Conditions: Cannabidiol Drug Induced Liver Injury Drug Interaction
Keywords: Cannabidiol CBD Liver enzyme elevation Drug interactions
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 241
Healthy volunteers: yes

Brief summary:
Cannabidiol (CBD) is available as a prescription drug product for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. At labeled doses up to 25 mg/kg/day, an increased risk of liver enzyme elevation and drug-induced liver injury has been observed. However, only limited evaluations of the risk of liver enzyme elevation of daily, lower dose CBD use are available. The potential for liver enzyme elevations with lower CBD doses with unapproved consumer products highlights a need for further research. In addition, CBD has the capacity to inhibit cytochrome P450 enzymes and uridine 5'-diphospho-glucuronosyltransferases, leading to potential drug-drug interactions with multiple common medications. The clinical significance of many of these interactions is also unclear. Furthermore, nonclinical studies have suggested the potential for CBD to cause reproductive and endocrine effects. As such, additional high-quality clinical pharmacology studies are needed to further characterize CBD's safety profile.

The objective of this study is to characterize the effects of daily CBD use at a dose within the range of what consumers are taking as unapproved CBD products on liver enzyme elevations, drug interactions, and endocrine measures.

Detailed description:
The cannabis plant contains bioactive compounds known as cannabinoids; delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prevalent cannabinoids in most varieties of cannabis. The Agricultural Improvement Act (Farm Bill) of 2018 removed hemp, defined as cannabis and derivatives of cannabis with extremely low concentrations of THC, from the definition of marijuana in the Controlled Substances Act. Following this, many CBD products have been made available to consumers. However, hemp products remain subject to regulation under the Federal Food Drug \& Cosmetic Act, when applicable (e.g., as drugs, foods, dietary supplements, cosmetics, veterinary products) and the growing CBD products market raises various safety concerns, especially with long-term use.

CBD is available as a prescription drug product for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. At labeled doses up to 25 mg/kg/day, an increased risk of liver enzyme elevation and drug-induced liver injury has been observed. However, only limited evaluations of the risk of liver enzyme elevation of daily, lower dose CBD use are available. The potential for liver enzyme elevations with CBD doses in unapproved consumer products highlights a need for further research to quantify risks at these doses. In addition, CBD has the capacity to inhibit cytochrome P450 enzymes and uridine 5'-diphospho-glucuronosyltransferases, leading to potential drug-drug interactions with multiple common medications. The clinical significance of many of these interactions is also unclear. Furthermore, nonclinical studies have suggested the potential for CBD to cause reproductive and endocrine effects. As such, additional high-quality clinical pharmacology studies are needed to further characterize CBD's safety profile.

This study will be divided into two parts.

In Part 1, 200 healthy subjects will be randomized to 5 mg/kg/day of CBD (150 subjects) or placebo (50 subjects) for 4 weeks with weekly laboratory assessments to characterize the percentage of participants with liver enzyme elevation (primary endpoint) or meeting withdrawal criteria for potential drug-induced liver injury (secondary endpoint). Additional secondary endpoints include the change from baseline after 4 weeks of daily CBD dosing for male reproductive (testosterone and inhibin B) and thyroid hormones (thyroid stimulating hormone \[TSH\], triiodothyronine \[T3\] and thyroxine \[T4\]) as secondary endpoints. Exploratory endpoints include additional characterization of liver findings and other blood biomarkers.

In Part 2, 40 healthy subjects will receive either oral citalopram (20 subjects) or morphine (20 subjects) at baseline and then again after receiving CBD 5 mg/kg/day to characterize the effect of daily cannabidiol use on the plasma concentration of citalopram and morphine. Citalopram was selected because it is a common prescription medication for depression and anxiety that is metabolized by CYP2C19 and CYP3A4, which CBD inhibits. Morphine was selected because it is a common opioid analgesic that is metabolized by UGT2B7, which CBD inhibits.

Arms:
arm 1: Subjects in this arm will receive oral solution cannabidiol at a dosage of 2.5 mg/kg twice a day, for a total of 5 mg/kg cannabidiol daily for 28 days. arm 2: Subjects in this arm will receive oral solution placebo twice a day for 28 days. arm 3: Subjects in this arm will receive citalopram (20 mg) on Day 1 and Day 13 and oral solution cannabidiol at a dosage of 2.5 mg/kg twice a day (5 mg/kg cannabidiol daily) for 12 days (Day 6-17). arm 4: Subjects in this arm will receive morphine (15 mg) on Day 1, Day 4, and Day 11 and oral solution cannabidiol at a dosage of 2.5 mg/kg twice a day (5 mg/kg CBD daily) for 9 days (Day 4-12).

Interventions: intervention 1: Cannabidiol intervention 2: Placebo intervention 3: Citalopram intervention 4: Morphine
Intervention descriptions: intervention 1: Cannabidiol (Epidiolex) will be administered orally 2.5 mg/kg twice daily (5 mg/kg/day) for 28 days in Part 1 and for 9 days (morphine cohort) or 12 days (citalopram cohort) in Part 2. intervention 2: Placebo will be administered orally twice daily for 28 days in Part 1 intervention 3: Citalopram (Celexa) will be administered once at 20 mg on days 1 and 13. intervention 4: Morphine will be administered once at 15 mg on days 1, 4, and 11.

Protocol document:
ICF_002.pdf: 
Study Title: Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and 
Drug Interactions 
 
Document Title: Informed Consent Form – Study No. SCR-016 
 
Document Date: 10 May 2024 
 
NCT Number: NCT06192589 


U.S. Food and Drug Administration / Protocol Number SCR-014  
Page 1 of 25  
 
Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
CONSENT TO TAKE PART IN A CLINICAL RESEARCH 
STUDY AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
Sponsor/Study Title: 
U.S. Food and Drug Administration, 
Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and 
Drug Interactions 
Protocol Number: 
SCR-016 
Principal Investigator: 
(Study Doctor) 
Melanie Fein, M.D. 
Telephone: 
800.597.4507 (Recruitment Department) 
855.622.8100 (24-hour urgent question/care) 
Additional Contact(s): 
Trupti I., Project Manager 
Karrielynn G., Study Manager 
Samuel B., Associate Study Manager 
Address: 
Spaulding Clinical Research, LLC 
525 S Silverbrook Dr. 
West Bend, WI 53095 
 
SUBJECT SCREENING # 
 
 
Please read this form carefully. Take time to ask the study doctor or study staff as many questions about 
the study as you would like. The study doctor or study staff can explain words or information that you 
do not understand. Reading this form and talking to the study doctor or study staff may help you decide 
whether to take part or not. If you decide to take part in this study, you must sign your name at the end 
of this form. You cannot take part in this research study until you sign and date this form. 
WHAT IS A VOLUNTEER INFORMED CONSENT? 
 
You are being asked to take part in a research study which will look to characterize the effects of daily 
cannabidiol (CBD) for 4 weeks at a dose within the range of what consumers are taking with unapproved 
CBD on liver enzyme elevations, drug interactions, and endocrine hormones. 
 
For the drug-drug interaction (DDI) studies, approved Food and Drug Administration (FDA) drugs will 
be used. These drugs are morphine and citalopram. However, the use of these drugs in this study in 
combination with CBD is investigational. 
Before you decide to take part, you should understand the possible benefits and risks associated with this 
study. This process is known as informed consent and means that you will: 
• 
Receive detailed information about this research study. 
• 
Have a chance to ask and receive answers to any questions you may have. 
• 
Be asked to read and sign this informed consent once you understand the study and wish to 
take part. 


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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
• 
Be given a signed and dated copy of this informed consent to keep. 
Taking part in this study is entirely voluntary. 
 
WHY ARE THESE DRUGS BEING STUDIED? 
 
The cannabis plant contains bioactive compounds known as cannabinoids; delta-9 tetrahydrocannabidiol 
(THC) and cannabidiol (CBD) are the most prevalent cannabinoids in most varieties of cannabis. CBD is 
available as a prescription drug product for the treatment of seizures associated with Lennox-Gastaut 
syndrome, Dravet syndrome, or tuberous sclerosis complex (Epidiolex is the name of the CBD product 
and is approved by the FDA for certain seizure disorders. At labeled doses up to 25 mg/kg/day, an 
increased risk of liver enzyme elevation has been observed. However, only limited evaluations of the risk 
of liver enzyme elevation of daily, lower dose CBD use are available. The potential for liver enzyme 
elevations with CBD doses in unapproved consumer products highlights a need for further research to 
quantify risks at these doses. In addition, CBD has the capacity to inhibit cytochrome P450 enzymes and 
uridine 5’-diphospho-glucuronosyltransferases, leading to potential drug-drug interactions with multiple 
common medications. The clinical significance of many of these interactions is also unclear. Furthermore, 
nonclinical studies have suggested the potential for CBD to cause reproductive and endocrine effects. As 
such, additional high-quality clinical pharmacology studies are needed to further characterize CBD's 
safety profile. 
 
Citalopram (Celexa) is a selective serotonin reuptake inhibitor (SSRI) indicated for treatment of major 
depressive disorder. Citalopram (Celexa) is orally administrated and available as 10 mg, 20 mg, and 40 
mg strength tablets. It is a substrate of the metabolizing enzyme CYP2C19 and CYP 3A4 that may be 
inhibited by CBD. 
 
Morphine sulfate tablet is an opioid agonist indicated for the management of moderate-severe acute and 
chronic pain. It is available in 15 mg and 30 mg oral tablets. Morphine is primarily metabolized by UDP- 
glucuronosyltransferase, which may be inhibited by CBD. 
 
WHO IS BEING ASKED TO TAKE PART IN THIS STUDY? 
 
Approximately 240 healthy male and female adult subjects, who meet the requirements following a 
screening visit, will be enrolled in the study. This study will be divided into 2 parts. The first part, in 
which only CBD is administered will consist of 200 total subjects. Part 2, in which drug interactions 
will be studied with citalopram and morphine, will include 40 subjects. 
 
You have been asked to take part in this study because you are in general good health, are 18-55 
(inclusive) years of age, have no history of heart or liver disease or other significant medical 
conditions, no history of allergies, and have not participated in another research study for an 
experimental drug (or a medical device) within 30 days of the first dose of study drug. 
 
HOW MUCH TIME IS REQUIRED TO TAKE PART IN THE STUDY? 
 
If you decide to take part in the study, you will be asked to attend a screening visit. If you pass the 
screening visit, you will return to the clinic for 2 inpatient stay periods. If selected to participate in Part 
1 of the study, each in-house period will last for 2 days and one night. Clinic visits will occur weekly 
for the three weeks between these inpatient visits. There will be a final clinic visit 6 days after the final 
inpatient stay. For Part 2 (the drug-drug interaction study), subjects will be assigned to a citalopram 
cohort (cohort also known as group) or a morphine cohort. For the citalopram cohort, the two inpatient 


U.S. Food and Drug Administration / Protocol Number SCR-014  
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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
stays will be 7 days and 6 nights. The second inpatient stay will begin 6 days after the check-out from 
the first inpatient stay. For the morphine cohort, the first inpatient stay will be 7 days and 6 nights, 
while the second inpatient stay will be 4 days and 3 nights. The second inpatient stay will begin 4 days 
after the check-out of the first inpatient stay. The final clinic visit will be on Day 24 for the citalopram 
group and Day 19 for the morphine group. 
The duration of your participation in the study from check-in to final follow-up will be up to 36 days if 
placed into Part 1 and up to 25 days if placed into Part 2. 
You may be asked to return to the clinic for follow up visits in 24-48 hours for additional liver function 
monitoring if liver function tests are elevated based on study doctor’s recommendations. These visits may 
continue every 24-48 hours or change to twice weekly or weekly depending on the values of the tests 
and/or if the values are worsening or improving. If your liver function values do increase additional 
testing may be required for other possible causes such as Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis 
D, and Hepatitis E and a number of other viruses. Hepatitis test results will be reported to the health 
authorities as required by state law. 
 
INFORMATION FOR FEMALE SUBJECTS 
You should not screen for this study if: 
 
There is any possibility that you may become, or are pregnant, 
• 
You have given birth in the last 3 months, or 
• 
You are breast feeding. 
 
You may screen for this study if you meet one of the following criteria: 
• 
You are of non-childbearing potential (non-childbearing potential includes post- 
menopausal females and females who have undergone a hysterectomy) 
• 
You have been strictly abstinent for 1 month before check-in (Day -1) and agree to remain 
strictly abstinent for the duration of the study and for at least 1 month after the last 
administration of study drug. 
• 
You are using two adequate methods of contraception (birth control) to avoid pregnancy 
throughout the study and for at least 3 months after last study drug administration. 
Adequate methods of contraception include use of two of the following categories of which one (1) must 
be a barrier method from Screening until at least 1 month after the end of the study. 
• 
Hormonal implants/patch, 
• 
Oral hormonal contraceptives, 
• 
Injectable hormones, 
• 
Intra-uterine device (IUD), 
• 
Approved cervical ring, 
• 
Diaphragm with spermicide or condom (female or male) with spermicide 
 
The use of spermicide alone and condom alone are not acceptable methods of contraception. 
 
Except for continuous abstinence (no sexual intercourse with a male partner), no method of birth 
control can be considered 100% reliable in preventing pregnancy. Although the risk of becoming 
pregnant is low with many methods, unplanned pregnancies may occur with all birth control methods. 
Most occur because of improper or irregular use of the birth control method. If you are usually not 
sexually active but become sexually active, you must follow the advice documented above regarding 
contraceptive methods. 


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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
All females enrolled in this study will have a pregnancy test performed at screening, before admission on 
Day -1 and the follow-up clinic visit on Day 35 (Part 1), Day 24 (Part 2- Citalopram cohort) or Day 19 
(Part 2- Morphine cohort) and/or early exit visits. 
 
Please be aware that a pregnancy test may not be positive until 12 days after conception (fertilization of 
the egg by sperm). Therefore, if you do not follow the study birth control requirements and/or your birth 
control method has failed, you will not be able to count on a negative test to confirm that you are not 
pregnant. 
 
If you know that you have not followed the study birth control requirements outlined above, then you 
must immediately inform us. You must not take any dose of the study drug if you have not followed 
these requirements. 
INFORMATION FOR MALE SUBJECTS 
You must agree to practice 2 highly effective methods of birth control (condom with spermicide) from 
check-in (Day -1) until at least 3 months after the last dose of study drug. The effect of the study drug on 
male sperm is unknown. In rare cases, drugs may damage sperm in ways that affect a child that is 
fathered. Male subjects may not donate sperm for 90 days after the end of the study. 
 
Periodic abstinence and withdrawal are not acceptable methods of contraception. 
 
HOW WILL YOU KNOW IF YOU ARE ELIGIBLE TO TAKE PART? 
 
You will need to fast for at least 8 hours prior to your arrival at Spaulding Clinical Research, LLC. for 
your screening visit, meaning you should not eat any food and should only have water to drink. 
At the beginning of the Screening visit, Informed Consent will be obtained. 
 
Before starting the study, the following screening procedures will be performed: 
• 
A complete medical history and physical examination (including height and weight 
measurements for Body Mass Index [BMI, a way to tell if your weight is proportional to 
your height]). 
• 
Assessment of blood pressure, respiratory rate, heart rate, and oral temperature. 
• 
A complete history of relevant allergies or drug sensitivities. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
You will be asked if you have taken any medication recently. 
• 
You will be asked if you have been feeling ill recently. 
• 
Clinical laboratory tests (urine and blood samples), including screening for drugs, alcohol, 
cotinine test and pregnancy tests (all female subjects), and testing for HIV, hepatitis B and C. 
Positive results of HIV or any hepatitis tests will be reported to local health authorities as 
required by state law. 
 
If you meet the “entry criteria” of the study, according to the study doctor, you will be tested again when 
you are admitted to Spaulding Clinical Research, LLC. You will have the entry criteria reviewed again 
to ensure that you still are eligible for the study. 
 
In addition, prior to admission you will have a diagnostic test performed to detect severe acute 
respiratory syndrome coronavirus 2 (called “coronavirus” from now on), which is the virus that causes 
COVID-19. Depending on the time required to return results, this may be performed ~2 days before 
check-in or may be performed on the check-in day. You will only be allowed to be admitted if your 


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Melanie Fein, M.D. 
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coronavirus test is negative. A positive result may be reported to local health authorities as required by 
state law. In addition, when entering the building for screening and check-in, triage for COVID-19 will 
take place. The exact details of what will occur at triage may change as additional information or testing 
is available, however as of now it is planned to include asking about any potential contacts with 
COVID- 19, signs and symptoms associated with COVID-19, temperature monitoring and antigen 
screening for coronavirus. You may need to be tested for COVID 19 several times during the study, 
upon admission, prior to discharge or if you develop symptoms during the study. 
 
HOW WILL THE STUDY BE DONE? 
 
Approximately 240 healthy adult subjects, both male and female will be enrolled in this study. The 
study will consist of two parts. Part 1 of the study includes 200 subjects evaluating liver tests, and 
reproductive and thyroid hormones. Part 2 will study 40 subjects for CBD drug-drug interactions. 
Part 1 
 
Day -1 
CBD Dosing Days 1-28 (5mg/kg/day) 
Day 29 
Day 35 
Day 1 
Day 7 
Day 14 
Day 21 
Day 28 
Check-in 
Check-out 
Clinic visit 
1 
Clinic visit 
2 
Clinic visit 
3 
Check-in 
Check-out 
Follow-up visit 
(Clinic visit 4) 
 
Part 2 
 
Citalopram DDI cohort 
Day -1 
Day 1 
CBD Dosing Days 6-17 (5 mg/kg/day) 
Day 18 
Day 24 
Day 6 
Day 12 
Day 13 
Check-in 
DDI drug Dosing 
(baseline) 
Check-out 
Check-in 
DDI drug Dosing 
(w/ CBD) 
Check-out 
Follow-up 
visit 
 
Morphine DDI cohort 
Day -1 
Day 1 
CBD Dosing Days 4-12 (5 mg/kg/day) 
Day 13 
Day 19 
Day 4 
Day 6 
Day 10 
Day 11 
Check-in 
DDI drug Dosing 
(baseline) 
DDI drug Dosing 
(w/ CBD) 
Check- 
out 
Check- 
in 
DDI drug Dosing 
(w/ CBD) 
Check- 
out 
Follow-up visit 
 
Once the study doctor determines that you are eligible to participate, you will be enrolled into Part 1 or 2. 
You will not be allowed to choose your part in which you receive the study treatments. Part 1 will be a 
double blinded study, neither you nor the study doctor or study staff will know which study treatment you 
are receiving—study drug or placebo. A placebo is a medically inactive substance which looks like the 
study drug. 
 
You will go through the same tests and procedures described below for any of the study treatments you 
receive. 
 
 


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WHAT TESTS AND PROCEDURES WILL BE USED IN THE STUDY? 
 
Check-in (Part 1: Days -1 and 28, Part 2 (Citalopram): Days -1 and 12, Part 2 (Morphine): Days -1 
and 10) 
Upon admission to Spaulding Clinical Research, LLC., you will be given an identity band to wear 
throughout your entire stay in the unit. 
 
You will need to fast for at least 8 hours prior to your arrival at Spaulding Clinical Research, LLC. for 
your check-in, meaning you should not eat any food and should only have water to drink. 
The following admission procedures will be performed: 
• 
Perform/review results from coronavirus test. 
• 
Medical history updates. 
• 
Physical examination. 
• 
Clinical laboratory tests (urine and blood samples), including screening for drugs, alcohol, 
cotinine test and pregnancy tests (all female subjects). 
• 
Assessment of blood pressure, respiratory rate, heart rate, and oral temperature. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
You will be asked for details of any medication taken since the screening or previous visit. 
• 
You will be asked if you have been ill since the screening or previous visit. 
• 
You will be asked if you complied with study restrictions. 
• 
You will be provided meals (lunch, dinner, and a snack). 
• 
Inclusion/Exclusion assessment and preparation for randomization (Part 1). Randomization 
means that you will be assigned by chance, like the flip of a coin, to either study group. 
The results from these tests will help the study staff determine whether you are still eligible to enter the 
study. 
In-house Study Treatment Period (Part 2 (citalopram): Days 1-5 and Days 13-17, Part 2 
(morphine): Days 1-5 and Days 11-12) 
• 
Adverse event (side effect) assessment and changes in concomitant medications 
• 
Study drug administration 
• 
Assessment of blood pressure, heart rate, respiratory rate, and oral temperature 
• 
Physical examination 
• 
Pharmacokinetic (PK) blood sampling 
• 
Clinical laboratory tests (blood sampling) 
• 
Meals 
Check Out (Part 1: Days 1 and 29, Part 2 (citalopram): Days 6 and 18, Part 2 (morphine): Days 6 and 
13) 
• 
Adverse event assessment and changes in concomitant medications 
• 
Physical examination 
• 
Pharmacokinetic (PK) blood sampling  
• 
Clinical laboratory tests (blood sampling) 
• 
Assessment of blood pressure, heart rate, respiratory rate, and oral temperature 
• 
After first checkout study medication will be provided for the time to the next clinic 
visit 
 


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At-home Study Treatment Period (Part 1: Days 2-6, 8-13, 15-20, and Days 22-27, Part 2 
(citalopram): Days 7-11, Part 2 (morphine): Days 7-9) 
• 
Twice-daily at-home study product dosing (taken with meals) 
Daily reminder texts will be sent to remind you to report any adverse events, changes in concomitant 
medications, and/or dosing concerns. You should not reply to the text message with any updates, but 
instead please call to report any adverse events, changes in concomitant medications and/or dosing 
concerns. 
 
Clinic Visits (Part 1: Days 7, 14, and 21) 
• 
Adverse event assessment and changes in concomitant medications 
• 
Pharmacokinetic (PK) blood sampling 
• 
Meal 
• 
Clinical laboratory tests (blood sampling) 
• 
Assessment of blood pressure, heart rate, respiratory rate and oral temperature 
• 
Administration of study product 
• 
Study drug dosing and study drug until next visit 
 
Follow-up (Part 1: Day 35, Part 2 (Citalopram): Day 24, Part 2 (Morphine): Day 19) 
• 
Adverse event assessment and changes in concomitant medications 
• 
Clinical laboratory tests (urine and blood samples) including pregnancy testing for all female 
subjects 
• 
Physical examination 
• 
Pharmacokinetic (PK) blood sampling 
• 
Assessment of blood pressure, heart rate, respiratory rate and oral temperature 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart) 
• 
Discharge from Spaulding Clinical after all events are completed 
 
At-home study treatment requirements and restrictions 
• 
Dose diary completion (completed after each at-home dose has been administered) 
• 
Dose is required to be stored in an area children can't access, the dose will not be in child safety 
packaging 
• 
Dose should be taken after eating breakfast and dinner at consistent times 
• 
Do not drive or operate heavy machinery until you know how the cannabidiol affects you 
End of Study/Follow Up Procedures 
• 
If you leave the study early, you will be asked to have all end of study procedures completed and 
required follow up procedures based on study doctor's recommendations. 
WHAT TESTS AND PROCEDURES WILL BE USED IN THE STUDY? 
 
Blood Sampling 
Pharmacokinetic (PK) blood samples will be collected for the measurement of levels of epidiolex, 
citalopram, morphine, and respective metabolites. 
If assigned to Part 1, approximately 6 PK blood samples will be taken on the following days: 
• 
Check-out Day 1, Clinic visit Day 7, clinic visit Day 14, clinic visit Day 21, check-out Day 
29, and at follow-up on Day 35  
 


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If you are assigned to Part 2 (citalopram cohort) approximately 26 PK samples will be collected as 
follows: 
• 
13 PK samples over 120 hours will be obtained during each in-house stay 
o Days 1 and 13: 8 PK samples 
▪ 
0, 1, 2, 3, 4, 6, 8, 12 hours 
o Days 2 and 14: 1 
▪ 
24 hours 
o Days 3 and 15: 1 
▪ 
48 hours 
o Days 4 and 16: 1 
▪ 
72 hours 
o Days 5 and 17: 1 
▪ 
96 hours 
o Days 6 and 18: 1 
▪ 
120 hours 
 
If you are assigned to Part 2 (morphine cohort), approximately 39 PK samples will be collected as 
follows: 
• 
13 PK samples over 48 hours will be obtained for each morphine drug interaction assessment 
o Days 1, 4 and 11: 11 PK samples 
▪ 
0, 15, 30, 45, 60, 90 minutes 
▪ 
2, 3, 4, 6, 12 hours 
o Days 2, 5 and 12: 1 
▪ 
24 hours 
o Days 3, 6 and 13: 1 
▪ 48 hours 
 
Each blood sample will be labeled with subject number, study number, study day, time point, event, and a 
barcode that matches that belonging to the subject. 
 
• 
For Part 1, separate blood samples will be collected for measurement of hormones, proteins, and 
lipids (e.g., cholesterol) in your blood prior to dosing on Day 1 and at check-out on Day 29. An 
additional blood sample on study days 1, 14, and 28 will also be collected to provide serum 
samples for cytokine and antibody testing. These blood samples will be processed to be used in 
cytokine (a type of protein that is made by certain immune and non-immune cells and has an 
effect on the immune system) and antibody (proteins that protect you when an unwanted 
substance enters your body) level testing. 
 
• 
For Part 2, an additional blood sample will be collected on the following days to provide serum 
samples for cytokine and antibody testing: 
o Morphine cohort: pre-dose, Day 4, Day 10, and Day 13  
o Citalopram cohort: pre-dose, Day 6, Day 12, and Day 18 
These blood samples will be processed to be used in cytokine (a type of protein that is made by certain 
immune and non-immune cells and has an effect on the immune system) and antibody (proteins that 
protect you when an unwanted substance enters your body) level testing. 
You will have numerous blood samples drawn during the entire study for study drug levels as shown 


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above, and 8 (Part 1) or 3 (Part 2) safety laboratory draws throughout the study. The blood samples may 
be taken by individual needle sticks into one of your arm veins, or, if necessary, by an indwelling 
catheter (a thin plastic tube placed in a vein in your arm). Additional blood samples may be obtained for 
safety reasons throughout the study based on the study doctor’s recommendations. Two tubes of blood 
will be drawn to store for the duration of the study and in the event, you test positive for an infection 
during the study we may test the tube of blood to compare the results to assess if you already had an 
existing condition. At the conclusion of the study, if not used, these tubes will be destroyed. 
Total number of blood samples for Part 1 will be approximately 19, for Part 2 citalopram cohort 33, and for 
Part 2 morphine cohort 46. 
If your liver function tests are elevated the study doctor or designee may recommend return visits that will 
include additional safety labs. The total blood volume for the safety labs associated with each visit will be 
approximately 21 mL or about 4 teaspoons/ 
 
The total amount of blood taken for the entire study will be approximately 156 mL or a little more than 0.5 
cup for Part 1, 258 mL or about 1 cup for the citalopram cohort of Part 2, and 333 mL or about 1.5 cups for 
the morphine cohort of Part 2. 
 
GENETIC TESTS  
 
A blood sample will be collected in both Parts for genetic testing.  
 
Participating in the study is optional but in order to be included in the study you must agree to the genetic 
testing. If you do not agree to the genetic testing please do not sign the consent form as you will not be able 
to participate in the study.  
 
This genetic test will be exploratory by nature and the results may or may not be reported in the study 
documentation. Genetic testing is done to study differences in how our bodies respond to or handle drugs. 
This research will look at genetic differences to better understand why people react or respond differently 
when they get the same drug. Any personal health information about you, including any genetic information, 
will be kept confidential. Your personal information will not be attached to the sample.  
Privacy Risks 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal for 
health insurance companies, group health plans and most employers to discriminate against you based on 
your genetic information. 
This law generally will protect you in the following ways: 
• Health insurance companies and group health plans may not request your genetic information that the 
sponsor will get from this research. 
• Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums. 
• Employers with 15 or more employees may not use your genetic information that the sponsor will get from 
this research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment. 
 


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Melanie Fein, M.D. 
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All health insurance companies and group health plans and all employers with 15 or more people must 
follow this law. 
Be aware that this Federal law does not protect you against genetic discrimination by companies that sell life 
insurance, disability insurance or long-term care insurance. 
POSSIBLE BENEFITS 
There is no direct benefit to you from participating in the genetic test. Your participation in the genetic test 
may help find better ways to treat diseases in the future. This may also help doctors and scientists understand 
why people react to drugs differently. This research may help identify who is more likely to respond to 
different drugs and who may experience side effects. 
Please ask the study staff to explain any words or information about the genetic testing you do not 
understand. 
WITHDRAWAL FROM STUDY AND REFUSAL TO PARTICIPATE  
If you consent to the genetic test and decide at a later date that you would like to withdraw your consent, you 
will need to do so by contacting your study doctor at the address listed on the first page of this consent form.  
Withdrawing consent will result in destruction of your genetic sample(s). However, if you withdraw your 
consent after the sample has been tested, the test results and research study/sample-related information must 
remain in any database(s) that were created for the research study. The reason for this is to comply with 
regulations that require us to make data available for review by the United States Food and Drug 
Administration (FDA) or other appropriate regulatory authorities, or if this research is used to support an 
application for FDA approval to market the study drug. 
If you withdraw consent for participation in the study or are discontinued (withdrawn) from the study, the 
sample you provided for genetic testing will continue to be available for testing unless you also withdraw 
your consent for the genetic test as stated above. 
Urine Sampling 
You will have urine samples collected at screening, first check-in day (Day – 1), each subsequent check-in 
for overnight stays (Part 1: Day 28 and Part 2: Day 12 or Day 10) and on the final follow-up visit (Part 1: 
Day 35 and Part 2: Day 24 or Day 19). These will be used to screen for either alcohol or drugs, and for 
routine safety analysis. Additional urine samples, which may include urine drug screens, may be obtained 
for safety reasons throughout the study based on the study doctor’s recommendations. 
 
ECG Measurements 
Safety ECG measurements will occur at screening, check-in day (Day -1) and on the follow-up visit 
(Part 1: Day 35 and Part 2: Day 24 or Day 19). Additional ECG measurements may be obtained for 
safety reasons throughout the study based on the study doctor’s recommendations. 
 
Some individuals may develop redness, irritation, skin breakdown or discoloration of the skin at the site 
of ECG electrodes placed on the chest/body. This may develop due to sensitivity to the electrodes or to 
our skin preparation procedure. In order to get the quality results we need, it is necessary for us to lightly 
scrub the skin with an abrasive pad to remove any skin impedance such as oil, dead skin cells and 
lotions. 
 


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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
WHAT ARE YOUR RESTRICTIONS DURING THE STUDY? 
 
You will need to avoid the following while taking part in this study, and most importantly from the time 
of your screening visit until you check in: In the event you are prescribed any medication by a treating 
provider or facility, it is important that you notify that provider that you are taking Epidiolex. Do not 
continue taking the Epidiolex without speaking with the study doctor. 
 
Restricted Item: 
Duration: 
Alcohol, Marijuana or marijuana-derived products, 
hemp or hemp-derived products, including CBD 
(except for provided study drug), and illicit drugs 
of any kind. 
Refrain from using any for the duration of the 
study. 
Caffeine or other xanthine containing products 
(for example, coffee, tea, cola or chocolate) 
24 hours prior to check-in until final check out. 
Grapefruit/grapefruit juice/grapefruit hybrids, 
pomelos, cranberries, pomegranates, star fruit, 
Seville oranges, apples, vegetables from the 
mustard green family (for example, kale, broccoli, 
watercress, collard greens, brussels sprouts, 
mustard) and charbroiled meats 
24 hours prior to check-in until final check out. 
Prescription medication 
14 days prior to dose until final check out. 
Aspirin or NSAIDs (example Ibuprofen, 
Naproxen) 
14 days prior to dose until final check out unless 
approved by the study doctor  
Complementary and alternative medicines  
28 days prior to first dose of study drug until final 
check out. 
Nicotine containing products: e.g., cigarettes, 
cigars, chewing tobacco, snuff, electronic 
cigarettes 
6 weeks prior to screening until final check out. 
Participation in another clinical study of an 
investigational drug or treatment with an 
investigational drug. 
30 days prior to screening until final check out. 
Acetaminophen 
Refrain from using for the duration of the study 
unless approved by the study doctor. 
St Johns wart or Kava melatonin 
Refrain from using for the duration of the study. 
You will receive a diet that does not contain any alcohol or caffeine. You may be required to eat each 
meal that is served to you and eat at a reasonable pace (within 25 minutes). 
A fasting period of 8 hours will be required prior to lipid profile sampling on check-out Days 1 and 29. 
Additionally, a fasting period of 4 hours will be required before all time points when clinical laboratory 
samples will be obtained. 
You may eat only meals and snacks that are provided to you during the periods of your stay. After 
checking out of the clinic there are no dietary restrictions aside from what is listed in the table above. 
You must be willing to comply with study rules, including the meal schedule (25 minutes to eat), 
attempting to void at specified times, remaining quiet, awake, undistracted, motionless, and seated 
during specified times, and avoiding vigorous exercise as directed throughout the duration of the study. 
On certain study days you may be required to get up very early (between 4 and 6 am) in order to 


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Melanie Fein, M.D. 
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complete study events. You may also be required to stay or wake up during the night to ensure study 
procedures can be completed. This will only be done when absolutely necessary and while it is 
important that you have sufficient rest during the study sometimes an early start to the day is 
unavoidable. 
Due to current precautions being taken for COVID-19, the following restrictions will be in place: 
• 
Subjects should be encouraged to wear masks except when in a private room without anyone else 
present or for a limited time for a study procedure (for example, study drug administration) 
when instructed by study staff. 
• 
Subjects must practice social distancing, which will include having a maximum of 2 subjects 
per room for overnight stays and access to common areas will be per clinical research site 
standards. While subjects are in house, meals will be served per clinical research site 
standards. Subjects will spend most of their time in their rooms except for specified times for 
walking in the halls (with masks recommended). 
• 
Subjects must practice regular handwashing with soap and water, scrubbing hands for at least 
20 seconds or with approved hand sanitizer as supplied by study staff. 
If new information becomes available, there could be other precautions that lead to additional restrictions. 
 
ARE THERE RISKS TO YOU IF YOU ARE IN THIS STUDY? 
 
Please be advised that for certain adverse events (AE) we may not administer medications but first try 
treatments such as heating pack, stretches, or hydration. Our study doctor will be notified if a medication 
may be needed to treat an AE. Following the study plan guidelines, the study doctor will assess your AE 
and develop a treatment plan. 
A combination of Epidiolex with Morphine or Citalopram may worsen adverse events. 
 
It is dangerous to mix Epidiolex with alcohol or any other drugs, including illicit drugs, certain prescription 
drugs and over counter drugs such antihistamines that can cause sedation. If you need any treatment by 
your own doctors or an emergency room advise the medical staff treating you that you are in a research 
study and the study drug you are taking. You should advise your primary care physicians of your 
participation in the study. If you are prescribed any medication during the study you must notify the study 
staff prior to taking any additional doses of study drug. 
 
Risks are possible side effects of the study drug, the positive control medicine, and those of taking blood 
and other medical procedures: 
For Cannabidiol (Epidiolex) 
• 
Abdominal effects – liver injury, abdominal pain, nausea, vomiting, diarrhea, and decreased or 
increased appetite 
• 
Hematologic effects – anemia (Low number of red blood cells that can causes tiredness and 
shortness of breath) 
• 
Neurological effects – feeling inebriated (drunk), somnolence (sleepiness), insomnia, poor 
sleep, fatigue (tired), malaise (feeling of uneasiness), depression, suicidal thoughts or behavior, 
irritable, anger (aggression), asthenia (feeling weak or lacking energy), drooling (increased 
saliva) or dry mouth, change in sense of taste, muscle spasms, impaired thinking, judgement, 
motor skills and gait disturbance (difficulty walking) 
• 
Do not drive or operate heavy machinery until you know how the cannabidiol affects you. 
• 
Renal effects – reversible elevation of creatinine (blood test of kidney function) 
• 
Skin effects – rash, redness, itching, and swelling 


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Melanie Fein, M.D. 
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• 
General effects – weight loss or gain, fever, infections including pneumonia and urinary tract 
infections 
• 
Less common side effects include: 
o Lung effects – low oxygen content in blood 
 
For Citalopram 
• 
Abdominal effects – nausea, diarrhea, constipation, and indigestion 
• 
Neurological effects – decreased libido (sexual desire), agitation, headache, dizziness, 
drowsiness, yawning, suicidal thoughts or behavior, and tremor (shakiness) 
• 
General effects – insomnia, ejaculation disorder, sweating increased, fatigue (feeling tired), 
somnolence (tiredness), impotence and anorgasmia (difficulty having an orgasm), dry mouth, 
hair loss, fever, increased sweating 
• 
Less common, but serious adverse events include: 
o Allergic reactions – hypersensitivity reactions, rash, swelling 
o Neurological effects – syncope (fainting), seizures, myoclonus (abnormal muscle 
movements) 
o Heart/blood vessel effects – QT interval prolongation (abnormal ECG), 
irregular heartbeat, abnormal blood clotting or bleeding 
o Abdominal effects – increased liver enzymes (possible liver damage) 
o Serotonin syndrome (usually when prescribed with another serotonergic medication 
which will not be done in this study – leads to fever, sweating, diarrhea and potential 
complications including seizures and muscle breakdown) 
For Morphine sulfate 
• 
Abdominal effects – abdominal pain, nausea, vomiting, diarrhea, constipation, and abnormal liver 
function tests 
• 
Neurological effects – seizure, headache, insomnia (difficulty sleeping), abnormal dreams 
(nightmares), asthenia (general weakness), lightheadedness, dizziness, agitation, anxiety, 
hallucinations, drowsiness (being sleepy), fatigue, tremor (shakiness) or muscle rigidity, 
amblyopia (double vision), and paresthesia (tingling) 
• 
Skin effects – itching and swelling 
• 
Urogenital effects: decreased libido (sexual desire), abnormal ejaculation, impotence, and urinary 
retention (difficulty passing urine) 
• 
Less common, but serious adverse events include: 
o Lung effects – respiratory depression/arrest (decreased/stopped breathing) 
o Heart/blood vessel effects – bradycardia (slow heart rate), blood circulatory 
depression and hypotension (decreased blood pressure), cardiac arrest and/or 
shock (heart, lung, and circulatory changes that are potentially life threatening) 
Problems or side effects that are not now known could also occur. You will be given any new 
information that may affect your willingness to start or continue in the study. During the study and 
following the study you may test positive for THC or marijuana, as well as opiates, on a drug screen. 
 
If you have a side effect of the study formulation, such as a skin rash or other visible injury, it might be 
useful to take a picture of the affected area to send to the sponsor. If the condition is on your face, all 
reasonable attempts will be made to disguise your facial features and hide your identity. It is possible that 
your face may be recognizable. By signing this consent, you authorize the study doctor or study staff to 
take such a picture and provide it to the sponsor. 
 
Suicide is a risk with the use of cannabidiol and citalopram. You must tell your study doctor right away if 
you have any thoughts about hurting yourself. 


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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
 
If you are having suicidal thoughts or feel in crisis, call the study doctor at the telephone number listed on 
the first page of this form. You can also call or text the National Suicide & Crisis Lifeline at 9-8-8 or 1- 
800-273-TALK (8255). The Lifeline numbers are answered 24 hours a day every day of the year by a 
skilled, trained counselor. You can also present to a healthcare provider, your local emergency room, or 
call 9-1-1 to be connected to local emergency services. 
 
Additional Risks 
As with any drug, it is possible that you could experience an allergic reaction to the study drug used in 
this study. Symptoms of any allergic reaction can include: 
• 
Rash 
• 
Hives 
• 
Itching 
• 
Difficulty breathing 
• 
Closing of the throat 
• 
Swelling of the lips, tongue or face 
• 
Rarely, death. 
 
If you think you are having a severe allergic reaction, while outside the study center call 9-1-1 and 
seek medical attention immediately. 
 
It is very important that you tell the study doctor and the study staff about any side effects that you 
might experience. 
You may experience side effects or discomforts that are not listed on this form. Tell your study doctor 
or study staff immediately if you have any problems. Your safety will be closely monitored during the 
course of the study. 
For Blood Draws 
• 
Fainting 
• 
Redness 
• 
Pain 
• 
Bruising 
• 
Rarely, there may be a small blood clot or infection at the site of the needle puncture 
An intravenous catheter (a thin plastic tube placed in a vein in your arm) may be placed at study doctor’s  
discretion to quickly deliver rescue medications in the event of an emergency situation or treatment such  
as IV fluids are needed. 
Intravenous catheter (IV) Risks 
• 
Redness 
• 
Pain 
• 
Infection 
• 
Bruising 
• 
damage to blood vessels 
• 
bleeding from the site of insertion 
• 
swelling in the area 
• 
allergic reaction to the adhesive tape that secures the IV in place 
• 
Rarely, there may be a small blood clots at the site of the needle puncture 


U.S. Food and Drug Administration / Protocol Number SCR-014  
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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
In instances where a nurse, a doctor, or a technician, sustains an exposure to your blood, tissue or body 
fluids by needle stick, cut or splash to mucosa or damaged skin, it may be necessary to test your blood, 
tissue, or body fluid sample for certain viral infections including Hepatitis B and C and HIV on the 
sample already available. This is to enable that person to receive appropriate counseling, monitoring and 
treatment if necessary. In this instance the study doctor or designee will offer you the information relevant 
to your health and advise you on the next steps. Confidentiality of your data will be respected at all times 
according to the state law. 
 
For Blood Pressure Monitoring 
The blood pressure cuff may also cause discomfort or bruising to the upper arm. 
Fasting 
Fasting could cause dizziness, headaches, stomach discomfort or fainting 
 
For ECG Monitoring 
You will be given a small portable heart monitor to wear. The monitor is connected by wires that are 
stuck to your chest, using tape or stickers. To attach the monitor wires, a small section of your chest 
might have to be shaved. You must return the monitor to the study staff. It is possible to be sensitive to 
the adhesives used on the electrodes that are applied to your chest when having an ECG performed. If this 
is the case, you could develop a temporary redness, irritation, skin breakdown, or discoloration of the skin 
where the electrodes were applied. 
HIV, Hepatitis B and C, and COVID-19 Testing 
The risks of HIV and Hepatitis B and C testing include psychological and social risks. A positive test can 
lead to restrictions in freedom of travel to some countries and possible prejudices in job employment, 
insurance eligibility, housing and other forms of discrimination. Positive HIV, Hepatitis B and C, and 
COVID-19 test results must be reported to health authorities under state law. A positive HIV, Hepatitis B 
or C and/or COVID-19 result will exclude you from participation in the study. 
 
Reproductive Risks 
The effects of the test drug on human pregnancy and the unborn child (fetus) are unknown. Therefore, 
for females it is very important that you do everything within your power not to become pregnant 
during this study and for 1 month following last dose. For males it is very important that you do 
everything within your power not to father a child or donate sperm during this study and for 3 months 
following the last dose. Please ensure that you follow the study birth control requirements outlined in 
the sections regarding information for male and female subjects above. 
 
If you become pregnant during the study, you will be withdrawn from the study immediately. Neither 
Spaulding Clinical Research, LLC. nor the sponsor will be responsible for the cost of any obstetric or 
related care, or for your child's care. Female subjects are agreeing, by signing and dating this form, that 
information about your pregnancy and birth of your child may be collected. The information collected 
will include your health and the health of your unborn child during pregnancy, pregnancy outcome 
(miscarriage, termination, live birth, etc.), and the health of the baby after it is born (up to 6 weeks after 
delivery). 
 
Partners of male subjects who become pregnant will be asked to sign a separate consent form to allow 
collection of the information listed above. Your information will be kept confidential in accordance with 
state and Health Insurance Portability and Accountability Act (HIPAA) law. 
COVID-19 Risks 
Despite the extra precautions (for example, COVID-19 triage at screening/check-in, coronavirus testing, 
mandatory masks for study subjects and study staff, social distancing, extra hand washing) that will be in 


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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
place, there is still a risk of developing COVID-19 just as there is when you are not at Spaulding Clinical. 
Tell your study doctor or study staff about any new symptoms you develop during the study. 
 
The U.S. Centers for Disease Control and Prevention (CDC) currently highlights that people with the 
following symptoms may have COVID-19: 
• 
Cough 
• 
Shortness of breath or difficulty breathing 
• 
Fever or chills 
• 
Fatigue (feeling tired) 
• 
Muscle or body aches 
• 
Headache 
• 
Sore throat 
• 
New loss of taste or smell 
• 
Congestion or runny nose 
• 
Nausea or vomiting 
• 
Diarrhea 
 
It is important to note that COVID-19 can also present with other symptoms and just because you develop 
any of the above symptoms does not mean that you have COVID-19. Your study doctor will evaluate if 
your symptoms warrant further isolation from other study subjects/staff, additional coronavirus testing, 
study termination and/or referral for treatment. 
NEW FINDINGS 
 
Your study doctor will tell you of any information learned during the course of the study that might 
cause you to change your mind about taking part in the study. You may contact the study doctor at any 
time after your participation ends to find out if any new information about this study has become 
available. 
 
WHAT IS THE ALTERNATIVE TO BEING IN THE STUDY? 
 
Since this is a study involving healthy subjects, your alternative is not to take part. 
 
WILL YOU BENEFIT FROM TAKING PART IN THE STUDY? 
 
You will not receive direct medical benefit from receiving the study drug. You may benefit by having 
your medical history recorded, undergoing a physical examination, and having blood and urine tests as 
they apply to this research project. 
Just by taking part in this research study, you may be helping future patients by providing important 
information about the study drug and by contributing to medical knowledge. 
WHO IS PAYING FOR THIS STUDY? 
 
The U.S. Food and Drug Administration is the Sponsor of the study. 
 
The U.S. Food and Drug Administration pays the study doctor to run this study. 
 
The study drug and all tests, procedures, and visits required by the study are provided at no cost to you. 
The sponsor, the U.S. Food and Drug Administration, pays for them. 


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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
Information about this study is confidential. This information belongs to the U.S. Food and Drug 
Administration. We ask that you keep it private. You can discuss this information in private with your 
doctor or family to talk about your healthcare or to decide about taking part in this study. 
 
WILL YOU BE PAID FOR BEING IN THIS STUDY? 
Compensation for screening is as follows: 
• 
$125.00 if you qualify and take part in a study. $125.00 for your time and inconvenience if you do 
not qualify for a study. 
• 
If the results of the drug and alcohol tests are positive, or if you attempt to falsify your drug screen 
you will not receive any compensation. 
• 
If you screen for the study, qualify and are enrolled, your screening payment will be included in 
your first stipend payment. If you are not accepted into the study your screening payment will be 
processed and provided within 7 calendar days of study enrollment. 
Compensation for this study is as follows: 
Part 1 
For subjects that complete the entire study (Day -1 to the final follow-up visit), you will receive up to 
$4800.00. This money covers the costs for time spent at the clinic and is to help cover travel expenses. This 
payment will be made in 7 separate payments as follows: 
• 
$1200.00 will be paid after all check out procedures have been completed at the end of Day 1 
($600.00/day), 
• 
$360.00 will be paid after all check out procedures have been completed at the end of Day 7, 
• 
$360.00 will be paid after all check out procedures have been completed at the end of Day 14, 
• 
$360.00 will be paid after all check out procedures have been completed at the end of Day 21, 
• 
$1200.00 will be paid after all check out procedures have been completed at the end of Day 29 
($600.00/day), 
• 
$360.00 will be paid after all check out procedures have been completed at the end of Day 35, 
• 
The remaining $960.00 will be paid after the follow up visit, and any additional follow up 
procedures are completed, and all results are reviewed. Once follow up procedures have been 
completed and accepted by study doctor your final payment will be processed and provided 
within 14 calendar days. 
• 
An additional $200 will be paid for participants who experience elevated liver enzymes 
and returned for follow-up visits and repeat laboratory assessments as requested by the 
principal investigator or designee. This will be paid after the final requested follow up 
visit, all additional follow up procedures are completed, and all results are reviewed. 
Once follow up procedures have been completed and accepted by study doctor your final 
payment will be processed and provided within 14 calendar days.  
If you withdraw from the study early, you will only be paid for the visits you completed. 
Part 2 (Citalopram cohort) 
 
For subjects that complete the entire study (Day -1 to the final follow-up visit), you will receive up to 
$5875.00. This money covers the costs for time spent at the clinic and is to help cover travel expenses. 
This payment will be made in 4 separate payments as follows: 
• 
$1763.00 will be paid after all check out procedures have been completed at the end of Day 6 
($252.00/day), 
• 
$1763.00 will be paid after all check out procedures have been completed at the end of Day 18 


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Melanie Fein, M.D. 
Advarra IRB Approved Version 10 May 2024 
 
 
($252.00/day), 
• 
$1175.00 will be paid after all check out procedures have been completed at the end of Day 24, 
• 
The remaining $1174.00 will be paid after the follow-up visit, and any additional follow-up 
procedures are completed, and all results are reviewed. Once follow up procedures have been 
completed and accepted by study doctor your final payment will be processed and provided 
within 14 calendar days. 
If you withdraw from the study early, you will only be paid for the visits you completed. 
Part 2 (Morphine cohort) 
For subjects that complete the entire study (Day -1 to the final follow-up visit), you will receive up to 
$4875.00. This money covers the costs for time spent at the clinic and is to help cover travel expenses. 
This payment will be made in 4 separate payments as follows: 
• 
$1862.00 will be paid after all check out procedures have been completed at the end of Day 6 
($266.00/day), 
• 
$1064.00 will be paid after all check out procedures have been completed at the end of Day 13 
($266.00/day), 
• 
$975.00 will be paid after all check out procedures have been completed at the end of Day 19, 
• 
The remaining $974.00 will be paid after the follow-up visit, and any additional follow-up 
procedures are completed, and all results are reviewed. Once follow up procedures have been 
completed and accepted by study doctor your final payment will be processed and provided 
within 14 calendar days. 
If you withdraw from the study early, you will only be paid for the visits you completed. 
NOTE: You may be required to return to the clinic for repeat blood test or other assessment (ECG, 
physical, vital signs) in between periods or after the final check out. This is considered part of the study 
and no additional compensation is available. Your final payment will not be released until all follow up 
procedures have been completed and accepted by the study doctor. Once follow up procedures have been 
completed and accepted by study doctor, your final payment will be processed and provided within 14 
calendar days. 
NOTE: If you meet eligibility criteria you may be asked to be an alternate subject. Alternate subjects are 
eligible subjects that are in addition to the number of subjects in the event an enrolled subject drops out 
before their dose can take place or in the event it is not safe for a subject to move forward with dosing. If 
you are selected as an alternate subject who has to stay the night in the clinic and you agree to participate 
as an alternate subject, you may receive up to $250 if you are not needed to dose. If you are selected as an 
alternate subject and you do not have to stay the night, you may receive up to $150. If you are needed to 
replace a subject, you will be paid as stated for participating in and completing the study. If you agree to 
be an alternate subject, you will have all of the predose procedures as the enrolled subjects so that if you 
are needed, you will be ready to participate. If you are not needed you will be discharged shortly after 
completion of the dosing round. 
No deductions for any state or federal withholding or any other similar taxes will be made and you are 
solely responsible for reporting such payments on your state and federal income tax returns. 
 
If you need to stay at Spaulding Clinical Research, LLC. For a longer period of time for safety reasons, 
you will be compensated at a rate proportional to the entire compensation for the study. 
If you are dismissed from the study for medical reasons OR if the study is temporarily or permanently 
halted, your compensation will be proportional to the time you spend in the study. 


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If you are dismissed from the study because you have not complied with the instructions of the study 
staff, no compensation is available. Non-compliance includes, but is not limited to, improper conduct, 
taking alcohol and/or any drugs (including recreational drugs), tampering with the study drug, or 
consuming any foods/beverages not allowed in the study. 
You must follow the inpatient clinic rules of conduct while you are taking part in this study. If you do not 
follow the rules, a deduction may be taken from your total stipend. You may not be able to take part in 
future studies at Spaulding Clinical Research. These rules will be reviewed with you at your first 
inpatient visit. 
 
By signing this consent, you expressly agree that you are an Independent Contractor for Spaulding 
Clinical Research, LLC. As an Independent Contractor, you will receive a 1099 form from Spaulding 
Clinical Research, LLC. The 1099 form shall document and report all payments and/or study stipends you 
received as an Independent Contractor for Spaulding Clinical Research, LLC. In addition, because you 
are an Independent Contractor and will be receiving payments and/or study stipends, those earnings are 
subject to wage garnishment. If Spaulding Clinical receives an Earnings Garnishment Notice (or similar) 
from a State or Federal legal entity, we will adhere to that garnishment. 
COMPENSATION FOR INJURY 
 
It is important that you follow carefully all the instructions given by the study doctor and his/her study 
staff regarding this study. 
If you become ill or are physically injured as a result of participation in this study, please contact the 
study doctor right away at the telephone number listed on page one of this consent form. He/she will 
treat you or refer you for treatment. 
Spaulding Clinical Research, LLC. and/or its affiliated institutions has not set aside funds to provide you 
with financial compensation or reimbursement for the cost of care provided to treat a research-related 
injury or for other expenses arising from a research-related injury. You or your insurer will be 
responsible for the payment of any medical treatments for research related injuries or illness. By signing 
and dating this consent form, you are not giving up any legal rights. If this research study is conducted in 
a negligent manner and you are injured as a direct result, you may be able to recover the costs of care 
and other damages from the individuals or organizations responsible for your injury as you still have the 
right to seek compensation for injury related to malpractice, negligence, fault, guilt or blame of those 
involved in the research. 
If you are required to stay in the clinic for a longer period for safety reasons, you will be compensated at 
a rate proportional to the entire compensation for the study. If you become ill or physically injured 
because of participation in this study, then you will be referred for treatment. 
 
PROTECTING THE PRIVACY OF YOUR HEALTH DATA 
 
Unless required by law, your name will not be disclosed outside the research clinic. Your name will be 
available only to the following people or agencies: the study doctor and study staff; and authorized 
representatives of the study doctor; Advarra Institutional Review Board (IRB), health authority 
inspectors, such as the U.S. Food & Drug Administration and the European Medicines Agency; study 
monitors and auditors; and authorized Clinical Research Organization representatives. The above- 
mentioned individuals will use the personal information collected as part of this study, including your 
medical records (“study information”) to check that the study is conducted correctly and to ensure the 
accuracy of the study information. These people are all obligated to maintain confidentiality by the 


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Melanie Fein, M.D. 
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nature of their work or are bound by confidentiality agreements. If required, the study doctor may 
contact your personal doctor to collect additional medical information and your past medical history. 
 
The study doctor may only share your study information with people whom you have permitted to see 
it. However, once your study information is shared as authorized, it may no longer be protected by 
federal law and may be re-disclosed without your permission. 
While participating in this study, the study doctor will replace your name with a special code that 
identifies you. This code, along with your study information, will be used by the U.S. Food and Drug 
Administration and their representatives, for the study purposes mentioned above and to help establish 
whether the study drug is safe and effective. Any data and/or biospecimens provided to the U.S. Food 
and Drug Administration will be coded (stripped of identifiers such as name, address, or account 
number) and the key allowing the code to be linked to your personal information will be kept by the 
study staff and never released to the agency. Therefore, the U.S. Food and Drug Administration will not 
be able to re-identify you. The U.S. Food and Drug Administration may share your coded information, 
as necessary, with the U.S. Food and Drug Administration affiliates who work within the scope of this 
consent; Advarra IRB and Regulatory agencies such as the National Health Authorities, and the 
European Medicines Agency. 
 
You should be aware that some countries may not offer the same level of privacy protection as you are 
used to in the country where you live or where this study is conducted. However, the U.S. Food and 
Drug Administration will keep any information it receives to the same standard of confidentiality as far 
as permitted by applicable local law. The U.S. Food and Drug Administration has also entered into 
agreements with third parties working for the U.S. Food and Drug Administration to secure adequate 
protection of your data and samples. 
 
The study information will be kept confidential within the limits of the law. The U.S. Food and Drug 
Administration may keep study samples and data collected for future research. Identifiers will be 
removed from your identifiable private information or identifiable biospecimens collected during this 
study so that data cannot be linked to you. The coded data and/or biospecimen could then be used for 
future research studies or distributed to another investigator for future research studies without additional 
informed consent. You will not be contacted about each of these future uses for additional informed 
consent. No additional participation time or procedures will be required beyond what is described above 
for the primary study. The coded data from the study will be replaced with a unique identifier and may 
be released to a data warehouse (location that will store the data) or used as part of a publication. It may 
be shared broadly for research purposes outside of the U.S. Food and Drug Administration and 
Spaulding Clinical Research, LLC. Other study doctors will have access to limited clinical and 
biological data such as age, gender, and disease status. Your samples will only be used for research 
purposes. It is also possible that your samples and data will never be used. Results of research done on 
your samples and data will not be available to your personal doctor. If the results of this study are 
published or presented in a meeting, you will not be named, and nobody will be able to tell that you were 
in the study from the publication or presentation. 
 
WHOM TO CONTACT ABOUT THIS STUDY? 
 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study such as: 
 
• 
Whom to contact in the case of a research-related injury or illness; 
• 
Payment or compensation for being in the study, if any; 
• 
Your responsibilities as a research subject; 


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Melanie Fein, M.D. 
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• 
Eligibility to participate in the study; 
• 
The study doctor’s or study site’s decision to withdraw you from participation; 
• 
Results of tests and/or procedures; 
Please contact the study doctor at the telephone number listed on the first page of this consent  
document. 
IF YOU SEEK EMERGENCY CARE, OR HOSPITALIZATION IS REQUIRED, ALERT THE 
TREATING PHYSICIAN THAT YOU ARE PARTICIPATING IN THIS RESEARCH STUDY. 
 
An institutional review board (IRB) is an independent committee established to help protect the rights of 
research subjects. If you have any questions about your rights as a research subject, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free: 
877-992-4724 
• 
or by email: 
adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: Pro00076109. 
An IRB is a group of people who review research studies to protect the rights and welfare of research 
subjects. 
 
IS YOUR PARTICIPATION VOLUNTARY? 
 
Yes, your participation in this study is strictly voluntary. You may refuse to take part in it, or you may 
stop participating at any time, even after signing this informed consent. There will be no penalty or loss 
of benefits to which you are otherwise entitled. However, if you decide to leave the study before it ends, 
the study doctor will need to see you before you are released from the study. 
The study doctor may also decide to remove you from the study at any time without your consent. The 
study doctor may choose to take you out of the study because of unexpected or serious side effects, or 
for other scientific, technical, or safety considerations. 
 
Examples of why you may be taken out of the study are: 
• 
Staying in the study would be harmful 
• 
You need treatment not allowed in this study 
• 
You failed to follow instructions 
• 
You become pregnant 
• 
The study is cancelled 
• 
Your study treatment arm is stopped 
If your participation ends for any reason, you will return to the study for the following study procedures: 
• 
Physical examination. 
• 
Pregnancy test (if necessary) 
• 
Body weight and body temperature 
• 
Blood pressure and pulse rate 
• 
ECG 
• 
Blood draws for hematology and chemistry 
• 
Blood draws for PK 


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• 
Urine will be collected for urinalysis 
• 
Assessment for adverse events and concomitant medications (if you are taking any medications 
at the same time you were participating in the study) 
If you should decide to leave the study, you should tell the study doctor or study staff. They will make 
sure that proper procedures are followed, and a final visit is made for your safety. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
 


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STATEMENT OF CONSENT 
 
I have read this form, and its contents were explained to me. I agree to be in this research study for the 
purposes listed above and I agree to the genetic testing . All of my questions were answered to my 
satisfaction. I will receive a signed and dated copy of this form for my records. I am not giving up any of 
my legal rights by signing this form. 
I agree to have photograph(s) to document adverse event(s) as applicable for this study. By signing this 
consent, I authorize the study doctor or study staff to take such a picture and provide it to the sponsor. 
 
 
/ 
/ 
 
 
Signature of Research Subject 
Date 
 
Printed Name of Research Subject 
Time (24hr) 
 
STATEMENT OF PERSON OBTAINING INFORMED CONSENT 
I have carefully explained to the subject the nature and purpose of the above study. There has been an 
opportunity for the subject to ask questions about this research study. I have been available to answer any 
questions that the subject has about this study. 
 
/ 
/ 
 
Initials of Person Obtaining Informed Consent 
Date 
 
 


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Melanie Fein, M.D. 
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HIPAA Authorization Agreement 
Permission to Review, Use and Release Information about You 
If you decide to be in this study, the study doctor and study staff will use and share health data about 
you to conduct the study. Health data may include: 
• 
Your name. 
• 
Address. 
• 
Phone number. 
• 
Date of birth. 
• 
Medical history. 
• 
Information from your study visits, including all test results. 
 
Health data may come from your study records or from existing records kept by your doctor or other 
health care workers. 
 
For this study, the study staff may share health data about you with authorized users. Authorized users 
may include: 
• 
Representatives of the U.S. Food and Drug Administration. (such as FDA representatives who 
may audit the research or receive reports of adverse events) 
• 
Representatives of Spaulding Clinical Research, LLC. 
• 
Representatives of Advarra IRB. (an Institutional Review Board that reviews this study) 
• 
Other U.S. governmental agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STIs) must be reported. 
• 
Governmental agencies of other countries. 
• 
Labs working with the sponsor on this study. 
• 
Other authorized users. 
The U.S. Food and Drug Administration and those working for the U.S. Food and Drug Administration 
may use the coded health data sent to them: 
• 
To see if the study drugs works and are safe. 
• 
To compare the study drug to other drugs. 
• 
For other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no longer be protected by federal 
privacy laws. 
 
Your permission to use and share health data about you will not end unless required by state law. If state 
law applies, your permission to use and share health data about you will end on December 31, 2060. 
 
You may take back your permission to use and share health data about you at any time by writing to the 
study doctor at the address listed on the first page of this form. If you do this, you will not be able to 
stay in this study. No new health data that identifies you will be gathered after your written request is 
received. However, health data about you that has already been gathered may still be used and given to 
others as described in this form. 
 
Your right to access your health data in the study records will be suspended during the study to keep from 
changing the study results. When the study is over, you can access your study health data. If you decide 
not to sign this form, you will not be able to take part in the study. 
 
 


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STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained. My questions have been answered. I voluntarily 
agree to allow study staff to collect, use and share my health data as specified in this form. I will receive 
a signed and dated copy of this form for my records. I am not giving up any of my legal rights by 
signing this form. 
 
/ 
/ 
 
Signature of Research Subject 
Date 
 
 
Printed Name of Research Subject 
STATEMENT OF PERSON OBTAINING AUTHORIZATION 
 
I have carefully explained to the subject the nature and purpose of this form. I have been available to 
answer any questions that the subject has about this form. 
 
/ 
/ 
 
Initials of Person Obtaining Authorization 
Date 

Prot_000.pdf: 
Study Title: Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and 
Drug Interactions 
 
Document Title: Clinical Study Protocol – Study No. SCR-016 
 
Document Date: 19 March 2024 
 
NCT Number: NCT06192589 


U.S. FOOD AND DRUG ADMINISTRATION  
 
Protocol Number: SCR-016 
(Version 3.0) 
 
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Page 1 of 72 
  
 
CLINICAL STUDY PROTOCOL 
  Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and 
Drug Interactions  
 
PROTOCOL NO. SCR-016 
  
Sponsor: 
U.S. Food and Drug Administration 
White Oak Building #64, Room 2072 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
 
Sponsor Study Lead: 
David Strauss, MD, PhD 
U.S. Food and Drug Administration 
Telephone: 301-796-6323 
Email: david.strauss@fda.hhs.gov 
 
 
Sponsor Medical 
Monitor: 
Keith Burkhart, MD 
U.S. Food and Drug Administration 
301-796-2226 
Email: keith.burkhart@fda.hhs.gov 
 
 
Project Manager: 
Jeffry Florian, PhD  
U.S. Food and Drug Administration  
Telephone: 301-796-4847  
Email: jeffry.florian@fda.hhs.gov 
 
 
 
Version of Protocol: 
3.0 
 
Date of Protocol: 
March 19, 2024 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed 
written consent of the U.S. Food and Drug Administration. 


U.S. FOOD AND DRUG ADMINISTRATION 
Protocol Number: SCR-016
(Version 3.0)
CONFIDENTIAL
Page 2 of 72
SPONSOR SIGNATURE PAGE
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following: 
x The ethical principles that have their origin in the Declaration of Helsinki;
x International Council for Harmonisation (ICH) harmonised tripartite guideline E6 (R2): Good 
Clinical Practice; and
x All applicable laws and regulations, including without limitation, data privacy laws and 
compliance with appropriate regulations, including human subject research requirements set 
forth by the Institutional Review Board (IRB). 
David Strauss, MD, PhD
U.S. Food and Drug Administration 
Date



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Protocol Number: SCR-016
(Version 3.0)
CONFIDENTIAL
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INVESTIGATOR SIGNATURE PAGE
I confirm that I have read and that I understand this protocol, the investigator brochure, and other 
product information provided by the sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following: 
x
The ethical principles that have their origin in the Declaration of Helsinki;
x
ICH harmonised tripartite guideline E6 (R2): Good Clinical Practice;
x
All applicable laws and regulations, including without limitation data privacy laws and 
regulations; 
x
Human subject research requirements set forth by the IRB; 
x
Regulatory requirements for reporting of serious adverse events (SAEs) defined in Section  
of this protocol; and 
x
Terms outlined in the Clinical Study Site Agreement.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Section 6 of this protocol. 
Melanie Fein, MD  
Principal Investigator 
                        
Date



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Table of Contents 
SPONSOR SIGNATURE PAGE .................................................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE ............................................................................................................ 3 
LIST OF TABLES ........................................................................................................................................ 6 
PROTOCOL SYNOPSIS ............................................................................................................................... 7 
1. 
INTRODUCTION .............................................................................................................................. 16 
2. 
STUDY OBJECTIVES ......................................................................................................................... 17 
3. 
ENDPOINTS .................................................................................................................................... 17 
3.1 PART 1 ............................................................................................................................................................... 17 
Primary Endpoint: ............................................................................................................................... 17 
Secondary Endpoint: ........................................................................................................................... 17 
Exploratory Endpoints: ........................................................................................................................ 17 
3.2 PART 2 (DRUG-DRUG INTERACTIONS) ...................................................................................................................... 17 
Primary Endpoints: .............................................................................................................................. 18 
Secondary Endpoints: .......................................................................................................................... 18 
Exploratory Endpoints: ........................................................................................................................ 18 
4. 
INVESTIGATIONAL PLAN ................................................................................................................. 18 
4.1 STUDY DESIGN....................................................................................................................................................... 18 
4.1.1. Risk/Benefit ............................................................................................................................... 21 
4.2 SELECTION OF STUDY POPULATION ............................................................................................................................ 23 
4.2.1 Inclusion Criteria......................................................................................................................... 23 
4.2.2 Exclusion Criteria ........................................................................................................................ 24 
4.3 SCREENING FAILURES .............................................................................................................................................. 27 
4.4 TERMINATION OF STUDY OR INVESTIGATIONAL SITE ...................................................................................................... 27 
4.4.1 Criteria for Termination of the Study ......................................................................................... 27 
4.4.2 Criteria for Termination of the Investigational Site .................................................................... 27 
4.5 CRITERIA FOR SUBJECT WITHDRAWAL ........................................................................................................................ 28 
4.5.1 Handling of Withdrawals ........................................................................................................... 29 
4.5.2 Replacement of Subjects ............................................................................................................ 29 
4.6 STUDY VISITS......................................................................................................................................................... 30 
4.6.1 Recruitment ................................................................................................................................ 30 
4.6.2 Compensation ............................................................................................................................ 30 


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4.6.3 Screening .................................................................................................................................... 30 
4.6.4 Study Periods .............................................................................................................................. 31 
4.7 STUDY PROCEDURES ............................................................................................................................................... 33 
4.7.1 Pharmacokinetic Assessments ................................................................................................... 33 
4.7.2 Endocrine Assessments .............................................................................................................. 35 
4.7.2 Lipid Assessments ....................................................................................................................... 35 
4.7.2 Proteomics Assessments ............................................................................................................ 35 
4.7.3 Safety Assessments .................................................................................................................... 36 
4.7.4 Demographics and Medical History ........................................................................................... 41 
4.8 STUDY TREATMENTS ............................................................................................................................................... 41 
4.8.1 Dose Selection and Rational ....................................................................................................... 41 
4.8.2 Treatments Administered and Schedule .................................................................................... 42 
4.8.3 Management of Clinical Supplies ............................................................................................... 44 
4.8.4 Blinding ...................................................................................................................................... 44 
4.8.5 Treatment Compliance ............................................................................................................... 45 
4.8.6 Prior and Concomitant Medications........................................................................................... 45 
4.8.7 Subject Restrictions .................................................................................................................... 45 
4.9 STATISTICAL METHODS............................................................................................................................................ 46 
4.9.1 Sample Size ................................................................................................................................. 47 
4.9.2 Analysis Populations ................................................................................................................... 47 
4.9.3 General Statistical Considerations ............................................................................................. 47 
4.9.4 Subject Disposition ..................................................................................................................... 48 
4.9.5 Demographics and Baseline Characteristics .............................................................................. 48 
4.9.6 Primary and Secondary Analyses ............................................................................................... 48 
4.9.10 Safety Analyses ........................................................................................................................ 49 
4.9.11 Interim Analyses ....................................................................................................................... 50 
4.9.12 Missing Data ............................................................................................................................ 50 
4.10 DATA QUALITY ASSURANCE ................................................................................................................................... 51 
4.11 DATA SHARING .................................................................................................................................................... 51 
5. 
ETHICAL CONSIDERATIONS ............................................................................................................. 51 
5.1 ETHICAL CONDUCT OF THE STUDY ............................................................................................................................. 51 
5.2 INSTITUTIONAL REVIEW BOARD (IRB) ........................................................................................................................ 51 
6. 
ADMINISTRATIVE PROCEDURES ..................................................................................................... 52 


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6.1 RESPONSIBILITIES OF THE INVESTIGATOR ..................................................................................................................... 52 
6.1.1 Form FDA 1572 ........................................................................................................................... 52 
6.1.2 Adherence to Protocol ................................................................................................................ 52 
6.1.3 Reporting Requirements............................................................................................................. 52 
6.1.4 Source Documentation ............................................................................................................... 52 
6.1.5 Retention of Records .................................................................................................................. 52 
6.1.6 Financial Disclosure and Obligations .......................................................................................... 53 
6.2 CONFIDENTIALITY AND DISCLOSURE OF DATA .............................................................................................................. 53 
6.3 SUBJECT CONSENT ................................................................................................................................................. 54 
6.4 DATA COLLECTION ................................................................................................................................................. 54 
6.5 PUBLICATIONS ....................................................................................................................................................... 54 
7. 
STUDY MANAGEMENT ................................................................................................................... 55 
7.1 MONITORING ........................................................................................................................................................ 55 
7.2 MANAGEMENT OF PROTOCOL AMENDMENTS AND DEVIATIONS ...................................................................................... 55 
7.2.1 Modification of the Protocol ...................................................................................................... 56 
7.2.2 Protocol Violations and Deviations ............................................................................................ 56 
REFERENCE LIST ..................................................................................................................................... 57 
8. 
APPENDICES ................................................................................................................................... 59 
APPENDIX A – SCHEDULE OF EVENTS – PART 1 .................................................................................................................. 59 
APPENDIX B – SCHEDULE OF EVENTS – PART 2.1 (CITALOPRAM) .......................................................................................... 62 
APPENDIX B – SCHEDULE OF EVENTS – PART 2.2 (MORPHINE) ............................................................................................ 64 
APPENDIX C – LIST OF ABBREVIATIONS ............................................................................................................................ 66 
LIST OF ABBREVIATIONS .................................................................................................................. 66 
APPENDIX D – DRUG-INDUCED LIVER INJURY ASSESSMENT .................................................................................................. 67 
APPENDIX E – PROTOCOL REVISION HISTORY .................................................................................................................... 68 
PROTOCOL REVISION HISTORY ....................................................................................................... 68 
 
 
LIST OF TABLES 
TABLE 4-1: CLINICAL LABORATORY TESTS & DIAGNOSTIC SCREENING TESTS ........................................ 3940 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Number: SCR-016 
Title: Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and Drug Interactions  
Investigators: Melanie Fein, MD     
Study Phase: 1 
Study Period: This is a 2-part study. The duration of study participation will be up to 36 days 
(excluding the screening period) for Part 1. The duration of study participation will be up to 24 
days (excluding the screening period) for Part 2. 
Study Site: Spaulding Clinical Research Unit, West Bend, Wisconsin 
Background and Motivation:  
The cannabis plant contains bioactive compounds known as cannabinoids; delta-9 
tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prevalent cannabinoids in 
most varieties of cannabis.1 The Agricultural Improvement Act (Farm Bill) of 2018 removed 
hemp, defined as cannabis and derivatives of cannabis with extremely low concentrations of 
THC, from the definition of marijuana in the Controlled Substances Act.1 Following this, many 
CBD products have been made available to consumers. However, hemp products remain 
subject to regulation under the Federal Food Drug & Cosmetic Act, when applicable (e.g., as 
drugs, foods, dietary supplements, cosmetics, veterinary products) and the growing CBD 
products market raises various safety concerns, especially with long-term use.1 
CBD is available as a prescription drug product for the treatment of seizures associated with 
Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex.2 At labeled doses 
up to 25 mg/kg/day, an increased risk of liver enzyme elevation and drug-induced liver injury 
has been observed.2,3 However, only limited evaluations of the risk of liver enzyme elevation of 
daily, lower dose CBD use are available.3,4 The potential for liver enzyme elevations with CBD 
doses in unapproved consumer products highlights a need for further research to quantify risks 
at these doses. In addition, CBD has the capacity to inhibit cytochrome P450 enzymes and 
uridine 5’-diphospho-glucuronosyltransferases, leading to potential drug-drug interactions with 
multiple common medications.2,5 The clinical significance of many of these interactions is also 
unclear. Furthermore, nonclinical studies have suggested the potential for CBD to cause 
reproductive and endocrine effects.6-8 As such, additional high-quality clinical pharmacology 
studies are needed to further characterize CBD's safety profile. 
This study will be divided into two parts.  
In Part 1, 200 healthy subjects will be randomized to 5 mg/kg/day of CBD (150 subjects) or 
placebo (50 subjects) for 4 weeks with weekly laboratory assessments to characterize the 


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percentage of participants with liver enzyme elevation (primary endpoint) or meeting 
withdrawal criteria for potential drug-induced liver injury (secondary endpoint). Additional 
secondary endpoints include the change from baseline to after 4 weeks of daily CBD dosing for 
male reproductive (testosterone and inhibin B) and thyroid hormones (thyroid stimulating 
hormone [TSH], triiodothryronine [T3] and thryroxine [T4]) as secondary endpoints. 
Exploratory endpoints include additional characterization of liver findings and other blood 
biomarkers. 
In Part 2, 40 healthy subjects will receive either oral citalopram (20 subjects) or morphine (20 
subjects) at baseline and then again after receiving CBD 5 mg/kg/day to characterize the effect 
of daily cannabidiol use on the plasma concentration of citalopram and morphine. Citalopram 
was selected because it is a common prescription medication for depression and anxiety that is 
metabolized by CYP2C19 and CYP3A4,9 which CBD inhibits.5 Morphine was selected because 
it is a common opioid analgesic that is metabolized by UGT2B7,10 which CBD inhibits.5 
Objectives: 
Part 1:  
To characterize the effects of daily cannabidiol use at a dose within the range of what 
consumers are taking as unapproved cannabidiol products on liver enzyme elevations and 
endocrine measures.   
Part 2:  
To characterize the effects of daily cannabidiol use at a dose within the range of what 
consumers are taking as unapproved cannabidiol products on drug interactions. 
Endpoints:  
Part 1: 
x Primary Endpoint: 
x Percentage of participants with an ALT (based on consensus criteria*) or AST 
liver enzyme elevation greater than three times the upper limit of normal (>3 × 
ULN)  
x Secondary Endpoints: 
x Percentage of participants meeting withdrawal criteria for potential drug-induced 
liver injury (DILI) 
x Change from baseline in total testosterone and inhibin B in male participants 
after CBD administration compared to placebo 


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x Change from baseline in thyroid stimulating hormone (TSH), total T3, and free 
T4 after CBD administration compared to placebo 
x Exploratory Endpoints: 
x Assessment of liver-related adverse events  
x Summary of CBD and metabolite pharmacokinetics 
x Proportion of subjects with abnormal laboratory (e.g., liver, endocrine) tests  
x Changes in additional laboratory and plasma proteome assessments 
*Consensus criteria for ALT elevation: ULN for ALT will be 33 U/L for males and 25 
U/L for females 
Part 2 (Drug Interactions): 
x Primary Endpoints: 
x Comparison of the area under the plasma concentration-time curve (AUC) and 
Cmax of citalopram when administered alone versus when co-administered with 
CBD after 7 days of CBD dosing 
x Comparison of the morphine AUC and Cmax when administered alone versus 
when co-administered with the first dose of CBD and after 7 days of CBD 
dosing  
x Secondary Endpoints: 
x Comparison of the AUC and Cmax of morphine metabolites when administered 
alone versus when co-administered with CBD  
x Exploratory Endpoints: 
x 
Additional PK parameters for citalopram, morphine, CBD, and metabolites, such 
as time of maximum concentration, half-life, apparent clearance, and apparent 
volume of distribution 
x 
PK parameters for CBD and metabolites 
Study Design: 
This is a two-part study. Part 1 is a randomized, double-blind, placebo-controlled, parallel study 
in 200 subjects (150 subjects receiving 5 mg/kg/day of CBD and 50 subjects receiving 
placebo). Part 2 is an open-label, sequential study in 40 subjects (two separate cohorts of 20 
subjects).  


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In Part 1, subjects will report to the study site for screening from Days -28 to -2 and then will 
return to the site on Day -1 for check-in, baseline assessments, and randomization. Subjects will 
check out from the clinical site on Day 1 (1 night in-house stay) following dosing and study 
assessments. Subjects will receive CBD or placebo for 28 days and will return to the study 
clinic on Day 28 for a single in-house day with check-out on Day 29. Subjects will have 3 clinic 
visits in between the in-house stays. The clinical site will contact subjects daily to  remind 
subjects regarding their requirements for drug administration. Subject will have a final follow-
up on Day 35. 
In the Part 2 citalopram drug-drug interaction (DDI) cohort, subjects will report to the study site 
for screening from Days -28 to -2 and then will return to the site on Day -1 for check-in and 
baseline assessments. Subjects will check-out from the clinical site on Day 6 (6 nights in-house 
stay) following dosing and study assessments. Subjects will return to the study clinic on Day 12 
for another 6 nights in-house stay with check-out on Day 18. Subjects will have one follow-up 
visit after the second check-out (Day 24). Subjects will receive CBD for 12 days (Day 6 to 17) 
and citalopram on Day 1 and Day 13. 
In the Part 2 morphine DDI cohort, subjects will report to the study site for screening from 
Days -28 to -2 and then will return to the site on Day -1 for check-in and baseline assessments. 
Subjects will check-out from the clinical site on Day 6 (6 nights in-house stay) following 
dosing and study assessments. Subjects will return to the study clinic on Day 10 for a 3 night 
in-house stay with check-out on Day 13. Subjects will receive CBD for 9 days (Day 4 to 12) 
and morphine on Day 1, Day 4, and Day 11.  Subjects will have one follow-up visit after the 
second check-out (Day 19).  
In both parts, the clinical site will contact the subjects daily on outpatient days to remind drug 
administration. Subjects will undergo assessments as described in the Study Summary and 
Schedule of Events (Appendix A: Schedule of Events Part 1 and Appendix B: Schedule of 
Events Part 2). 
Subject Population: 
Approximately 240 healthy subjects are planned for enrollment.  
Recruitment materials (e.g., internet, radio, and print advertisements, social media posts) will 
be approved by the local Institutional Review Board (IRB, i.e., Advarra) before telephone 
screening. Subjects will be offered payment for Screening and participation in the study, but no 
special incentives are offered. 


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Study Drugs, Dosage, and Route of Administration:  
x Cannabidiol (Epidiolex) oral solution will be administered to approximately 190 
participants (150 in Part 1 and 40 in Part 2). Dosing is 5 mg/kg/day administered in 
divided doses twice daily (i.e. 2.5 mg/kg twice daily).  
x Oral placebo solution (matching characteristics of cannabidiol solution). Placebo will be 
administered twice daily to approximately 50 participants in Part 1.  
x DDI substrate drugs: oral morphine (15 mg) and oral citalopram (20 mg). Of the 
participants in Part 2, 20 will receive morphine and 20 will receive citalopram. 
For Part 1, subjects will be administered CBD on Day 1 and provided with adequate drug for 
at-home dosing on Days 2 through 6 at check-out. At the clinic visit on Day 7, subjects will 
receive dosing for the day as well as at-home dosing for Days 8 through 13. This will be 
repeated for clinic visits on Day 14 (primary study drug to cover dosing on Days 15 through 20) 
and Day 21 (primary study drug to cover dosing on Days 22 through 27). Subjects will continue 
to receive CBD twice daily after returning for check-in on Day 28 (last dose in the evening of 
Day 28).   
For Part 2, subjects in the citalopram cohort will be administered CBD on Day 6 and subjects in 
the morphine cohort will be administered CBD on Day 4. Both Part 2 cohorts will be provided 
with adequate drug for at-home dosing at check-out. Subjects will continue to receive CBD 
twice daily after returning for check-in on Day 12 (citalopram DDI cohort) and Day 10 
(morphine DDI cohort). The total number of days of CBD dosing will be 12 for the citalopram 
cohort and 9 for the morphine cohort.  Subjects will be administered the DDI substrate drug on 
Days 1 and 13 (citalopram DDI cohort) and Days 1, 4, and 11 (morphine DDI cohort). 
Key Inclusion Criteria: 
Subject is a healthy, non-smoking man or woman, 18 to 55 years of age, inclusive, who weighs 
at least 50 kg (110 lbs) and has a body mass index of 18.5 to 33.0 kg/m2, inclusive, at Screening 
and check-in.  Healthy to be defined as subject having no clinically significant findings from 
medical history, physical examination, 12–lead ECG, vital sign measurements, and clinical 
laboratory evaluations. 
Key Exclusion Criteria:  
Subjects will be excluded from this study if they have: 
1) Abnormal liver labs at screening or check-in (Day-1), defined as any of the following 
(tests may be repeated once for confirmation at screening and check-in):  
a) Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 
1.5 × ULN. (The ULN for ALT will be 33 U/L for males and 25 U/L for 
females) 


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b) Total bilirubin (TBL) > ULN 
c) International normalized ratio (INR) > 1.3  
2) Use or intend to use any medications/products in the 14 days prior to check-in (Day -1), 
unless deemed acceptable by the investigator  
For a more detailed listing of inclusion/exclusion criteria, refer to sections 4.2.1 and 4.2.2 of the 
protocol. 
Sample Collection 
Number of samples collected throughout the study can be found in the Schedule of Events (see 
Appendices A and B). Unscheduled pharmacokinetic and proteomics samples will be collected 
in subjects from Part 1 who discontinue due to liver enzyme elevation as part of monitoring.   
Pharmacokinetic Assessments: 
The pharmacokinetic blood samples (6 mL each) will be collected into tubes containing 
K2EDTA, inverted several times to mix the blood with the anticoagulant, and placed in an ice 
bath. Within 30 minutes of collection, the samples will be centrifuged for 10 minutes, at 
3000 relative centrifugal force (RCF), at 4°C, by a study team member.  
The plasma will be separated using a disposable plastic pipette and approximately half of the 
plasma will be transferred into duplicate cryotube vials labeled as Aliquot A (primary) and 
Aliquot B (backup). The plasma samples will be appropriately labeled and stored frozen at –
70°C or below within 30 minutes after aliquoting until shipment. Temperature monitoring logs 
should be maintained and accessible for review by the study monitor.  
The Aliquot A samples (primary) will be shipped first, on dry ice, to the bioanalytical 
laboratory at FDA for processing when requested by the sponsor. The Aliquot B samples 
(backup) will be held for a second shipment after completion of all Aliquot A sample 
shipment(s) and the timing of the Aliquot B shipment will be communicated by the sponsor. 
Pharmacokinetic blood samples will be collected by direct venipuncture or by inserting an 
intravenous (IV) catheter on the following days. 
For Part 1, a single blood sample will be collected on days 1, 7, 14, 21, 29, and 35. Total 
number of PK blood samples will be 6 per subject for Part 1. 
For the Part 2 (citalopram DDI cohort), 13 PK samples will be obtained with each citalopram 
dose. Total number of PK blood samples will be 26 per subject for Part 2 (citalopram cohort). 
For the Part 2 (morphine DDI cohort), 13 PK samples will be obtained with each morphine 
dose. Total number of PK blood samples will be 39 per subject for Part 2 (morphine cohort). 
For detailed timing of PK sampling, refer to 4.7.1.1 Pharmacokinetic Sample Collection.   


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Additional Laboratory Assessments (Part 1):  
For Part 1, blood samples for assessment of changes from baseline in different endocrine, 
lipids, and plasma proteins will be collected on Day 1 (morning, prior to dosing) and at check-
out on Day 29 (morning, time-matched to the initial pre-dose assessment). 
Blood samples will be collected by direct venipuncture or by inserting an intravenous (IV) 
catheter. Using red top tubes (no additives), approximately 8-10 mL of blood will be collected 
and processed for analysis. Additional details for sample collection and sample processing are 
in Section 4.7.2 to 4.7.4. 
Safety Assessments: 
Safety will be evaluated in terms of adverse events (AEs), clinical laboratory results 
(hematology, serum chemistry, and urinalysis), vital sign measurements (blood pressure, heart 
rate, respiratory rate, and oral body temperature), safety 12-lead ECG, and physical 
examination findings.  
Sample Size Determination: 
Approximately 190 healthy participants planned for enrollment will be administered CBD. For 
Part 1, the primary endpoint is the percentage of CBD administered participants with an ALT 
(based on consensus criteria*) or AST liver enzyme elevation greater than three times the ULN.  
Assuming the true event rate is 6%, the study has 95% probability of observing 5 or more 
events with ALT or AST liver enzyme elevation greater than three times the ULN. Assuming 
the true observed drug-induced liver injury (DILI) event rate is 2%, the study has a 93% percent 
probability of observing 1 or more event. 
In Part 1, change from baseline comparisons will be performed for various endocrine measures 
(e.g., total testosterone, inhibin B, TSH, total T3, and free T4). Sample size for the study is not 
powered for any of these comparisons nor are any adjustments planned for multiplicity.  
In Part 2, comparisons will be performed on changes in exposure for two different substrate 
drugs following administration with CBD. Assuming no more than 20% discontinuations per 
arm, 30% intra-subject variability, and a two-sided test at the 0.05 significance level, the 
sample size would have 90% power to detect a 30% increase in exposure when the substrate 
drugs are co-administered with CBD. 


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Statistical Methods: 
All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of summary 
statistics. Demographic and baseline characteristics will be summarized overall and by 
treatment for all subjects. The number of subjects who enroll in the study and the number and 
percentage of subjects who complete each assessment will be presented. The frequency and 
percentage of subjects who withdraw or discontinue from the study and the reason for 
withdrawal or discontinuation will be summarized. 
Descriptive statistics will be used to summarize demographic and baseline subject 
characteristics. For continuous variables, the mean, median, standard deviation (SD), minimum, 
and maximum values will be reported. For categorical (nominal) variables, the number and 
percentage of subjects (or observations) will be reported. 
Primary Analysis (Part 1): 
The primary endpoint is the percentage of subjects with an ALT (based on consensus criteria) 
or AST liver enzyme elevation greater than three times the upper limit of normal (ULN). 
Results will be reported as percentage with a 95% confidence interval (CI).  
Secondary and Exploratory Analysis (Part 1): 
The secondary liver endpoint is the percentage of participants with drug-induced liver injury (as 
defined by international consensus criteria). Analysis and reporting will be performed similar to 
the primary endpoint. Exploratory liver endpoints include the percentage of participants with 
ALT or AST above different thresholds. Additional liver analysis details will be specified in the 
Statistical Analysis Plan (SAP). 
Endocrine endpoints will include the changes from baseline in serum total testosterone and 
inhibin B in males after CBD administration compared to placebo. Change from baseline in 
thyroid stimulating hormone, total T3, and free T4 in both males and females after CBD 
administration compared to placebo will also be assessed.  
The percentage of subjects with either abnormal testosterone (males only) or abnormal 
laboratory tests will also be reported. Results will be presented as point estimates with 
associated 95% CI.  
Additional details for secondary and exploratory analyses will be specified in the Statistical 
Analysis Plan (SAP). 
Primary Analysis (Part 2): 
The primary analysis for Part 2 will be a comparison of the area under the plasma 
concentration-time curve (AUC) and Cmax of citalopram or morphine when administered alone 
versus when co-administered with CBD (for morphine, this will include with the first dose of 


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CBD and after 7 days of CBD dosing). Additional details will be specified in the Statistical 
Analysis Plan (SAP).  
Secondary and Exploratory Analysis (Part 2): 
For the secondary PK endpoints, AUC and Cmax for morphine metabolites (alone and when co-
administered with CBD) will be analyzed using the same approach as the primary PK 
endpoints. 
Additional exploratory PK parameters for citalopram, morphine, CBD, and metabolites, such as 
time of maximum concentration, half-life, apparent clearance, and apparent volume of 
distribution will be analyzed using noncompartmental methods based on actual sampling times. 
All parameters will be calculated using statistical software. Mean and individual concentration 
time profiles will be presented in graphs. 
Additional details will be specified in the Statistical Analysis Plan (SAP). 
Safety (Part 1 and Part 2): 
The safety population will include all subjects who receive at least 1 dose of the study drug. All 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
incidence of AEs, organized by system organ class and preferred term, will be summarized with 
a focus on treatment-emergent AEs. Vital sign measurements will be summarized using 
descriptive statistics by time point. All values will be evaluated for clinically notable results. 
Data for additional safety parameters (e.g., physical examination findings) will be listed. 
Date of Protocol: J March 19, 2024 
 
 
 


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1. INTRODUCTION 
The cannabis plant contains bioactive compounds known as cannabinoids; delta-9 
tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prevalent cannabinoids in most 
varieties of cannabis.1 The Agricultural Improvement Act (Farm Bill) of 2018 removed hemp, 
defined as cannabis and derivatives of cannabis with extremely low concentrations of THC, from 
the definition of marijuana in the Controlled Substances Act.1 Following this, many CBD 
products have been made available to consumers. However, hemp products remain subject to 
regulation under the Federal Food Drug & Cosmetic Act, when applicable (e.g., as drugs, foods, 
dietary supplements, cosmetics, veterinary products) and the growing CBD products market 
raises various safety concerns, especially with long-term use.1 
Cannabidiol (CBD) is extracted from Cannabis sativa L. plants. Pure CBD typically contains less 
than 0.1% (w/w) tetrahydrocannabinol (THC). CBD is available as a prescription drug product 
for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or 
tuberous sclerosis complex.2 At labeled doses up to 25 mg/kg/day, an increased risk of liver 
enzyme elevation has been observed.2,3 However, only limited evaluations of the risk of liver 
enzyme elevation of daily, lower dose CBD use are available.3,4 The potential for liver enzyme 
elevations with CBD doses in unapproved consumer products highlights a need for further 
research to quantify risks at these doses. In addition, CBD has the capacity to inhibit cytochrome 
P450 enzymes and uridine 5’-diphospho-glucuronosyltransferases, leading to potential drug-drug 
interactions with multiple common medications.2,5 The clinical significance of many of these 
interactions is also unclear. Furthermore, nonclinical studies have suggested the potential for 
CBD to cause reproductive and endocrine effects.6-8 As such, additional high-quality clinical 
pharmacology studies are needed to further characterize CBD's safety profile. 
This study will be divided into two parts.  
In Part 1, 200 healthy subjects will be randomized to 5 mg/kg/day of CBD (150 subjects) or 
placebo (50 subjects) for 4 weeks with weekly laboratory assessments to characterize the 
percentage of participants with liver enzyme elevation (primary endpoint) or meeting withdrawal 
criteria for potential drug-induced liver injury (secondary endpoint). Additional secondary 
endpoints include the change from baseline to after 4 weeks of daily CBD dosing for male 
reproductive (testosterone and inhibin B) and thyroid hormones (thyroid stimulating hormone 
[TSH], triiodothryronine [T3] and thryroxine [T4]) as secondary endpoints. Exploratory 
endpoints include additional characterization of liver findings and other blood biomarkers. 
In Part 2, 40 healthy subjects will receive either oral citalopram (20 subjects) or morphine (20 
subjects) at baseline and then again after receiving CBD 5 mg/kg/day to characterize the effect of 
daily cannabidiol use on the plasma concentration of citalopram and morphine. Citalopram was 
selected because it is a common prescription medication for depression and anxiety that is 
metabolized by CYP2C19 and CYP3A4,9 which CBD inhibits.5 Morphine was selected because 
it is a common opioid analgesic that is metabolized by UGT2B7,10 which CBD inhibits.5 
 


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2. STUDY OBJECTIVES 
Part 1: 
To characterize the effects of daily cannabidiol use at a dose within the range of what consumers 
are taking as unapproved cannabidiol products on liver enzyme elevations and endocrine 
measures.   
Part 2:  
To characterize the effects of daily cannabidiol use at a dose within the range of what consumers 
are taking as unapproved cannabidiol products on drug interactions. 
3. ENDPOINTS 
3.1 Part 1 
Primary Endpoint: 
x Liver: Percentage of participants with an ALT (based on consensus criteria*) or 
AST liver enzyme elevation greater than three times the upper limit of normal (> 
3 × ULN)  
Secondary Endpoint: 
x Percentage of participants meeting withdrawal criteria for potential drug-induced 
liver injury (DILI) 
x Change from baseline in total testosterone and inhibin B in male participants after 
CBD administration compared to placebo 
x Change from baseline in thyroid stimulating hormone (TSH), total T3, and free 
T4 after CBD administration compared to placebo  
Exploratory Endpoints: 
x Assessment of liver-related adverse events  
x Summary of CBD and metabolite pharmacokinetics 
x Proportion of subjects with abnormal laboratory (e.g., liver, endocrine) tests  
x Changes in additional laboratory and plasma proteome assessments 
*Consensus criteria for ALT elevation: ULN for ALT will be 33 U/L for males and 25 U/L 
for females 
3.2 Part 2 (Drug-Drug Interactions) 


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Primary Endpoints: 
x Comparison of the area under the plasma concentration-time curve (AUC) and 
Cmax of citalopram when administered alone versus when co-administered with 
CBD after 7 days of CBD dosing 
x Comparison of the morphine AUC and Cmax when administered alone versus 
when co-administered with the first dose of CBD and after 7 days of CBD dosing  
     Secondary Endpoints: 
x Comparison of the AUC and Cmax of morphine metabolites when administered 
alone versus when co-administered with CBD  
      Exploratory Endpoints: 
x Additional PK parameters for citalopram, morphine, and metabolites, such as time 
of maximum concentration, half-life, apparent clearance, and apparent volume of 
distribution 
x PK parameters for CBD and metabolites 
4. INVESTIGATIONAL PLAN 
4.1 Study Design 
Part 1 
Part 1 is a randomized, double-blind, placebo-controlled, parallel study in 200 subjects over a 
single treatment period of 28 days. Oral solution CBD at a dosage of 2.5 mg/kg twice a day, for a 
total of 5 mg/kg CBD daily, will be administered to the treatment group of 150 subjects. The 
placebo control group will consist of 50 subjects. Subjects will report to the study site for 
screening from Days -28 to -2 and then will return to the site on Day -1 for check-in and baseline 
assessments. Subjects will check-out from the clinical site on Day 1 (1-night in-house stay) 
following dosing and study assessments. Subjects will receive take-home doses of CBD or 
placebo for 28 days and will return to the study clinic on Day 28 for a single in-house day with 
check-out on Day 29. Subjects will have 3 clinic visits in between the in-house stays. The 
clinical site will have daily follow-ups with subjects during out-patient days  to remind subjects 
regarding their requirements for drug administration. Subjects will have one follow-up visit on 
Day 35. Chemistry and hematology assessments will be performed on days -1, 1, 7, 14, 21, 28, 
29, and 35. Endocrine assessments will be performed on days 1 and 29.  
The study design is as follows: 
 
CBD Dosing Days 1-28 (5mg/kg/day) 
 
 


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Day -1
Day 1
Day 7
Day 14
Day 21
Day 28
Day 29
Day 35
Check-in 
Check-out
Clinic visit 
1 
Clinic visit
2 
Clinic visit 3 
Check-in
Check-out
Follow-up visit
(Clinic visit 4)
Part 2
Part 2 is an open-label, sequential study in 40 subjects. This part will consist of two treatment 
cohorts, a citalopram DDI cohort and a morphine DDI cohort. Each treatment cohort will consist 
of 20 subjects.  
In the citalopram DDI cohort, subjects will report to the study site for screening from Days -28 to 
-2 and then will return to the site on Day -1 for check-in and baseline assessments. Subjects will 
check-out from the clinical site on Day 6 (6 nights in-house stay) following dosing and study 
assessments. Subjects will return to the study clinic on Day 12 for another 6 nights in-house stay 
with check-out on Day 18. Subjects will have one follow-up visit after the second check-out 
(Day 24). Subjects will receive CBD for 12 days (Day 6 to 17) and citalopram on Day 1 and Day 
13. 
In the morphine DDI cohort, subjects will report to the study site for screening from Days -28 to 
-2 and then will return to the site on Day -1 for check-in and baseline assessments. Subjects will 
check-out from the clinical site on Day 6 (6 nights in-house stay) following dosing and study 
assessments. Subjects will return to the study clinic on Day 10 for a 3 night in-house stay with 
check-out on Day 13. Subjects will receive CBD for 9 days (Day 4 to 12) and morphine on Day 
1, Day 4, and Day 11.  Subjects will have one follow-up visit after the second check-out (Day 
19). 
In both parts, the clinical site will have daily follow-ups after the first check-out visit subjects 
return for the second check-in visit to remind drug administration.   


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The study design is as follows:
Citalopram DDI cohort 
Day -1
Day 1
CBD Dosing Days 6-17 (5 mg/kg/day)
Day 18
Day 24
Day 6
Day 12
Day 13
Check-in
DDI drug Dosing
(baseline)
Check-out
Check-in
DDI drug Dosing
(w/ CBD)
Check-out
Follow-up 
visit
Morphine DDI cohort
Day -1
Day 1
CBD Dosing Days 4-12 (5 mg/kg/day)
Day 13
Day 19
Day 4
Day 6
Day 10
Day 11
Check-in
DDI drug Dosing
(baseline)
DDI drug Dosing
(w/ CBD)
Check-
out
Check-
in
DDI drug Dosing
(w/ CBD)
Check-
out
Follow-up visit


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Parts 1 and 2 
During the screening visit (Days -28 to -2 for both Part 1 and Part 2), the inclusion and exclusion 
criteria will be reviewed to ensure the subject is appropriate for the study. The informed consent 
form will be reviewed with the subject by a member of the study team and the subject will be 
encouraged to ask questions to ensure he or she has a good understanding of the study. If the 
subject is eligible and agrees to participate, the subject will be asked to sign the informed consent 
form before any study-specific procedure is performed, including randomization. 
After the consent process is complete, demographic data, medical history, and concomitant 
medications will be recorded. A physical examination will be performed by a study team 
member. Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be 
performed. Female subjects must have a negative pregnancy test result. Screening tests will be 
performed within 28 days of and no later than 1 day before Day –1 for both parts. Subjects will 
undergo assessments as described above and in the Study Summary and Schedule of Events 
(Appendix A & B).
Subjects will be discharged from the study after completion of all study procedures. If a subject 
discontinues from the study prematurely, all procedures scheduled for the end of the study will 
be performed. Meal timing and components, activity levels, and general conditions in the study 
clinic will be as similar as possible on the treatment days. Subjects previously screened, but not 
initially enrolled in a cohort will be allowed to rescreen.
4.1.1. Risk/Benefit
Subjects will be informed that participation in a human clinical pharmacology study like the 
present one cannot be of benefit to healthy volunteers. Nevertheless, the information from the 
physical examination, vital sign measurements, and laboratory test results may be shared with 
the subject’s personal physician if this is the subject’s choice. Subjects will be informed that it is 
also their choice to inform their personal physician that they are participating in this research 
study. 


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Subjects will be informed that their contribution to the study is of major importance to agencies 
like the FDA to understand the effects of CBD on liver safety, endocrine measures, and drug-
drug interactions.  However, since this is a study involving healthy volunteers, subjects will be 
informed that they have the option not to participate. 
Subjects will be informed that they may be exposed to risks associated with the pharmacological 
properties of the study drug and the study procedures. The following summary of potential AEs 
for the study drugs will be provided to and discussed with the subjects.  
1. Oral cannabidiol 5 mg/kg/day: The most common adverse events include somnolence, 
decreased appetite, diarrhea, ALT/AST elevation, fatigue, malaise, asthenia, rash, 
insomnia/sleep disorder, and infection.2  
2. Oral citalopram 20 mg: The most common adverse events include fever, arthralgia, myalgia, 
anorexia, agitation, somnolence, insomnia, sinusitis, ejaculation disorder (primarily 
ejaculatory delay), decreased libido, and impotence.11  
3. Oral morphine 15 mg: The most common adverse events include constipation, nausea, 
sleepiness, lightheadedness, dizziness, drowsiness, vomiting, and sweating.12  
Selected doses of individual drugs are within the FDA approved labeled doses. 
x 
Cannabidiol – Cannabidiol (Epidiolex) will be administered orally 2.5 mg/kg BID for a 
total of 5 mg/kg/day for 28 days in Part 1 and for 9 days (morphine cohort) or 12 days 
(citalopram cohort) in Part 2. Labeled dosing initiates treatment at 5 mg/kg/day. Dosing 
is capped at 25 mg/kg/day for maximum maintenance dosage. DDI interactions can occur 
with drugs that are strong inducers/inhibitors of CYP3A4 or CYP2C19 and substrates of 
UGT1A9, UGT2B7, CYP2C8, CYP2C9, and CYP2C19. Studies with cannabidiol have 
initiated dosing at up to 25 mg/kg/day for 26 weeks13, which is higher dosing and for a 
longer duration than proposed for this study. 
x Citalopram – Citalopram (Celexa) will be administered once at 20 mg on days 1 and 13. 
Citalopram’s initial dosage is 20 mg once daily with or without food and may increase to 
a maximum of 40 mg once daily.11 DDI interaction included CYP2C19 inhibitor. The 
maximum recommended dose of citalopram is 20 mg/day for patients who are taking 
concomitant CYP2C19 inhibitor since it may lead to increased blood levels of citalopram 
and risk of QT prolongation or Torsade de Pointes.14 
x Morphine – Morphine will be administered once at 15 mg on days 1, 4, and 11, which is 
within the range of labeled dosing. The initial dosage of morphine sulfate tablet is 15-30 
mg every 4 hours as needed, but due to the risk of addiction, abuse, and misuse with 
opioids, it is recommended to use the lowest effective dosage for the shortest duration.12  
The study drugs will not be administered to anyone who is pregnant. All women must take a 
pregnancy test before receiving any study drug in this study. All women of childbearing potential 
enrolled on this study will be informed that they must use effective birth control methods 


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(abstinence, intrauterine device, and contraceptive foam and a condom [i.e., double-barrier 
method]) during treatment. Subjects will be informed that they must notify the investigator if 
they or their female partners become pregnant during the study. If a subject becomes pregnant, 
she will be informed that neither Spaulding Clinical Research nor the sponsor will be responsible 
for the cost of any obstetric or related care, or for the child’s care. Female subjects will also be 
informed of the importance of not becoming pregnant for 30 days following last medication 
dose. Male subjects will be informed of the importance of not fathering a child or donating 
sperm for 3 months following the last dose. 
Subjects will be informed that insertion of an IV catheter may be required for blood sample 
collection and, during insertion of the catheter, soreness, bruising, or infection at the insertion 
site are possible but unlikely. Subjects will also be informed that dizziness and lightheadedness 
may occur during direct venipuncture, insertion of the IV catheter, or during blood collection. 
Subjects will be informed that the confidentiality of their data will be respected at all times 
according to state law, and the study personnel handling their study data are bound by 
confidentiality agreements. 
Subjects will be informed that they may eat only meals and snacks that are provided during 
periods of their stay in the study clinic, and that they must consume each meal that is served at a 
reasonable pace (within 25 minutes). 
Subjects will be informed that extra precautions will be put in place, including required 
screening tests, that will limit the risk of COVID-19. Precautions will be documented in a 
COVID-19 risk management plan. Subjects will be informed that despite the extra precautions 
there is still a risk of them contracting COVID-19. Any changes to the COVID-19 precautions 
(e.g., due to updated CDC recommendations or new testing becoming available) will be 
documented in the COVID-19 risk mitigation plan.  
Subjects will be informed that the study drug and all tests, procedures, and visits required by the 
study are provided at no cost to them. If subjects become ill or physically injured because of 
participation in this study, they will be informed that costs of treatment will not be covered by 
the sponsor. 
4.2 Selection of Study Population 
Subjects will be screened, and the data collected will be reviewed by the principal investigator. 
Only those subjects who meet all the eligibility criteria will be enrolled. Approximately 
240 healthy subjects are planned for enrollment of which approximately 190 subjects will be 
administered CBD in parts 1 and 2. The DDI substrate drugs of oral morphine and oral 
citalopram will be used in part 2, with 20 subjects receiving morphine and 20 subjects receiving 
citalopram as per the schedule of events.  
4.2.1 Inclusion Criteria 


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Subjects who meet all the following inclusion criteria will be eligible to participate in the study:  
1. Subject signs an IRB approved written informed consent and privacy language as per 
national regulations (e.g., Health Insurance Portability and Accountability Act 
authorization) before any study related procedures are performed.  
2. Subject is a healthy, non-smoking man or woman, 18 to 55 years of age, inclusive, who 
weighs at least 50 kg (110 lbs) and has a body mass index of 18.5 to 33.0 kg/m2, inclusive, 
at Screening and check-in (Day -1). 
3. Subject has normal medical history findings, clinical laboratory results, vital sign 
measurements, 12-lead ECG results, and physical examination findings at screening or, if 
abnormal, the abnormality is not considered clinically significant (as determined and 
documented by the investigator or designee). 
4. Subject must have a negative test result for alcohol and illicit drugs at screening and check-
in (Day -1).  
5. Participants must agree to refrain from using any of the following for the duration of the 
study: alcohol, nicotine containing products, marijuana or marijuana-derived products, 
hemp or hemp-derived products, including CBD (except for provided study drug), and 
illicit drugs of any kind. 
6. Subject must test negative for severe acute respiratory syndrome corona virus 2 (SARS-
CoV-2) by a rapid antigen test at check-in for all study periods. If a subject’s test comes 
back as invalid, the test can be repeated. 
7. Female subjects must be of non-childbearing potential (non-childbearing potential includes 
post-menopausal females defined as spontaneous amenorrhea for at least 12 months with 
FSH in the post-menopausal range and females who have undergone a hysterectomy) or, if 
they are of childbearing potential, they must: 1) have negative serum HCG at screening and 
check-in 2) have been strictly abstinent for 1 month before check-in (Day -1) and agree to 
remain strictly abstinent for the duration of the study and for at least 1 month after the last 
application of study drug; OR 3) be practicing 2 highly effective methods of birth control 
(as determined by the investigator or designee; one of the methods must be a barrier 
technique) from Screening until at least 1 month after the end of the study.   
8. Male subjects must agree to practice 2 highly effective methods of birth control (as 
determined by the investigator or designee) beginning at check-in (Day -1) until at least 3 
months after the last dose of study drug. Male subjects may not donate sperm for 90 days 
after the end of the study.  
9. Subject agrees to and is highly likely (as determined by the investigator) to comply with the 
protocol defined procedures and to complete the study. 
4.2.2 Exclusion Criteria 


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Subjects who meet any of the following exclusion criteria will not be eligible to participate in the 
study:  
1. Abnormal liver labs at screening on check-in (Day –1), defined as any of the following 
(tests may be repeated once for confirmation at screening and check-in):  
a. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 
× ULN. (The ULN for ALT will be 33 U/L for males and 25 U/L for females.) 
b. Total bilirubin (TBL) > ULN.  
c. International normalized ratio (INR) > 1.3  
2. Use or intend to use any medications/products in the 14 days prior to check-in (Day -1), 
unless deemed acceptable by the investigator  
3. Subject is currently participating in another clinical study of an investigational drug or 
has been treated with any investigational drug within 30 days or 5 half-lives (whichever 
is longer) of dosing for this study.  
4. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, 
snuff, electronic cigarettes) within 6 weeks of Screening. Subjects must refrain from 
using these throughout the study. 
5. Subject has consumed alcohol, xanthine-containing products (e.g., tea, coffee, chocolate, 
cola), caffeine, kava melatonin, St Johns Wart, grapefruit, or grapefruit juice within 
24 hours of check-in. Subjects must refrain from ingesting these throughout the study.  
6. Subject is unable to tolerate a controlled, quiet study conduct environment, including 
avoidance of music, television, movies, games, and activities that may cause excitement, 
emotional tension, or arousal during the prespecified time points (e.g., before and during 
CBD dosing).  
7. Subject has a history of consuming more than 14 units of alcoholic beverages per week 
within 6 months before Screening, has a history of alcoholism or 
drug/chemical/substance abuse within 2 years before Screening (Note: 1 unit = 12 ounces 
of beer, 4 ounces of wine, or 1 ounce of spirits/hard liquor). 
8. Subject has a positive test result for alcohol or drugs of misuse (amphetamines, 
barbiturates, benzodiazepines, cocaine, alcohol, opiates, phencyclidine, propoxyphene, 
and methadone) at Screening or Check-in (Day -1 [both Parts]; Day 10 [morphine DDI]; 
Day 12 [citalopram DDI]). Subject has a positive test result for cannabinoids (THC) at 
screening or Day -1. 
9. Subject has a history of opioid or narcotic misuse. 
10. Subject has a history of suicidal ideation or previous suicide attempts 


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11. Subject has a history or evidence of a clinically significant disorder, condition, or disease 
(e.g., cancer, human immunodeficiency virus [HIV], hepatic or renal impairment) that, in 
the opinion of the investigator, would pose a risk to subject safety or interfere with the 
study evaluation, procedures, or completion.   
12. Subject has a diagnosis of COVID-19 or any signs or symptoms that are consistent with 
COVID-19 per CDC recommendations at screening or check-in (Day -1). These include 
subjects with fever or chills, cough, shortness of breath or difficulty breathing, fatigue, 
muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or 
runny nose, nausea or vomiting,  diarrhea, or other symptoms indicative of likely 
COVID-19 in the opinion of the investigator.  
13. Subject has known or suspected allergies or sensitivities to the study drug or placebo 
components (e.g., sucralose, sesame).  
14. Subjects with a documented hypersensitivity reaction to cannabidiol 
15. Subjects with a documented medical history of clinical disorders related to mood, anxiety 
or panic, including diagnosed depression, generalized anxiety disorder or panic attacks. 
16. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, 
Crohn’s disease, irritable bowel syndrome). Uncomplicated cholecystectomies and 
appendectomies may be included at the investigator’s discretion. 
17. Subject has clinical laboratory test results (hematology, serum chemistry and urinalysis) 
at Screening or Check-In that are outside the reference ranges provided by the clinical 
laboratory and considered clinically significant by the investigator. Tests may be repeated 
once for confirmation at both Screening and Check-In.   
18. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus 
antibodies, or hepatitis B surface antigen.  
19. Subject has a mean systolic blood pressure <85 or >145 mmHg or a mean diastolic blood 
pressure <45 or >95 mmHg at either Screening or Check-in. Blood pressure will be 
measured in triplicate after the subject has been resting in a supine position for a 
minimum of 5 minutes.  
20. Subject is unable or unwilling to undergo multiple venipunctures for blood sample 
collection because of poor tolerability or is unlikely to complete the study due to poor 
venous access.  
21. Female subject is currently pregnant or lactating or was within 3 months of the study.  
22. Subject has had any significant blood loss, donated 1 unit (450 mL) of blood or more, or 
received a transfusion of any blood or blood products within 60 days, or donated plasma 
within 7 days before Check-in. 


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23. Subject has any other condition that precludes his or her participation in the study (as 
determined by the investigator). 
4.3 Screening Failures 
Subjects who sign and date the informed consent form but who fail to meet the inclusion and 
exclusion criteria are defined as screening failures. A screening log, which documents the subject 
initials and reason(s) for screening failure, will be maintained by the investigator for all 
screening failures. A copy of the log should be retained in the investigator’s study files. 
If a subject fails the screening process because of an abnormal laboratory result, they can receive 
a copy of the results upon request. The investigator will determine if follow-up for the abnormal 
laboratory result is needed and will encourage the subject to follow up with his or her personal 
physician as appropriate. All subjects will be informed as to the reason(s) they are excluded from 
study participation, even if follow-up is not required. If a subject fails the screening process 
because of a positive test result for human immunodeficiency virus or hepatitis, the positive 
result will be reported to local health authorities as required by law. 
4.4 Termination of Study or Investigational Site 
4.4.1 Criteria for Termination of the Study 
The study will be completed as planned unless one of the following criteria is satisfied that 
requires early termination of the study. 
x New information regarding the safety or efficacy of the study drug(s) that indicates a change 
in the known risk profile for the study drug(s), such that the risk is no longer acceptable for 
subjects participating in the study. 
x One or more serious adverse events (SAEs) that are determined to be related to the study 
drug occur. SAEs are defined as events that result in death, are life-threatening, or require 
hospitalization.  
x Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety. 
4.4.2 Criteria for Termination of the Investigational Site 
The study site may be terminated if the site (including the investigator) is found in significant 
violation of GCP, the protocol, the contractual agreement, or is unable to ensure adequate 
performance of the study. 
In the event that the sponsor elects to terminate the study or the investigational site, a study-
specific procedure for early termination will be provided by the sponsor; the procedure will be 
followed by the applicable investigational site during the course of termination. 


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4.5 Criteria for Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn by the investigator without the approval of the subject based on the investigator’s 
clinical judgment. A subject is not required to provide a written request to withdraw from the 
study; however, a written request is required if a subject withdraws consent for his or her 
personal data to be used for study related purposes. 
A subject may be discontinued for any of the following reasons: 
x AE: The subject has experienced an AE that, in the opinion of the investigator, requires early 
termination. The appropriate electronic case report form (eCRF) must be completed for each 
AE. If a subject is discontinued from the study due to an AE, the investigator is required to 
follow up with the subject until the event resolves or becomes stable. If a subject dies during 
the study, the cause of death must be reported as a serious AE (SAE), with an outcome of 
death noted in the eCRF. 
x Withdrawal Criteria for Potential Drug-Induced Liver Injury (DILI): laboratory results 
meeting any of the following criteria. 
o ALT or AST > 3 x ULN (ULN for ALT is 33 U/L for males and 25 U/L for 
females) with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%) OR 
o $/7HOHYDWLRQî8/18/1IRU$/7LV8/IRUPDOHVDQG8/IRU
females) OR 
o $/3HOHYDWLRQî8/1ZLWKDFFRPSDQ\LQJHOHYDWLRQVRI**7LQWKHDEVHQFH
of known bone pathology driving the rise in ALP level) OR 
o $/7HOHYDWLRQî8/1DQGELOLUXELQFRQFHQWUDWLRQ!î8/1 
When subject withdrawal occurs due to potential DILI, the study drug will be discontinued, and 
monitoring will still be continued to document subsequent liver test results and resolution of 
biochemical abnormalities. Wherever possible, the investigator should arrange for the subject to 
return to the clinical site as soon as possible (within 24 hours of notice of abnormal results) for 
repeat assessment of laboratory results to confirm that the subject meets the trial discontinuation 
criteria as well as to obtain detailed history and to perform a physical examination. Subjects 
should be followed with frequent (every 24 to 48 hours) repeat clinical laboratory assessments 
and any other appropriate assessments until all abnormalities normalize (in the investigator’s 
opinion) or return to the baseline state. The subject will be discontinued from the study and 
returned to the study site for repeat and follow-up assessments. These follow-up steps are 
outlined in more detail in a separate procedures document. 


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x Protocol Violation: The subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unnecessary risk to the subject’s 
health. 
x Withdrawal by Subject: The subject (or other responsible individual [e.g., caregiver]) wishes 
to withdraw from the study in the absence of a medical need. 
NOTE: Withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
category. 
x Study Terminated by Sponsor: The sponsor, IRB, FDA, or other regulatory agency 
terminates the study. 
x Pregnancy: The subject is found to be pregnant. 
NOTE: If the subject is found to be pregnant, the subject must be withdrawn immediately. 
The pregnancy will be followed up to term, and the outcome, including any premature 
termination will be recorded. All live births must be followed for a minimum of 30 days or 
until the first well-baby visit. 
x Other. 
NOTE: This category records withdrawals caused by an accidental or a medical emergency, 
unblinding, and other rare cases. The specific reason should be recorded in the comment 
space of the eCRF. 
4.5.1 Handling of Withdrawals 
The investigator may terminate a subject’s study participation at any time during the study when 
the subject meets the criteria described in Section 4.5. In addition, a subject may discontinue his 
or her participation without giving a reason at any time during the study. Subjects will be 
informed that their participation in the study is voluntary, that refusal to participate will involve 
no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may 
discontinue participation at any time without penalty or loss of benefits to which the subject is 
otherwise entitled. 
Should a subject’s participation be discontinued, the primary reason for termination must be 
recorded. In addition, efforts should be made to perform all procedures scheduled for the early 
termination visit.  
4.5.2 Replacement of Subjects 
Approximately 240 healthy subjects are planned for study enrollment with Part 1 having 150 
subjects randomized to CBD dosing and 50 subjects to placebo control. Approximately 40 
healthy subjects are planned for enrollment in Part 2 (20 subjects per DDI cohort). Replacement 
subjects may be assigned depending on discontinuations during Part 1 and 2. 


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4.6 Study Visits 
4.6.1 Recruitment 
Recruitment materials (e.g., internet, radio, and print advertisements, social media posts) will be 
approved by the local IRB before telephone screening. The sponsor is responsible for registration 
of the study on clinicaltrials.gov. Recruitment may not occur until the study is fully registered on 
clinicaltrials.gov. 
4.6.2 Compensation 
Subjects will be offered payment for Screening; however, if the results of their alcohol and drug 
screening tests are positive, they will not be compensated. Subjects who complete the entire 
study will receive payment according to the schedule provided in the informed consent form. No 
special incentives are offered. Final payment will not be released until all follow-up procedures 
have been completed and accepted by the investigator. 
If a subject chooses to withdraw from the study prematurely, he or she will only be compensated 
for completed days. If subjects are withdrawn for medical reasons or if the study is halted 
temporarily or permanently, the subjects will receive compensation proportional to the time 
spent in the study. No compensation will be provided if a subject is dismissed from the study for 
noncompliance (e.g., improper conduct, ingesting alcohol and/or drugs [including recreational 
drugs], tampering with the study drug, consuming any prohibited foods or beverages). 
If subjects are required to stay in the clinic for a longer period for safety reasons, they will be 
compensated at a rate proportional to the entire compensation for the study. If a subject becomes 
ill or physically injured because of participation in this study, the subject will be referred for 
treatment. 
4.6.3 Screening  
The following procedures and assessments will be performed at Screening for both parts (Days -
28 to –2): 
x Obtain informed consent/HIPAA authorization. The informed consent process will be 
performed by a clinical research nurse in a private room. The subject will be given unlimited 
time to ask questions regarding study participation, and each subject will be questioned to 
ensure their understanding. 
After informed consent is obtained: 
x Review inclusion/exclusion criteria to confirm subject eligibility 
x Record demographic information 
x Measure height, weight, and calculate body mass index 


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x Perform serology screening (HIV antigen/antibody [Ag/Ab] Combo 1/2, HepC antibody, 
HBsAg) 
x Record medical history 
x Perform alcohol and drug screening (amphetamines, barbiturates, benzodiazepines, cocaine, 
alcohol, opiates, phencyclidine, propoxyphene, cannabinoids (THC), and methadone) 
x Perform urine cotinine test 
x Perform a serum pregnancy test (female subjects only) 
x Perform FSH assessment (postmenopausal [i.e., spontaneous amenorrhea for at least 12 
months] female subjects only)   
x Record prior medications 
x Monitor for AEs 
x Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
x Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) 
x Perform a safety 12 lead ECG 
x Perform a complete physical examination 
4.6.4 Study Periods 
4.6.4.1 Check-In (Day -1) 
The following procedures and assessments will be performed at check-in (Day -1 for both parts): 
x Perform/review results from SARS-CoV-2 rapid antigen test  
x Review inclusion/exclusion criteria to confirm subject eligibility 
x Review medical history  
x Perform targeted physical examination 
x Weight measurement  
x Perform alcohol and drug screening (amphetamines, barbiturates, benzodiazepines, cocaine, 
alcohol, opiates, phencyclidine, propoxyphene, cannabinoids (THC), and methadone) 
x Perform liver function tests (ALT, AST, GGT, ALP, PT/INR, TBili)    


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x Perform urine cotinine test 
x Perform a serum pregnancy test (female subjects only) 
x Admit subject to the study clinic 
x Randomization (after completion of check-in procedures or just before dosing on Day 1 of 
each study period) (Only Part 1)  
x Record concomitant medications 
x Monitor for AEs 
x Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
x Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) 
x Perform a safety 12 lead ECG  
4.6.4.2 Treatment 
The following procedures and assessments will be performed during the treatment period. Please 
refer to the Schedule of Events (Appendix A and B) for the specific days of assessments. 
x Monitor for AEs 
x Record concomitant medications 
x Administer study drug according to Schedule of Events (Appendix A and B). Administration 
of study drug [Part 1: clinic visits and Day 28, Part 2: Day 12 (citalopram) and Day 10 
(morphine)] can occur prior to review of safety labs. 
x Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature).  
x Perform targeted physical examination (at investigator’s discretion) 
x Collect PK blood samples (6 mL) at timepoints specified in Section 4.7.1.1. Blood samples 
will be collected by direct venipuncture or by inserting an intravenous (IV) catheter. 
x Collect blood samples for laboratory tests.  
x Collect whole blood sample for pharmacogenetic testing (Only Part 2) 
 
4.6.4.3 Discharge (or Early Termination) 


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The following procedures and assessments will be performed before a participant is discharged 
at the end of the study or at early termination: 
x Perform liver function tests (ALT, AST, GGT, ALP, PT/INR, TBili)    
x Record concomitant medications 
x Monitor for AEs 
x Measure height, weight, and calculate body mass index 
x Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
x Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) 
x Perform a serum pregnancy test (female subjects only) 
x Collect PK blood sample (6 mL)  
x Perform a safety 12-lead ECG  
x Perform a complete physical examination 
x Discharge subject from the study clinic after completion of all study procedures 
4.7 Study Procedures 
4.7.1 Pharmacokinetic Assessments 
4.7.1.1 Pharmacokinetic Sample Collection  
Pharmacokinetic blood samples will be collected by direct venipuncture or by inserting an IV 
catheter. In Part 1, a single blood sample will be collected on Day 1, Day 7 (clinic visit), Day 14 
(clinic visit), Day 21 (clinic visit), Day 29, and a final sample collection at follow-up on Day 35. 
Clinic visits may be completed outside of the listed visit day per investigator’s decision. Total 
number of PK blood samples will be 6 per subject for Part 1. Each blood sample will be labeled 
with subject number, study number, study day, time point, event, and a barcode that matches that 
belonging to the subject. All lab collections will take place predose and within 1 hour of 
mealtime.  
Part 1 PK collections: 
x Days 1, 7, 14, 21, 29, 35 
For Part 2, both the citalopram and morphine DDI cohorts will have 13 PK samples obtained 
during each in-house stay. Total number of PK blood samples will be 26 per subject for the 
citalopram DDI cohort and 39 per subject for the morphine DDI cohort. Each blood sample will 


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be labeled with subject number, study number, study day, time point, event, and a barcode that 
matches that belonging to the subject. 
Part 2 PK collections: 
x Citalopram DDI cohort 
o Days 1 and 13: 8 PK samples 
 0, 1, 2, 3, 4, 6, 8, 12 hours 
o Days 2 and 14: 1  
 24 hours 
o Days 3 and 15: 1 
 48 hours 
o Days 4 and 16: 1 
 72 hours 
o Days 5 and 17: 1 
 96 hours 
o Days 6 and 18: 1 
 120 hours 
 
x Morphine cohort 
o Days 1, 4 and 11: 11 PK samples 
 0, 15, 30, 45, 60, 90 minutes  
 2, 3, 4, 6, 12 hours 
o Days 2, 5 and 12: 1 
 24 hours 
o Days 3, 6 and 13: 1 
 48 hours 
4.7.1.2 Pharmacokinetic Specimen Handling 
The PK blood samples (6mL each) will be collected into tubes containing K2EDTA, inverted 
several times to mix the blood with the anticoagulant, and placed in an ice bath. Within 30 
minutes of collection, the samples will be centrifuged for 10 minutes, at 3000 RCF, at 4°C, by a 
study team member. 
The plasma will be separated using a disposable plastic pipette and equally aliquoted into 
duplicate cryotube vials labeled as Aliquot A (primary) and Aliquot B (backup). The plasma 
samples will be appropriately labeled and stored frozen at -70°C or below within 30 minutes 
after aliquoting until shipment. Temperature monitoring logs should be maintained and 
accessible for review by the study monitor.  
The Aliquot A samples (primary) will be shipped first, on dry ice, to the bioanalytical laboratory 
at FDA for processing when requested by the sponsor. The Aliquot B samples (backup) will be 
held for a second shipment after completion of all Aliquot A sample shipment(s) and the timing 
of the Aliquot B shipment will be communicated by the sponsor. None of the PK blood samples 
will be stored at the clinical facility for future use. 


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4.7.1.3 Pharmacokinetic Parameters 
The following PK parameters will be determined for Part 2 which will include citalopram and 
morphine with or without CBD.  
x Maximum observed plasma concentration (Cmax) 
x Area under the plasma concentration time curve (AUC) 
x Time at which Cmax occurs (Tmax) 
x Elimination rate constant (Kel) 
x Terminal half-life (t1/2)  
4.7.2 Endocrine Assessments 
Endocrine assessments will be collected in Part 1 on the study days outlined below to determine 
total testosterone and inhibin B for males, and thyroid panel with TSH values for all participants. 
Blood samples will be collected by direct venipuncture or by inserting an intravenous (IV) 
catheter. Using red top tubes (no additives), approximately 8-10 mL of blood samples will be 
collected to provide sufficient serum for all scheduled assays—total testosterone, inhibin B, and 
thyroid function (TSH, total T3, free T4).  
For Part 1, blood samples for endocrine assessment will be collected on Day 1 (morning, prior to 
dosing) and at check-out on Day 29 (morning, time-matched to the initial pre-dose assessment).  
4.7.2 Lipid Assessments 
For the lipid assessment, approximately 5 mL of whole blood will be collected and processed for 
serum. Blood samples will be collected by direct venipuncture or by inserting an intravenous 
(IV) catheter. Samples will be collected into red top tubes (no additives).  
For Part 1, blood samples for lipid assessments will be collected on Day 1 (morning, prior to 
dosing) and at check-out on Day 29 (morning, time-matched to the initial pre-dose assessment). 
Lipid assessments will include total cholesterol, LDL, HDL, and triglycerides. 
4.7.2 Proteomics Assessments 
For the proteomics assessments, approximately 5 mL of whole-blood samples will be collected 
and processed for plasma. Whole blood should be collected in BD Vacutainer® Venous Blood 
Collection Tubes containing EDTA (or any other primary blood collection tube containing 
EDTA as anticoagulant) and stored at room temperature (15–25°C) or 4°C before processing 
within 1 hour. Heparin-containing blood collection tubes should not be used as this anticoagulant 
can interfere with downstream analyses.  


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Plasma samples should be processed, aliquoted (approximately 700 μL volumes), and placed 
into the -80C freezer within 2 hours of collection.  
For Part 1, blood samples for proteomics assessments will be collected on Day 1 (morning, prior 
to dosing) and at check-out on Day 29 (morning, time-matched to the initial pre-dose 
assessment).  
4.7.3 Safety Assessments 
Safety will be evaluated in terms of AEs, clinical laboratory results (hematology, serum 
chemistry, and urinalysis), vital sign measurements (blood pressure, heart rate, respiratory rate, 
and oral body temperature), safety 12 lead ECG results, and physical examination findings.  
4.7.3.1 Adverse Events 
4.7.3.1.1 Adverse Event Definitions 
An AE is defined as any untoward and/or unintended sign, including an abnormal clinical 
laboratory finding, symptom, or disease temporally associated with the use of a study drug, 
whether or not considered related to the study drug. Events or conditions that increase in 
frequency or severity during or as a consequence of use of a drug in human clinical trials will 
also be considered AEs. 
A treatment emergent adverse event (TEAE) is defined as an AE that begins after study drug 
administration. 
An unexpected AE is any AE having a specificity or severity not consistent with the current 
investigator’s brochure for the study drug(s). 
A serious adverse event (SAE) is defined as any AE occurring at any dose that meets the 
following criteria: 
x Results in death, 
x Is life threatening, 
x Requires hospitalization or prolongation of existing hospitalization, 
x Results in persistent or significant disability or incapacity, 
x Results in a congenital anomaly/birth defect due to exposure prior to conception or during 
pregnancy, or 
x Is an important medical event that may not meet the previous criteria but, based upon 
appropriate medical judgment, jeopardizes the subject or requires medical or surgical 
intervention to prevent one of the outcomes listed previously. 
4.7.3.1.2 Adverse Event Reporting 


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The recording of AEs will begin after the subject signs the informed consent form and will 
continue until discharge (or early termination). All AEs, whether serious or nonserious and 
whether or not related to the study drug, must be recorded in the eCRF. Study subjects will be 
instructed to warn study staff if he or she has any unexpected symptoms. In addition, all subjects 
will receive a reminder telephone call approximately 24 h before check-in. 
Any SAE (whether expected or unexpected) must be entered into the eCRF system and reported 
by email to the medical monitor or designee using the SAE Reporting Form within 24 h of the 
investigator or study clinic staff becoming aware of the event. It is the responsibility of the 
investigator to report all SAEs to the medical monitor, to provide the most complete report 
possible, and to assess each SAE for its relationship to the study drug. The investigator is 
responsible for obtaining follow-up information on all SAEs and submitting follow-up SAE data. 
Any unexpected SAEs must be reported promptly to the investigator’s IRB as per the IRB’s 
requirements. 
In the event of a fatal or life-threatening SAE, the sponsor will notify the appropriate FDA 
authorities within 7 calendar days of receipt of the report. The sponsor will follow all 7 day alert 
reports with a written report within 10 working days of receipt of the case. Serious AE cases that 
concern nonfatal, non-life-threatening events that are unexpected and at least possibly related to 
the study drug will be submitted in writing to the FDA within 10 working days of receipt. 
Furthermore, any AEs that are not expected, occur at a higher frequency, or would require 
modification of the study protocol and/or informed consent must be reported to the FDA within 
10 working days. 
Adverse events that are assessed by the investigator as possibly or probably related to the study 
drug will be followed until they resolve or stabilize. All SAEs will be followed until resolution. 
4.7.3.1.3 Assessment of Severity 
The investigator will assess the severity of each AE using the following scale: 
x Mild: The subject is aware of the AE but is still able to perform all activities; minimal or no 
medical intervention or therapy is required. 
x Moderate: The subject has to discontinue some activities due to the AE; minimal or no 
medical intervention or therapy is required. 
x Severe: The subject is incapacitated by the AE and is unable to perform normal activities; 
significant medical intervention or therapy is required, and hospitalization is possible. 
4.7.3.1.4 Assessment of Causality 


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The investigator will assess the causal relationship/relatedness of each AE to the study drug 
using the following scale: 
x Not Related: Onset of the AE has no reasonable temporal relationship to administration of 
the study drug, a causal relationship to administration of the study drug is biologically 
implausible, or the event is attributed to an alternative etiology. 
x Unlikely Related: Onset of the AE has a reasonable temporal relationship to study drug 
administration and although a causal relationship is unlikely, it is biologically plausible. 
x Possibly Related: Onset of the AE has a strong temporal relationship to administration of the 
study drug, cannot be explained by the subject’s clinical state or other factors, and a causal 
relationship is biologically plausible. 
x Probably Related: Onset of the AE shows a distinct temporal relationship to administration of 
the study drug that cannot be explained by the subject’s clinical state or other factors, the AE 
is a known reaction to the product or chemical group or can be predicted by the product’s 
pharmacology. 
4.7.3.1.5 Pregnancy 
A serum pregnancy test will be performed for female subjects at the time points presented in the 
Schedule of Events (Appendix A and B). If a subject becomes pregnant while on the study, this 
should be reported immediately to the investigator, the subject will be withdrawn from the study 
and the medical monitor and the subject will be instructed to follow up with his or her personal 
physician. All pregnancies are to be reported as an AE and followed for outcome. 
4.7.3.2 Clinical Laboratory Tests 
Clinical laboratory and diagnostic screening tests will be performed at the time points presented 
in the Schedule of Events and will be collected in accordance with acceptable laboratory 
procedures. Clinical laboratory testing will be performed by the clinical study contractor(s). The 
clinical laboratory tests that will be performed are presented in Table 4-1. Unused clinical 
laboratory test samples will not be stored for future use. 


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Table 4--1: Clinical Laboratory Tests & Diagnostic Screening Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
White blood cell count (with 
automated differential) 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (total, direct, and indirect) 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine (including calculated 
creatinine clearance by CKD-EPI) 
Gamma-glutamyl transferase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Uric acid 
 
Specific laboratory tests (Part 1): 
Total and free testosterone 
Inhibin B 
Thyroid stimulating hormone 
Triiodothyronine (total T3) 
Thyroxine (free T4) 
Lipid Panel 
 
Additional assessments in subjects for 
liver enzyme monitoring: 
 
International normalized ratio (INR) 
Prothrombin time 
Appearance 
Bilirubin 
Blood 
Color 
Glucose 
Ketones 
Leukocyte esterase 
Microscopic examination: red blood cells, 
white blood cells, epithelial cells, bacteria, 
crystals, and casts (if present) 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Diagnostic Screening Tests: 
Serum 
Urine 
Whole Blood 
Serology (human 
immunodeficiency virus 
Ag/Ab Combo 1/2, hepatitis C 
virus antibody, and hepatitis B 
surface antigen) 
Female Subjects Only 
Human chorionic gonadotropin 
(for pregnancy) 
Follicle-stimulating hormone 
Drug screen including amphetamines, 
barbiturates, benzodiazepines, cocaine, 
alcohol, cannabinoids (THC) 
(excluded for Day 28 check-in, Part 1), 
opiates, phencyclidine, propoxyphene, 
methadone, and cotinine 
  
Pharmacogenetic testing may be performed 
(CYP2C19, Day-1 Part 2 citalopram cohort; 
UGT2B7, Day -1 and Part 2 morphine 
cohort). Additional details will be provided in 
a separate laboratory document. 
Other 
SARS-CoV2 rapid antigen test  


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Clinical laboratory results will be reviewed by the investigator or designee together with data in 
the eCRF. Any values outside the reference range will be evaluated for clinical significance. If a 
value is determined to be clinically significant, the subject will be instructed to follow up with 
his or her personal physician. The investigator or designee may repeat the clinical laboratory 
tests if deemed appropriate. The investigator will maintain a copy of the laboratory accreditation 
and the reference ranges for the laboratory used. 
4.7.3.2.1 
Assessment and Reporting of Potential Cases of Drug-Induced Liver Injury 
The investigational site is required to submit to the sponsor the laboratory results for any subject 
after admission to the study that meets one of the following criteria:  
x ALT or AST > 3 x ULN (ULN for ALT is 33 U/L for males and 25 U/L for females) 
with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%) 
OR 
x ALT elevation î8/18/1IRU$/7is 33 U/L for males and 25 U/L for females)  
OR 
x ALP elevation î8/1(with accompanying elevations of GGT in the absence of 
known bone pathology driving the rise in ALP level)  
OR 
x ALT elevation î8/1DQGbilirubin concentration > 2 × ULN 
When subject withdrawal occurs due to potential Drug-Induced Liver Injury (DILI), the 
study drug will be discontinued, and monitoring will still be continued to document 
subsequent liver test results and resolution of biochemical abnormalities. Laboratory results 
meeting any one of the above criteria, along with a copy of baseline laboratory results, must 
be sent to the the sponsor within 24 hours of becoming aware of the results. Wherever 
possible, the investigator should arrange for the subject to return to the clinical site as soon as 
possible (within 24 hours of notice of abnormal results) for repeat assessment of laboratory 
results to confirm that the subject meets the trial discontinuation criteria as well as to obtain 
detailed history and to perform a physical examination. Subjects should be followed with 
frequent (every 24 to 48 hours) repeat clinical laboratory assessment and any other 
appropriate assessments until all abnormalities normalize (in the investigator’s opinion) or 
return to the baseline state. The subject will be discontinued from the study and returned to 
the study site for repeat and follow-up assessments. These follow-up steps are outlined in 
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In addition, the severity of all instances of DILI are to be assessed according to the International 
DILI Expert Working Group’s severity index15 (Appendix D). This severity assessment will 
occur in addition to the AE reporting procedures detailed in 4.7.3.1.2 (Adverse Event Reporting).  
4.7.3.3 Vital Sign Measurements 
Vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
measured using an automated device at the time points presented in the Schedule of Events ( and 
B). Vital signs may be repeated at investigator discretion. 
4.7.3.4 Safety 12-lead Electrocardiograms 
12-lead ECGs will be obtained with the subjects in the supine position before recording. ECGs 
will be overread by a physician. If an abnormality is observed, the subject will be instructed to 
follow up with his or her personal physician. 
4.7.3.5 Physical Examinations 
A complete physical examination will be performed at the time points presented in the Schedule 
of Events (Appendix A and B). 
The complete physical examination will include, but not be limited to, assessments of the head, 
eyes, ears, nose, throat, skin, thyroid, nervous system, respiratory system, cardiovascular system, 
abdomen (liver and spleen), lymph nodes, and extremities. Height, weight (without shoes and 
wearing the lightest possible clothing), and calculation of body mass index will be performed at 
Screening and check-out. 
If a clinically significant abnormality is observed upon physical examination, the subject will be 
instructed to follow up with his or her personal physician. 
4.7.4 Demographics and Medical History 
Demographic data (date of birth, gender, race, and ethnicity) will be collected at Screening. 
Each subject will provide a complete medical history at Screening that will be reviewed at 
check-in. Specific information relating to any prior or existing medical conditions/surgical 
procedures will be recorded in the subject’s eCRF. 
4.8 Study Treatments 
4.8.1 Dose Selection and Rational  
Cannabidiol (Epidiolex) oral solution will be obtained for 190 participants (150 in Part 1 and 40 
in Part 2) to receive cannabidiol twice daily as per the Schedule of Events. All dosing will be 
oral. Anticipated dosing is 5 mg/kg/day administered in divided doses twice daily (i.e. 2.5 mg/kg 
twice daily). Oral placebo solution (matching characteristics of cannabidiol solution) will be 
obtained for 50 participants in Part 1 to receive placebo twice daily as per the schedule of events. 


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Cannabidiol’s label indicates a maximum dosage of 20 mg/kg/day, therefore the proposed study 
dose of 5 mg/kg/day is lower than the maximum therapeutic dose noted in the label. Data from a 
recent meta-analysis marked 400 mg/day as an upper limit of what can be considered low dose 
CBD and attainable using over the counter CBD products.16 In this study, total daily dosing will 
be in line with this threshold (200 mg twice daily for an 80 kg person). The anticipated DDI 
substrate drugs are oral morphine and oral citalopram. Of the participants in Part 2, 20 will 
receive morphine and 20 will receive citalopram as per the schedule of events.  
4.8.2 Treatments Administered and Schedule 
Study drugs for both parts will be administered by a clinical research nurse on the study clinic 
floor during check-ins and in-house stays. The pharmacist or investigator will be available if 
needed during study drug administration. Oral study drugs (Part 2) will be administered with 
240 mL of room -temperature water. During study days not on site, subjects will be required to 
take the study drugs twice daily at home. A member of the study team will follow up daily with 
each subject to ensure compliance with dosing schedule. Because levels of CBD may be affected 
by food, subjects will be instructed to take CBD consistently with regards to meals. Subjects will 
be instructed to take CBD after eating breakfast and dinner during at-home days. During in-
house stays, CBD will be given approximately 30 minutes after the start of breakfast and dinner. 
A fasting period of 4 hours will be required before all time points when clinical laboratory 
samples will be obtained. In addition, for Part 1, a fasting period of 8 hours will be required prior 
to lipid profile sampling on check-out Days 1 and 29. 
For Part 1 and Part 2, each instance of primary study drug administration will consist of an 
identical volume of prepared study drug oral solution. Placebo solution will be used to match 
treatments when needed. A study drug diary, designed by the clinical site and approved by the 
local IRB, will be given to each subject to monitor study drug tolerance and patient outcomes. 
4.8.2.1 Method of Assigning Subjects to Treatment Sequence 
4.8.2.1.1 Randomization Process 
The project biostatistician will create the specifications that will be used to generate the 
randomization schedule. The specifications will be based on the protocol requirements and 
appropriate statistical programming with consideration for study design, number of treatments, 
number of subjects planned for enrollment, stratification, and blocking. 
Based on these specifications, the project biostatistician (or designee) will generate a dummy 
randomization schedule. The schedule is generated in R.  
The project biostatistician (or designee) distributes the ‘dummy’ randomization schedule to 
specified personnel and pharmacy for review. Any change (e.g., change in block size, change in 
stratification levels) that requires an update to the specifications will reset this process. Minor 
changes (e.g., display formatting) will not require a change to the specifications. 


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After the approval of the ‘dummy’ randomization schedule, the project biostatistician (or 
designee) transfers the program used to generate the ‘dummy’ schedule to the randomization 
biostatistician (unblinded), who is an independent party and will not be participating in any 
programming or statistical decisions for the study before breaking the blind. No transfer is 
necessary if the unblinded randomization biostatistician also created the ‘dummy’ 
randomization. 
The randomization biostatistician is responsible for generating the final randomization schedule. 
The output is sent only to designated unblinded recipients, who will maintain a secured digital 
and printed copy for their use. 
Archival of the programs and output is accomplished by the creation of an encrypted, password-
protected ZIP file containing the program and output file(s). The ZIP file is copied to a secure 
storage drive on the sponsor’s site. 
Randomization will occur after informed consent is obtained in Part 1, either after completion of 
check-in procedures on Day -1 or just before dosing on Day 1. Approximately 200 healthy male 
and female subjects are planned for enrollment in Part 1 (150 subject receiving CBD and 50 
receiving placebo). 
All randomization information will be secured and housed in a locked storage area, accessible 
only by the randomization personnel and the assigned pharmacist and his or her verifier. 
4.8.2.1.2 Identity of Study Drugs 
Cannabidiol (Epidiolex) is indicated for the treatment of seizures associated with Lennox-
Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. It is extracted from 
Cannabis sativa L. plants. Cannabidiol (Epidiolex) is a clear, colorless to yellow liquid available 
in 100 mg/mL oral solution. The compound cannabidiol is a white to pale yellow crystalline 
solid, insoluble in water but soluble in organic solvents. Cannabidiol has a molecular weight of 
314.46, and molecular formula is C21H30O2.2 
Citalopram (Celexa) is a selective serotonin reuptake inhibitor (SSRI) indicated for treatment of 
major depressive disorder. Citalopram hydrobromide occurs as a fine, white to off-white powder, 
and sparingly soluble in water and ethanol. Citalopram (Celexa) is orally administrated tablet 
available as 10 mg, 20 mg, and 40 mg strength tablets contain 12.49 mg, 24.98 mg, and 49.96 
mg of citalopram hydrobromide, respectively. Citalopram has a molecular weight of 405.35, and 
molecular formula is C20H22BrFN2O.11 
Morphine sulfate tablet is an opioid agonist indicated for the management of moderate-severe 
acute and chronic pain. It is available in 15 mg and 30 mg for oral administration. Morphine 
sulfate USP is a white to off-white crystalline powder or a fine white to light yellow powder, it is 
soluble in water and slightly soluble in alcohol but is practically insoluble in chloroform or ether. 
Morphine sulfate has a molecular weight of 668.80, and molecular formula is 
C34H40N2O10S.12 


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Placebo solution will be supplied by the clinical site.  
4.8.3 Management of Clinical Supplies 
4.8.3.1 Study Drug Packaging and Storage 
The active study drugs will be obtained from commercial sources. Storage instructions for the 
active study drugs are as follows: 
x Cannabidiol solution should be stored at 20° to 25°C (68° to 77°F) with excursions 
permitted from 15° to 30°C (59° to 86°F). Do not refrigerate or freeze. Use within 12 
weeks of first opening the bottle, then discard any remainder.2 
x Citalopram tablets should be stored at 25°C (77°F) with excursions permitted from 15° to 
30°C (59° to 86°F).11 
x Morphine tablets should be stored at 20° to 25°C (68° to 77°F) and protected from 
moisture.12 
Placebo solution will be supplied by the clinical site and stored per USP requirements. 
4.8.3.2 Study Drug Accountability 
Good clinical documentation practices will be employed to record the receipt, storage conditions, 
accountability, and use or return of the study drug. The study drug will be stored in a secure 
location with access to the study personnel who will be managing the storage, dispensing, and 
accountability of the study drug. 
Upon completion or termination of the study, final accountability review by the study monitor, 
and written authorization from the sponsor, all unused and/or partially used study drug should be 
returned or destroyed at the study clinic. It is the investigator’s responsibility to ensure that the 
sponsor has provided written authorization for study drug disposal, the disposal process follows 
the study clinic’s standard operating procedures, and appropriate records of the disposal are 
documented and maintained. No unused study drug may be disposed until fully accounted for by 
the study monitor (or designee). Documentation of unused study drug should include subject 
number, medication identity (medication #, period #), date, and quantity of study drug used. 
4.8.4 Blinding 
Part 1 of the study will be double-blind, and the blind will be maintained through a 
randomization schedule held by the dispensing pharmacist. The pharmacist (and designated staff 
member responsible for confirmation of study drug dose) will be unblinded to subject treatment 
assignment; however, the pharmacist will not perform any study procedures other than study 
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Additional details regarding blinding can be found in the Spaulding Blinding SOP which will be 
followed to ensure the blind is maintained throughout the study. 
4.8.4.1 Breaking the Blind 
The study drug blind will not be broken by the investigator or designee unless information 
concerning the study drug is necessary for the medical treatment of the subject. For unblinding a 
subject, the randomization information for unblinding can be obtained by contacting the 
dispensing pharmacist. The sponsor or medical monitor must be notified immediately if the study 
drug blind is broken. The date, time, and reason that the blind was broken will be recorded in the 
source documents. If the blind is broken by the investigator or designee, the study drug must be 
stopped immediately, and the subject must be withdrawn from the study. Data or specimens 
already collected from subjects who discontinue prematurely and for whom the blind is broken 
will be made available for analysis if needed. 
4.8.5 Treatment Compliance 
For in-house visits, all doses of the study drug will be administered in the study clinic either 
under direct observation of or administered by clinic personnel and recorded in the eCRF. If a 
subject vomits after dosing, the event will be documented as an AE. For outpatient days, subjects 
will be contacted daily by clinical site staff regarding dosing and reminded to consistently take 
the study drug approximately 30 minutes after the start of breakfast and dinner. For out-patient 
visits or second check-in days, an inventory of study drug consumed and study drug remaining 
will be completed. 
4.8.6 Prior and Concomitant Medications 
Subjects are prohibited from using any prescription or nonprescription drugs (including aspirin 
or NSAIDs and excluding  contraceptives) within 14 days or 5 half-lives (whichever is longer), 
or complementary and alternative medicines within 28 days before the first dose of study drug. 
This includes prescription or nonprescription ophthalmic drugs. Note the only drugs permitted 
are contraceptives. Subjects will be asked if they have used any of medication and their 
responses will be recorded on the eCRF. 
Subjects are also prohibited from currently participating in another clinical study of an 
investigational drug and may not have been treated with any investigational drug within 30 days 
or 5 half-lives (whichever is longer) of the compound. 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. During the study, low dose acetaminophen or 
ibuprofen may be allowed with investigator's approval for minor symptoms. 
4.8.7 Subject Restrictions 
Subjects are not allowed to use nicotine containing products (e.g., cigarettes, cigars, chewing 
tobacco, snuff, electronic cigarettes) within 6 weeks before Screening. In addition, subjects are 


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not allowed to ingest alcohol, xanthine containing products (e.g., tea, coffee, chocolate, cola), 
caffeine, kava melatonin, St Johns Wart, grapefruit, or grapefruit juice within 24 h of check-in of 
all study periods. Subject must refrain from ingesting alcohol, xanthine containing products (e.g., 
tea, coffee, chocolate, cola), caffeine, kava melatonin, St Johns Wart, grapefruit, or grapefruit 
juice throughout the entire study. Subjects are not allowed to use aspirin or NSAIDs within 
14 days before the first dose of study drug. Subjects will be asked if they have used any of these 
substances and their responses will be recorded on the eCRF. 
Subjects must be able to tolerate a controlled, quiet study conduct environment, including 
avoidance of music, television, movies, games, and activities that may cause excitement, 
emotional tension, or arousal during prespecified times throughout the duration of the study. 
Subjects must be willing to comply with study rules; attempting to void at specified times; 
remaining quiet, awake, undistracted, motionless, and supine during specified times; and 
avoiding vigorous exercise as directed throughout the duration of the study. 
A fasting period of at least 4 hours will be required before all time points when clinical 
laboratory samples will be obtained. In Part 1, all subjects will fast overnight for a minimum of 8 
hours (no food or fluid except water) before blood collection for lipid testing on check-out days 1 
and 29. Standardized meals will be served at consistent times relative to dosing for in-house 
days, and no food or fluids will be served containing caffeine. Outside of mealtimes, the subjects 
will only be allowed to intake water, which will be available ad libitum. Due to current 
precautions being taken for COVID-19, the following restrictions will be in place: 
x Subjects should be encouraged to wear masks except when in a private room without anyone 
else present or for a limited time for a study procedure (e.g., study drug administration or 
eating) when instructed by staff.  
x Subjects must practice social distancing, which will include having a maximum of 2 subjects 
per room for overnight stays and access to common areas will be per clinical research site 
standards. While subjects are in house, meals will be served per clinical research site 
standards. Subjects will spend most of their time in their rooms except for specified times for 
walking in the halls (with masks recommended). 
x Subjects must practice regular handwashing with soap and water, scrubbing hands for at least 
20 seconds or with approved hand sanitizer as supplied by study staff.  
Designated isolation rooms will be set up to segregate any participant(s) that develop any 
symptoms of concern while housed in the unit and COVID-19 testing will be done when deemed 
necessary by the Investigator. If new information becomes available, there could be other 
precautions that lead to additional restrictions that will be documented in the COVID-19 Risk 
Management Plan and/or the study specific COVID-19 Procedure Plan. 
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4.9.1 Sample Size 
A total of 240 healthy subjects are planned for enrollment and approximately 190 of these will be 
administered CBD. The primary endpoint is the percentage of CBD administered participants 
with an ALT (based on consensus criteria*) or AST liver enzyme elevation greater than three 
times the ULN.  Assuming the true event rate is 6%, the study has 95% probability of observing 
5 or more events with ALT or AST liver enzyme elevation greater than three times the ULN. 
Assuming the true observed drug-induced liver injury event rate is 2%, the study has a 93% 
percent probability of observing 1 or more event. 
In Part 1, change from baseline comparisons will be performed for various endocrine laboratory 
measures (e.g., total testosterone, inhibin B, TSH, total T3, and free T4). Sample size for the 
study is not powered for any of these comparisons nor are any adjustments planned for 
multiplicity.  
In Part 2, comparisons will be performed on changes in exposure for two different substrate 
drugs following administration with CBD. Assuming no more than 20% discontinuations per 
arm, 30% intra-subject variability, and a two-sided test at the 0.05 significance level, the sample 
size would have 90% power to detect a 30% difference in exposure when the substrate drugs are 
co-administered with CBD.  
4.9.2 Analysis Populations 
Part 1 
The liver safety analysis population will include all subjects who receive at least 1 dose of any of 
the study drugs and have liver lab data (ALT and AST) for the treatment period collected before 
dosing and at 1 or more time points after dosing. The liver safety analysis population will be 
used for all liver safety analyses. 
The laboratory analysis population will include subjects that have laboratory/proteomics 
measures (e.g., free and total testosterone, inhibin B, TSH, total T3, free T4, lipid panel, 
proteomics) from pre-dose on Day 1 and check-out on Day 29 (time-matched to Day 1). The 
laboratory population will be used for all analyses involving change from baseline in 
laboratory/proteomics measures.  
The safety population will include all subjects who receive at least 1 dose of the study drug. 
Part 2 
The PK population will include all subjects who receive the study drug and have at least 1 
estimable PK parameter after dosing with the substrate drug alone and with the substrate drug in 
combination with CBD.  
The safety population will include all subjects who receive at least 1 dose of the study drug. 
4.9.3 General Statistical Considerations 


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All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of summary 
statistics. Demographic and baseline characteristics will be summarized overall and by treatment 
for all subjects. 
4.9.4 Subject Disposition 
The number of subjects who enroll in the study and the number and percentage of subjects who 
complete each assessment will be presented. The frequency and percentage of subjects who 
withdraw or discontinue from the study and the reason for withdrawal or discontinuation will be 
summarized. 
4.9.5 Demographics and Baseline Characteristics 
Descriptive statistics will be used to summarize demographic and baseline subject 
characteristics. For continuous variables, the mean, median, standard deviation (SD), minimum, 
and maximum values will be reported. For categorical (nominal) variables, the number and 
percentage of subjects (or observations) will be reported. 
4.9.6 Primary and Secondary Analyses 
Part 1 
The primary endpoint is the percentage of subjects with an ALT (based on consensus criteria) or 
AST liver enzyme elevation greater than three times the upper limit of normal (ULN). Results 
will be reported as percentage with a 95% confidence interval.  The secondary liver endpoint is 
the percentage of participants meeting withdrawal criteria for potential drug-induced liver injury. 
Analysis and reporting will be performed similar to the primary endpoint. 
Secondary endpoints involving laboratory measures will include the changes from baseline in 
serum total testosterone and inhibin B in males after CBD administration compared to placebo. 
Change from baseline in thyroid stimulating hormone, total T3, and free T4 in both males and 
females after CBD administration compared to placebo will also be assessed. These analyses will 
use a mixed-effect analysis approach. The model will include treatment as fixed effects and 
subject as a random effect. Testing will be two-sided, and a significant increase will be 
concluded if the two-sided 95% CI excludes 0. In addition, the percentage of subjects with either 
abnormal total testosterone (males only) or abnormal laboratory tests will also be reported. 
Results will be presented as point estimates with associated 95% CI. 
Part 2 
The primary analysis for Part 2 will be a comparison of the area under the plasma concentration-
time curve (AUC) and Cmax of citalopram or morphine when administered alone versus when co-
administered with CBD (for morphine, this will include after co-administration with CBD for 1-
day and 7-days). The PK parameters (AUC and Cmax) will be analyzed using noncompartmental 
methods based on actual sampling times. Using linear mixed-effects modeling, comparisons of 


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log-transformed PK parameters will be performed. Treatment will be a fixed effect. Subject will 
be included as a random effect on the intercept. Treatment differences on the log-scale will be 
estimated for the PK parameters. Geometric mean ratio and 90% CI will be obtained by 
exponentiation of the treatment effect and 90% CI based on the log-transformed scale.  
For the secondary PK endpoints, AUC and Cmax for morphine metabolites (alone and when co-
administered with CBD) will be analyzed using the same approach as the primary PK endpoints. 
4.9.6.1 Additional Analyses 
Part 1 
Assessment of liver-related adverse events will be performed consistent with FDA’s Guidance 
for Industry on Drug-Induced Liver Injury: Premarketing Clinical Evaluation. This will include 
but is not limited to the following categorical and visual summaries: 
x 3x-, 5x-, 10x-, and 20x ULN elevations of AST, ALT, and either ALT or AST. 
x Any elevations of bilirubin; elevated TBL to >2x ULN. 
x Any elevations of ALP >1.5xULN. 
x Elevation of ALT or AST (>3x ULN) accompanied by elevated bilirubin (>1.5x ULN, 
>2x ULN). 
x Elevation of ALT or AST in temporal association with nausea, vomiting, anorexia, 
abdominal pain, or fatigue. 
Portions of collected blood samples from this study will be used for evaluating laboratory 
measures and differentially expressed plasma proteins. Additional details regarding the methods 
for the exploratory analyses will be described in a separate protocol. Steady state CBD and 
metabolite drug concentrations will be summarized by visit using descriptive statistics. 
Part 2 
Additional exploratory PK parameters for citalopram, morphine, CBD, and metabolites, such as 
time of maximum concentration, half-life, apparent clearance, and apparent volume of 
distribution will be analyzed using noncompartmental methods based on actual sampling times. 
All parameters will be calculated using statistical software. Mean and individual concentration 
time profiles will be presented in graphs. 
4.9.10 Safety Analyses 
 
4.9.10.1 Adverse Events 
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities. The incidence of TEAEs, organized by system organ class and frequency, will be 


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summarized by seriousness, severity, relationship to treatment, and by treatment at onset of the 
TEAE. A detailed listing of serious AEs and TEAEs leading to withdrawal will also be provided. 
 
4.9.10.2 Clinical Laboratory Tests 
Clinical laboratory results will be reviewed by the investigator or designee together with data in 
the eCRF. Any values outside the reference range will be evaluated for clinical significance. If a 
value is determined to be clinically significant, the subject will be instructed to follow up with 
his or her personal physician. The investigator or designee may repeat the clinical laboratory 
tests if deemed appropriate. The investigator will maintain a copy of the laboratory accreditation 
and the reference ranges for the laboratory used. 
Clinical laboratory results (hematology, serum chemistry, and urinalysis) will be summarized 
using descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum). 
Clinical laboratory results will be classified as normal or abnormal, according to the reference 
ranges of the individual parameter. The number and percentage of subjects with abnormal 
laboratory results will be provided. No statistical testing will be performed on clinical laboratory 
data. 
 
4.9.10.3 Vital Sign Measurements 
Vital sign measurements and changes from baseline will be summarized using descriptive 
statistics (number of subjects, mean, SD, minimum, median, and maximum) by treatment and 
time points as specified in Section 4.7.3.3. 
  
4.9.10.4 Safety 12-lead Electrocardiograms  
12-lead ECGs will be obtained with the subjects in the supine position for a minimum of 10 
minutes before recording. ECGs will be overread by a physician or other trained clinical team 
staff. If an abnormality is observed, the subject will be instructed to follow up with his or her 
personal physician. 
 
4.9.10.5 Physical Examinations 
 Physical examination findings will be presented in a data listing, and abnormal physical 
examination findings will be recorded as AEs. 
 
4.9.10.6 Other Safety Data 
All concomitant medication usage and medications that changed in daily dose, frequency, or 
both since the subject provided informed consent will be summarized for each subject. 
4.9.11 Interim Analyses 
No interim analyses are planned. 
4.9.12 Missing Data 


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Missing data will not be imputed. Data that are excluded from the descriptive or inferential 
analyses will be included in the subject data listings. This will include data from subjects not in 
the particular analysis population, measurements from unscheduled visits, or extra measurements 
that may arise from 2 or more analyses of the biofluid sample at the same time point. Details on 
the handling of missing data will be further described in the Statistical Analysis Plan (SAP). 
4.10 Data Quality Assurance 
Completed eCRFs are required for each subject randomly assigned to treatment. Electronic data 
entry will be accomplished through the ClinSpark® remote electronic data capture system, which 
allows for on-site data entry and data management. This system provides immediate, direct data 
transfer to the database, as well as immediate detection of discrepancies, enabling site 
coordinators to resolve and manage discrepancies in a timely manner. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and subsequently any investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records. 
 
Furthermore, the investigator retains full responsibility for the accuracy and authenticity of all 
data entered into the electronic data capture system. The completed dataset and their associated 
files are the sole property of the sponsor and should not be made available in any form to third 
parties, except for appropriate governmental health or regulatory authorities, without written 
permission of the sponsor. 
4.11 Data Sharing 
De-identified subject-level data may be released to other researchers (including through a data 
warehouse or as a part of a publication) to enable secondary research. Additional secondary 
research may also be performed by the sponsor. 
5. ETHICAL CONSIDERATIONS 
5.1 Ethical Conduct of the Study 
This study will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human subjects adopted by the 18th World Medical Association 
General Assembly, Helsinki, Finland, 1964 and later revisions, as well as United States Title 45 
Code of Federal Regulations (CFR) Part 46 GCP, and International Council for Harmonisation 
(ICH) guidelines describing technical requirements for registration of pharmaceuticals for human 
use. 
5.2 Institutional Review Board (IRB) 
The FDA Project Lead or investigator will provide the designated IRB with all required 
documents, including the study protocol and informed consent form. The study will not be 
initiated until appropriate IRB approval is obtained from the designated IRB. The investigator 


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will provide the FDA Project Lead with copies of the approval documents for the protocol, 
informed consent form, and all recruiting materials. The designated IRB will also receive copies 
of any original or amended information sheets or pamphlets given to the study subject in support 
of the informed consent process and any advertisements or other recruitment material. Such 
materials will not be employed in the study before approval by the designated IRB. 
 
Subjects will be informed that they have the right to contact the IRB or Office for Human 
Research Protections if they have any questions, concerns, complaints, or believe they have been 
harmed by the participation in this research study as a result of investigator negligence. Subjects 
will be given the address and phone number of the IRB. 
6. ADMINISTRATIVE PROCEDURES 
6.1 Responsibilities of the Investigator  
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes may be reported to the IRB but 
will not result in protocol amendments. 
6.1.1 Form FDA 1572 
The investigator will complete and sign the Form FDA 1572. 
6.1.2 Adherence to Protocol  
The investigator agrees to conduct the study as outlined in this protocol in accordance with the 
ICH E6(R2) and all applicable guidelines and regulations. 
6.1.3 Reporting Requirements 
 
By participating in this study, the investigator agrees to submit reports of SAEs according to the 
timeline and method outlined in the protocol. In addition, the investigator agrees to submit 
reports to the IRB as appropriate. The investigator also agrees to provide the sponsor with an 
adequate report shortly after completion of the investigator’s participation in the study. 
6.1.4 Source Documentation 
By participating in this study, the investigator agrees to maintain adequate case histories for the 
subjects treated as part of the research under this protocol. The investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories. 
6.1.5 Retention of Records  
The investigator agrees to keep the records stipulated in this protocol and those documents that 
include (but are not limited to) the study-specific documents, identification log of all 


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participating subjects, medical records, source worksheets, all original signed and dated informed 
consent forms, subject authorization forms regarding the use of personal health information (if 
separate from the informed consent form), copies of all eCRFs, query responses, and detailed 
records of drug disposition, to enable evaluations or audits from regulatory authorities, the 
sponsor, or its designees. 
Furthermore, ICH 4.9.5 requires the investigator to retain essential documents specified in 
Section 8 of ICH E6(R2) until at least 2 years after the last approval of a marketing application 
for a specified drug indication being investigated or, if an application is not approved, until at 
least 2 years after the investigation is discontinued and regulatory authorities are notified. In 
addition, ICH 4.9.5 states that the study records should be retained until an amount of time 
specified by applicable regulatory requirements or for a time specified in the clinical study site 
agreement between the investigator and sponsor. 
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
6.1.6 Financial Disclosure and Obligations 
The investigator is required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
45 CFR 46. In addition, the investigator must provide to the sponsor a commitment to update this 
information promptly if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
Neither the sponsor nor the study clinic is financially responsible for further testing or treatment 
of any medical condition that may be detected during the screening process. 
6.2 Confidentiality and Disclosure of Data 
All subjects will sign a HIPAA compliant authorization form containing the mandated core 
elements and requirements before participation in this clinical study. The sponsor and designees 
affirm and uphold the principle of the subject’s right to protection against invasion of privacy. 
Throughout this study, a subject’s source data will only be linked to the sponsor’s electronic data 
capture system database or documentation via a unique identification number. As permitted by 
all applicable laws and regulations, limited subject attributes such as gender, age or date of birth, 
and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires that the investigator allow review of the subject’s original medical records 
(source data or documents) by the study monitor, representatives from any regulatory authority 
(e.g., FDA), the sponsor’s designated auditors, and the appropriate IRB. These medical records 
will include, but will not be limited to, clinical laboratory test result reports, ECG reports, 


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admission and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process. 
Copies of any subject source documents that are provided to the sponsor must have personally 
identifiable information removed (i.e., subject name, address, and other identifier fields not 
collected in the subject’s eCRF). 
Data will be maintained and backed up in the electronic data capture system. All access to the 
data is protected by username and password, and each staff member and all sponsor staff will 
have separate access that requires a separate username and password. Access is only given to site 
staff and requested sponsor staff who have completed the appropriate training. 
6.3 Subject Consent 
Written informed consent in compliance with 45 CFR 46 will be obtained from each subject 
before entering the study or performing any unusual or nonroutine procedure that involves risk to 
the subject. An informed consent template may be provided by the sponsor to the study clinic. If 
any institution-specific modifications to study related procedures are proposed or made by the 
study clinic, the consent should be reviewed by the sponsor or its designee or both before IRB 
submission. Once reviewed, the consent will be submitted by the investigator to the IRB for 
review and approval before the start of the study. If the informed consent form is revised during 
the course of the study, all active participating subjects must sign the revised form. 
Before enrollment, each prospective subject will be given a full explanation of the study and be 
allowed to read the approved informed consent form. The informed consent process will be 
performed by a clinical research nurse in a private room. The subject will be given unlimited 
time to ask questions regarding study participation, and each subject will be questioned to ensure 
their understanding. Once the investigator is assured that the subject understands the implications 
of participating in the study, the subject will be asked to give consent to participate in the study 
by signing the informed consent form. 
The investigator will provide a copy of the signed informed consent form to the subject. The 
original form will be maintained in the subject’s medical records at the site. 
6.4 Data Collection 
Full details of procedures for data collection and handling will be documented in the data 
management plan, which is initiated with the final protocol receipt. The data management plan is 
a changing document that evolves over the course of the study and is finalized by database lock. 
6.5 Publications 
No information related to or generated by this study will be released to the public until it has 
been reviewed by the sponsor. The sponsor shall own intellectual rights for the data and analysis 


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resulting from this study. Authorship on publications will be determined by standard journal 
requirements. 
7. STUDY MANAGEMENT 
7.1 Monitoring 
The sponsor or its designee will monitor the study to ensure that it is being conducted according 
to the protocol, GCP standards, and applicable region-specific requirements, and to ensure that 
study initiation, conduct, and closure are adequate. The investigators and the study clinic staff 
will be expected to cooperate fully with the study monitors and personnel or agents of the 
sponsor and be available during monitoring visits to answer questions sufficiently and to provide 
any missing information. The investigators and their institutions will permit direct access to 
source data/documents for study related monitoring activities, audits, IRB reviews, and 
regulatory inspections. 
During any on-site visits, the study monitor will:  
x Check and assess the progress of the study 
x Review all informed consent forms 
x Review study data collected 
x Conduct source document verification 
x Identify any issues and address their resolution 
x Verify that the facility remains acceptable 
x Conduct study drug accountability 
These monitoring activities will be done in order to verify that the:  
x Data are authentic, accurate, and complete. 
x The safety and rights of the subjects are being protected. 
x The study is being conducted in accordance with the currently approved protocol (including 
any amendments), GCP, and all applicable regulatory requirements. 
In addition, the sponsor, designated auditors, and government inspectors must be allowed access 
to eCRFs, source documents, and other study files that may be required to evaluate the conduct 
of the study. 
7.2 Management of Protocol Amendments and Deviations 


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7.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent immediate 
hazard to the subject, must be submitted to the sponsor or designee and reviewed and approved 
by the local IRB before implementation. Amendments to the protocol must be submitted in 
writing to the investigator’s IRB for approval before subjects are enrolled into an amended 
protocol. 
7.2.2 Protocol Violations and Deviations 
Any significant protocol deviations that the investigator or study clinic staff believes are of major 
importance (e.g., incorrect randomizations, subject enrolled but not eligible) should be reported 
to the sponsor and the investigator’s IRB as soon as possible. Significant protocol deviations 
may include the following: 
x Deviations from the inclusion/exclusion criteria that may affect subject safety 
x Deviations (omission or delay) of safety monitoring procedures 
x Deviations in the administration of the study drug 
x Deviations in obtaining informed consent 
All subjects who are enrolled and receive the study drug, regardless of whether they have a 
major protocol violation, must continue to be followed for safety for all follow-up study visits. 
 


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Reference list 
1. U.S. Food and Drug Administration (FDA) Science Board. (2022, June 3). Background 
materials for the June 14, 2022 meeting of the Science Board to the FDA. Retrieved from 
https://www.fda.gov/advisory-committees/advisory-committee-roster/science-board-
fda/2022-meetings#event-materials. 
2. Cannabidiol (Epidiolex ®) oral solution label obtained from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf 
3. Lo, LA, Christiansen, A, Eadie, L, Strickland, JC, Kim, DD, Boivin, M, et al. 
Cannabidiol-associated hepatotoxicity: A systematic review and meta-analysis. J Intern 
Med. 2023; 293: 724–752. 
4. Crippa JAS, Zuardi AW, Guimarães FS, et al. Efficacy and Safety of Cannabidiol Plus 
Standard Care vs Standard Care Alone for the Treatment of Emotional Exhaustion and 
Burnout Among Frontline Health Care Workers During the COVID-19 Pandemic: A 
Randomized Clinical Trial. JAMA Netw Open. 2021;4(8):e2120603. 
doi:10.1001/jamanetworkopen.2021.20603 
5. U.S. Food and Drug Administration (FDA). Clinical Pharmacology and 
Biopharmaceutics Review. Retrieved from 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000ClinPharm
R.pdf 
6. EFSA NDA Panel (EFSA Panel on Nutrition, Novel Foods and Food Allergens), Turck, 
D, Bohn, T, Castenmiller, J, De Henauw, S, Hirsch-Ernst, KI, Maciuk, A, Mangelsdorf, I, 
McArdle, HJ, Naska, A, Pelaez, C, Pentieva, K, Siani, A, Thies, F, Tsabouri, S, Vinceti, 
M, Cubadda, F, Frenzel, T, Heinonen, M, Marchelli, R, Neuhäuser-Berthold, M, Poulsen, 
M, Prieto Maradona, M, Schlatter, JR, Trezza, V, van Loveren, H, Albert, O, Dumas, C, 
Germini, A, Gelbmann, W, Kass, G, Kouloura, E, Noriega Fernandez, E, Rossi, A and 
Knutsen, HK, 2022. Statement on safety of cannabidiol as a novel food: data gaps and 
uncertainties. EFSA Journal 2022; 20(6):7322, 25 pp. 
https://doi.org/10.2903/j.efsa.2022.7322 
7. Carvalho, RK, Andersen, ML, Mazaro-Costa, R. The effects of cannabidiol on male 
reproductive system: A literature review. J Appl Toxicol. 2020; 40: 132–150. 
https://doi.org/10.1002/jat.3831 
8. Tallon, MJ, Child, R. Subchronic oral toxicity assessment of a cannabis extract. 
Regulatory Toxicology and Pharmacology. 2023; 144. 
https://doi.org/10.1016/j.yrtph.2023.105496. 
9. Anderson, LL, Doohan, PT, Oldfield, L, Kevin, RC, Arnold, JC, Berger, M, Amminger, 
PG, McGregor, IS. Citalopram and Cannabidiol: In Vitro and In Vivo Evidence of 
Pharmacokinetic Interactions Relevant to the Treatment of Anxiety Disorders in Young 


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People. Journal of Clinical Psychopharmacology. 41(5):p 525-533, DOI: 
10.1097/JCP.0000000000001427 
10. Armstrong, SC, Cozza, KL. Pharmacokinetic Drug Interactions of Morphine, Codeine, 
and Their Derivatives: Theory and Clinical Reality, Part I. Psychosomatics. 2003, 
44:2:167-171. https://doi.org/10.1176/appi.psy.44.2.167. 
11. Citalopram (Celexa ®) tablet label obtained from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020822s041lbl.pdf 
12. Morphine Sulfate tablet label obtained from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022207s010lbl.pdf 
13. Iannone LF, Arena G, Battaglia D. Results From an Italian Expanded Access Program on 
Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox-Gastaut 
Syndrome. Front Neurol. 2021 May 20;12:673135. doi: 10.3389/fneur.2021.673135. 
14. Sharbaf Shoar N, Fariba KA, Padhy RK. Citalopram. StatPearls 
https://www.ncbi.nlm.nih.gov/books/NBK482222/ 
15. Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, Hunt CM, 
Wilke RA, Avigan M, Kaplowitz N, Bjornsson E, Daly AK. Case definition and 
phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011 
Jun;89(6):806-15. doi: 10.1038/clpt.2011.58. Epub 2011 May 4. PMID: 21544079. 
16. Arnold JC, McCartney D, Suraev A, McGregor IS. The safety and efficacy of low oral 
doses of cannabidiol: An evaluation of the evidence. Clin Transl Sci. 2023 Jan;16(1):10-
30. doi: 10.1111/cts.13425. Epub 2022 Oct 19. PMID: 36259271 
 
 
  
 
 
 
 


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8. APPENDICES
Appendix A – Schedule of Events – Part 1


 
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Appendix B – Schedule of Events – Part 2.1 (Citalopram)


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Appendix B – Schedule of Events – Part 2.2 (Morphine) 


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Appendix C – List of Abbreviations 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
Ag/Ab 
antigen/antibody 
AUC 
area under the concentration time curve  
BID 
twice daily 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease of 2019 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HepC 
hepatitis C 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kel 
elimination rate 
Kg 
kilogram 
LH 
Luteinizing Hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
milligram 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PD 
PVD 
Pharmacodynamic 
Pharmacovigilance Department  
PK 
pharmacokinetic 
QA 
quality assurance 
QD 
once daily 
QTc 
heart rate-corrected QT interval 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOP 
standard operating procedure 
t1/2TEAE 
terminal half-life treatment-emergent adverse event 
 


 
 
Appendix D – Drug-Induced Liver Injury Assessment 
The threshold criteria for definition of a case DILI as well as the severity grading score 
are listed below15. 
Definitions for DILI include one of the following thresholds: 
i) 
 5 × ULN elevation in ALT (ULN for ALT is 33 U/L for males and 25 
U/L for females) OR 
ii) 
 2 × ULN elevation in ALP (with accompanying elevations of 
GGT in the absence of known bone pathology driving the rise in 
ALP level) OR 
iii) 
 3 × ULN elevation in ALT and simultaneous elevation of bilirubin 
concentration exceeding 2 × ULN 
Severity grading of DILI based on the International DILI Expert Working Group’s 
severity index (4-point scale): 
1. Mild: ALT  5 × ULN or ALP  2 × ULN and TBL < 2 × ULN 
2. Moderate: ALT  5 × ULN or ALP  2 × ULN and TBL  2 × ULN, or 
symptomatic hepatitis 
3. Severe: ALT  5 × ULN or ALP  2 × ULN and TBL  2 × ULN, and 
symptomatic hepatitis and 1 of the following criteria: 
- 
,15 
- Ascites and/or encephalopathy, disease duration < 26 weeks, and 
absence of underlying cirrhosis 
- 
Other organ failure due to DILI 
4. Fatal/transplantation: Death or liver transplantation due to DILI 
 
 
 
 
 
 
 
 


 
 
Appendix E – Protocol Revision History 
PROTOCOL REVISION HISTORY 
Protocol 
Number 
Version 
Effective 
Date 
Summary of Changes 
SCR-016 
1.0 
08 December 
2023 
1. Developed initial protocol 
SCR-016 
2.0 
21 December 
2023 
1.  Typographical changes made throughout the 
protocol. 
2. Principal investigator updated to Dr. Melanie 
Fein, MD.  
3. Part 1 exploratory endpoint added: “Summary 
of CBD and metabolite pharmacokinetics.” 
4. Part 2 exploratory endpoint added: “PK 
parameters for CBD and metabolites.”  
5. For Key Exclusion Criteria #1, the threshold for 
International Normalized Ratio (INR) changed 
from 1.27 to 1.3.  
6. For section 3.1: 
x Part 1 exploratory endpoint removed 
“Change from baseline in additional 
laboratory tests after CBD administration 
compared to placebo.”  
7. For section 4.1.1 Risk/Benefit: 
x The following text removed: “For AEs, 
acetaminophen 1000 mg q8 hours, as 
needed, will be provided.”  
8. For section 4.2.2: 
x exclusion criteria #8 updated to “Subject 
has a positive test result for alcohol or 
drugs of misuse (amphetamines, 
barbiturates, benzodiazepines, cocaine, 
alcohol, opiates, phencyclidine, 


 
 
Protocol 
Number 
Version 
Effective 
Date 
Summary of Changes 
propoxyphene, and methadone) at 
Screening or Check-in (Day -1 [both 
Parts]; Day 10 [morphine DDI]; Day 12 
[citalopram DDI]).”  
9. For section 4.2.2: 
x exclusion criteria #9, added “Day –1” 
10. For sections 4.5 Criteria for Subject 
Withdrawal and 4.7.3.2.1 Assessment and 
Reporting of Potential Cases of Drug-Induced 
Liver Injury: 
x The following language added “When 
subject withdrawal occurs due to potential 
Drug-Induced Liver Injury (DILI), the 
study drug will be discontinued, and 
monitoring will still be continued to 
document subsequent liver test results and 
resolution of biochemical abnormalities.”  
x Follow-up liver assessment timing 
changed from to “24 to 48 hours.”  
x Language added: “These follow-up steps 
are outlined in more detail in Supplement 
A: LFT Elevation Evaluation.”  
11. For section 4.5.1 Handling of Withdrawals, 
removed, “Any data and samples collected before 
subject withdrawal will become the property of 
the sponsor.” 
12. For sections 4.6.3 Screening and 4.6.4.1 
Check-In (Day -1):  
x “Cannabinoids (THC)” added to list of 
drugs screened for.  
x Added the following testing language: 
“Perform FSH assessment 


 
 
Protocol 
Number 
Version 
Effective 
Date 
Summary of Changes 
(postmenopausal [i.e., spontaneous 
amenorrhea for at least 12 months] female 
subjects only).”      
13. For section 4.6.4.1 Check-in (Day –1) and Part 
1 SOE, complete physical exam changed to 
targeted physical exam and a weight collection 
added to list of assessments. 
14.  For section 4.7.2 Lipid Assessments, added 
“Lipid assessments will include total cholesterol, 
LDL, HDL, and triglycerides.”  
15. For section 4.8.7 Subject Restrictions and 
4.2.2 Exclusion criteria, kava melatonin and St 
Johns Wart added to list of exclusion criteria and 
restricted supplements.   
16. For section 4.9.2 Analysis Populations, added 
the following language: 
x “...with the substrate drug alone and with 
the substrate drug in combination with 
CBD.” 
17. For section 4.9.6 Additional Analyses, added: 
x “...the following categorical and visual 
summaries.” 
x “Steady state CBD and metabolite drug 
concentrations will be summarized by visit 
using descriptive statistics.” 
18. Appendix B updated to accurately reflect 
events. 
SCR-016 
3.0 
19th March 
2024 
1. For synopsis and section 4.1 Study Design, 
added the language “…to remind subjects 
regarding their requirements for…” 


 
 
Protocol 
Number 
Version 
Effective 
Date 
Summary of Changes 
2. For section 4.2.1 Inclusion Criteria, added 
“Day -1” to inclusion number 2 and 4. 
3. For section 4.2.2 Exclusion Criteria, exclusion 
#1 was updated to include “screening or 
check-in (Day -1)” and #12 was further 
updated to add “a diagnosis of COVID-19” 
4. For section 4.2.2 Exclusion Criteria, exclusion 
#16 added “Uncomplicated cholecystectomies 
and appendectomies may be included at the 
investigator’s discretion.” 
5. For section 4.2.2 Exclusion Criteria, blood 
pressure values updated to the following: 
“Subject has a mean systolic blood pressure 
<85 or >145 mmHg or a mean diastolic blood 
pressure <45 or >95 mmHg at either Screening 
or Check-in.   
6. For section 4.6.4.2 Treatment, “Collect whole 
blood sample for pharmacogenetic testing 
(Only Part 2)” was added and removed from 
4.6.4.1 Check-in 
7. For section 4.6.4.2 Treatment, added 
“Administration of study drug [Part 1: clinic 
visits and Day 28, Part 2: Day 12 (citalopram) 
and Day 10 (morphine)] can occur prior to 
review of safety labs.” 
8. For section 4.7.1.1 Pharmacokinetic Sample 
Collection “ Clinic visits may be completed 
outside of the listed visit day per investigator’s 
decision.” And “ All lab collections will take 
place predose and within 1 hour of mealtime” 
was added.  


 
 
 
Protocol 
Number 
Version 
Effective 
Date 
Summary of Changes 
9. For section 4.7.3.3 Vital Sign Measurements, 
added “Vital signs may be repeated at 
investigator discretion.” 
10. For section 4.8.6 Prior and Concomitant 
Medications, removed “oral” from “oral 
contraceptives” and added “During the study, 
low dose acetaminophen or ibuprofen may be 
allowed with investigator’s approval for minor 
symptoms.” 
11. For Appendix A and B Schedule of Events and 
Section 4.6.4.1, pharmacogenetic testing was 
removed 
12. For Appendix A and B Schedule of Events, 
“PCR” removed from Covid testing 


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SAP_001.pdf: 
Study Title: Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and 
Drug Interactions 
 
Document Title: Statistical Analysis Plan – Study No. SCR-016 
 
Document Date: 8 April 2024 
 
NCT Number: NCT06192589 


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 1 of 16 
 
 
Statistical Analysis Plan  
   
 
SCR-016 Clinical Study to Evaluate Cannabidiol Liver 
Enzyme Elevations and Drug Interactions    
 
Sponsor: 
U.S. Food and Drug Administration 
White Oak Building #64, Room 2072 
10903 New Hampshire Avenue 
Silver Spring, MD 20993   
Sponsor Study Lead: 
David Strauss, MD, PhD 
Director, Division of Applied Regulatory Science  
U.S. Food and Drug Administration 
Telephone: 301-796-6323 
Email: david.strauss@fda.hhs.gov 
Sponsor Medical 
Monitor: 
Keith Burkhart, MD 
U.S. Food and Drug Administration 
Telephone: 301-796-2226 
Email: keith.burkhart@fda.hhs.gov 
 
Project Manager: 
Jeffry Florian, PhD 
U.S. Food and Drug Administration  
Telephone: 301-796-4847 
Email: jeffry.florian@fda.hhs.gov  
 
Version of SAP: 
1.0 
Date of SAP: 
April 8, 2024 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed 
written consent of the U.S. Food and Drug Administration. 
 
 


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 2 of 16 
 
 
Sponsor Signatures Page 
 
Prepared by 
 
 
 
 
Pablo Salcedo, MD  
Pharmacokineticist  
Division of Applied Regulatory Science   
U.S. Food and Drug Administration 
 
 
 
Date 
 
 
 
 
Approved by 
Jeffry Florian, PhD 
Associate Director 
Division of Applied Regulatory Science 
U.S. Food and Drug Administration 
 
 
Date 
 
 
Pablo Salcedo -S
Digitally signed by Pablo Salcedo -S 
Date: 2024.04.08 16:35:18 -04'00'
Jeffry Florian -S
Digitally signed by Jeffry Florian -S 
Date: 2024.04.08 16:40:08 -04'00'


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 3 of 16 
 
 
Table of Contents 
Sponsor Signatures Page ..................................................................................................................2 
1 
Introduction ..............................................................................................................................5 
2 
Study Objectives ......................................................................................................................5 
2.1 
Part 1 ................................................................................................................................ 5 
2.2 
Part 2 (Drug Interactions) ................................................................................................. 5 
3 
Study Endpoints .....................................................................................................................5 
3.1 
Primary Endpoints ......................................................................................................... 5 
3.1.1 
Part 1 ............................................................................................................................ 5 
3.1.2 
Part 2 ............................................................................................................................ 5 
3.2 
Secondary Endpoints ...................................................................................................... 5 
3.2.1 
Part 1 ............................................................................................................................ 5 
3.2.2 
Part 2 ............................................................................................................................ 6 
3.3 
Exploratory Endpoints ................................................................................................... 6 
3.3.1 
Part 1 ............................................................................................................................ 6 
3.3.2 
Part 2 ............................................................................................................................ 6 
4 
Study Overview .......................................................................................................................6 
4.1 Study Design ............................................................................................................................6 
4.1.1 
Part 1 .................................................................................................................................6 
4.1.2 
Part 2 (Drug Interactions) ..................................................................................................7 
4.2 Sample Size ..............................................................................................................................9 
4.2.1 
Part 1 .................................................................................................................................9 
4.2.2 
Part 2 (Drug Interactions) ..................................................................................................9 
5 
Analysis Populations ................................................................................................................9 
5.1.1 
Part 1 .................................................................................................................................9 
5.1.2 
Part 2 ...............................................................................................................................10 
6 
Data Screening and Quality Assurance ...............................................................................10 
6.1 Missing Data ..........................................................................................................................10 
6.2 Data Quality Assurance ........................................................................................................11 
6.3 Data Sharing...........................................................................................................................11 


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 4 of 16 
 
 
7 
General Statistical Considerations ......................................................................................11 
7.1 Subject Disposition ...............................................................................................................11 
7.2 Demographic and Baseline Characteristics ........................................................................11 
7.3 Primary Analysis ..................................................................................................................12 
7.3.1 
Part 1 ...............................................................................................................................12 
7.3.2 
Part 2 (Drug Interactions) ...............................................................................................12 
7.4 Secondary Analyses ..............................................................................................................13 
7.4.1 
Part 1 ...............................................................................................................................13 
7.4.2 
Part 2 (Drug Interactions) ...............................................................................................13 
7.5 Exploratory Analyses ...........................................................................................................14 
7.5.1 
Part 1 ...............................................................................................................................14 
7.5.2 
Part 2 (Drug Interactions) ...............................................................................................15 
8 
Safety Analyses .....................................................................................................................15 
8.1.1 
Adverse Events ..............................................................................................................15 
8.1.2 
Clinical Laboratory Tests (Other Than Specified in Planned Analyses) ...................16 
8.1.3 
Vital Sign Measurements (Other Than Specified in Planned Analyses) ....................16 
8.1.4 
Safety 12-lead Electrocardiograms ..............................................................................16 
8.1.5 
Physical Examinations ..................................................................................................16 
8.1.6 
Other Safety Data ...........................................................................................................16 
9 
References ..............................................................................................................................16 
 
 
 


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 5 of 16 
 
 
1 Introduction 
This document outlines the proposed statistical methods for data analysis of data collection from 
Protocol ‘SCR-016 Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and Drug 
Interactions.’ 
2 Study Objectives 
2.1 Part 1 
x To characterize the effects of daily cannabidiol (CBD) use at a dose within the range of 
what consumers are taking as unapproved CBD products on liver enzyme elevations and 
endocrine measures.   
2.2 Part 2 (Drug Interactions) 
x To characterize the effects of daily CBD use at a dose within the range of what 
consumers are taking as unapproved CBD products on drug interactions. 
3 Study Endpoints 
3.1 Primary Endpoints 
3.1.1 Part 1 
x Percentage of participants with an ALT (based on consensus criteria*) or AST liver 
enzyme elevation greater than three times the upper limit of normal (>3 × ULN) 
[*Consensus criteria for ALT elevation: ULN for ALT will be 33 U/L for males and 25 
U/L for females].  
3.1.2 Part 2 
x Comparison of the area under the plasma concentration-time curve (AUC) and maximum 
concentration (Cmax) of citalopram when administered alone versus when co-administered 
with CBD after 7 days of CBD dosing. 
x Comparison of the morphine AUC and Cmax when administered alone versus when co-
administered with the first dose of CBD and after 7 days of CBD dosing.   
3.2 Secondary Endpoints 
3.2.1 Part 1  
x Percentage of participants meeting withdrawal criteria for potential drug-induced liver 
injury (DILI). 
x Change from baseline in total testosterone and inhibin B in male participants after CBD 
administration compared to placebo.  


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 6 of 16 
 
 
x Change from baseline in thyroid stimulating hormone (TSH), total T3, and free T4 after 
CBD administration compared to placebo. 
3.2.2 Part 2 
x Comparison of the AUC and Cmax of morphine metabolites when administered alone 
versus when co-administered with CBD.    
3.3 Exploratory Endpoints 
3.3.1 Part 1 
x Assessment of liver-related adverse events.  
x Summary of CBD and metabolite pharmacokinetics. 
x Proportion of subjects with abnormal laboratory (e.g., liver, endocrine) tests.   
x Changes in additional laboratory, vital signs, and plasma proteome assessments. 
3.3.2 Part 2 
x Additional PK parameters for citalopram, morphine, and metabolites, such as time of 
maximum concentration, half-life, apparent clearance, and apparent volume of 
distribution. 
x PK parameters for CBD and metabolites. 
4 Study Overview 
4.1 Study Design  
4.1.1 Part 1 
Part 1 is a randomized, double-blind, placebo-controlled, parallel study in 200 subjects (150 
subjects receiving 5 mg/kg/day of CBD and 50 subjects receiving placebo). Subjects will report 
to the study site for screening from Days -28 to -2 and then will return to the site on Day -1 for 
check-in, baseline assessments, and randomization. Subjects will check out from the clinical site 
on Day 1 (1 night in-house stay) following dosing and study assessments. Subjects will receive 
CBD or placebo for 28 days and will return to the study clinic on Day 28 for a single in-house 
day with check-out on Day 29. Subjects will have 3 clinic visits in between the in-house stays. 
The clinical site will contact subjects daily to confirm drug administration. Subject will have a 
final follow-up on Day 35. 
The study design is as follows:  
 
Day -1 
CBD Dosing Days 1-28 (5mg/kg/day) 
 
Day 29 
 
Day 35 
Day 1 
Day 7 
Day 14 
Day 21 
Day 28 


Statistical Analysis Plan
SCR-016 Clinical Study 
Page 7 of 16
Check-in
Check-out
Clinic visit 
1
Clinic visit 
2
Clinic visit 
3
Check-in
Check-out
Follow-up visit 
(Clinic visit 4)
4.1.2 Part 2 (Drug Interactions)
Part 2 is an open-label, sequential study in 40 subjects (two separate cohorts of 20 subjects). In 
the Part 2 citalopram drug-drug interaction (DDI) cohort, subjects will report to the study site for 
screening from Days -28 to -2 and then will return to the site on Day -1 for check-in and baseline 
assessments. Subjects will check-out from the clinical site on Day 6 (6 nights in-house stay) 
following dosing and study assessments. Subjects will return to the study clinic on Day 12 for 
another 6 nights in-house stay with check-out on Day 18. Subjects will have one follow-up visit 
after the second check-out (Day 24). Subjects will receive CBD for 12 days (Day 6 to 17) and 
citalopram on Day 1 and Day 13.
In the Part 2 morphine DDI cohort, subjects will report to the study site for screening from Days 
-28 to -2 and then will return to the site on Day -1 for check-in and baseline assessments. 
Subjects will check-out from the clinical site on Day 6 (6 nights in-house stay) following dosing 
and study assessments. Subjects will return to the study clinic on Day 10 for a 3 night in-house 
stay with check-out on Day 13. Subjects will receive CBD for 9 days (Day 4 to 12) and 
morphine on Day 1, Day 4, and Day 11.  Subjects will have one follow-up visit after the second 
check-out (Day 19). 
The study design is as follows:
Citalopram DDI cohort 


Statistical Analysis Plan
SCR-016 Clinical Study 
Page 8 of 16
Day -1
Day 1
CBD Dosing Days 6-17 (5 mg/kg/day)
Day 18
Day 24
Day 6
Day 12
Day 13
Check-in
DDI drug Dosing 
(baseline)
Check-out
Check-in
DDI drug Dosing 
(w/ CBD)
Check-out
Follow-up 
visit
Morphine DDI cohort
Day -1
Day 1
CBD Dosing Days 4-12 (5 mg/kg/day)
Day 13
Day 19
Day 4
Day 6
Day 10
Day 11
Check-in
DDI drug Dosing 
(baseline)
DDI drug Dosing 
(w/ CBD)
Check-
out
Check-
in
DDI drug Dosing 
(w/ CBD)
Check-
out
Follow-up visit


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 9 of 16 
 
 
4.2 Sample Size 
4.2.1 Part 1 
A total of 240 healthy subjects are planned for enrollment and approximately 190 of these will be 
administered CBD. In Part 1, 200 healthy subjects will be randomized to 5 mg/kg/day of CBD 
(150 subjects) or placebo (50 subjects). The primary endpoint is the percentage of CBD 
administered participants with an ALT (based on consensus criteria*) or AST liver enzyme 
elevation greater than three times the ULN. Assuming the true event rate is 6%, the study has 
95% probability of observing 5 or more events with ALT or AST liver enzyme elevation greater 
than three times the ULN. Assuming the true observed drug-induced liver injury event rate is 
2%, the study has a 93% percent probability of observing 1 or more event. 
In Part 1, change from baseline comparisons will be performed for various endocrine laboratory 
measures (e.g., total testosterone, inhibin B, TSH, total T3, and free T4). Sample size for the 
study is not powered for any of these comparisons. No adjustments are planned for multiplicity. 
4.2.2 Part 2 (Drug Interactions) 
In Part 2, 40 healthy subjects will receive either oral citalopram (20 subjects) or morphine (20 
subjects). Comparisons will be performed on changes in exposure for two different substrate 
drugs following administration with CBD. Assuming no more than 20% discontinuations per 
arm, 30% intra-subject variability, and a two-sided test at the 0.05 significance level, the sample 
size would have 90% power to detect a 30% difference in exposure when the substrate drugs are 
co-administered with CBD.   
5 Analysis Populations  
5.1.1 Part 1 
The liver safety analysis population will include all subjects who receive at least 1 dose of the 
study drug and have at least one on-treatment liver and hematology lab assessment. Subjects in 
the liver safety analysis population will be used for the planned primary, secondary, and 
exploratory analyses related to liver enzyme elevations and liver events.  
Sensitivity analyses for liver safety will also be conducted for the following additional analysis 
populations defined based on completion of minimum durations of continuous study drug 
dosing: 
x Subjects who complete at least 1 week of dosing and have at least one on-treatment liver 
and hematology lab assessment (i.e., excludes subjects who discontinue due to 
tolerability in the first week)  


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 10 of 16 
 
 
x Subjects who complete at least 2 weeks of dosing, were not discontinued due to 
adherence, and have at least one on-treatment liver and hematology lab assessment (i.e., 
excludes subjects who discontinue due to tolerability and those discontinued for 
repeatedly missing scheduled dosing as assessed by daily site check-ins and out-patient 
visit product accountability)  
The laboratory analysis population will include all subjects that have endocrine, laboratory, vital 
signs, and proteomics measures from pre-dose Day 1 and check-out on Day 29 (time-matched to 
Day 1). These criteria will apply to separately to each individual endocrine, laboratory (i.e., free 
and total testosterone, inhibin B, TSH, total T3, free T4, lipid panel), vital sign, or proteomics 
measure. Subjects in the laboratory analysis population will be used for the planned secondary 
and exploratory analyses related to endocrine, laboratory, vital signs, and proteomics measures. 
The PK population will include all subjects who receive at least one dose of study drug and have 
at least one on-treatment PK sample collected. Subjects in the PK analyses population will be 
used for the planned exploratory analyses related to CBD pharmacokinetics. 
The safety population will include all subjects who receive at least one dose of any of the study 
drugs.  
5.1.2 Part 2 
The PK population will include all subjects who receive the study drug and have at least 1 
estimable PK parameter (AUC0-t, AUC0-inf, or Cmax) after dosing with the substrate drug alone 
and with the substrate drug in combination with CBD. Subjects in the PK analyses population 
will be used for the planned primary, secondary, and exploratory analyses related to CBD 
pharmacokinetics. 
The safety population will include all subjects who receive at least one dose of any of the study 
drugs.  
6 Data Screening and Quality Assurance 
6.1 Missing Data  
The following approaches will be used for the handling of missing and incomplete data: 
x Missing data will not be imputed.  
x Data that are excluded from the descriptive or inferential analyses will be included in the 
subject data listings. This will include data from unscheduled visits or extra 
measurements that may arise from 2 or more analyses of the biofluid sample at the same 
time point.  
x PK measurements below the lower limit of quantification will be set to zero for all 
analyses. 


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 11 of 16 
 
 
6.2 Data Quality Assurance 
Completed eCRFs are required for each subject randomly assigned to treatment. Electronic data 
entry will be accomplished through the ClinSpark® remote electronic data capture system, which 
allows for on-site data entry and data management. This system provides immediate, direct data 
transfer to the database, as well as immediate detection of discrepancies, enabling site 
coordinators to resolve and manage discrepancies in a timely manner. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and subsequently any investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records. 
 
Furthermore, the investigator retains full responsibility for the accuracy and authenticity of all 
data entered into the electronic data capture system. The completed dataset and their associated 
files are the sole property of the sponsor and should not be made available in any form to third 
parties, except for appropriate governmental health or regulatory authorities, without written 
permission of the sponsor. 
6.3 Data Sharing 
De-identified subject-level data may be released to other researchers (including through a data 
warehouse or as a part of a publication) to enable secondary research. Additional secondary 
research may also be performed by the sponsor.  
7 General Statistical Considerations  
All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of summary 
statistics. Demographic and baseline characteristics will be summarized by study Part and by 
treatment for all subjects. 
7.1 Subject Disposition  
The number of subjects who enroll in the study and the number and percentage of subjects who 
complete each assessment will be presented for each study Part. The frequency and percentage of 
subjects who withdraw or discontinue from the study and the reason for withdrawal or 
discontinuation will be summarized for each study Part. 
7.2 Demographic and Baseline Characteristics 
Descriptive statistics will be used to summarize demographic and baseline subject characteristics 
for each study Part. For continuous variables, the mean, median, standard deviation (SD), 
minimum, and maximum values will be reported. For categorical (nominal) variables, the 
number and percentage of subjects (or observations) will be reported. 


Statistical Analysis Plan  
 
 
 
 
                   SCR-016 Clinical Study  
 
 
 
Page 12 of 16 
 
 
7.3  Primary Analysis  
7.3.1 Part 1 
Percentage of participants with an ALT (based on consensus criteria) or AST liver enzyme 
elevation greater than three times the upper limit of normal (> 3 × ULN)  
The primary endpoint for Part 1 is the percentage of subjects with an ALT (based on consensus 
criteria) or AST liver enzyme elevation greater than three times the upper limit of normal (ULN). 
The proportions of subjects exceeding 3x ULN for ALT and AST will be summarized separately 
for each treatment group. Results will be reported as percentages with a 95% confidence interval 
(CI) based on a Kaplan-Meier analysis. The analysis will be performed on the liver safety 
analysis population. Separate percentages will be reported for both treatment groups. The 
analysis will be repeated for all populations described as part of sensitivity analyses. 
7.3.2 Part 2 (Drug Interactions) 
Comparison of the area under the plasma concentration-time curve (AUC) and Cmax of 
citalopram when administered alone versus when co-administered with CBD after 7 days of 
CBD dosing 
The primary analysis for the Part 2, citalopram cohort will include a comparison of the area 
under the plasma concentration-time curve extrapolated to infinity (AUC0-inf), AUC from time 0 
to the last quantifiable concentration (AUC0-t), and Cmax of citalopram when administered alone 
versus when co-administered with CBD. 
The PK parameters (AUC0-inf and AUC0-t) will be analyzed using noncompartmental methods 
based on actual sampling times, using dosing of citalopram as time zero. AUC0-inf will only be 
included if the subject has 3 or more concentration values on the terminal portion of the 
pharmacokinetic curve and with an adjusted coefficient of determination (R2) greater than 0.80. 
Cmax will be based on maximum observed concentration of citalopram.   
Using linear mixed-effects modeling, comparisons of log-transformed PK parameters will be 
performed. Treatment will be a fixed effect. Subject will be included as a random effect on the 
intercept. Treatment differences on the log-scale will be estimated for the PK parameters. 
Geometric mean ratio and 90% CI will be obtained by exponentiation of the treatment effect and 
90% CI based on the log-transformed scale. Testing will be two-sided, and a significant change 
will be concluded if the two-sided 90% CI excludes 1. The analysis will be performed on the Part 
2 PK population. No adjustment will be performed for multiplicity. 
Comparison of the morphine AUC and Cmax when administered alone versus when co-
administered with the first dose of CBD and after 7 days of CBD dosing   


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The primary analysis for Part 2 morphine cohort will also include a comparison of the AUC0-inf, 
AUC0-t, and Cmax of morphine when administered alone versus when co-administered with CBD. 
Comparisons will be performed between morphine administration alone and after co-
administration with CBD for 1-day and 7-days. The PK parameters will be analyzed using the 
same methods described above. Testing will be two-sided, and a significant change will be 
concluded if the two-sided 90% CI excludes 1. The analysis will be performed on the Part 2 PK 
population. No adjustment will be performed for multiplicity. 
7.4 Secondary Analyses 
7.4.1 Part 1  
Percentage of participants meeting withdrawal criteria for potential drug-induced liver injury 
(DILI) 
The secondary liver safety endpoint is the percentage of participants meeting withdrawal criteria 
for potential drug-induced liver injury, as defined in section 4.7.3.2.1 of the study protocol 
(Assessment and Reporting of Potential Cases of Drug-Induced Liver Injury). Analysis and 
reporting will be performed in similar fashion to the Part 1 primary endpoint using the liver 
safety analysis population and populations described as part of sensitivity analyses. 
Change from baseline in total testosterone and inhibin B in male participants after CBD 
administration compared to placebo 
Change from baseline in total testosterone and inhibin B in males after CBD administration 
compared to placebo will be analyzed using a mixed-effect analysis approach. The model will 
include treatment as fixed effects and subject as a random effect. Contrasts from the model will 
be used to compare CBD vs placebo.  Testing will be two-sided, and a significant increase will 
be concluded if the two-sided 95% CI excludes 0.  
Change from baseline in thyroid stimulating hormone (TSH), total T3, and free T4 after CBD 
administration compared to placebo 
Change from baseline in thyroid stimulating hormone, total T3, and free T4 in both males and 
females after CBD administration compared to placebo will also be assessed. These analyses will 
be conducted in the same fashion as described above for total testosterone and inhibin B. The 
analysis will be conducted on the laboratory analysis population. 
7.4.2 Part 2 (Drug Interactions) 
Comparison of the AUC and Cmax of morphine metabolites when administered alone versus when 
co-administered with CBD 


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Part 2 secondary PK endpoints, AUC0-inf, AUC0-t, and Cmax for morphine metabolites (alone and 
when co-administered with CBD), will be analyzed using the same approach as the Part 2 
primary PK endpoints described above in 7.3.2. The analysis will be conducted using the Part 2 
PK population (morphine cohort). 
7.5 Exploratory Analyses 
7.5.1 Part 1  
Assessment of liver-related adverse events 
As part of the exploratory analyses for Part 1, liver-related adverse events will be assessed 
according to FDA’s Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation 1. Categorical and visual summaries of liver-related adverse events will be produced 
based on the following criteria by treatment arm. Results will be reported as percentages with a 
95% CI. The analysis will be performed on the liver safety analysis population and repeated for 
all populations described as part of sensitivity analyses:  
x Elevations of 3x, 5x, 10x, and 20x the ULN for both ALT and AST. 
x Any elevations in bilirubin. 
x Any elevations in TBL (Total Bilirubin) > 2x ULN. 
x Any elevations in ALP (Alkaline Phosphatase) > 1.5x ULN. 
x Elevations in ALT or AST > 3x ULN accompanied by elevated bilirubin (> 1.5x ULN, 
>2x ULN). 
x Elevations in ALT or AST in temporal association with nausea, vomiting, anorexia, 
abdominal pain, or fatigue. 
Summary of CBD and metabolite pharmacokinetics 
Steady state CBD and metabolite drug concentrations will be determined using descriptive 
statistics and the Part 1, PK population. 
Percentage of subjects with abnormal laboratory (e.g., liver, endocrine) tests  
The percentage of subjects meeting predefined criteria for abnormal liver, endocrine, and other 
laboratory tests will be summarized along with 95% CI for each treatment group. All analyses 
will be conducted using the safety population. 
Changes in additional laboratory assessments 


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For other laboratory measures, the change from baseline will be compared between treatment 
groups (CBD and placebo) using a mixed-effect analysis approach. These analyses will be 
conducted in the same fashion as described for total testosterone and inhibin B. The analysis will 
be conducted on the laboratory analysis population. An analysis plan for plasma proteomic 
markers will be specified in a separate document. 
7.5.2 Part 2 (Drug Interactions) 
Additional PK parameters for citalopram, morphine, and metabolites, such as time of maximum 
concentration, half-life, apparent clearance, and apparent volume of distribution. 
Additional exploratory PK parameters for citalopram, morphine, and metabolites, such as time of 
maximum concentration (Tmax), half-life (t1/2), terminal elimination rate constant (Kel), apparent 
clearance (CL/F), and apparent volume of distribution (V/F) will be analyzed using 
noncompartmental methods based on actual sampling times. All parameters will be calculated 
using statistical software. Mean and individual concentration time profiles will be presented in 
graphs. 
x Tmax – Time of maximum concentration corresponding to observed Cmax 
x Kel - The terminal elimination rate constant, which will be determined from the terminal 
slope of the log-concentration curve using linear regression 
x Half-life (t1/2) - calculated using the elimination rate constant as ln(2)/Kel 
x CL/F – calculated using dose/AUC0-inf 
x V/F – calculated using CL/F / Kel  
 
PK parameters for CBD and metabolites 
PK parameters for CBD and metabolites, such as AUCss (steady state AUC from time of CBD 
dosing with the substrate to time of next CBD dose), Cmax, Tmax, t1/2, Kel, CL/F, and V/F will be 
analyzed using noncompartmental methods based on actual sampling times. All parameters will 
be calculated using statistical software. Parameters will be calculated for the first CBD dose on 
Day 4 and 11 (morphine cohort) and Day 13 (citalopram cohort). Mean and individual 
concentration time profiles will be presented in graphs. 
8 Safety Analyses 
8.1.1 Adverse Events 
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities. The incidence of TEAEs, organized by system organ class and frequency, will be 


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summarized by seriousness, severity, relationship to treatment, and by treatment at onset of the 
TEAE. A detailed listing of serious AEs and TEAEs leading to withdrawal will also be provided. 
8.1.2 Clinical Laboratory Tests (Other Than Specified in Planned Analyses)  
Clinical laboratory results (hematology, serum chemistry, and urinalysis) will be summarized 
using descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum). 
Clinical laboratory results will be classified as normal or abnormal, according to the reference 
ranges of the individual parameter. The number and percentage of subjects with abnormal 
laboratory results will be provided. No statistical testing will be performed on clinical laboratory 
data. 
8.1.3 Vital Sign Measurements (Other Than Specified in Planned Analyses) 
Vital sign measurements and changes from baseline will be summarized using descriptive 
statistics (number of subjects, mean, SD, minimum, median, and maximum) by treatment and 
time points as specified in the protocol. 
8.1.4 Safety 12-lead Electrocardiograms  
12-lead ECGs will be obtained with the subjects in the supine position for a minimum of 10 
minutes before recording. ECGs will be overread by a physician. If an abnormality is observed, 
the subject will be instructed to follow up with his or her personal physician. 
8.1.5 Physical Examinations  
Physical examination findings will be presented in a data listing, and abnormal physical 
examination findings will be recorded as AEs. 
8.1.6 Other Safety Data  
All concomitant medication usage and medications that changed in daily dose, frequency, or 
both since the subject provided informed consent will be summarized for each subject. 
9 References 
1. U.S. Food and Drug Administration (FDA) Science Board. Drug-Induced Liver Injury: 
Premarking Clinical Evaluation. Retrieved from 
https://www.fda.gov/media/116737/download.