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Is the cardiovascular system a therapeutic target for cannabidiol? Dr Saoirse E. O’Sullivan, School of Graduate Entry Medicine and Health, Royal Derby Hospital, University of Nottingham, Derby, The cannabidiol CBD, which performs an opposing function to the element THC that is behind cannabis’ psychoactive effect, is growing in popularity across the globe. It is now used relatively widely to treat anxiety and other disorders, and is available in high-street stores throughout the UK. Scientific research has e 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

Is the cardiovascular system a therapeutic target for cannabidiol?

Dr Saoirse E. O’Sullivan, School of Graduate Entry Medicine and Health, Royal Derby Hospital, University of Nottingham, Derby, DE22 3DT, UK. Tel.: 01332 724643, Fax: 01332 724626, E-mail: [email protected]

Abstract

Cannabidiol (CBD) has beneficial effects in disorders as wide ranging as diabetes, Huntington’s disease, cancer and colitis. Accumulating evidence now also suggests that CBD is beneficial in the cardiovascular system. CBD has direct actions on isolated arteries, causing both acute and time-dependent vasorelaxation. In vitro incubation with CBD enhances the vasorelaxant responses in animal models of impaired endothelium-dependent vasorelaxation. CBD protects against the vascular damage caused by a high glucose environment, inflammation or the induction of type 2 diabetes in animal models and reduces the vascular hyperpermeability associated with such environments. A common theme throughout these studies is the anti-inflammatory and anti-oxidant effect of CBD. In the heart, in vivo CBD treatment protects against ischaemia-reperfusion damage and against cardiomyopathy associated with diabetes. Similarly, in a different model of ischaemia-reperfusion, CBD has been shown to reduce infarct size and increase blood flow in animal models of stroke, sensitive to 5HT1A receptor antagonism. Although acute or chronic CBD treatment seems to have little effect on haemodynamics, CBD reduces the cardiovascular response to models of stress, applied either systemically or intracranially, inhibited by a 5HT1A receptor antagonist. In blood, CBD influences the survival and death of white blood cells, white blood cell migration and platelet aggregation. Taken together, these preclinical data appear to support a positive role for CBD treatment in the heart, and in peripheral and cerebral vasculature. However, further work is required to strengthen this hypothesis, establish mechanisms of action and whether similar responses to CBD would be observed in humans.

Introduction

Cannabidiol (CBD) is an abundant, non psychoactive, plant derived cannabinoid (phytocannabinoid) whose stereochemistry was first described in 1963 by Mechoulam and colleagues [1]. Isolation of the chemical structure of CBD revealed it to be a classical cannabinoid closely related to cannabinol and Δ −9 -tetrahydrocannabinol (THC). Since its isolation, a range of synthetic analogues have been synthesized based on the classic cannabinoid dibenzopyran structure, including abnormal CBD (Abn-CBD), O-1918 and O-1602 [2, 3]. CBD is reported to have a diverse pharmacology which is reviewed in depth elsewhere [4]. In brief, CBD shows antagonism of the classical cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors in the low nanomolar range, yet has agonist/inverse agonist actions at micromolar concentrations. Other receptor sites implicated in the action of CBD include the orphan G protein coupled receptor GPR55, the putative Abn-CBD receptor, the transient receptor potential vanilloid 1 (TRPV1) receptor, α1-adrenoreceptors, µ opiod receptors and 5HT1A receptors [4]. It has also been shown that CBD activates and has physiological responses mediated by peroxisome proliferator activated receptor γ (PPARγ) [5–7]. As well as a rich pharmacology, CBD is suggested to have therapeutic potential in a vast range of disorders including inflammation, oxidative stress, cancer, diabetes, gastrointestinal disturbances, neurodegenerative disorders and nociception [8–12]. Evidence is also now accumulating that there are positive effects of CBD in the vasculature. It is the aim of this review to examine this evidence and establish whether or not the cardiovascular system is a potential therapeutic target for CBD. A recent review of the safety and side effects of CBD concluded that CBD appears to be well tolerated at high doses and with chronic use in humans [13], and thus has the potential to be taken safely into the clinic. Indeed, CBD is one of the active ingredients of the currently licensed medication, Sativex®.

Vascular effects of cannabinoids

The acute vascular effects of cannabinoid compounds have been well studied in a range of models. In a variety of in vivo and in vitro models, phytocannabinoids and endogenous cannabinoids (endocannabinoids) have been shown to cause vasorelaxation. However, the potency, efficacy and mechanisms of action often differ. For example, early work in rabbit cerebral arteries showed that THC and the endocannabinoid anandamide (AEA) caused vasorelaxation that was dependent on cyclooxygenase (COX) activity [14]. Later, Randall et al. [15] showed AEA-induced vasorelaxation in the perfused rat mesenteric bed that was inhibited by antagonism of the CB1 receptor and inhibition of potassium hyperpolarization. The vasorelaxant effects of AEA in rat arteries are also dependent on the vessel size in that the maximal response to AEA is greater in small resistance vessels and includes an endothelial-dependent component that is not observed in larger arteries [16]. In rat aortae, the vasorelaxant response to AEA is not sensitive to CB1 antagonism or TRPV1 desensitization, but is sensitive to Gi/o protein inhibition using pertussis toxin (PTX) [17]. Further differences in cannabinoid effects can be found when comparing the same arterial bed of differing species. In rabbit aortae, AEA causes greater maximal relaxation than observed in rat aortae through a SR141716A (1 µ m ) sensitive pathway which is dependent on the endothelium [18]. It has also been shown that cannabinoid responses are dependent on the cannabinoid compound used. For example, the endocannabinoids AEA and N-arachidonoyl-dopamine (NADA) cause similar degrees of vasorelaxation in rat aortae, but by different mechanisms [17]. These studies highlight the complexity of acute vasodilator actions of cannabinoids on the vasculature (for a full review see [19]).

In addition to the direct vascular effects of cannabinoids, a large number of studies now suggest that endocannabinoids are mediators of myocardial infarction and ischaemic/reperfusion injury, cardiovascular risk factors and atherosclerosis [20–22]. The potential therapeutic uses of cannabinoids other than CBD in cardiovascular diseases, including cardioprotection, stroke, arrhythmias and atherosclerosis, have been reviewed elsewhere [22–24].

Direct vascular effects of CBD

Work to date investigating the vascular effects of cannabinoids has primarily concentrated on the response to endocannabinoids, THC and synthetic ligands, with only limited studies conducted using CBD. However, the effects of the CBD analogue, Abn-CBD, have been characterized. Jarai et al. [25] showed that Abn-Cbd caused hypotension in both CB1 +/+ /CB2 +/+ and CB1 −/− /CB2 −/− mice. The effects of Abn-CBD were inhibited by high. concentrations of SR141716A, endothelium denudation and CBD. In this paper, CBD was shown to antagonize the vasorelaxant effects of Abn-CBD and AEA. Begg et al. [26] showed in human umbilical vein endothelial cells (HUVECs) that Abn-CBD causes hyperpolarization through PTX-sensitive activation of large conductance calcium activated potassium channels (BKCa). Similarly, in rat isolated mesenteric arteries, Abn-CBD causes vasorelaxation that is dependent on the endothelium, SR141716A sensitive pathways and potassium channel hyperpolarization through large, intermediate and small conductance calcium activated potassium (BKCa/IKCa/SKCa) channels [27]. Interestingly, the previous work reported an endothelial-independent pathway that involved Abn-CBD modulation of the Ca 2+ channels. The findings of endothelial dependent and independent components of Abn-CBD-induced vasorelaxation is in agreement with a similar study of the same year showing that in rat mesenteric arteries, vasorelaxation to Abn-CBD was inhibited by PTX incubation and incubation with another CBD anologue, O-1918, and indeed this was dependent on the endothelium [28]. More recently it has been shown that Abn-CBD causes vasorelaxation in the human pulmonary artery through similar mechanisms [29]. Taken together, these findings offer support to the presence of an endothelial bound Gi/o protein coupled receptor that causes vasorelaxation through hyperpolarization that is activated by Abn-CBD.

Fewer studies have investigated the vascular effects of CBD. Jarai and colleagues [25] found no effect of perfusing 10 µM CBD on vascular tone in phenylephrine-constricted rat mesenteric vascular bed. However, in arterial segments taken from the rat mesenteric vascular bed that have been mounted onto a Mulvany-Halpern myograph and constricted with phenylephrine, CBD causes a concentration-dependent near-maximal vasorelaxation [28]. Unfortunately, this study did not probe the mechanisms underlying this vasorelaxant effect of CBD in rat mesenteric arteries.

In human mesenteric arteries, we have very recently shown that CBD causes vasorelaxation of U46619 and endothelin-1 pre-constricted arterial segments (Stanley & O’Sullivan, 2012, under review). In human mesenteric arteries, CBD-induced vasorelaxation has a pEC50 in the mid-micromolar range which is similar to that observed in rat mesenteric arteries. However, CBD-induced vasorelaxation in human arteries has a maximal response of ∼40% reduction of pre-imposed tone. We went on to show that CBD-induced vasorelaxation in human mesenteric arteries is endothelium-dependent, involves CB1 receptor activation and TRPV channel activation, nitric oxide release and potassium hyperpolarization ( Figure 1 ) (Stanley & O’Sullivan, 2012, under review).

Direct vascular effects of CBD measured in isolated arteries. TRPV, transient receptor potential vanilloid; NO, nitric oxide; CB1, cannabinoid receptor 1; PPARγ, peroxisome proliferator activated receptor gamma; SOD, superoxide dismutase

It is interesting to note that Ruiz-Valdepenas et al. [34] recently showed that CBD inhibited lipopolysaccharide (LPS)-induced arteriolar and venular vasodilation. LPS has been suggested to cause hypotension through activation of a novel as yet unidentified cannabinoid receptor which could be inhibited by SR141716A but not AM251 [35]. Since CBD is suggested to be an antagonist of this receptor [25], this could explain how CBD inhibits LPS-induced vasodilation.

Time-dependent vasorelaxant effects of CBD (and PPARγ agonism)

PPARγ agonists have been shown to have positive cardiovascular effects, which include increased availability of nitric oxide, reductions in blood pressure and attenuation of atherosclerosis [36, 37]. Some of the beneficial effects of PPARγ ligands are brought about by anti-inflammatory actions, including inhibition of pro-inflammatory cytokines, increasing anti-inflammatory cytokines and inhibition of inducible nitric oxide synthase (iNOS) expression (for review see [38]). Increasing evidence has indicated that cannabinoids are capable of binding to, activating and causing PPAR–mediated responses [39]. We have shown that the major active ingredient of cannabis, THC, activates PPARγ, and that THC causes time-dependent, endothelium-dependent, PPARγ-mediated vasorelaxation of the rat isolated aorta [40, 41]. Subsequently, we tested whether CBD might also activate PPARγ and that this might mediate some of the pharmacological effects of cannabidiol. In these experiments we showed that CBD is a weak/partial agonist at the PPARγ receptor which increases PPARγ transcriptional activity in PPARγ overexpressing HEK293 cells, and CBD binds to the PPARγ ligand binding domain with an IC50≍ 5 µ m [5]. Like THC, CBD (at concentrations above 100 nM) was also found to cause a time-dependent vasorelaxation of rat aortae. This time-dependent vasorelaxation was inhibited using the PPARγ antagonist GW9662 or the superoxide dismutase (SOD) inhibitor diethyldithiocarbamate (DETCA). Increased SOD activity promotes vasorelaxation through reductions in reactive oxygen species, and our data are in agreement with other work showing PPARγ ligands cause the induction of Cu/Zn-SOD [42]. However, it should be noted that recent work has suggested the use of TZDs may lead to decreases in cardiovascular function and could prompt incidents such as acute myocardial infarction, heart failure and stroke [43–45]. Side effects associated with PPARγ ligands include weight gain, oedema and increased plasma lipoproteins [46]. However, weak/partial agonists at the PPARγ receptor may be void of these detrimental side effects [46]. CBD may prove to have therapeutic utility as a low affinity agonist of PPARγ.

Haemodynamic effects of CBD

Few studies to date have examined the haemodynamic responses to CBD. One study has shown that in pentobarbitone anaesthetized rats, that CBD (50 µg kg −1 i.v. but not 10 µg kg −1 ) causes a significant but transient 16 mmHg fall in mean arterial blood pressure without affecting heart rate [47]. However, other studies do not report any acute effects of in vivo treatment with CBD on baseline heart rate or blood pressure in animal studies [48, 49]. In a recent review, Bergamaschi et al. [13] concluded that CBD treatment in humans did not result in changes in blood pressure or heart rate. Thus, the majority of evidence suggests there is no effect of CBD on haemodynamics. However, as has been observed with other cannabinoid compounds, the potential hypotensive effects of CBD may need to be revealed in models of raised blood pressure. Additionally, any change in haemodynamics that might occur may be rapid [47] and therefore not observed in chronic treatment studies.

CBD is known to be anxiolytic. CBD treatment reduces anxiety related to public speaking or fearful stimuli in humans [10]. A number of studies have now also shown that CBD reduces the cardiovascular response to anxiety or stressful situations. Resstel and colleagues have shown in Wistar rats that a single dose of CBD (10 or 20 mg kg −1 i.p.) reduced the heart rate and blood pressure response to conditioned fear [49] or to acute restraint stress [48]. The inhibitory effect of CBD on the cardiovascular response to stress was shown to be inhibited by WAY100635, a 5HT1A receptor antagonist. This effect appears to be mediated in the brain, as the same effect of CBD on cardiovascular responses could be mimicked when CBD was injected into the bed nucleus of the stria terminalis (a limbic structure) [50]. The potential ability of CBD treatment in humans to reduce the cardiovascular (as well as behavioural) response to stress could have significant effects on the development of atherosclerosis and hypertension, which are known to be accelerated by stress [51, 52].

Cardioprotective effects of CBD

Several studies have shown that CBD is beneficial in preventing ischaemia-reperfusion damage in the liver [53, 54] and brain [55]. In 2007, Durst and colleagues first showed that in vivo treatment with CBD (5 mg kg −1 i.p. pre-ischaemia and then for 7 days after) significantly reduced the infarct size of hearts where the left anterior descending (LAD) coronary artery had been ligated, and this was associated with a reduction in infiltrating leucocytes and circulating interleukin (IL)-6 concentrations. Furthermore, they showed that this cardioprotective effect of CBD could not be mimicked in vitro, and suggested that the cardioprotective effects of CBD are due to a systemic immunomodulatory effect rather than a direct effect on the heart [56]. Walsh et al. [47] subsequently showed that a single dose of CBD (50 µg kg −1 i.v.) given 10 min pre-ischaemia or 10 min pre-reperfusion could significantly reduce infarct size after LAD coronary artery ligation. This was also associated with a reduction in ventricular ectopic beats, suggesting an additional anti-arrhythmic role for CBD. Rajesh et al. [57] showed that 11 weeks in vivo treatment with CBD (20 mg kg −1 i.p.) significantly reduced cardiac dysfunction in diabetic mice, associated with decreased myocardial inflammation, oxidative stress, nitrative stress and fibrosis, mediated by reduced nuclear factor-κB activation (NFκB), reduced mitogen-activated protein kinase (MAPK) activation and reduced expression of adhesion molecules and tumour necrosis factor (TNF). Other studies have found that the anti-inflammatory effects of CBD via NFκB are not mediated by CB1, CB2 or Abn-CBD receptor activation [58].

Together, these data suggest that in vivo treatment with CBD has significant cardioprotective effects, which may be through a direct action on the heart or via a general anti-inflammatory, anti-oxidant mechanism (see Table 1 ).

Table 1

The current body of evidence supporting a therapeutic role for CBD in cardiovascular disorders

Vasculoprotective effects of CBD

There is a growing body of evidence that administration of CBD can ameliorate the negative effects of conditions associated with endothelial dysfunction. The high glucose conditions associated with diabetes have been reported as a causal factor in endothelial dysfunction. High glucose promotes inhibition/uncoupling of endothelial nitric oxide, increased superoxide production, increased actions of constrictor prostanoids, decreased actions of vasorelaxant prostanoids and increased reactive oxygen species [59]. Alongside these changes, high glucose is also reported to increase leucocyte adhesion and monocyte endothelial migration [60], which has been reported to be through NFκB activity [61].

In human coronary artery endothelial cells, prolonged exposure to high glucose has been shown to cause increased levels of adhesion molecules (ICAM-1 and VCAM-1), disruption of the endothelial barrier, mitochondrial superoxide production, iNOS and NFκB expression [62]. These effects were all reduced when the cells were co-incubated with CBD compared with high glucose alone. CBD also decreased monocyte adhesion and trans-endothelial migration, which are key elements in the progression of atherosclerosis. Neither the CB1 nor CB2 receptors were responsible for mediating the effects of CBD [62]. Using an in vivo model of diabetic retinopathy, El-Remessy et al. [63] similarly found that CBD treatment (10 mg kg −1 , every 2 days, i.p.) prevented vascular hyperpermeability at the blood−retinal barrier (BRB), and protected the retina against oxidative damage, inflammation and an increase in adhesion molecules. Thus, CBD-mediated protection of the vasculature in a model of diabetes may lead to a reduction in complications such as retinopathy, although this could also be driven by the neuroprotective effects of CBD.

Sepsis-related encephalitis, modelled by parenteral injection of LPS in mice, induces profound arteriolar dilation, resulting in brain hyperaemia and blood−brain barrier (BBB) disruption [34]. Administration of CBD (3 mg kg −1 i.v.) at the same time as LPS maintained BBB integrity, inhibited LPS-induced arteriolar and venular vasodilation, leucocyte margination, and suppressed excessive nitric oxide production. Although cerebral blood flow (CBF) was not measured directly, the results observed from various parameters led the authors to suggest that CBD had ameliorated the LPS-induced drop in CBF [34].

We have carried out some preliminary experiments examining the ability of CBD to modulate vasodilator responses. Using the Zucker diabetic rat model of type 2 diabetes, where endothelium-dependent vasorelaxation is known to be impaired, we showed that incubation of the aorta for 2 h with CBD (10 µ m ) significantly enhanced the vasorelaxant response to acetylcholine, an endothelium-dependent vasodilator [64]. We have similarly shown that incubation with CBD enhances the vasorelaxant response to acetylcholine in the spontaneously hypertensive rat (O’Sullivan, unpublished data).

Taken together these studies show that in vitro and in vivo, using cell culture, isolated tissue and animal models, CBD has been demonstrated to reduce the negative effects of high glucose, diabetes and inflammation on the vasculature and on vascular hyperpermeability. As yet, the receptor sites of action for CBD in some of these studies remain unclear, but a common theme is the reduction in inflammatory markers (see Table 1 ).

CBD in models of stroke

Administration of endogenous, synthetic or phytocannabinoids has been shown to provide neuroprotection using a variety of in vivo and in vitro disease models, including stroke [65]. The neuroprotective potential of CBD in ischaemic stroke was first explored by Hampson and colleagues [66], where they subjected rats to middle cerebral artery occlusion (MCAO) and demonstrated that CBD, given at onset of insult (5 mg kg −1 , i.v.) and 12 h after surgery (20 mg kg −1 i.p.), reduced infarct size and neurological impairment by 50–60%. Similarly, post ischaemic administration of CBD (1.25 to 20 mg kg −1 , i.p.) protected against ischaemia-induced electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils after MCAO [67]. More recently, it has been shown that CBD (3 mg kg −1 i.p.) reduced infarct volume following MCAO, independent of CB1 receptor or TRPV1, but sensitive to the 5HT1A receptor antagonist WAY100135 (10 mg kg −1 , i.p.) [68, 69]. Furthermore, CBD (3 mg kg −1 i.p.) provided neuroprotection even when administered up to 2 h post reperfusion without the development of tolerance [70, 71].

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CBF is reduced or completely abolished in certain areas of the brain during ischaemic stroke, thus, restoring CBF to provide adequate perfusion is of great importance. CBD has been shown to be successful in increasing CBF, as measured by laser-Doppler flowmetry, following MCAO and after reperfusion (3 mg kg −1 i.p.) [69–71]. The increased CBF induced by CBD (3 mg kg −1 i.p.) was partially decreased by 5HT1A receptor antagonism, suggesting that CBD may exert these beneficial effects, at least in part, via the serotonergic 5HT1A receptor [69]. Exposing newborn piglets to hypoxia-ischaemia, Alvarez and colleagues [72] also demonstrated the ability of CBD (0.1 mg kg −1 i.v., post insult) to provide neuroprotection in a manner that included the preservation of cerebral circulation.

As previously discussed, administration of CBD (3 mg kg −1 i.v.) at the same time as LPS maintains BBB integrity [34]. Although CBF was not measured directly, the results observed from various parameters led the authors to suggest that CBD had ameliorated the LPS-induced drop in CBF [34]. BBB disruption is an important facet in the pathophysiology of ischaemic stroke [73]. Therefore, CBD-mediated preservation of this barrier, as demonstrated in other disease models could represent another mechanism of CBD-mediated protection in ischaemic stroke. Agonism of PPARγ may represent another mechanism of action for the beneficial effects of CBD in stroke. Several groups have found that synthetic PPARγ agonists, thiazolidinediones (TZDs), a class of drugs used to improve insulin sensitivity, reduced infarct size and improved functional recovery from stroke in rats [74–78]. Improvement is associated with reduced inflammation which is a probable mechanism of recovery, and, importantly, improvement is seen whether TZDs are administered before or after MCAO [75, 77]. Recently, in vivo CBD treatment has been shown to have neuroprotective effects in an Alzheimer’s disease model which were inhibited with a PPARγ antagonist [6]. Similarly, we have shown in a cell culture model of the BBB that CBD restores the enhanced permeability induced by oxygen glucose deprivation, which could be inhibited by a PPARγ antagonist (Hind & O’Sullivan, unpublished observations).

In summary, CBD provides neuroprotection in animal and in vitro models of stroke. In addition to any direct neuroprotective effects of CBD, this is mediated by the ability of CBD to increase cerebral blood flow and reduce vascular hyperpermeability in the brain (see Table 1 ).

Haematological effects of CBD

In addition to the effects of CBD on the heart and vasculature, there is evidence that CBD also influences blood cell function. Early studies showed that CBD increases phospholipase A2 expression and lipooxygenase products in platelets [79] and that CBD inhibits adenosine or epinephrine stimulated platelet aggregation [80], and more recently, collagen stimulated platelet aggregation [47]. 5-HT release from platelets has been shown to be decreased by CBD [81] or not affected by CBD [80].

In white blood cells, CBD induces apoptosis of fresh human monocytes [82] and human leukaemia cell lines [83, 84], which the later study showed was dependent on CB2 activation, but not CB1 or TRPV1. However, CBD can also prevent serum-deprived cell death of lymphoblastoid cells in serum-free medium by anti-oxidant mechanisms [85]. McHugh et al. [86] showed that CBD itself did not affect neutrophil migration, but that CBD inhibited formyl-Met-Leu-Phe-OH (fMLP)-stimluated neutrophil migration. CBD also inhibits monocyte adhesion and infiltration [62] and white blood cell margination in cerebral blood vessels after LPS treatment [34]. CBD significantly inhibits myeloperoxidase (which is expressed in neutrophils, monocytes and some populations of human macrophages) activity at 1 h and 20 h after reperfusion in mouse MCAO models [70, 87]. CBD also causes a dose-dependent suppression of lymphocyte proliferation in a murine collagen-induced arthritis model [88].

Together these studies show that CBD influences both the survival and death of white blood cells, white blood cell migration and platelet aggregation, which could underpin the ability of CBD to delay or prevent the development of cardiovascular disorders.

Conclusion

In summary, this review has presented evidence of the positive effects of CBD in the cardiovascular system, summarised in Table 1 . In isolated arteries, direct application of CBD causes both acute and time-dependent vasorelaxation of preconstricted arteries and enhances endothelium-dependent vasorelaxation in models of endothelial dysfunction. In vivo, CBD treatment does not appear to have any effect on resting blood pressure or heart rate, but does reduce the cardiovascular response to various types of stress. In vivo, CBD treatment has a protective role in reducing the effects of cardiac ischaemia and reperfusion, or in reducing cardiac dysfunction associated with diabetes. Similarly, CBD has a protective role in reducing the ischaemic damage in models of stroke, partly due to maintaining cerebral blood flow. In models of altered vascular permeability, CBD reduces the hyperpermeability of the BRB in diabetes and BBB hyperpermeability after LPS injection. Similarly, CBD ameliorates the negative effects of a high glucose environment on cell adhesion molecules and barrier function. Together, these data suggest that the cardiovascular system is indeed a valid therapeutic target for CBD. However, the target sites of action for CBD remain to be established for most of these responses. Whether these responses to CBD will translate into the human cardiovascular system also remains to be established.

Competing Interests

SOS has received research funding from GW Pharmaceuticals.

REFERENCES

1. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006; 147 :S163–S71. [PMC free article] [PubMed] [Google Scholar]

3. Razdan RK. Structure-activity relationship of classical cannabinoids. In: Reggio PH, editor. The Cannabinoid Receptors. New York: Humana Press; 2009. pp. 3–19. [Google Scholar]

4. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008; 153 :199–215. [PMC free article] [PubMed] [Google Scholar]

5. O’Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA. Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol. 2009; 612 :61–8. [PubMed] [Google Scholar]

6. Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, De Filippis D, Cipriano M, Carratu MR, Iuvone T, Steardo L. Cannabidiol reduces Abeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement. PLoS ONE. 2011; 6 :e28668. [PMC free article] [PubMed] [Google Scholar]

7. De Filippis D, Esposito G, Cirillo C, Cipriano M, De Winter BY, Scuderi C, Sarnelli G, Cuomo R, Steardo L, De Man JG, Iuvone T. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS ONE. 2011; 6 :e28159. [PMC free article] [PubMed] [Google Scholar]

8. Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006; 66 :234–46. [PubMed] [Google Scholar]

9. Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F, Izzo AA. Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. Br J Pharmacol. 2008; 154 :1001–8. [PMC free article] [PubMed] [Google Scholar]

10. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr. 2008; 30 :271–80. [PubMed] [Google Scholar]

11. Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L. Cannabidiol: a promising drug for neurodegenerative disorders? CNS Neurosci Ther. 2009; 15 :65–75. [PMC free article] [PubMed] [Google Scholar]

12. Booz GW. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med. 2011; 51 :1054–61. [PMC free article] [PubMed] [Google Scholar]

13. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011; 6 :237–49. [PubMed] [Google Scholar]

14. Ellis EF, Moore SF, Willoughby KA. Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin. Am J Physiol Heart Circ Physiol. 1995; 269 :H1859–64. [PubMed] [Google Scholar]

15. Randall MD, Alexander SPH, Bennett T, Boyd EA, Fry JR, Gardiner SM, Kemp PA, McCulloch AI, Kendall DA. An endogenous cannabinoid as an endothelium-derived vasorelaxant. Biochem Biophys Res Commun. 1996; 229 :114–20. [PubMed] [Google Scholar]

16. O’Sullivan S, David AK, Michael DR. Heterogeneity in the mechanisms of vasorelaxation to anandamide in resistance and conduit rat mesenteric arteries. Br J Pharmacol. 2004; 142 :435–42. [PMC free article] [PubMed] [Google Scholar]

17. O’Sullivan SE, Kendall DA, Randall MD. Vascular effects of [Delta]9-tetrahydrocannabinol (THC), anandamide and N-arachidonoyldopamine (NADA) in the rat isolated aorta. Eur J Pharmacol. 2005; 507 :211–21. [PubMed] [Google Scholar]

18. Mukhopadhyay S, Chapnick BM, Howlett AC. Anandamide-induced vasorelaxation in rabbit aortic rings has two components: G protein dependent and independent. Am J Physiol Heart Circ Physiol. 2002; 282 :H2046–54. [PubMed] [Google Scholar]

19. Randall DM, Kendall AD, O’Sullivan SE. The complexities of the cardiovascular actions of cannabinoids. Br J Pharmacol. 2004; 142 :20–6. [PMC free article] [PubMed] [Google Scholar]

20. Batkai S, Pacher P. Endocannabinoids and cardiac contractile function: pathophysiological implications. Pharmacol Res. 2009; 60 :99–106. [PMC free article] [PubMed] [Google Scholar]

21. Montecucco F, Di Marzo V. At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction. Trends Pharmacol Sci. 2012; 33 :331–40. [PubMed] [Google Scholar]

22. Tuma RF, Steffens S. Targeting the endocannabinod system to limit myocardial and cerebral ischemic and reperfusion injury. Curr Pharm Biotechnol. 2012; 13 :46–58. [PubMed] [Google Scholar]

23. Durst R, Lotan C. The potential for clinical use of cannabinoids in treatment of cardiovascular diseases. Cardiovasc Ther. 2011; 29 :17–22. [PubMed] [Google Scholar]

24. Singla S, Sachdeva R, Mehta JL. Cannabinoids and atherosclerotic coronary heart disease. Clin Cardiol. 2012; 35 :329–35. [PMC free article] [PubMed] [Google Scholar]

25. Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A. 1999; 96 :14136–41. [PMC free article] [PubMed] [Google Scholar]

26. Begg M, Mo F-M, Offertáler L, Bátkai S, Pacher P, Razdan RK, Lovinger DM, Kunos G. G protein-coupled endothelial receptor for atypical cannabinoid ligands modulates a Ca2+-dependent K+ current. J Biol Chem. 2003; 278 :46188–94. [PubMed] [Google Scholar]

27. Ho WS, Hiley CR. Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. Br J Pharmacol. 2003; 138 :1320–32. [PMC free article] [PubMed] [Google Scholar]

28. Offertaler L, Mo F-M, Bátkai S, Liu J, Begg M, Razdan RK, Martin BR, Bukoski RD, Kunos G. Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol. 2003; 63 :699–705. [PubMed] [Google Scholar]

29. Kozlowska H, Baranowska M, Schlicker E, Kozlowski M, Laudanski J, Malinowska B. Identification of the vasodilatory endothelial cannabinoid receptor in the human pulmonary artery. J Hypertens. 2007; 25 :2240–8. [PubMed] [Google Scholar]

30. Deutsch DG, Goligorsky MS, Schmid PC, Krebsbach RJ, Schmid HH, Das SK, Dey SK, Arreaza G, Thorup C, Stefano G, Moore LC. Production and physiological actions of anandamide in the vasculature of the rat kidney. J Clin Invest. 1997; 100 :1538–46. [PMC free article] [PubMed] [Google Scholar]

31. O’Sullivan SE, Kendall DA, Randall MD. Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA) Br J Pharmacol. 2004; 141 :803–12. [PMC free article] [PubMed] [Google Scholar]

32. Zygmunt PM, Petersson J, Andersson DA, H-h C, Sorgard M, Di Marzo V, Julius D, Hogestatt ED. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999; 400 :452–7. [PubMed] [Google Scholar]

33. Zygmunt PM, Andersson DA, Hogestatt ED. Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. J Neurosci. 2002; 22 :4720–7. [PMC free article] [PubMed] [Google Scholar]

34. Ruiz-Valdepenas L, Martinez-Orgado JA, Benito C, Millan A, Tolon RM, Romero J. Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study. J Neuroinflammation. 2011; 8 :5. doi: 10.1186/1742-2094-8-5 . [PMC free article] [PubMed] [Google Scholar]

35. Batkai S, Pacher P, Jarai Z, Wagner JA, Kunos G. Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors. Am J Physiol Heart Circ Physiol. 2004; 287 :H595–600. [PMC free article] [PubMed] [Google Scholar]

36. Bishop-Bailey D. Peroxisome proliferator-activated receptors in the cardiovascular system. Br J Pharmacol. 2000; 129 :823–34. [PMC free article] [PubMed] [Google Scholar]

37. Hsueh WA, Bruemmer D. Peroxisome proliferator-activated receptor gamma: implications for cardiovascular disease. Hypertension. 2004; 43 :297–305. [PubMed] [Google Scholar]

38. Szeles L, Torocsik D, Nagy L. PPARgamma in immunity and inflammation: cell types and diseases. Biochim Biophys Acta. 2007; 1771 :1014–30. [PubMed] [Google Scholar]

39. O’Sullivan SE. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol. 2007; 152 :576–82. [PMC free article] [PubMed] [Google Scholar]

40. O’Sullivan SE, Tarling EJ, Bennett AJ, Kendall DA, Randall MD. Novel time-dependent vascular actions of [Delta]9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem Biophys Res Commun. 2005; 337 :824–31. [PubMed] [Google Scholar]

41. O’Sullivan SE, Kendall DA, Randall MD. Further characterization of the time-dependent vascular effects of Δ −9 tetrahydrocannabinol. J Pharmacol Exp Ther. 2006; 317 :428–38. [PubMed] [Google Scholar]

42. Hwang J, Kleinhenz DJ, Lassegue B, Griendling KK, Dikalov S, Hart CM. Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production. Am J Physiol Cell Physiol. 2005; 288 :C899–905. [PubMed] [Google Scholar]

43. Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ. 2009; 339 :b2942. [PMC free article] [PubMed] [Google Scholar]

44. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, Kelman JA. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA. 2010; 304 :411–8. [PubMed] [Google Scholar]

45. Filion KB, Joseph L, Boivin JF, Suissa S, Brophy JM. Thiazolidinediones and the risk of incident congestive heart failure among patients with type 2 diabetes mellitus. Pharmacoepidemiol Drug Saf. 2011; 20 :785–96. [PubMed] [Google Scholar]

46. Gelman L, Feige JN, Desvergne B. Molecular basis of selective PPARgamma modulation for the treatment of Type 2 diabetes. Biochim Biophys Acta. 2007; 1771 :1094–107. [PubMed] [Google Scholar]

47. Walsh SK, Hepburn CY, Kane KA, Wainwright CL. Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. Br J Pharmacol. 2010; 160 :1234–42. [PMC free article] [PubMed] [Google Scholar]

48. Resstel LB, Tavares RF, Lisboa SF, Joca SR, Correa FM, Guimaraes FS. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009; 156 :181–8. [PMC free article] [PubMed] [Google Scholar]

49. Resstel LB, Joca SR, Moreira FA, Correa FM, Guimaraes FS. Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res. 2006; 172 :294–8. [PubMed] [Google Scholar]

50. Gomes FV, Resstel LB, Guimaraes FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology. 2011; 213 :465–73. [PubMed] [Google Scholar]

51. Kumari M, Grahame-Clarke C, Shanks N, Marmot M, Lightman S, Vallance P. Chronic stress accelerates atherosclerosis in the apolipoprotein E deficient mouse. Stress. 2003; 6 :297–9. [PubMed] [Google Scholar]

52. Toot JD, Reho JJ, Novak J, Dunphy G, Ely DL, Ramirez RJ. Colony social stress differentially alters blood pressure and resistance-sized mesenteric artery reactivity in SHR/y and WKY male rats. Stress. 2011; 14 :33–41. [PubMed] [Google Scholar]

53. Fouad AA, Jresat I. Therapeutic potential of cannabidiol against ischemia/reperfusion liver injury in rats. Eur J Pharmacol. 2011; 670 :216–23. [PubMed] [Google Scholar]

54. Mukhopadhyay P, Rajesh M, Horvath B, Batkai S, Park O, Tanchian G, Gao RY, Patel V, Wink DA, Liaudet L, Hasko G, Mechoulam R, Pacher P. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic Biol Med. 2011; 50 :1368–81. [PMC free article] [PubMed] [Google Scholar]

55. Lafuente H, Alvarez FJ, Pazos MR, Alvarez A, Rey-Santano MC, Mielgo V, Murgia-Esteve X, Hilario E, Martinez-Orgado J. Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. Pediatr Res. 2011; 70 :272–7. [PubMed] [Google Scholar]

56. Durst R, Danenberg H, Gallily R, Mechoulam R, Meir K, Grad E, Beeri R, Pugatsch T, Tarsish E, Lotan C. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. Am J Physiol Heart Circ Physiol. 2007; 293 :H3602–7. [PubMed] [Google Scholar]

57. Rajesh M, Mukhopadhyay P, Batkai S, Patel V, Saito K, Matsumoto S, Kashiwaya Y, Horvath B, Mukhopadhyay B, Becker L, Hasko G, Liaudet L, Wink DA, Veves A, Mechoulam R, Pacher P. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 2010; 56 :2115–25. [PMC free article] [PubMed] [Google Scholar]

58. Kozela E, Pietr M, Juknat A, Rimmerman N, Levy R, Vogel Z. Cannabinoids Delta(9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem. 2010; 285 :1616–26. [PMC free article] [PubMed] [Google Scholar]

59. Vanhoutte PM, Shimokawa H, Tang EHC, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol. 2009; 196 :193–222. [PubMed] [Google Scholar]

60. Tsao PS, Niebauer J, Buitrago R, Lin PS, Wang BY, Cooke JP, Chen YD, Reaven GM. Interaction of diabetes and hypertension on determinants of endothelial adhesiveness. Arterioscler Thromb Vasc Biol. 1998; 18 :947–53. [PubMed] [Google Scholar]

61. Hamuro M, Polan J, Natarajan M, Mohan S. High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration. Atherosclerosis. 2002; 162 :277–87. [PubMed] [Google Scholar]

62. Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Drel VR, Obrosova IG, Pacher P. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol. 2007; 293 :H610–9. [PMC free article] [PubMed] [Google Scholar]

63. El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai N-T, Caldwell RB, Liou GI. Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am J Pathol. 2006; 168 :235–44. [PMC free article] [PubMed] [Google Scholar]

64. Stanley CP, O’Sullivan SE. Characterisation of cannabidiol-induced vasorelaxation in human mesenteric arteries. Proceedings of the British Pharmacological Society. 2011. Available at http://www.pA2online.org/abstracts/vol9issue3abst098p.pdf (last accessed 11 July 2012)

65. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006; 58 :389–462. [PMC free article] [PubMed] [Google Scholar]

66. Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J. Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci. 2000; 899 :274–82. [PubMed] [Google Scholar]

67. Braida D, Pegorini S, Arcidiacono MV, Consalez GG, Croci L, Sala M. Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci Lett. 2003; 346 :61–4. [PubMed] [Google Scholar]

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68. Hayakawa K, Mishima K, Abe K, Hasebe N, Takamatsu F, Yasuda H, Ikeda T, Inui K, Egashira N, Iwasaki K, Fujiwara M. Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism. Neuroreport. 2004; 15 :2381–5. [PubMed] [Google Scholar]

69. Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke. 2005; 36 :1077–82. [PubMed] [Google Scholar]

70. Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M, Orito K, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M. Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem. 2007; 102 :1488–96. [PubMed] [Google Scholar]

71. Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu AX, Fujioka M, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M. Repeated treatment with cannabidiol but not delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology. 2007; 52 :1079–87. [PubMed] [Google Scholar]

72. Alvarez FJ, Lafuente H, Rey-Santano MC, Mielgo VE, Gastiasoro E, Rueda M, Pertwee RG, Castillo AI, Romero J, Martinez-Orgado J. Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr Res. 2008; 64 :653–8. [PubMed] [Google Scholar]

73. Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke. 2011; 42 :3323–8. [PMC free article] [PubMed] [Google Scholar]

74. Shimazu T, Inoue I, Araki N, Asano Y, Sawada M, Furuya D, Nagoya H, Greenberg JH. A peroxisome proliferator-activated receptor-gamma agonist reduces infarct size in transient but not in permanent ischemia. Stroke. 2005; 36 :353–9. [PubMed] [Google Scholar]

75. Sundararajan S, Gamboa JL, Victor NA, Wanderi EW, Lust WD, Landreth GE. Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia. Neuroscience. 2005; 130 :685–96. [PubMed] [Google Scholar]

76. Zhao X, Zhang Y, Strong R, Grotta JC, Aronowski J. 15d-Prostaglandin J2 activates peroxisome proliferator-activated receptor-gamma, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab. 2006; 26 :811–20. [PubMed] [Google Scholar]

77. Luo Y, Yin W, Signore AP, Zhang F, Hong Z, Wang S, Graham SH, Chen J. Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. J Neurochem. 2006; 97 :435–48. [PubMed] [Google Scholar]

78. Lee J, Reding M. Effects of thiazolidinediones on stroke recovery: a case-matched controlled study. Neurochem Res. 2007; 32 :635–8. [PubMed] [Google Scholar]

79. White HL, Tansik RL. Effects of delta 9-tetrahydrocannabinol and cannabidiol on phospholipase and other enzymes regulating arachidonate metabolism. Prostaglandins Med. 1980; 4 :409–17. [PubMed] [Google Scholar]

80. Formukong EA, Evans AT, Evans FJ. The inhibitory effects of cannabinoids, the active constituents of Cannabis sativa L. on human and rabbit platelet aggregation. J Pharm Pharmacol. 1989; 41 :705–9. [PubMed] [Google Scholar]

81. Volfe Z, Dvilansky A, Nathan I. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Int J Clin Pharmacol Res. 1985; 5 :243–6. [PubMed] [Google Scholar]

82. Wu HY, Chang AC, Wang CC, Kuo FH, Lee CY, Liu DZ, Jan TR. Cannabidiol induced a contrasting pro-apoptotic effect between freshly isolated and precultured human monocytes. Toxicol Appl Pharmacol. 2010; 246 :141–7. [PubMed] [Google Scholar]

83. Gallily R, Even-Chena T, Katzavian G, Lehmann D, Dagan A, Mechoulam R. Gamma-irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leuk Lymphoma. 2003; 44 :1767–73. [PubMed] [Google Scholar]

84. McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M. Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol. 2006; 70 :897–908. [PubMed] [Google Scholar]

85. Chen Y, Buck J. Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J Pharmacol Exp Ther. 2000; 293 :807–12. [PubMed] [Google Scholar]

86. McHugh D, Tanner C, Mechoulam R, Pertwee RG, Ross RA. Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Mol Pharmacol. 2008; 73 :441–50. [PubMed] [Google Scholar]

87. Hayakawa K, Mishima K, Irie K, Hazekawa M, Mishima S, Fujioka M, Orito K, Egashira N, Katsurabayashi S, Takasaki K, Iwasaki K, Fujiwara M. Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism. Neuropharmacology. 2008; 55 :1280–6. [PubMed] [Google Scholar]

88. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 2000; 97 :9561–6. [PMC free article] [PubMed] [Google Scholar]

89. Stanely CP, O’Sullivan SE. CB1, TRPV1 and the endothelium mediate vasorelaxation to cannabidiol in human mesenteric arteries. 2012. Under review.

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

Does CBD Lower Resting Heart Rate?

The cannabidiol CBD, which performs an opposing function to the element THC that is behind cannabis’ psychoactive effect, is growing in popularity across the globe.

It is now used relatively widely to treat anxiety and other disorders, and is available in high-street stores throughout the UK.

Scientific research has established that CBD has many benefits, including lowering blood pressure and risk of suffering a stroke.

But there are several claims about other potential health reasons to take the product, and in some circles it has been suggested that the compound can decrease resting heart rate, so we’ve taken a look at the findings of studies over the years.

There’s certainly evidence that CBD can lower resting heart rate in stressful conditions, although it’s unclear if it has the same effect in non stressful circumstances or normal day-to-day life.

The research into this area goes back over a decade, with a study in 2009 finding that rats’ heart rate and blood pressure was decreased when they were exposed to a stressful situation and had been given a dose of CBD.

Then, two years later, researchers carried out a human study . They gave participants either a large dose of CBD or a placebo before a public-speaking event, and found that the group given CBD had lower blood pressure, heart rate, and anxiety levels.

However, a later study in 2017 found that CBD actually raised the resting heart rate of healthy males in normal conditions despite lowering blood pressure.

So although studies do indicate that CBD causes heart rate to remain lower when individuals are exposed to stressors, the evidence suggests it fails to decrease resting heart rate. Bear this in mind when you see claims the product can reduce heart rate.

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.

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.

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).

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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.

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.

References

1. Figueredo VM. The time has come for physicians to take notice: the impact of psychosocial stressors on the heart. Am J Med. 2009; 122 (8):704–712. doi: 10.1016/j.amjmed.2009.05.001. [PubMed] [CrossRef] [Google Scholar]

2. Perk J, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) Eur Heart J. 2012; 33 (13):1635–1701. doi: 10.1093/eurheartj/ehs092. [PubMed] [CrossRef] [Google Scholar]

3. Goldberg AD, et al. Ischemic, hemodynamic, and neurohormonal responses to mental and exercise stress. Experience from the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) Circulation. 1996; 94 (10):2402–2409. doi: 10.1161/01.CIR.94.10.2402. [PubMed] [CrossRef] [Google Scholar]

4. Costa B. On the pharmacological properties of Delta9-tetrahydrocannabinol (THC) Chem Biodivers. 2007; 4 (8):1664–1677. doi: 10.1002/cbdv.200790146. [PubMed] [CrossRef] [Google Scholar]

5. Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002; 42 (11 Suppl):11S–19S. [PubMed] [Google Scholar]

6. Stanley CP, Hind WH, O’Sullivan SE. Is the cardiovascular system a therapeutic target for cannabidiol? Br J Clin Pharmacol. 2013; 75 (2):313–322. doi: 10.1111/j.1365-2125.2012.04351.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

7. Rajesh M, et al. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol. 2007; 293 (1):H610–H619. doi: 10.1152/ajpheart.00236.2007. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

8. Rajesh M, et al. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 2010; 56 (25):2115–2125. doi: 10.1016/j.jacc.2010.07.033. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

9. El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai NT, Caldwell RB, Liou GI. Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am J Pathol. 2006; 168 (1):235–244. doi: 10.2353/ajpath.2006.050500. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

10. O’Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA. Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol. 2009; 612 (1-3):61–68. doi: 10.1016/j.ejphar.2009.03.010. [PubMed] [CrossRef] [Google Scholar]

11. Stanley CP, Hind WH, Tufarelli C, O’Sullivan SE. Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation. Cardiovasc Res. 2015; 107 (4):568–578. doi: 10.1093/cvr/cvv179. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

12. Walsh SK, Hepburn CY, Kane KA, Wainwright CL. Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. Br J Pharmacol. 2010; 160 (5):1234–1242. doi: 10.1111/j.1476-5381.2010.00755.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

13. Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães FS. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009; 156 (1):181–188. doi: 10.1111/j.1476-5381.2008.00046.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

14. Choi DC, Furay AR, Evanson NK, Ostrander MM, Ulrich-Lai YM, Herman JP. Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic-pituitary-adrenal axis activity: implications for the integration of limbic inputs. J Neurosci. 2007; 27 (8):2025–2034. doi: 10.1523/JNEUROSCI.4301-06.2007. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

15. Sultan SR, Millar SA, England TJ, O’Sullivan SE. A Systematic Review and Meta-Analysis of the Haemodynamic Effects of Cannabidiol. Front Pharmacol. 2017; 8 :81. [PMC free article] [PubMed] [Google Scholar]

16. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl) 1982; 76 (3):245–250. doi: 10.1007/BF00432554. [PubMed] [CrossRef] [Google Scholar]

17. Martin-Santos R, et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012; 18 (32):4966–4979. doi: 10.2174/138161212802884780. [PubMed] [CrossRef] [Google Scholar]

18. Fusar-Poli P, et al. Distinct effects of 9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009; 66 (1):95–105. doi: 10.1001/archgenpsychiatry.2008.519. [PubMed] [CrossRef] [Google Scholar]

19. Bergamaschi MM, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011; 36 (6):1219–1226. doi: 10.1038/npp.2011.6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

20. Sidney S. Cardiovascular consequences of marijuana use. J Clin Pharmacol. 2002; 42 (11 Suppl):64S–70S. [PubMed] [Google Scholar]

21. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008; 153 (2):199–215. doi: 10.1038/sj.bjp.0707442. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

22. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015; 172 (3):737–753. doi: 10.1111/bph.12944. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

23. Penumarti A, Abdel-Rahman AA. The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure. J Pharmacol Exp Ther. 2014; 349 (1):29–38. doi: 10.1124/jpet.113.209213. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

24. McHugh D, Page J, Dunn E, Bradshaw HB. Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br J Pharmacol. 2012; 165 (8):2414–2424. doi: 10.1111/j.1476-5381.2011.01497.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

25. Schwartz CE, Durocher JJ, Carter JR. Neurovascular responses to mental stress in prehypertensive humans. J Appl Physiol. 2011; 110 (1):76–82. doi: 10.1152/japplphysiol.00912.2010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

26. Barcroft H, Brod J, Hejl BZ, Hirsjarvi EA, Kitchin AH. The mechanism of the vasodilatation in the forearm muscle during stress (mental arithmetic) Clin Sci. 1960; 19 :577–586. [PubMed] [Google Scholar]

27. Lind AR, Taylor SH, Humphreys PW, Kennelly BM, Donald KW. THE CIRCULATIORY EFFECTS OF SUSTAINED VOLUNTARY MUSCLE CONTRACTION. Clin Sci. 1964; 27 :229–244. [PubMed] [Google Scholar]

28. Delius W, Hagbarth KE, Hongell A, Wallin BG. Manoeuvres affecting sympathetic outflow in human muscle nerves. Acta Physiol Scand. 1972; 84 (1):82–94. doi: 10.1111/j.1748-1716.1972.tb05158.x. [PubMed] [CrossRef] [Google Scholar]

29. Sander M, Macefield VG, Henderson LA. Cortical and brain stem changes in neural activity during static handgrip and postexercise ischemia in humans. J Appl Physiol. 2010; 108 (6):1691–1700. doi: 10.1152/japplphysiol.91539.2008. [PubMed] [CrossRef] [Google Scholar]

30. Ishii K, et al. Differential contribution of ACh-muscarinic and β-adrenergic receptors to vasodilatation in noncontracting muscle during voluntary one-legged exercise. Physiol Rep. 2014; 2 (11):e12202. [PMC free article] [PubMed] [Google Scholar]

31. Hudson BD, Hébert TE, Kelly ME. Physical and functional interaction between CB1 cannabinoid receptors and beta2-adrenoceptors. Br J Pharmacol. 2010; 160 (3):627–642. doi: 10.1111/j.1476-5381.2010.00681.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

32. Victor RG, Leimbach WN, Seals DR, Wallin BG, Mark AL. Effects of the cold pressor test on muscle sympathetic nerve activity in humans. Hypertension. 1987; 9 (5):429–436. doi: 10.1161/01.HYP.9.5.429. [PubMed] [CrossRef] [Google Scholar]

33. Mathias CJ, Bannister R. Investigation of autonomic disorders. In: Bannister R, Mathias CJ, eds. Autonomic Failure. A textbook of clinical disorders of the autonomic nervous system. Oxford:Oxford University Press;1992:255–290. [Google Scholar]

34. Yamamoto K, Iwase S, Mano T. Responses of muscle sympathetic nerve activity and cardiac output to the cold pressor test. Jpn J Physiol. 1992; 42 (2):239–252. doi: 10.2170/jjphysiol.42.239. [PubMed] [CrossRef] [Google Scholar]

35. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008; 4 (1):245–259. [PMC free article] [PubMed] [Google Scholar]

36. O’Sullivan SE, Bell C. Training reduces autonomic cardiovascular responses to both exercise-dependent and -independent stimuli in humans. Auton Neurosci. 2001; 91 (1-2):76–84. doi: 10.1016/S1566-0702(01)00288-0. [PubMed] [CrossRef] [Google Scholar]

37. Tzadok M, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016; 35 :41–44. doi: 10.1016/j.seizure.2016.01.004. [PubMed] [CrossRef] [Google Scholar]

38. Fusar-Poli P, et al. Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol. Int J Neuropsychopharmacol. 2010; 13 (4):421–432. doi: 10.1017/S1461145709990617. [PubMed] [CrossRef] [Google Scholar]

39. O’Connell BK, Gloss D, Devinsk O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav. doi: 10.1016/j.yebeh.2016.11. [published online ahead of print February 8, 2017]. https://doi.org/10.1016/j.yebeh.2016.11.012. [PubMed] [CrossRef] [Google Scholar]

40. Schutte AE, Huisman HW, van Rooyen JM, Malan NT, Schutte R. Validation of the Finometer device for measurement of blood pressure in black women. J Hum Hypertens. 2004; 18 (2):79–84. doi: 10.1038/sj.jhh.1001639. [PubMed] [CrossRef] [Google Scholar]

41. Johnson JM, Taylor WF, Shepherd AP, Park MK. Laser-Doppler measurement of skin blood flow: comparison with plethysmography. J Appl Physiol Respir Environ Exerc Physiol. 1984; 56 (3):798–803. [PubMed] [Google Scholar]

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