Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and Drug Interactions

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Subject signs an institutional review board (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.

Exclusion Criteria:

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):

   1. 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.)
   2. Total bilirubin (TBL) \> ULN.
   3. 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 \[Part 2, morphine DDI\]; Day 12 \[Part 2, citalopram DDI\]).
9. Subject has a positive test result for cannabinoids (THC) at screening or Day -1.
10. Subject has a history of opioid or narcotic misuse.
11. Subject has a history of suicidal ideation or previous suicide attempts
12. 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.
13. Subject has any signs or symptoms that are consistent with Coronavirus Disease 2019 (COVID-19) per Center for Disease Control (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, or diarrhea may have COVID-19. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator.
14. Subject has known or suspected allergies or sensitivities to the study drug or placebo components (e.g., sucralose, sesame).
15. Subjects with a documented hypersensitivity reaction to cannabidiol
16. Subjects with a documented medical history of clinical disorders related to mood, anxiety or panic, including diagnosed depression, generalized anxiety disorder or panic attacks.
17. 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.
18. 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.
19. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
20. 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.
21. 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.
22. Female subject is currently pregnant or lactating or was within 3 months of the study.
23. 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.
24. Subject has any other condition that precludes his or her participation in the study (as determined by the investigator).