Does CBD Oil Raise Your Heart Rate

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Can consuming cannabis increase your risk of heart attack? Read all about the research on the effects of cannabis on your heart and cardiovascular system. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study 1 Division of Medical Sciences & Graduate Entry Medicine, University of Nottingham, Royal

How Does Cannabis Consumption Affect Heart Rate?

There are over 630,000 deaths annually in the United States due to heart disease, which represent nearly a quarter of all deaths. An additional 140,000 deaths result from stroke. Cannabis consumers are used to warnings about the potential damage the drug is doing to their brain, but what about their heart? Could cannabis be affecting our cardiovascular health?

The cardiovascular system is made up of the heart and blood vessels that transport blood throughout your body (the “cardio” part of the term refers to the heart, while “vascular” refers to the system of blood vessels, veins, and arteries). When the cardiovascular system isn’t working properly, it can lead to a heart attack, where part of the heart muscle dies, or a stroke, which is the blockage or rupture of blood vessels that then deprives brain cells of their necessary nutrients and causes them to die.

In a recent meta-analysis , researchers scrutinized 24 articles that investigated the impacts of cannabis on cardiovascular risk factors (such as cholesterol levels, obesity rates, and diabetes) and cardiovascular events like stroke and heart attack. They concluded that there’s insufficient evidence that cannabis use has any effect on heart attacks or stroke, or increases their risk factors. In fact, the researchers found some evidence that cannabis use may be associated with lower risk for obesity.

So are cannabis consumers in the clear? Not so fast. The authors note that many of the studies were limited by elevated risk of bias and poor control over cannabis exposure levels and frequency. Also, because levels of the euphoric cannabinoid THC are on the rise , it’s difficult to generalize the effects of cannabis use over the last few decades using today’s use patterns.

But what caused scientists and physicians to propose a link between cannabis and cardiovascular risk factors in the first place?

Increase in Cannabis-Related Health Complications in the Clinic

With the number of cannabis consumers increasing, so have the number of cannabis-related cardiovascular events . The problem is that the cannabis consumers showing up in emergency rooms are often young with few other risk factors, leading many to believe that cannabis itself is playing a role.

Most studies looking at the impact of cannabis on cardiovascular health only control for general use patterns, not type of cannabis.

One study found that risk of heart attack increases nearly five-fold within the hour of using cannabis. Another found that weekly cannabis use more than quadruples stroke risk. You’d predict then, that if cannabis access increases with legalization, cardiovascular deaths would go up. Indeed they d o , and the effect is strongest in states with more lax dispensing regulations.

Well, that sounds frightening. If it’s true, how could another study conclude that there’s no sufficient evidence for cannabis’ effect on cardiovascular complications?

Variability in Cannabis Type and Use Patterns Makes Studies in Humans Challenging

Your average dispensary has a massive range of cannabis products available. Some are rich in THC, while others are low in THC. Some have high levels of other cannabinoids, like cannabidiol (CBD), which can have opposite effects on the brain and body as THC. But most studies looking at the impact of cannabis on cardiovascular health only control for general use patterns, not type of cannabis.

The studies usually don’t control for THC consumption or the presence of other cannabinoids. The larger assessments of the impact of statewide legalization on cardiovascular events in the state’s population don’t even assess whether these events occurred in cannabis users, thereby assuming that increased cannabis access is the variable that changed the mortality rate. So when someone says that “cannabis use” increases risk for cardiovascular events, the next questions should be “what type of cannabis? And how often are they using?”

To better understand the impact of cannabis on the heart and vasculature, let’s unpack the contribution that the endogenous cannabinoid receptors type I and II (CB1 and CB2) have on cardiovascular function.

The Impact of CB1 Receptors on Heart Rate and Heart Attack Risk

THC activates CB1 receptors to decrease blood pressure and increase heart rate. (Elysse Feigenblatt/Leafly)

CB1 receptors are found all over the body’s cardiovascular system. They’re on the heart muscle, surround blood vessels, and regulate the brain nerves that control heart rate. So there’s plenty of reason to believe THC-rich cannabis could impact cardiovascular function.

Increased Heart Rate

Activation of CB1 receptors by THC can increase heart rate by 20-50 beats per minute. This increase occurs in order to compensate for the reduction in blood pressure caused by THC. Blood pressure is lowered because THC increases the diameter of blood vessels, forcing the heart to work harder in order to pump blood. Some reports find that the heart must work 30% harder in the presence of high levels of THC.

Effects on Arteries

CB1 receptor activation also increases plaque buildup in arteries, which increases risk of atherosclerosis, a disease characterized by the narrowing of arteries that can lead to heart attack and stroke. This effect occurs through two main mechanisms.

First, activating CB1 receptors increases the amount of harmful chemicals called reactive oxygen species, which damage the walls of arteries. The damage to the artery walls initiates an immune response that attracts special immune cells known as macrophages. These macrophages become part of the wall of the artery.

This is worsened by a second effect of activating CB1 receptors, which increases the amount of the “bad” low-density lipoprotein (LDL) cholesterol of the macrophages that adhere to the walls of the artery. Elevated levels of reactive oxygen species have an exacerbated effect on plaque buildup, increasing risk of heart attack and stroke.

The Effects of CB2 Receptors on Cardiovascular Health

While drugs that activate CB1 receptors can have negative effects on cardiovascular health, drugs that selectively activate CB2 receptors have beneficial effects on heart health.

Low doses of THC have been shown to reduce plaque buildup and risk for atherosclerosis.

CB2 receptors are mostly expressed in immune cells, but their levels increase in other parts of the body after injury or in disease. Therefore, they’re not only a good target to reduce the harmful effects of CB1 receptors on heart health, they can be a promising target to lessen the damage caused by injury or cardiovascular attack.

Activating CB2 receptors reduces the inflammation and free radicals that increase plaque buildup in arteries and elevate risk for heart attack and stroke. Through this anti-inflammatory effect, if a heart attack or stroke does occur, activating CB2 receptors reduces the extent of damage .

Is THC Dangerous for Cardiovascular Health?

The answer depends on the dose. THC can activate both CB1 and CB2 receptors, but low doses of THC appear to most strongly activate CB2’s pro-cardiovascular health effects. At higher doses, THC’s effect on CB1 receptors overrides its effect on CB2 receptors and has a net negative impact on cardiovascular health.

In fact, low doses of THC have been shown to reduce plaque buildup and risk for atherosclerosis. This beneficial low-dose effect is thought to come from THC’s activation of CB2 receptors and not CB1 receptors, suggesting that THC’s ability to activate CB2 receptors can protect the heart, while its activation of CB1 receptors can hurt it.

How Other Cannabinoids Affect Cardiovascular Health

Left: THC directly stimulates the CB1 receptor. This interaction underlies the major psychoactive effects of cannabis consumption. Right: CBD reduces, or “antagonizes,” THC’s ability to stimulate CB1 receptors. (Amy Phung/Leafly)

Two of the most abundant phytocannabinoids other than THC are CBD and tetrahydrocannabivarin (THCV). CBD can block THC’s ability to activate CB1 receptors and could protect against some of the harm caused by the drop in blood pressure and elevated heart rate caused by THC alone.

On its own, CBD is a potent antioxidant and neutralizes harmful free radicals. It also has strong anti-inflammatory abilities which can reduce the damage caused by activation of CB1 receptors. Indeed, CBD has beneficial effects on cardiovascular risk factors and improves recovery in animal models of heart attack and stroke.

THCV has pro-cardiovascular effects by blocking CB1 receptor function at low doses. It’s through this mechanism that THCV is thought to reduce insulin sensitivity in obese mice, which reduces risk for cardiovascular events. And like CBD, THCV has been shown to be safe in Phase II clinical trials. THCV becomes an activator of CB1 receptors at high does, but in most strains of cannabis, THCV levels are too low to activate them.

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Synthetic Cannabinoids Can Cause Death

Synthetic cannabinoids , particularly those that try to mimic THC, have been linked with numerous severe health consequences . Given the impact that activating CB1 receptors can have on cardiovascular health, this shouldn’t be surprising.

For instance, synthetic canna binoids like “K2” and “Spice” are 2-100 times better at activating CB1 receptors than THC. Even after a single use, synthetic cannabinoids have been linked with numerous cases of medical emergencies involving dangerously low blood pressure, abnormal heart rhythms, and kidney failure, that sometimes results in death .

Cannabis and Heart Risks in Summary

Despite this seemingly bleak picture, cardiovascular events only represent 2% of all medical reports related to cannabis. Cannabis’ relationship with cardiovascular health remains unclear, and we’re left inferring its effects from the impacts of THC on its own or generalizing from the effects of activating CB1 or CB2 receptors in preclinical animal models.

Emerging evidence suggests that cannabis use increases risk for cardiovascular events, but these studies fail to control for THC levels consumed, the presence of additional and often counteracting cannabinoids (e.g., CBD), duration and frequency of use, and consumption method. Regardless of how you interpret the risk, just be sure stay away from synthetic cannabinoids like K2 and Spice—that junk can kill you.

A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study

1 Division of Medical Sciences & Graduate Entry Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.

Garry D. Tan

2 The NIHR Oxford Biomedical Research Centre, Oxford Centre for Diabetes, Endocrinology & Metabolism, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

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Saoirse E. O’Sullivan

1 Division of Medical Sciences & Graduate Entry Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.

1 Division of Medical Sciences & Graduate Entry Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.

2 The NIHR Oxford Biomedical Research Centre, Oxford Centre for Diabetes, Endocrinology & Metabolism, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

Associated Data

Abstract

BACKGROUND. Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans.

METHODS. Nine healthy male volunteers were given 600 mg of CBD or placebo in a randomized, placebo-controlled, double-blind, crossover study. Cardiovascular parameters were monitored using a finometer and laser Doppler.

CONCLUSIONS. This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.

Introduction

Epidemiological studies have shown a positive relationship between long-term stress and the development of cardiovascular disease (1). Factors like social isolation, low socioeconomic status, depression, stressful family and work life, and anxiety are associated with an increased risk of the development and accelerated progression of existing cardiovascular disease. Current European guidelines on the prevention of cardiovascular disease have emphasized the importance of tackling these factors (2). Mental stress induces myocardial ischaemia in patients with stable coronary artery disease, and this appears to be mediated by adrenal release of catecholamines (3).

Cannabinoids (CBs) are compounds that bind to CB receptors or are structurally similar to compounds that bind to CB receptors. They include endogenously produced compounds (called endocannabinoids), synthetic compounds and phytocannabinoids obtained from the Cannabis sativa plant. There are over 80 known types of phytocannabinoids, the most widely studied of which is Δ 9 tetrahydrocannabinol (Δ 9 -THC or THC), which is responsible for the psychoactive properties of cannabis (4). The other major phytocannabinoid is cannabidiol (CBD), which does not have psychoactive properties. CBD is currently the focus of much research due to its potential in a number of therapeutic areas, as it has been shown to have antiinflammatory, anticonvulsant, antioxidant, anxiolytic, antinausea, and antipsychotic properties (5). A number of preclinical studies have also shown beneficial effects of CBD in a range of disorders of the cardiovascular system (6). A CBD/THC combination (Sativex/Nabiximols, GW Pharmaceuticals) is licensed for the treatment of spasticity in multiple sclerosis, and CBD alone (Epidiolex, GW Pharmaceuticals) has entered an expanded access program in children with intractable epilepsies (Dravet syndrome and Lennox-Gastaut syndrome). Epidiolex has also received orphan designation status for the treatment of neonatal hypoxia-ischaemic encephalopathy.

CBD has multiple desirable effects on the cardiovascular system. It attenuates high glucose–induced proinflammatory changes in human coronary artery endothelial cells (7) and myocardial dysfunction associated with animal models of diabetes (8), and it preserves endothelial integrity in diabetic retinal microvasculature (9). In vivo administration of CBD before cardiac ischemia and reperfusion also reduces ventricular arrhythmias and infarct size. CBD also causes both acute and time-dependent vasorelaxation in isolated arteries in rats and humans (10–12). There is also evidence from animal studies that CBD modulates the cardiovascular response to stress. Resstel and colleagues (13) showed in rats that i.p. injection of CBD (10 and 20 mg/kg, –30 min) reduced restraint stress–induced cardiovascular response and behavior. Both these effects were blocked by preadministration of WAY100635 (0.1 mg/kg), a 5-hydroxytryptamine 1A (5HT1A) antagonist. These effects appear to be mediated centrally and involve the bed nucleus of the stria terminalis (BNST), a limbic structure that modulates neuroendocrine responses to acute stress (14).

Our recent systematic review showed us that there are no dedicated studies in humans to date, to our knowledge, looking at the effect of CBD on either resting cardiovascular measurement or on the responses to stress, with continuous monitoring of CV parameters (15). Therefore, the aim of the present study was to investigate whether CBD decreases the cardiovascular response to stress after the administration of a single dose of CBD (600 mg) in healthy volunteers, with the hypothesis that blood pressure would be reduced by CBD. Noninvasive cardiovascular measurements were used along with stress tests in the form of mental arithmetic, isometric exercise, and the cold pressor test.

Results

Ten male subjects were recruited, but 1 withdrew for personal reasons. The mean age, weight, and height of the volunteers were 23.7 ± 3.2 years, 77.5 ± 6.4 kg, and 178.6 ± 4.5 cm (mean ± SD).

Effect of CBD on resting cardiovascular parameters.

Changes in resting cardiovascular parameters after a single dose (600 mg) of cannabidiol (CBD) in healthy volunteers (n = 9).

The effects of placebo (closed square) and CBD (open square) on systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), mean arterial blood pressure (MAP) (C), heart rate (HR) (D), stroke volume (SV) (E), cardiac output (CO) (F), ejection time (EJT) (G), total peripheral resistance (TPR) (H), and forearm blood flow (I), measured continuously over 2 hours after drug ingestion, except for forearm blood flow. Forearm blood was measured over a time period of 2 minutes just before the start and in between the stress tests. Dotted line denotes baseline values between the stress tests. Repeated measures 2-way ANOVA; mean ± SEM (*/ + / # P < 0.05, **/ ++ / ## P < 0.01 using Bonferroni’s post-hoc analysis; + and # represent significant change in any parameter over time seen with placebo and CBD, respectively; denotes overall significant difference between 2 treatments).

There was a trend toward reduction in total peripheral resistance (TPR, Figure 1H ) with CBD in the latter half of the resting period, and a significant reduction in forearm skin blood flow before the start of the stress tests ( Figure 1I ; P < 0.01).

Effect of CBD on cardiovascular parameters mental stress.

The individual blood pressure responses of healthy volunteers to the stresses are presented in Figure 2 , showing the average baseline systolic or diastolic blood pressure in the 4 minutes preceeding the stress test, the peak response during stress, and the average recovery response in the 4 minutes after the stress test.

Individual systolic and diastolic blood pressure responses to all stress tests after a single dose (600 mg) of cannabidiol (CBD) or placebo in healthy volunteers (n = 9).

Green color coding shows subjectS who had a reduced (compared with placebo) blood pressure response to stress after taking CBD, and red color coding shows an increased blood pressure response to stress after taking CBD.

Mental stress test.

Cardiovascular response to mental stress after a single dose (600 mg) of cannabidiol (CBD) in healthy volunteers (n = 9).

The effects of placebo (closed square) and CBD (open square) on systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), mean arterial blood pressure (MAP) (C), heart rate (HR) (D), stroke volume (SV) (E), cardiac output (CO) (F), ejection time (EJT) (G), total peripheral resistance (TPR) (H), and forearm blood flow (I), measured continuously just before, during, and after mental arithmetic test (dotted line denotes stress test period), except for forearm blood flow. Measurements for forearm blood flow were made over a 2-minute window just before, during, and after the stress test. Repeated measures 2-way ANOVA; mean ± SEM (+ and # denote significant change in a parameter during the stress period seen with placebo and CBD, respectively). + / # P < 0.05, ++ /# # P < 0.01.

Exercise stress test.

Cardiovascular parameters in response to exercise stress after a single dose (600 mg) of cannabidiol (CBD) in healthy volunteers (n = 9).

The effects of placebo (closed square) and CBD (open square) on systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), mean arterial blood pressure (MAP) (C), heart rate (HR) (D), stroke volume (SV) (E), cardiac output (CO) (F), ejection time (EJT) (G), total peripheral resistance (TPR) (H), and forearm blood flow (I), measured continuously just before, during, and after isometric exercise test (dotted line denotes stress test period), except for forearm blood flow. Measurements for forearm blood flow were made over a 2-minute window just before, during, and after the stress test. Repeated measures 2-way ANOVA; mean ± SEM (*/ + / # P < 0.05; **/ ++ / ## P < 0.01; ***/ ### P < 0.001; ****/ #### P < 0.0001 using Bonferroni post-hoc analysis; + and # denote significant change in a parameter during the stress period seen with placebo and CBD respectively).

Cold stress test.

Cardiovascular response to cold stress after a single dose (600 mg) of cannabidiol (CBD) in healthy volunteers (n = 9).

The effects of placebo (closed square) and CBD (open square) on systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), mean arterial blood pressure (MAP) (C), heart rate (HR) (D), stroke volume (SV) (E), cardiac output (CO) (F), ejection time (EJT) (G), total peripheral resistance (TPR) (H), and forearm blood flow (I), measured continuously just before, during, and after cold pressor test (dotted line denotes stress test period), except for forearm blood flow. Measurements for forearm blood flow were made over a 2-minute window just before, during, and after the stress test. Repeated measures 2-way ANOVA; mean ± SEM (*/ + / # P < 0.05, **/ ++ P < 0.01, ***/ +++ P < 0.001, ****P < 0.0001 using Bonferroni post-hoc analysis; + and # denote significant change in a parameter during the stress period seen with placebo and CBD, respectively).

Looking at the individual response to the cold pressor test, 8 of 9 subjects had a lower SBP during the cold stress and in the recovery period after taking CBD ( Figure 2 ). Six of 9 subjects had a lower DBP during the cold pressor, and 7 of 9 subject had a lower DBP in the recovery period after taking CBD ( Figure 2 ).

Discussion

Based on preclinical evidence, the aim of this study was to test the hypothesis that CBD would reduce the cardiovascular response to stress in healthy volunteers. We found that resting blood pressure was lower after subjects had taken CBD and that CBD blunted the blood pressure response to stress, particularly in the pre- and poststress periods. Post-hoc analysis showed an overall trend of lower SBP, MAP, DBP, SV, TPR, forearm skin blood flow, and left ventricular EJT and a higher HR in subjects who had taken CBD. These hemodynamic changes should be considered for people taking CBD and suggest that further research is warranted to establish whether CBD has any role in the treatment of cardiovascular disorders.

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We have shown for the first time that to our knowledge that, in humans, acute administration of CBD reduces resting blood pressure, with a lower stroke volume and a higher heart rate. This response may be secondary to the known anxiolytic properties of CBD (16) and may account for the lack of anticipatory rise in blood pressure seen with placebo. These findings are in contrast to previous studies in humans, where CBD at the same dose did not affect baseline cardiovascular parameters (17–19), although changes in the cardiovascular system were not the primary outcome of these studies. In the present study, CV parameters were measured continuously, while in previous studies, monitoring for SBP, DBP, and HR were performed manually at only 1, 2, or 3 hours after drug delivery. Additionally, our subjects were cannabis naive, while the subjects of other studies had used cannabis in the past. Since tolerance may develop to the hemodynamic response to CBs in humans, this may explain the differences between studies.

THC, the major psychoactive component of cannabis, is known to cause tachycardia and orthostatic hypotension in humans (20), a hemodynamic response similar to that observed to CBD in the present study. THC is a partial agonist at both CB1 and CB2 receptors (21), and the effects of THC on heart rate are mediated through CB1 receptors (20). CBD does not bind with any great affinity to CB1, but it can interact indirectly by augmenting CB1 receptors’ constitutional activity or endocannabinoid tone, the so called indirect agonism (22). We recently showed that CBD also causes endothelium-dependent vasorelaxation in isolated human mesenteric arteries through CB1 activation (11). Therefore, it is possible that the changes in hemodynamics brought about by CBD are mediated through CB1.

CBD may cause sympathoinhibition (through CB1 or some other mechanism), thereby preventing an increase in blood pressure and cardiac output, causing a compensatory rise in heart rate to maintain cardiac output. Indeed, the changes in SBP preceded any changes in HR. Another possibility is that CBD inhibits cardiac vagal tone, thereby increasing heart rate (despite any potential sympathoinhibition). A recent study in male Sprague-Dawley rats showed that GPR18 activation in the rostral ventrolateral medulla (RVLM) by abnormal CBD (Abn-CBD) resulted in reduced blood pressure and increased heart rate (23) (similar to that observed in the present study). The same study showed that pretreatment with atropine and propranolol fully abrogated the HR response, suggesting a role for the autonomic nervous system. CBD is a weak partial agonist at GPR18 (24).

Effect of CBD on cardiovascular parameters in response to mental stress.

Mental arithmetic has been shown to cause a rise in MAP and muscle sympathetic nerve activity (MSNA) (25) and vasodilatation in forearm skeletal muscle (26). In our study, none of the cardiovascular parameters other than HR, DBP, and SV were affected, suggesting that the level of stress to this test was minimal. This could be because of the added visual stimulus of a computer screen, which would have helped volunteers perform the task. Overall, there was trend for lower SBP, DBP, MAP, SV, TPR, and forearm skin blood flow in subjects who had taken CBD, particularly in the pre– and post–stress test periods. Like resting cardiovascular parameters, these changes may indicate anxiolytic effects of CBD and/or generalized sympathoinhibition.

Effect of CBD on cardiovascular parameters in response to exercise stress.

Isometric exercise produces a pressor response, via sympathoexcitation, originating in the contracting muscle and relayed to the RVLM via the nucleus of solitary tract. The end result is a rise in heart rate and cardiac output and vasoconstriction in nonexercising organs (27–29). There is increased skeletal muscle blood flow in the nonexercising limb, which is sensitive to atropine and propranolol (30). A similar response was seen in our study, where isometric exercise caused a significant rise in SBP, DBP, MAP, and HR and an increase in forearm blood flow, although this was significant in the placebo group only. Subjects who had taken CBD had reduced blood pressure during the exercise stress test, and this was most pronounced in the pre- and posttest period. Before the exercise stress, HR was higher and SV lower in volunteers when they had taken CBD, and this trend continued throughout exercise stress and in the poststress period. There was also a significant reduction in EJT with CBD, which represents a reciprocal change to increased HR. The rise in cutaneous blood flow was only seen with placebo and not with CBD, possibly suggesting reduced β2 adrenergic–mediated vasodilatation, which could be a result of general sympathoinhibition or a specific effect at the β2 adrenoceptors. The tissue distribution of β2 adrenoceptors and CB1 receptors overlaps in many tissues, including in the cardiovascular system (31). At the cellular level, a complex physical and functional interaction between these 2 receptors has been demonstrated; there is evidence of cointernalization of β2 adrenoceptors with CB1 receptors, leading to desensitisation of β2 adrenoceptors (31).

Effect of CBD on cardiovascular parameters in response to cold stress.

Cold stress causes intense sympathoexcitation, producing a tachycardic and pressor response, and an increase in MSNA (32, 33). The pressor response is due to an initial rise in CO, in response to increased HR and a later increase in MSNA, causing vasoconstriction. Both MAP and TPR show a linear correlation with MSNA during cold stress (34). In our study, cold stress produced a pressor response in both groups, but, interestingly, while SBP and MAP continued to rise with placebo throughout the test period, the pressor response to cold was blunted in subjects who had taken CBD, and SBP and MAP were significantly lower. In keeping with this, TPR was lower with CBD than placebo, suggesting a possible inhibition of sympathetic outflow. This could also be due to analgesic properties of CBD (35), reducing cold stress and therefore minimizing the sympathetic response (also explaining why the cold pressor test was affected more by CBD than the exercise test). In the animal study of Resstel and colleagues (13), the authors suggested that the modulation of cardiovascular response was most likely secondary to attenuation of emotional response to stress. However, given our findings that CBD produced similar changes in cardiovascular parameters — though to a variable degree — during rest and stress, this may indicate that CBD also has direct cardiovascular effects.

Safety and tolerance.

CBD was well tolerated, and there were no adverse events on the day of stress tests. None of the subjects reported any adverse events over the following week.

Conclusion.

Our data show that a single dose of CBD reduces resting blood pressure and the blood pressure response to stress, particularly cold stress, and especially in the post-test periods. This may reflect the anxiolytic and analgesic effects of CBD, as well as any potential direct cardiovascular effects. CBD also affected cardiac parameters but without affecting cardiac output. Giving the increasing use of CBD as a medicinal product, these hemodynamic changes should be considered for people taking CBD. Further research is also required to establish whether CBD has any role in the treatment of cardiovascular disorders such as a hypertension.

Methods

Study design.

The study was a randomized, crossover design with each subject given CBD (BN: K12067A) or placebo (both gifts from GW Pharmaceuticals) in a capsule in a double-blind fashion, with a minimum time interval of at least 48 hours (range 3–16 days), taking place at the Division of Medical Sciences, School of Medicine, Royal Derby Hospital. Allocation was decided by a coin toss, and block randomization was employed by S.E. O’Sullivan, who assigned participants. K.A. Jadoon carried out all study visits, and data analysis was blinded.

During an initial visit, subjects were familiarized with the stress tests and with noninvasive cardiovascular (CVS) monitoring, and an electrocardiogram (ECG) was done to rule out any preexisting cardiac conditions. Subjects were advised to fast overnight, to avoid beverages containing caffeine or alcohol, and to avoid strenuous exercise for 24 hours before each of the 2 study visits. Two hours after CBD/placebo was administered, subjects performed various stress tests (36). Noninvasive cardiovascular monitoring using Finometer and laser Doppler flowmetry was carried out during the 2 hours to assess changes in baseline parameters and during the stress test periods.

Visit days.

Upon arrival, subjects were rested for 10–15 minutes, and their baseline blood pressure and heart rate were recorded using a digital blood pressure (BP) monitor. Participants were given a standardized breakfast, and 15 minutes later, they were given either oral CBD (600 mg) or placebo in a double-blind fashion. This is a dose known to cause anxiolytic effects in humans and is comparable with what is used clinically (19, 37–39). Study medication consisted of capsules containing either 100 mg of CBD or excipients, which were a gift from GW Pharmaceuticals. There was no difference between the 2 formulations in color, taste, or smell.

Two hours afterward, subjects were asked to perform the stress tests (36). Timing of the tests was chosen to coincide with peak plasma levels for CBD (18). All the experiments were performed in a sitting position under ambient temperature conditions. Maximum voluntary contraction for the isometric hand grip test was assessed for each subject prior to administering study medication.

After administration of CBD or placebo, subjects remained seated, either doing nothing, reading, or using a computer. During this time, subjects were connected to a calibrated Finometer (Finapres Medical Systems), which uses a finger-clamp method to detect beat-to-beat changes in digital arterial diameter using an infrared photoplethysmograph (40). The Finometer gives a continuous signal of beat-to-beat changes in blood pressure and blood flow, and it uses this signal to derive other parameters, including systolic, diastolic, and mean blood pressure; interbeat interval; heart rate and left ventricular ejection time; stroke volume; cardiac output; and systemic peripheral resistance. Baseline cardiovascular data was recorded for 2 hours following administration of CBD or placebo. Forearm blood flow was measured using a calibrated laser Doppler flowmeter (Perimed) (41). For each recording, 5 images of microcirculation were taken, over an area 19 mm × 19 mm, using the upper third of the left forearm under high resolution. After 2 hours, subjects underwent the cardiovascular stress tests in the following order: mental arithmetic, isometric exercise, and cold pressor test.

The mental arithmetic test consisted of calculating a sum every 2 second for 2 minutes. Subjects were seated in front of a computer screen, and a PowerPoint presentation delivered a slide with a simple mathematical sum of a 3-digit number minus a smaller number (e.g., 317 – 9, 212 – 11, 185 – 7) every 2 seconds; the subject had to give the answer verbally. In the isometric exercise stress test, using a dynamometer, handgrip was maintained at 30% of maximum voluntary contraction (MVC) for 2 min. For the cold pressor test, subjects immersed their left foot (up to ankle) in ice slush (temperature 4°C–6°C) for 2 minutes. Cardiovascular parameters were measured continuously using the Finometer, while skin blood flow measurements were taken just before, during, and 5 minutes after each test. Each stress test lasted for 2 minutes, and there was a recovery period of at least 10 minutes.

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Statistics.

Data were analyzed using repeated measures ANOVA to determine the effect of treatment and time on different variables using GraphPad PRISM version 6.02. Level of significance was set at α = 0.05 and values presented as mean ± SEM. Sidak’s post-hoc test was used to see treatment affect at various time points. Data were not unblinded until after statistical analysis.

Study approval.

Ten healthy young male volunteers, mean age 24 years (range 19–29), with no underlying cardiovascular or metabolic disorders, were recruited for this study, which was approved by the University of Nottingham Faculty of Medicine Ethics Committee (study reference E18102012). Written informed consent was obtained according to the Declaration of Helsinki. Exclusion criteria included any significant cardiovascular or metabolic disorder or use of any medication. All the volunteers were nonsmokers and had taken no prescribed or over-the-counter medication within a week prior to randomization. No volunteers had ever used cannabis.

Author contributions

KAJ helped with study design, researched data, wrote the manuscript, and reviewed/edited the manuscript. GDT reviewed/edited the manuscript. SEO was involved in study design and reviewed/edited the manuscript.

Supplementary Material

Acknowledgments

GT is supported by the NIHR Oxford Biomedical Research Centre Programme. The views expressed are those of the author and not necessarily those of the NHS, the NIHR, or the Department of Health.

Footnotes

Conflict of interest: GW Pharma supplied the cannabidiol (CBD) and placebo but did not fund the study.

Reference information:JCI Insight. 2017;2(11):e93760. https://doi.org/10.1172/jci.insight.93760.

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