NCT06192589

Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and Drug Interactions

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 241 (actual)
• Sponsor: Food and Drug Administration (FDA) · Federal
• Sex: All
• Age: 18 Years – 55 Years
• Healthy volunteers: Accepted

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.

Conditions

• Cannabidiol
• Drug Induced Liver Injury
• Drug Interaction

Interventions

Type	Name	Description
DRUG	Cannabidiol	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.
DRUG	Placebo	Placebo will be administered orally twice daily for 28 days in Part 1
DRUG	Citalopram	Citalopram (Celexa) will be administered once at 20 mg on days 1 and 13.
DRUG	Morphine	Morphine will be administered once at 15 mg on days 1, 4, and 11.

Timeline

• Start date: 2024-02-08
• Primary completion: 2024-09-06
• Completion: 2024-09-06
• First posted: 2024-01-05
• Last updated: 2025-07-31
• Results posted: 2025-07-31

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study