Interaction Between Cannabidiol, Meal Ingestion, and Liver Function

Study Overview
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Brief Summary
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According to a recent consumer poll, over 20 million Americans regularly use cannabidiol (CBD). Moreover, 64 million Americans (over 25% of the population) report trying CBD at least once within the previous 2 years. Since the passing of the 2018 Agriculture Improvement Act, the use of hemp-derived products, such as CBD, is highly prevalent across North America. The acceleration of the use of CBD has outpaced our understanding of the associated potential risks and benefits, and the way it is processed within the body. In the current proposed project, investigators wish to continue our ongoing collaboration with Caliper Foods, a Colorado-based manufacturer of CBD products. The focus of this project is three-fold: (1) investigators will compare the pharmacokinetics of different formulations of ingestible CBD; (2) investigators will examine the potential two-way interaction between a meal and one formulation of ingestible CBD; and, (3) investigators will examine the influence of different formulations of CBD on markers of liver function.

Detailed Description
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Pharmacokinetics describes the speed in which something that is ingested is made available within the body (i.e. bioavailability).There are many different preparations/formulations of CBD and they may differ from one another with regards to their pharmacokinetics. One important consideration when evaluating CBD formulations is the pharmacokinetic goal and intended use. For example, if the indication for the CBD is to treat acute pain, then a faster time to peak concentration (Tmax) and higher maximal concentration (Cmax) may be desirable, and also may help to decrease the risk of overdose due to premature repeat self administration. Alternatively, as a chronic treatment for anxiety, a larger area under the curve (AUC) may be preferable if a user follows a regular dosing schedule. One purpose of the proposed project is to compare the pharmacokinetics of different formulations of CBD. The formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). Several previous studies have demonstrated an influence of eating on the pharmacokinetics of ingested CBD. The general consensus appears to be that prior ingestion of a high-fat meal increases the maximal concentration of circulating CBD (Cmax) and lowers the time to attain peak circulating concentration (Tmax). One purpose of the proposed project is to study the influence of a standardized meal on the pharmacokinetics of a CBD formulation. Little is known about the influence of ingested CBD on postprandial metabolism. The thermic effect of feeding (i.e. the increase in metabolic rate above resting metabolism) is considered an important physiological determinant of energy balance, and therefore also of weight gain or loss. Further, the dynamics of circulating glucose and triglycerides following a meal are reflective of metabolic health and predictive of future cardiometabolic disease risk. CBD has been purported to have a variety of beneficial physiological properties, including anti-inflammatory and antioxidant actions. Either of these individual properties alone could favorably modify postprandial metabolism, given that CBD potentially does both, it appears likely that CBD might improve the physiological regulation of postprandial metabolism. One purpose of the proposed project is to determine the influence of CBD on postprandial metabolism. The liver plays a critical regulatory role in postprandial metabolism, and also with the physiological processing of cannabinoids. The relationship between the use of cannabinoids and liver health is unclear. While early studies implied that exposure of the liver to very high daily dosing of cannabinoids may be detrimental, more recent studies are suggesting that some cannabinoids, including CBD, may have therapeutic potential for the treatment of non-alcoholic fatty liver disease. The acute effects of low dose CBD (e.g. 30 mg) on liver function in healthy adults have not been well described, and may be influenced by the formulation of the CBD product (i.e. whether it is water or lipid soluble). One purpose of the proposed project is to determine the acute influence of different formulations of CBD on circulating markers of liver function.

Official Title
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Interaction Between Cannabidiol, Meal Ingestion, and Liver Function

Conditions
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Metabolism, Liver Function, Pharmacokinetics

Intervention / Treatment
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* Dietary Supplement: Cannabidiol (CBD) powder formulation
* Dietary Supplement: Cannabidiol (CBD) Oil based tincture formulation
* Dietary Supplement: Cannabidiol (CBD) Gum Arabic, maltodextrin base formulation
* Dietary Supplement: Cannabidiol (CBD) Gum Arabic, sorbitol base formulation
* Dietary Supplement: Cannabidiol (CBD) Isolate in water formulation
* Dietary Supplement: CBD matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be greater than 18 years of age Weigh more than 110 pounds Have a body mass index greater than 25kg/m^2 Be free of any gastrointestinal or metabolic diseases Be able to refrain from use of any Cannabis or cannabis containing products for three days prior to participating in the study. Exclusion Criteria: Less than 18 years of age Pregnant or breastfeeding Food allergies Autoimmune disorders or with compromised immune function, Celiac disease Inflammatory bowel Diseases Gastrointestinal cancers Diabetes HIV Adverse reactions to ingesting Cannabis spp. or cannabis-containing products (including, but not limited to, marijuana, CBD oils, or CBD/THC containing food products) Taking any of the follow medications: steroids, HMG-CoA reductase inhibitors, calcium channel blockers, antihistamines, HIV antivirals, immune modulators, benzodiazepines, antiarrythmics, antibiotics, anesthetics, antipsychotics, antidepressants, anti-epileptics, beta blockers, proton pump inhibitors, NSAIDs, angiotension II blockers, oral hypoglycemic agents, and sulfonylureas.

Ages Eligible for Study
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Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Two Visits Including A Test Meal<br>Separated by a minimum of 4 days. | Dietary Supplement: Cannabidiol (CBD) powder formulation<br>* T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate<br>Dietary Supplement: CBD matching Placebo<br>* Matching Placebo<br>|
| Experimental: Five Visits Not Involving A Test Meal<br>Separated by a minimum of 14 days. | Dietary Supplement: Cannabidiol (CBD) powder formulation<br>* T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate<br>Dietary Supplement: Cannabidiol (CBD) Oil based tincture formulation<br>* 30 mg CBD isolate in MCT oil (1:1 ratio of CBD to Medium Chain Triglycerides oil)<br>Dietary Supplement: Cannabidiol (CBD) Gum Arabic, maltodextrin base formulation<br>* 10% CBD Gum Arabic, maltodextrin base<br>Dietary Supplement: Cannabidiol (CBD) Gum Arabic, sorbitol base formulation<br>* 10% CBD Gum Arabic, sorbitol base<br>Dietary Supplement: Cannabidiol (CBD) Isolate in water formulation<br>* formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare different formulations of CBD Pharmacokinetic Time to Maximum Concentration- (Tmax) | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be sampled at standardized intervals over 4-hours to calculate Tmax (hours). | Venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Compare different formulations of CBD Pharmacokinetic maximum concentration-(Cmax). | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be sampled at standardized intervals over 4-hours to calculate Cmax (ng/mL). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Compare different formulations of CBD Pharmacokinetic area under the curve representing total cannabidiol exposure between 0 and 4 h (AUC 0-4) | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be sampled at standardized intervals over 4-hours to calculate AUC 0-4 (h x ng/mL). | Venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Compare different formulations of CBD Pharmacokinetic area under the curve an estimate of total exposure to CBD over time (AUC 0-inf). | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be sampled at standardized intervals over 4-hours to calculate AUC 0-inf (h x ng/mL). | Venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Compare different formulations of CBD Pharmacokinetic amount of time it takes to decrease the circulating concentration to half of its initial value (t1/2). | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be sampled at standardized intervals over 4-hours to calculate t1/2 (h). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Compare different formulations of CBD Pharmacokinetic rate at which CBD is absorbed into the body (Ka). | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be sampled at standardized intervals over 4-hours to calculate Ka(1/h). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Compare different formulations of CBD Pharmacokinetic rate at which CBD is removed from the body (Ke). | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be sampled at standardized intervals over 4-hours to calculate Ke (1/h). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Compare different formulations of CBD Pharmacokinetic volume of distribution- (Vd) | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be sampled at standardized intervals over 4-hours to calculate Vd (L). | Venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine the Pharmacokinetic parameter Tmax of a T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate after standardized meal | At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts the time to attain peak circulating concentration Tmax (h). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine the Pharmacokinetic parameter Cmax of a T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate after standardized meal | At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD Cmax (ng/L). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine the Pharmacokinetic parameter AUC 0-4 of a T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate after standardized meal | At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD AUC 0-4 (hxng/mL). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine the Pharmacokinetic parameter AUC 0-inf of a T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate after standardized meal | At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD AUC 0-inf (hxng/mL). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine the Pharmacokinetic parameter t1/2 of a T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate after standardized meal | At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD t1/2 (h). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine the Pharmacokinetic parameter Ka of a T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate after standardized meal | At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD Ka (1/h). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine the Pharmacokinetic parameter Ke of a T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate after standardized meal | At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD Ke (1/h). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine the Pharmacokinetic parameter Vd of a T-P-S-10 Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate after standardized meal | At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD Vd (L). | venous blood will be sampled at standardized intervals over 4-hours: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration. | 
| Determine ingested CBD on postprandial metabolism via indirect calorimetry | At the 2 randomized visits Including a Test Meal measure resting metabolic rate (RMR- kcal/day) followed immediately by ingestion of a liquid meal and a single 30 mg dose of Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate or a placebo. | Change from the 2 randomized visits Including a test meal separated by 4 days | 
| Determine ingested CBD on postprandial metabolism via measurements of glucose | At the 2 randomized visits Including a Test Meal measure blood glucose at standardized intervals after ingestion of a liquid meal and a single dose of Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate or a placebo. | Compare 2 randomized visits Including a test meal collected at 90,150,210,725 minutes. | 
| Determine ingested CBD on postprandial metabolism via measurements of insulin | At the 2 randomized visits Including a Test Meal measure insulin at standardized intervals after ingestion of a liquid meal and a single dose of Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate or a placebo. | Compare 2 randomized visits Including a test meal collected at 90,150,210,725 minutes. | 
| Determine ingested CBD on postprandial metabolism via measurements of triglycerides | At the 2 randomized visits Including a Test Meal measure triglycerides at standardized intervals after ingestion of a liquid meal and a single dose of Caliper powder - 30 mg CBD in the form of 300 mg of 10% CBD isolate or a placebo. | Compare 2 randomized visits Including a test meal collected at 90,150,210,725 minutes. | 
| Determine the change in the acute influence of liver function, alanine aminotransferase (ALT), with the different formulations of CBD. | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be collected at standardized intervals and analyzed for alanine aminotransferase (ALT). | Change from baseline at time 0, 60, 120 minutes for each formulation, visits separated by 14 days | 
| Determine the change in the acute influence of liver function, albumin, with the different formulations of CBD. | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be collected at standardized intervals and analyzed for albumin. | Change from baseline at time 0, 60, 120 minutes for each formulation, visits separated by 14 days | 
| Determine the change in the acute influence of liver function, alkaline phosphatase, with the different formulations of CBD. | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be collected at standardized intervals and analyzed for alkaline phosphatase. | Change from baseline at time 0, 60, 120 minutes for each formulation, visits separated by 14 days | 
| Determine the change in the acute influence of liver function, aspartate aminotransferase, with the different formulations of CBD. | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be collected at standardized intervals and analyzed for aspartate aminotransferase. | Change from baseline at time 0, 60, 120 minutes for each formulation, visits separated by 14 days | 
| Determine the change in the acute influence of liver function, total bilirubin, with the different formulations of CBD. | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be collected at standardized intervals and analyzed for total bilirubin. | Change from baseline at time 0, 60, 120 minutes for each formulation, visits separated by 14 days | 
| Determine the change in the acute influence of kidney function, blood urea, with the different formulations of CBD. | The different formulations will be standardized for CBD dose (30 mg) but will differ in their preparation (e.g. water vs. fat-soluble). At the 5 randomized Visits Not Including A Test Meal venous blood will be collected at standardized intervals and analyzed for blood urea. | Change from baseline at time 0, 60, 120 minutes for each formulation, visits separated by 14 days |