Clinical trial NCT04201197: Interactions Between Cannabinoids and Cytochrome P450-Metabolized Drugs
Official title: Interactions Between Cannabinoids and Cytochrome P450-Metabolized Drugs
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Drug-Interactions
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Washington State University
name: National Center for Complementary and Integrative Health (NCCIH)
First posted: 2019-12-17
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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).

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.

Eligibility 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.

Primary outcomes:
measure: Losartan Area Under the Curve (AUC) in Plasma
timeFrame: 24 hours
measure: Peak Change From Baseline Number of Correct Trials on Paced Auditory Serial Addition Task (PASAT)
timeFrame: 8 hours
measure: Peak Change From Baseline Cognitive Performance as Assessed by the Divided Attention Task
timeFrame: 8 hours
measure: Drug Effect Questionnaire (DEQ) - Peak Score for Feel Drug Effect
timeFrame: 24 hours
measure: Number of Correct Trials on the Digit Symbol Substitution Task (DSST)
timeFrame: 8 hours
measure: Peak Change From Baseline Beats Per Minute for Heart Rate (HR)
timeFrame: 8 hours
Secondary outcomes:
measure: Caffeine AUC in Plasma
timeFrame: 24 hours
measure: Omeprazole AUC in Plasma
timeFrame: 24 hours
measure: Dextromethorphan AUC in Plasma
timeFrame: 24 hours
measure: Midazolam AUC in Plasma
timeFrame: 24 hours
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Ryan Vandrey, PhD
role: PRINCIPAL_INVESTIGATOR
References: