Clinical Study to Evaluate Cannabidiol Liver Enzyme Elevations and Drug Interactions

NCT06192589 | Completed Phase 1 Results FDA Drug

• 1 other identifier: SCR-016
• Study Type: interventional
• Target: 241
• Locations: 1 country
• Sites: 1

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.

Conditions

Cannabidiol; Drug Induced Liver Injury; Drug Interaction

Keywords

Cannabidiol; CBD; Liver enzyme elevation; Drug interactions

Outcome Measures

Primary Outcomes (5)

• Part 1 - Percentage of Participants With an Alanine Transaminase (ALT) or Aspartate Aminotransferase (AST) Liver Enzyme Elevation Greater Than Three Times the Upper Limit of Normal (> 3 × ULN).

  The upper limit of normal (ULN), based on consensus criteria, for the liver transaminase ALT (Alanine transaminase) is defined as 33 U/L for males and 25 U/L for females. An ALT evaluation three times the ULN for males would be 99 U/L and 75 U/L for females.

  Days 1 through 35

• Part 2 - Area Under the Plasma Concentration-time Curve (AUC) of Citalopram When Administered Alone Versus When Co-administered With Cannabidiol After 7 Days of CBD Dosing.

  AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis. 13 PK samples will be obtained with each citalopram dose for a total number of 26 PK samples per citalopram cohort participant. The outcome measure reported will be the geometric mean ratio for citalopram alone compared to citalopram after 7 days of CBD dosing.

  0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after each citalopram dose (Days 1 and 13)

• Part 2 - Maximum Concentration (Cmax) of Citalopram When Administered Alone Versus When Co-administered With CBD After 7 Days of Cannabidiol Dosing.

  Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis. 13 PK samples will be obtained with each citalopram dose for a total number of 26 PK samples per citalopram cohort participant. The outcome measure reported will be the geometric mean ratio for citalopram alone compared to citalopram after 7 days of CBD dosing.

  0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after each citalopram dose (Days 1 and 13)

• Part 2 - Morphine AUC When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of CBD Dosing.

  AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine alone compared to morphine after 7 days of CBD dosing.

  0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11)

• Part 2 - Morphine Cmax When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of Cannabidiol Dosing.

  Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine alone compared to morphine after 7 days of CBD dosing.

  0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11)

Secondary Outcomes (10)

• Part 1 - Percentage of Participants Meeting Withdrawal Criteria for Potential Drug-induced Liver Injury (DILI).

  Days 1 through 35

• Part 1 - Change From Baseline in Total Testosterone in Male Participants After Cannabidiol Administration Compared to Placebo.

  Days 1 and 29

• Part 1 - Change From Baseline in Inhibin B in Male Participants After Cannabidiol Administration Compared to Placebo.

  Days 1 and 29

• Part 1 - Change From Baseline in Thyroid Stimulating Hormone (TSH) After Cannabidiol Administration Compared to Placebo.

  Days 1 and 29

• Part 1 - Change From Baseline in Total T3 After Cannabidiol Administration Compared to Placebo.

  Days 1 and 29

Study Arms (4)

Cannabidiol (Part 1)

ACTIVE COMPARATOR

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.

Drug: Cannabidiol

Placebo (Part 1)

PLACEBO COMPARATOR

Subjects in this arm will receive oral solution placebo twice a day for 28 days.

Drug: Placebo

Cannabidiol and Citalopram Drug Interaction (Part 2)

ACTIVE COMPARATOR

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).

Drug: Cannabidiol; Drug: Citalopram

Cannabidiol and Morphine Drug Interaction (Part 2)

ACTIVE COMPARATOR

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).

Drug: Cannabidiol; Drug: Morphine

Interventions

Cannabidiol DRUG

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.

Also known as: Epidiolex

Cannabidiol (Part 1); Cannabidiol and Citalopram Drug Interaction (Part 2); Cannabidiol and Morphine Drug Interaction (Part 2)

Placebo DRUG

Placebo will be administered orally twice daily for 28 days in Part 1

Placebo (Part 1)

Citalopram DRUG

Citalopram (Celexa) will be administered once at 20 mg on days 1 and 13.

Also known as: Celexa

Cannabidiol and Citalopram Drug Interaction (Part 2)

Morphine DRUG

Morphine will be administered once at 15 mg on days 1, 4, and 11.

Cannabidiol and Morphine Drug Interaction (Part 2)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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).
• 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).
• Subject must have a negative test result for alcohol and illicit drugs at screening and check-in (Day -1).
• 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.
• 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.
• 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.
• 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.
• Subject agrees to and is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

You may not qualify if:

• 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):
• 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.)
• Total bilirubin (TBL) \> ULN.
• International normalized ratio (INR) \> 1.3
• Use or intend to use any medications/products in the 14 days prior to check-in (Day -1), unless deemed acceptable by the investigator
• 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.
• 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.
• 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.
• 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).
• 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)
• 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 \[Part 2, citalopram DDI\]).
• Subject has a positive test result for cannabinoids (THC) at screening or Day -1.
• Subject has a history of opioid or narcotic misuse.
• Subject has a history of suicidal ideation or previous suicide attempts
• 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.

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• Spaulding Clinical Research LLC: collaborator

Study Sites (1)

Spaulding Clinical Research

West Bend, Wisconsin, 53095, United States

Location

Related Publications (17)

• 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.

  BACKGROUND

• 2. Cannabidiol (Epidiolex ®) oral solution label obtained from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf

  BACKGROUND

• Lo LA, Christiansen A, Eadie L, Strickland JC, Kim DD, Boivin M, Barr AM, MacCallum CA. Cannabidiol-associated hepatotoxicity: A systematic review and meta-analysis. J Intern Med. 2023 Jun;293(6):724-752. doi: 10.1111/joim.13627. Epub 2023 Mar 13.

  PMID: 36912195 BACKGROUND

• Crippa JAS, Zuardi AW, Guimaraes FS, Campos AC, de Lima Osorio F, Loureiro SR, Dos Santos RG, Souza JDS, Ushirohira JM, Pacheco JC, Ferreira RR, Mancini Costa KC, Scomparin DS, Scarante FF, Pires-Dos-Santos I, Mechoulam R, Kapczinski F, Fonseca BAL, Esposito DLA, Pereira-Lima K, Sen S, Andraus MH, Hallak JEC; Burnout and Distress Prevention With Cannabidiol in Front-line Health Care Workers Dealing With COVID-19 (BONSAI) Trial Investigators. 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 Aug 2;4(8):e2120603. doi: 10.1001/jamanetworkopen.2021.20603.

  PMID: 34387679 BACKGROUND

• 5. U.S. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000ClinPharmR.pdf

  BACKGROUND

• 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

  BACKGROUND

• Carvalho RK, Andersen ML, Mazaro-Costa R. The effects of cannabidiol on male reproductive system: A literature review. J Appl Toxicol. 2020 Jan;40(1):132-150. doi: 10.1002/jat.3831. Epub 2019 Jul 17.

  PMID: 31313338 BACKGROUND

• Tallon MJ, Child R. Subchronic oral toxicity assessment of a cannabis extract. Regul Toxicol Pharmacol. 2023 Oct;144:105496. doi: 10.1016/j.yrtph.2023.105496. Epub 2023 Sep 19.

  PMID: 37734651 BACKGROUND

• Anderson LL, Doohan PT, Oldfield L, Kevin RC, Arnold JC, Berger M, Amminger GP, McGregor IS. Citalopram and Cannabidiol: In Vitro and In Vivo Evidence of Pharmacokinetic Interactions Relevant to the Treatment of Anxiety Disorders in Young People. J Clin Psychopharmacol. 2021 Sep-Oct 01;41(5):525-533. doi: 10.1097/JCP.0000000000001427.

  PMID: 34121064 BACKGROUND

• Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part I. Psychosomatics. 2003 Mar-Apr;44(2):167-71. doi: 10.1176/appi.psy.44.2.167.

  PMID: 12618536 BACKGROUND

• 11. Citalopram (Celexa ®) tablet label obtained from https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020822s041lbl.pdf

  BACKGROUND

• 12. Morphine Sulfate tablet label obtained from https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022207s010lbl.pdf

  BACKGROUND

• Iannone LF, Arena G, Battaglia D, Bisulli F, Bonanni P, Boni A, Canevini MP, Cantalupo G, Cesaroni E, Contin M, Coppola A, Cordelli DM, Cricchiuti G, De Giorgis V, De Leva MF, De Rinaldis M, d'Orsi G, Elia M, Galimberti CA, Morano A, Granata T, Guerrini R, Lodi MAM, La Neve A, Marchese F, Masnada S, Michelucci R, Nosadini M, Pilolli N, Pruna D, Ragona F, Rosati A, Santucci M, Spalice A, Pietrafusa N, Striano P, Tartara E, Tassi L, Papa A, Zucca C, Russo E, Mecarelli O; CBD LICE Italy Study Group. 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. eCollection 2021.

  PMID: 34093420 BACKGROUND

• Sharbaf Shoar N, Fariba KA, Padhy RK. Citalopram. 2023 Nov 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK482222/

  PMID: 29489221 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Florian J, Salcedo P, Burkhart K, Shah A, Chekka LMS, Keshishi D, Patel V, Yang S, Fein M, DePalma R, Matta M, Strauss DG, Rouse R. Cannabidiol and Liver Enzyme Level Elevations in Healthy Adults: A Randomized Clinical Trial. JAMA Intern Med. 2025 Sep 1;185(9):1070-1078. doi: 10.1001/jamainternmed.2025.2366.

  PMID: 40622698 DERIVED

MeSH Terms

Conditions

Chemical and Drug Induced Liver Injury

Interventions

Cannabidiol; Citalopram; Morphine

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning

Intervention Hierarchy (Ancestors)

Cannabinoids; Terpenes; Hydrocarbons; Organic Chemicals; Propylamines; Amines; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Jeffry Florian
• Organization: U.S. Food and Drug Administration

Jeffry.Florian@fda.hhs.gov

301-796-4847

Study Officials

• Melanie Fein, MD

  Spaulding Clinical Research LLC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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 drug preparation and dispensing. Part 2 is an open label study.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: This is a two-part study. Part 1 is a randomized, double-blind, placebo-controlled, parallel study in 200 subjects (150 subjects receiving cannabidiol and 50 subjects receiving placebo). Part 2 is an open-label, sequential study in 40 subjects (two separate cohorts of 20 subjects).

Study Record Dates

• First Submitted: December 18, 2023
• First Posted: January 5, 2024
• Study Start: February 8, 2024
• Primary Completion: September 6, 2024
• Study Completion: September 6, 2024
• Last Updated: July 31, 2025
• Results First Posted: July 31, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: The data will become available at the time of manuscript publication.
• Access Criteria: No restrictions.

Locations

US (1)