Interactions Between Cannabinoids and Cytochrome P450-Metabolized Drugs

Study Overview
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Brief Summary
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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
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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.

Official Title
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Interactions Between Cannabinoids and Cytochrome P450-Metabolized Drugs

Conditions
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Drug-Interactions

Intervention / Treatment
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* Drug: Inje cocktail
* Drug: THC Cannabis extract
* Drug: THC/CBD Cannabis Extract


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Losartan Area Under the Curve (AUC) in Plasma | Area under the curve concentration (h*ng/mL) of losartan in plasma using data points obtained 0, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 24 hours | 
| Peak Change From Baseline Number of Correct Trials on Paced Auditory Serial Addition Task (PASAT) | Computerized version of Paced Auditory Serial Addition Task will be administered to assess working memory performance. Reported data reflect the peak change from baseline in the total correct trials out of 90 recorded (lower scores indicate worse performance) obtained 1, 2, 3, 4, 6, or 8 hours post-dose. | 8 hours | 
| Peak Change From Baseline Cognitive Performance as Assessed by the Divided Attention Task | Cognitive performance will be evaluated with the Divided Attention Task. Reported data reflect the peak change from baseline performance measured as the mean distance (in computer pixels) of the mouse cursor from the central stimulus recorded 1, 2, 3, 4, 6, or 8 hours post-dose. Higher scores indicate worse performance. | 8 hours | 
| Drug Effect Questionnaire (DEQ) - Peak Score for Feel Drug Effect | 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. Peak rating within 24 hours post-dose is reported. | 24 hours | 
| Number of Correct Trials on the Digit Symbol Substitution Task (DSST) | Computerized version of Digit Symbol Substitution Task will be administered to assess psychomotor performance. Results reported reflect the peak change from baseline on the total correct trials in 90 seconds (lower scores indicate worse performance) assessed 1, 2, 3, 4, 6, or 8 hours post-dose. | 8 hours | 
| Peak Change From Baseline Beats Per Minute for Heart Rate (HR) | HR will be obtained using an automated monitor to evaluate changes in beats per minute as a function of conditions. Data reflect the peak change from baseline measured 1, 2, 3, 4, 6, or 8 hours post-dose. | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Caffeine AUC in Plasma | Area under the curve concentration (h*ng/mL) of caffeine in plasma using data points obtained 0, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 24 hours | 
| Omeprazole AUC in Plasma | Area under the curve concentration (h*ng/mL) of omeprazole in plasma using data points obtained 0, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 24 hours | 
| Dextromethorphan AUC in Plasma | Area under the curve concentration (h*ng/mL) of dextromethorphan in plasma using data points obtained 0, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 24 hours | 
| Midazolam AUC in Plasma | Area under the curve concentration (h*ng/mL) of midazolam in plasma using data points obtained 0, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 24 hours |