A Single-arm, Open-label Feasibility Pilot of Cannabidiol as an Adjunct to Sublingual Buprenorphine on Cue-induced Cravings Among Individuals With Opioid Use Disorder
Phase: PHASE2
Conditions: Opioid-use Disorder
Sponsor: Brigham and Women's Hospital

 
 
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Cannabidiol Use to Reduce Cravings in Individuals with Opioid Use Disorder on Buprenorphine 
 
 
 
 
NCT04192370 
 
 
 
 
 
Document Date: 12/17/21 
 
 

 
 
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Detailed Protocol 
 
Title: A single-arm, open-label feasibility pilot of cannabidiol as an adjunct to buprenorphine or 
methadone on cue-induced cravings among individuals with opioid use disorder 
 
Principal Investigator: Joji Suzuki, MD 
 
Version Date: 12/17/2021 
 
I. Background and Significance:  
 
 
Retention in medication treatment for opioid use disorder (OUD) decreases 
overdose mortality: Medication treatment for OUD with buprenorphine, methadone, or 
extended-release naltrexone reduces the risk for overdose by 70%.1,2 As such, the current director 
of National Institute on Drug Abuse (NIDA) cites the increase in access to medications for OUD 
as one of the four central aims in reversing the opioid crisis.3 However, treatment dropout rates 
remain unacceptably high—approximately 50% of patients will have discontinued treatment 6 
months after initiation.4 Therefore, there is a critical need to ensure patients not only have access 
to medications, but also are retained in treatment longer.  
 
Cravings play a central role in OUD relapse and treatment discontinuation: There is 
a substantial body of research indicating that high rates of treatment discontinuation are due to 
the emergence of intense cravings to use illicit opioids in response to cues—which are reminders 
of the drug such as drug paraphernalia.5–7 The brains of individuals with OUD are highly 
susceptible to experiencing strong cravings in response to environmental cues, and strength of 
the cravings correlates positively with the severity of the illness.8–10 Even among individuals with 
OUD who have been abstinent for over a year, strong cravings can be elicited in response to 
cues.11 Therefore, much of the research so far in improving treatment retention on medications 
for OUD have focused on helping patients learn how to avoid triggers and to manage their 
cravings if they do emerge.12–14 
 
Psychosocial treatments as adjuncts to medications have not been as helpful as 
hoped: Interventions such as cognitive-behavioral therapy and relapse prevention teach skills to 
reduce exposure to cues and to learn how to manage cravings.15 Unfortunately, in numerous 
randomized clinical trials among patients with OUD on buprenorphine, these treatments were less 
effective than one would hope for in improving treatment retention or suppressing the use of illicit 
opioids.16 As such, there is a critical need to identify novel strategies that will improve retention in 
medication treatment for OUD. 
 
Cannabidiol (CBD) has emerged as a possible adjunct to OUD treatment: CBD is a 
non-psychoactive and non-addictive constituent in marijuana. Both animal and human studies 
have identified that CBD possesses antiepileptic, anxiolytic, antipsychotic and other therapeutic 
properties, while producing minimal if any adverse effects.17,18 While the mechanisms of action 
are being elucidated, CBD is an inverse agonist at the cannabinoid receptors and appear to target 
brain regions that mediate cue-induced cravings.19 CB1 and CB2 receptors are densely located 
in striatal regions that mediate reward function, and also modulates serotonin and opioid 
receptors.20 Cannabinoid receptors also modulate nociception, inhibit pro-inflammatory 
molecules, and display synergism with systems that influence analgesia such as the endogenous 
opioid system.21 In animals, CBD administration blocks the reward-facilitating effects of morphine, 
reduces opioid withdrawal symptoms, and attenuates cue-induced relapse among abstinent 

 
 
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rats.19,20,22 In 2018, CBD was approved by the FDA for the treatment of pediatric seizures, and 
reclassified as a Schedule V drug, opening up the path for human trials.  
 
CBD reduces cue-induced cravings for individuals with OUD who are not taking any 
medications: To date, there are two double-blind, placebo-controlled randomized trials for CBD 
for OUD which have been published, but only among abstinent individuals not taking 
medications.20,22 In both studies, either CBD (400mg or 800mg) or placebo were administered for 
3 days, and the increase in cravings in response to heroin-related cues was measured. Results 
showed greater reduction in cue-induced cravings among those taking CBD compared to placebo, 
with minimal adverse effects. This adds to the growing body of data suggesting the relevance of 
CBD in modulating the attentional saliency of drug related cues which contribute to the risk for 
relapse.   
 
Impact of CBD on cue-induced cravings among individuals stabilized on 
buprenorphine is not known: A prior study of individuals with OUD who are receiving 
buprenorphine for detoxification (i.e. several days of tapering dose of buprenorphine) noted that 
participants remained highly reactive to cues.8 Results from patients on long-term methadone 
treatment implies that cue-reactivity may decrease over time.11,23 Given that long-term medication 
treatment remains the gold-standard approach, a critical question that remains unanswered is 
whether CBD can be used as an adjunct to buprenorphine treatment to reduce cue-induced 
cravings. If promising, the preliminary data will be used to seek NIDA R01 or R21 funding to 
conduct a placebo-controlled, double-blind, randomized clinical trial to examine the impact of CBD 
on cue-induced cravings among individuals with OUD taking medications. Longer-term, our goal 
is to examine the impact of CBD on treatment retention for OUD as an adjunct to medications in 
trials of longer duration. We will study the effectiveness of this approach with specific medical and 
psychiatric populations with OUD. 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. 
 
Individual differences in pain processing and central sensitization: Psychophysics, 
which is the careful and systematic testing of sensory processing in humans in a laboratory 
setting, with standardized equipment and protocols, has revealed important differences amongst 
individuals taking opioid analgesics, including higher pain sensitivity.24–28  Specifically, central 
sensitization is a process by which the spinal nociceptive system responds to sustained noxious 
peripheral input by amplifying the transmission of this signal, and has proven to be an important 
mechanism in the development of chronic pain in preclinical research.29–34  A clinical correlate of 
central sensitization is temporal summation of repetitive painful stimuli.35 Importantly, variability 
in temporal summation, measured by the increase in pain sensation during a sequence of 
stimuli, is observed among individuals and groups and may indicate an individual’s endogenous 
analgesic response.36 Temporal summation has been shown to distinguish differences between 
low- and high- opioid users37,  and risk for opioid misuse.38 By including a quantitative sensory 
testing (QST) assessment of both pressure pain threshold/tolerance and temporal summation of 
pain (TSP) in this study, we will gain valuable pilot data on: (1) how much patients with OUD on 
buprenorphine exhibit central sensitization, and how they may differ from chronic pain patients 
and healthy volunteers (from our other studies); and (2) how CBD impacts central sensitization, 
by performing a pair-wise comparison of temporal summation of pain of patients before and 
after they begin taking CBD. 
 
 
II. Specific Aims: 
 

 
 
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Study Aim:  
To determine the impact of CBD on cue-induced cravings among individuals with OUD on 
buprenorphine or methadone treatment. 
• 
In a single-arm, open-label study, subjects will receive 600mg of oral CBD once daily for 
3 consecutive days. Cue-induced cravings will be assessed before and after the 
intervention. We hypothesize that cue-induced cravings after CBD administration will be 
reduced by 50% compared to cue-induced cravings prior to the intervention. 
 
III. Subject Selection:  
 
The proposed study is a single-arm, open-label feasibility pilot. The study will enroll 12 adult 
subjects (including 2 pilot subjects) with OUD currently receiving treatment with buprenorphine 
or methadone. 
 
Inclusion criteria: 
• 
Diagnosis of DSM-5 opioid use disorder, severe 
• 
Currently in treatment with methadone or buprenorphine 
 
Exclusion criteria: 
• 
Requiring level of care higher than outpatient treatment for alcohol, sedative/hypnotics, 
or stimulants 
• 
Any current mood episode requiring level of care higher than outpatient treatment 
• 
History of psychotic disorder 
• 
Currently pregnant 
• 
Hepatic liver enzymes greater than 3x upper normal limit 
• 
Hypersensitivity to cannabinoids or sesame oil (CBD solution comes in sesame oil 
emulsion) 
• 
Currently taking any medications with known significant pharmacokinetic interactions 
with CBD 
 
IV. Subject enrollment:  
 
 
 
Adults with a DSM-5 diagnosis of OUD and who are currently in treatment with 
buprenorphine or methadone will be recruited. Inclusion and exclusion criteria are listed above, 
which are designed to favor internal validity given the preliminary nature of this trial, and to 
recruit as homogenous of a group of subjects as possible. Patients with OUD at Brigham and 
Women’s Hospital (BWH) and Brigham and Women’s Faulkner (BWF) Addiction Recovery 
Program (ARP) will be recruited via Patient Gateway for possible inclusion. Subjects will also be 
recruited from the Partners Clinical Trials website, http://Rally.partners.org, as well as print 
advertisements and flyers, which will also be distributed to local methadone and buprenorphine 
clinics. Subjects will also be recruited via automated IRB-approved recruitment emails sent from 
their providers at BWH Bridge and/or BWFH ARP through the “Patient Gateway Blast.” All study 
visits will be conducted at the BWH Center for Clinical Investigation. Study staff will perform a 
preliminary screen to establish suitability for the study. If suitable, a study staff will obtain 
informed consent and apply the inclusion and exclusion criteria. If the subject meets the full 
inclusion and exclusion criteria, the subject will be enrolled. Subjects will not be enrolled from 
among the Investigator’s own patients as the Principal Investigator is no longer seeing any 
patients clinically. 
 
V. Study procedures:  

 
 
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Overall approach: After obtaining informed consent, participants will complete the baseline 
assessments as outlined in Table 1.  The subject will then be scheduled for their study visits 2 
and 3.     
 
Schedule of visits and assessments:  
The blood and urine 
samples (see Table 
1) collected during 
the Baseline Visit 1 
and Post-Exposure 
Visit 3 will be used 
only for 
inclusion/exclusion 
purposes. 
Specifically, 
participants who are 
currently pregnant (as 
confirmed by the 
pregnancy test), have 
hepatic liver enzymes 
greater than three 
times the upper 
normal limit (as 
confirmed by the liver 
function tests, or LFTs), or who are not taking their buprenorphine as clinically prescribed (as 
confirmed by the urine toxicology) will be excluded. Other inclusion/exclusion criteria not 
dependent on blood and urine samples are detailed elsewhere in this protocol. Baseline 
measures and the pre-exposure cue-induced cravings, anxiety, and pain assessments will both 
be conducted before the CBD administration. The first oral CBD administration will occur during 
Visit 2, following the pre-exposure assessment. Participants will be instructed to take the second 
and third oral CBD doses at home, and will be asked to complete a drug diary which will also 
assess general craving and adverse effects. Participants will be asked to take their regular dose 
of sublingual buprenorphine at their regular time, and to return to the BWH Center for Clinical 
Investigation for Visit 3 following their last home administration of oral CBD. Follow-up 
assessments, including post-exposure cue-induced cravings, anxiety, and pain assessments, 
will occur after administration of CBD. During Visits 2 and 3, general craving, anxiety, and pain 
scales will also be administered before the cue-reactivity paradigm. There will also be 
continuous physiological monitoring (vital signs: heart rate, blood pressure, respiration rate, 
oxygen saturation, and temperature) during Visits 2 and 3. Table 1 summarizes the schedule of 
visits and assessments.  
 
Cannabidiol:  
Subjects will receive 600mg of oral CBD for 3 days in an open-label fashion. Cannabidiol will be 
provided using Epidiolex™ oral solution 100mg/mL. Drug will be procured by the BWH 
Investigational Drug Services (IDS) pharmacy. The first dose will be administered at the BWH 
Center for Clinical Investigation during Visit 2 following the pre-exposure cue-induced cravings 
assessment, while doses 2 and 3 will be self-administrated at home. The CBD will be repacked 
in pre-drawn syringes for the subjects to self-administer at home. Cannabidiol will be stored at 
room temperature (68 to 77 F) in its original bottle and in an upright position. Once opened, 
Cannabidiol has a shelf life of 84 days. 
 

 
 
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Primary outcome (cue-induced 
cravings): 
The cue-induced cravings, anxiety, and 
pain assessment will be conducted 
before 
and 
after 
the 
CBD 
administration. Subjects will be shown 
both heroin-related and neutral images 
on 
a 
computer 
screen 
using 
a 
standardized protocol used in previous 
studies (Figure 1).8 The order in which 
the cues will be presented will be 
randomized and counter balanced. 
Subjects 
will 
rate 
their 
cravings, 
anxiety, and pain on a visual analog scale of 0 to 10. The images will not be repeated to limit 
habituation to the visual cues. Instead the images will be similarly matched, and utilize images 
that have evoked strong responses in prior studies.8 The cue exposure procedure will end with a 
standardized relaxation and debriefing exercise.  It is important to note that cue-exposure is a 
safe paradigm for studying craving in this population when employing debriefing procedures.39  
 
Cue-induced craving procedure: Participants will be presented with a series of 20 heroin-
specific or neutral images.  Images will be presented on a computer using a timed stimulus 
presentation on Microsoft PowerPoint. Participants will view both presentations (heroin-specific 
and neutral) for one minute each, and after presentation of all images will complete the paper-
and-pencil ratings of opioid craving, anxiety, and pain scales. This task is anticipated to take 
between 10-15 minutes to complete, depending on participant speed of responding. Participants 
will complete a standardized relaxation procedure after completion of the cue-reactivity test. 
 
Quantitative Sensory Testing (QST) Procedure: QST consists of two parts: 1) Pressure pain 
threshold and tolerance, determined by a pressure algometer; 2) Temporal summation, measured 
using repeated mechanical pinprick. 
 
1) Pressure pain threshold: Pressure algometry is the most commonly used test for static 
mechanical pressure sensation in the skin and in deep tissues. Pressure algometers 
deliver a firm and quantifiable pressure through a flat base applied to the skin. The 
electronic pressure algometer that we will use (Wagner Instruments) is a hand-held 
algometer utilizing a pressure-sensitive strain gauge, covered by a 0.5 cm2 circular 
probe. The probe is covered with a soft polypropylene disk, to avoid injury to the skin.  
The pressure applied through the probe is transduced, amplified, and converted to 
electrical reading on a digital display. The pressure will be slowly increased (1 lb/s) and 
the participant will be asked to note when they first feel pain and when they want the 
pressure to stop , which will be recorded as the pressure pain threshold and tolerance, 
respectively.40 This process will be repeated on the trapezius and the forearm, 
alternating between sides of the body with 20 seconds between measurements.  
 
2) Temporal summation testing methods: Mechanical pinprick pain will be assessed in a 
similar manner to our previous studies,26,41 using standardized weighted pinprick 
applicators similar to those described by Rolke et al,42 using a range of forces (128 mN, 
256mN and 512mN) which result in a painful sensation in most subjects.43 First, a single 
stimulation of the lower force pinprick will be applied to the dorsal aspect of the index 
finger between the first and second interphalangeal joints of each hand while resting 
palm down on a flat surface such  as a table or armrest, and then rated by the subject on 

 
 
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a scale of 0-10. The weight probe that induces at least some pain, but not more than 
3/10 pain will be determined, and this probe used for repeated testing. After a break of at 
least 10 seconds, a train of 10 stimuli will be applied at the same spot, at a rate of 1 
stimulation/second. The subject will rate pain on a scale of 0-10 after the first, fifth and 
tenth stimulus, then rate any ongoing pain 15 seconds after cessation of the last 
stimulus (painful aftersensations).  Temporal summation will be calculated as the change 
in pain score between the highest and lowest pain ratings in a train. 
 
Alternative approach for temporal summation of pain assessment: Tonic, deep-tissue, 
mechanical stimulation will be applied using a rapid cuff inflator (Hokanson) wrapped 
around the leg, centered around the middle of the gastrocnemius muscle in a similar 
manner to our previous studies. Pressure will then be increased at approximately 5-10 
mmHg/s, at which time participants will be asked to note when they first start feeling pain 
and then when they feel as though the pain is a 4/10. At this point the cuff will be 
deflated. Participants will be given a 30 second break. The cuff will be re-inflated to this 
previously identified pressure and held for two minutes (or until participant asks to stop), 
at which point the cuff will be deflated. Participants will be asked to rate their pain every 
30 seconds, as well as to rate any painful after sensations after cuff deflation. Temporal 
summation will be calculated as the change in pain score between the highest and 
lowest pain ratings in the 2 minutes.  
 
Figures 2 and 3 below summarize the schematic order of Visit 2 (Pre-exposure) and Visit 3 
(Post-Exposure), respectively. 
 
Compensation: Participants will be reimbursed for travel/parking, $100 for completing the baseline 
visit, $50 for completing visit 3, and $100 for completing visit 3 ($250 total for completing all visits).  
 
Pilot subjects:  
The first 2 subjects will be pilot subjects to review standard procedures. Dosage of the 
medication, side effects, cue-induced cravings assessments, and safety protocol will be 
carefully evaluated to ensure that all risks are minimized for our participants. Data from pilot 

 
 
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subjects will be especially critical for fine-tuning the baseline cue-reactivity assessment, in that 
we want to ensure participants will be sufficiently reactive to cues at baseline. If the pilot 
subjects show insufficient baseline cue-reactivity, one potential modification would be the 
development of more appropriate evocative cues. 
 
Timeline:  
The proposed project’s timeline is 
shown in Table 2. We have 
submitted the application for an 
FDA IND exemption (and have 
received the FDA IND exemption 
letter as of November 13, 2019), 
followed by the submission to the 
Partners IRB and registration of 
our trial with ClinicalTrials.gov. 
The PI will also obtain the 
Schedule V research license 
needed to conduct this trial. The 
first two months of the project will 
be devoted to hiring and training 
of research staff on the cue-induced craving protocol, and pilot testing of 2 subjects.  
Recruitment will continue for 8 months, or until target enrollment of 10 subjects is reached. The 
final month will be devoted to data analysis, manuscript preparation, and providing a final 
update to the BRI Research Oversight Committee and the BWH Health & Technology Sub-
Committee/McGraw Family Foundation. If successful, we will utilize this preliminary data to 
submit a NIDA R01 or R21 application in Year 2 for a double-blind, placebo-controlled, 
randomized trial of CBD for OUD patients on buprenorphine. 
 
Potential difficulties:  
• 
Insufficient recruitment: The director of the BWH Bridge Clinic is a collaborator to help identify 
potential subjects. The PI directs the BWF Addiction Recovery Program that treats OUD with 
buprenorphine. Together there are over 200 active patients with OUD in those programs 
receiving buprenorphine. As such, we are confident in the ability to recruit a sufficient number 
of subjects to complete the study in the proposed timeline. Nevertheless, we will also recruit 
potential subjects using Rally (rally.partners.org), and internet advertisements such as 
Craigslist. In total, we expect to screen 25-30 patients per month with these strategies, 
enrolling at least 5% of those we screen, leading to the target enrollment of 10 subjects in 8 
months.  
• 
Insufficient baseline cue-reactivity: Cue-reactivity among OUD patients taking buprenorphine 
for at least one month is not known. Prior studies have demonstrated that OUD patients 
stabilized long-term on methadone remain cue-reactive, but at lower levels.23,44 In the study 
by one of the consultants to this project (Dr McHugh), subjects taking buprenorphine for 
detoxification (i.e. for a few days) were sufficiently reactive to cues.8 As such, in order to 
ensure enrollment of subjects who are cue-reactive, we will enroll subjects who have been 
stable for at least a month, but not more than one year of treatment. We believe this will ensure 
enrollment of the most homogenous population of subjects who are sufficiently reactive to 
cues. In addition, we will evaluate cue-induced anxiety (on a visual analog scale of 0 to 10) 
concurrently, which will provide valuable information about the impact of CBD even if subjects 
do not respond with cravings to cues.  

 
 
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• 
Sex differences in cue-reactivity: Prior research has indicated that females may be more 
reactive to cues.20 Our pilot study will not be powered to detect sex differences. Nevertheless, 
based on the results of this study, future studies can be powered sufficiently to account for 
sex differences in cue-reactivity.   
 
 
VI. Biostatistical analysis: 
 
 
Our primary interest in this pilot study is in estimating the effect sizes and variance in the 
outcomes to inform the design of a larger randomized trial. We will calculate the effect size 
representing the magnitude of change over time in the cue-reactivity score, defined as the 
difference in scores between heroin-related and neutral cues. The primary outcome is the 
change in cue-induced craving from pre-exposure to post-exposure. If the change in cravings is 
normally distributed, then a paired-samples t-test will be used to examine the statistical 
significance of the change in cue-induced craving. Accounting for the possibility of reduced cue-
reactivity for participants taking buprenorphine compared to those not taking any medications, 
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. 
 
VII. 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 cue-exposure, suicidal ideation, cannabidiol 
medication, buprenorphine medication, and cue-reactivity safety. 
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 

 
 
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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 
developed. The candidate is a board certified psychiatrist, and will be able to ensure that 
appropriate services are received.  
Adverse reactions to cue-exposure: The cue exposure procedure 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 is a safe paradigm for studying craving in this population when employing debriefing 
procedures.39 
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 M.I.N.I. screen or 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 pilot trial will receive 600mg of 
cannabidiol for 3 consecutive days. 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. This protocol has been reviewed by the Center for Drug Evaluation and Research at 
the Food and Drug Administration to determine whether it meets the regulatory criteria for an 
exemption from the requirement for the submission, and we received the FDA IND exemption 
letter November 13, 2019. 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.20,22 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 potential risks. The principal investigator will continually assess and 
monitor adverse effects both during and after cannabidiol administration, as noted in the 
Schedule of Measures. 
Buprenorphine medication safety: All subjects in this pilot trial will be stable on 
buprenorphine prior to enrolling, and were thus previously deemed appropriate for the 
medication by their buprenorphine-waived physician. Buprenorphine has been tested 
extensively and is FDA-approved for the treatment of OUD. Indeed, medication-assisted 

 
 
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treatment (with buprenorphine, methadone or naltrexone) is the standard of care for the 
treatment of OUD. Because buprenorphine is a partial mu-opioid agonist, the medication can in 
some individuals cause intoxication, especially if used intravenously. As such, only the 
combination tablet that contains naloxone will be used, unless the participant has a documented 
allergy to naloxone. The combination tablet will produce a clinically significant opioid withdrawal 
if injected. All participants will be told of this reaction, and will also be asked to refrain from 
injecting the medication. Buprenorphine can also cause a mild euphoria and respiratory 
depression, but much less than compared to full agonists. The candidate has extensive 
experience managing OUD patients with buprenorphine, and is well versed in the appropriate 
clinical management of any emergent side effects from buprenorphine. Subjects will also be 
advised that ingesting buprenorphine with other sedative drugs, such as benzodiazepines, 
dramatically raises the possibility for a synergistic reaction that can cause an overdose or even 
death. Individuals with any underlying liver disease or have a history of hepatitis C will be 
informed that buprenorphine use has been rarely associated with liver failure, and that liver 
function test will be obtained. Subjects will be informed that buprenorphine medication should 
be stored in a secure location, ideally with a lock-box, to ensure no one else can access the 
medication including children.  
Cue-reactivity testing safety: The risks associated with the proposed study are 
minimal.  It is hypothesized that participants may experience mild to moderate and transient 
opioid craving in response to images.  All participants will be currently in stable treatment with 
sublingual buprenorphine.  Nonetheless, if a participant experiences more than mild to 
moderate distress at any time during the study, he or she will be given the option to discontinue 
participation and to meet with a research staff member.  Study staff will conduct informal 
assessment of craving following completion of the study and if the distress persists, the principal 
investigator will be notified to determine whether further assessment is indicated. Dr. Suzuki is 
extensively trained in managing patient in acute distress. 
Pressure pain and temporal summation of pain testing: All procedures will be 
performed only with the approval of Partners Human Research Committee. Written informed 
consent will be obtained from every subject by one of the study team members. We will 
demonstrate the nociceptive testing during the consent process, performing the procedure in 
front of potential subjects, and offering participants the option to discontinue quantitative 
sensory testing at any time. There is a slight chance of mild transient bruising associated with 
use of the algometer. In our experience with previous studies, this is quite rare (< 5 % of cases). 
No skin breakage has been observed by investigators in previous studies or reported in 
literature with the specially machined pinprick probes. Despite not breaking the skin, all pinprick 
probes will be disinfected in a 10% bleach solution between participants. Both QST measures 
(pressure algometer and pinprick probes) will be demonstrated to the patient on study staff as 
part of the informed consent process. 
 
VIII. Potential 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. 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 treatment is an FDA-approved treatment for the treatment of 
OUD, and reduces illicit opioid use and related morbidities associated with opioid use disorders. 
This study will generate valuable information about the effect of combining cannabidiol with 
stable doses of buprenorphine for patients with OUD. The results will help inform the direction 

 
 
12 
 
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. 
 
 
IX. 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. All study staff are primarily located at 
Brigham and Women’s Hospital. Study safety meetings, including the principal investigator, 
study coordinators, and study physicians will occur regularly to review the progress of currently-
enrolled subjects and any reported side effects. 
 
 
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. 
 
 
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.  
 
 
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