The Influence of Cannabis Inhalation During Exercise on Cardiovascular Health and Function: Exploring the Optimal Balance of Cannabinoids and Mode of Administration to Decrease Risk and Maximize Benefits
Phase: EARLY_PHASE1
Conditions: Cannabis, Cardiovascular Risk Factor
Sponsor: Jamie Burr

The Influence of Cannabis Inhalation During Exercise on 
Cardiovascular Health and Function: Exploring the Optimal Balance of 
Cannabinoids and Mode of Administration to Decrease Risk and 
Maximize Benefits 
PROTOCOL IDENTIFIER: 
UOG-HPL-CAN (REB# 18-11-013) 
PROTOCOL VERSION AND 
DATE:  
v.3 
August 11, 2020 
SPONSOR:  
Dr. Jamie Burr 
Associate Professor 
50 Stone Road East 
Guelph, Ontario,  
N1G 2W1, Canada 
Tel: (519) 824-4120 
AUTHORIZING SIGNATORY 
FOR PROTOCOL AND 
AMENDMENTS: 
Dr. Jamie Burr 
 
PRINCIPAL INVESTIGATOR 
(S): 
 
Dr. Jamie Burr 
Associate Professor 
50 Stone Road East 
Guelph, Ontario,  
N1G 2W1, Canada 
Tel: (519) 824-4120 
QUALIFIED INVESTIGATOR 
Dr. Margo Mountjoy 
Sports Medicine 
50 Stone Road East 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
 
ii 
Guelph, Ontario 
N1G 2W1, Canada 
Tel: 519-885-5426 ext. 21122 
Name(s) and address(es) of 
the clinical laboratory(ies) and 
other medical and/or technical 
department(s) and/or 
institutions involved in the 
trial. 
 
Human Performance and Health Research Laboratory 
Department of Human Health and Nutritional Sciences 
University of Guelph 
50 Stone Road East 
Guelph, Ontario 
N1G 2W1 

  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis ............................................................................................................................................... 1 
1.2 
Schema ................................................................................................................................................ 3 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 4 
2 
INTRODUCTION ........................................................................................................................................... 4 
2.1 
Study Rationale ................................................................................................................................... 4 
2.2 
Background .......................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment ................................................................................................................... 6 
2.3.1 
Known Potential Risks .................................................................................................... 6 
2.3.2 
Known Potential Benefits ............................................................................................... 7 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................... 7 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................... 9 
4 
STUDY DESIGN .......................................................................................................................................... 10 
4.1 
Overall Design ................................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design ............................................................................................. 11 
4.3 
Justification for Dose ........................................................................................................................ 12 
4.4 
End of Study Definition ..................................................................................................................... 12 
5 
STUDY POPULATION ................................................................................................................................ 13 
5.1 
Inclusion Criteria: .............................................................................................................................. 13 
5.2 
Exclusion Criteria .............................................................................................................................. 13 
5.3 
Lifestyle Considerations ................................................................................................................... 14 
5.4 
Screen Failures ................................................................................................................................. 14 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 15 
6 
STUDY INTERVENTION ............................................................................................................................ 15 
6.1 
Study Intervention(s) Administration .............................................................................................. 15 
6.1.1 
Study Intervention Description .................................................................................... 15 
6.1.2 
Dosing and Administration ........................................................................................... 15 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................... 16 
6.2.1 
Acquisition and accountability ..................................................................................... 16 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................... 16 
6.2.3 
Product Storage and Stability ...................................................................................... 16 
6.2.4 
Preparation ..................................................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 16 
6.4 
Study Intervention Compliance ....................................................................................................... 17 
6.5 
Concomitant Therapy ....................................................................................................................... 17 
6.5.1 
Rescue Medicine ........................................................................................................... 18 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 18 
7.1 
Discontinuation of Study Intervention ............................................................................................ 18 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................................. 18 
7.3 
Lost to Follow-Up .............................................................................................................................. 19 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 19 
8.1 
Efficacy Assessments ...................................................................................................................... 19 
8.2 
Safety and Other Assessments ...................................................................................................... 20 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 21 

  
 
iii 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 21 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................. 21 
8.3.3 
Classification of an Adverse Event ............................................................................. 22 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 22 
8.3.5 
Adverse Event Reporting ............................................................................................. 23 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 23 
8.3.7 
Reporting Events to Participants ................................................................................. 24 
8.3.8 
Events of Special Interest ............................................................................................ 24 
8.3.9 
Reporting of Pregnancy ................................................................................................ 24 
8.4 
Unanticipated Problems ................................................................................................................... 24 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................ 24 
8.4.2 
Unanticipated Problem Reporting ............................................................................... 24 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 25 
9 
STATISTICAL CONSIDERATIONS . ........................................................................................................ 25 
9.1 
Statistical Hypotheses ...................................................................................................................... 25 
9.2 
Sample Size Determination ............................................................................................................. 26 
9.3 
Populations for Analyses ................................................................................................................. 26 
9.4 
Statistical Analyses ........................................................................................................................... 26 
9.4.1 
General Approach ......................................................................................................... 26 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................ 27 
9.4.3 
Analysis of the Secondary Endpoint(s) ...................................................................... 27 
9.4.4 
Safety Analyses ............................................................................................................. 27 
9.4.5 
Baseline Descriptive Statistics .................................................................................... 27 
9.4.6 
Planned Interim Analyses ............................................................................................ 27 
9.4.7 
Sub-Group Analyses ..................................................................................................... 28 
9.4.8 
Tabulation of Individual participant Data. ................................................................... 28 
9.4.9 
Exploratory Analyses .................................................................................................... 28 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 28 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 28 
10.1.1 
Informed Consent Process .......................................................................................... 28 
10.1.2 
Study Discontinuation and Closure ............................................................................. 29 
10.1.3 
Confidentiality and Privacy ........................................................................................... 29 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 30 
10.1.5 
Key Roles and Study Governance .............................................................................. 30 
10.1.6 
Clinical Monitoring ......................................................................................................... 30 
10.1.7 
Quality Assurance and Quality Control ...................................................................... 30 
10.1.8 
Data Handling and Record Keeping ........................................................................... 31 
10.1.9 
Protocol Deviations ....................................................................................................... 31 
10.1.10 
Publication and Data Sharing Policy .......................................................................... 31 
10.1.11 
Conflict of Interest Policy .............................................................................................. 32 
10.2 
Additional Considerations ................................................................................................................ 32 
10.3 
Abbreviations ..................................................................................................................................... 32 
10.4 
Protocol Amendment History ........................................................................................................... 34 
11 
REFERENCES ............................................................................................................................................. 35 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP). The Principal Investigator-Sponsor will assure that no deviation 
from, or changes to the protocol will take place without prior agreement from Health Canada, or 
the Institutional Review Board (IRB), except where necessary to eliminate an immediate 
hazard(s) to the trial participants. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials have 
been submitted to the IRB for review and approval.  Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled.  Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the 
study.  All changes to the consent form will be IRB approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, 
using a previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
The Influence of Cannabis Inhalation During Exercise on 
Cardiovascular Health and Function: Exploring the Balance of 
Cannabinoids and Mode of Administration to Decrease Risk and 
Maximize Benefits 
Study Description: 
The current study will examine the acute cardiovascular response to 
cannabis consumption at rest, and when combined with exercise. It 
will examine the influence of inhalation method, and cannabinoid 
concentration.   
Objectives: 
 
Primary Objective:  
Determine the effects of cannabis consumption at rest and during 
exercise on the human cardiovascular system 
Secondary Objective:  
Investigate the influence of consumption methods (smoking vs. 
vaporizing) and cannabinoid balances (i.e. THC vs. CBD).   
Determine the effects of cannabis consumption on exercise 
performance 
 
 
Endpoints: 
Primary Endpoints: Carotid-Femoral Pulse Wave Velocity, Brachial 
Artery Flow-Mediated Dilation, Cardiac Function (dynamics), Muscle 
Sympathetic Nerve Activity 
Secondary Endpoints: Blood Pressure, Heart Rate, Work 
Completed, Rate Pressure Product, Rating of Perceived Exertion 
Study Population: 
20, healthy male and female recreational cannabis users aged 19-
45yr will be recruited for the current study 
 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
All activities will be performed at the Human Performance and 
Health Research Laboratory in the Department of Human Health and 
Nutritional Sciences, College of Biological Sciences, at the 
University of Guelph. All research will be conducted in Guelph, 
Ontario, Canada. Participants will healthy volunteers.  

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Description of Study 
Intervention: 
Participants will consume 100mg of cannabis via smoking or 
vaporizing. Cannabis consumed will possess THC and CBD ratios of 
either 13.6±2.7%:<1%, or <1%:14.5±2.9%. 
Study Duration: 
It is estimated that the current study will require a 12 month period 
for completion, beginning from the onset of study enrollment, to the 
completion of data analysis 
Participant Duration: 
Depending on degree of involvement, participant duration of this 
study will be either 6 weeks, or 10 weeks. 
 
 

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1.2 SCHEMA 
 
Visit 0 
Introductory 
Visit 
 
 
Visit 1 
Exercise 
Control Visit 
 
 
Visit 2-5 
Phase I 
Cannabis 
Visits 
 
 
 
 
Visits 2-5 
Phase I 
Cannabis + 
Exercise  
Visits 
 
 
 
Visit 6-9 
Phase II 
Cannabis 
Visits 
 
 
 
Visit 6-9 
Phase II 
Cannabis + 
Exercise 
Visits 
 
 
Figure 1. Schematic breakdown of study structure, and schedule of measures. 
 
 
Obtain informed consent, screen for participant eligibility, obtain measures 
of height, weight, ECG, blood pressure, and heart rate. Measure maximal 
aerobic capacity via VO2 max test. 

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1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
 
Procedure 
Introductory Visit (Visit 
0), Day 0 
Exercise Control Visit 
(Visit 1), Day 7±1 day 
Phase I Cannabis Visit 
(Visit 2), Day 14±1 day 
Phase I Cannabis + 
Exercise Visit (Visit 3), 
Day 21±1 day 
Phase I Cannabis Visit 
(Visit 4), Day 28±1 day 
Phase I Cannabis + 
Exercise Visit (Visit 5), 
Day 35±1 day 
Phase II Cannabis Visit 
(Visit 6), Day 42±1 day 
Phase II Cannabis + 
Exercise Visit (Visit 7), 
Day 49±1 day 
Phase II Cannabis Visit 
(Visit 8), Day 56±1 day 
Phase II Cannabis + 
Exercise Visit (Visit 9), 
Day 63±1 day 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility Questionnaire 
X 
 
 
 
 
 
 
 
 
 
Physical Activity Readiness 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure and Heart Rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inquiry of Changes to Health and 
Prescription Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VO2 Max Test 
X 
 
 
 
 
 
 
 
 
 
Pulse Wave Velocity 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brachial Artery FMD 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiography 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
20 Minute Maximal Cycling Exercise 
 
X 
 
X 
 
X 
 
X 
 
X 
Vaporization of High THC Cannabis 
 
 
X 
X 
 
 
 
X 
X 
 
Smoking of High THC Cannabis 
 
 
 
 
X 
X 
 
 
 
 
Vaporization of High CBD Cannabis 
 
 
 
 
 
 
X 
 
 
X 
Indirect Calorimetry/CPET 
X 
X 
 
X 
 
X 
 
X 
 
X 
Microneurography (MSNA) 
 
 
X 
 
 
 
 
 
 
 
Stress Echocardiography 
 
 
X 
 
X 
 
X 
 
X 
 
Measurement of Continuous Blood 
Pressure 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Impedance Cardiography 
 
X 
 
X 
 
X 
 
X 
 
X 
Drug Effects Questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
This study will use a randomized crossover design. Phase I of this study will occur prior to the initiation of phase II. If a participant 
enters the study in phase II, but did not participate in phase I, they will be required to complete the introductory and exercise 
control visits. Visits 2-5 and 6-9 will occur in a randomized order, which will be individualized for each participant.   
 
2 
 
INTRODUCTION 
 
2.1 STUDY RATIONALE  
 
Cannabis is used by a large number of Canadians, with a lifetime prevalence of use of 42.5%, 
and 12.2% of Canadians reporting having used cannabis in the past year1. With the recent 
change in federal legislation legalizing recreational use, cannabis consumption is likely to 
increase. Given its previously illicit status globally, there is a significant lack of research 
examining the effects of recreational cannabis use on cardiovascular function. This lack of 
knowledge on the effects on human physiology is a gap that must be filled given the possible 
increase in widespread use among Canadians. Studies performed in animal models suggest a 
number of adverse cardiovascular effects of cannabis consumption, including reduced 
endothelial function, increased arterial stiffness, and sympathetic nerve activity2–4. Each of these 
outcomes have been implicated as risk factors for cardiovascular disease5–7. One area that has 
been especially unexamined is the unique physiological effects of cannabis of varied 
cannabinoid compositions, specifically high and low concentrations of delta-9-

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tetrahydracannabinol (THC) and cannabidiol (CBD). Additionally, minimal research has 
examined the different effects of two popular methods of consumption, smoking and vaporizing. 
Preliminary evidence has suggested that vaporizing removes some of the harmful components 
associated with smoking, such as the intake of particulate and carbon monoxide8,9. Research 
has also identified numerous adverse cardiovascular effects of smoking THC-containing 
cannabis, in addition to other harmful pro-inflammatory and pro-oxidant effects4. In contrast, 
CBD has been identified as possessing anti-inflammatory10 and anti-oxidant effects11,12. 
Understanding consumption of cannabis of varied cannabinoid content through different 
methods of intake on the cardiovascular system is necessary to properly understand the health 
risks of recreational cannabis use, and how such risks can be mitigated. Unsurprisingly, no 
research has been conducted on whether or not these cardiovascular effects persist under the 
additional cardiovascular stress of exercise. This question becomes of relevance considering 
recent evidence that suggests that concurrent cannabis use with exercise is increasingly 
common13. Furthermore, exercise is a well-established transient stress that can induce 
temporary arterial stiffening14, impaired endothelial function15, and increased myocardial 
workload16. The independent effects of cannabis and exercise have never been 
comprehensively tested in combination and, thus, the current study seeks to identify the 
cardiovascular response to this combined stimulus. 
 
2.2 BACKGROUND  
 
Plant species of the Cannabis genus have been used by humans for millennia, with the earliest 
use possibly occurring as early as 8000BC17. Despite its long history of use by humans, both 
the physiological effects and the therapeutic potential associated with cannabis consumption 
remain incompletely understood. A substantial proportion of clinical research focusing on 
cannabis has attempted to evaluate its efficacy for treating non-communicable diseases such as 
multiple sclerosis and epilepsy, as well as for treatment of pain18–20. Due in part to this work, 
cannabis can now be physician prescribed to patients in a number of countries globally21. While 
a large body of clinical research has aided in unveiling the utility of cannabis in improving a 
range of outcomes, a comprehensive understanding of the physiological effects of the plant is 
lacking.  
 
It is well established that consumption of cannabis can induce a state of euphoria, commonly 
referred to as a subjective “high”. The primary mechanism responsible for these effects is the 
interaction between delta-9-tetrahydrocannabinol (THC), commonly the most abundant 
cannabinoid in cannabis22; and the endogenous cannabinoid receptor 1 (CB1)23. When 
cannabis is consumed, concentrations of dopamine are increased in the brain24, leading to a 
“high”. A large proportion of recreational cannabis use can be attributed to the psychoactive 
effects associated with cannabis consumption. Despite cannabis being best known for 
containing THC and consequentially possessing neurological effects, species of the plant 
contain over 100 different cannabinoids22, and cannabinoid receptors are expressed by 
numerous types of cells throughout the body25.  
 
Previous research has associated cannabis use with the occurrence of stroke26 and myocardial 
infarction27. In light of this finding, subsequent research has identified that CB1, and the second 
putative endogenous cannabinoid receptor 2 (CB2), are expressed throughout the different 
components of the cardiovascular system28,29. To date there is a lack of knowledge regarding 
both the long-term cardiovascular consequences of cannabis consumption, and the acute 
cardiovascular response. The impact of cannabinoid exposure on the cardiovascular system 
has been tested in numerous in vitro and in vivo models with equivocal results; in some cases, 

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suggesting detrimental effects and others suggesting therapeutic potential. In murine models, 
regular cannabinoid treatment has been demonstrated to attenuate the development of 
atherosclerosis30 and provide cardioprotection31. Conversely, acute cannabinoid exposure, 
acute secondhand cannabis smoke, and habitual cannabis smoking have been associated with 
decrements in cardiac function28, impaired vascular endothelial cell function3, and vascular 
aging32, respectively. These contrasting findings clearly demonstrate the complexity of the 
cardiovascular consequences of acute and habitual cannabis. 
 
Given the lack of a comprehensive understanding of short- and long-term cannabis use on 
cardiovascular health, the need for such an investigation is pertinent to public health. 
Understanding the cardiovascular consequences of long-term use would allow policy makers to 
continue to develop informed health recommendations and warnings regarding recreational 
cannabis use. The necessity of this knowledge is accentuated by the recent legalization of 
recreational use, and a likely increase in cannabis consumption amongst the general public. 
 
The current trial seeks to observe the acute cardiovascular response to cannabis consumption 
using cardiovascular measures that have been identified as predictive of long-term 
cardiovascular health. These outcomes will provide insight into the potential long-term impact of 
recreational cannabis consumption on cardiovascular health.  
 
2.3 RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Largely owing to elicit status, a comprehensive risk profile of cannabis consumption has not 
been developed. There does, however, exist a number of immediate and long-range risks. It has 
been established that consumption of cannabis containing THC results in impairments in 
cognition and memory33,34. In addition to these impairments, users may experience panic 
attacks35. The most severe psychological risk of consuming cannabis is the development of a 
mild to severe psychotic episode36, which occurs on rare occasions. The diverse effects of 
cannabis on the brain have resulted in the recommendation that cannabis should not be 
consumed prior to operating motor vehicles. Impairment may typically last between 3-4 hours37, 
with some evidence indicating that in impairment can persist for 6-8 hours38.  
 
In addition to immediate psychological risks, cannabis consumption is associated with a number 
of physical risks. Smoking cannabis can result in a transient sinus tachycardia39. Reports have 
associated cannabis use with acute cardiovascular events27 and stroke26, although a causative 
relationship has not been established. Despite these physical risks, cannabis is largely 
considered safe40. In rare instances, cannabis consumption can induce hyperemesis41.  
 
Cannabis use may also present immediate economic risks to some individuals. Due to the long-
standing elicit status and the only recent legalization of recreational use, many employers still 
prohibit cannabis use by employees. 
 
Long-range risks of cannabis use are less understood than acute risks. Physical and 
psychological risks have been identified, however, certain long-range risks have not been 
directly attributed to cannabis itself, due to the existence of certain behaviors or requisite 
activities associated with use. Physical long-range risks include reductions in pulmonary 
function42–44, respiratory infection45, and alterations in brain structure46. Long-term cannabis use 
has been associated with an increased rate of development of schizophrenia47,48, mood and 

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anxiety disorders49, and bipolar disorder50. Early habitual recreational cannabis use is a strong 
risk factor for development of cannabis use disorder51. Although not fully understood, cannabis 
use in adolescents has been associated with lower educational attainment52. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The benefits of cannabis and cannabinoids have largely been derived from clinical and pre-
clinical studies examining cannabis and cannabinoids for their efficacy in treating symptoms of 
chronic disease. Acutely, cannabis and cannabinoids have been reported to suppress nausea 
and vomiting53, with particular efficacy in patients receiving chemotherapy54. Cannabis has also 
been shown to be effective in stimulating appetite55, leading to the approval of Dronabinol (THC) 
prescription for the treatment of HIV-related anorexia by the U.S. Food and Drug 
Administration56. Particular interest in the ability of cannabis to treat neurological disorders 
exists, as its therapeutic potential has been examined in patients with epilepsy57, chronic 
neuropathic pain58–60, and multiple sclerosis61–63. In patients with non-cancer pain, evidence 
exists to suggest that cannabis may be efficacious in reducing symptoms64.  Cannabis may also 
be an effective treatment strategy for improving spasticity in multiple sclerosis62. Cannabis 
containing CBD may also possess anti-epileptic effects in children and young adults with 
treatment-resistant epilepsy65.   
 
It is important to highlight that the therapeutic benefits of cannabis have largely been explored in 
animal models and clinical populations. Of interest to non-clinical populations, cannabis and 
certain cannabinoids may have beneficial effects on mood66,67.  This benefit, however, is 
founded upon a limited evidence base, as the strongest evidence that exists to support mood-
elevating effects of cannabis have been demonstrated in a population of patients suffering from 
major depression secondary to chronic disease59,68–70. Whether or not this benefit exists with 
recreational use remains to be examined. In addition CBD has been shown to be anxiolytic71,72. 
Similar to mood elevating effects, anxiolytic effects have not been demonstrated in a non-clinical 
population, though it has been demonstrated using animal models73.  
 
Of particular interest to the present study is the anecdotal and reported benefits of cannabis use 
during prolonged exercise. Recently, it has been reported that cannabinoids are the most widely 
used performance enhancing substance by ultra-endurance athletes74. This is the first published 
report that supports the widespread use of cannabis during ultra-endurance exercise; a 
previously anecdotal fact. The perceived benefit of cannabinoids in ultra-endurance exercise 
may be explained by the potential anti-nausea and anxiolytic effects that have been 
demonstrated in clinical populations. Intriguingly, studies examining the effects of cannabis 
smoking on work capacity provide contradictory results, suggesting that cannabis reduces 
exercise capacity2 and reduces the time to onset of angina during exercise75. In interpreting 
these contradictory reports, it should be noted that the effects of cannabis consumption on 
exercise performance have not been rigorously examined76, thereby justifying one of the aims of 
the present study.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The large number of pre-clinical studies and clinical trials that have examined medicinal 
cannabis use in the treatment of chronic disease have resulted in a large body of literature; 
detailing many potential benefits and risks of cannabis use. Largely owing to interest in the 
therapeutic potential of cannabis across a multitude of disease populations, far less effort has 
been directed toward understanding the risk-benefit profile of recreational cannabis use in a 

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non-clinical population. As of October 2018, recreational cannabis use was legalized in Canada 
for individuals aged 19 and older. Given the already prominent use of cannabis1 among 
Canadians, and a potential increase in use associated with legalization, the need for an 
understanding of the risk-benefit profile of cannabis under recreational conditions is pertinent. 
Furthermore, the recently published reports of the prominence of cannabis use in endurance 
sport74 warrants the need for a greater understanding of the interaction between cannabis and 
exercise.  
 
When assessing the risk-benefit profile of recreational cannabis use, it must be considered that 
the majority of recreational users are seeking the euphoric effects associated with the subjective 
“high”. Beyond this largely subjective effect that may be considered a benefit only by some, the 
most beneficial effects to a healthy individual using cannabis recreationally might be considered 
the effects on mood and anxiety; effects about which the existence remains uncertain. A further 
confounding factor that must be considered is the method of consumption employed with 
recreational use. Recreational cannabis use is commonly performed by smoking, vaporizing, 
and by ingestion. Smoking is reported to be the most common method of consumption, a 
process that involves inhalation of carcinogens and combusted material77. Given the harmful 
nature of this behavior that commonly occurs concomitantly with cannabis use, characterizing 
the risk benefit profile of recreational use is challenging at this time.  
 
Despite lacking a robust list of potential benefits of recreational use in healthy individuals, the 
justification for an investigation into the acute physiological effects of consumption is counter 
balanced by the rarity of acute adverse effects entirely attributable to cannabis use in these 
individuals. Cannabis induced hyperemesis and cannabis induced psychotic episodes are 
rare78. While other more consequential risks of cannabis use such as acute coronary syndrome 
and stroke have been suggested4, no investigation has identified a causal relationship. These 
reported acute cardiovascular risks are especially intriguing given the increasing popularity of 
use by athletes in and out of competition13. Exercise is a potent transient cardiovascular stress, 
and many questions surrounding the effects of the combined stimulus of exercise and cannabis 
remain. Despite reports of acute risks of cannabis consumption, it should be noted that 
presently a much larger evidence-base suggests that recreational cannabis use is associated 
with long rather than short term health consequences.  
 
Although the acute risks of cannabis use appear to be rare, current knowledge suggests that 
they may be inherent to use and therefore should be minimized, but cannot be completely 
avoided. An effective approach to ensuring participant safety in the context of cannabis use 
requires pre-eminent planning in the case of known acute risks, and selection of a population 
that does not possess an elevated risk of experiencing the most commonly reported adverse 
effects. The present study will monitor participants following cannabis consumption to ensure 
participant safety. Participants will be monitored until the effects of cannabis have subsided. 
Further, a dosage has been selected that is less potent and smaller than what is available for 
typical recreational use. Choice of dosage was selected as a dose that is likely to exert 
physiologically meaningful effects, but not impose elevated risk to participants. Participants in 
the present study will be experienced users, who will not be unfamiliar with the effects of 
consumption. Additionally, participants possessing commonly known risk factors that may 
predispose to acute risk will be excluded.  
 
The present study will examine primary endpoints that have been correlated with long term 
cardiovascular health. Therefore, the results will provide substantial insight into the potential 
long-term health risks of recreational cannabis use without exposing participants to repeated 
long-term exposure to cannabis. Another advantage of the present study will be the examination 

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of these predictive outcomes under differing conditions in which cannabis is commonly used 
recreationally; namely, with different cannabinoid compositions and different consumption 
modalities. The present study will provide the most comprehensive examination of the 
cardiovascular response to recreational cannabis use to date under multiple ecologically valid 
conditions. It will also provide novel insights into the interaction between cannabis use and 
exercise. 
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
The primary objective of 
the current study is to 
determine the acute 
effects of cannabis 
consumption at rest and 
during exercise on the 
human cardiovascular 
system, with particular 
focus on the influence of 
method of consumption 
(smoking vs. 
vaporizing), and 
cannabinoid 
composition (THC vs. 
CBD). 
 
The primary endpoints will be 
measures of arterial stiffness, 
endothelial function, muscle 
sympathetic nerve activity, 
and cardiac function. 
 
Arterial stiffness and 
endothelial function will be 
assessed via carotid-femoral 
pulse wave velocity and 
brachial artery flow-mediated 
dilation. 
 
Muscle sympathetic nerve 
activity (MSNA), or 
mironeurography, will be 
characterized using indices of 
sympathetic outflow, such as 
burst incidence and burst 
frequency. 
 
Cardiac function will be 
assessed using 
echocardiography. Primary 
endpoints will be measures of 
systolic function, diastolic 
function, and tissue 
mechanics. These measures 
include but are not limited to 
ejection fraction, E/A ratio, 
myocardial twist, and 
myocardial strain. 
Carotid-femoral pulse wave velocity 
has been chosen as a primary 
endpoint as it has been shown that 
cigarette smoking, which is not 
dissimilar to cannabis smoking in 
many ways, results in arterial 
stiffening both acutely and 
chronically. Furthermore, the 
relationship between pulse wave 
velocity and risk of cardiovascular 
events has been well documented. 
Previous research has identified 
that a 1SD increase in pulse wave 
velocity is correlated with a 16-20% 
increase in risk for cardiovascular 
events79.  
 
Similar to pulse wave velocity, 
brachial artery flow-mediated 
dilation has been shown to have 
predictive value in determining risk 
of cardiovascular events in healthy 
subjects80. 
Microneurography (MSNA) will 
allow recording of the electrical 
activity of sympathetic nerves. This 
technique provides insight into the 
autonomic control of the 
cardiovascular system. This 
technique will further allow 
exploration of the mechanisms 
underlying other primary outcomes. 
Burst incidence and burst 
frequency are commonly reported 
measures of muscle sympathetic 
nerve activity. 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Ejection fraction, E/A ratio, cardiac 
twist, and cardiac torsion have all 
been chosen as these are standard 
measures for evaluating each 
respective aspect of cardiac 
function. Each of these measures 
are clinically relevant and 
commonly reported in current 
cardiac literature.  
Secondary 
 
 
The secondary objective 
of the present study is 
to determine how 
consumption of 
cannabis prior to 
exercise affects 
performance. 
 
Secondary endpoints will be 
used to evaluate 
physiological responses to 
exercise and will include 
objective measures of work 
capacity. 
 
These endpoints, which will 
be performed using in-lab 
cycle ergometry include, 
average power output, 
distance travelled, rating of 
perceived exertion, oxygen 
consumption, cardiac output, 
heart rate, blood pressure, 
and rate-pressure product.  
 
Each secondary endpoint has been 
selected in order to examine 
subjective, and physiological 
responses to exercise.  
 
Cardiac output, heart rate, oxygen 
consumption, and rate pressure-
product have all been selected in 
order to examine how cannabis 
consumption may alter the 
physiological response to exercise. 
The response in each of these 
variables is well characterized 
during normal exercise.  
 
Average power output and distance 
travelled have been selected as 
objective measures of 
performance, and will be examined 
to explore the relationship between 
any physiological perturbations 
associated with cannabis, and 
actual work capacity. 
 
Rating of perceived exertion will be 
measured to explore the 
psychological effects of cannabis 
consumption experienced during 
exercise. 
Tertiary/Exploratory  
 
 
N/A 
N/A 
N/A 
 
4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
 
The study will use a randomized cross-over design. It will be structured by division into two 
phases. Both phases will examine the acute cardiovascular response to cannabis consumption, 

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both at rest and during exercise. Phase I will examine if and how this response differs whether 
cannabis is smoked or vaporized. Phase II will examine how this response is influenced by 
cannabinoid concentration within inhaled cannabis. Phase II of the current study will use a 
single-blind design, with participants being unaware of the relative cannabinoid concentrations 
of the cannabis they consume. Cannabis will be inhaled using methods of smoking (phase I 
only) or vaporization (phase I and II). Each experimental study visit (study visits 2-9), 100mg of 
cannabis will be consumed via one of the two aforementioned methods of inhalation, followed 
by a subsequent rest period, or by 20 minutes of exercise. Primary endpoints will be examined 
pre- and post-consumption each visit (with the exception of muscle sympathetic nerve activity, 
which will only be performed on a single study visit), while secondary endpoints will be recorded 
during exercise.  
 
Each phase of the study will require participants to complete an introductory and control visit, as 
well as 4 experimental study visits, where cannabis inhaled under alternating conditions (phase 
I: smoking vs. vaporizing high THC cannabis, phase II: high CBD cannabis vs. high THC 
cannabis) followed by exercise, or a time-matched rest period. The order in which these visits 
will occur will be randomized, and individualized for each participant. A within-subjects design 
will be utilized, so that each participant completes each condition. High THC cannabis used will 
be the cannabis strain “Rex”, while the high CBD strain will be “Kalea”. The dose size and 
strength will not be altered throughout the course of the study.  
 
Continuous blood pressure, heart rate, and electrocardiogram monitoring will occur prior to, and 
during cannabis administration (prior to exercise) on all visits where cannabis is consumed. This 
procedure will be followed throughout the entirety of the 40-minute cannabis consumption 
period. If either systolic or diastolic blood pressure exceeds 160mmHg or 90mmHg at rest, 
respectively, exercise will not be performed, and the study visit will not continue. If heart rate 
exceeds 100bpm or falls below 40bpm at rest, exercise will not be performed, and the study visit 
will not continue. 
 
All research will be performed within the department of Human Health and Nutritional Sciences 
at the University of Guelph.  
 
There are no planned interim analyses planned for the current trial.  
 
A sub-group analysis will be performed, with participants divided by sex, to determine the 
existence of any sex differences in primary and secondary endpoints.  
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
A within subject design has been chosen for this study due to potential variability in primary 
endpoints between individuals. Specifically, variation in pulse wave velocity and flow-mediated 
dilation. Published reference values for pulse wave velocity in our selected age group may 
range between 3.92m/s and 8.26m/s81. This substantial range requires a within-subjects design 
to allow for meaningful assessment of the effects of cannabis on arterial stiffness. Similar to 
pulse wave velocity, flow-mediated dilation may vary substantially between and within subjects, 
with values as high as 20% reported in healthy individuals80. This design is further warranted 
due to the choice of secondary endpoints. Exercise performance, and the accompanying 
physiological responses, are highly dependent on numerous factors that are likely to vary 
between individuals. Such factors include weight, fitness level, and familiarity with cycling. This 
further warrants the need for a within subject design, as these variables would have to be 

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matched if using parallel groups. Even if groups were matched, there is a strong likelihood that 
significant variability would exist in performance metrics.   
 
The proposed study does not employ a placebo-control or a double-blind design. This is a 
consequence of the challenge owed to masking the device used to inhale cannabis in phase I. 
Vaporization and smoking are distinct methods of cannabis inhalation, and as such different 
devices must be used, making blinding difficult. A single-blind design will be utilized in phase II, 
in that participants will not be aware of the strain of cannabis they are consuming. Although 
collection will not be double-blind, investigators will be blind to condition during data analysis. 
 
Randomization of the order of experimental visits in each phase will occur to combat 
improvement in performance as a result of better of pacing strategies, or improvements in 
fitness. Randomization will be performed using a randomization software (www.random.org). 
The order in which visits will occur will be individualized to each participant. 
 
4.3 JUSTIFICATION FOR DOSE 
 
For all cannabis administration a standard 100mg dose of dried cannabis flower will be 
consumed by smoking or vaporization. Depending on the experimental condition, cannabis will 
be either Rex (13.6±2.7% THC, <0.5%CBD dry weight) or Kalea (<1% THC, 14.5±2.9% CBD 
dry weight). This dose will not be altered throughout the course of the study and will be given to 
all participants. 
 
A 100mg dose of dried cannabis flower was selected based upon published recommendations82 
suggesting that maximum daily cannabis use for individuals prescribed medical cannabis should 
not exceed 400mg daily, and should be consumed over 4 doses each day. The selection of this 
singular dose was also made with consideration to the context of the cannabis use in the 
selected population. The current study will examine recreational cannabis users, who have 
consumed cannabis in the past year whose use has not exceeded an average of twice per 
week. Given that recreational users are being examined, the quantity of commercially available 
products for recreational use was used to inform the dosage. In Ontario, cannabis is sold nearly 
exclusively through the Ontario government’s online platform (https://ocs.ca). This online 
platform features a large range of pre-rolled cannabis products that contain 0.33-1g of dried 
cannabis flower with THC and CBD concentrations up to 28% dry weight and 13% dry weight, 
respectively83,84. Although this 100mg dose of Rex and Kalea may be seemingly small, previous 
evidence indicates that a dose of this size is sufficient to elicit cardiovascular responses to 
smoking and vaporization of cannabis85. 
 
A recent summary of the safety of CBD indicate that a dosage of 15-160mg of CBD have been 
used in studies with no ill effects86. Additionally, the dose of ~15mg of CBD was chosen to 
closely parallel the CBD content of inhaled products commercially available through the Ontario 
government. There is currently no evidence examining the effect of CBD on primary endpoints 
of the present study. It is therefore difficult to quantify how CBD impacts primary outcomes 
Thus, selecting dose based on safety and ecological validity was used as the primary 
justification. 
 
4.4 END OF STUDY DEFINITION 
 

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A participant is considered to have completed the study if he or she has completed either phase 
I or phase II of the study including the last scheduled procedure shown in the Schedule of 
Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 INCLUSION CRITERIA:   
 
To be eligible to participate in each phase study, an individual must meet all of the following 
criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study  
3. Male or female, aged 19-45yr 
4. In good general health as evidenced by medical history and free of chronic disease 
5. Must be experienced with cannabis use. This requires recreational cannabis use of a 
minimum of once per week in the past 30 days as confirmed by urine test 
6. Experience consuming cannabis recreationally by vaping dried cannabis 
 
 
5.2 EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Deemed unfit to exercise by the PARQ+.  
The goal of the present study is to examine the acute cardiovascular response to 
cannabis consumption at rest and during exercise. As such participants must be able to 
safely complete the pre-determined exercise protocol. 
2. Current or past diagnoses of substance abuse disorder 
3. Failure of recreational substance urine screening test 
o Substances to be tested for include: Cocaine, Crack, Morphine, Heroin, 
Fentanyl, Amphetamines, Ecstasy, Methamphetamine, Spice and AB-
Pinaca (synthetic cannabis), Methcathinones, LSD, and Ketamine. 
4. Current, past, or strong family history of psychosis, or has previously 
experienced a cannabis-related psychotic episode 
5. Current or past diagnoses of cannabis use disorder 
6. Current or past diagnoses of any mood or anxiety disorder 
Exclusion criteria 2-5 will be implemented to ensure that no individuals are enrolled in 
the study who could carry an elevated risk of experiencing a severe cannabis related 
adverse event (such as cannabis induced hyperemesis, or a psychotic episode). Each of 
these exclusion criteria represent contraindications for cannabis prescription.  
7. Identified ECG abnormalities 
8. Systolic blood pressure exceeding 160mmHg 
9. Diastolic blood pressure exceeding 90mmHg 
10. Resting heart rate exceeding 100bpm, or lower than 40bpm 
11. Diagnosed with respiratory disease  
12. Diagnosed with cardiovascular disease 
13. Diagnosed with liver disease  

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14. Diagnosed with kidney disease 
Individuals with cardiovascular, respiratory, liver, or kidney diseases will be excluded 
from this study as primary and secondary endpoints may be confounded by disease 
states.  
15. Is Pregnant or planning to be pregnant 
It is not currently established how cannabis consumption by a pregnant woman impacts 
a developing fetus. As such, females who are planning to be, or are pregnant will be 
excluded as a precautionary measure. 
a. Female subjects of childbearing potential and male subjects when sexually active 
with a female of childbearing potential must agree to use contraception for the 
duration of the trial.  
i. For female subjects of childbearing potential, contraception methods 
include: 
1. A highly effective method of contraception (such as oral hormonal 
contraceptives, IUD, IUS, bilateral tubal ligation);  
2. Double barrier method defined as the use of a male condom with 
cervical cap/diaphragm with spermicide;  
3. Male partner with a confirmed successful vasectomy; OR 
4. Abstinence defined as refraining from heterosexual intercourse 
consistent with the preferred and usual lifestyle of the subject. 
ii. For male subjects when sexually active with a female of childbearing 
potential, contraception methods include 
1. Vasectomy (confirmed successful); 
2. Condom with spermicide; OR 
3. Abstinence defined as refraining from heterosexual intercourse 
consistent with the preferred and usual lifestyle of the subject. 
 
16. Currently taking prescription medication (excluding contraceptive medication) 
17. Is a cigarette smoker 
It is well established that cigarette smoking negatively impacts numerous endpoints 
evaluated in the current study. As such no cigarette smokers will be included. 
 
5.3 LIFESTYLE CONSIDERATIONS 
 
The day of each experimental visit, participants are asked to: 
• 
Refrain from cannabis consumption for the 48 hours prior to the beginning of each visit. 
(Confirmed by urine THC test, positive test result will result in rescheduling) 
• 
Refrain from consumption of alcohol for the 24 hours prior to the beginning of each visit. 
• 
Refrain from exercising vigorously for 24 hours prior to the beginning of each visit. 
• 
Refrain from caffeine consumption for 8 hours prior to the beginning of each visit. 
• 
Refrain from vitamin supplementation for 8 hours prior to the beginning of each visit. 
• 
Fast for 6 hours prior to the beginning of each visit 
• 
Avoid operating a motor vehicle for the entirety of the date of a study visit where 
cannabis is consumed 
• 
Arrange to have a trusted individual escort them to their residence following completion 
of their study visit. 
 
5.4 SCREEN FAILURES  
 

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If a participant who consents to participate in this study but is deemed ineligible via a screening 
assessment (PARQ+, Eligibility Questionnaire) will not have identifying information recorded. 
Only the reason for ineligibility will be recorded. Responses to the PARQ+ or eligibility 
questionnaire will be destroyed. Individuals who do not meet the criteria for participation in this 
trial will not be rescreened.  
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
We seek to recruit 20 individuals per phase, 10 of which will be female and 10 of which will be 
male. Participants will be recruited from the community in Guelph, Ontario. In line with our IRB 
approved methods, recruitment posters will be posted at the University of Guelph and around 
the city. A social media posting will be sent via Twitter from the official Human Performance and 
Health Research Laboratory account. Additionally, the study poster will be presented to 
students in undergraduate lectures at the University of Guelph. Participants may also be 
recruited by word of mouth. Each participant who completes a session of microneurography will 
be compensated $100 CAD in line with typical institutional procedures.  
 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
The two cannabis strains examined in the current study are Rex and Kalea (See accompanying 
Investigator’s Brochure). These cannabis strains will be given in the form of dried cannabis 
flower. Each of these cannabis strains are produced by MedReLeaf. Both Rex and Kalea are 
harvested from Cannabis sativa. These strains have been selected as they differ substantially in 
their concentration of the two most abundant cannabinoids THC and CBD. Rex will contain 
13.6±2.7% THC and <1% CBD by dry weight; Kalea will contain <1% THC and 14.5±2.9% CBD 
by dry weight. For more detail about the investigational products please see the accompanying 
Investigator’s Brochures.  
6.1.2 DOSING AND ADMINISTRATION 
 
All cannabis consumed in relation to the current study will be done so during a study visit, within 
a laboratory setting in a specifically designed cannabis administration chamber. Participants will 
not be required to consume cannabis for the purpose of the study outside of their visits to the 
laboratory. 
 
In each study visit a standard dosage of 100mg of Rex or Kalea will be administered to 
participants, who will consume via inhalation of smoke or vapor. Participants will be seated in a 
chamber designated for cannabis consumption. One investigator will retrieve a pre-weighed 
100mg dose of the appropriate dried cannabis flower, depending on the phase of study, and the 
study visit being completed. The investigator will load the 100mg cannabis dose into either a 
glass smoking apparatus or a “Mighty Medic” vaporizer. The vaporizer or smoking apparatus will 
be given to the participant within the cannabis chamber.  
 
Cannabis will be inhaled according to a standardized inhalation procedure. This procedure 
involves 5 seconds of inhalation, 10 seconds wherein smoke or vapor is held in, and 45 

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seconds of rest. This procedure will be repeated until all cannabis has been exhausted. After 
receiving the full dose of cannabis, an investigator will guide the participant out of the chamber. 
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Aurora Cannabis Inc. will provide the exact amounts of Rex and Kalea needed for the 
completion of the study by 20 individuals. As the required sample size has been determined to 
be 20 individuals, with each participant consuming 100mg of cannabis on four separate 
occasions, per phase of study, 12 grams of Rex and 4 grams of Kalea will be required. An 
additional 3 grams of Rex and an extra gram of Kalea will be purchased to account for the 
potential of participant drop-out. Cannabis will be stored in a locked safe in a room with 
restricted access. Only members of the investigatory team will have access to the room where 
the cannabis is stored, and the room will not be accessed alone by any researcher. The safe will 
be secured to the wall of the room. Each entry to the room for the access of cannabis will be 
recorded in a log, where time of exit and entry, and purpose of entry will be recorded. 
Additionally, all cannabis will be immediately inventoried upon receipt, and a constant record will 
be kept of how much cannabis is removed at any time. Cannabis will be organized into pre-
weighed 100mg samples, and will be labelled by sample number. Any time cannabis is 
removed, the responsible individual will be required to record what sample was removed. 
Weekly checks of cannabis inventory will be performed. Any excess cannabis that remains at 
the end of the data collection period will be destroyed. Cannabis will be ground and mixed with 
equal parts soil before being discarded.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Please see the investigator’s brochure for information related to formulation, appearance, 
packaging, and labeling. Each brochure was prepared by MedReLeaf, a subsidiary of Aurora 
Cannabis Inc. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Each strain of cannabis will be stored locked safe in a room with restricted access. Samples will 
be stored in 100mg preparations. 
 
 
6.2.4 PREPARATION 
 
Prior to receiving any cannabis, the investigatory team will label and prepare child resistant jars 
that will contain individual 100mg dosages. Each container will be labelled with a sample 
number for tracking purposes. These containers will be kept in the safe. Upon receiving a 
shipment of cannabis, an investigator will transport the cannabis to the room for storage. They 
will then pre-weigh 100mg samples using a digital scale, and place a 100mg dose of dried 
cannabis flower into each container. A master list of which strain each sample number 
corresponds to will be kept.  
 
At the point in each study visit where the participant is prepared for cannabis consumption, two 
members of the research team will retrieve the appropriate cannabis sample from the safe. The 
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The smoking apparatus will be prepared by placing the entirety of one dose into the bowl portion 
of the glass smoking apparatus. The device will then be given to the participant to begin the 
inhalation protocol. 
 
The Mighty Medic vaporizer will be loaded according to the manufacturer’s instructions. The 
cooling unit will be rotated 90° in the counterclockwise direction. One dose will then be placed in 
the now exposed filling chamber. The cooling unit will be moved to the initial position, and the 
vaporizer will be set to a temperature of 190°C and given to the participant to begin the 
inhalation protocol. 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
As the current study utilizes a randomized crossover (within subject) design, no randomization 
to independent groups is necessary. Instead, the order in which experimental study visits take 
place will be randomized, and individualized to each participant. Upon enrollment in the study, 
the individualized order of study visits will be determined using a random number generating 
software (https://www.random.org). Each study visit will be assigned a number from 1-4. 
Random numbers will be generated, and the order of study visits will correspond to the order in 
which the numbers were generated by the software.  
 
Phase I of this study will not be blinded owing to challenges in masking the device used to 
inhale cannabis. Phase II will be single blinded, with the strain of cannabis consumed 
unbeknownst to the participant. Participants will not be unblinded to the study conditions at any 
point. All investigators will however be blind to condition during data analysis. 
 
Primary and secondary endpoints used in this study are robust in preventing observer bias. 
Each primary endpoint will be determined using computer software, while secondary endpoints 
will also be determined by the use of automatic devices that provide data that is not modifiable 
by investigators. During any analysis, the investigator will be blinded to condition 
 
6.4 STUDY INTERVENTION COMPLIANCE 
 
At all times during cannabis consumption, a minimum of two members of the research team will 
be present to ensure compliance to the inhalation protocol. They will guide participants through 
the protocol and ensure that they comply with the protocol timing . If participants intentionally 
deviate from protocol (holding breath, taking secondary breaths) they will be instructed to refrain 
during future cycles. If deviation continues data will not be collected during that study visit, and 
the protocol will be stopped. Acceptable deviations may occur, such as participants coughing. In 
the instance of coughing, the protocol will be paused until the participant is ready to resume. 
While monitoring, researchers will evaluate when all cannabis has been exhausted. At this point 
the inhalation protocol will be ceased.  
 
6.5 CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed 
only by a properly authorized/licensed clinician. Medications to be reported are concomitant 
prescription medications, over-the-counter medications and supplements. 
 

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6.5.1 RESCUE MEDICINE 
 
The study site will not supply rescue medication as dried cannabis flower is not being examined 
in the context of treatment of disease or symptom relief. 
   
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
 
If a participant experiences a cannabis-related severe adverse at any point during participation 
in the study, or new information regarding their health becomes available to them that would 
contraindicate cannabis use, they will be immediately discontinued from further trials. 
Investigators will inquire whether there have been any changes in health or prescription 
medication status each study visit. Severe cannabis related adverse events will be classified 
using the adverse event form, but will also by default include any instance of cannabis induced 
hyperemesis or any degree of psychosis. If a participant voluntarily withdraws, they will not be 
required to provide a reason, and no further data collection will occur. However, if a participant 
decides to withdraw following consumption of cannabis during a study visit, they will be required 
to remain in the laboratory for 4 hours following the moment of consumption, so that their safety 
may be monitored. Any adverse event that occurs will be recorded using an adverse event form. 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. This 
includes during the inhalation procedure.  
 
If a participant wishes to withdraw during or after the inhalation of cannabis they will be required 
to remain in the laboratory for the requisite recovery period of 4 hours. Each hour subjective 
effects, heart rate, and blood pressure will be measured.  
 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
• 
Pregnancy 
• 
If any severe adverse event (AE), or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the 
participant 
• 
If the participant reports meeting an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
• 
Participant unable to complete study procedures 
The reason for participant discontinuation or withdrawal from the study will be recorded. 
Participants who discontinue the study will be replaced to ensure that the required pre-
determined statistical power is met. 
 

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7.3 LOST TO FOLLOW-UP 
 
A participant will be considered withdrawn if he or she fails to return for a scheduled visit and is 
unable to be contacted by the study staff.  
 
The following actions must be taken if a participant fails to return to the laboratory for a required 
study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within one 
day, and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed withdrawn, the investigator or designee will make an 
effort to regain contact with the participant. These contact attempts will be documented. 
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 EFFICACY ASSESSMENTS  
 
Participants will be screened for eligibility using two separate screening procedures during the 
introductory visit. The first screening procedure will be an investigator generated eligibility 
questionnaire. This questionnaire will evaluate whether the participant fits inclusion criteria and 
does not meet any exclusion criteria. The second screening tool will be the PARQ+, a validated 
questionnaire designed to determine whether participants are fit to safely exercise. The PARQ+ 
may determine that a participant requires clearance from their physician. If they do not obtain a 
signed doctor’s note, they will not be eligible to be participate. All screening procedures will 
occur during the introductory visit, and within one week of the exercise control visit. Additionally, 
at the start of each study visit participants will be asked if there have been any changes to their 
health status, or prescription medication status. 
 
Efficacy assessments of primary objectives are as follows: 
• 
Arterial stiffness will be assessed before and after cannabis consumption with and 
without subsequent exercise under each condition, during each study visit. Carotid-
femoral pulse wave velocity will be used to determine arterial stiffness. Carotid-femoral 
pulse wave velocity will be measured by placing a tonometer probe at the site of the 
carotid and femoral pulse. Pulse waveforms will be juxtaposed against a lead-II 
electrocardiogram to determine pulse wave velocity. 
• 
Endothelial function will be characterized before and after cannabis consumption with 
and without exercise under each condition during each study visit. Endothelial function 
will be measured using brachial artery reactive hyperemic flow-mediated dilation. The 
brachial artery will be imaged using a General Electric Vivid-i ultrasound system. After 1 
minute of imaging, a tourniquet placed on the antecubital fossa will be inflated to 
220mmHg for a period of 5 minutes will imaging continues. After this period 3 minutes of 
ultrasound imaging will be recorded to assess the vasodilatory response to occlusion. 
The relative (%) change in arterial diameter following release of the tourniquet will be the 
primary endpoint.  
• 
Muscle sympathetic nerve activity will only be performed before and after vaporizing of 
high THC cannabis. Microneurography will be performed by inserting a tungsten 
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bundle, baseline activity will be recorded for a maximum of 10 minutes. Participants will 
then follow the standard smoking protocol, while sympathetic activity is recorded during 
the rest period. 
• 
Cardiac function will be assessed using echocardiography. Echocardiography will be 
performed prior to exercise during the exercise control visit, and will be performed after 
consumption of cannabis on each study visit. Ejection fraction, E/A ratio, myocardial 
twist, and myocardial strain have all been chosen as these are standard measures for 
evaluating respective aspects of cardiac function. The heart will be viewed via the 
parasternal and apical imaging windows, and will be imaged using the Vivid-I ultrasound 
system.  
 
Efficacy assessments of secondary objectives are as follows: 
• 
Blood pressure, heart rate, and myocardial oxygen demand will be determined using a 
Finapres device which measures beat-to-beat heart rate and blood pressure using a 
finger cuff. The product of these two endpoints will represent the rate-pressure product, 
an indicator of myocardial oxygen demand. These outcomes will be assessed in the 20-
minute period following cannabis consumption during each study visit. Therefore, 
recordings will take place at rest and during exercise depending on the given study visit.  
• 
Indirect calorimetry will be performed during all exercise bouts, and will be used to 
evaluate oxygen consumption and other cardio-respiratory measures such as respiratory 
exchange ratio, minute ventilation, and caloric expenditure. Participants will be 
instrumented prior to each exercise bout, and measurement will only take place during 
the exercise bout. 
• 
Participants will also be asked to provide ratings of perceived exertion every 2 minutes 
during each exercise bout. Ratings will be collected using the 6-20 Borg scale of 
perceived exertion.  
• 
Exercise performance will be quantified by numerous endpoints such as average power 
output, and total work completed in the allotted exercise period (20 minutes). These 
outcomes will be assessed using the manufacturer software provided with the cycle 
ergometer that will be used in all exercise bouts.  
 
No results of primary or secondary endpoints will be shared with participants until the 
completion of the data collection period. If participants wish to see results from any of the 
primary or secondary endpoints, all results will be provided in aggregate.   
 
8.2 SAFETY AND OTHER ASSESSMENTS 
 
The two screening procedures (Eligibility Questionnaire, PARQ+) will be implemented in order 
to ensure that only participants who are fit to exercise, and who possess no characteristics that 
contraindicate medicinal cannabis use will be included in the study. As previously mentioned, 
each of these questionnaires will attempt to identify specific characteristics that suggest that 
study inclusion would not be recommended for a given individual.  
 
Participant safety will be monitored throughout each study visit via investigator supervision of 
study procedures, monitoring of vital signs, electrocardiogram, imaging assessments, and 
questionnaires. Additionally, adverse events will be recorded throughout each study visit in 
detail, should they occur. 
 
Upon arrival to the laboratory participants will have their seated blood pressure measured prior 
to each incidence of cannabis consumption or exercise. Participants must fall in the 

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normotensive range in order for continuation of study procedures. Blood pressure and heart rate 
will be recorded throughout all study procedures following cannabis consumption. Additionally, 
participant’s heart rate will be monitored via electrocardiogram. Digital electrocardiographic 
measures will not be analyzed following study visits; however, it will be monitored during each 
study visit. In the event of electrocardiographic abnormalities, study procedures will be halted. If 
electrocardiogram abnormalities are detected and medical attention is necessary, emergency 
services will be immediately contacted. The principal investigator will be responsible for 
monitoring for electrocardiogram abnormalities. The principal investigator is trained to do so 
through his certification as a Certified Exercise Physiologist, accredited by the Canadian Society 
for Exercise Physiology.  
 
In the assessment of certain primary endpoints, ultrasound imaging of the brachial artery and 
the heart will occur. If any vascular or cardiac abnormalities become evident to investigators, 
then emergency services will be contacted, if necessary. As the investigators performing these 
measures are not physicians, they will not attempt any further specialized imaging, or provide a 
diagnosis to the participant. 
 
Throughout each smoking protocol, a member of the investigatory team will supervise 
participants to ensure maximal adherence. If the participant engages in behaviors that are likely 
to augment the cannabis dosage, such as prolonged breath holding, they will be instructed to 
cease such behaviors. This investigator supervision will ensure that participants are receiving 
the desired dose of cannabis. 
 
After completion of study procedures, participants will be required to remain in the laboratory for 
a period of 4 hours beginning from the end of the cannabis inhalation procedure. This period of 
monitored recovery has been implemented in an effort to minimize the subjective effects of 
cannabis experienced by participants prior to their release from the laboratory. In addition, 
participants will be required to complete the drug effects questionnaire each hour following the 
completion of study procedures. This questionnaire will evaluate the extent to which participants 
are experiencing the subjective effects of cannabis. If participants indicate that they are still 
experiencing subjective effects at the end of the 4-hour recovery period via the DEQ, they will 
be required to remain until effects have subsided. Blood pressure and heart rate will also be 
monitored throughout the recovery period. Measurements will be taken each hour with the 
administration of the DEQ. 
  
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An adverse event will be defined according to the ICH-GCP as: Any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product (see the ICH Guideline 
for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting)87. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 

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A serious adverse event will be defined according to the ICH-GCP as: Any untoward medical 
occurrence that at any dose: 
• 
results in death, 
• 
is life-threatening, 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity, 
or 
• 
is a congenital anomaly/birth defect (see the ICH Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting). 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
Severity of adverse events will be classified from mild to life-threatening. All classifications are 
defined as:  
• 
Mild: Awareness of sign or symptom, but easily tolerated 
• 
Moderate: Discomfort enough to cause interference with normal daily activities 
• 
Severe: Inability to perform normal daily activities 
• 
Life Threatening: Immediate risk of death from the reaction as it occurred 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by a 
member of the investigatory team who examines and evaluates the participant based on 
temporal relationship and his/her judgment. The degree of certainty about causality will be 
graded using the categories below. In a clinical trial, the study product must always be suspect. 
The following scale of relatedness will be used: 
• 
Not related: An adverse event which is not related to the study 
• 
Unlikely: An adverse event for which an alternative explanation is more likely 
• 
Possible: An adverse event which might be due to the study. An alternative explanation 
is inconclusive. The relationship in time is reasonable; therefore, the causal relationship 
cannot be excluded. 
• 
Probable: An adverse event which might be due to the study. The relationship in time is 
suggestive. An alternate explanation is less likely. 
• 
Definite: An adverse event which cannot be reasonably explained by alternative 
explanation. The relationship in time is very suggestive. 
 
 
8.3.3.3 EXPECTEDNESS  
 
Dr. Jamie Burr will be responsible for determining whether an adverse event is expected or 
unexpected.  An adverse event will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information provided in the Investigator’s 
Brochure. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 

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The occurrence of an adverse event or serious adverse event may come to the attention of 
study personnel during study visits and interviews of a study participant. Participants will be told 
in the initial study visit that they should report any adverse events they are experiencing after 
completing any study procedures.  
 
All adverse events including local and systemic reactions not meeting the criteria for serious 
adverse events will be captured on the adverse event form. Information to be collected includes 
event description, time of onset, assessment of severity, relationship to study product (assessed 
by an investigator), and time of resolution/stabilization of the event. All adverse events occurring 
while in the study must be documented appropriately regardless of relationship. All adverse 
events will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an adverse event. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as an 
adverse event.  
 
8.3.5 ADVERSE EVENT REPORTING  
 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
event.  If a serious adverse event occurs, expedited reporting will follow local and international 
regulations, as appropriate. 
 
All adverse events will be reported on the adverse event form.  Adverse events should be 
reported using concise medical terminology on the form for collection of serious adverse event 
information. Dr. Jamie Burr will be responsible for completing and signing off all adverse event 
reports. Adverse drug reactions will be reported to the IRB and Health Canada within 15 days. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
If a serious adverse event occurs, expedited reporting will follow local and international 
regulations, as appropriate. Health Canada and IRB requirements for reporting of serious 
adverse events will be followed. 
If a serious adverse event occurs, the PI-Sponsor is to be notified within 24 hours of awareness 
of the event by any investigator. In particular, if the serious adverse event is fatal or life-
threatening, notification to the PI-Sponsor must be made immediately, irrespective of the extent 
of available adverse event information.  In the event that the investigator does not become 
aware of the occurrence of a serious adverse event immediately, the investigator is to report the 
event to the IRB and Health Canada within 24 hours after learning of it and document the time 
of his/her first awareness of the adverse event. 
 
For all serious adverse events, the investigator is obligated to pursue and obtain any relevant 
information. In addition, an investigator may be requested to obtain specific additional follow-up 
information in an expedited fashion. In general, this will include a description of the adverse 
event in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality. Information on other possible causes of the 
event, such as concomitant medications and illnesses must be provided. 
 

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Serious Adverse events will be noted and recorded on adverse event recording sheets 
according to ICH GCP. The standards for reporting serious adverse events, as defined in the 
ICH guideline (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, ICH Harmonized Guideline) will be strictly followed by study investigators. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Participants in this study will not be informed of any adverse events experienced by other 
participants. If the investigatory team discovers any incidental findings that suggest the 
participant seek medical attention, they will be informed immediately, and their participation in 
the study will be suspended until they have seen a physician. Only once they have obtained 
written permission from their physician, can they continue participation in the study.  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
There are no events of special interest that are likely to occur other than those discussed in 
previous sections. 
 
8.3.9 REPORTING OF PREGNANCY  
 
Upon screening, participants will be required to complete an eligibility questionnaire, which will 
enquire if the participant is pregnant or planning to be pregnant. If participants indicate they are 
or are planning to be pregnant they will not be enrolled in the study. All female participants will 
be required to provide a urine sample in order to complete a urine pregnancy test. If the next 
study visit occurs more than 30 days after the initial visit, the test will be repeated. If a 
participant becomes pregnant during study participation they will be withdrawn from the study. 
Pregnancy will be reported as the reason for withdrawal. 
 
 
8.4 UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
An unanticipated problem will be defined as any incident, experience, or outcome that meets 
ALL of the following criteria: 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the REB-
approved research protocol and informed consent document, or the Investigator 
Brochure; and (b) the characteristics of the research participant population being 
studied; and 
• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the [investigational product(s)] or procedures involved in the research); and 
• 
Suggests that the research places research participants or others at a greater risk of 
harm (including physical, psychological, economic, ethical or social harm) than was 
previously known or recognized. 
. 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 

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The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• 
UPs that are serious adverse events will be reported to the IRB within 2 days of the 
investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB within 7 days of the investigator becoming 
aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures) within 7 days of the IRB’s receipt of the report 
of the problem from the investigator. 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Participants will be made aware of any unanticipated problems that have occurred that may 
indicate that the risk/benefit ratio of study participation has changed.  
 
9 
STATISTICAL CONSIDERATIONS .  
 
9.1 STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
1. Pulse Wave Velocity will be increased following exercise, smoking high THC 
cannabis, and vaporizing high THC cannabis relative to resting baseline; effects of 
cannabis consumption and exercise are likely to be additive. Vaporizing high CBD 
cannabis will not increase pulse wave velocity. 
2. Percent flow mediated dilation will be decreased following exercise and smoking high 
THC cannabis; effects are likely to be additive. Vaporizing both high THC and high 
CBD cannabis will not decrease percent flow mediated dilation.  
3. Ejection fraction will be decreased following smoking and vaporizing high THC 
cannabis. Exercise and vaporization of high CBD cannabis will not be associated 
with reductions in ejection fraction.  
4. E/A Ratio will be decreased following high THC cannabis smoking only.  
5. Myocardial strain will be decreased following high THC cannabis smoking and 
vaporizing only. 
6. Myocardial twist will be decreased following high THC cannabis smoking and 
vaporizing only. 
7. Burst Frequency will be increased following high THC cannabis only. 
8. Burst Incidence will be increased following high THC cannabis only. 

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• 
Secondary Efficacy Endpoint(s): 
1. Systolic Blood Pressure will be increased following cannabis consumption and will be 
decreased following all bouts of exercise.  
2. Diastolic blood pressure will be unchanged under all conditions 
3. Heart rate will be increased following cannabis consumption and exercise. 
4. Stroke volume will be increased with exercise, and will be reduced following 
cannabis consumptions. These competing effects will result in an attenuation of 
increases in stroke volume when exercise is preceded by cannabis consumption. 
5. Cardiac output will be unchanged under all conditions 
6. Work completed will be reduced when preceded by cannabis consumption of all 
forms  
7. Average power output will be reduced when preceded by cannabis consumption of 
all forms  
8. Oxygen consumption will be reduced when exercise is preceded by consumption of 
high THC cannabis 
9. Rating of Perceived Exertion will be increased following consumption of high THC 
cannabis 
10. Rate-pressure product will be increased during exercise, when the bout is preceded 
by cannabis consumption. 
 
9.2 SAMPLE SIZE DETERMINATION 
 
In accordance with our power calculation, 15 participants are required to have a power of at 
least 0.8 with an alpha of 0.05, for expected changes in measures of endothelial function (pilot 
work, change in FMD in response to exercise pre = 4.8 ± 2.5 %, post = 2.7 ± 1.7%) (FMD in rats 
in response to cannabis smoke, pre = 7.5 ± 2.5%, post = 2.4 ± 1.4 %)3, artery stiffness (pilot 
work, change in PWV pre = 7.4 ± 1.3 m/s, post (at rest) = 6.0 ± 1.3 m/s) and cardiac function 
(pilot work, peak longitudinal strain: pre = -18.3 ± 1.2 %, post = -17.0 ± 1.9 %), therefore we will 
recruit 20 participants in each phase of the study to account for potential dropout. 
 
9.3 POPULATIONS FOR ANALYSES 
 
Only participants who complete all study procedures will be included for analysis of efficacy 
endpoints. All participants who consume cannabis at any time will be included in the analysis of 
safety endpoints. 
 
9.4 STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Our study will be divided into two phases each of which will be analyzed independently. All 
tests of significance will be two-tailed, and statistical significance will be based upon an 
alpha error probability of 5% and a power for 80%. The data will be evaluated using both 
parametric and non-parametric tests, as applicable. If the data are found to be not normally 
distributed, the raw data will be transformed using an appropriate transformation model in 
order to perform the parametric assessments. Non-parametric tests will be performed on 
raw data. The data will be assessed as continuous and will be presented as means with 
standard deviations. A one-way analysis of covariance will be used to assess the treatment 

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effects (Phase I: exercise, vaporizing THC, smoking THC, vaporizing + exercise THC, 
smoking THC + Exercise, Phase II: exercise, vaporizing THC, vaporizing CBD, vaporizing + 
exercise THC, Vaporizing CBD + Exercise) on the primary endpoints. Covariates will be 
introduced into the models in order to assess the impact of certain potential factors on 
outcome, including fitness, blood pressure, resting heart rate, and any other factors that are 
observed during the study that appear to potentially influence the outcome. 
 
Our secondary endpoints will be assessed using a repeated measures one-way ANOVA 
and paired t-tests. If there are significant interactions differences between pairs of means 
will be determined with a Bonferroni post-hoc test. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
All primary endpoints will be measured as continuous variables and will be repeated after each 
intervention performed on a given study visit. A one-way ANCOVA will be used to assess 
treatment effects. Covariates will include basic cardiovascular and haemodynamic variables that 
may confound primary endpoints. These covariates include heart rate, blood pressure, and 
pulse wave velocity. Results will be presented as adjusted means with standard deviations. 
Primary endpoints will only be analyzed for participants who complete the entirety of at least 
one phase of the proposed study. Missing data will be imputed using mean imputation from all 
other measurements collected from the given participant. Outliers will be included and excluded 
in independent analysis, both of which will be reported.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Analysis of secondary endpoints will be independent of analysis of primary endpoints. All 
secondary endpoints will be measured as continuous variables and will be reported as adjusted 
means with standard deviations. Repeated measures one-way ANOVA and paired Student’s t-
tests will be used for analyses. If there are significant interactions differences between pairs of 
means will be determined with a Bonferroni post-hoc test. Missing data will be imputed using 
mean imputation from all other measurements collected from the given participant. Outliers will 
be included and excluded in independent analysis, both of which will be reported.  
 
9.4.4 SAFETY ANALYSES 
 
Safety analysis will be performed using summary statistics during treatment interventions. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities and 
will have severity, and relationship of adverse event to study intervention presented by System 
Organ Class and preferred term groupings. Each instance of an adverse event will be presented 
as a discrete event.  Duration of events, severity, relationship to intervention, expectation, and 
outcome will be presented. Adverse events that lead to premature discontinuation will be 
presented in a table, along with all treatment-emergent serious adverse events.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline characteristics of participants will be presented in a table. No descriptive statistics 
other than mean and standard deviation will be presented as the proposed study uses a within-
subjects design.  
 
9.4.6 PLANNED INTERIM ANALYSES  

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No interim analysis is planned for the proposed study. Phase I of this study will be completed in 
advance of phase II, and as such efficacy and safety analyses for phase I may occur before the 
completion of phase II. The results of phase I will not be used to modify the desired sample size 
or planned analyses of phase II. 
 
9.4.7 SUB-GROUP ANALYSES 
 
Sub-analysis of each primary and secondary endpoint will be performed based upon sex. This 
analysis will be performed identically to all efficacy and safety analyses with the only adjustment 
being the exclusion of the sex not of interest.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA. 
 
Data collected from each participant will be recorded by measure and study visit. Each 
participant will be assigned a study ID. 
 
9.4.9 EXPLORATORY ANALYSES 
 
There are no planned exploratory analyses in the current study. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS  
 
A consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to 
starting intervention/administering study intervention.  The consent document is submitted with 
this protocol. 
 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. The consent form has 
been Institutional Review Board (IRB)-approved and the participant will be asked to read and 
review the document. The participant will be provided the consent document in advance of their 
first study visit. During the first laboratory visit, an investigator will explain the study to the 
participant and answer any questions that may arise. A verbal explanation will be provided in 
terms suited to the participant’s comprehension of the purposes, procedures, and potential risks 
of the study and of their rights as research participants.  Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participant will 
sign the informed consent document prior to any procedures being done specifically for the 
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from the study at any time, without prejudice. A copy of the informed consent document will be 
given to the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the 
participant undergoes any study-specific procedures.  
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal 
Investigator-Sponsor will promptly inform study participants and the Institutional Review Board, 
and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators. 
This confidentiality is extended to cover all individual test results collected during this study, in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the principal investigator-sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
 
Upon enrollment into the study, each participant will be assigned a participant ID. A master list 
of all ID’s will be kept separate from all study results. Data collected will be labelled only with 
participant ID’s. Upon completion of data collection, the master list linking identifying information 
to participant IDs will be destroyed. Study participant research data, which is for purposes of 
statistical analysis and scientific reporting, will be stored within the laboratory of Dr. Burr and will 
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identifying information. Digital study data used by research staff will be secured and password 
protected.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
No biological specimens will be obtained in this study. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator-
Sponsor 
Qualified Investigator 
Dr. Jamie Burr PhD 
Dr. Margo Mountjoy MD, PhD 
University of Guelph 
University of Guelph 
50 Stone Road E 
50 Stone Road E 
(519) 824-4120x52591 
 
(519) 885-5426x21122 
burrj@uoguelph.ca 
mmsportdoc@uoguelph.ca 
 
 
10.1.6 CLINICAL MONITORING 
 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Conference on Harmonization Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s).  
 
Dr. Kerry Ritchie will act as the monitor for this clinical trial. She will be located on-site, and will 
conduct a minimum of three monitoring visits. These visits will include an initiation visit, an 
interim monitoring visit, and a close out visit. The initial visit will involve the PI and the 
investigatory team in addition to the monitor. In this meeting the protocol, investigational 
product, SOP’s, ICH-GCP, Health Canada regulations, AE reporting, protocol deviation, and 
stakeholder responsibilities will be discussed to ensure all parties understand their roles in the 
study. During the interim visit, certain items will be reviewed for data verification for all 
participants, while other items will be viewed for only a selection of participants. Monitoring 
reports will be distributed to the entire investigatory team following the interim visit. The close 
out visit will involve a review of all documentation for accuracy and completeness. 
 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality management of study conduct, data collection, documentation, and completion will be 
performed.  
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated, documented (recorded), and reported in 
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(ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), 
Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring, and inspection by local and 
regulatory authorities. Any deficiencies or quality control issues identified by the monitor will be 
corrected by the investigatory team. 
 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data will be recorded in encrypted digital files for the purpose of analysis. All hard copy data 
recorded will be archived within the lab of Dr. Jamie Burr. Regular monitoring will ensure that all 
hard copy data will be correct in both hard copies and electronic records. Participant’s inclusion 
in the study will be recorded via archiving of the consent form and all hard copy data. All 
investigators will be held responsible for proper data handling procedures. A master list of 
participant IDs will be maintained throughout the course of data collection and analysis. After 
this period, the master list will be destroyed and all individual data will be completely de-
identified. 
 
10.1.8.2 
STUDY RECORDS RETENTION  
 
Study documents and de-identified individual data will be retained for 25 years after the 
completion of the data collection period. This time period of retention is in accordance with the 
requirements of the IRB. No records will be destroyed without the written consent of the IRB. It 
is the responsibility of the investigator-sponsor destroy these documents when they are no 
longer required to be retained. 
 
10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or International 
Conference on Harmonization Good Clinical Practice (ICH GCP). The noncompliance may be 
either on the part of the participant or the investigators. As a result of deviations, corrective 
actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and record 
deviations within 2 working days of identification of the protocol deviation, or within 2 working 
days of the scheduled protocol-required activity.  All deviations must be addressed in study 
documents.  
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 

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This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy. It requires scientists to submit final 
peer-reviewed journal manuscripts to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be 
made to publish results in peer-reviewed journals.  Data from this study may be requested from 
other researchers 25 years after the completion of the primary endpoint by contacting Dr. Jamie 
Burr.  
 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the cannabis 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the 
design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. 
Furthermore, persons who have a perceived conflict of interest will be required to have such 
conflicts managed in a way that is appropriate to their participation in the design and conduct of 
this trial.  The study leadership in conjunction with the University of Guelph has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 
10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA Analysis of Covariance 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSDS 
Material Safety Data Sheet 
NIH  
National Institutes of Health 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 

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SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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