Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Due to its complex mechanism of action, CBD may affect the cardiovascular system in different ways. Thus, we reviewed the influence of CBD on this system in health and disease to determine the potential risk of cardiovascular side effects during CBD use for medical and wellness purposes and to elucidate its therapeutic potential in cardiovascular diseases. Administration of CBD to healthy volunteers or animals usually does not markedly affect hemodynamic parameters. Although CBD has been found to exhibit vasodilatory and antioxidant properties in hypertension, it has not affected blood pressure in hypertensive animals. Hypotensive action of CBD has been mainly revealed under stress conditions. Many positive effects of CBD have been observed in experimental models of heart diseases (myocardial infarction, cardiomyopathy, myocarditis), stroke, neonatal hypoxic ischemic encephalopathy, sepsis-related encephalitis, cardiovascular complications of diabetes, and ischemia/reperfusion injures of liver and kidneys. In these pathological conditions CBD decreased organ damage and dysfunction, oxidative and nitrative stress, inflammatory processes and apoptosis, among others. Nevertheless, further clinical research is needed to recommend the use of CBD in the treatment of cardiovascular diseases.
The most common cause of brain damage in neonates is perinatal hypoxic-ischemic encephalopathy caused by asphyxia. Cannabidiol is considered as promising neuroprotectant after neonatal hypoxia-ischemia and as mentioned above, in European Union, this compound has even orphan drug status in perinatal asphyxia. The largest number of evidence of protective CBD action in HIE is based on studies in newborn piglets submitted to hypoxia-ischemia. Beneficial effects of CBD on experimental neonatal HIE include alleviation of decreased brain activity, neuronal metabolism impairment, excitotoxicity, histopathological changes in brain, neuronal necrosis and/or apoptosis, astroglial and/or microglial activation, neuroinflammation and oxidative stress in brain. CBD can also diminish distant inflammatory lung damage associated with brain hypoxia-ischemia-induced injury. In addition, CBD might diminish hypoxia-ischemia-induced decrease in blood pressure. However, high dose of CBD (50 and 25 mg/kg; the most common dose in previous studies was 1 mg/kg) induced significant hypotension in some piglets (CBD 50 mg/kg in two out of four piglets and CBD 25 mg/kg in one out of four piglets). In addition, one piglet suffered fatal cardiac arrest after CBD infusion at dose of 50 mg/kg. Thus, caution should be taken during treatment with high doses of CBD due to possible occurrence of cardiovascular side effects. Beneficial effects of CBD have been also revealed in mouse and rat models of neonatal HIE (Table 4). It is noteworthy, that CBD shows a broader therapeutic time window than reported for hypothermia and other neuroprotective treatments. The protective action of CBD in hypoxia-ischemia-induced brain injury occurs, at least in part, through CB2 and 5-HT1A receptors. Studies in forebrain slices from newborn mice underwent oxygen and glucose deprivation revealed that, in addition to CB2 receptors, adenosine receptors (mainly A2) can also mediate neuroprotective effects of CBD. However, some authors reported that CBD (at low or high doses) did not exhibit any neuroprotective properties in experimental models of neonatal HIE. Nevertheless, CBD can enhance protective effects of hypothermia, a gold standard for treating infants with HIE.
The anti-inflammatory and vascular-stabilizing effects of CBD have been also revealed in the murine encephalitis induced by lipopolysaccharide (LPS) administration (Table 4). LPS evoked arteriolar and venular vasodilation, enhanced leukocyte margination, increased expression of proinflammatory TNF-α and COX-2, higher levels of oxidative stress markers (malondialdehyde and 4-hydroxynonenal) and disruption of the blood–brain barrier. Treatment with CBD alleviated almost all these LPS-induced changes (with exception of oxidative stress markers), and in addition reduced inducible NOS expression. Thus, CBD may offer an option for treating sepsis-related encephalitis and encephalopathy.
Cannabidiol has been shown to be protective against ischemia/reperfusion injury of the kidneys and liver (Table 4). This type of damage can occur during shock and surgery or transplantation of these organs. In a rat model of renal ischemia/reperfusion injury, CBD significantly reduced histopathological changes in kidneys and decreased serum creatinine (marker of renal function). The nephroprotective effect of CBD was associated with ameliorated ischemia/reperfusion-induced oxidative and nitrative stress, inflammation and apoptosis. Similar protective effects were obtained in rodents submitted to ischemia/reperfusion of the liver. Thus, CBD reduced serum transaminases (markers of liver damage) and histopathological changes, cell death, oxidative and nitrative stress, and inflammation in the liver. It has been shown that the mechanism of this hepatoprotective action may include attenuated activation of NF-κB, p38 MAPK and JNK by CBD. In vitro studies in human liver sinusoidal cells showed that CBD can attenuate TNF-α-induced expression of adhesion molecules (ICAM-1 and VCAM-1) and polymorphonuclear cells adhesion to liver sinusoidal cells. This corresponds with CBD-induced decrease of ICAM-1 expression and neutrophil infiltration in the mice liver submitted to ischemia/reperfusion injury. Hepatoprotective effects of CBD seem not to be dependent on cannabinoid receptors, as they were not attenuated by CB1 and CB2 antagonists in vitro and were still presented in CB2 knockout mice. In summary, CBD has a great therapeutic potential in preventing and alleviating ischemia/reperfusion injury of different organs such as heart, brain, kidneys and liver.
This article has reviewed the effects of cannabidiol, a non-intoxicating cannabis component with a wide therapeutic potential and good safety profile, on the cardiovascular system under physiological and pathological conditions (summarized in Figure 5). CBD might affect the cardiovascular system via different direct and indirect mechanisms. A detailed determination of CBD impact on the cardiovascular system is important considering the still-increased usage of this compound for therapeutic (including self-medication) or recreational purposes. However, with a few exceptions, the effect of CBD on the cardiovascular system under physiological conditions appears to be negligible, which confirms a good safety profile of this cannabinoid. On the other hand, potential CBD application for the treatment of cardiovascular disorders is considered. In experimental pathological conditions, such as hypertension, heart diseases, stroke, neonatal hypoxia-ischemia, diabetes or hepatic and renal ischemia/reperfusion injury, the protective effect of CBD associated with its anti-inflammatory, antioxidant, antiapoptotic, vasculoprotective, cardioprotective or neuroprotective effects is often revealed. Despite its vasodilatory properties, CBD has not been demonstrated to exhibit hypotensive action in animal models of hypertension. However, this compound might lower stress-induced increases in blood pressure in both humans and animals. Nevertheless, it should be emphasized that almost no clinical research has been done with CBD in diseases of the cardiovascular system and, hence, its therapeutic potential is not translated into clinical practice. Further studies, especially clinical investigations, are warranted to recommend the use of CBD in the treatment of cardiovascular disorders.
