Interactions Between Cannabinoids and Cytochrome P450-Metabolized Drugs

• ClinicalTrials.gov Identifier: NCT04201197
• Recruitment Status: Completed
• First Posted: December 17, 2019
• Last Update Posted: August 12, 2022
• Sponsor: Johns Hopkins University
• Collaborators: Washington State University; National Center for Complementary and Integrative Health (NCCIH)
• Information provided by (Responsible Party): Johns Hopkins University

Study Description

Brief Summary:

This study will evaluate drug-drug interactions between cannabis extracts containing Tetrahydrocannabinol (THC) and THC+ Cannabinoids (CBD) and probe drugs for select CYP450 pathways including: caffeine (CYP1A2), omeprazole (CYP2C19), losartan (CYP2C9), dextromethorphan (CYP2D6), and midazolam (CYP3A).

Condition or disease	Intervention/treatment	Phase
Drug-Interactions	Drug: Inje cocktail; Drug: THC Cannabis extract; Drug: THC/CBD Cannabis Extract	Phase 1

Detailed Description:

Despite the widespread use and availability of cannabis products, substantive deficiencies remain regarding the potential risks for cannabis or cannabinoids to precipitate adverse interactions with conventional drugs. Evidence from the few systematic clinical studies that have been conducted suggests that THC and CBD can inhibit metabolism of other drugs, via interactions with cytochrome P450 (CYP) enzymes, a large family of enzymes involved in the metabolism of numerous drugs and foreign chemicals in the body. Accordingly, evaluating the potential for drug-drug interactions between cannabis-derived products and common CYP-metabolized drugs merits further investigation. This double-blind, randomized crossover design study will evaluate whether, and to what extent, oral administration of cannabis extracts containing high doses of CBD and/or THC alter the pharmacokinetics of 5 drugs metabolized via CYP pathways including: caffeine (CYP1A2), omeprazole (CYP2C19), losartan (CYP2C9), dextromethorphan (CYP2D6), and midazolam (CYP3A). Healthy adults will complete three experimental dosing sessions, in which participants will orally ingest brownies containing (1) a high THC cannabis extract with a target THC dose of 40mg, (2) a high CBD cannabis extract with a target CBD dose of 1350mg + a THC dose of 40mg, or (3) placebo. In all three experimental dosing sessions, consumption of the cannabis extract infused brownie will be followed by ingestion of a drug "cocktail" comprised of commercial formulations of therapeutic or subtherapeutic doses of each drug. This collection of probe drugs, coined the Inje Cocktail, has been demonstrated to be safe, both administered alone and with various CYP450 inhibitors. At baseline and following administration of the study drugs, a battery of subjective, physiological, and cognitive performance assessments will be completed and biological specimens obtained. Each session will consist of a 12-hour outpatient drug administration visit and a 1-hour outpatient visit the subsequent day for additional biospecimen collection, cognitive testing, and subjective drug effect questionnaires. The study will conclude when 18 participants complete all 3 experimental sessions. The outcomes of this study will be useful to inform clinical decision-making regarding co-administration of cannabinoid-containing products with drugs that are either commonly prescribed by physicians or readily available over-the-counter.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: Placebo controlled, double blind
• Primary Purpose: Basic Science
• Official Title: Interactions Between Cannabinoids and Cytochrome P450-Metabolized Drugs
• Actual Study Start Date: November 10, 2020
• Actual Primary Completion Date: March 16, 2022
• Actual Study Completion Date: July 28, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Inje Cocktail; Single oral administration of caffeine (100mg), omeprazole (20mg), losartan (25mg), dextromethorphan (30mg), and midazolam (1mg)	Drug: Inje cocktail; Acute drug exposure
Experimental: Inje Cocktail + THC extract; Single oral administration of Inje Cocktail + brownie infused with cannabis extract containing 20mg THC	Drug: Inje cocktail; Acute drug exposure; Drug: THC Cannabis extract; Acute drug exposure
Experimental: Inje Cocktail + THC/CBD extract; Single oral administration of Inje Cocktail + brownie infused with cannabis extract containing 20mg THC and 640mg CBD	Drug: Inje cocktail; Acute drug exposure; Drug: THC/CBD Cannabis Extract; Acute drug exposure

Outcome Measures

Primary Outcome Measures :

1. Losartan Area Under the Curve (AUC) in plasma [ Time Frame: 24 hours ]
   Area under the curve concentration (mg/mL) of losartan in plasma
2. Number of Correct Trials on Paced Auditory Serial Addition Task (PASAT) [ Time Frame: 24 hours ]
   Computerized version of Paced Auditory Serial Addition Task will be administered to assess working memory performance. Will report the total correct trials out of 90 recorded (lower scores indicate worse performance).
3. Cognitive performance as assessed by the Divided Attention Task [ Time Frame: 24 hours ]
   Cognitive performance will be evaluated with the Divided Attention Task. Will be measured as the mean distance (in computer pixels) of the mouse cursor from the central stimulus.
4. Drug Effect Questionnaire (DEQ) - Feel Drug Effect [ Time Frame: 24 hours ]
   The DEQ will be used to obtain subjective ratings of "feel drug effects". Score range from 0 (none) to 100 (extreme) using a 100mm line anchored with none/extreme designation.
5. Number of Correct Trials on the Digit Symbol Substitution Task (DSST) [ Time Frame: 24 hours ]
   Computerized version of Digit Symbol Substitution Task will be administered to assess psychomotor performance. Will report the total correct trials in 90 seconds (lower scores indicate worse performance).
6. Beats per minute for Heart Rate (HR) [ Time Frame: 24 hours ]
   HR will be obtained using an automated monitor to evaluate changes in beats per minute as a function of conditions.

Secondary Outcome Measures :

1. Caffeine AUC in plasma [ Time Frame: 24 hours ]
   Area under the curve concentration (mg/mL) of caffeine in plasma
2. Omeprazole AUC in plasma [ Time Frame: 24 hours ]
   Area under the curve concentration (mg/mL) of omeprazole in plasma
3. Dextromethorphan AUC in plasma [ Time Frame: 24 hours ]
   Area under the curve concentration (mg/mL) of dextromethorphan in plasma
4. Midazolam AUC in plasma [ Time Frame: 24 hours ]
   Area under the curve concentration (mg/mL) of midazolam in plasma

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy adult between 18-50 years old
• BMI between 18 to 34 kg/m2
• Willing to use birth control
• Willing to abstain from all medications and citrus fruits for the duration of the study

Exclusion Criteria:

• Medical or psychiatric illness judged by the investigator to put the participant at greater risk of experiencing an adverse event due to drug exposure or completion of other study procedures.
• Use of medications which, in the opinion of the investigator or medical staff, will interfere with the study outcomes or the safety of the participant.
• Clinically significant impairment of kidney, liver, or thyroid function (serum creatinine >1.2 mg/ml (kidney), liver function tests >3x the upper limit of normal (alanine amino transferase >99 U/L; aspartate amino transferase > 99 U/L), and thyroid stimulating hormone > 4.2 uIU/ml), or evidence of current anemia based on blood chemistry testing.
• History of adverse events associated with the ingestion of cannabis or any medications in the Inje cocktail judged by the investigator to present an undue risk of harm to the participant.

Contacts and Locations

Locations

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21224

Sponsors and Collaborators

Johns Hopkins University

Washington State University

National Center for Complementary and Integrative Health (NCCIH)

Investigators

• Principal Investigator: Ryan Vandrey, PhD; Johns Hopkins University

More Information

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT04201197
• Other Study ID Numbers: IRB00207237; U54AT008909 ( U.S. NIH Grant/Contract )
• First Posted: December 17, 2019
• Last Update Posted: August 12, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: We will share protocol information and data to other scientists with reasonable requests for data sharing.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: After publication of the primary outcomes. Availability is indefinite.
• Access Criteria: Send request to PI.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Dronabinol; Hallucinogens; Physiological Effects of Drugs; Psychotropic Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists