This narrative review gathers recent data on the possible potential of cannabidiol in the treatment of COVID-19 with an eye on angiogenesis and endothelial dysfunction. Keywords included cannabidiol AND angiogenesis OR endothelial cell as well as coronavirus disease 2019 OR COVID-19 AND angiogenesis OR endothelial dysfunction and searched databases consisted of PubMed and Scopus with no time limitation (search time: September 2021). The authors separated and extracted the results through two steps: first, reading the title/abstract of articles, and in case of matching with the primary concept of review, the full text was read and extracted.
Concept
Cannabinoids are well-known for their anti-angiogenic and anti-inflammatory potentials (Norooznezhad and Norooznezhad 2017; 2016; Norooznezhad et al. 2016; Baban et al. 2021). So far, some studies have suggested these compounds as a possible treatment for COVID-19 among which none have discussed their potential to inhibit endothelial cell dysfunction or pathologic angiogenesis (Rossi et al. 2020; Costiniuk and Jenabian 2020; Mohammed et al. 2020; Malinowska et al. 2021). Regarding the role of angiogenesis and endothelial dysfunction in the pathogenesis of COVID-19 and the already mentioned potent anti-inflammatory properties of CBD, it seems that this compound might be effective in the treatment of severe COVID-19 by affecting multiple pathways.
Angiogenesis and endothelial dysfunction in COVID-19
Recently, upon our review research on the role of angiogenesis and endothelial dysfunction in COVID-19 (Norooznezhad and Mansouri 2021), we found that among many EC surface receptors, angiotensin-converting enzyme 2 (ACE2) receptor associates most with COVID-19 infection. As it has been shown, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects the endothelial cells using this receptor (Varga et al. 2020). Also, autopsies have revealed higher numbers of ACE2 positive endothelial cells in the lungs of COVID-19 patients compared to healthy cases (Ackermann et al. 2020).
Ackerman et al., have shown that pathologic angiogenesis, as well as micro thromboembolism, occurs in non-survivor COVID-19 patients. Moreover, through their investigation, endothelialitis and endothelial cell dysfunction were observed as well in the patients diagnosed with SARS-CoV-2 infection. As they have stated, the expression of pro-angiogenic and pro-inflammatory factors involved in angiogenesis is significantly increased in patients with COVID-19 compared to the uninfected control tissues. Among these factors, hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP-2), interleukin 6 (IL-6), insulin-like growth factor 1 (IGF-1), and FLT-1 or VEGF receptor 1 were more notable (Ackermann et al. 2020).
In another study, it was shown that plasma levels of VEGF-A, platelet-derived growth factor AA (PDGF-AA), and PDGF-AB/BB in non-intensive care unit (ICU) patients were significantly higher than controls. Also, in expired ICU admitted patients, the levels of plasminogen activator inhibitor-1 (PAI-1), follistatin, and angiopoietin 2 (Ang2) were found to be significantly higher than those of survivors. Moreover, Ang2, endoglin, fibroblast growth factor (FGF), FLT-3L, and PAI-1 were significantly higher in ICU admitted patients compared to other COVID-19 individuals (Pine et al. 2020). According to another investigation, COVID-19 patients with increased D-dimer and C reactive protein (CRP) levels as well as creatinine, lymphopenia, and decreased SpO2 levels experienced significant levels of soluble E-selectin and Ang2 (Smadja et al. 2020).
Cannabidiol, angiogenesis, and endothelial cells
As mentioned, cannabinoids have been studied for their strong anti-inflammatory potentials and ability to inhibit/decrease various important pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Other than the anti-inflammatory potential, cannabinoids also have shown notable anti-angiogenic potential (Norooznezhad and Norooznezhad 2016, 2017; Norooznezhad et al. 2016; Mansouri and Norooznezhad 2019). Cannabinoids exert their biological activity through two main G protein-coupled receptors of CB1 and CB2 (Shahbazi et al. 2020). These receptors are expressed in a wide range of tissues and cells. Among the cannabinoids, some have an affinity to one or both of these receptors rendering them an agonist or antagonist potential. The CB1 receptor is expressed on smooth muscle cells of arterioles (Howlett and Abood 2017), endothelial cells (Liu et al. 2000), and certain other cells and tissues (Howlett and Abood 2017). CB2 receptor, with no psychoactive properties, has also been found on the vascular endothelial cells (Blázquez et al. 2003) as well as many other organs and tissues (Howlett and Abood 2017).
As Solinas et al., have demonstrated, CBD could inhibit endothelial cell tube formation and morphogenesis by decreasing cellular proliferation without inducing apoptosis or exerting any toxic effect. Also, one of the other inhibited pathways of angiogenesis by CBD is endothelial cells migration. In this regard, CBD has been illustrated to decrease the expression of uPA, MMP-9, PAI-1, PDGF-AA, and IL-8 (up to 50%) in human endothelial cells (Solinas et al. 2012). Furthermore, investigations have cleared that CBD could decrease vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) expression, monocytes adhesion potential to endothelial cells, the endothelial barrier integrity, mitochondrial superoxide generation, and activation of NF-κB in high glucose-treated endothelial cells (Rajesh et al. 2007). Also, another study on a CBD hydroxyquinone (HU-331) showed the higher potential of this specific cannabinoid on the inhibition of angiogenesis (considering total vessel number, length, and area) induced by VEGF and FGF. HU-331 is also known to be able to decrease the von Willebrand factor (VWF) in human endothelial cells (Kogan et al. 2006). According to the studies, CBD has been identified to inhibit heparin cocktail-induced angiogenesis through suppression of VEGF and TNF-α. This agent also inhibits endothelial cell proliferation (inducing cytostasis but not apoptosis), migration, and invasion by suppressing different angiogenic factors such as PDGF, MMP-2, MMP-9, and IL-8 (Solinas et al. 2012). Also, in a viral in vivo model, CBD was demonstrated to decrease inflammation by affecting endothelial cells via VCAM-1, an endothelial-expressed protein for leukocytes transmigration (Mecha et al. 2013). It is also believed that CBD could increase the human mesenteric artery vasorelaxation. Interestingly, CBD can decrease NF-κB and phosphorylated c-Jun N-terminal kinases (JNK); thus, preventing the phosphorylation of eNOS (Stanley et al. 2015). In a diabetic model of cardiac dysfunction, CBD treatment has resulted in cardiac function improvement through inhibition of NF-κB leading to decreased VCAM-1, ICAM-1, and TNF-α expressions as well as decreasing other agents involved in oxidative stress (Rajesh et al. 2010). Altogether, it seems that other than affecting endothelial cells in the cardiovascular system, CBD could positively improve cardiac function in patients with COVID-19. Similar to its cardioprotective effects, CBD could show protective properties in other organs such as the kidney, liver, and nervous systems as well (Malinowska et al. 2021).
Endothelial cell dysfunction and some of the pro-angiogenic factors are directly associated with ARDS (Ackermann et al. 2020; Norooznezhad and Mansouri 2021). A recent in vivo study on viral infection-induced ARDS evaluated the outcomes of CBD treatment. It has been shown that CBD not only increases O2 saturation to the normal value but also reduces IL-6, TNF-α, and INF-γ levels. Another interesting point in this study was the reduced neutrophil and increased lymphocytes count following CBD treatment (Khodadadi et al. 2020). As has been demonstrated, increased neutrophils to lymphocytes ratio (NLR) as well as lymphopenia alone are among the poor prognostic factors in patients with COVID-19 (Norooznezhad et al. 2020a; Terpos et al. 2020). Also, it has been shown that the administration of CBD has decreased pro-inflammatory cytokines (e.g. IL-6 and TNF-α) in an animal model of ARDS (Khodadadi et al. 2020). All in all, it seems that CBD could be considered as an effective treatment option functioning through the most important pathways involved in pathologic angiogenesis and endothelial cell dysfunction. Figure 1 shows some of the possible potentials of CBD on angiogenesis and endothelial dysfunction in SARS-CoV-2 infection.
Clinical use of cannabidiol
As already mentioned, CBD is a non-psychoactive phytocannabinoid that has been used in many trials for a wide variety of diseases. In Jun 2018, the Food and Drug Administration (FDA) of the United States approved an oral solution of CBD under the brand name of Epidiolex® for two rare forms of epilepsy, Lennox-Gastaut and Dravet syndromes or tuberous sclerosis complex (TSC) in young children 1 year of age and older. Upon this decision, Epidiolex® became the first FDA-approved cannabinoid in history. (Brunetti et al. 2020). Recently, a pilot randomized, parallel-arm, double-blind investigation has been performed on the anti-inflammatory activity of CBD in healthy adults. After the administration of CBD, their peripheral blood mononuclear cells (PBMCs) were harvested and cultured with lipopolysaccharide (LPS). A significant decrease was observed in TNF-α levels from their PBMCs upon previous exposure to CBD compared to the cells collected before CBD treatment (Hobbs et al. 2020). However, similar to any other medication, CBD has certain side effects which are considered not serious. Among the described side effects of CBD, somnolence, fatigue, hepatic abnormalities, vomiting, and diarrhoea are the most prevalent (Huestis et al. 2019). Also, drug-drug interaction with COVID-19 medications should also be kept in mind while using CBD (Malinowska et al. 2021). It is noteworthy to mention that a combination of CBD and THC (Sativex; THC: CBD in 1:1 ratio) has been approved for the treatment of MS-associated spasticity in 25 countries except for the US (Khalsa et al. 2021).