Drug-Interactions
Conditions
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.
Interventions
DRUGInje cocktail
Acute drug exposure
DRUGTHC Cannabis extract
Acute drug exposure
DRUGTHC/CBD Cannabis Extract
Acute drug exposure
Sponsors
Washington State University
National Center for Complementary and Integrative Health (NCCIH)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Placebo controlled, double blind
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Change From Baseline Beats Per Minute for Heart Rate (HR) | 8 hours | 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. |
| Peak Change From Baseline Number of Correct Trials on Paced Auditory Serial Addition Task (PASAT) | 8 hours | 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. |
| Peak Change From Baseline Cognitive Performance as Assessed by the Divided Attention Task | 8 hours | 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. |
| Drug Effect Questionnaire (DEQ) - Peak Score for Feel Drug Effect | 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. Peak rating within 24 hours post-dose is reported. |
| Number of Correct Trials on the Digit Symbol Substitution Task (DSST) | 8 hours | 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. |
| Losartan Area Under the Curve (AUC) in Plasma | 24 hours | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Omeprazole AUC in Plasma | 24 hours | 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 |
| Dextromethorphan AUC in Plasma | 24 hours | 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 |
| Midazolam AUC in Plasma | 24 hours | 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 |
| Caffeine AUC in Plasma | 24 hours | 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 |
Countries
United States
Participant flow
Pre-assignment details
This was a within-subjects design, so all participants were exposed to all three conditions in a randomized order.
Participants by arm
| Arm | Count |
|---|---|
| All Evaluable Study Completers All study completers completed the following three conditions, in a randomized order:
1. Single oral administration of Inje Cocktail: caffeine (100mg), omeprazole (20mg), losartan (25mg), dextromethorphan (30mg), and midazolam (1mg)
2. Single oral administration of Inje Cocktail + brownie infused with cannabis extract containing 20mg THC
3. Single oral administration of Inje Cocktail + brownie infused with cannabis extract containing 20mg THC and 640mg CBD | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | All Evaluable Study Completers |
|---|---|
| Age, Continuous | 30 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 0 / 22 | 0 / 22 | 8 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 22 |
Outcome results
Primary
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.
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Drug Effect Questionnaire (DEQ) - Peak Score for Feel Drug Effect | 9.4 Score on a scale | Standard Deviation 27.8 |
| Inje Cocktail + THC | Drug Effect Questionnaire (DEQ) - Peak Score for Feel Drug Effect | 59.2 Score on a scale | Standard Deviation 31.1 |
| Inje Cocktail + THC/CBD | Drug Effect Questionnaire (DEQ) - Peak Score for Feel Drug Effect | 72.8 Score on a scale | Standard Deviation 25.9 |
Primary
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
Time frame: 24 hours
Population: This was a within-subjects design in which all participants were exposed to all three conditions in a randomized order.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Losartan Area Under the Curve (AUC) in Plasma | 164 h*ng/mL | Geometric Coefficient of Variation 74 |
| Inje Cocktail + THC | Losartan Area Under the Curve (AUC) in Plasma | 185 h*ng/mL | Geometric Coefficient of Variation 72 |
| Inje Cocktail + THC/CBD | Losartan Area Under the Curve (AUC) in Plasma | 289 h*ng/mL | Geometric Coefficient of Variation 66 |
Primary
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.
Time frame: 8 hours
Population: All participants were exposed to each of the 3 conditions
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Number of Correct Trials on the Digit Symbol Substitution Task (DSST) | 2.5 Correct trials | Standard Deviation 7.5 |
| Inje Cocktail + THC | Number of Correct Trials on the Digit Symbol Substitution Task (DSST) | -2.7 Correct trials | Standard Deviation 11.2 |
| Inje Cocktail + THC/CBD | Number of Correct Trials on the Digit Symbol Substitution Task (DSST) | -9.9 Correct trials | Standard Deviation 17.6 |
Primary
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.
Time frame: 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Peak Change From Baseline Beats Per Minute for Heart Rate (HR) | -4.4 Beats per minute | Standard Deviation 12.4 |
| Inje Cocktail + THC | Peak Change From Baseline Beats Per Minute for Heart Rate (HR) | 10.1 Beats per minute | Standard Deviation 14.1 |
| Inje Cocktail + THC/CBD | Peak Change From Baseline Beats Per Minute for Heart Rate (HR) | 25.4 Beats per minute | Standard Deviation 20.9 |
Primary
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.
Time frame: 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Peak Change From Baseline Cognitive Performance as Assessed by the Divided Attention Task | -2.1 Computer pixels | Standard Deviation 9.4 |
| Inje Cocktail + THC | Peak Change From Baseline Cognitive Performance as Assessed by the Divided Attention Task | 15.9 Computer pixels | Standard Deviation 24.7 |
| Inje Cocktail + THC/CBD | Peak Change From Baseline Cognitive Performance as Assessed by the Divided Attention Task | 32.7 Computer pixels | Standard Deviation 39.2 |
Primary
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.
Time frame: 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Peak Change From Baseline Number of Correct Trials on Paced Auditory Serial Addition Task (PASAT) | -1.1 Correct trials | Standard Deviation 14.2 |
| Inje Cocktail + THC | Peak Change From Baseline Number of Correct Trials on Paced Auditory Serial Addition Task (PASAT) | -6.6 Correct trials | Standard Deviation 19.1 |
| Inje Cocktail + THC/CBD | Peak Change From Baseline Number of Correct Trials on Paced Auditory Serial Addition Task (PASAT) | -22.7 Correct trials | Standard Deviation 24.6 |
Secondary
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
Time frame: 24 hours
Population: This was a within-subjects design in which all participants were exposed to all three conditions in a randomized order.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Caffeine AUC in Plasma | 18948 h*ng/mL | Geometric Coefficient of Variation 58 |
| Inje Cocktail + THC | Caffeine AUC in Plasma | 18554 h*ng/mL | Geometric Coefficient of Variation 61 |
| Inje Cocktail + THC/CBD | Caffeine AUC in Plasma | 26264 h*ng/mL | Geometric Coefficient of Variation 56 |
Secondary
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
Time frame: 24 hours
Population: This was a within-subjects design in which all participants were exposed to all three conditions in a randomized order.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Dextromethorphan AUC in Plasma | 10.4 h*ng/mL | Geometric Coefficient of Variation 108 |
| Inje Cocktail + THC | Dextromethorphan AUC in Plasma | 13.2 h*ng/mL | Geometric Coefficient of Variation 112 |
| Inje Cocktail + THC/CBD | Dextromethorphan AUC in Plasma | 13.6 h*ng/mL | Geometric Coefficient of Variation 104 |
Secondary
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
Time frame: 24 hours
Population: This was a within-subjects design in which all participants were exposed to all three conditions in a randomized order.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Midazolam AUC in Plasma | 23 h*ng/mL | Geometric Coefficient of Variation 101 |
| Inje Cocktail + THC | Midazolam AUC in Plasma | 24 h*ng/mL | Geometric Coefficient of Variation 75 |
| Inje Cocktail + THC/CBD | Midazolam AUC in Plasma | 36 h*ng/mL | Geometric Coefficient of Variation 84 |
Secondary
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
Time frame: 24 hours
Population: This was a within-subjects design in which all participants were exposed to all three conditions in a randomized order.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Inje Cocktail + Placebo | Omeprazole AUC in Plasma | 385 h*ng/mL | Geometric Coefficient of Variation 90 |
| Inje Cocktail + THC | Omeprazole AUC in Plasma | 379 h*ng/mL | Geometric Coefficient of Variation 86 |
| Inje Cocktail + THC/CBD | Omeprazole AUC in Plasma | 1183 h*ng/mL | Geometric Coefficient of Variation 86 |