Cannabidiol and CES1 Interactions in Healthy Subjects

An Assessment of the Drug Interaction Potential Between Oral Cannabidiol (Epidiolex®) and the CES1 Substrate Methylphenidate in Healthy Volunteers

The proposed study will assess the drug interaction potential between oral cannabidiol (Epidiolex®) and the carboxylesterase 1 (CES1) substrate methylphenidate (Ritalin®) in 12 healthy research subjects

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: Drug: dl-Methylphenidate plus Cannabidiol; Drug: dl-Methylphenidate plus Cannabidiol Placebo solution

Detailed Description

Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as an OTC supplement, a component of medical cannabis, and a prescriptive treatment of childhood epilepsies. In vitro studies suggest CBD may inhibit a number of drug-metabolizing enzymes, including carboxylesterase 1 (CES1). The aim of this study was to evaluate effect of CBD on the disposition of the CES1 substrate methylphenidate (MPH). This was a randomized, placebo-controlled, crossover study involving 12 healthy subjects. Each subject ingested 750 mg of CBD solution, or alternatively, a placebo solution twice daily for a 3-day run-in period followed by an additional CBD dose (or placebo) and a single 10 mg dose of MPH and completed serial blood sampling for pharmacokinetic analysis. MPH and CBD concentrations were measured by liquid chromatography with tandem mass spectrometry.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Signed Informed Consent
• Age: 21-45 years
• Gender: males and females (50:50)
• Race or ethnicity: no restrictions
• Body Mass Index (BMI) between 18.5 to 28 kg/m2 (inclusive)
• Satisfactory completion of the screening medical history, physical exam, and laboratory evaluations.
• Females of child-bearing potential must have a negative urine pregnancy test prior to enrollment and avoid pregnancy during study participation.
• With the exception of oral contraceptives, subjects must not be taking prescription or OTC medication for the duration of study participation
• Subjects must have no ongoing use of any botanical/nutritional supplement, vitamin, or energy drink for the duration of study participation

Exclusion Criteria:

• The presence of a known allergy, hypersensitivity, or adverse reaction to CBD or cannabis, or sesame seed oil
• The presence of a known allergy, hypersensitivity, or adverse reaction to methylphenidate or dexmethylphenidate (Focalin®)
• A history (within the past year) or presence of clinically significant cardiovascular, cerebrovascular, renal, hepatic, gastrointestinal, pulmonary, immunological, hematological, endocrine, or neurologic disease will render subjects ineligible for the study.

• The presence of any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion including;

  1. Gastric bezoar
  2. Swallowing disorders
  3. Strictures
  4. Fistulas
  5. GI obstruction
  6. Severe dsyphasgia
  7. Crohn's disease
  8. Diverticulitis
  9. A positive urine pregnancy test.
  10. A positive Urine Drug Screen
  11. Any concomitant prescription medication, OTC medication, herbal or other dietary supplement or vitamins during the study period.

All subjects must be medication-free from 7 Days before initiation of the first active study day, through the duration of the study. This exclusion the use of vitamins, herbal preparations and OTC supplements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CBD, then placebo; Subjects received a three day run in of CBD 750 mg orally twice daily (administered as as 7.5 mL of Epidiolex® solution [100 mg/ml]). On day four, all subjects returned to the clinical research center to receive one oral dose of CBD 750 mg (administered as as 7.5 mL of Epidiolex® solution [100 mg/ml]) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast). After a minimum washout period of five days, subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution (no CBD) orally twice daily. On day four, all subjects returned to the clinical research center to receive one oral dose of 7.5 mL of Epidiolex® placebo solution (no CBD) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).	Drug: dl-Methylphenidate plus Cannabidiol; Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL Epidiolex® solution; Other Names: Epidiolex®; Ritalin®; Drug: dl-Methylphenidate plus Cannabidiol Placebo solution; Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL of Epidiolex® placebo solution; Other Names: Epidiolex®; Ritalin®
Experimental: Placebo, then CBD; Subjects received a three day run in of 7.5 ml of Epidiolex® placebo solution (no CBD) orally twice daily. On day four, all subjects returned to the clinical research center to receive one oral dose of 7.5 mL of Epidiolex® placebo solution (no CBD) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast). After a minimum washout period of five days, subjects received a three day run in of CBD 750 mg orally twice daily (administered as as 7.5 mL of Epidiolex® solution [100 mg/ml]). On day four, all subjects returned to the clinical research center to receive one oral dose of CBD 750 mg (administered as as 7.5 mL of Epidiolex® solution [100 mg/ml]) and one 10 mg tablet of dl-methylphenidate (Ritalin®) orally in a fed state (a 30 minute standardized breakfast).	Drug: dl-Methylphenidate plus Cannabidiol; Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL Epidiolex® solution; Other Names: Epidiolex®; Ritalin®; Drug: dl-Methylphenidate plus Cannabidiol Placebo solution; Subjects will be administered one 10 mg tablet of dl-methylphenidate (Ritalin®) plus 7.5 mL of Epidiolex® placebo solution; Other Names: Epidiolex®; Ritalin®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in the Geometric Mean Ratio (GMR) of the Peak Concentration (Cmax) Will be Compared Between the Two Exposure Conditions; i.e. Methylphenidate + CBD vs Methylphenidate + Placebo.	Plasma methylphenidate (MPH) concentrations for both arms were determined by using a liquid-liquid extraction method and LC-MS/MS analysis. Peak concentration (Cmax) was reported as observed for each subject. The geometric mean ratios (GMR) of the Cmax for MPH were compared between the two exposure conditions, i.e., MPH with CBD versus MPH with placebo. In brief, if the 90% confidence interval (CI) of GMR for Cmax between the CBD group and placebo group extend beyond the FDA's established bioequivalent limits of 0.8-1.25, the result was interpreted to represent a DDI. In our case, a GMR greater than 1.25 would be indicative of a DDI, since CBD would impair CES1's ability to efficiently metabolize MPH, thus a higher ratio of Cmax's of MPH in our CBD group relative to our placebo group.	8 hours
Differences in the Geometric Mean Ratio (GMR) of the Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate Will be Compared Between the Two Exposure Conditions; i.e. Methylphenidate + CBD vs Methylphenidate + Placebo.	All methylphenidate plasma concentrations were quantified using liquid-liquid extraction method and LC-MS/MS analysis. The terminal elimination rate constant (λz) was estimated by linear least-squares regression of the terminal portion of the plasma concentration (on natural logarithmic scale)-time curve. The area under the plasma concentration-time curve of methylphenidate AUC 0-8h were calculated according to the linear trapezoidal rule. AUC8-inf was extrapolated by using the last observed concentration of MPH (Clast) and dividing it by λz. AUC0-8 was added to AUC8-inf to get AUCinf. The GMR of the AUCinf for MPH were compared between the two exposure conditions, i.e., MPH with CBD versus MPH with placebo. In brief, if the 90% confidence interval (CI) of GMR for Cmax between the CBD group and placebo group was beyond the FDA's established bioequivalent limits of 0.8-1.25, the result was interpreted to represent a DDI. A GMR greater than 1.25 would be indicative of a DDI.	0-8 hours (determined), 8 hours-infinity (extrapolated)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Methylphenidate Plasma Concentration (Cmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms.	Plasma methylphenidate (MPH) concentrations for both arms were determined by using a liquid-liquid extraction method and LC-MS/MS analysis. Peak concentration (Cmax) was reported as observed for each subject (highest observed plasma concentration of methylphenidate).	8 hours
Time to Peak Methylphenidate Plasma Concentration (Tmax) for Methylphenidate and CBD Arms and Methylphenidate and Placebo Arms.	Plasma methylphenidate (MPH) concentrations for both arms were determined by using a liquid-liquid extraction method and LC-MS/MS analysis. The time to peak plasma methylphenidate concentrations (Tmax) was reported as observed for each subject.	8 hours
Area Under the Time Curve 0-8hours (AUC0-8h) for Methylphenidate for the Two Exposure Conditions; Methylphenidate and CBD and Methylphenidate and Placebo.	All methylphenidate plasma concentrations were quantified using liquid-liquid extraction method and LC-MS/MS analysis. The area under the plasma concentration-time curve of methylphenidate AUC 0-8h was calculated according to the linear trapezoidal rule.	8 hours
Area Under the Time Curve 0-infinity (AUCinf) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo.	All methylphenidate plasma concentrations were quantified using liquid-liquid extraction method and LC-MS/MS analysis. The terminal elimination rate constant (λz) was estimated by linear least-squares regression of the terminal portion of the plasma concentration (on natural logarithmic scale)-time curve. The area under the plasma concentration-time curve of methylphenidate AUC 0-8h were calculated according to the linear trapezoidal rule. AUC8-inf was extrapolated by using the last observed concentration of MPH (Clast) and dividing it by λz. AUC0-8 was added to AUC8-inf to get AUCinf.	0-8 hours (determined), 8 hours-infinity (extrapolated)
Half Life Determination (t1/2) for Methylphenidate for the Two Exposure Conditions for Methylphenidate and CBD and Methylphenidate and Placebo.	All methylphenidate plasma concentrations were quantified using liquid-liquid extraction method and LC-MS/MS analysis. The terminal elimination rate constant (λz) was estimated by linear least-squares regression of the terminal portion of the plasma concentration (on natural logarithmic scale)-time curve. The elimination half-live (t1/2) was then calculated using the formula t1/2 = 0.693/λz.	8 hours

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Consortium for Medical Marijuana Clinical Outcomes Research
• Investigators: Principal Investigator: John Markowitz, Pharm.D, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2021
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: October 22, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Actual): July 18, 2024
• Last Update Submitted That Met QC Criteria: June 20, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Anticonvulsants; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Methylphenidate; Cannabidiol
• Other Study ID Numbers: IRB202002547-A; OCR39758 (Other Identifier: UF OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes