Cannabidiol Effects on Cardiovascular System and Exercise Responses

Study Overview
=================
Brief Summary
-----------------
To identify the autonomic effects of recreationally-relevant doses of cannabidiol (CBD) in an older population, and to evaluate the effect of CBD on exercise performance and recovery.

Detailed Description
-----------------
Heart rate variability (HRV) analysis is a common method used to evaluate the function of the autonomic nervous system. While heart rate is the number of heart beats per minute, HRV is the fluctuation of the time intervals between those beats (interbeat intervals). If the interbeat intervals are too similar, this is an indication of an unhealthy heart. A major influence on heart rate (and thus interbeat interval), is the autonomic nervous system which is divided into two branches: sympathetic and parasympathetic. HRV represents the balance between both systems, with higher HRV being associated with greater parasympathetic activity, and lower HRV with greater sympathetic activity. While there is no optimal level of HRV, a higher HRV is associated with reduced stress and good health, and a lower HRV is associated with chronic diseases and cardiovascular risk. The current study will evaluate the effect of recreationally-relevant doses of CBD (25-200mg) on resting HRV in older adults (aims 1&2). Investigators will also look at the effects of CBD on cardiovascular fitness by having participants complete a maximum graded exercise test under the influence of a placebo and again after ingesting a single dose of CBD (aims 3&4).

Official Title
-----------------
Cannabidiol Effects on Cardiovascular System and Exercise Responses

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Cannabidiol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: male or female 18+ years (aims 3&4) 50+ years (aims 1&2) participants must agree to fast for 4 hours and abstain from food or beverages containing alcohol, caffeine, or CBD for 12 hours prior to each experimental session participants must agree to avoid exercise for 6 hours prior to each experimental session completion of Health History Screening Questionnaire with report indicating overall good health ability to comprehend and satisfactorily comply with protocol requirements written informed consent given prior to study participation low-risk for VO2max testing (aims 3&4) Exclusion Criteria: women who are pregnant or lactating participants who have a history of adverse reactions to cannabidiol current medications that might influence the cardiovascular and/or autonomic systems any cardiac, pulmonary, renal, or metabolic disease walking difficulty (aims 3&4) waiting for a stress test for a medical reason (aims 3&4) medical contraindication to performing a treadmill stress test (aims 3&4)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Each participant will receive a different dose in consecutive weeks (one of which is a placebo), thus serving as their own control.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will ingest 3ml of non-CBD containing MCT (medium-chain triglycerides) oil. | Drug: Placebo<br>* Placebo oral product formulated in MCT (medium chain triglyceride) oil<br>|
| Experimental: Cannabidiol 25 mg<br>Participants will ingest 3ml of MCT (medium-chain triglycerides) oil containing 25 mg of CBD. | Drug: Cannabidiol<br>* Cannabidiol oral product formulated in MCT (medium chain triglyceride) oil<br>* Other names: CBD;|
| Experimental: Cannabidiol 50 mg<br>Participants will ingest 3ml of MCT (medium-chain triglycerides) oil containing 50 mg of CBD. | Drug: Cannabidiol<br>* Cannabidiol oral product formulated in MCT (medium chain triglyceride) oil<br>* Other names: CBD;|
| Experimental: Cannabidiol 200 mg<br>Participants will ingest 3ml of MCT (medium-chain triglycerides) oil containing 200 mg of CBD. | Drug: Cannabidiol<br>* Cannabidiol oral product formulated in MCT (medium chain triglyceride) oil<br>* Other names: CBD;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in heart rate variability (HRV) as assessed by time-domain analysis: standard deviation of RR intervals. | Time-domain measurements quantify the amount of variability of the heart's interbeat (RR) intervals and include the metric: standard deviation of RR intervals (SDNN). Higher values indicate greater HRV. | 4 weeks | 
| Change in heart rate variability (HRV) as assessed by time-domain analysis: root mean square of successive differences. | Time-domain measurements quantify the amount of variability of the heart's interbeat (RR) intervals and include the metric: root mean square of successive differences (RMSSD). Higher values indicate greater HRV. | 4 weeks | 
| Change in heart rate variability (HRV) as assessed by frequency-domain analysis: high-frequency (HF). | Frequency-domain measurements estimate the distribution of absolute or relative power into four heart rate oscillation frequency bands: ultra-low-frequency (ULF), very-low-frequency (VLF), low-frequency (LF) and high-frequency (HF). A high HF reflects parasympathetic dominance. | 4 weeks | 
| Change in heart rate variability (HRV) as assessed by frequency-domain analysis: low-frequency (LF). | Frequency-domain measurements estimate the distribution of absolute or relative power into four heart rate oscillation frequency bands: ultra-low-frequency (ULF), very-low-frequency (VLF), low-frequency (LF) and high-frequency (HF). LF reflects both sympathetic and parasympathetic activity. | 4 weeks | 
| Change in heart rate variability (HRV) as assessed by frequency-domain analysis: LF/HF ratio. | A low LF/HF ratio reflects parasympathetic dominance, whereas a high LF/HF ratio reflects sympathetic dominance. | 4 weeks | 
| Change in magnitude of autonomic stress test responses as assessed by changes in blood pressure. | Responses to autonomic stress test include a change in blood pressure if sympathetic outflow is activated. The magnitude of change will be compared before and after CBD ingestion. | Week 5 | 
| Change in magnitude of autonomic stress test responses as assessed by changes in heart rate. | Responses to autonomic stress test include a change in heart rate if parasympathetic outflow is activated. The magnitude of change will be compared before and after CBD ingestion. | Week 5 | 
| Maximal oxygen consumption (VO2max) | Maximum oxygen consumption will be calculated during treadmill test (using the Bruce Protocol) | 8 days | 
| Heart rate | Change in heart rate will be assessed throughout session | through study completion, an average of 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure | Change in blood pressure will be assessed throughout session | through study completion, an average of 4 weeks | 
| Borg's Category-Ratio Scale for Rating of Perceived Exertion | The Borg Scale is a self-reporting instrument assessing intensity of perceived exertion on a 0 to 10 scale, 0 being rest and 10 maximal effort. | 8 days |