The Impact of Product Formulation on the Pharmacokinetics and Pharmacodynamics of Cannabis Edibles

Study Overview
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Brief Summary
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This study will examine the pharmacokinetics and pharmacodynamics of delta-9-tetrahydrocannabinol (THC)-infused chocolates, gummies, and drinks. Healthy adults (N=40) will complete 9 drug administration sessions, including an overnight stay prior to each session. Participants will consume THC containing products in a fasted state; following drug administration, the participants will complete cognitive and psychomotor tasks, subjective assessments, have blood collected, and vital signs monitored.

Detailed Description
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The purpose of this study is to examine the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 popular types of cannabis edibles: THC-infused chocolates, gummies, and drinks. This study will utilize a rigorous double-blind, placebo-controlled, within-subjects design. Healthy adults (N=40; 20 males, 20 females) will complete 9 outpatient drug administration sessions in a randomized order. After 8 hours of monitored fasting, participants will consume 1 of 3 types of edibles (chocolates, gummies, or drinks) that are representative of current retail cannabis products. Products will contain 0 (placebo), 10, or 25mg THC. PD assessments include a battery of cognitive/psychomotor performance tasks shown to be sensitive to oral cannabis at these doses and subjective drug effects. Blood samples will be drawn to measure THC and its primary metabolites. Vital signs will be recorded. These procedures will be completed during each of the 9 study sessions.

Official Title
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The Impact of Product Formulation on the Pharmacokinetics and Pharmacodynamics of Cannabis Edibles

Conditions
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Cannabis Use

Intervention / Treatment
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* Drug: Cannabis
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Have provided written informed consent. Be between the ages of 21 and 55. Be in good general health based on screening procedures (e.g., physical exam, medical history interview, vital signs, routine blood tests). Test negative for illicit drugs (including cannabis) and test negative for alcohol (0% BAC) at screening and before any study sessions. Not be pregnant or nursing (if female). All females must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test at admission for each session. Have prior experience using THC-dominant cannabis. Have a body mass index (BMI) in the range of 16 to 38 kg/m2. Have not donated blood in the past 30 days. Exclusion Criteria Self-reported use of illicit drugs (e.g., amphetamine, cannabis, cocaine, methamphetamine, MDMA, LSD, ketamine, heroin, psilocybin, prescription medications not prescribed to the person) in the past 30 days. History of significant allergic reaction or significant hypersensitivity to cannabis or to any of the other ingredients in the study products. Current concomitant medication use that may interact with the study drug including inhibitors and inducers of CYP2CP and CYP3A4 as well as highly-protein bound drugs and drugs with a narrow therapeutic index such as warfarin, cyclosporine, and amphotericin B. History of or current evidence of a significant medical condition that, in the opinion of the investigator or medical staff, will impact the participant's safety or interfere with study outcomes. Evidence of current psychiatric condition (based on MINI for DSM-5). Been in treatment previously for cannabis use disorder. Receiving of any drug as part of a research study within the past 30 days. History of epilepsy or other serious medical condition.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 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
Interventional Model Description: All participants will complete all dose conditions in a randomized order.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Gummy<br>Participants will self-administer a gummy containing 0mg THC | Drug: Placebo<br>* Placebo will be orally ingested<br>|
| Experimental: Low Dose Gummy<br>Participants will self-administer a gummy containing 10mg THC | Drug: Cannabis<br>* Cannabis will be orally ingested<br>* Other names: marijuana;|
| Experimental: High Dose Gummy<br>Participants will self-administer a gummy containing 25mg THC | Drug: Cannabis<br>* Cannabis will be orally ingested<br>* Other names: marijuana;|
| Placebo Comparator: Placebo Chocolate<br>Participants will self-administer chocolate containing 0mg THC | Drug: Placebo<br>* Placebo will be orally ingested<br>|
| Experimental: Low Dose Chocolate<br>Participants will self-administer chocolate containing 10mg THC | Drug: Cannabis<br>* Cannabis will be orally ingested<br>* Other names: marijuana;|
| Experimental: High Dose Chocolate<br>Participants will self-administer chocolate containing 25mg THC | Drug: Cannabis<br>* Cannabis will be orally ingested<br>* Other names: marijuana;|
| Placebo Comparator: Placebo Beverage<br>Participants will self-administer a beverage containing 0mg THC | Drug: Placebo<br>* Placebo will be orally ingested<br>|
| Experimental: Low Dose Beverage<br>Participants will self-administer a beverage containing 10mg THC | Drug: Cannabis<br>* Cannabis will be orally ingested<br>* Other names: marijuana;|
| Experimental: High Dose Beverage<br>Participants will self-administer a beverage containing 25mg THC | Drug: Cannabis<br>* Cannabis will be orally ingested<br>* Other names: marijuana;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Working memory performance as assessed by the 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. Total correct trials out of 90 recorded is primary outcome (lower scores indicate worse performance). | 8 hours | 
| Psychomotor performance as assessed by the Correct Trials on the Digit Symbol Substitution Task(DSST) | Computerized version of Digit Symbol Substitution Task will be administered to assess psychomotor performance. Total correct trials in 90 seconds is primary outcome (lower scores indicate worse performance). | 8 hours | 
| Attention as assessed by the Mean Distance from the Center Target Stimulus on the Divided Attention Task (DAT) | Computerized version of the Divided Attention Task will be administered to assess attention. Mean distance (in computer pixels) of the mouse cursor from the center target stimulus is primary outcome (lower scores indicate worse performance). | 8 hours | 
| Executive functioning as assessed by the Mean Distance from the Center Target Stimulus on the Divided Attention Task (DAT) | Computerized version of the Divided Attention Task will be administered to assess executive functioning. Mean distance (in computer pixels) of the mouse cursor from the center target stimulus is primary outcome (lower scores indicate worse performance). | 8 hours | 
| DRiving Under the Influence of Drugs (DRUID) application global impairment score - Acute cognitive impairment | Acute cognitive impairment will be assessed with global impairment score(range 0-100) on the DRUID app (higher scores indicate greater impairment). | 8 hours | 
| DRUID application global impairment score - Acute behavioral impairment | Acute behavioral impairment will be assessed with global impairment score(range 0-100) on the DRUID app (higher scores indicate greater impairment). | 8 hours | 
| Like Drug Effect as assessed by the Drug Effect Questionnaire (DEQ) | The DEQ will be used to obtain subjective ratings of like drug effect. Score range from 0 (none) to 100 (extreme) using a 100mm line anchored with none/extreme designation. | 8 hours | 
| Want to take again as assessed by the Drug Effect Questionnaire | The DEQ will be used to obtain subjective ratings of want to take drug again. Score range from 0 (none) to 100 (extreme) using a 100mm line anchored with none/extreme designation. | 8 hours | 
| CMax for THC | Blood concentrations of THC will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The maximum concentrations (Cmax) is determined as the highest concentration reached for each individual. | 8 hours | 
| AUC for THC | Blood concentrations of THC will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The area under the curve (AUC) is calculated across all timepoints, minus the baseline. | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CMax for THC metabolite - 11-OH-THC | Blood concentrations of 11-OH-THC will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The maximum concentrations (Cmax) is determined as the highest concentration reached for each individual. | 8 hours | 
| CMax for THC metabolite- THCCOOH | Blood concentrations of THCCOOH will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The maximum concentrations (Cmax) is determined as the highest concentration reached for each individual. | 8 hours | 
| AUC for THC metabolite - 11-OH-THC | Blood concentrations of 11-OH-THC will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The area under the curve (AUC) is calculated across all timepoints, minus the baseline. | 8 hours | 
| AUC for THC metabolite - THCCOOH | Blood concentrations of THCCOOH will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The area under the curve (AUC) is calculated across all timepoints, minus the baseline. | 8 hours | 
| Tmax for THC | Blood concentrations of THC will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. Time to max concentration (Tmax) will be calculated for each cannabinoid. | 8 hours | 
| Tmax for THC metabolite - 11-OH-THC | Blood concentrations of 11-OH-THC will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. Time to max concentration (Tmax) will be calculated for each cannabinoid. | 8 hours | 
| Tmax for THC metabolite - THCCOOH | Blood concentrations of THCCOOH will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. Time to max concentration (Tmax) will be calculated for each cannabinoid. | 8 hours | 
| Cmax for CBD | Blood concentrations of CBD will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The maximum concentrations (Cmax) is determined as the highest concentration reached for each individual. | 8 hours | 
| Cmax for CBN | Blood concentrations of CBN will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The maximum concentrations (Cmax) is determined as the highest concentration reached for each individual. | 8 hours | 
| Cmax for CBG | Blood concentrations of CBG will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The maximum concentrations (Cmax) is determined as the highest concentration reached for each individual. | 8 hours | 
| AUC for CBD | Blood concentrations of CBD will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The area under the curve (AUC) is calculated across all timepoints, minus the baseline. | 8 hours | 
| AUC for CBN | Blood concentrations of CBN will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The area under the curve (AUC) is calculated across all timepoints, minus the baseline. | 8 hours | 
| AUC for CBG | Blood concentrations of CBG will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. The area under the curve (AUC) is calculated across all timepoints, minus the baseline. | 8 hours | 
| Tmax for CBD | Blood concentrations of CBD will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. Time to max concentration (Tmax) will be calculated for each cannabinoid. | 8 hours | 
| Tmax for CBN | Blood concentrations of CBN will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. Time to max concentration (Tmax) will be calculated for each cannabinoid. | 8 hours | 
| Tmax for CBG | Blood concentrations of CBG will be measured using quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis. Time to max concentration (Tmax) will be calculated for each cannabinoid. | 8 hours | 
| Psychomotor performance as assessed by attempted Trials on the Digit Symbol Substitution Task(DSST) | Computerized version of Digit Symbol Substitution Task will be administered to assess psychomotor performance. Number of attempted trials is a secondary outcome. | 8 hours | 
| Working memory performance as assessed by Reaction Time on Paced Auditory Serial Addition Task (PASAT) | Computerized version of Paced Auditory Serial Addition Task will be administered to assess working memory performance. The secondary outcome is the mean reaction time (in milliseconds) to select correct responses. | 8 hours | 
| Attention as assessed by the Number of peripheral integers correct on Divided Attention Task (DAT) | Computerized version of the Divided Attention Task will be administered to assess attention. The secondary outcome is the number of peripheral stimuli correctly identified. | 8 hours | 
| Executive functioning as assessed by the Number of peripheral integers correct on Divided Attention Task (DAT) | Computerized version of the Divided Attention Task will be administered to assess executive functioning. The secondary outcome is the number of peripheral stimuli correctly identified. | 8 hours | 
| Unpleasant Drug Effect as assessed by the Drug Effect Questionnaire | The DEQ will be used to obtain subjective ratings of unpleasant drug effect. Score range from 0 (none) to 100 (extreme) using a 100mm line anchored with none/extreme designation. | 8 hours | 
| Feel Drug Effect as assessed by the Drug Effect Questionnaire- | The DEQ will be used to obtain subjective ratings of feel drug effect. Score range from 0 (none) to 100 (extreme) using a 100mm line anchored with none/extreme designation. | 8 hours |