Cannabidiol Pharmacotherapy for Comorbid Opioid Addiction and Chronic Pain
Phase: EARLY_PHASE1
Conditions: Addiction
Sponsor: Yale University

YALE UNIVERSITY     
School of Medicine 
 
  
 
 
 
 
June 20, 2025 
Re: NCT05076370  
Attached please find the most recent protocol for the study, “Safety and Tolerability of Cannabidiol Among 
Persons with Opioid Use Disorder Receiving Methadone or Buprenorphine” (PI: De Aquino; NCT05076370).  
The goal of the study is to examine the safety, tolerability, and efficacy of oral cannabidiol (Epidiolex) as an 
adjunctive treatment for persons with comorbid opioid use disorder and chronic pain who receive opioid 
agonist maintenance treatment. 
This human laboratory crossover study will include a total of 40 participants across two consecutive phases: 
One open-label phase including 6 participants (NCT05076370), and one placebo-controlled phase including 34 
participants (NCT04587791). We obtained initial approval for the open-label study on 07/02/2020, and 
continuing reapproval for the placebo-controlled phase on 04/17/2025.  
In the open-label phase, we administered single doses of 400 mg, 800 mg, and 1200 mg of CBD, across 3 test 
sessions, using a dose-escalation paradigm. The open-label phase will ensure the collection of critical safety 
data and inform the subsequent placebo-controlled phase. The placebo-controlled phase will administer 
placebo, 400 mg, 800 mg, and 1200 mg of CBD, across 4 test sessions, in a random order. This study is 
conducted at the VA Connecticut Healthcare System and at Yale University and has been approved by the 
Institutional Review Board of both institutions (VA Connecticut Healthcare Human Subjects Subcommittee and 
Yale University Human Investigation Committee).  
Attached please find the up-to-date study protocol. If you have any questions, please do not hesitate to contact 
me at 203- 923-5711 Ext. 12916 or at the email address provided in this letter. 
 
Sincerely, 
 
 
 
Joao P. De Aquino, M.D. 
 
 
 
Department of Psychiatry 
VA Connecticut Healthcare System,  
950 Campbell Avenue, West Haven, 
Connecticut, 06516  
Phone: 203-932-5711x12916 
Fax: 203-937-3422 
Email: joao.deaquino@yale.edu 
 
 
Joao P. De Aquino, M.D. 
Assistant Professor of Psychiatry, 
Yale School of Medicine 
Assistant Chief of Inpatient Psychiatry, 
Clinical Neuroscience Research Unit (CNRU) 
Connecticut Mental Health Center 

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A. PRINCIPAL INVESTIGATOR: Joao P. De Aquino, M.D.* 
B. CO-INVESTIGATORS: Mehmet Sofuoglu, M.D., Ph.D.*, Mohini Ranganathan, M.D.*, Suprit Parida, 
M.D.* 
Authorized Prescribers: Joao P. De Aquino, M.D., Mehmet Sofuoglu, M.D., Ph.D., Mohini 
Ranganathan, M.D., Suprit Parida, M.D., Julio Nunes, M.D.*, Scott Matthews, M.D.* 
 
Research Personnel: Stephanie Dwy, R.N.*, Stacy Minnix, B.S.W.*, Christopher Cryan*, Julia 
Meyerovich, M.S.*, Rebecca Suh, B.A.*, Simon Asnes, B.S.* 
* will have access to PHI and be able to obtain informed consent 
C.  TITLE: Cannabidiol Pharmacotherapy for Comorbid Opioid Use Disorder and Chronic Pain 
D.  PURPOSE:  
The overarching goal of this study is to evaluate the potential of Cannabidiol (CBD) as an adjunctive 
treatment for comorbid opioid use disorder (OUD) and chronic pain. This is a randomized, placebo-
controlled, crossover human laboratory study investigating the dose-dependent safety and acute effects 
of CBD on measures of pain and opioid craving in outpatients with OUD receiving medication-assisted 
treatment (MAT) with methadone or buprenorphine.   
D.1. Hypothesis: 
Treatment with CBD will be safe and well tolerated, and lead to improvement in vulnerability states that 
underlie the risk of relapse. Specifically, we hypothesize that: 
a.  Primary Hypothesis: 
• Acute administration of CBD will be safe and well-tolerated by people with comorbid OUD 
and chronic pain who are on opioid agonist maintenance. Safety will be thoroughly measured with 
the Systematic Assessment for Treatment Emergent Events (SAFTEE) for adverse effects, the 
Drug Effects Questionnaire (DEQ) for abuse potential, and the Continuous Performance Test 
(CPT) and the Hopkins Verbal Learning Test (HVLT) for cognitive effects of CBD. 
b.  Secondary Hypotheses:  
• Acute administration of CBD will lead to reduction of pain sensitivity, measured by 
assessments that include Quantitative Sensory Testing (QST) of thermal pain. 
• Reduction of cue-induced craving and attentional bias to opioid cues, measured by 
assessments that include a visual probe task and the Heroin Craving Questionnaire (HCQ-14). 
c.  Exploratory Hypotheses: 
• The above-mentioned effects will be influenced by the participants’ biological sex. 
E. BACKGROUND: 
E1. The need to develop novel treatments for comorbid OUD and chronic pain. In the grip of the opioid 
crisis, it has been increasingly recognized that OUD and chronic pain have multiple points of interface. 
Growing evidence has shown that opioids increase pain sensitivity over time 1,2. Opioid craving and 
chronic pain also share clinical features and neuroadaptive traces that promote frequent relapse 3. 
Consequently, efforts to treat people with comorbid OUD and chronic pain have only been partially 
successful 4. Particularly among this population, opioid agonist maintenance may provide limited pain 
and craving relief 5. As result of inadequately treating these clinically relevant processes, the risk of 
relapse is increased.  
While methadone is still a widely used medication for comorbid OUD and chronic pain, not only it is 
associated with pain hypersensitivity (hyperalgesia), but as a full opioid agonist, it causes dose-
dependent gastrointestinal, cardiac, endocrine, and immune adverse effects – leading to lower quality of 

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life and high utilization of healthcare services 6-9. Collectively, these challenges highlight the need for 
novel therapeutics that can be used alone or in combination with opioid agonists.  
E2. The endocannabinoid (eCB) system as an emergent treatment target for comorbid OUD and chronic 
pain. The endogenous opioid and the eCB systems share signaling pathways central to pain control and 
reward 10,11. Consistent with this notion, mounting preclinical data indicate that cannabinoids may curtail 
pain and opioid-seeking behavior. A meta-analysis of dozens of non-human primate and rodent studies 
showed that the opioid dose required to produce the same acute analgesic effect was up to 9.5 times 
lower, when co-administered with a cannabinoid agonist 12. Further, convergent research shows that 
cannabinoids may reduce opioid self-administration in animals made opioid-dependent 13-15. Importantly, 
these synergistic interactions between cannabinoids and opioids may be leveraged for treatment 
purposes, as their co-administration does not potentiate hypoactivity and respiratory depression 15. 
E3. Scientific evidence vs. public opinion regarding the therapeutic efficacy of cannabinoids. To this 
date, 62% of U.S. states have authorized the use of cannabinoids for chronic pain 16. A growing number 
of states have also added OUD to the list of qualifying conditions 17. In stark contrast, treatment services 
for OUD and chronic pain often demand abstinence from cannabinoids as a sign of clinical stability 18. 
Such discrepancy accentuates the need for high-quality clinical research. In healthy humans, a meta-
analysis of experimental studies indicates that cannabinoids increase pain threshold and tolerability, 
likely by influencing affect-related pain modulation in the central nervous system 19.  Dysfunction in pain 
modulation is core feature of chronic pain, aggravating treatment refractoriness when OUD and chronic 
pain are comorbid 1,4,20-22. Yet, in disproportion to the clinical significance of the problem, thus far all prior 
studies investigating the efficacy of cannabinoids for pain relief excluded people with OUD. Only two 
studies examined the effects of oral delta-9-tetrahydrocannabinol (THC), the main psychoactive 
component of cannabis, on people with chronic pain on long-term opioid analgesic therapy (LTOT) 23,24. 
Although these studies suggested synergistic analgesia between opioids and THC, it is not clear if the 
results are generalizable to chronic pain patients with OUD. Further, there has been some concern 
about the use of THC, a compound with abuse potential, among individuals with OUD. Hence, nearly all 
the evidence on how cannabinoids affect people with OUD is observational, and the effects of 
cannabinoids in comorbid OUD and chronic pain remain to be studied systematically 25-29. 
E4. Why Cannabidiol (CBD)? CBD is a non-addictive cannabinoid with a wide safety margin – an 
especially important consideration for people with comorbid OUD and chronic pain. In 2018, CBD 
received FDA approval for treating rare forms of epilepsy 30. Since then, marked enthusiasm has 
mounted surrounding novel therapeutic applications, including chronic pain and OUD. CBD’s anti-
hyperalgesic and analgesic properties have been established across various preclinical models of pain 
(i.e., neuropathic, thermal, and inflammatory) 31-38. Among the mechanisms proposed to account these 
properties is the suppression of brain- and spinal- mechanisms of central pain-sensitization 39-41. CBD is 
also believed to enhance affect-related pain inhibition in key brain areas responsible for modulating pain 
42. Moreover, converging preclinical and human data indicate CBD’s potential to reduce opioid craving 
and relapse 43,44. In a human laboratory study involving recently abstinent people with OUD, oral CBD 
(400 or 800 mg) reduced cue-induced opioid craving, with large effect sizes 45. Notably, cue-induced 
craving is a key mechanism in relapse that is not adequately treated by opioid agonist treatments 46. 
Altogether, CBD’s pharmacological profile draws attention as a compelling two-pronged strategy to 
improve the treatment of people with comorbid OUD and chronic pain, who are heavily represented in 
populations receiving methadone maintenance 47.  
Although CBD has been safely co-administered with fentanyl in humans 48, it has not yet been given with 
methadone or buprenorphine. The high prevalence of chronic pain among people receiving methadone 
and buprenorphine maintenance, combined with the frequent and controlled dispensation, offers 
advantages in terms of participant safety, feasibility, and recruitment.  
Hence, this study will entail a human laboratory study establishing the safety of CBD in people with 
comorbid OUD and chronic pain who are on methadone or buprenorphine. This study will assess the 
effects of CBD on key treatment targets – pain sensitivity and cue-induced opioid craving. In this 

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manner, this study will yield information not only on the safety of CBD, but also on CBD’s optimal 
analgesic and anti-craving dose for OUD and chronic pain. 
In summary, this study will evaluate the safety and efficacy of CBD for comorbid OUD and chronic pain, 
which cause extremely high morbidity and mortality nationwide. Since high pain sensitivity, cue-induced 
craving, and attentional bias for opioid cues increase the risk of relapse in this population, a human 
laboratory study will improve our understanding of the dose-related safety and efficacy of CBD to 
counteract these processes. 
F.  SIGNIFICANCE: 
As outlined above, CBD has shown potential for improving several vulnerability states that underlie the 
risk of relapse. CBD’s novel mechanisms of action as compared to the currently available drugs to treat 
OUD and chronic pain, and extremely favorable side effect profile, make it a compelling compound for 
investigation as novel agent to treat comorbid OUD and chronic pain – both to expand upon the 
currently available therapeutics and to limit the medical comorbidity associated with current therapies.   
G.  PARTICIPANTS: 
An initial safety pilot phase will recruit six participants: three receiving treatment with methadone and three 
receiving treatment with buprenorphine. If the results of the pilot study support the safety of CBD 
administration in this clinical sample, 75 participants will be enrolled for the general study with comorbid 
OUD and chronic pain, for a total of 34 completers – 22 subjects (11 men and 11 women) receiving 
methadone and 12 subjects (6 men and 6 women) receiving buprenorphine. This number of enrolled 
participants is expected to account for both screen fails and dropouts. Both sub-studies will enroll 
participants who do not currently require an inpatient hospitalization.  
G.1. Inclusion Criteria: 
• Males and females, Veterans and non-Veterans, aged between 18 and 70 years old. 
• Diagnosed with OUD and currently enrolled in methadone or buprenorphine maintenance 
treatment. 
• Having chronic pain, uniformly operationalized as grade II (high-intensity) non-cancer pain for ≥ 6 
months 49. 
• Capable of providing informed consent in English. 
• Compliant in opioid maintenance treatment and on a stable dose for four weeks or longer. 
• Not meeting DSM-5 criteria for substance use disorders other than OUD or tobacco use disorder 
within the last 12 months. 
• No current medical problems deemed contraindicated for participation by principal investigator. 
• For women, not pregnant as determined by pregnancy screening; not breast-feeding; using 
acceptable birth control methods. Acceptable contraception for females includes oral 
contraceptives, contraceptive depot injections, contraceptive subdermal implants, intrauterine 
devices, or surgical contraception methods. Acceptable contraception for males includes 
condoms or surgical contraception methods. 
G.2. Exclusion Criteria: 
• Other current major psychiatric disorders deemed clinically unstable by the principal investigator, 
such as severe depression and/or active suicidal ideation.  
• Having experienced major psychosocial stressors recently (≤ 6 weeks before enrollment), at the 
discretion of the principal investigator. 
• Methadone dose under 30 mg or over 150 mg/day. 
• Buprenorphine dose over 24 mg per day. 
• Having received inpatient psychiatric treatment recently (≤ 60 days before enrollment). 
• Candidates receiving products containing either THC or CBD will be excluded. All participants will 
be asked to abstain from cannabinoids. Prior to receiving the study medication on the first test 
session, participants’ cannabinoid use will be assessed using a quantitative point-of-care 

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urine 11-nor-9-carboxy-THC concentration test with a cut-off of ≤ 50 mg/mL 146,147. If a 
participant tests greater than ≤ 50 mg/mL, they will be asked to abstain for an additional 7 to 
14 days. If 14 days after their initial THC concentration test the participant continues to test 
positive, they will not be allowed to participate in the study.   
• A physician will carefully evaluate participants for use of over-the-counter or prescription 
psychoactive drugs known to affect pain threshold or pain tolerance (including NSAIDS, 
serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g. venlafaxine, duloxetine), 
gabapentinoids, tricyclic antidepressants (e.g., nortriptyline, amitriptyline), anticonvulsant 
medications (e.g., topiramate, carbamazepine)). Only participants who are on stable doses 
(i.e., consistent daily administration of the medication for at least three months at the same 
dose following the last dose change, either increase or decrease) of these medications, and 
whose dosing schedules allow participation in the study visits, thus excluding instances of 
single-dose or temporary dosing of the medication, will be eligible as determined by principal 
investigator. If possible, the morning dose will be administered after the study visit.  
• Current, regular use of benzodiazepines, other prescription opioids, or platelet inhibitors (e.g., 
clopidogrel, apixaban, ticagrelor). 
• Current weight of less of 60 kg. 
• Allergy to sesame seed oil, which is an ingredient of the CBD formulation used. 
• Serious medical or neurological illness or treatment for a medical disorder that could interfere with 
study participation as determined by principal investigator. 
• Participants who have elevation of liver enzymes (ALT and/or AST) 2x above the normal limit or 
higher. 
H. PRIVACY: 
All information that is obtained from participants will be used for the specifically stated purposes that are 
described in this Project Description, and after approval by the HSS. The personal identifiers that are 
necessary for this research and that will be obtained are the following: Name, Medical Record Number, 
Age, Gender, Medical and Psychiatric History, and Laboratory Examination. The procedures for data 
collection and recruitment of participants, described elsewhere in the project description, are the least 
intrusive consistent with obtaining the information necessary to complete this project.  
Mehmet Sofuoglu M.D., Ph.D., Joao P. De Aquino, M.D., and Ellen Mitchell R.N will review medical 
records to extract research information. All members of the research team will review, use, and record 
the minimum amount of information necessary to accomplish the goals outlined in the protocol. No study 
related procedures will invade into participant’s privacy.  
All members of the research team have been trained on HIC and VHA privacy regulations and policies 
and training are current. The data collected as part of this study may be made available to the VA, the 
US FDA, and NIDA. Participants are informed of these possibilities in the consent form. Demographic 
and outcome data described earlier will be collected as part of this study. Personnel listed on protocol 
will have access to data containing PHI. As noted above, limited PHI may be disclosed to the FDA, as 
required. 
The settings in which informed consent discussions, other participant interviews or research procedures 
occur will provide the same privacy protections that would exist if these discussions, interviews, or 
procedures were carried out for required clinical care (private rooms, drawn curtains, etc.). The 
information will be used for this project, or disclosed to others, only as permitted by the Privacy Act, the 
HIPAA Privacy Rule, and VA policy. 
The hardcopy data will be stored in locked file cabinets on the campus of VA Connecticut Healthcare 
System. Some electronic data including demographic data, screening data, laboratory data and RN/MD 
progress notes about each visit, etc. will be stored on the VA CPRS system. 
I. SELECTION: 

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Participants will be recruited through the VA methadone and buprenorphine clinics, as well as through 
community (i.e., APT Foundation and New Era) and Opioid Treatment Programs. After the initial phone 
screening, potential participants will undergo a comprehensive evaluation, which will include medical, 
psychiatric, and drug use histories as well as physical, psychiatric, and laboratory examinations (see 
K.2. “Screening”).  
If participants are noncompliant (i.e., repeated no-shows) participation will be terminated. 
J. RECRUITMENT: 
Potential participants will be identified through responses to flyers, web postings craigslist, as well as 
clinicaltrials.gov and BuildClinical. Furthermore, the research team will reach out to local mental health 
and substance use disorder treatment facilities – including local methadone and buprenorphine clinics – 
for patient referrals.  
Participants will be asked to contact research staff through the advertisement methods listed above. If a 
participant responds to an advertisement, they will be contacting study staff. If a participant is referred 
from substance use disorder or mental health facility, research staff will require that the participant’s 
clinician contacts the participant first and then refers the participant to the research clinic. Participants 
known to us from participation in other studies who agreed to be re-contacted will also be contacted. 
The PI and some co-investigators may provide clinical care to some potential participants and/or may 
work in the clinic where some potential participants are treated. 
J.1. Build Clinical Screening: Build Clinical is an additional service that improves the predictability of 
recruitment. It involves operationalizing the study’s enrollment criteria in an online questionnaire, ahead 
of the phone screening. Build Clinical services have been successfully utilized by several investigatory 
at Yale and State of Connecticut Department of Mental Health and Addiction Services 
J.2. Phone Screening: Participants who respond to the various recruitment strategies will be provided 
the Mental Illness Research, Education and Clinical Center (MIRECC) central recruitment telephone 
number to contact a member of the research team. At the first telephone contact, a brief telephone 
prescreening will be conducted with the verbal assent of the participant. The purpose of the 
prescreening is to save both potential participants and the research staff a considerable amount of time 
and effort.  Participants find it quite burdensome to commit the time and effort for a face-to-face 
screening only to find out that they are ineligible for some obvious exclusion criterion e.g., age. At the 
very beginning of the telephone prescreening, potential participants will be first provided a summary of 
the studies they may be interested in. They will also be asked about allergies that may interfere with 
participation in the study (i.e., sesame allergies).  
If a participant expresses an interest in participating in one of the studies, the participants will be told the 
following:  
“We would like to ask you some general information to determine whether you might 
qualify for the study. This information will only be used to determine your eligibility to 
participate in research. This information will be stored in secure research files. If you 
do not want any information about you stored, we will terminate this interview now. If 
you agree to proceed ahead with this preliminary interview and seem to be eligible to 
participate in this study, we may invite you for a face-to-face meeting.” 
If they pass the initial brief screening for the study, they will then come into the clinic for a full screening 
evaluation. Upon arrival, the participants will be given the detailed consent form to read and will be 
asked questions to make sure that the participants understand the procedures and their rights and 
written informed consent will be obtained. Information collected during the phone screen will only be 
used if the participant continues to participate in the study. 

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J.3. Face to Face Screening: This will include written informed consent followed by screening 
procedures. Please see screening section under research plan for more details. 
J.4. Consent Procedures: Potential participants will be invited to meet with the research staff, who will 
fully explain the risks and procedures as outlined in the consent form. After reviewing this information 
and answering questions, informed consent will be obtained from all participants. A copy of the consent 
form will be provided to all participants. After signing the consent form, participants will proceed with 
screening. Once all screening procedures have been collected, research staff as well as the principal 
investigator will review all relevant information and determine, based on the inclusion and exclusion 
criteria, if the participant will be enrolled in the study and continue with the remaining study procedures. 
Participants already on pharmacotherapy specified in the protocol will continue use of the medications 
while participating in the current study. Participants will not be taken off their current medications for 
participation in this study.  
K. RESEARCH PLAN: 
K.1. Study design:  This project will consist of 2 sub-studies.  
K.1.1. Pilot safety data sub-study: The first study will be a pilot study in which 6 participants (3 receiving 
methadone, and 3 receiving buprenorphine) will receive ascending doses of CBD, to determine its safety 
and tolerability of this medication. Participants will be stratified based on whether they are receiving 
methadone and buprenorphine. This open-label phase will inform the conduction of the general study. 
Participants will be receiving either buprenorphine (up to 24 mg/day sublingual tablets) or methadone 
from their designated opioid treatment program and will thereby be at steady state at enrollment. 
Participants will receive consecutive doses of 400 mg, 800 mg, and 1200 mg, over a total of 3 test 
sessions, with at least 72 hours of interval between each test session, using a dose-escalation 
paradigm.  
If we encounter no clinically significant sedation or serious adverse events during the test session, 
participants will be eligible to receive the next CBD dose – at least 72 hours later. Clinically significant 
sedation will be defined as Agitation and Calmness Evaluation Scale (ACES) scores of 7 (marked 
calmness) or higher at any point during the session, or no return to baseline – assessed with vital signs, 
Mini Mental Status Exam (MMSE), and a field test – 3 hours after the administration of buprenorphine, 
or 4 hours after the administration of methadone. Serious adverse events will be defined in accordance 
with FDA guidelines. If 2 participants experience clinically significant sedation, defined as above, or 
serious adverse events, study enrollment will be stopped until the Data Safety Monitoring Board 
(DSMB). examines the findings. Randomization to distinct doses of CBD, using the general study design 
described below, will not occur before the safety data is analyzed, in consultation with the DSMB. 
K.1.2 General study: This is a double-blind, randomized, placebo-controlled, cross-over human 
laboratory study. Thirty-four male and female participants with OUD on MAT will be asked to arrive at 
approximately the same time each morning, coordinating with attendance at their opioid maintenance 
clinic. Participants will be stratified based on whether they are receiving methadone or buprenorphine. 
This will ensure that the safety and efficacy of CBD can be tested in each arm. On test days, all 
participants will be asked to refrain from caffeine, nicotine, and will be fasting on the test days. A study 
nurse will confirm with their respective program that participants did not receive either methadone or 
buprenorphine that morning and will call the program when testing is complete to permit dispersal of that 
day’s methadone or buprenorphine dose. Participants will undergo a variety of cognitive and self-report 
measures, as well as assessments to confirm restraint from illicit drug use and lack of adverse effects of 
medication. Participants are asked to have blood draws during testing session, but this is optional.  
Participants who give permission to have this blood drawn will have an IV placed will have it placed the 
morning of each test session. If a subject chooses not to have an IV, only safety bloods will be drawn. 
Prior to their daily methadone or buprenorphine dose and thus at trough plasma levels of opioid, 
participants will receive CBD (400 mg, 800 mg, 1200 mg) or placebo, over a total of four sessions. 
Subsequently, all participants will undergo laboratory testing of measures relevant to vulnerability to 
relapse, including physiological, subjective, and cognitive outcomes. Participants will be observed for at 

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least 6 hours after the administration of CBD/placebo, and for 2 hours after the administration of 
buprenorphine/methadone. In case participants experience any sedation beyond these time points, 
observation will continue, —consistent with procedures in our research clinic (HSS #JD002). The order 
of study medication administration will be counterbalanced to reduce perceived bias of study participants 
and staff. 
Justification for not requiring blood testing during test sessions: The primary aim of our study is to 
establish the safety and analgesic and craving suppression efficacy of cannabidiol (CBD) among 
persons with opioid use disorder who are receiving opioid agonist therapy. Our study was designed to 
look at pharmacodynamic effects of CBD in this population, rather than to investigate the relationship 
between pharmacokinetic and pharmacodynamic effects of CBD. Accordingly, drug levels are an 
exploratory outcome. 
While the blood collection does not represent a “critical data point” of this study, collecting these data in 
a subset of participants will allow establishing the feasibility of conducting adequately powered 
pharmacokinetic studies — a next logical step of our research. 
In conducting this work, we observed that, since a substantial proportion of our participants have a 
history of intravenous drug use, obtaining an intravenous line can often be challenging and may require 
multiple attempts that can produce participant discomfort. Therefore, by giving the participants the 
choice of opting out of this procedure, we will reduce participant burden without compromising the 
scientific aims of the study. 
K.2. Screening (Pilot and General Studies): At the screening session, the following procedures will 
take place: 
1. The participant will receive a full, written explanation of study procedures and sign a consent form. 
Any questions will be answered, and a physician or nurse will be available to answer any 
medical questions. 
2. Participants will be evaluated with a detailed medical and psychiatric history. 
3. Complete physical examination (including vital signs, height, weight and abdominal circumference). 
4. Laboratory tests, including standard screening blood tests (CBC with differential and platelet count, 
electrolytes, creatinine, BUN, liver enzymes, TSH), a urinalysis, urine toxicology use, urine 
pregnancy test (for premenopausal females), and electrocardiogram (EKG).  
5. Participants will complete several questionnaires pertaining to personality. 
6. IQ will be measured at screening using the Wechsler Test of Adult Reading or a comparable IQ 
measurement tool.   
The screening process will take approximately 2 hours. 
K.3. Consenting (Pilot and General Studies): Participants who meet entry criteria will be invited to 
meet with the research staff, who will fully explain risks and procedures as outlined in the consent form. 
After reviewing this information and answering questions, informed consent will be obtained from all 
participants. A copy of the consent form will be provided to all participants.   
The consent process is a multistep process, whereby information about the risks and benefits of the 
study will be provided to potential participants across several sessions. The number of sessions over 
which this information will be provided will depend on how well the participant understands and retains 
the information. The process begins with the participant initiating contact via telephone. The research 
staff will provide a brief description of the study following which the participant is screened by a member 
of the research team. Thereafter, potentially eligible candidates are scheduled for a face-to-face 
interview. Participants will also be informed of all potential risks of participation. Participants will be 
required to read the informed consent form and the investigator will additionally describe the risks and 
discomforts. 
To ensure that the study participant understands the study, the participant will be asked questions about 
the study procedures and the risks associated with participation. If any concern arises that the study 
participant did not fully understand the study, the PI may decide that the participant is not suitable for 

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participation. This process generally takes about one hour. If the participant is still interested after all 
questions have been answered, the PI or staff member consenting, will ask the participant to sign the 
informed consent form. Participants will be informed that they can decline to participate in the study 
without penalty and given the opportunity to withdraw from the study prior to analysis of their data. 
Following the resolution of any questions, the participants will be asked to sign the consent form if 
he/she agrees to participate. 
Great care will be taken to ensure that the participant is able to give informed consent. If any concern 
arises that the study participant did not fully understand the study, the principal investigator may decide 
that the participant is not suitable for participation.  
This process will involve careful explanation of the consent form by a member of the research staff.  
Non-research clinicians will be involved in the process when available.  
K.4. Justification of Cannabidiol Dose and Administration (Pilot and General Studies): FDA-
approved Cannabidiol, produced under Current Good Manufacturing Practice (cGMP), will be obtained 
from G.W. Pharmaceuticals, as “Epidiolex”. The bioavailability of oral CBD is 13-19% and the elimination 
half-life is 56-61 hours 50. CBD is metabolized primarily in the liver, through the enzymes CYP3A4, 
UGTA7, UGTA and UGT2B7 isoforms 51,52. Importantly, CBD has a wide safety margin and was well-
tolerated when co-administered with fentanyl, a high-potency opioid, in humans 48. The product will be 
stored in the VACHS research pharmacy as per package instructions. The research pharmacy will 
prepare CBD oil-based solutions and matching placebos, which will be administered by mouth by the 
study physician or nurse. CBD will be administered 24 hours after the last methadone/buprenorphine 
dose. A new IND is being pursued specifically for this project. 
CBD is a non-rewarding compound with a wide safety margin 30. Further, CBD has been shown to 
produce central effects including hypnotic, anticonvulsive, anxiolytic and neuroprotective effects 53.  CBD 
has been found to be a potent non-competitive inhibitor at CB-1 and CB-2 receptors 54 in addition to an 
allosteric modulator at kappa-opioid receptors, normalizing glutamatergic impairments induced by heroin 
self-administration 43. Moreover, CBD has been used in large clinical trials investigating its antipsychotic 
potential without significant adverse events 55,56.  
The oral doses of CBD administered in this study will range from 400 mg to 1200 mg. Relatively low 
doses (400 mg) of oral CBD had anti-craving efficacy and were well-tolerated by people with OUD 45. 
Hence, 400 mg will be the lowest dose used in this proposal involving people with comorbid OUD and 
chronic pain. In preclinical studies, the doses of CBD required to inhibit pain were between 10 and 50 
mg/kg 31-38,42. Even though CBD was safe and well tolerated in doses up to 4500 mg in adults (FDA 
Briefing Document, April 19, 2018, NDA 210365 Cannabidiol), the maximum recommended dose 
approved by the FDA is 20 mg/kg daily 57. The highest dose used in this study will be below maximum 
dose recommended by the FDA (up to 1200 mg in this study, compared to 1400 mg in a 70 kg or 155 lb 
person). Although higher doses can be used, this is a reasonable first step. Similarly, since CBD has 
never been administered to people comorbid OUD and chronic pain who are on opioid agonist 
maintenance, single doses in an open-label, dose-escalation paradigm will be used an initial safety 
procedure in pharmacotherapy development. The open-label, pilot safety phase will inform the doses 
used in the general study.  
Although the half-life of CBD is up to 61 hours, its pharmacodynamic effects are short-lived, so that the 
interval of 72 hours between test sessions is not expected to generate carryover effects. First, Hurd and 
colleagues did not find carryover effects when administering 400 mg or 800 mg of CBD to recently 
abstinent persons with OUD, with intervals of 3-4 days between each test session 45. Notably, as in the 
current protocol, the first 2 of the 4 test sessions in this study were conducted following a single-dose of 
CBD 45. Second, the lack of carryover effects after a 72-hour interval is consistent with local experience 
conducting Phase 1 and Phase 2 human laboratory studies involving the administration of cannabinoids.  
For instance, Skosnik and colleagues studied individual and interactive effects of THC and CBD among 
healthy humans, with an interval of 72 hours between each test session 58. Third, other lines of evidence 
support the notion of a non-linear relationship between the clinical and pharmacokinetic effects of CBD – 

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such that the pharmacokinetics of CBD can vary widely, often without alteration in clinical effects. For 
instance, administering CBD with food may alter its pharmacokinetics, without significant change in its 
clinical effects: Among adults with epilepsy, in the fed state, the average Cmax of CBD was 14 times 
higher, and the AUC0‐∞ was 4 times higher, compared to the unfed state; conversely, the antiseizure, 
neuropsychological, and safety profile of CBD remained unchanged in both conditions 59. Fourth, the 
relationship between the clinical – or pharmacodynamic – effects of drugs and their pharmacokinetic 
properties are often non-linear. This is especially true for highly lipid soluble drugs like cannabinoids, 
including THC and CBD. For example, although THC metabolites stay in the organism for several days 
or weeks – THC’s elimination half-life ranges from 25 to 36 hours –, clinical effects like analgesia or 
sedation last only several hours. 
As a result, cannabinoids like THC and CBD are often administered twice daily when used clinically, 
rather than once every 3 to 4 days, as if the pharmacokinetic and clinical effects were linear. We have 
an ongoing randomized, placebo-controlled, within-subject human laboratory study administering single 
doses of oral THC (10 mg or 20 mg) to persons with opioid use disorder treated with methadone, also 
has an interval of 72 hours between test sessions.  
The latter study has been recently reviewed and approved by the VA HSS (MS0056) and the Yale IRB 
(Protocol # 2000027065; NCT04025359). Fifth, prior studies conducted at our center suggest that a 
longer interval is likely to increase attrition of the study population – persons with comorbid opioid use 
disorder and chronic pain –, such that data collection may be compromised. Finally, we are considering 
the pharmacokinetic effects of CBD on the main study outcomes, as exemplified by the repeated 
measurements of CBD and opioid levels in our protocol. Notably, both the FDA and NIDA are in 
accordance with the proposed interval of 72 hours. 
For the general study Research Pharmacy will create a randomization sheet for this general study. Both 
the research team and participants will be blind to the randomization.  
An Environmental Assessment is not required because the action requested qualifies for a categorical 
exclusion per 21 CFR 25.31(e). To the applicant’s knowledge, no extraordinary circumstances exist per 
21 CFR 25.15(d). 
K.5. Placebo (General Study):  The study interventions include CBD (open-label safety phase); and 
CBD or placebo (general study, following the safety phase). The container in which the study medication 
and placebo are dispensed will be labeled according to 21 CFR 312.6. “Caution: New Drug--Limited by 
Federal (or United States) law to investigational use.” This study will recruit individuals receiving opioid 
agonist MAT. This study will not interfere with standard of care and will be in addition to treatment as 
usual. Safety assessments will be done in person during the scheduled experimental sessions. 
Furthermore, participants will be encouraged to remain compliant with their regular treatment sessions 
and medications. 
K.6. Outcome Measures (Pilot and General Studies): 
Data Collection Methods (General Study): In order to enhance the reliability of the data collection and 
analysis process, the web-based software toolset REDCap (Research Electronic Data Capture) will be 
utilized in this study. REDCap is a secure, web application designed for electronic collection, 
management, and storage of clinical research data. The system includes features for HIPAA compliance 
including real-time data entry validation (e.g., for data types and range checks), a full audit trail, user-
based privileges, de-identified data export mechanism to numerous statistical packages (e.g., SPSS, 
SAS, Stata, and R), and integration with the institutional Active Directory. REDCap is also compliant with 
FDA requirements, and hence is the ideal system of this FDA-supervised study (see Section M.4 for 
details). Notably, REDCap@Yale is being used in VA HSS-approved protocols (e.g., HSS #1586389), 
and the version of REDCap used in the current study has several additional layers of safety, due to is 
compliance with FDA requirements (please see section M.4. for details). 
Following informed written consent, participants will be assigned a unique study ID, which will be used 
across all REDCap surveys during both screening and experimental sessions. Once in the database, 

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participants will only be able to complete surveys via a scannable QR code provided by a research 
assistant. All REDCap data collection will be done on Yale-managed iPads. Only personable identifiable 
information (PII) (e.g.) email, age in years, and sex/gender) will be collected, no personal health 
information (PHI) will be entered into REDCap. Assisted by study staff, participants will have the option 
of using a study-specific email, rather than their personal email.  
The option to use traditional paper-survey’s will be provided if participants prefer not to use 
computerized behavioral data collection. 
Experimental Session Measures 
Safety Assessments 
Screening for alcohol intoxication: Before the start of each session, participants will be screened for 
alcohol intoxication by clinical examination (e.g., neurological exam and field test) and laboratory 
assessment (urine ethyl glucuronide testing). The use of breathalyzers will be limited due to the risk of 
exposure to SARS-CoV-2 through aerosols.  
Systematic Assessment of Side Effects (SAFTEE): To monitor adverse events from the study 
medications, the SAFTEE will be administered before and after each experimental session. This is a 
symptom checklist 60 that has been used successfully in our previous studies to assess possible side 
effects of study medications. It includes information regarding severity of any presenting side effects, as 
well as the course of action taken by study staff in response. 
Vital Signs: Heart rate, respiratory rate, blood pressure and pulse oximetry will be monitored throughout 
the session. 
Neuropsychological battery: For cognitive performance, we chose tests that are likely to be sensitive to 
CBD’s effects in our patient sample, such as the Continuous Performance Test (CPT) and the HVLT 
(Hopkins Learning Verbal Test). Continuous Performance Test (CPT) – will assess attention, 
concentration, and working memory. The outcomes will be percent correct responses and reaction time 
61. Hopkins Verbal Learning Test (HVLT) – will measure verbal memory. The outcome will be delayed 
recall 62. Both the CPT and HVLT have been used to measure cognitive performance in prior studies 
with CBD 45,63. 
Opioid Withdrawal Symptom Checklist (OWSC): This instrument will measure opioid withdrawal 
symptoms 64. 
Drug Effects Questionnaire (DEQ): Participants will rate the following items from "not at all" to 
"extremely" on a 100-mm scale: “alert,” “calm,” “confused,” “depressed,” “confused,” “high,” “anxious,” 
“sedated,” “tired,” “social,” “self-confident,” “talkative,” “hungry,” “feeling the drug strength,” “feel good 
drug effects,” “feel bad drug effects,” and “want more drug.” These items are commonly used to assess 
effects of drugs 65.  
Mini Mental Status Examination (MMSE): The Mini-Mental State Examination (MMSE) or Folstein test is 
a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive 
impairment 66. 
Agitation Calmness Evaluation Scale (ACES): The ACES consists of a single item that rates overall 
agitation and sedation at the time of evaluation, where 1 indicates marked agitation; 2, moderate 
agitation; 3, mild agitation; 4, normal behavior; 5, mild calmness; 6, moderate calmness; 7, marked 
calmness; 8, deep sleep; and 9, unarousable. The ACES is a well-validated instrument to assess 
sedation and has been used in various clinical trials 67,68. 
Field Test: The field test will consist of a finger-to-nose test; a walk-and-turn test; a Romberg test. 
During the finger-to-nose test, participants will be asked to bring tip of the index finger up to touch the tip 
of the nose while his/her eyes are closed and his/her head is tilted slightly back, six times – three with 
each hand. During the walk and turn test, participants will be asked to take nine heel-to-toe steps along 
a straight line. After taking nine heel-to-toe steps, participants will then be directed to turn on one foot 

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and return in the same exact manner in the opposite direction. During the Romberg test, participants will 
be asked to stand with their feet together, head tilted back, and eyes closed for 30 seconds. The study 
physician will look for clues of changes from baseline, such as any loss of psychomotor coordination, 
loss of balance, eyelid/body tremors, muscle tone, and ability to follow directions. 
Positive and Negative Affect Schedule (PANAS): This is a 20-item, widely used measure of momentary 
mood states, has been found to be sensitive to the mood-altering effects of several substances 69. 
 Its reliability and validity have been extensively evaluated (Ref). The PANAS consists of 20 emotion 
words, with 10 loading on the Positive Affect factor and 10 on the Negative Affect factor (10). Sample 
words for Positive Affect include “alert”, “inspired”, and “enthusiastic”. Sample words for Negative Affect 
include “distressed”, “upset”, and “guilty”. Participants rate the degree to which they endorse each item 
on a rating scale (1 = very slightly or not at all; 5 = extremely). Items are then totaled to create a score 
for each factor: Positive Affect and Negative Affect. Higher scores represent greater endorsement of the 
construct. High levels of The PANAS will be used during each session and at each weekly outpatient 
session to measure the effects of CBD on mood. 
Pain Assessments 
Brief Pain Inventory – Short Form (BPI-SF): The BPI-SF is a self-report questionnaire that assesses 
severity of pain, impact of pain on daily function, location of pain, pain medications, and amount of pain 
relief in the past 24 hours or the preceding week 70. It will be used during screening and before 
experimental sessions.  
Quantitative Sensory Testing (QST) of Thermal Pain: This is a reliable, dynamic, and computerized 
method of quantifying distinct mechanisms of the pain experience, measuring top-down pain inhibition 
and bottom-up pain facilitation (Figure 4). QST measures are sensitive to the effects of cannabinoids 73, 
important biomarkers of chronic pain, and predictors of the pain treatment response 74,75.  
Conditioned Pain Modulation (CPM): CPM measures top-down pain inhibition, by leveraging the “pain 
inhibits pain phenomena”. Higher CPM reflects supra-spinal pain modulation 76.  
Temporal Summation of Pain (TSP): TSP involves the repeated administration of noxious stimuli, 
indexing bottom-up pain facilitation 77. Higher TSP indicates the increased firing of ascending pre-
synaptic neurons, reflecting mechanisms of central sensitization. 
Pain Visual Analog Scale (VAS): The pain VAS will be used by participants as a secondary rating scale 
for pain severity before, during, and after pain testing. This scale contains a horizontal line, anchored by 
verbal descriptors of “no pain” and “pain as bad as it could be”. Participants will place a vertical line at 
the point that best indicates their present pain 79. 
Pain Catastrophizing Scale (PCS): This is a 13-item self-report scale to measure pain catastrophizing. 
Each item is rated on a 5-point scale: 0 (Not at all) to 4 (all the time). It contains three subscales: 
magnification, rumination, and helplessness 80. 
Craving and Attentional Bias Assessments  
Heroin Craving Questionnaire (HCQ-14): This instrument will measure cue-induced urges to use heroin, 
which are highly relevant for persons with comorbid OUD and chronic pain receiving opioid agonist 
maintenance 45,81.  
Opioid Attentional Bias (AB):  The primary AB measure will be a visual probe (VP) task 60. VP tasks rely 
on a tendency for individuals to respond faster to probes (e.g., small dots) when they are presented in 
an attended region of a visual display61. In the task used in this study, a drug-related word is presented 
next to a neutral word for 500 milliseconds. Subsequently, a probe (e.g., a dot) replaces the drug word 
or the neutral word. The participant’s task is to indicate the location of the probe as quickly as possible 
by pressing one of two buttons on the mobile device. Faster responses when the probe replaces the 
drug word is interpreted as an AB to drug cues. A drug Stroop task will also be used to assess 
generalization of training effects to a second AB measure. Drug Stroop tasks are a form of emotional 

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Stroop widely used in addiction studies79. Longer latency to name the color of a word when it is a drug 
word compared to when it is a neutral word is indicative of an AB to drug words. For all AB tasks, opioid 
words will be presented in separate blocks in counterbalanced order. As in our Preliminary Studies, 
neutral words are common indoor/ household (e.g., couch) and outdoor items (e.g., fence) equivalent to 
the cocaine (e.g., smoke) and opioid words (e.g., smack) in length and frequency of use in the English 
language. For opioid words, we focused on both heroin and prescription opioid medications. 
Immediately before and after the opioid dot probe task participants will be asked estimate cue-elicited 
craving with a VAS. The difference of these ratings will be used to index cue-elicited craving. 
Intake and Follow-up Measures 
Timeline Follow-Back Assessment Method (TLFB): Drug use for the past 30-day period prior to study, 
participation and throughout the period of study participation will be obtained using this self-report 
measure. Participants are given a blank calendar covering the specified time interval and are asked to 
retrospectively reconstruct their drug use over that time interval. The process is facilitated by 
establishing anchor points (e.g., holidays, anniversaries, major national events, etc.). It can be scored to 
provide the number of days on which various levels of drug use occurred. The time-line method has 
good test-retest reliability and good validity for verifiable events. It has been used in numerous studies to 
assess substance use. 
Childhood Trauma Questionnaire (CTQ): This is one of the most sensitive tools for quantifying early 
maltreatment, and it measures five categories of childhood maltreatment: Emotional, Sexual and 
Physical Abuse (EA, SA and PA), and Emotional and Physical Neglect (EN and PN) 82. Scores on the 
CTQ, specifically, correlate with both the onset and course of mental illness, As well as the structure, 
function and connectivity of critical brain regions associated with resilience and vulnerability to life 
stressors (i.e., amygdala). This outcome measure will be included in the intake session because of the 
potential role of trauma as moderator of the cannabinoid and opioid response 83. 
Hamilton Depression Rating Scale (HDRS) 84: The HDRS is the one of most widely used clinician-
administered depression assessment scale. The original version has 17 items pertaining to symptoms of 
depression experienced over the past week. This instrument will be used to assess depressive 
symptoms during screening. Candidates who meet criteria for severe depression will be excluded and 
referred for treatment.  
Columbia Suicide Severity Rating Scale (C‐SSRS) 85: The C‐SSRS is a measure used to identify and 
assess individuals at risk for suicide. Participants with active suicidal ideation will be excluded from the 
study and referred for treatment.  
K.7. Biological Specimen Collection / Phlebotomy (Pilot and General Studies): Biological 
specimens will be collected at baseline for safety/routine lab work, as well as to examine the effect of 
administration of CBD on serum methadone/buprenorphine levels, since these drugs are CYP450 
3A4 substrates 52 (Table 2). Further, we will collect potential biomarkers, including cytokines (TNF-
alpha, IL-6, and IL-10) and endocannabinoid levels (e.g., 2-Arachidonoylglycerol and anandamide) 
for exploring the relationship between cannabinoid therapeutics, analgesia, and opioid-mediated 
inflammation. Your information or biospecimens collected as part of the research, even if identifiers 
are removed, will not be used, or distributed for future studies.  
There will be a total of five blood draws in this study, one at screening and four at each test session. 
Over the course of the study, less than 175 ml (3/4 of a cup) of blood will be drawn. Participants may 
choose to not have blood draw during the testing sessions, and therefore not have an IV catheter 
placed. Those who choose not to have an IV placed during the test sessions, will have just safety 
bloods drawn 80ml (1/3 of a cup) over the course of four test sessions. Notably, the amount of blood 
drawn at screening and on each of the study visit is well within the Red Cross blood standards. 

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K.8. Schedule of Study Visits (Pilot and General Studies):  Participants will have the following 
visits (Table 1A and 1B): 
Table 1A. Experimental Design for the Pilot Study 
Day 0 
Day 1 
Day 4 
Day 7 
Day 14 
IS 
Lab Assessments 
ES 
ES 
ES 
Lab Assessments 
FU 
 
Day 0: Screening. 
Day 1:  First experimental session, where the first dose of study medication will be administered, 
and laboratory experiments will be conducted. 
Day 4: Second experimental session. 
Day 7: Third experimental session. 
Day 10: Follow-up telephone contact. 
 
 
 
 
 
Abbreviations: IS: Initial Screening; ES: Experimental Session; FU: Follow-up telephone contact 
Day 0: Screening. 
Day 1:  First experimental session, where the first dose of study medication will be administered, 
and laboratory experiments will be conducted. 
Day 4: Second experimental session  
Day 7: Third experimental session. 
Day 10: Fourth experimental session. 
Day 17: Follow-up telephone contact. 
* The same schedule of events (Table 2) applies to the pilot study and the general study, except for time point 0 
minutes. The difference is that in the pilot study, participants will receive 400 mg of CBD on the first test session, 
Table 1B. Experimental Design for the General Study 
Day 0 
Day 1 
Day 4 
Day 7 
Day 10 
Day 17 
IS 
Lab Assessments 
ES 
ES 
ES 
ES 
Lab Assessments 
FU 
Table 2. Schedule of Events During the Experimental Sessions* (72 hours apart) 
Timepoint 
Measures and Events 
Baseline 
VS, physical exam, ACES, MMSE, field test, Lab Assessments, EKG, SOWS, 
breathalyzer, urine drug testing, plasma opioid (methadone/buprenorphine) level, 
TLFB, SAFTEE, DEQ, CPT, HVLT, PANAS, AB, HCQ-14, PCS 
0 min * 
Cannabidiol (400, 800, 1200 mg) or placebo* administration 
30 min 
VS, SOWS, DEQ, PANAS  
60 min 
VS, DEQ, PANAS 
90 min 
VS, SOWS, cue session, AB, HCQ-14, pain measures 
plasma drug levels (blood) 
120 min 
VS, DEQ, PANAS, pain measures 
150 min 
VS, SOWS, DEQ, PANAS, pain measures 
180 min 
VS, DEQ, PANAS, CPT, HVLT 
210 min 
VS, SOWS, DEQ, PANAS, pain measures, methadone/buprenorphine 
administration 
240 min to 420 min 
(buprenorphine) or 480 min 
(methadone) 
VS, DEQ, PANAS, SAFTEE, HCQ-14, 
Plasma opioid and CBD levels, safety bloods and Lab Assessments (Day 10) 
Safety monitoring: VS, MMSE, ACES, field test hourly for at least 2 hours after the 
administration of methadone/buprenorphine → discharge if VS, MMSE, ACES are 
back to baseline 
Follow-up 
Safety follow-up by phone 8 hours after the administration of 
methadone/buprenorphine   

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800 mg in the second test session, and 1200 mg in the third test session, using dose-escalation and stopping 
criteria described in this protocol (Section K.1. subsection K.1.1). Conversely, the general study will have a 
randomized, placebo-controlled design, so participants will be assigned to CBD (400 mg, 800 mg, 1200 mg CBD) 
or placebo in a random order (Section K.1, subsection K.1.2.). 
K.9. Sample Size Determination and Power Analysis (General Study): There are no preliminary data 
on the effects of CBD on individuals with OUD who are receiving MAT, to calculate the sample size for 
this study. In a recent human laboratory study, CBD, compared to placebo, blocked cue-induced craving 
with large effect sizes 45,86 . To detect a more conservative (d=0.64) difference in the attentional bias, 
craving and pain sensitivity paradigm used, using a within-subject design, given α = 0.05 and β = 0.2 
(80% power), 34 subjects will be required for the general study. We expect this sample size will also allow 
us to detect CBD-induced changes in cue-induced craving. To achieve this sample size, considering a 
historical attrition rate of 25%, we will expect to enroll a total of 46 participants (30 methadone and 16 
buprenorphine). 
K.10. Data Analysis Methods (Pilot and General Studies): To preserve the blind, a data entry 
operator will enter all study data into an electronic database using double data entry procedures. The 
data will first be scanned for potential outliers and influential observations using graphical and statistical 
tools. All outcomes will be summarized descriptively and assessed for normality prior to analysis using 
normal probability plots and Kolmogorov test statistics. Transformations or nonparametric analyses will 
be performed as necessary.  All tests will be two-sided and considered statistically significant at 
alpha=.05. All analyses will be performed using SAS, version 9.3 (SAS Institute Inc., Cary, NC). 
Aim #1: To determine the safety of acute CBD administration (400 mg, 800, 1200 mg) to people with 
OUD and chronic pain who are on opioid agonist maintenance. Hypothesis #1: Acute CBD 
administration will be safe and tolerable. Safety of CBD will be assessed with: the SAFTEE for adverse 
events; the DEQ items “I like the drug effect” and “I want more of the drug I received” for abuse 
potential; and by percent correct responses/reaction time in the CPT, and delayed recall in the HVLT, for 
cognitive performance. All safety outcomes will be tabulated, and descriptive analyses will be 
conducted. Dose conditions will be compared with regards to the frequency and severity of adverse 
events, abuse potential and cognitive effects. The PI, in consultation with the DSMB, will determine the 
dose with the best safety profile. 
Aim #2: To determine if CBD (400, 800 mg, 1200 mg) vs. placebo reduces pain sensitivity and 
attentional bias for opioids and cue-induced craving, elicited by visual probes. Hypothesis #2: The CBD 
dose required to reduce pain sensitivity and cue-induced craving will be between 400 and 1200 mg. We 
will fit separate mixed-effects models for each outcome measure. The models will include the within-
subject factor drug (CBD 400 mg, 800 mg, 1200 mg or placebo), time of assessment, and interaction 
between these terms. We will also consider order effects for experimental session day (1, 2, 3 or 4) and 
several different correlation structures for the repeated measures within individuals and will select the 
best fitting one based on Schwartz Bayesian information criterion. We will also explore the effects of 
potential covariates including sex, cannabis use frequency, opioid withdrawal severity, plasma opioid 
levels, and affective states. SAS PROC MIXED will be used for the mixed-model analyses 87. 
Exploratory Aims: Linear mixed models will be used to assess sex differences, and if CBD is more 
effective than placebo in the exploratory outcomes. 
L. RISKS AND BENEFITS (Pilot and General Studies):  
L.1. Risks: The risks associated with this study include those related to:1) Cannabidiol administration, 
2) psychiatric evaluation and study assessments, 3) phlebotomy, 4) loss of confidentiality and privacy,  
L.1.1 Cannabidiol Administration: CBD has been shown to be safe and well-tolerated in doses up to 750 
mg, 1500 mg, and 4500 mg in adults (FDA Briefing Document, April 19, 2018, NDA 210365 
Cannabidiol). Doses even up to 6000 mg, investigated in healthy individuals, resulted in no severe 
effects 50. However, the FDA maximum recommended dose is 20mg/kg daily 57. Although methadone, 

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buprenorphine, and CBD are CYP450 3A4 substrates, CBD was safe and well tolerated when co-
administered with intravenous fentanyl, a high-potency synthetic full opioid-agonist 48. Participants 
receiving medications that may have clinically significant interactions with CBD (e.g., platelet inhibitors, 
other prescription opioids, or benzodiazepines) will be excluded.  
The highest dose of CBD used in the proposed studies is still below the maximum FDA approved dose. 
An open-label, dose-escalation phase will be conducted to establish the safety of CBD administration in 
this clinical population. The most common adverse reactions (10% or more for CBD and greater than 
placebo) are: somnolence, decreased appetite, diarrhea, transaminase elevations, fatigue, malaise, and 
asthenia, rash, insomnia, sleep disorder, poor-quality sleep, and infections. However, the extent to 
which CBD effects are perceived as unpleasant depends on the context and route of administration, and 
can be reduced by using the oral route, and preparing individuals in advance for the possible responses. 
Using our open-label, dose-escalation paradigm, we collected safety data of three different doses of 
CBD (400 mg, 800 mg, and 1200 mg) among 4 participants receiving a mean methadone dose of 91.2 
mg (SD=10.31). There was no evidence of sedation, which was thoroughly measured with the ACES, 
MMSE, and a field test. Notably, unlike methadone, buprenorphine is a partial opioid agonist; therefore, 
the risk of sedation following the administration of CBD is expected to be lower when given with 
buprenorphine than with methadone. Please see DSMB report attached for details. 
L.1.2. Psychiatric Evaluation and Study Assessments: Participants will undergo a Structured Clinical 
Interview for DSM-5 conducted by a research assistant and a psychiatric and medical evaluation during 
screening. The diagnostic interviews may cover issues, which are stressful to a person, for example, 
questions regarding the experience of paranoid thoughts or social isolation. Thus, they may experience 
some distress during these interviews. During the laboratory assessments, study participants may 
experience transient increase in craving and level of pain or become tired or frustrated. They will be 
encouraged to take breaks if they wish to do so. It is also possible that some individuals may experience 
discomfort during the interviews, when they are asked to talk about their psychiatric symptoms. 
Participants may feel bored, tired, exhausted, discouraged, or distressed by the questionnaires or 
testing. During the QST laboratory assessments of Study 1, study participants may experience a 
transient increase in thermal pain, opioid craving, or overall discomfort. 
L.1.3. Phlebotomy: Blood will be drawn weekly during the study to monitor medication levels as well as 
safety labs. Blood will be drawn on four occasions during the test sessions using an IV line. There are 
usually no serious medical problems with blood drawing, but there may be pain at the venipuncture site 
or bruising or infection may occur. These risks can be minimized by having these procedures performed 
by experienced personnel using good clinical technique. Approximately one ounce of blood will be 
drawn during the initial screening. In addition, blood will be sampled during study for plasma drug levels 
and safety bloods. Additionally, the amount of blood drawn at screening and on each of the study visit 
will be approximately 30cc which is within the Red Cross blood standards. 
L.1.4. Loss of Confidentiality and Privacy: Participation in any research study may involve the risk of loss 
of confidentiality or privacy. Overseeing agencies may inspect records, and future investigators may use 
data. Additionally, no protected health information will be collected or stored in the REDCap database. 
Only PII (e.g., email) is necessary in order to enroll participants into the REDCap system. No PHI will be 
collected or stored in REDCap. Access to study data in REDCap will be restricted to the members of the 
study team with authentication through University NetID credentials.  
The REDCap@Yale database and web server are housed on secure platforms that are backed up daily. 
REDCap@Yale meets the security standards for use with high-risk data as set forth by the Yale 
Information Security Office. REDCap@Yale is also compliant with FDA requirements (please see 
Section M.4 for details). All participant information will be kept confidential and only members of the 
investigative team with appropriate HIC and HIPAA training will have access to the study data. 
Information that could be used to identify participants individually will be stored on the VA encrypted 
investigators drive. Only authorized research staff will have access to this information. As with all paper 
records containing identities, containing identities will be stored in locked cabinets, and will be available 
only to authorized staff. Data will be maintained and secured in locked file cabinets or password 

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protected on the VA investigator drive. A numbering code will be used to assign a unique identifier to 
each participant. A certificate of confidentiality (CoC) has been issued for this study, as it is funded by 
the National Institute of Health. Notably, the CoC is issued as a term and condition of the award, rather 
than as a physical certificate.  
L.2. Risk/Benefit Ratio:  The potential risks for study participation are moderate because both 
proposed studies include the administration of CBD, which is not an approved an approved 
pharmacotherapy for OUD or chronic pain. Additionally, one of the proposed studies involves 
temporarily inducing pain and opioid craving, although in a controlled human laboratory environment. 
The proposed studies have a favorable risk: benefit ratio because they may lead to new treatment 
approaches for patients with OUD and chronic pain. These studies will be the first step in establishing 
the risks and benefits of cannabinoid-based interventions for comorbid OUD and chronic pain, paving 
the way for future investigation aimed at reducing the adverse consequences of opioid agonist 
treatment, such as respiratory depression – a strategy that holds promise for saving lives. Finally, since 
several U.S. states are authorizing the use of cannabinoids as adjunctive or substitutes for opioid 
agonist treatment, high-quality, experimental data collected in the proposed studies will contribute to 
evidence-based decision-making to guide patients, healthcare providers and future policy makers. 
M. SAFETY 
M.1. Protection of Participants (Pilot and General Studies): 
M.1.2. Screening: Participants will be recruited exclusively from OTPs, which provide both psychiatric 
and addiction treatment. The screening process has been optimized to reduce the risk of participating in 
the study. Participants with a clinically unstable psychiatric disorder, including severe depression and/or 
active suicidal ideation, or any recent psychosocial stressor that might increase the level of risk of taking 
part, will be excluded. This assessment will be stringently made using the stated inclusion/exclusion 
and, where stipulated, the discretion of the primary investigators in discussion with the study physician. 
All participants will undergo a Structured Clinical Interview for DSM-5 conducted by a research assistant, 
screening bloodwork will be draw, a urine test will also be collected to test for drugs and pregnancy, and 
a psychiatric evaluation (including psychiatric history, drug use history, the physical examination, and 
the laboratory studies) by a specialized addiction psychiatrist with experience in treating individuals with 
OUD.  
M.1.3. Study Visits: Participants’ comfort with all study procedure will be monitored throughout the study. 
Participants will be informed that they can withdraw (themselves and their data) without justification at 
any time. Subjects who choose to have an IV placed will have it placed the morning of each test 
session. Those who choose not too or an IV couldn’t be placed a nurse or phlebotomist will only draw 
safety bloods during each test session. A member of the research team will be present with the 
participants during all the testing.  
All equipment adheres to local institutional safety standards. A physician will remain on hand with 
access to a crash cart with emergency medications if necessary. 
After testing, study staff will inquire after the participant’s general wellbeing. A physician will conduct a 
thorough assessment before participants are discharged.  
Participants who experience elevation of liver enzymes above 3x the normal limit or significant sedation 
will have their individual participation terminated. In the event we encounter these adverse events in 
more than 3 participants, we will consult with the DSMB overseeing this study. The DSMB will 
independently review the safety data and make recommendations. 
Participants will be reminded not to drive before each test session, they must confirm transportation prior 
each test session. 
Study staff will check medications for potential pharmacokinetic interactions before each dose session. 
Participants will be asked to inform study staff if new medications for pain are started. If other 
prescription opioids, benzodiazepines, or platelet inhibitors are started, their participation in the study will 

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be discontinued. If participants require a dose increase in their opioid agonist treatment during the study, 
their participation will be discontinued. 
The QST tasks employed in this protocol have been safely and widely used. While thermal testing 
induces pain, risks to the individual are minimal because: 1) the pain in transient and subsides 
immediately after the stimulus is withdrawn; 2) the level of pain experienced by participants will be below 
their tolerance level. Further, risk of thermal injury is reduced by: 1) the built-in shutdown system in the 
stimulator that prevents the delivery of prolonged or high-intensity stimuli; 2) the lock out of the stimulus 
above 47 °C; 3) the electronic thermometer that measures the temperature at the surface before and 
during each use. Notably, participants will be instructed that they may stop any procedure at any time, 
with no adverse consequence. Before discharge, the study physician will evaluate participants for any 
residual discomfort. 
Required private identifiable information about individuals will be collected by the research staff and be 
used for research purposes and charting after consent is obtained. This information includes the results 
from laboratory tests for blood and urine, EKG and physical examination results. Study team members 
will collect required research data through study procedures as outlined in this protocol and record it in 
confidential research records and protected computer files. Data will be stored at the VA in a manner 
that is compliant with HIC regulations. All information obtained in this research study will be kept 
confidential and only be made available to the investigators. In all records of this research study, 
participants will be identified by a unique identifier number code known only to researchers working 
directly on this protocol. These codes will not be derived from participants PHI (e.g., name, date of birth 
etc.). A master list of participant names along with unique identifier number will be kept in a locked 
cabinet in the in Building 36 and the electronic records will be kept in VA intranet (investigator-drive). 
Procedures to ensure confidentiality follow the regulations and policies of the VA Connecticut Healthcare 
System. If the results of this research study are reported in any scientific meetings or literature, 
participants will not be identified by name or photograph. Records will be maintained according to FDA 
Good Clinical Practice guidelines to ensure protection of confidentiality and security of records. The 
Human Studies Subcommittee (HSS), which approves the completion of this study, may inspect study 
records. All protected health information collected specifically for this research will be secured in the 
manner described above. The data will be stored in a secure location- we anticipate that the data will be 
stored for at least 10-15 years.  
If participants report any threats of violence to a child or elderly person, this will be reported to the 
Department of Health and Human Services. Threats of violence to self or others will be assessed by the 
principal investigator who will determine appropriate reporting procedures. Furthermore, positive HIV, 
hepatitis B, or C results will be reportable to the Connecticut Department of Public Health. 
Participants will be closely monitored for worsening of symptoms or side effects. They will be provided 
with a 24-hour access to study personnel to discuss any concerns. Participants will be given a wallet 
card indicating they are taking experimental medication and directions for how to determine what they 
are taking in case of an emergency. 
Evidence of clinical worsening will be assessed as operationalized for clinical trials conducted by our 
group and approved by the HSS. Clinical emergence will include: 
1. Emergence of new SI/HI or SI/HI with intent 
2. Significant worsening not otherwise specified by the patient’s clinician or PI 
These factors will result in the participant discontinuing from the study.  
The research team of the New England MIRECC will work closely with clinicians at the VA Hospital and 
other treatment facilities in the community, and routinely communicate with them. In regard to this study, 
communication with the outpatient psychiatrist is as follows: 
1. During screening, study staff confirm the study criteria and participant participation with 
the participant’s primary clinician (verbally/written). 

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2. As notified to the patient during consent, all concerns will be immediately 
communicated to the primary clinician and will be documented (verbally/written). 
3. Additionally, the participant’s primary clinician is updated each week via the research 
clinical notes.  
4. Please note, if the participant meets one of the criteria for discontinuation, this will be 
communicated verbally with the participant’s primary clinician and will be documented in the 
participant’s chart. The study team will closely coordinate the stabilization of the patient 
(including inpatient hospitalization if needed) and transfer of care to outpatient treatment as has 
been previously successfully done in other studies. 
M.2. Data Safety and Monitoring Plan (Pilot and General Studies): This is a moderate risk study, and 
no serious adverse events are expected. The safety data is reviewed after every test day, during weekly 
research team meetings, and will be suspended or modified if indicated. The principal investigator will 
conduct a data and safety review at least quarterly and at any time a serious adverse event occurs. 
During the review process the principal investigator will evaluate whether the study should continue 
unchanged, require modification, continue, or close enrollment. 
In accordance with FDA guidelines, an adverse event is defined as “any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related”. An adverse event 
(also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the study 
medication and does not imply any judgment about causality. 
A mild adverse is defined as one that results in transient discomfort, not requiring intervention or 
treatment; does not limit or interfere with daily activities (e.g., insomnia, mild headache). 
A moderate adverse is defined as an event that is sufficiently discomforting so as to limit or interfere with 
daily activities; may require interventional treatment. 
A severe adverse is defined as an event that leads to incapacitating with inability to work or perform 
usual activity; or events that result in significant symptoms that prevent normal daily activities and may 
require invasive intervention. 
An adverse event or suspected adverse reaction will be considered “serious” if: Death, a life-threatening 
adverse event, inpatient hospitalization, or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
Adverse events will be graded in severity as follows: 
0 
No adverse event or within normal limits 
1 
Mild adverse event 
2 
Moderate adverse event 
3 
Severe adverse event 
4  Serious adverse event 
Severe and serious adverse events will be reported to the Human Investigation Committee (HIC) within 
24 hours. Other adverse events will be reported to the HIC in a timely manner, using the following 
predefined causal relationships: 
i. Definite: Adverse event(s) will clearly be related to investigational agent(s) or other 
intervention 
ii. Probable: Adverse event(s) will likely be related to investigational agent(s) 
iii. Possible: Adverse event(s) may be related to investigational agent(s) 
iv. Unlikely: Adverse event(s) will doubtfully be related to investigational agent(s) 

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v. Unrelated: Adverse event(s) will clearly not be related to the investigational agents(s) 
Serious unanticipated adverse events will be reported immediately to the VA Connecticut Healthcare 
System institutional review boards and any appropriate funding and regulatory agencies.  Serious 
anticipated adverse events will be reported immediately to the institutional review boards and others 
whenever their magnitude or frequency exceeds expectations.  
Adverse events will be reported to the HIC, HSS and any appropriate funding and regulatory agencies. 
The investigator will apprise fellow investigators and key study personnel of all serious and 
unanticipated adverse events that occur during the conduct of this research project. Adverse events will 
be graded as per HIC policy.  
The PI will evaluate all adverse events and determine whether the adverse event affects the risk/benefit 
ratio of the study and whether modifications to the protocol or consent form are required.  A summary of 
the adverse events will be reported to the institutional review boards periodically or, at minimum, when 
re-approval of the protocol is sought.  The summary will include number of participants enrolled and a 
summary of graded adverse events to date. Adverse events will also be reported to NIDA through the 
Serious Adverse Event Tracking and Reporting System (SAETRS). 
M.3. Data Safety Monitoring Board (DSMB) (Pilot and General Studies): A Data Safety Monitoring 
Board has been assembled for this study. Un-blinded safety data will be provided to the committee for 
monitoring. DSMB reports will be provided to the HIC. Any serious, unanticipated, and related adverse 
events will be reported to the VA-HSS. DSMB reports will also be sent to NIH/NIDA. 
M.4. Loss of Confidentiality (Pilot and General Studies): There is a risk of loss of confidentiality in 
this study. All participant information will be kept confidential and only members of the investigative team 
with appropriate HIC and HIPAA training will have access to the study data. Data will be maintained and 
secured in locked file cabinets or password protected electronic media. A numbering code will be used 
to assign a unique identifier to each participant. A certificate of confidentiality (CoC) has been issued for 
this study, as it is funded by the National Institute of Health. Notably, the CoC is issued as a term and 
condition of the award, rather than as a physical certificate. 
REDCap is 21 CFR Part 11 ready, which means that REDCap meets the technical software 
specifications that are required by the FDA. Further, REDCap has a number of data security and 
protection features including: 1) Authentication uses the Yale Active Directory encrypted with Kerberos 
via SLDAP, such that user passwords are never stored locally, and password strength and expiry meet 
Yale University IT security policies; 2) role-based security with individualized access and permissions; 
built-in data validation and data cleaning; 3) all web-based communications are protected by the Yale 
enterprise firewall and encrypted with TLS; 4) secure configuration, Ubuntu CIS (Center for Internet 
Security), that conforms to best practice and compliance standards; 5) daily back-ups and incremental 
snapshots ensure against the possibility of data loss or corruption. REDCap instance is located on an 
internal OSUWMC network. Remote access to this network can be obtained over an encrypted VPN 
tunnel (AnyConnect). This VPN uses Protocol: DTLS and Cipher: RSA_AES_128_SHA1. Background 
checks are performed on all staff that are on the network or obtaining VPN access. Moreover, access to 
study data in REDCap will be restricted to the members of the study team with authentication through 
Yale University NetID credentials. REDCap is already being used in VA HSS-approved protocols (e.g, 
HSS #1586389). 
M.5. Psychiatric Evaluation and Study Assessments (Pilot and General Studies): It is worth noting 
that our participants will be recruited exclusively from OTPs, which provide both psychiatric and 
addiction treatment. Participants will be seen every 3 days for 4 experimental sessions. Before each 
experimental session, participants will be required to refrain from consuming alcoholic beverages and 
drugs during study participation, which will be verified by urine drug screening and breathalyzer 
measurements before the sessions. If results indicate non-adherence with these study procedures, the 
session will be rescheduled. Repeatedly non-adherent participants will be discharged from the study. 
Since our participants are provided with a light snack before each test session, and a small meal at the 

ver. 05.05.2025 
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end of each test session, we ask our participants to not eat after midnight on the day of your test 
sessions. However, you can drink your usual amount of coffee or caffeinated beverage before each test 
session. 
A physician and a member of the research team will be present with the participants during all the 
testing, monitoring participants’ comfort with all study procedures, using equipment that adheres to local 
institutional safety standards. Participants will be informed that they can take breaks or withdraw 
(themselves and their data) from the study without justification at any time. After testing, study staff will 
inquire about the participant’s general well-being. Participants will be made aware that, if they 
experience a clinically significant worsening of mood symptoms, or if active suicidal ideation emerges, 
they will be escorted to the nearest psychiatric emergency room.  
A physician will conduct a thorough evaluation before discharge after each experimental session. 
Participants may be observed until craving subsides. In the event participants test positive for non-
medical substance use or breathalyzer indicate recent alcohol use, the experimental sessions will be 
rescheduled until clinical stability is ensured. Regular treatment with opioid agonists will be continued 
during the study. One week after completing the four experimental sessions, participants will be 
contacted by telephone for another safety follow-up. 
M.6. CBD Administration (Pilot and General Studies): The doses selected for this study are within 
the FDA-approved range and we expect them to be safe and well tolerated. CBD has been safely co-
administered with opioid agonists with much higher potency than methadone/buprenorphine, such as 
fentanyl 48. Participants will be thoroughly assessed at each study visit for the development of adverse 
effects, abuse potential and cognitive deficits. Symptoms of OUD will also be assessed. 
A research addiction psychiatrist will perform a comprehensive evaluation if participants state that they 
noticed a worsening of symptoms or adverse effects. Notably, a pilot study will be conducted to establish 
the safety of CBD administration in this clinical population. Results from this pilot study will inform the 
conduction of the general study. 
M.7. Risks of Blood Draws (Pilot and General Studies): Due to the risks associated with phlebotomy 
procedures, participants who have donated blood within eight weeks to the present study will be 
excluded. Participants will be told that they should not give blood for at least eight weeks.  
N. INFORMED CONSENT (Pilot and General Studies): 
The informed consent form (see attached), which will be given to the participating participants, explains 
all the information pertaining to this study such as the objectives of the study, all the procedures, risks 
and benefits, confidentiality, safety measurements, payment, and other aspects of the study. 
Understanding of the information is verified using a questionnaire (see attached). 
O. CONFIDENTIALITY (Pilot and General Studies): 
All participant information will be kept confidential and only members of the investigative team with 
appropriate HIC/HSS and HIPAA training will have access to the study data. A numbering code will be 
used to assign a unique identifier to each participant. This study will be conducted with support from the 
National Institute of Drug Abuse (NIDA), under an IND issued by the US FDA.  
Therefore, data collected as part of this study may be made available to the VA, the US FDA and NIDA. 
Participants are informed of these possibilities in the consent form. 
Demographic and outcome data described earlier will be collected as part of this study. Personnel listed 
on protocol will have access to data containing PHI. As noted above, limited PHI may be disclosed to 
the VA and the FDA, as required. 
The hardcopy data will be stored in locked filing cabinets on the campus of VA Connecticut Healthcare 
System. Some electronic data including demographic data, screening data, laboratory data and RN/MD 
progress notes about each test day etc. will be stored on the VA CPRS system. All phone screen 

ver. 05.05.2025 
Page 21 of 28 
information obtained will be stored behind the VA firewall. Other outcome data in electronic format will 
be stored either on 1) a limited access computer encrypted using VA approved encryption software, 2) a 
VACHS server, or 3) any other server that is approved by VACHS. If data is stored on a computer using 
VA encrypted software, those data will be backed up on a backup device that will be stored in a locked 
cabinet in Building 36 and encrypted using VA approved encryption software. 
Data will be shared with employees at the VA not listed on this protocol and other collaborators not listed 
above. However, if this occurs, data will be stripped of PHI before it is shared. For example, data 
stripped of PHI will be shared with statisticians, laboratory personnel who conduct assays and others. 
P. LOCATION OF STUDY (Pilot and General Studies):  
The study will be conducted at the VA Connecticut Healthcare System, West Haven Campus. 
Q. COMPENSATION TO PARTICIPANTS (Pilot and General Studies):  
All participants will be compensated with cash or checks for their participation. They will receive $50 for 
the initial screening and $200 for each of the test sessions and $20 dollars for transportation for each 
test session. Compensation of an additional $20 will offered if participants need to return to the clinic for 
additional procedures. Finally, upon study completion, participants who referrer other candidates will 
also be compensated $20 for each referred candidate who is enrolled in the study. 
Participants will be compensated only for the visits they participate in. If a study visit is cancelled 
because the participant fails to follow pre-visit restrictions such as refraining from illicit drugs, alcohol, 
and caffeine, then they will not be compensated for that day. 
Costs for Participation (Economic Considerations): Participants will not be charged for any aspects of 
this study. 
R. FUNDING SOURSE (Pilot and General Studies):  
NIH (grant 1K23DA 052682-01, PI: De Aquino) and the VISN-1 MIRECC will fund both sub-studies in 
this protocol. CBD and placebo will be provided by Greenwich Biosciences. 
S. DURATION (Pilot and General Studies):  
Expected duration of the study of the pilot study will be of 6-8 months. The expected duration of the 
general study will be of approximately 30 months.   
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ver. 05.05.2025 
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Consent Questionnaire 
This is a questionnaire to help us to test your understanding of the study protocol. For you to qualify for 
this study, you will need to pass this test. To pass this test, you will need to score at least a 75% and also 
get all three questions underlined.  
 
You will have only 2 chances to take this test. Incorrect answers on your first attempt will tell us those 
parts of the study you did not understand well, so that we can go over the consent form again with you. If 
you answer more than 5 questions wrong at your first attempt, you will not be considered for this study. 
1. Will you need to stop taking your medications (methadone or buprenorphine) as part of this study?  
Yes 
No 
Maybe 
I can’t decide 
2. What medications might you receive?  
Cannabidiol 
Prozac 
Paxil 
Ativan 
3. Will you be able to choose what medication that you may receive in this study?  
Yes 
No 
Maybe 
I can’t decide 
4. During the study, will you or the study doctor or the research team know exactly which study medication 
you are on?  
Yes 
No 
Maybe 
I can’t decide 
5. Could your symptoms get temporarily worse during this study?  
Yes 
No 
Maybe 
I can’t decide 
6. Will blood be drawn for this study? 
Yes 
No 
Maybe 
I can’t decide 
7. Can the study medication have side effects?  
Yes 
No 
Maybe 
I can’t decide 
8. Name at least 2 side effects of the study medication: 
 
____________________________  
____________________________ 
9. Once you start the study, are you free to stop at any time?  
Yes 
No 
Maybe 
I can’t decide 
10. What would happen to your regular treatment if you dropped out of the study?  
a. Treatment with regular 
clinician will end 
b. Treatment with regular 
clinician will continue 
c. Don’t know 
11. Will you be hospitalized for this study?  
Yes 
No 
Maybe 
I can’t decide 
12. Will you get paid for taking part in this study?  
Yes 
No 
Maybe 
I can’t decide 
 
 
________________________________________/ _____________________ 
Signature  
 
 
 
 
       Date 
 

ver. 05.05.2025 
Page 28 of 28 
WALLET CARD (1D) 
IMPORTANT 
The holder of this card is participating in a clinical study with an investigational drug called cannabidiol, 
as an adjunctive treatment for opioid use disorder.  
 
Treatment Period: 
From: __________________________ 
To:     __________________________ 
EMERGENCY CONTACT 
If this participant presents to you for treatment, please contact the research clinic below and ask for the 
cannabidiol (CBD) study: 
 
Doctor:             Joao P. De Aquino, M.D.  
 
Phone:              203-932-5711 x1-2916                            HSS# 1584988 
Doctor:            Mehmet Sofuoglu, M.D., Ph.D.               HIC# 2000029286 
   
Phone:              203-932-5711 x1-4809                   .      
 
          24 Hour Emergency:         203-974-7560             . 
 
 
Dial 0 for the operator and ask that the on-call research psychiatrist be paged.