaluation is for an “off-label” indication of 
cannabidiol, it does not involve a route of administration or dosage level or use in a patient population or 
other factor that significantly increases the risks (or decreases the acceptability of the risks) associated 
with the use of the Epidiolex (cannabidiol). The proposed dose is within FDA-approved mg/kg maximum 
daily dose limits. There are now two randomized placebo-controlled studies of administering 400mg or 
800mg of cannabidiol to participants with opioid use disorder with no adverse effects. Nonetheless, 
cannabidiol may cause participants to experience side effects such as: somnolence; decreased appetite; 
diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor 
quality sleep; infections; and suicidal thoughts or actions. All participants will be told of these potential 
side effects, and the screening procedures, including liver function tests, are in place to minimize these 


 
 
 
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potential risks. The principal investigator will continually assess and monitor adverse effects both during 
and after cannabidiol administration, as noted in the Schedule of 
 
8. 
Benefits 
 
No benefits can be guaranteed from participation in the study. However, all enrolled participants will be 
receiving an adjunctive agent that is hypothesized to help reduce cue-induced cravings associated with 
their opioid use disorder, and it is possible that at least some subjects will experience a decrease in the 
severity of their cravings or stress-reactivity. An extensive screening procedure will ensure that 
individuals entering the trial will have no contraindications. Trained research personnel will perform all 
study procedures to minimize risks, discomforts, and adverse effects. Buprenorphine and methadone 
treatment are FDA-approved treatment for the treatment of OUD, and reduces illicit opioid use and 
related morbidities associated with OUD. This study will generate valuable information about the effect 
of combining cannabidiol with stable doses of buprenorphine or methadone for patients with OUD. The 
results will help inform the direction needed to take in developing effective strategies to improve the care 
of OUD patients taking medications. If successful, this line of research has the potential to significantly 
impact clinical practice of treating OUD by providing a viable medication adjunct to existing evidenced-
based therapies. 
 
 
9. 
Statistical Analysis 
 
For all analyses, descriptive statistics will be used to summarize the data. All comparisons will utilize paired 
t-tests or non-parametric tests where appropriate. Alpha will be set at 0.05 for all analyses. 
Primary outcome:  
• 
Cue-reactivity: Cue-reactivity will be defined as the difference between baseline craving scores 
and the craving scores in response to opioid-related or neutral cues.   
Secondary outcome: 
• 
Subjective cravings: Craving scores will be rated on a 0 to 10 visual analog scale for each of the 3 
items.   
• 
Attentional bias: This is calculated as the difference in reaction time (RT) between when the probe 
replaced the neutral compared with the opioid-related images (i.e. RTneutral – RTopioid). 
• 
Delayed discounting: Based on their responses to the MCQ, the rate of discounting, or k value, is 
calculated, which range from 0.00016 to 0.25. Higher values indicate greater discounting and 
impulsivity.  
• 
Impulsive decision making: A net score from the IGT is calculated by subtracting the number of 
disadvantageous selections from the number of advantageous selections (i.e. (C+D) - (A+B)), 
where negative scores indicate decision-making that favors immediate rewards despite negative 
consequences.   


 
 
 
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• 
Distress tolerance: This is measured as the length of time in number of seconds that participants 
engage in the third MTPT task.  
• 
Subjective stress reactivity: Subjective stress reactivity will be calculated as the difference in the 
negative affect score from PANAS before and after the stressor task.  
• 
Physiologic stress reactivity: Physiologic stress reactivity will be calculated as the difference in 
salivary cortisol levels and skin conductance before and after the stressor task. 
Power analysis: The estimated mean change in cue-induced cravings scores from prior studies is -1.5 (SD 1.5). 
Based on this estimate, and a conservative estimate of a correlation of r=0.60 between the two time points, a 
sample size of 10 is needed for 88% power and two-tailed alpha set at 0.05 for a paired-samples t-test. A point 
estimate of the difference in the change and the 95% confidence interval will be reported. Conversely, if the 
change in cravings is not normally distributed, then a sum rank test will be used. 
 
 
10.   Monitoring and Quality Assurance 
 
 
The Principal Investigator, Dr. Joji Suzuki, will be responsible for monitoring the safety of all subjects. 
The PI or study staff will review all data collection forms on an ongoing basis for data completeness and 
accuracy as well as protocol on a regular basis (i.e. weekly). Study staff are located at Brigham and 
Women’s Hospital in Boston, MA, and Rutland Regional Medical Center in Rutland, Vermont. Study 
safety meetings, including the principal investigator, study coordinators, and study physicians will occur 
weekly to review the progress of currently-enrolled subjects and any reported side effects. 
 
INSTRUCTIONS 
Delete grey Instructions box upon completion of this section 
 
 
Describe the plans that will be followed by study staff for monitoring and quality assurance, 
including: 
• 
Adverse event criteria and reporting procedures 
• 
Planned safety monitoring, e.g., data monitoring committee (DMC)/data and safety 
monitoring board (DSMB), independent monitor, PI-monitored, etc., including planned 
frequency of review. If DMC/DSMB monitored, include either charter as separate 
attachment or complete DMC/DSMB APPENDIX 
• 
Outcomes monitoring, including planned frequency of review. 
• 
Study stopping rules as applicable 
• 
Internal monitoring of source data, protocol adherence, and recordkeeping, including 
which staff will be responsible and planned frequency of review 
• 
Independent monitoring of source data as applicable 


 
 
 
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Data collected will be shared by investigators at BWH as well as with investigators at Rutland Regional 
Medical Center using MGB Dropbox Business. Regarding sharing of data with the study sponsor, the 
principal investigator will be required to provide regular written progress reports. No identifiable 
information will be shared with the sponsor.  
 
Data collected at Rutland Regional Medical Center will only be kept for record-keeping requirements, 
and will not be used for future studies not described in this protocol. If the participant wished to withdraw 
their data from then we will withdraw the participant from the study as outlined in the protocol. Subjects 
who wish to withdrawal their data can ask the PI to do so.  We are concurrently seeking IRB approval 
from Rutland Regional Medical Center.  
 
The Principal Investigator will assess all patients with regard to stopping criteria. This study will be 
stopped prior to its completion if: (1) the intervention is associated with adverse effects that call into 
question the safety of the intervention; (2) difficulty in study recruitment or retention will significantly 
impact the ability to evaluate the study endpoints; (3) any new information becomes available during the 
trial that necessitates stopping the trial; or (4) other situations occur that might warrant stopping the trial. 
 
11.   Privacy and Confidentiality 
 
☒ Study procedures will be conducted in a private setting 
☒ Only data and/or specimens necessary for the conduct of the study will be collected 
☒ Data collected (paper and/or electronic) will be maintained in a secure location with appropriate 
protections such as password protection, encryption, physical security measures (locked 
files/areas) 
☒ Specimens collected will be maintained in a secure location with appropriate protections (e.g. 
locked storage spaces, laboratory areas) 
☒ Data and specimens will only be shared with individuals who are members of the IRB-approved 
research team or approved for sharing as described in this IRB protocol 
☒  Data and/or specimens requiring transportation from one location or electronic space to another 
will be transported only in a secure manner (e.g. encrypted files, password protection, using 
chain-of-custody procedures, etc.) 
☒   All electronic communication with participants will comply with Mass General Brigham secure 
communication policies 
☒ Identifiers will be coded or removed as soon as feasible and access to files linking identifiers with 
coded data or specimens will be limited to the minimal necessary members of the research team 
required to conduct the research 
☒ All staff are trained on and will follow the Mass General Brigham policies and procedures for 
maintaining appropriate confidentiality of research data and specimens 
☐ The PI will ensure that all staff implement and follow any Research Information Service Office 
(RISO) requirements for this research 
☐ Additional privacy and/or confidentiality protections 


 
 
 
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Subject Identification 
 
 
 
 
Confidentiality is of utmost importance given the sensitive nature of the illness and data collected. During 
research there is always a possibility for a breach of confidentiality, which may potentially cause 
personal, social, occupational, legal, and other harm. Our research team is very aware of the importance 
of maintaining strict confidentiality and has prior experience dealing with sensitive information. The 
following precautions will be used to protect the privacy of participants and maintain confidentiality of 
research data: all staff will be trained in confidentiality and data security procedures; privacy will be 
maintained by conducting all study procedures in private hospital rooms or in close, sound-proof rooms; 
data will be de-identified and coded with unique ID numbers; data will be securely stored in locked filing 
cabinets in locked rooms; electronic data will be stored in password protected documents located on 
password protected computers and secure servers; the key linking participants names and ID numbers will 
be stored in a separate password protected document in a password protected computer; access to data 
storage areas will be restricted to authorized study personnel; and all analysis will be conducted on de-
identified data. While breach of confidentiality is possible, these safeguards will ensure that such a breach 
will be highly unlikely.  
 
 
12.   References 
 
1. 
Substance Abuse and Mental Health Services Administration. Key substance use and mental  
health indicators in the United States: Results from the 2017 National Survey on Drug Use and Health  
(HHS Publication No. SMA  18-5068, NSDUH Series H-53). (2018). 
2. 
Sordo, L. et al. Mortality risk during and after opioid substitution treatment: systematic review 
and meta-analysis of cohort studies. BMJ 357, j1550 (2017). 
3. 
Morgan, J. R. et al. Characterizing initiation, use, and discontinuation of extended-release 
buprenorphine in a nationally representative United States commercially insured cohort. Drug Alcohol 
Depend. 225, 108764 (2021). 
4. 
Field, M., Marhe, R. & Franken, I. H. A. The clinical relevance of attentional bias in substance 
use disorders. CNS Spectr. 19, 225–230 (2014). 
5. 
Kirby, K. N. & Petry, N. M. Heroin and cocaine abusers have higher discount rates for delayed 
rewards than alcoholics or non-drug-using controls. Addict. Abingdon Engl. 99, 461–471 (2004). 
6. 
McHugh, R. K. et al. Assessing craving and its relationship to subsequent prescription opioid use 
among treatment-seeking prescription opioid dependent patients. Drug Alcohol Depend. 145, 121–126 
(2014). 
7. 
Amato, L., Minozzi, S., Davoli, M. & Vecchi, S. Psychosocial combined with agonist 
maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. 
Cochrane Database Syst. Rev. CD004147 (2011) doi:10.1002/14651858.CD004147.pub4. 
8. 
Carroll, K. M. & Weiss, R. D. The Role of Behavioral Interventions in Buprenorphine 
Maintenance Treatment: A Review. Am. J. Psychiatry appiajp201616070792 (2016) 
doi:10.1176/appi.ajp.2016.16070792. 


 
 
 
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Subject Identification 
9. 
Hindocha, C. et al. Cannabidiol reverses attentional bias to cigarette cues in a human 
experimental model of tobacco withdrawal. Addict. Abingdon Engl. (2018) doi:10.1111/add.14243. 
10. 
Hurd, Y. L. et al. Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-
Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial. 
Am. J. Psychiatry appiajp201918101191 (2019) doi:10.1176/appi.ajp.2019.18101191. 
11. 
Chye, Y., Christensen, E., Solowij, N. & Yücel, M. The Endocannabinoid System and 
Cannabidiol’s Promise for the Treatment of Substance Use Disorder. Front. Psychiatry 10, 63 (2019). 
12. 
McHugh, R. K., Trinh, C. D., Griffin, M. L. & Weiss, R. D. Validation of the craving scale in a 
large sample of adults with substance use disorders. Addict. Behav. 113, 106651 (2021). 
13. 
McHugh, R. K., Park, S. & Weiss, R. D. Cue-induced craving in dependence upon prescription 
opioids and heroin. Am. J. Addict. 23, 453–458 (2014). 
14. 
Kirby, K. N., Petry, N. M. & Bickel, W. K. Heroin addicts have higher discount rates for delayed 
rewards than non-drug-using controls. J. Exp. Psychol. Gen. 128, 78–87 (1999). 
15. 
Upton, D. J., Kerestes, R. & Stout, J. C. Comparing the Iowa and Soochow Gambling Tasks in 
Opiate Users. Front. Neurosci. 6, (2012). 
16. 
Field, M. & Cox, W. M. Attentional bias in addictive behaviors: a review of its development, 
causes, and consequences. Drug Alcohol Depend. 97, 1–20 (2008). 
17. 
McHugh, R. K., Nguyen, M. D., Fitzmaurice, G. M. & Dillon, D. G. Behavioral strategies to 
reduce stress reactivity in opioid use disorder: Study design. Health Psychol. 39, 806–814 (2020). 
18. 
Strong, D. et al. The computeried mirror tracing task version 1. (2003). 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A 
 
Data Monitoring Committee / Data and Safety Monitoring Board 
Appendix 
 
 
 


 
 
 
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Subject Identification 
• 
To be completed for studies monitored by Data Monitoring Committee (DMC) or Data and Safety 
Monitoring Board (DSMB) if a full DMC/DSMB charter is not available at the time of initial IRB 
review. 
• 
DMC/DSMB Charter and/or Roster can be submitted to the IRB later via Amendment, though these 
are not required.  
 
A Data Monitoring Committee (DMC) or Data and Safety Monitoring Board (DSMB) will be convened 
for safety monitoring of this research study.  The following characteristics describe the DMC/DSMB 
convened for this study (Check all that apply): 
 
☐ The DMC/DSMB is independent from the study team and study sponsor. 
 
☐ A process has been implemented to ensure absence of conflicts of interest by DMC/DSMB 
members. 
 
☐ The DMC/DSMB has the authority to intervene on study progress in the event of safety concerns, 
e.g., to suspend or terminate a study if new safety concerns have been identified or need to be 
investigated.   
 
☒ Describe number and types of (i.e., qualifications of) members: 
The PI will serve as the data monitor given the small size of the study and low risk associated the use of a 
single dose of CBD. Given that this study will enroll a total of 10 subjects to receive a single dose of 
CBD 600mg or placebo, that study end points are not serious events (i.e. cue-reactivity), the risks 
associated with CBD is low, and that the study is completed rather quickly, the PI will serve as the data 
monitor.  The PI will promptly report any adverse events to the IRB and the FDA where appropriate. 
 
 
☐  Describe planned frequency of meetings: 
Click or tap here to enter text. 
 
☐ DMC/DSMB reports with no findings (i.e., “continue without modifications”) will be submitted 
to the IRB at the time of Continuing Review. 
 
☐ DMC/DSMB reports with findings/modifications required will be submitted promptly (within 5 
business days/7 calendar days of becoming aware) to the IRB as an Other Event.  
   
 
 
 


 
 
 
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Subject Identification 
Protocol Title: Cannabidiol on reward-and stress-related neurocognitive processes in individuals with 
opioid use disorder: A double-blind, placebo-controlled, cross-over trial 
 
Principal Investigator: Joji Suzuki, MD  
 
Site Principal Investigator:       
 
Description of Subject Population: Patients with opioid use disorder who are receiving buprenorphine 
or methadone treatment 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
 
If you decide to take part in this research study, you must sign this form to show that you want to 
take part.  We will give you a signed copy of this form to keep. 
 
 
Key Information 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  Your decision won’t change the 
medical care you get within Mass General Brigham now or in the future.   
 
The following key information is to help you decide whether or not to take part in this research 
study.  We have included more details about the research in the Detailed Information section that 
follows the key information. 
 
 
 
 
Why is this research study being done? 
 


 
 
 
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Subject Identification 
We are doing this research study to find out if using cannabidiol (CBD, also known as Epidiolex) along 
with buprenorphine or methadone can help patients with opioid use disorder by reducing their cravings 
and stress. 
 
How long will you take part in this research study? 
 
If you decide to join the research study, it will take you about 2 weeks to complete the study. During this 
time, we will ask you to make three study visits to Brigham and Women’s Hospital in Boston, MA. 
 
What will happen if you take part in this research study? 
 
The study requires 3 visits over the course of 2 weeks to the Clinical Trials Hub at Brigham and Women’s 
Hospital. Each visit lasts between approximately 45 minutes to 2 hours. In the first study visit, we will ask 
you about your psychiatric and medical history, obtaining your blood and urine sample, as well as asking 
about your mood and cravings.  In the second visit, you will receive either cannabidiol or placebo. Neither 
you or the study staff will know if you are receiving cannabidiol or placebo. After that, we will be using a 
computerized assessment tool to conduct several psychological tests to measure how your brain reacts. 
On the third visit, you will receive cannabidiol or placebo, and repeat the same assessments. You will 
receive both cannabidiol and placebo, but the order will be randomized so that if you receive cannabidiol 
in the second visit, you will receive placebo in the third visit.  If you receive placebo on the second visit, 
you will receive cannabidiol on the third visit.  
 
Why might you choose to take part in this study? 
 
We cannot promise any benefits to you from taking part in this research study. However, 
possible benefits may include a reduction in cravings and stress related to your opioid use 
disorder. Others with opioid use disorder may benefit in the future from what we learn in this 
study. 
 
Why might you choose NOT to take part in this study? 
 
Taking part in this research study has some risks and requirements that you should consider carefully.   
 
Important risks and possible discomforts to know about include possibility for a breach of confidentiality, 
and experiencing emotional distress related to answering questions about substance use and other 
personal behaviors.  
 
A detailed description of side effects, risks, and possible discomforts can be found later in this consent 
form in the section called “What are the risks and possible discomforts from being in this research 
study?” 


 
 
 
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Subject Identification 
 
What other treatments or procedures are available for your condition? 
 
You do not have to take part in this research study to be treated for substance use disorder. Other 
treatments or procedures that are available to treat substance use disorder include: 
• 
Individual psychotherapy or group therapy 
• 
Peer recovery services, like Narcotics Anonymous (NA) 
Talk with the study doctor if you have questions about any of these treatments. 
 
If you have questions or concerns about this research study, whom can 
you call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.   
Joji Suzuki, MD  is in charge of this research study. You can call him if you have questions 
about the study, scheduling of appointments or study visits at 617-732-5752 between M-F 9am-
5pm.
 
If you want to speak with someone not directly involved in this research study, please contact the Mass 
General Brigham IRB office.  You can call them at 857-282-1900. 
 
You can talk to them about: 
▪ 
Your rights as a research subject 
▪ 
Your concerns about the research 
▪ 
A complaint about the research 
▪ 
Any pressure to take part in, or to continue in the research study 
 


 
 
 
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Subject Identification 
Detailed Information 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results.  You can search this Web site at any time. 
 
Why is this research study being done? 
 
We are doing this research study to find out if using cannabidiol (CBD) along with buprenorphine or 
methadone can help patients with their opioid use disorder. You will not receive buprenorphine or 
methadone as a part of this research study; in order to be able to take part in this study you must already 
be receiving buprenorphine or methadone as part of your standard clinical care. 
 
Cannabidiol is a non-psychoactive and non-addictive constituent in cannabis. Cannabidiol is approved by 
the U.S. Food and Drug Administration (FDA) for the treatment of seizures associated with two rare and 
severe forms of epilepsy. However, cannabidiol is not approved by the FDA to treat opioid use disorder.  
 
This research will compare cannabidiol to placebo. The placebo looks exactly like cannabidiol but 
contains no cannabidiol. During the study you may get a placebo instead of cannabidiol. Placebos are 
used in research studies to see if the results are due to the study drug or other reasons. At some time 
during the study, we will give you cannabidiol. At another time, we will give you placebo. 
 
Who will take part in this research? 
 
We are asking you to take part in this research study because you have a diagnosis of opioid use disorder, 
and you have been receiving a stable dose of buprenorphine or methadone treatment. Opioid use disorder 
is defined as a problematic pattern of opioid use that leads to serious impairment or distress. Doctors use a 
specific set of criteria to determine if a person has a substance use problem.  
 
About 20 subjects will take part in this research study. About 5 subjects will complete the research study 
at Brigham and Women’s Hospital (BWH) in Boston MA. 
 
The President and Fellows of Harvard College, a non-profit organization, is paying for this research to be 
done. 
 
What will happen in this research study? 
 
At the beginning of the study we will ask you questions to see if you are eligible to take part in the study. 
If you are deemed eligible to proceed with the study, we will ask you to sign this consent form before we 
do any study procedures.  
 


 
 
 
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Subject Identification 
Screening and Baseline Visit (Visit 1) 
 
The Screening and Baseline Visit will take about 45 minutes.  At this visit, we will ask you a 
number of questions and do some tests to see if you qualify to take part in this research study.  
The study doctor will review the results of these tests and procedures.  If you don’t qualify, the 
study doctor will tell you why.   
 
At this visit, we will: 
• Ask you about your medical history, including questions about mental health 
• 
Ask you to fill out some questionnaires about your mental and emotional health, physical 
symptoms, and your general health and well-being  
• Ask you about medications you are taking 
• 
Draw a blood sample 
• 
Ask you for a urine sample 
• 
Test your urine for certain drugs  
• Test your urine for pregnancy, if you are a female able to become pregnant.  
Pregnant women cannot take part in this research study. 
• Monitor your vital signs (blood pressure, heart rate) 
 
Urine Drug Screen 
During this study, we will test your urine for certain drugs, including cannabis and illegal drugs 
like cocaine. The results of the urine drug test will not become part of your medical record. 
These test results will, however, remain part of your study record. 
 
Study Visit 2: CBD or placebo 
 
Visit 2 will take about 2 hours to complete.  At this visit we will: 
• 
Have you take your first dose of cannabidiol or placebo. You nor the study staff will 
know which one you are taking, but you will eventually take both in the course of the 
study.  
• 
Ask you about your cravings for opioids, mood, anxiety, pain, and the use of any alcohol 
or drugs in the past week.  
• 
Ask you to complete 5 psychological tests to test your cravings in response to seeing 
images related to drugs, two tests on decision making, attention to drug-related images, 
and your response to a stressor. These tests will all be administered by a computer. 
• 
Ask you to provide 3 saliva samples during the psychological tests. 
• 
Ask you to complete a debriefing exercises 
 
Study Visit 3: CBD or placebo 
 


 
 
 
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Subject Identification 
Visit 3 will take about 2 hours to complete. The exact same procedure will be followed during 
this visit as compared to the previous, except the drug that you will receive. At this visit we will: 
• 
Have you take your second dose of cannabidiol or placebo. You nor the study staff will 
know which one you are taking, but you will have taken both in the course of the study.  
• 
Ask you about your cravings for opioids, mood, anxiety, pain, and the use of any alcohol 
or drugs in the past week.  
• 
Ask you to complete 5 psychological tests to test your cravings in response to seeing 
images related to drugs, two tests on decision making, attention to drug-related images, 
and your response to a stressor. These tests will all be administered by a computer. 
• 
Ask you to provide 3 saliva samples during the psychological tests. 
• 
Ask you to complete a debriefing exercises 
 
 
Also, the study doctor may take you out of the study without your permission.  This may happen because: 
• 
The study doctor thinks it is best for you to stop taking the study drug 
• 
You develop a condition (such as suicidal thoughts) that needs emergency care 
• 
You can’t make the required study visits 
• 
The Sponsor decides to stop the study 
• 
We stop doing the study for other reasons 
 
If this happens, the study doctor will explain why you need to stop taking part in the study.  We will ask 
you to come in for a final study visit as described above. 
 
Study Information Included in Your Electronic Medical Record 
A notation that you are taking part in this research study may be made in your electronic medical record. 
Information form the research that relates to your general medical care may be included in the record (for 
example: lists f allergies, results of standard blood tests done at the hospital labs). 
 
Please ask your study doctor if you have any questions about what information will be included in your 
electronic medical record. 
 
Sending study information to research collaborators outside Mass General Brigham 
We will send your study information and/or samples to researchers working with us at Rutland 
Regional Medical Center. We will label all your study materials with a code instead of your 
name. The key to the code connects your name to your study information and samples. We will 
keep the key to the code her at Mass General Brigham and will not share it with our research 
collaborators. No one outside of Mass General Brigham will know which study information or 
samples are yours. 
 


 
 
 
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Subject Identification 
How may we use and share your samples and health information for other 
research?
 
The information we collect in this study may help advance other research.  If you join this study, 
we may remove all information that identifies you (for example, your name, medical record 
number, and date of birth) and use these de-identified samples and data in other research.  It 
won’t be possible to link the information or samples back to you.  Information and/or samples 
may be shared with investigators at our hospitals, at other academic institutions or at for-profit, 
commercial entities.  You will not be asked to provide additional informed consent for these 
uses. 
 
Will you get the results of this research study? 
 
You and your doctor should not expect to get information about the results of the research study or the 
results of your individual participation in the research study.  We will study samples and information 
from many people.  It could take many years before anyone knows whether the results have any meaning.  
There is a small chance that we could find out something from the study that might be important to your 
health.  If this happens, we may contact you to find out if you would like to learn more.  However, even if 
we find something important to your health, we cannot guarantee that you will be contacted. 
 
 
What are the risks and possible discomforts from being in this research  
 
Risks of Taking Cannabidiol 
 
Taking cannabidiol may cause you to have one or more of the side effects listed below. 
 
Common side effects: 
• 
Sleepiness 
• 
Decreased appetite 
• 
Diarrhea 
• 
Increase in liver enzymes 
• 
Feeling very tired and weak 
• 
Rash 
• 
Sleep problems 
• 
Infections 
 
Less common side effects: 
• 
Suicidal thoughts or actions (about 1 in 500) 
 


 
 
 
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There may be other risks of cannabidiol that are currently unknown. 
 
Cannabidiol may cause liver problems. Call the study doctor right away if you develop any of these signs 
and symptoms of liver problems during treatment with cannabidiol: 
• 
loss of appetite, nausea, vomiting; fever 
• 
feeling unwell, unusual tiredness 
• 
yellowing of the skin or the whites of the eyes (jaundice) 
• 
itching 
• 
unusual darkening of the urine 
• 
right upper stomach area pain or discomfort 
 
Cannabidiol may cause you to feel sleepy, which may get better over time. Other medicines (e.g. 
clobazam) or alcohol may increase sleepiness. Do not drive, operate heavy machinery, or do other 
dangerous activities until you know how cannabidiol affects you. 
 
Like other antiepileptic drugs, cannabidiol may cause suicidal thoughts or actions in a very small number 
of people, about 1 in 500. Call the study doctor right away if you have any of these symptoms, especially 
if they are new, worse, or worry you: 
• 
thoughts about suicide or dying 
• 
attempt to commit suicide 
• 
new or worsening depression 
• 
new or worsening anxiety 
• 
feeling agitated or restless 
• 
panic attacks 
• 
trouble sleeping (insomnia) 
• 
new or worsening irritability  
• 
acting aggressive, being angry, or violent 
• 
acting on dangerous impulses 
• 
an extreme increase in activity and talking (mania) 
• 
other unusual changes in behavior or mood 
 
As with any drug, an allergic reaction can occur.  Allergic reactions can be mild or more serious, and can 
even result in death.  Common symptoms of an allergic reaction are rash, itching, skin problems, swelling 
of the face and throat, or trouble breathing.  If you think you are having an allergic reaction, call the study 
doctor right away.  If you are having trouble breathing, call 911 immediately.  
 
Risks to an Embryo or Fetus, or to a Breastfeeding Infant 
 


 
 
 
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The effect of cannabidiol on an embryo or fetus (developing baby still in the womb), or on a 
breastfeeding infant, is unknown and may be harmful.  Because of these unknown risks, women 
cannot take part in this study if they are: 
• Pregnant 
• Trying to become pregnant  
• Breastfeeding 
 
If you are a menopausal woman and have not had a menstrual period for the past 12 months or more, you 
will not need to have a pregnancy test.  Also, if you have had any well-documented method of surgical 
sterilization, you will not need to have a pregnancy test.  Methods of surgical sterilization include having 
had a hysterectomy (removal of the uterus), bilateral oophorectomy (removal of both ovaries), a tubal 
ligation (having your tubes tied), and transvaginal occlusion (plugging the opening of the tubes with a 
coil).  All other female subjects must have a negative pregnancy test before starting the study drug. 
 
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below.  You must use birth control for the entire study and for at least one 
(1) month after your last dose of study drug.  
 
Acceptable birth control methods for use in this study are: 
• hormonal methods, such as birth control pills, patches, injections, vaginal rings, or 
implants 
• barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, 
cream, or gel that kills sperm) 
• intrauterine device (IUD) 
• abstinence (no sex) 
 
If you miss a period, or think you might be pregnant during the study, you must tell the study 
doctor immediately.  If you become pregnant, you must stop taking the study drug and stop 
taking part in the study.   
 
Risks of Taking Cannabidiol with Other Medications 
 
Do not take valproate, clobazam, theophylline, caffeine, alcohol, bupropion, efavirenz, diflunisal, 
propofol, fenofibrate, gemfibrozil, lamotrigine, morphine, lorazepam, phenytoin, or diazepam while you 
are in the study. Taking these drugs and cannabidiol together may cause serious side effects. 
 
For your safety during this study, call your study doctor BEFORE you take any: 
• 
new medications prescribed by your own doctor 
• 
other medications sold over-the-counter without a prescription 
• 
dietary or herbal supplements 


 
 
 
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Subject Identification 
 
Only a small number of people have taken cannabidiol.  Therefore, we don’t know about all the side 
effects that can happen when taking cannabidiol with other drugs. 
 
Risks of Blood Draws 
 
You may have a bruise (a black and blue mark) or pain where we take the blood samples.  There is also a 
small risk of infection, lightheadedness, and/or fainting.  
 
 
Risks of Gathering Sensitive Information 
 
Some people may find answering questions about their emotional state and substance use or other 
personal behaviors upsetting. Although safeguards are put in place to protect your privacy, it is possible 
that a breach in confidentiality could occur. In that event, there is a risk of confidential sensitive 
information being accessible by others. This could be emotionally distressing. 
 
Risks Regarding the Psychological tests 
 
As described above, we will be using a computerized psychological tests to see how cannabidiol affects 
your cravings, decision making, attention to drugs, and reaction to stressors. Some of these tests will 
show you images that might resemble situational or environmental triggers in your life that could 
typically cause you to crave opioids. There is a possibility that you could experience mild to moderate 
opioid cravings in response to the images shown in the cue-reactivity testing. This could be emotionally 
distressing.  There are measures in place to assess your well-being after the procedure, including a 
standard relaxation and debriefing exercise. If needed, you will be referred for further clinical evaluation 
and assistance.  
 
If we learn information from you during this study that indicates an intent to seriously harm others or 
yourself, we may be required by law to share that information with third parties, including public safety 
or law enforcement authorities, and may take other precautions to protect against such harm. 
 
What are the possible benefits from being in this research study? 
 
You may not benefit from taking part in this research. Others with opioid use disorder may benefit in the 
future from what we learn in this study.  
 
What other treatments or procedures are available for your condition? 
 


 
 
 
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Subject Identification 
You do not have to take part in this research study to be treated for substance use disorder. Other 
treatments or procedures that are available to treat substance use disorder include: 
 
- individual psychotherapy or group therapy 
- peer recovery services, like Narcotics Anonymous (NA) 
 
Talk with the study doctor if you have questions about any of these treatments. 
 
Can you still get medical care within Mass General Brigham if you don’t 
take part in this research study, or if you stop taking part?  
 
Yes.  Your decision won’t change the medical care you get within Mass General Brigham now or in the 
future.  There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive.  
 
We will tell you if we learn new information that could make you change your mind about taking part in 
this research study. 
 
What should you do if you want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed.  
 
Will you be paid to take part in this research study? 
 
We will pay you $100 for completing the baseline visit, $50 for completing the second visit, and then 
$100 for completing the third visit. 
 
We may be using an approved outside vendor (Advarra Technology Solutions) to make these payments to 
you via a reloadable credit card-based system, called Advarra Participants Payments. This secure system 
is similar to a gift card or credit card.   
 
If you are paid by this system, you will be given a Participants Payments Visa card when you enroll in the 
study. Once the card is activated, the study team will add a payment after each paid visit you complete. 
The payment should be available to you within a day. You may use the card anywhere Visa cards are 
accepted, such as at a grocery store.      
 


 
 
 
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Subject Identification 
We will need to collect your Social Security Number in order to make these payments, and it will be 
shared securely with the company that runs the card-based system.  Payments like this are considered 
taxable income.  If you receive more than $600, the payment will be reported to the IRS as income by the 
hospital. 
 
If you provide a receipt for something like travel expenses and we can cover that, that is not considered 
taxable income.  Reimbursement of expenses will not be made using the Participant Payments card. 
 
We will pay for parking in the hospital garage during study visits if you require parking.  
 
We will pay for the cost of your public transportation (MBTA) up to $30 total, and/or parking in the 
hospital garage up to $30 total.  
 
What will you have to pay for if you take part in this research study? 
 
The President and Fellows of Harvard College, a non-profit organization is providing the funding to 
purchase the cannabidiol at no cost to you. 
 
Study funds will pay for all study-related procedures and study visits that are done only for research. 
 
We may bill your health insurer for, among other things, routine items and services you would 
have received even if you did not take part in the research. You will be responsible for payment 
of any deductibles and copayments required by your insurer for this routine care or other billed 
care. If you have any questions about costs to you that may result from taking part in the 
research, please speak with the study doctors and study staff. If necessary, we will arrange for 
you to speak with someone in Patient Financial Services about these costs. 
 
What happens if you are injured as a result of taking part in this 
research study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this research 
study.  We reserve the right to bill your insurance company or other third parties, if appropriate, for the 
care you get for the injury.  We will try to have these costs paid for, but you may be responsible for some 
of them.  For example, if the care is billed to your insurer, you will be responsible for payment of any 
deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay you or give 
you other compensation for an injury, should one occur.  However, you are not giving up any of your 
legal rights by signing this form. 
 


 
 
 
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Subject Identification 
If you think you have been injured or have experienced a medical problem as a result of taking part in this 
research study, tell the person in charge of this study as soon as possible.  The researcher's name and 
phone number are listed in the beginning of this consent form.
If you take part in this research study, how will we protect your privacy? 
 
Federal law requires Mass General Brigham to protect the privacy of health information and 
related information that identifies you.  We refer to this information as “identifiable 
information.” 
 
In this study, we may collect identifiable information about you from: 
• Past, present, and future medical records 
• Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable information and why they may need 
to do so: 
• Mass General Brigham researchers and staff involved in this study 
• The sponsor(s) of the study, and people or groups it hires to help perform this research or 
to audit the research 
• Other researchers and medical centers that are part of this study 
• The Mass General Brigham ethics board or an ethics board outside Mass General 
Brigham that oversees the research 
• A group that oversees the data (study information) and safety of this study 
• Non-research staff within Mass General Brigham who need identifiable information to do 
their jobs, such as for treatment, payment (billing), or hospital operations (such as 
assessing the quality of care or research) 
• People or groups that we hire to do certain work for us, such as data storage companies, 
accreditors, insurers, and lawyers 
• Federal agencies (such as the U.S. Department of Health and Human Services (DHHS) 
and agencies within DHHS like the Food and Drug Administration, the National 
Institutes of Health, and the Office for Human Research Protections), state agencies, and 
foreign government bodies that oversee, evaluate, and audit research, which may include 
inspection of your records 
• Public health and safety authorities, if we learn information that could mean harm to you 
or others (such as to make required reports about communicable diseases or about child 
or elder abuse) 


 
 
 
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Subject Identification 
• Other:        
 
Some people or groups who get your identifiable information might not have to follow the same 
privacy rules that we follow and might use or share your identifiable information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your identifiable information to perform additional research on 
various products or conditions, to obtain regulatory approval of its products, to propose new 
products, and to oversee and improve its products’ performance.  We share your identifiable 
information only when we must, and we ask anyone who receives it from us to take measures to 
protect your privacy.  The sponsor has agreed that it will not contact you without your 
permission and will not use or share your identifiable information for any mailing or marketing 
list.  However, once your identifiable information is shared outside Mass General Brigham, we 
cannot control all the ways that others use or share it and cannot promise that it will remain 
private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your identifiable information.  Your permission to use and share 
your identifiable information does not expire. 
 
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifiable information will not be used for these 
purposes without your specific permission. 
 
Your Privacy Rights 
 
You have the right not to sign this form that allows us to use and share your identifiable 
information for research; however, if you don’t sign it, you can’t take part in this research study. 
 
You have the right to withdraw your permission for us to use or share your identifiable 
information for this research study.  If you want to withdraw your permission, you must notify 
the person in charge of this research study in writing.  Once permission is withdrawn, you cannot 
continue to take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others, and such information may continue to be used for certain 
purposes, such as to comply with the law or maintain the reliability of the study. 
 


 
 
 
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Subject Identification 
You have the right to see and get a copy of your identifiable information that is used or shared 
for treatment or for payment.  To ask for this information, please contact the person in charge of 
this research study.  You may only get such information after the research is finished.  
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
▪ 
I have read this consent form. 
▪ 
This research study has been explained to me, including risks and possible benefits (if any), other 
possible treatments or procedures, and other important things about the study. 
▪ 
I have had the opportunity to ask questions. 
▪ 
I understand the information given to me. 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to be used 
and shared as described above. 
 
 
 
 
 
 
 
 
Subject 
Date Time (optional) 
 
 
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
▪ 
I have explained the research to the study subject. 
▪ 
I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date Time (optional)


 
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Consent Form Version:  4/21/2022 
 
Statistical Analysis Plan 
 
Descriptive statistics were used to summarize the data. The differences in heart rate, systolic blood 
pressure, and diastolic blood pressure recordings at 60 minutes post-dosing of CBD or placebo and at 
baseline values were compared. Cue-induced craving was calculated as the difference in post-cue craving 
scores in response to drug-related cues minus pre-cue craving scores. Attentional bias was calculated as 
the difference in reaction time to neutral cues and drug-related cues among drug-neutral trials with a 
correct response, such that positive scores indicated attentional bias towards drug-related cues. Scores 
from the IGT was calculated as the sum of the numbers selected from decks C and D, minus the number 
of cards selected from decks A and B. Delayed discount was calculated using a standardized conversion 
from the MCQ. Distress tolerance was measured as the number of seconds that participants persisted in 
the third trial of the MPTP. Paired t-test were used in all analyses, with alpha set at 0.05.