A Randomized Placebo-Controlled Evaluation of the Safety of Oral Cannabidiol in a Clinically Relevant Model of Opioid Withdrawal
Phase: PHASE1
Conditions: Opioid Withdrawal, Opioid Craving, Opioid Use Disorder
Sponsor: Johns Hopkins University

 
Cover page 
 
Oral Cannabidiol for Opioid Withdrawal 
NCT04238754 
June 28, 2021 
 

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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JHM IRB - eForm A – Protocol 
 
 
 
• Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
• When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
************************************************************************************** 
1. 
Abstract 
a. Provide no more than a one-page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research. 
 
Based on preclinical research and emerging human research, cannabidiol (CBD; a major constituent of the 
cannabis plant) is a promising pharmacotherapy for the treatment of opioid withdrawal.  Most recently, 
CBD decreased cue-induced craving and anxiety (two common withdrawal symptoms) among abstinent 
heroin-dependent individuals relative to placebo.  Despite promising data, there are no funded studies 
which are prospectively designed to rigorously test the ability of CBD to decrease opioid withdrawal 
symptoms.  As of June 2018, Epidiolex, an oral formulation of plant-derived pure CBD, has been approved 
by the U.S. Food and Drug Administration (FDA) for treating severe forms of epilepsy and can be 
prescribed for other off-label indications.  Epidiolex has a low side effect and high safety profile. 
Preclinical evidence has suggested that the cannabinoid system contributes meaningfully to the opioid 
withdrawal syndrome and withdrawal symptom severity. Given the recent FDA approval of Epidiolex, and 
a growing interest to develop existing pharmaceuticals to address issues related to OUD and its recovery, 
we are proposing a pilot study to examine the safety of Epidiolex in a human laboratory model of clinically 
relevant withdrawal.  Results may be used to support an R01 grant application to more closely examine this 
hypothesis. 
 
2. 
Objectives  
 
The objective of this research study is to collect data to support a NIDA grant application.  Data collected 
for this study will establish: (1) the safety of administering two dosing regimens of Epidiolex within our 
withdrawal paradigm and (2) the feasibility of our withdrawal paradigm for demonstrating clinically 
meaningful increases in withdrawal. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
The increasing prevalence of opioid use disorder (OUD) is a public health crisis contributing to substantial 
economic and societal burden1 2.  The treatment of OUD, even with the most efficacious interventions, is 
characterized with high rates of relapse (i.e., > 50% relapsed within 6 months of treatment initiation)3.  
Managing withdrawal is critical for ensuring successful treatment retention and outcomes 4-8.  Adjunctive 
pharmacotherapy is one way to address persistent opioid withdrawal symptoms and craving.  Based on 
preclinical research and emerging human research, cannabidiol (CBD; a major constituent of the cannabis 

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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plant) is a promising pharmacotherapy for the treatment of OUD.  There is preclinical support that the 
endocannabinoid system is influential in the expression of opioid withdrawal9.  Cannabinoid type 1 (CB1)  
receptors are co-localized with mu-opioid receptors and cannabinoid agonists and endocannabinoid 
catabolic enzyme inhibitors have all shown evidence for opioid withdrawal suppression9-11.   
 
Over the last 40 years, preclinical evidence has accumulated indicating that CBD can mitigate symptoms of 
opioid withdrawal and decrease opioid seeking behavior in rodent models12-18.  In clinical research, 
retrospective analyses indicate that the use of cannabis products may be helpful for increasing opioid 
treatment retention19-21.  Two human lab studies (N= 6 and n = 42) on this topic demonstrated that a single 
dose of oral CBD decreased cue-induced craving and anxiety (two common withdrawal symptoms) among 
recently abstinent heroin-dependent individuals relative to placebo22 23.  In an effort to further characterize 
the clinical utility of CBD, we recently conducted a crowdsourcing survey study which determined that 
individuals with OUD with CBD use indicated that CBD helped mitigate the following opioid withdrawal 
symptoms: anxiety (76%), sleep problems (45%), restlessness (36%),  and/or bone/muscle aches (36%). 
 
Despite promising data, there are no funded studies which are prospectively designed to rigorously test the 
ability of CBD to decrease opioid withdrawal symptoms.  As of June 2018, Epidiolex, an oral formulation 
of plant-derived pure CBD, has been approved by the U.S. Food and Drug Administration (FDA) for 
treating severe forms of epilepsy and can be prescribed for other off-label indications.  In September of 
2018, the DEA determined Epidiolex was a schedule V drug, further reducing barriers to conduct research 
with this promising pharmacotherapy.  Epidiolex is remarkable for its wide safety profile alone and with 
opioids and its negligible abuse liability and is therefore appealing to use among high-risk clinical 
populations.  Therefore, we plan to conduct a pilot study to establish the feasibility of our withdrawal 
paradigm and the safety of cannabidiol to treat withdrawal in a controlled setting. Within this context, we 
have incorporated two cue-attentional bias tasks which will allow us to identify the mechanisms by which 
CBD may reduce cue-induced craving and anxiety and whether changes in cue-reactivity influences 
suboptimal decision making.  First, the visual probe task will expose participants to opioid-related and 
neutral cues and evaluate the role of these cues in attentional bias.  This protocol will include two periods 
of exposure to opioid-related cues.  Length of visual cue-exposure represent distinct assays for attentional 
bias; cues shorter than 200 ms measure automatic processing, cues longer than 500 ms measure controlled 
attention processing.  Previous research has shown CBD influences automatic processing for cigarette-
related cues but not controlled processing.  To date, this effect has not been studied for opioid-related cues.  
The second cue-task will evaluate whether the presence of opioid-related cues influence decisions about 
money.  This will allow us to evaluate whether CBD impacts not only influences cue-reactivity but also 
related suboptimal decision making.  While participants complete this task, we will also collect eye 
tracking data using the Gazepoint eye tracking device, which tracks eye movement on a computer screen 
with a machine-vision camera.  These data may support a larger NIH grant application to study the efficacy 
and mechanisms of cannabidiol to treat opioid withdrawal in a rigorously controlled lab study.  
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
Study Design Overview: This study is a within-subject comparison of placebo and 800 mg of CBD. 
Participant will attend two residential sessions.  Participants will receive active drug during one session and 
placebo on the other.  The sequence of the sessions (Placebo, Active or Active, Placebo) will be 
randomized for all participants. Each of the two inpatient sessions will last 3-days /2-nights and will be 
scheduled at least one week apart.  During the sessions, participant’s will not take their regular daily 
methadone dose in order to produce an abstinence-induced withdrawal syndrome, which will allow 

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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researchers to replicate realistic elevations in withdrawal symptoms under controlled laboratory 
conditions23. This inpatient study design will provide a mechanism for rigorously assessing the initial 
feasibility and safety of CBD to mitigate clinically-relevant opioid withdrawal symptoms among 
individuals with opioid use disorder.  Participants will take the study drug (800mg CBD/20mL) once every 
12 hours for a total of 4 doses. This dosing regimen has been selected based upon evidence that four doses 
are required for Epidiolex to reach steady-state levels and that this dosing regimen is well-tolerated (23). 
Following study drug administration, participants will complete standardized opioid withdrawal measures 
and a behavioral task that can assess whether CBD reduces opioid valuation. At the end of the study, 
participants will be provided with their routine dose of methadone and transitioned back into methadone 
treatment. This model is a scientifically rigorous and feasible way to conduct this initial assessment and 
will provide the efficacy and safety data necessary to support a more thorough examination of CBD for 
opioid withdrawal management. This provides an expedient and cost-efficient way to collect the data 
necessary to support a formal NIDA R01 grant submission.  
 
Recruitment/Screening. Participants will be recruited through methadone clinics using our 
established and successful methods, and through respondent driven sampling. We will provide incentives 
($10)  to participants who refer a potential participant to the study who completes a screening visit.  
Individuals will complete a phone-screen for initial eligibility requirements and be invited for a remote 
consenting and screening visit. During the COVID-19 crisis, participants will be consented virtually.  
Participants will be able to review the consent form electronically using a secure IRB compliant method, 
and will be able to securely sign and submit the form after they have been provided ample time to read and 
ask questions related to the protocol.   Participants will promptly receive an electronic form of the consent 
and can also receive a printed version via mail, at their request.  Virtual consenting will follow IRB 
guidelines for virtual consenting procedures and will occur prior to any data collection.  
When possible, we will use DocuSign, the Institution’s approved and 21 CFR Part 11-compliant 
software, to obtain a secure electronic signature. Once the IRB approves this process, we will use the IRB-
approved consent form(s) as the base for the DocuSign template. The IRB-approved document will not be 
altered other than to overlay locations where signatures, initials, dates or other DocuSign fields will be 
added to create the study-specific DocuSign template. We will send the consent to the participant via 
DocuSign, providing a participant-specific code in advance of sending the document via DocuSign, that 
will be required when the participant accesses and signs the consent. The consent discussion may take place 
via phone or video conference (e.g. Zoom). Participants will be given adequate time to consider the 
research study and ask questions prior to signing the consent form. When ready to sign, the participant will 
enter their code, verifying that the person signing the consent is the person that we spoke with previously, 
and sign the consent within the DocuSign system. Once the participant has electronically signed, the study 
team member obtaining informed consent will be notified that the electronic form is ready for his or her 
signature. Once signing is completed by all parties, both the study team and the participant can download 
the signed consent as a PDF. The study team will also have access to the audit log and the Certificate of 
Completion.  
 
Self-report portions of the screen, including several questionnaires related to their medical and mental 
health and drug use history, will be done virtually (via phone or Zoom) with study staff.  For persons who 
do not have access to phones or when participant privacy might be challenging (e.g., for persons without 
stable housing), we will conduct self-report portions of the screen in a private room at the BPRU with 
Zoom connection to study staff in another room, to minimize participant/staff interaction. If deemed 
eligible based on self-report and interviewer-based questionnaires, participants will be scheduled to 
complete a brief in-person medical assessment consisting of a blood draw that will be tested for medical 
eligibility and a medical history and physical.  Participants will also provide a urine sample to be tested for 

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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evidence of illicit opioid and other drug use and pregnancy (if applicable). Participants will also complete 
computerized tasks (e.g., Visual Probe Task and the Cue-concurrent Choice Task) to characterize baseline 
drug cue reactivity. Participants will sign a medical release which will allow research staff to contact the 
participant’s provider to confirm (1) methadone maintenance dose and length of dose. All participants will 
be asked to sign a contraception contract in which they will agree to use an effective form of birth control 
for up to 30 days following the final session day.  
 
Session Procedures.  
Description of procedures to minimize risk during the COVID-19 pandemic for in-person sessions:  
It is not possible to conduct a portion of the screening and the inpatient protocol remotely due to the need to 
collect biological measures (e.g., blood, urine) for eligibility determination and to have continuous medical 
supervision and care during the supervised taper.  However, there are specific safety procedures that will be 
put into place to minimize person-to-person contact in the context of the COVID-19 pandemic.  First, 
during all in-person sessions, all participants will be required to wear a properly fitting face surgical grade 
mask while in the laboratory.  The exception to this policy will be when the participant is alone in their 
residential room at the Clinical Research Unit (CRU) with nobody else present. Facemasks which meet 
these requirements will be provided to participants at no cost.   Second, participants will be asked about 
potential COVID-19 symptoms upon arrival to each session and possible exposure to COVID-19.  Any 
subject who arrives reporting symptoms indicative of COVID-19 per the JHU clinical screening algorithm 
will be required to return home and participation will be paused for at least 2 weeks after which a health 
care professional must clear a return to participation (e.g., with a negative COVID-19 test).  Third, 
participants must adhere to the CRU policies for COVID-19 which are uploaded in the supplemental 
document section.  This will be provided to participants at a screening visit and/or the first day of their 
enrollment into the residential portion of the study. 
The CRU policies stipulate that participants must remain in their residential rooms unless 
completing study related activities that must take place in another room (i.e., electrocardiograms).  In order 
to address issues related to isolation or boredom, participants will have access to various recreational 
activities in their room including video games and stationary bicycling.  Participants will also be allowed to 
bring materials from their home including books and magazines.   
 
This will be a within subject comparison. Each participant will attend two 3-day inpatient sessions during 
which they will receive active drug during one session and placebo on the other.  The placebo will be a 
flavor-matched cherry liquid syrup.  2 syringes of 10mL of Study Drug + Flavored syrup (4mL Epidiolex, 
6mL flavored syrup per syringe) and 2 syringes of 10mL Placebo (flavored syrup) will be administered via 
the oral route under double-blind conditions. The sequence of the sessions (Placebo, Active or Active, 
Placebo) will be randomized and counter-balanced for all participants. Note that we do not anticipate safety 
issues with Epidiolex because of its extremely high safety profile. Participants will take the study drug once 
every 12 hours and will receive a total of 4 doses. This dosing regimen has been selected based upon 
evidence that four doses are required for Epidiolex to reach steady-state levels and that this dosing regimen 
is well-tolerated (23).  Cannabidiol (Epidiolex) will be flavor-masked with cherry-syrup by our research 
pharmacy to ensure double-blind administration.  Epidiolex dose and cherry syrup will be delivered in 2 x 
10 mL oral syringes. 
 
Eligible participants will attend two residential sessions that will last 3-days/2-nights.  Study procedures 
will take place at the Behavioral Pharmacology Research Unit’s Residential Research Unit (RRU) and the 
Clinical Research Unit (CRU); both located on the Johns Hopkins Bayview Medical Campus.  Previous 
studies suggest this design will provide a sufficient observation period to produce abstinence-induced 
withdrawal (24). Patients will be instructed to arrive at the BPRU the morning of Day 1. Research staff will 
contact the participant’s methadone prescribing clinic to confirm the participant did not receive their dose 

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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that morning. After collecting vitals and testing a urine sample for pregnancy and to confirm abstinence 
from illicit drugs, participants will receive 50% of their prescribed methadone dose, which will be prepared 
by the BPRU pharmacy, to consume under staff observation at BPRU. This dose will produce modest 
suppression of participant opioid withdrawal for an acute period of time, which will provide an opportunity 
for them to become acquainted with the session procedures while still ensuring they will show prominent 
signs of withdrawal during the study period. Initial vitals and urine testing will take place at the BPRU.  
The participant then will be transferred to the CRU where they will remain until the end of the 3rd day. 
Participants will be assessed for symptoms of opioid withdrawal and complete measures of drug craving 
and anxiety periodically throughout Day 1. The first dose of study drug (placebo or Epidiolex) will be 
administered in the afternoon (e.g., 18:00 +/- 1:00 hour) on Day 1 at the CRU.  
 
Participants will complete withdrawal ratings on a regular basis (e.g., every 4 hours) before and after study 
drug administration, except for when the participant is sleeping. This schedule will be based on the 
pharmacokinetic profile of CBD (21). Vital signs will also be measured every time withdrawal assessments 
occur (Figure 1).  
 
 
 
 
On Day 3, participants will complete a cue-induced craving task and a Cue-concurrent Choice Task, and a 
Methadone Valuation Task described below. Withdrawal ratings will continue up to study discharge on 
Day 3 and acceptability ratings of the study drug will be collected prior to discharge. Participants will be 
discharged in the afternoon on Day 3, one hour after finishing the Methadone Valuation Task. At any 
point a participant can elect to resume regular methadone dosing and remain at the unit to complete study 
participation. However, participants who take their dose before beginning the Methadone Valuation Task 
he or she will not be able to participate in the Methadone Valuation Task.  Finally, before participants 
leave, medical staff will collect a blood sample to be tested for liver enzyme levels.  For an overview of 
study procedures, please reference Figure 1.  
 
Methadone Valuation Task: The morning of Day 3, participants will complete baseline withdrawal ratings 
and be presented with the opportunity to take 50% of their usual methadone maintenance dose or earn 
money. For every 60 minutes up to 14:00 that the participant does not take the dose, they will earn a small 
amount of money (Total potential earnings= $100). At the end of the period, all participants who have not 
yet requested their methadone dose will receive it. All Day 3 methadone doses will be 50% of the 
participant’s prescribed dose. Participants will be required to remain on the unit under observation until 
06:00
Administer 
Study Drug
Day 1
Day 2
Day 3
4:00
4:00
4:00
12:00
12:00
12:00
20:00
20:00
20:00
08:00
Participants arrive,
take 50% of regular 
maintenance dose
18:00
Administer 
Study Drug
08:00
Methadone 
Valuation Task
Methadone 
provided if not 
yet consumed
Discharge
18:00
Administer 
Study Drug
06:00
Administer 
Study Drug
Figure 1. Timeline of inpatient session with approximate timing for study procedures. Gray circles indicate when 
measures of opioid withdrawal, craving, and anxiety are assessed.

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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17:00 to provide sufficient opportunity for peak effects of methadone to occur. At that time, all participants 
who show no signs of respiratory distress (SP02<96, respiration rate <8 breaths per minute) and feel safe to 
leave will be discharged. 
 
All participants will be required to stay in the unit until 17:00, to prevent them from selecting methadone 
in order to end the study prematurely and to provide an opportunity for withdrawal to decrease in severity 
before they leave. The purpose of this task is to assess the objective, behavioral economic value the 
participant places on methadone as a withdrawal-relieving medication following accumulated exposure to 
Epidiolex vs. placebo. We have developed this task by translating preclinical methodology and we will 
use this opportunity to determine whether this task is an appropriate method to include in a formal R01 
application.   
 
Visual Probe Task: The effects of CBD on attentional bias to opioid-related cues will be evaluated with a 
visual probe task.  In the task, a series of opioid (target) and composition-matched neutral (non-target) 
images are shown. Each trial begins with a fixation point before presenting a pair of images then appears on 
the left and right of the screen for either a short (e.g., 200 ms) or long (e.g., 500 ms) duration to assess 
automatic orientating and controlled attention processing, respectively. Image pairs are replaced by a probe 
(an arrow pointing upwards or downwards) in the location of either the neutral or opioid-related image. The 
probe remains on screen until the participant responds to identify the probe orientation (upwards or 
downwards) by pressing one of two appropriate response keys as quickly and accurately as possible 
(defined as a ‘correct trial’ if a correct response was made). Probes replace the opioid-related and neutral 
images equally often. The position of image type, probe location and stimulus duration is counterbalanced. 
Trials are displayed in a single block with each pair presented eight times, producing both critical and 
neutral trials. The task begins with four buffer trials. Trial order is randomized each time the task is run.  
 
Cue-concurrent Choice Task:  The effects of opioid-related cues on concurrent choice will be evaluated 
using a cued concurrent choice task.  Participants will be instructed that they will be asked to make 
choices about different amounts of money that they would like to earn.  Participants will be instructed that 
they should consider the choices carefully because they will randomly receive five of the monetary 
outcomes they chose. This task consists of a series of trials in which concurrent choice is evaluated 
between two monetary values (e.g., $0.10 versus $0.05). Each concurrent choice is immediately preceded 
by two visual stimuli presented side-by-side. On opioid trials, one image is opioid-related and the other is 
a paired neutral image. Opioid-related images include depictions of prescription pills or heroin and/or 
related drug paraphernalia. Paired neutral images are chosen to match the number of objects, color, and 
size of opioid images. On neutral filler trials, both images are unrelated to opioids or opioid paraphernalia 
(e.g., furniture pieces). All trials begin with a fixation point presented for 1000 ms in the center of the 
screen. The two visual stimuli then replaced the fixation point and are displayed for 2000 ms. Finally, a 
monetary value appears below each image and participants are instructed to select the monetary reinforcer 
they want to receive. Participants will receive their money choices from 20 random trials which could earn 
them an additional $5. Potential earnings will be explained prior to starting the task to increase 
engagement with the task. 
 
Methadone Reinduction: At the end of the Methadone Valuation Task, all participants who have not yet 
requested the methadone dose will receive their dose. All Day 3 methadone doses will be 50% of the 
participant’s prescribed dose. Participants will be required to remain on the unit under observation until 
17:00 to provide sufficient opportunity for peak effects of methadone to occur. At 17:00, all participants 
who show no signs of respiratory distress (SP02<96, respiration rate <8 breaths per minute) and feel safe 
to leave will be discharged. Any participant who is unable to leave will be observed until he/she is safe ot 

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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leave or will be readmitted to the CRU one additional night. Participants will be expected to return to 
routine care upon methadone reinduction and study discharge.  
 
Diet Considerations: All participants will receive a calorie-controlled, low-fat, caffeine-free diet and 
grapefruit juice will not be permitted at any time.  Food restrictions will be in place for 1 hour before and 
after study drug dosing to promote consistency in absorption across administrations and individuals. 
 
b. Study duration and number of study visits required of research participants. 
 
The study consists of one screening visit and, if eligible, two 3-day/2-night inpatient sessions scheduled 
approximately 1 week apart. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
All participants will receive placebo during one of the residential sessions to provide the most rigorous test 
of our study hypothesis that CBD will reduce the severity of some opioid withdrawal symptoms. This 
within-subject design will allow us to collect the strongest data with the smallest possible sample size. 
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
 
Routine Care will be suspended for the purpose of causing spontaneous withdrawal to assess the primary 
study outcome. Participants will be returned to routine dosing upon completion of the residential study 
session. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
A placebo control will be used to rigorously assess the study hypotheses. 
 
f. Definition of treatment failure or participant removal criteria. 
 
Participants will be removed from the study if they withdraw consent or are unable to tolerate the study 
procedures or medication. We will remove participants if they become noncompliant with study tasks or if 
information emerges that suggests the study procedures or drugs are contraindicated in the study sample. 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
Study participation will suspend standard of care treatment while participants are completing the inpatient 
study sessions.  Upon discharge, and in the case of the study ending prematurely, treatment as usual will 
resume as it was prior to the study session. Participants will be fully informed about the study design so 
they can make an informed decision regarding their participation.  
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria:  
• Aged 18-55 
• Medically cleared to take study medication 
• Are not pregnant or breast feeding 

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
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• Willing to comply with the study protocol 
• Provides urine that tests positive for methadone 
• Maintained on 40-120 mg of daily methadone with no dose changes in the past 2 weeks (verified 
through a medical release with the participant’s provider) 
 
Exclusion Criteria: 
• Meet DSM-5 criteria for past year alcohol/substance use disorder other than opioid use disorder 
• Previous adverse reaction to a cannabinoid product 
• Urine sample that tests positive for drug other than methadone 
• Self-report any illicit drug use or cannabinoid use in the past 7 days 
• Presence of any clinically significant medical/psychiatric illness judged by the investigators to put 
subject at elevated risk for experiencing an adverse events 
• Past year suicidal behavior as assessed via the Columbia Suicide Severity Rating Scale 
• History of seizure disorder 
• Past 14 day use of any of the following contraindicated medications: 
o Clobazam, Valporate 
o Moderate or strong inhibitors of CY3A4 or CYPC19 (with the exception of methadone) 
o Strong CYP3A4 or CYP2C19 inducers 
o UGT1A9, UGT2B7, CYP1A2, CYP2C8, CYP2C9, CYP2C19 substrates (with the 
exception of caffeine). 
o CNS depressants that are contraindicated with Epidiolex 
• Breathalyzer that tests positive for alcohol prior to session admission  
• Self-reported consumption of grapefruit juice within 24 hours of session admission 
• Have a history of clinically significant cardiac arrhythmias or vasospastic disease 
• Have circumstances that the study investigators believe are contraindicated with study participation 
and/or would interfere with study participation (e.g., impending jail). 
• Moderate-severe hepatic impairment as indicated by ALT or AST levels > 3x ULN and/or 
Bilirubin levels >2x ULND as evidenced by a blood test. 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Study Drugs: Cannabidiol and Methadone 
 
a. Cannabidiol (Epidiolex) has been strategically chosen for this study because it is a widely-used, 
commercially-available Schedule V cannabinoid medication that is currently indicated for seizure control 
in persons with Lennox-Gastaut syndrome and severe infantile myoclonic epilepsy, but which could be 
prescribed off-label for the adjunctive treatment of clinical pain.  Epidiolex is the only FDA-approved 
formulation of cannabidiol and we are proposing to administer 800 mg. Epidiolex has been 
administered safely to individuals with polydrug use in single doses up to 4500mg and in healthy 
participants in single doses up to 6000mg 24,25.  In open-label clinical trials among individuals with epilepsy 
and tuberous sclerosis complex patients, Epidiolex was well tolerated at doses up to 50 mg/kg/day (3500 
mg/day in a 70 kg person) for a 3-month period26,27.  Doses up to 1500mg twice daily were well tolerated 
among healthy adult participants for a 7-day period25. Epidiolex is an oral solution that will be purchased 
commercially, the research pharmacy will prepare the dose and a flavor-matched control for placebo 
dosing. A recent pharmacokinetic study reported that a 200mg dose of Epidiolex, administered orally, 
reached peak concentrations in 2-3 hours and had a half-life of 8-9 hours.  It is highly lipophilic and subject 
to extensive first-pass metabolism via the CYP 1A1, 2D6, and 2C9 pathways, which yields an active 

Date: 06/28/2021 
Principal Investigator: Cecilia Bergeria, Ph.D. 
Application Number: IRB00232412 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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metabolite (7-OH-CBD). 7-OH-CBD is believed to contribute to cannabidiol’s efficacy for seizure control 
and has a half-life of 13.3 hours, with no evidence of psychoactive effects(143).   
Epidiolex is an oral solution that will be purchased commercially, and our research pharmacy will 
prepare the dose and a flavor-matched control for placebo dosing. A recent pharmacokinetic study reported 
that a 750mg dose of Epidiolex, administered orally, reached peak concentrations in 5-6 hours after 
administration.  The same study reported that a 1500mg dose of Epidiolex, administered orally, reached 
peak concentrations 6-7 hours after administration. CBD is highly lipophilic and subject to extensive first-
pass metabolism via the CYP 1A1, 2D6, and 2C9 pathways, which yields an active metabolite (7-OH-
CBD). 7-OH-CBD is believed to contribute to cannabidiol’s efficacy for seizure control and has a half-life 
of 13.3 hours, with no evidence of psychoactive effects. 
 
b. Methadone Hydrochloride Oral Solution will be administered to participants at their prescribed dose or 
less for its indicated use (maintenance therapy for opioid use disorder). Using our standard procedure, we 
will procure the participant’s written permission to contact his or her provider to confirm (1) the 
participant’s enrollment in a methadone maintenance program for opioid dependence, (2) the participant’s 
daily dose of methadone and (3) the length of time the participant has been maintained on their current 
dose.  Methadone will be administered in a way that is within the participant’s normal dosing regimen with 
the exception that we will be administering it at our residential research unit and that one dose will be less 
than what is normally prescribed (Day 1), another dose will be omitted (Day 2) and the final dose may be 
delayed (Day 3).  Methadone is a commercially-available Schedule II medication that is currently indicated 
for management of pain, detoxification treatment of opioid addiction and maintenance treatment of opioid 
addiction.  
Following oral administration, the bioavailability of methadone ranges between 36 to 100% and 
peak plasma concentrations are achieved between 1 and 7.5 hours. Published reports indicate that after 
multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 and 126 L/h, 
and the terminal half-life (T1/2) was highly variable and ranged between 8 and 59 hours in different 
studies28,29. Methadone undergoes hepatic N-demethylation by cytochrome P450enzymes, principally 
CYP3A4, CYP2B6, CYP2C19 and to a lesser extent by CYP2C9 and CYP2D6. Since methadone is 
lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and 
other tissues may prolong the duration of methadone action despite low plasma concentrations. 
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
 
Cannabidiol: Cannabidiol is a constituent of the cannabis plant that is being actively investigated for 
efficacy in a wide range of potential indications (including anxiety and alcohol/substance use disorders, as 
evidenced by clinicaltrials.gov entries) because of its unique pharmacological mechanisms of action. 
Specifically, it acts as an inverse agonist on the cannabinoid CB1 and CB2, as a 5-HT1a agonist, as a 
positive modulator of the transient receptor vallinoid-1 (TRPV1) receptor, and as an allosteric modulator of 
the mu and delta opioid receptors10 11.  The  only empirical human studies that have examined the effects of 
cannabidiol in the context of opioid use reported that cannabidiol can reduce opioid craving and associated 
anxiety in persons with opioid use disorder.  There is preclinical support that the endocannabinoid system is 
influential in the expression of opioid withdrawal.  Cannabinoid type 1 (CB1) receptors are co-localized 
with mu-opioid receptors and cannabinoid agonists and endocannabinoid catabolic enzyme inhibitors have 
all shown evidence for opioid withdrawal suppression9 11.  Furthermore, over the last 40 years, preclinical 
evidence has accumulated indicating that CBD can mitigate symptoms of opioid withdrawal and decrease 
opioid seeking behavior in rodent models.  Together these data suggest that CBD warrants further 
examination as a legitimate treatment for opioid withdrawal symptoms. Safety studies have demonstrated 

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that CBD is well-tolerated in combination with the highly potent opioid fentanyl among individuals with a 
history of opioid use disorder28.  Finally, unlike some other cannabinoids, cannabidiol is believed to be 
relatively void of euphoric and psychoactive effects, as evidenced by an abuse liability examination that 
reported therapeutic (750mg) and supratherapeutic doses (1500mg and 4500mg) demonstrated little to no 
signal for abuse potential relative to alprazolam and dronabinol comparators24.  
 
Epidiolex will be administered via the oral route, which is the FDA-approved route of administration. 
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
N/A 
 
7. 
Study Statistics 
a. Primary outcome variable. 
Feasibility: 
• Number of participants who complete the study as intended 
• Peak change in withdrawal scores (Subjective Opiate Withdrawal Scale; SOWS29) 
during abstinence-induced withdrawal- this will provides evidence that withdrawal will 
be sufficiently quantifiable to use this model to examine Epidiolex suppression of 
withdrawal in a large-scale R01-type trial. 
 
Safety: 
• Frequency of Adverse Events (excluding symptoms of opioid withdrawal) reported 
under each condition (0, 800mg CBD) 
• Number of participants whose AST/ALT levels >3xULN at the end of the session 
according to a blood test at the end of the active drug condition 
 
Initial Efficacy: 
• Efficacy will be assessed by comparing the following outcomes between the active 
(CBD) and placebo-dosing sessions: 
o Withdrawal symptom suppression, measured through daily self-report ratings of 
withdrawal on the SOWS, evaluated as Total score and individual scores. Scores 
will be evaluated using area-under-the-curve for each day as well as peak daily 
rating.  
o Number of 30-minute intervals for which the participant selected money over 
methadone during the methadone evaluation task  
 
b. Secondary outcome variables. 
Acceptability: 
• Percent of participants who would recommend their medication to a family member or 
friend trying to taper down from opioid medications 
• Visual analog ratings of the degree to which the medication suppressed opioid 
withdrawal symptoms 
• Participant rating of medication acceptance on a 5-point acceptance rating scale 
• Attentional bias measured by the visual probe task and the cue-concurrent choice task 
 
c. Statistical plan including sample size justification and interim data analysis. 
 

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This is a within-subject pilot study to support an R01 trial.  Results will be primarily evaluated 
descriptively because the study will not be sufficiently powered or designed for formal between-
group testing. Outcomes described above will be used as preliminary data within an R01 
application.  
 
d. Early stopping rules. 
 
Participants will be discharged from the study if they leave the residential unit against medical 
advice, request to be removed from the study, express suicidal thoughts, are noncompliant with 
study tasks, or if new information becomes available to suggest this study may cause them more 
than minor harm.  
 
The study will be stopped if any of the following criteria are met: 1) participant death during 
participant or 2) five participants have AST/ALT values 3X ULN at the end of the study relative 
to baseline (collected at screening) levels. 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
Risks Associated with Cannabidiol: Cannabidiol has few contraindications. It should not be 
administered to persons with known sensitivity to cannabidiol. Epidiolex is extensively 
metabolized by the liver, therefore persons with moderate-severe hepatic impairment (defined in 
the FDA product label as ALT or AST levels >3x ULN and/or Bilirubin levels >2x ULN) who 
might have different plasma concentrations of Epidiolex as a result of liver impairment will also 
be excluded. Epidiolex has been reported to produce somnolence or sedation in up to 32% of 
patients (compared to 11% of patients receiving placebo) and this may be further exacerbated in 
persons who are taking other CNS depressants. The FDA also recommends that persons 
receiving any antiepileptic drug, of which Epidiolex is one, be screened for suicidal behaviors 
prior to beginning drug administration. Additional side effects reported in clinical trial 
examinations of Epidiolex for seizure indications in adult and child populations include 
decreased appetite, diarrhea, weight decrease, gastroenteritis, lethargy, fatigue/malaise, 
insomnia, irritability/agitation, drooling, gait disturbance, rash, hypoxia, and infections.  A 
determination of the safety of CBD during pregnancy has not yet been made. 
 
Risks Associated with Methadone: The risks associated with methadone are well known and it 
is notable that we will not be administering any dose of methadone that is higher than the dose 
the participant already receives as part of his or her routine methadone maintenance treatment. 
The potential acute side effects of methadone relevant to our protocol include constipation, 
nausea, sleepiness, vomiting, tiredness, headache, dizziness, and abdominal pain. Like other 
opioids, methadone is contraindicated in patients with respiratory depression or acute bronchial 
asthma or hypercarbia.  
 
Both methadone and Epidiolex are metabolized by CYP3A4. Although methadone will not be 
co-administered with Epidiolex, it is possible that methadone may still be undergoing 
metabolization early in the study because of its long half-life. We will monitor for any adverse 
events and believe there will be little risk of negative interactions because Epidiolex will be 
titrating up as methadone plasma levels are decreasing. The most likely effect is that participants 
will experience a more delayed onset in withdrawal from methadone, which we will be able to 
visualize as a result of our placebo control condition.  

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b. Steps taken to minimize the risks. 
 
Protection against Epidiolex risks: We have experience in the administration of study 
medications in laboratory settings and therefore anticipate few problems. Participants will be 
informed of the potential side effects and risks associated with the study drug administration. 
Participants will be free to discontinue study participation at any time without consequence. We 
will also conduct psychiatric screening during the Screening session to ensure that patients with 
current or history of psychiatric events, namely history of suicidality, are excluded from study 
participation. Further, all participants will be informed about the potential side effects of the 
study medications and will be permitted to end study participation at any time if they experience 
negative events, with no consequences.  Both methadone and Epidiolex are metabolized by 
CYP3A4. Although methadone will not be co-administered with Epidiolex, it is possible that 
methadone may still be undergoing metabolization early in the study because of its long half-
life. We will monitor for any adverse events and believe there will be little risk of negative 
interactions because Epidiolex will be titrating up as methadone plasma levels are decreasing. 
The most likely effect is that participants will experience a more delayed onset in withdrawal 
from methadone, which we will be able to visualize as a result of our placebo control condition.  
 
Protection Against Methadone Risks: Our group has experience in the administration of 
methadone and other opioids in laboratory settings and anticipate few problems. Importantly, 
we will not administer methadone in amounts greater than what is normally prescribed to the 
participant.  All drug administration will take place at the residential research unit under 
supervision of medical and research staff. 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
All study events will be monitored during weekly meetings between the study investigators and 
we will follow all IRB guidance and recommendations regarding the reporting of unanticipated 
problems of study deviations. All such problems and deviations will be documented and if they 
do not meet the criteria for immediate reporting, they will be submitted to the IRB as part of the 
continuing review (or when otherwise requested).  
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
Participants are all receiving methadone for the purpose of OUD outside of the study activities,  
and we do not believe this study poses any legal risks associated with breach of confidentiality.  
 
e. Financial risks to the participants. 
 
Participants will not incur any cost for study participation. All study medications will be 
provided to them at no cost. 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
There is no direct benefits to participants for participating in the study. This information will be 
used to support a NIDA-grant application that will help launch Co-I Bergeria’s research career. 
In addition, this information has incredible value for society, by evaluating improved methods 

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for managing withdrawal we will be able to provide empirical information to help inform 
providers as to whether CBD is an appropriate treatment resource. This is also important 
because CBD is widely-endorsed as providing therapeutic benefit but there is little-to-know 
empirical support for this approach. Thus, our data will be among the first to provide insight 
into the safety profile and potential efficacy of combining CBD with methadone in persons with 
OUD. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 
Participants will receive $30 for completing the screening visit. Participants will be paid $900 for 
study participation ($450/session), up to $5 for the cue-concurrent choice task at the end of each 
session, and will have the opportunity to earn an additional $100 in the behavioral task at the end of 
each session, for a total potential earning of $1140. This compensation is consistent with our 
previous studies. Participants will be compensated using reloadable credit cards that do not permit 
money to be withdrawn from ATMs so will not receive cash payments.  
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
 
All study-related costs will be paid for by the study. 
 
 
 

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