Interaction Between Cannabidiol, Meal Ingestion, and Liver Function

Not Applicable

Completed

Conditions: Liver Function
Pharmacokinetics
Metabolism

Interventions: Dietary Supplement: Cannabidiol (CBD) powder formulation
Dietary Supplement: Cannabidiol (CBD) Oil based tincture formulation
Dietary Supplement: CBD matching Placebo
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

Registration Number: NCT04971837

Lead Sponsor: Colorado State University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Five Visits Not Involving A Test Meal	Cannabidiol (CBD) Gum Arabic, sorbitol base formulation	Separated by a minimum of 14 days.
Five Visits Not Involving A Test Meal	Cannabidiol (CBD) Isolate in water formulation	Separated by a minimum of 14 days.
Five Visits Not Involving A Test Meal	Cannabidiol (CBD) Oil based tincture formulation	Separated by a minimum of 14 days.
Two Visits Including A Test Meal	Cannabidiol (CBD) powder formulation	Separated by a minimum of 4 days.
Five Visits Not Involving A Test Meal	Cannabidiol (CBD) powder formulation	Separated by a minimum of 14 days.
Two Visits Including A Test Meal	CBD matching Placebo	Separated by a minimum of 4 days.
Five Visits Not Involving A Test Meal	Cannabidiol (CBD) Gum Arabic, maltodextrin base formulation	Separated by a minimum of 14 days.

Primary Outcome Measures

Name	Time	Method
Pharmacokinetic Time to Maximum Concentration- (Tmax) for Different Formulations of CBD	Venous blood will be sampled at standardized intervals: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration.	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 (minutes).
Pharmacokinetic Maximum Concentration-(Cmax) for Different Formulations of CBD	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.	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).
Pharmacokinetic Area Under the Curve Representing Total Cannabidiol Exposure Between 0 and 4 h (AUC 0-4) for Different Formulations of CBD	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.	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 (min x ng/mL).
Pharmacokinetic Area Under the Curve an Estimate of Total Exposure to CBD Over Time (AUC 0-inf) for Different Formulations of CBD	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.	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 (mins x ng/mL).
Pharmacokinetic Amount of Time it Takes to Decrease the Circulating Concentration to Half of Its Initial Value (t1/2) for Different Formulations of CBD	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.	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 (mins).
Pharmacokinetic Rate at Which CBD is Absorbed Into the Body (Ka) for Different Formulations of CBD	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.	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).
Pharmacokinetic Rate at Which CBD is Removed From the Body (Ke) for Different Formulations of CBD	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.	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).
CBD Pharmacokinetic Volume of Distribution- (Vd) for Different Formulations of CBD	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.	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).
Pharmacokinetic Parameter Tmax of a Formulation 725 After a Standardized Meal	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.	At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts the time to attain peak circulating concentration Tmax (mins).
Pharmacokinetic Parameter Cmax of a Formulation 725 After a Standardized Meal	venous blood will be sampled at standardized intervals over: 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration.	At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD Cmax (ng/L).
Pharmacokinetic Parameter AUC 0-4 of Formulation 725 After a Standardized Meal	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.	At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD AUC 0-4 (min x ng/mL).
Pharmacokinetic Parameter AUC 0-inf of Formulation 725 After a Standardized Meal	venous blood will be sampled at standardized intervals 0, 10, 20, 30, 45, 60, 120, 180, and 240 minutes and will be analyzed to compare circulating CBD concentration.	At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD AUC 0-inf (min x ng/mL).
Pharmacokinetic Parameter t1/2 of Formulation 725 After a Standardized Meal	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.	At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD t1/2 (h).
Pharmacokinetic Parameter Ka of Formulation 725 After a Standardized Meal	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.	At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD Ka (1/h).
Pharmacokinetic Parameter Ke of Formulation 725 After a Standardized Meal	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.	At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD Ke (1/h).
Pharmacokinetic Parameter Vd of Formulation 725 After a Standardized Meal	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.	At the 2 randomized visits Including a Test Meal, determine if a high-fat meal impacts maximal concentration of circulating CBD Vd (L).
Ingested CBD on Postprandial Metabolism Via Indirect Calorimetry	Randomized visit Including a test meal collected during 235 minutes of TEF	At the 2 randomized visits Including a Test Meal Thermic Effect of Feeding (TEF) Under the Curve was calculated from standardized intervals prior to and after ingestion of a liquid meal and a single dose of Formulation 725.
Ingested CBD on Postprandial Metabolism Via Measurements of Glucose	Compare 2 randomized visits Including a test meal collected at baseline,10,20,30,45,60,90,120,150,180,210, and 240 minutes.	At the 2 randomized visits Including a Test Meal, glucose Area Under the Curve was calculated from standardized intervals after ingestion of a liquid meal and a single dose of Formulation 725.
Ingested CBD on Postprandial Metabolism Via Measurements of Insulin	Compare 2 randomized visits Including a test meal collected at baseline,10,20,30,45,60,90,120,150,180,210, and 240 minutes.	At the 2 randomized visits Including a Test Meal insulin Area Under the Curve was calculated from standardized intervals after ingestion of a liquid meal and a single dose of Formulation 725.
Ingested CBD on Postprandial Metabolism Via Measurements of Triglycerides	Compare 2 randomized visits Including a test meal collected at baseline,10,20,30,45,60,90,120,150,180,210, and 240 minutes.	At the 2 randomized visits Including a Test Meal triglyceride Area Under the Curve was calculated from standardized intervals after ingestion of a liquid meal and a single dose of Formulation 725.
Acute Influence of Liver Function, Alanine Aminotransferase (ALT), With the Different Formulations of CBD.	Change from baseline at time 0, 60, 240 minutes for each formulation, visits separated by 14 days	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).
Acute Influence of Liver Function, Albumin, for Different Formulations of CBD.	Change from baseline at time 0, 60, 240 minutes for each formulation, visits separated by 14 days	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.
Acute Influence of Liver Function, Alkaline Phosphatase, With the Different Formulations of CBD.	Change from baseline at time 0, 60, 240 minutes for each formulation, visits separated by 14 days	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.
Acute Influence of Liver Function, Aspartate Aminotransferase, With the Different Formulations of CBD.	Change from baseline at time 0, 60, 240 minutes for each formulation, visits separated by 14 days	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.
Acute Influence of Liver Function, Total Bilirubin, With the Different Formulations of CBD.	Change from baseline at time 0, 60, 240 minutes for each formulation, visits separated by 14 days	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.
Acute Influence of Kidney Function, Blood Urea, With the Different Formulations of CBD.	Change from baseline at time 0, 60, 240 minutes for each formulation, visits separated by 14 days	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.
CBD on Postprandial Metabolism Via Indirect Calorimetry	Compare 2 randomized visits Including a test meal collected during 45 minutes of resting metabolic rate	At the 2 randomized visits including a Resting Metabolic Rate prior to and after ingestion of a single dose of Formulation 725 or placebo.