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Interactions Between Cannabinoids and Cytochrome P450-Metabolized Drugs

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04201197
Recruitment Status : Completed
First Posted : December 17, 2019
Last Update Posted : August 12, 2022
Sponsor:
Collaborators:
Washington State University
National Center for Complementary and Integrative Health (NCCIH)
Information provided by (Responsible Party):
Johns Hopkins University

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.

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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

Resource links provided by the National Library of Medicine


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




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



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04201197


Locations
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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
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Principal Investigator: Ryan Vandrey, PhD Johns Hopkins University
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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    Key Record Dates
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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