Cannabidiol (CBD) is the second most abundant phytocannabinoid, after Δ⁹-tetrahydrocannabinol (THC) (Pertwee, 2006; Tambaro and Bortolato, 2012) and was first isolated from the cannabis extract in 1940 (Adams et al., 1940). The pharmacological actions of CBD are complex; CBD has a low affinity to the cannabinoid receptor 1 (CB₁) and cannabinoid receptor 2 (CB₂) (Thomas et al., 2007; Pertwee, 2008), and targets a wide range of other receptors including 5-hydroxytryptamine (5-HT_1a), transient receptor potential vanilloid receptor 1 (TRPV1), peroxisome proliferator-activated receptors (PPARs) and G protein-coupled receptor 55 (GPR55) (Pertwee, 2008; Stanley et al., 2013a). It is suggested that CBD may have therapeutic effects in a variety of disorders including diabetes, gastrointestinal disturbances, cancer, oxidative stress, inflammation and in cardiovascular disease (Russo and Guy, 2006; Capasso et al., 2008; Zuardi, 2008; Iuvone et al., 2009; Booz, 2011). CBD may also have desirable effects in multiple neurological and psychological disorders, including dystonia, schizophrenia, epilepsy and Parkinson's disease (Consroe et al., 1986; Leweke et al., 2012; Chagas et al., 2014; Devinsky et al., 2016). In a recent open-label trial investigating the effects of CBD (Epidiolex, 2–50 mg/kg) on 214 young patients with treatment-resistant epilepsy, CBD reduced seizure frequency and demonstrated an acceptable safety profile (Devinsky et al., 2016). Epidiolex was also safe and well tolerated in refractory epilepsy secondary to tuberous sclerosis and for epileptic spasms, highlighting its potential as a new treatment for refractory epilepsy (Abati et al., 2015; Geffrey et al., 2015).

Pre-clinical studies on the effects of CBD on the cardiovascular system have shown that CBD causes endothelium- and nitric oxide-dependent vasorelaxation of isolated human mesenteric arteries (Stanley et al., 2015) and PPARγ-dependent vasorelaxation of the rat aorta (O'sullivan et al., 2009). CBD also improves vasorelaxation in the femoral arteries of Zucker diabetic fatty rats via enhanced production of vasodilator COX-1/2-derived products acting at EP4 receptors (Stanley et al., 2013b; Wheal et al., 2014). CBD also decreases myocardial infract size in a rat model of ischaemia/reperfusion injury (Durst et al., 2007), attenuates myocardial dysfunction and inflammation in an animal model of diabetes (Rajesh et al., 2007), and attenuates inflammatory and oxidative stress changes induced by high glucose in human coronary artery cells (Rajesh et al., 2010). CBD also reduces cerebral vascular inflammation and associated dilatation induced by lipopolysaccharide in mice (Ruiz-Valdepenas et al., 2011), infarct size in animal models of stroke (England et al., 2015) and reduced blood brain barrier permeability (Hind et al., 2016). These effects on the cerebral vasculature appear to involve 5HT_1A and PPARγ. Together, these pre-clinical studies might suggest that the cardiovascular system is a therapeutic target for CBD (Stanley et al., 2013a). However, despite these many vascular effects of CBD, it is not yet clear whether CBD administration alters haemodynamics under control or pathological situations.

Given the increasing clinical use of CBD, and the numerous effects of CBD in the cardiovascular system, the aim of the present study was to systematically review and analyse in vivo studies evaluating the effects of CBD on alterations in haemodynamics.

From the initial 1016 search results, 277 relevant publications were identified from three databases (Medline, EMBASE, and PubMed). Of these, 25 articles met the inclusion criteria (see Figure 1). A summary of the data extracted from included studies is shown in Table 1.

The aim of this study was to determine whether CBD alters haemodynamics in vivo. Our analysis has shown that acute and chronic dosing of CBD had no effect on BP, HR, or BF under control conditions. However, in stressful situations, CBD reduces the increase in MBP and HR observed in rats. Subgroup analysis revealed that acute CBD administration increases HR in mice and rats, and increases CBF in mouse models of stroke. Our analysis has highlighted the limited amount of human research carried out to date, and suggests that further work is required to assess the haemodynamic and regional BF impact of acute and chronic CBD administration in healthy volunteers and patients.

Overall, our meta-analysis showed that acute and chronic dosing of CBD had no effect on BP, HR, or BF under control conditions. However, there was significant heterogeneity with regards to species and model, dose and route of administration, and method and time of endpoint measurement (see Table 1) which makes it difficult to compare studies. It is possible that species differences may play a role. For example, Bright et al. found a significant increase in HR and BP with CBD (0.5 and 1 mg/kg) in anesthetized dogs (Bright et al., 1974, 1975), however, no changes were seen with CBD (25 mg /kg) in the HR of anesthetized rabbits (Borgen and Davis, 1974). It is also worth noting that most of the human data reviewed did not show any significant effects of CBD while significant effects were observed in animal studies. The time of cardiovascular measurements is also very important. For example, in a study that examined the cardioprotective effect of CBD (50 μg/kg i.v.) in rats showed that BP was significantly reduced post-CBD treatment compared to control two and a half hours post-ischaemia (Walsh et al., 2010). However, another study assessing CBD at the same dose and route of administration on cardiac arrhythmia (Gonca and Darici, 2015) found no change in BP, although this was only measured 11 min post-ischaemia, thus any potential later changes in haemodynamics are not reported. A greater number of homogenous studies are required to assess the haemodynamic effects of CBD under control conditions.

Our systematic review has highlighted that there are a limited number of studies examining changes in regional BF with CBD, with studies to date only examining changes in cerebral or myocardial BF. From the limited studies available, our analysis showed there were no significant changes in BF overall post-CBD administration. However, in mice and piglet models of stroke, either intraperitoneal or intravenous administration of CBD (3 mg/kg or 0.1 mg/kg, respectively) significantly reduced the infarct volume and increased the CBF after acute and chronic dosing (Mishima et al., 2005; Hayakawa et al., 2007a,b; Alvarez et al., 2008). Similarly, in a rabbit model of myocardial infarction, CBD treatment of 100 μg/kg modestly reduced the size of myocardial ischaemic injury and increased myocardial BF (Feng et al., 2015). Together, this suggests that further investigation on the effects of CBD on regional BF, particularly in pathological situations, is warranted.

There was no relationship found between the dose of CBD and the effect size. However, in conscious monkeys, toxicology studies showed that very large doses of CBD (150–300 mg/kg) caused bradycardia, and CBD doses >200 mg/kg caused heart failure and death (Rosenkrantz et al., 1981). However, it is worth noting that this would be equivalent to a dose of 14,000 mg in a 70 kg human. Intracisternal administration of CBD had no effect on the increase in BP or HR induced by acute restraint stress in rats while systemic administration did (Granjeiro et al., 2011). Similarly, no effect was seen in BP after intracerebral CBD injection in rats (Gomes et al., 2013). This suggests that systemic administration of CBD is required to observe changes in haemodynamics.

Although CBD did not affect haemodynamics under control conditions, our analysis did reveal effects of CBD in pathological situations. For example, in piglet models of hypoxic injury, intravenous administration of CBD (0.1 mg/kg) maintained a stable BP after hypoxic injury compared to control animals where a reduction in BP was observed (Alvarez et al., 2008). Also, in rats conditioned to stress (i.e., restraint or fear), CBD reduced the increase in HR and MBP (Resstel et al., 2006, 2009; Gomes et al., 2012). However, in mouse models of stroke there was no significant change in MBP or HR post-CBD (Mishima et al., 2005; Hayakawa et al., 2007a, 2008). This suggests that CBD may regulate the haemodynamics when they are altered at times of stress or acute illness.

Most of the identified relevant studies were pre-clinical, and data concerning the effects of CBD on haemodynamics in humans is limited (n = 36 for BP, n = 87 for HR). A single oral dose of CBD (320 μg/kg, 1 mg/kg, 100, 300, 600 or 1200 mg) had no effect on BP or HR in healthy volunteers under control or stressful situations (Belgrave et al., 1979; Zuardi et al., 1982, 1993; Gong et al., 1984; Borgwardt et al., 2008; Bhattacharyya et al., 2009, 2010; Fusar-Poli et al., 2009; Bergamaschi et al., 2011; Hallak et al., 2011; Winton-Brown et al., 2011; Martin-Santos et al., 2012). Likewise, after repeated CBD dosing of 1200 mg or 3 mg/kg for 20 or 30 days, respectively there were no apparent effects on HR, BP, or ECG compared with other treatment groups (Cunha et al., 1980; Gong et al., 1984). In clinical trials, chronic administration of CBD 300 mg, 10 mg/kg or 800 mg for 4½ months, 6 or 4 weeks, respectively, incurred no changes on the ECG, BP, or HR in patients of epilepsy, Huntington or schizophrenia disorders (Cunha et al., 1980; Consroe et al., 1991; Leweke et al., 2012). However, repeated oral dosing of CBD increasing from 100 to 600 mg/day over 6 weeks induced a reduction in standing BP by 10–20 mmHg in patients with dystonic movement disorders (Consroe et al., 1986). Conversely, a single dose of CBD (40 mg) given to patients with intraocular pressure increased systolic BP at 60 and 90 min post-sublingual administration (Tomida et al., 2006). Two studies of healthy volunteers and patients with social anxiety disorders showed CBD (400 mg) increased cerebral BF on the left parahippocampal and right posterior cingulate gyrus, respectively, but not in other brain regions when compared to control (Crippa et al., 2004, 2011). Bhattacharyya et al. (2010) suggested that the CBD effects on regional brain function during multi-tasking may be related to its effects on CBF (Bhattacharyya et al., 2010). Conversely, Borgwardt et al. (2008) suggested that the neural effects observed after CBD administration are unlikely to be a consequence of vascular effects, including CBF (Borgwardt et al., 2008). Together, this data would suggest that there are limited haemodynamic effects of CBD in humans, although further studies where this is the primary endpoint are warranted based on pre-clinical data reviewed in the present study.

This meta-analysis and systematic review has highlighted the haemodynamic effects of CBD administration in vivo. The positive effects induced by CBD include maintaining the fall in BP after global hypoxia, reducing the increase in MBP and HR post-stress, and increasing BF in ischaemia-reperfusion models. It is possible that beneficial effects of CBD on haemodynamics occurs when the cardiovascular system is abnormally altered, suggesting that CBD may be used as a treatment for various cardiovascular disorders, such as hypertension, myocardial infarction and stroke. However, the findings from the reviewed studies were predominately preclinical and significant effects were only observed in animals. Data from human studies investigating the effects of CBD on haemodynamics is still very limited and we suggest that further research in humans under pathological conditions is required.

SO and TE: Substantial contributions to the conception or design of the work. All authors: The analysis and interpretation of data for the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.