Clinical trial NCT03787628
Conditions: Opioid-use Disorder
Keywords: Buprenorphine Cannabidiol Opioid Use disorder
Sponsor: University of California, Los Angeles
Start date: 2022-05-19; Completion date: 2024-03-12
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research aims to determine the effects and safety of cannabidiol (CBD) (ATL5 softgel capsules) as an adjunctive therapy for patients who have Opioid Use Disorder and are taking buprenorphine + naloxone or methadone. Buprenorphine + naloxone and methadone is an approved treatment for Opioid Use Disorder, but relapse to opioid misuse is common among patients who receive this treatment. Finding an adjunctive treatment for these patients would be helpful.

We will recruit participants from the Tarzana Treatment Center (TTC) in the San Fernando Valley. They will be receiving buprenorphine + naloxone or methadone as part of residential therapy. Potential participants who pass initial screening and wish to continue in the study will provide written, informed consent and will complete a 2-day evaluation, including blood and urine tests, questionnaires about their mood, medical, psychiatric and drug use history and physical exam.

Up to 60 participants who meet all eligibility criteria will be invited to complete baseline assessments (blood and urine tests, questionnaires), and will be assigned randomly to receive CBD (600 mg/day) or placebo, corresponding to two groups of up to 30 participants each.

After the baseline measurements, participants will take part in a 28-day treatment phase for 4 weeks. They will take the study medication under supervision (CBD 300 mg twice daily or placebo). Questionnaires on opioid craving, withdrawal, and mood symptoms will be administered daily during the treatment period, excluding weekends. After the 28-day intervention, participants will complete the questionnaires and undergo urine drug tests in 4 weekly follow-up visits.

The study will last \~10 weeks, comprising three periods: a screening period (2-weeks when participants are stabilized on buprenorphine + naloxone or methadone in residential treatment at the Tarzana Treatment Center), a treatment period (4 weeks when study CBD or placebo is administered at Tarzana Treatment Center), and a follow-up period (4 weeks after termination of the test intervention).

Detailed description:
This will be a randomized, double-blind, placebo controlled, study of cannabidiol (CBD) (600 mg/day) as an adjunctive therapy to buprenorphine + naloxone or methadone in patients who have Opioid Use Disorder and are receiving residential behavioral therapy, including cognitive behavioral therapy. The primary endpoint will be safety and tolerability of CBD in these patients, as indicated by the incidence of treatment-emergent adverse events (n/% per group). Participants will be evaluated via measurement of cardiovascular parameters (heart rate, blood pressure, and cardiac rhythm and conduction on EKG), other vital signs, liver enzymes, pulse oximetry, adverse events, and pharmacokinetics. Secondary measures will include cue-induced craving, reductions in spontaneous craving, opioid withdrawal, and negative affective states.

Patients will be recruited from the Tarzana Treatment Center (TTC) in the San Fernando Valley, where buprenorphine + naloxone or methadone (as part of their treatment) and CBD (as part of this protocol) will be administered. Tarzana Treatment Centers, Inc. is a community-based, private non-profit behavioral healthcare organization located in Southern California with several agency sites, including the one in the San Fernando Valley, where this protocol will be conducted. TTC delivers drug and alcohol use treatment, has been accredited by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) since 1987, and has a workforce that includes physicians, psychologists, and nurses. TTC's substance use treatment approach includes residential programs that are overseen by a Program Director and are staffed by a clinical supervisor, operations supervisor, counselors, interns, nursing staff and 24/7 technicians. Groups and services include an education group, process group, 12-step, family group, mental health services and recreation skills. Cognitive-behavioral treatment is used in both individual and group therapy to address craving and relapse issues and in the treatment of mental health problems.

Up to 75 participants who meet all eligibility criteria will be invited to complete baseline assessments (blood and urine tests, questionnaires), and will be assigned randomly to receive CBD or placebo, corresponding to two groups of up to 30 participants each. Within each group, participants will be randomized by baseline buprenorphine plasma level (either below or ≥ 2 ng/ml).

The study will comprise three periods: 1) a screening period (\~7-14-days) while participants are stabilized on buprenorphine + naloxone; 2) a 4-week treatment period when study medication will be administered; and 3) a 4-week follow-up period after termination of treatment with the study medication. Cue-induced craving sessions will be conducted at three times: Day 0 (baseline), Day 7 (when a steady state of CBD should have been reached; half-life of CBD after oral administration is 18-32 h), and Day 28 (end of treatment).

Adherence to medication in the trial will be assured as the participant will take the test medication (CBD or placebo) under supervision daily. Blood samples will be collected to determine plasma concentrations of CBD, buprenorphine, and laboratory assessments of safety. Cue-induced craving and other measures of craving and affect will be collected repeatedly during the study.

Arms: arm 1: Thirty participants who meet all eligibility criteria will be randomized to receive CBD (ATL5; Ananda Scientific) at a dose of 600 mg. arm 2: Thirty participants who meet all eligibility criteria will be randomized to receive placebo.
Interventions: intervention 1: Cannabidiol (CBD) 600 mg intervention 2: Placebo
Intervention descriptions: intervention 1: CBD (300 mg) will be administered orally twice daily in the morning and again in the afternoon. The active ingredient in the Ananda investigational new drug, ATL5, is cannabidiol (CBD), extracted from hemp, at a 10% strength (softgel capsules with 100 mg/ml of CBD per capsule). The novel formulation is based on the principle that a water-free mixture of some concentrated inactive ingredients (excipients) self-assemble spontaneously into liquid nanodomains that contain the active component CBD. ATL5 Softgel Capsules will be manufactured by Baxco Pharmaceutical Inc. (California, USA) under cGMP conditions. intervention 2: The placebo softgel capsule formulation will have a composition with the same relative proportions as the CBD ATL5 Softgel Capsules. This formulation will be manufactured by Baxco Pharmaceutical Inc. under cGMP conditions. The amount (number of softgel capsules) of placebo will be administered to match that of the active compound, daily in the morning and afternoon for each of 28 days.

Protocol documents:
Prot_002.pdf: 
PROTOCOL  
 
Date: July 27, 2023 
 
NCT #: 03787628 
 
Title of Study: Cannabidiol Effects on Craving and Relapse Prevention in Opioid Use Disorder 
 
Name of Sponsor/Company: University of California at Los Angeles (UCLA) 
 
Name of Investigational Product: ATL5 softgel capsules (10% CBD) 
Name of Active Ingredient: Cannabidiol 
 
Study Center: Tarzana Treatment Center 
 
All test procedures involving human subjects will be conducted only at this site in the U.S. Data 
analysis will be conducted at the Jane and Terry Semel Institute, David Geffen School of Medicine, 
UCLA 
 
Site Principal Investigator: Edythe D. London, Ph.D. 
Site Co-Investigators: Richard De La Garza, II, Ph.D.  
Larissa Mooney, M.D. (Medically Responsible Individual) 
 
Phase of Development: Phase 2 
 
INTRODUCTION 
 
Opioid Use Disorder (OUD), involving prescription opioids or heroin, is a public health emergency 
leading to unprecedented drug-related mortality in the United States,1-3 underscoring the need for 
innovative medical treatments for OUD. Several mediations are available for treatment of OUD. Of the 
opioid agonists, used, buprenorphine has a more favorable safety profile than methadone, but retention 
in treatment is low for both medications.4,5 The opioid receptor antagonist naltrexone is also used for 
patients with OUD, but it has even lower adherence.5 
Positive findings from preclinical and clinical studies provide a rationale for the use of cannabidiol 
(CBD) in the clinical trial proposed here. In animal models, CBD has behavioral effects suggesting that 
CBD may offer benefit in relapse prevention for patients with OUD. These effects include the 
attenuation of opioid reward and conditioned reinstatement of opioid-seeking behavior, stress-induced 
drug-seeking and reductions in anxiety- and impulsivity-like behaviors.6,7 Moreover, a Phase 2, 
randomized, double-blind, placebo-controlled, pilot study found that a single dose of CBD (400 or 800 
mg) decreased cue-induced opioid craving and blunted anxiety.8,9 
Although promising findings suggest that CBD can reduce craving and anxiety, and attenuate 
opioid-related reward, rigorous clinical trials are needed to establish the full potential and determine 
the optimal dosage of CBD as adjunctive therapy for OUD. This is the background and rationale for 
the proposed study. Success in this project can reduce opioid–related deaths by providing a medication 
that will prevent relapse to opioid use, which puts individuals with OUD at risk for death from an 
opioid overdose. 


STUDY OBJECTIVES 
The overall goal of the proposed work is to perform a study on the effects of ATL5 in patients with 
OUD, receiving medication-assisted treatment with buprenorphine (transmucosal formulations, e.g., 
buprenorphine + naloxone) or methadone. ATL5 is CBD, extracted from hemp, at a 10% strength 
(softgel capsules with 100 mg/ml of CBD per capsule). 
Primary Objective: To evaluate the safety and tolerability of CBD (600 mg/day) and its 
pharmacokinetic interaction with buprenorphine metabolism in the study population. 
Based on prior work, CBD is expected to be well-tolerated and safe in patients with OUD8,9, but 
safety signals (vital signs and laboratory test results) will be assessed. Because CBD inhibits 
cytochrome P450 isozymes including CYP3A,10 which is the primary mechanism for hepatic 
buprenorphine N-dealkylation,11 we will evaluate whether CBD poses potential safety concerns 
associated with buprenorphine or methadone treatment. We will seek to understand the drug-drug 
interaction for safe and effective treatment of OUD and to identify an optimal adjunctive dose of CBD 
for patients receiving buprenorphine or methadone treatment. We predict a drug-drug interaction 
between CBD and buprenorphine, whereby CBD will inhibit buprenorphine metabolism and increase 
the buprenorphine/norbuprenorphine concentration ratio. [Note:  Intestinal and hepatic CYP3A activity 
only slightly affect human methadone N –demethylation.] 
Secondary Objective: To determine the extent to which CBD (600 mg/day) reduces cue- induced 
craving for opioids. 
CBD is expected to reduce cue-induced opioid craving (secondary outcome). Other outcomes 
are also expected to be affected: spontaneous craving and negative affect. 
 
METHODOLOGY 
General Experimental Design: This will be a randomized, double-blind, placebo-controlled study 
of ATL5 (CBD) (600 mg/day, [300 mg twice daily]) as adjunctive therapy to buprenorphine or 
methadone for patients with OUD, who are receiving inpatient behavioral therapy, including 
cognitive behavioral therapy. 
Endpoints: The primary endpoint will be safety and tolerability of CBD in these patients, and it will 
be assessed via measurement of adverse events. Pharmacokinetic analyses will evaluate potential 
drug-drug interactions of CBD with buprenorphine metabolism. The secondary outcome measure 
will be cue-induced craving for opioids, assessed using the Desires for Drug Questionnaire (DDQ)16 
in the context of an opioid cue-induction paradigm in the laboratory session before CBD dosing on 
Day 0 (baseline without CBD) to scores on Days 7 and 28 (after adjunctive treatment with CBD) (see 
Criteria for Evaluation below). 
Other Outcome Measures: 
• spontaneous opioid craving, assessed using the Penn Alcohol-Craving Scale, as modified to assess 
opioid craving17 
• affect, assessed using the Positive and Negative Affect Schedule (PANAS)18 
• anxiety assessed by State subscale of the Spielberger State-Trait Anxiety Inventory19 
• blood pressure, heart rate, and respiratory rate during the laboratory sessions 
• Plasma levels of CBD 
• plasma levels of buprenorphine  
Participant Recruitment: Patients will be recruited from the Tarzana Treatment Center in the San 
Fernando Valley (TTC), where buprenorphine or methadone (as part of their treatment) and CBD (as 
part of this protocol) will be administered.a Tarzana Treatment Centers, Inc. is a community-based, 
private non- profit behavioral healthcare organization located in Southern California with several 
agency sites, including the one in the San Fernando Valley, where this protocol will be conducted. 


TTC delivers drug and alcohol use treatment, has been accredited by the Joint Commission on 
Accreditation of Healthcare Organizations (JCAHO) since 1987, and has a workforce that includes 
physicians, psychologists, and nurses. TTC’s substance use treatment approach includes residential 
programs that are overseen by a Program Director and are staffed by a clinical supervisor, operations 
supervisor, counselors, interns, nursing staff and 24/7 technicians. Groups and services include 
education group, process group, 12-step, family group, mental health services and recreation skills. 
Cognitive-behavioral treatment is used in both individual and group therapy to address craving and 
relapse issues and in the treatment of mental health problems. 
Randomization to Treatment: Up to 60 patients who meet all eligibility criteria will be randomized 
to receive CBD or placebo (up to 30 patients per group): CBD 600 mg/day (300 mg twice daily). 
Within each cohort, patients will be randomized by baseline plasma buprenorphine level (either below 
or ≥ 2 ng/mL) 
Dosing and Testing Schedule: The study will comprise three periods: a 14-day screening period 
while patients are stabilized on buprenorphine), a 28-day treatment period (CBD 600 mg/day or 
placebo), and a 28-day follow-up period after termination of treatment with medication. 
Laboratory sessions using a craving cue-induction paradigm will be conducted before dosing on 
Day 0 (baseline) and on Days 7 and 28 after adjunctive treatment with CBD. 
Note: Participants will all be maintained on buprenorphine or methadone, which are robust, effective 
treatment for OUD that diminish cravings, and helps to protect participants if relapse occurs. Thus, 
conducting cue reactivity tests in the presence of opioid agonist medication is inherently less risky 
than in individuals with untreated OUD. Total scores > 70 on the Desire for Drug Questionnaire 
(scores ranging from 14 to 98) will be reassessed after participants remain in study visit area for 15 
min and again at 30 min if the score remains above 70. Research staff will check in with participants 
to provide support and resources as requested, or to coordinate care with current clinical staff at TTC. 
Adherence to medication in the trial will be assured as the patient will take the test medication 
(CBD or placebo) under supervision. Blood samples will be collected to determine plasma 
concentrations of CBD and its metabolites (7-hydroxy CBD and 7-carboxy CBD), buprenorphine and 
methadone and their metabolites as well as the endocannabinoids anandamide and 2-AG, which may 
contribute to the response to CBD and laboratory assessments of safety. Retention in treatment (this 
trial plus buprenorphine + naloxone) will be assessed over the 28-day medication (CBD or placebo) 
treatment period and weekly follow-up assessments for the subsequent month (28-day follow-up 
period). 
Duration of Treatment and Dropout. Duration of inpatient treatment with buprenorphine or 
methadone (outside the scope of this protocol) is generally for about one month at the Tarzana 
Treatment Center (TTC), and buprenorphine or methadone is often continued after a client leaves TTC. 
The treatment phase of this study of CBD vs. placebo is 28 days. If a participant decides to stop taking 
buprenorphine or methadone and/or leave TTC before completing the 28-day intervention described in 
this protocol, they will be withdrawn from the study and will receive compensation for the portion of 
the study that they completed.  
Number of Patients Planned: Approximately up to 60 patients will be 
recruited.  
• The active treatment group will include up to 30 patients receiving CBD (600 mg/day). 
• The control group will include up to 30 patients receiving placebo. 
  
a Because buprenorphine or methadone will not be administered as a study medication and will be 
managed by the participant’s X-waivered prescriber, study personnel will not directly adjust  doses of 
these medications if participants endorse withdrawal or craving symptoms. However, with 
participants’ consent, we will attempt to communicate this info to the participant’s clinician for 
consideration of dose adjustment. 


Diagnosis and Main Criteria for Inclusion (see Table 1 below): Patients will be 21-65 years of age 
and will meet criteria for current (over the 3 months before enrollment) OUD on the basis of the Mini 
International Neuropsychiatric Interview (MINI) 7.0.2 for DSM-5. They will have reported opioid use 
in the 60 days before evaluation and will be receiving a stable maintenance dose of 12 mg 
buprenorphine in a formulation including naloxone (buprenorphine/naloxone ratio of 4/1) or without 
naloxone or methadone for at least 7 days at the same maintenance dose. 
When administered via the sublingual route, buprenorphine-naloxone is a safe and effective 
treatment for OUD that has a high therapeutic index and a ceiling effect for respiratory depression that 
reduces the likelihood of adverse outcomes. A buprenorphine dose range of 12 mg daily is a usual 
dosage for residents at the TTC and was selected to produce substantial occupancy of mu- opioid 
receptors. A 16-mg buprenorphine maintenance dose significantly decreases whole-brain mu- opioid 
receptor availability by 80 ± 2% relative to placebo, with nonsignificant increases in receptor 
occupancy by 32 mg of buprenorphine.20 Occupancy of mu opioid receptors by buprenorphine 
correlates well with plasma levels of the medication and with questionnaire-based opioid withdrawal 
symptoms and attenuation of response to hydromorphone.21 
Key Exclusion Criteria (see Table 2 below):  
Patients will be excluded for physiological dependence on alcohol or a sedative-hypnotic drug, requiring 
medical detoxification, receiving medication-assisted treatment with naltrexone, and showing signs of 
acute opioid withdrawal symptoms (score of 5 on the Clinical Opiate Withdrawal Scale, COWS).  
Because Cue-induced craving for opioids will be a secondary outcome, participants will be 
screened to eliminate those who do not report sufficient craving in response to visual cues (pictures). 
Those who do not have a craving score of at least 50 (on a visual analogue scale with a maximum score 
of 100) for at least one image within one category (groups of images may be separated into smoking 
cues, pills and bottles, and injection paraphernalia). For example, for injection cues, a picture of a 
needle and syringe may elicit a craving response, though other images in the same group (i.e., picture 
of arm with vein bulging) do not elicit craving. 
Exclusion criteria also include clinically significant medical conditions; and AIDS or current HIV 
seropositivity (as HIV positive individuals entering the Tarzana Treatment Center generally have 
medication treatment with antiviral and/or non-antiviral therapies that have potential interactions with 
CBD). Pregnancy and lactation also will be exclusion criteria. Because of evidence that CBD affects 
ovarian function, women with hormone values outside the normal range on a test battery will be 
evaluated with ultrasound; those who have evidence of ovarian suppression will be excluded. 
Screening labs/tests will include direct bilirubin (D Bili) and liver function tests (LFT), baseline 
ECG, and pregnancy test for women. Parameters for exclusion include: 
a. AST or ALT greater than or equal to 3Xs ULN. 
b. Bilirubin greater than or equal to 1.5 Xs ULN. 
c. Clinically significant abnormalities on EKG 
Table 1. Inclusion criteria 
• 
Ability to read and speak English and has provided written informed consent. 
• 
Age of 18-65 years (inclusive). 
• 
Meeting criteria for an OUD according to the MINI for ≥ 3 months before screening. 
• 
Self-report of opioid use in the 30 days before screening; verified by treatment center records. 
• 
On a stable dose of 12 mg buprenorphine, either alone, or in combination with naloxone 
(buprenorphine/naloxone ratio of 4/1) or methadone for at least 7 days prior to staring and for the duration 
of the treatment phase of the study. 
• 
If female, being surgically sterile or willing to use birth control (e.g., oral contraceptives, condoms, intrauterine 
device) or willingness to abstain from sex throughout the study. 
• 
Body Mass Index (BMI) between 17.5 and 35 kg/m2; total body weight > 110 lb (50 kg). 
• 
Currently in residential treatment at the Tarzana Treatment Center. 


d. Pregnancy test positive. 
Based on Epidiolex® (CBD oral solution) label section 7, "Drug Interactions", we will exclude 
participants who are taking the following medications: strong a) inducers of CYP3A4 or CYP2C19 
(e.g., rifampin, due to the potential to decrease CBD plasma levels); and b) substrates of UGT1A9 
(e.g., diflunisal, propofol, fenofibrate), UGT2B7 (e.g., gemfibrozil, lamotrigine, morphine, lorazepam), 
CYP2B6 (e.g., bupropion, efavirenz), CYP2C19 (e.g., clobazam, diazepam) due to potential to 
inhibition of enzyme activity by CBD).  
 
Investigational Product and Mode of Administration: ATL5, which is CBD, extracted from hemp, at 
a 10% strength (softgel capsules with 100 mg/ml of CBD per capsule) or matching placebo. The 
formulation that was selected for this clinical trial contains CBD and excipients as here: 
a) emulsifying agents: Cremophor EL (Polyoxyl 35 castor oil), Tween 80 (Polysorbate 80), 
Plurol® Oleique (polyglyceryl-3 dioleate); 
b) cwe o-surfactant: propylene glycol; 
c) oil: Labrosol® (caprylocapryol polyoxyl-8 glycerides), medium chain triglycerides; 
d) antioxidant: BHT (butylated hydroxytoluene). 
Table 2. Exclusion Criteria 
• History of sensitivity to a CBD product or any of the ingredients in the study drug, including glycerin or 
gelatin. 
• A condition that may affect drug absorption (e.g., gastrectomy). 
• Taking a medication that has clinically significant interactions with CBD or are contraindicated for the 
study (check with study physician). 
• Positive urine test for THC at screening. 
• Self-report of using CBD at screening. 
• PK analysis at screening showing evidence of CBD use (any level > 0). 
• Physiological dependence on alcohol or a sedative-hypnotic benzodiazepine drug. 
• Current medication-assisted treatment with naltrexone. 
• Acute opioid withdrawal symptoms, as defined by a score on the COWS > 4. . 
• Clinical laboratory finding of AST or ALT > 3 times the upper limit of normal (ULN) or bilirubin > 1.5 
times ULN. 
• AIDS or HIV positive status (because treatment medications have potential interactions with CBD). 
• Pregnancy or lactation. 
• Clinically significant EKG abnormalities, as determined by the study physician, including the following: 
QTc >450 msec (men) or >470 (women) or QRS interval >120 msec (If QTc or QRS interval exceed these 
cutoff points, EKG will be repeated twice and the average of the three QTc values used to determine 
eligibility.), congenital long QT syndrome, history of prolonged QT in the 3 months before screening, 
corrected QT interval (Fridericia’s – QTcF) >450 msec (male) or >470 msec (female) or history of risk 
factors for Torsades de Pointes. 
• For women: any value outside reference ranges on a hormonal battery [estradiol, follicle-stimulating 
hormone, free thyroxine index, luteinizing hormone, prolactin, T3 uptake, thyroid-stimulating hormone, and 
thyroxine], followed by an abnormal ovarian ultrasound finding. 
• Clinically significant cardiovascular, hematologic, hepatic, renal, or endocrine abnormalities, as determined 
by the study physician. 
• Meeting criteria on the MINI for schizophrenia, Bipolar I disorder, psychotic disorder, having active suicidal 
ideation, or suicide attempt in the past 12 months. Or, answers “yes” to questions 4 or 5 on C-SSRS. NOTE: 
Participants with other psychiatric conditions, such as major depression, generalized anxiety, dysthymia, 
social phobia or specific phobia may be enrolled in the study if they are clinically stable. 
• On the cue-induced opiate craving task at screening, the participant does not have a score of at least 50 (on a 
visual analogue scale with a maximum score of 100) for at least one image within one category. Note: 
Groups of images may be separated into smoking cues, pills and bottles, and injection paraphernalia. For 
example, for injection cues, a picture of a needle and syringe may elicit a craving response, though other 
images in the same group (i.e., picture of arm with vein bulging) do not elicit craving. 


ATL5 Softgel Capsules will be manufactured by Baxco Pharmaceutical Inc., (California, USA) 
under cGMP conditions. They will be administered orally as indicated below. 
Dosage and Duration of Treatment: The planned study will evaluate ATL5 (300 mg, BID). The 
treatment period with CBD or placebo will be 28 days. Participants will be in the study for up to 10 
weeks, including follow-up evaluation after completion of the 28-day treatment period. 
Dose Justification: CBD will be tested at 600 mg daily. This dose was selected on the basis of safety 
data from human studies. In a previous clinical trial, doses of CBD as high as 50 mg/kg (i.e., 350 mg for 
a 70-kg participant) were well tolerated.22 Doses between 300 and 1500 mg have been used in humans 
without toxicity or serious adverse events.23-29 Forty-two subjects received 200 mg of CBD four times 
daily (total 800 mg per day) for 2 to 4 weeks to treat schizophrenia without notable side effects.30 A 
review of 132 reports, which included animal and human studies, concluded that CBD was well-tolerated 
in humans, at doses of up to 1500 mg/day31fo 
Sixty subjects were dosed to date in a pediatric pharmacokinetic trial with doses ranging from 10 
mg/kg/day up to 40 mg/kg/day32; these doses were generally well tolerated, and no clinically significant 
safety concerns were identified, even in adolescents. In addition, 24 adults received doses of 20 mg/kg 
CBD (up to ~2000 mg as a single dose) (INS011-15-043) in a study evaluating the effects of food (fasting 
and a high-fat meal) on absorption of CBD. In that study, and in another that evaluated food effects on 
CBD absorption in 8 healthy adults (INS011-16-093), there were no safety issues and very few adverse 
events. 
In a study of heroin-abstinent patients with OUD, 400 mg and 800 mg CBD were shown to be safe 
and well-tolerated when given with intravenous fentanyl.33 Specifically, Systematic Assessment for 
Treatment Emergent Events (SAFTEE) data were similar between CBD dose groups, and there was no 
respiratory depression and no cardiovascular complications during any test session. However, no study 
has yet evaluated the effect of CBD as an adjunctive therapy to buprenorphine or methadone. Given the 
known safety and efficacy of CBD, we will compare CBD to placebo to determine whether CBD reduces 
cue- induced craving for opioids (primary outcome measure) and has other effects, such as relapse 
prevention in patients with OUD when used as an adjunctive therapy to buprenorphine or methadone. 
Reference Therapy, Dosage, and Mode of Administration: The reference therapy will be placebo, 
consisting of softgel capsules that match the active test medication in appearance. The placebo softgel 
capsule formulation is composed of polyoxyl 35 polysorbate 80, plurol- oleique CC 497, propylene 
glycol, caprylocapryol polyoxyl-8 glycerides, medium chain triglycerides and BHT, in the same 
relative proportions as the ATL5 Softgel Capsules. The softgel shell will be composed of caramel 
color, gelatin, glycerin and purified water. 
This formulation also will be manufactured by Baxco Pharmaceutical Inc. under cGMP conditions. 
Safety Assessments and Monitoring: The following tests and procedures will be performed for 
safety monitoring throughout the study. 
a. Comprehensive metabolic panel, CBC with differential, and urinalysis    
      Key tests: AST, ALT and INR levels 
      Sampling times: Days -7 to 0 (screening), Days 7, 14, 21 and 28 (treatment), and Days 
35, 42, 49 and 56 (follow-up). 
b. Assessment of Sedation 
Instruments and measures: Observed Observer’s Assessment of Alertness/Sedation Scale (OAAS) and 
pulse oximetry 
Assessment times: Days -7 to 0 (screening), and Days 1-28 (treatment), 
and Days 29, 30, 31, 33, 35, 42, 49 and 56 (follow up). 
c. Electrocardiogram 
Safety parameters: evidence of arrhythmia, recent MI, and 3rd degree heart block 


Assessment times: Days -7 to 0 (screening) and Day 28 (treatment). 
d. Ovarian hormone battery 
Hormone assays: estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), 
prolactin, T3 uptake (THBR), thyroid-stimulating hormone (TSH), thyroxine (T4). 
If abnormality is seen, ultrasound will be obtained. 
Assessment times: Days -7 to 0 (screening), Days 7, 14, 21, and 28 (treatment), 
and Days 35, 42, 49 and 56 (follow up). 
e. Suicidality 
Assessment: Columbia Suicide Severity Rating Scale (C-SSRS) 
Assessment times: Days -7 to 0 (screening), and Days 7, 14, 21, and 28 (treatment). 
 
Interventions and Stopping Criteria: 
a. Dosing will be stopped for slowed respiration and hypoxia (O2 saturation <94% on room air for 2 
consecutive days with evidence of no response to dose adjustment). 
b. Patients who become hypoxic (<90% O2 saturation on room air) or sedated (OASS scale 
score <4) will be referred/transported to the ED (call 911); CBD dose will be held until medical 
assessment and stabilization, and if restarting medication is deemed appropriate by the study 
MD, the daily total study medication dose will be halved. 


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