Dear editor,
An aberrant release of cytokines and proinflammatory molecules is
closely related to lung injury, multiorgan failure and ultimately poor
prognosis in the new Severe Acute Respiratory Syndrome - Coronavirus –
2 (SARS-CoV2) pandemic [1].
Such uncontrolled release of cytokines, namely interleukin (IL)-1ß,
IL-6, monocyte chemoattractant protein (MCP)-1, paralleled with the
decreased natural killer cells may result in the so-called ‘cytokine
storm’. Immune dysregulation, rather than viremia levels per se ,
has been related to the massive proinflammatory cytokine secretion by
alveolar macrophages, and subsequent CD4+ and
CD8+ T cell dysfunction observed in SARS-CoV infection
[2]. Hence, until specific vaccines become available, the use of
antiviral agents alone may not be sufficient to stop the cytokine storm
and respiratory distress in severely-ill patients. In the attempt of
reducing their overall mortality, it is therefore essential to identify
new therapeutics able of mitigating the cytokine storm [3].
Nonetheless, redundancies within the complex cytokine network still
represent a major obstacle to monoclonal antibodies therapies. The ideal
drug candidate should be already in use for other indications, have a
favorable safety profile and a multitargeted action, able to
synergistically mitigate the cytokine storm, acting as an
immunomodulatory rather than an immunosuppressant drug.
In a recent paper, high-cannabidiol (CBD) Cannabis Sativa extracts have
been reported to downregulate Angiotensin-converting enzyme 2 (ACE2) and
Transmembrane Serine Protease 2 (TMPRSS2) receptors, crucial viral
gateways in oral, lung and intestinal epithelia constituting important
routes of SARS-CoV2 invasion [4]. By downregulating ACE2 and TMPRSS2
receptors, CBD could be used to prevent SARS-CoV2 entry into susceptible
hosts but most importantly, it could reduce the bioavailability of ACE2
receptors in infected tissues, thus limiting the progression of the
disease. These newly described effects pair with its well-described
immunomodulatory activities, making of CBD a promising candidate drug.
Non-psychotropic phytocannabinoid CBD is indeed considered one of the
most interesting emerging molecules in the field of pharmacology, since
it exerts a wide range of therapeutic effects, ranging from
anticonvulsive, sedative, hypnotic, antipsychotic, anti-cancer,
anti-inflammatory and neuroprotective activities [5]. Lacking of the
unwanted psychotropic effects of marijuana derivatives, CBD has little
binding affinity to cannabinoid receptors (acting as allosteric
modulator of cannabinoid CB1 receptors) and a favorable safety profile
in humans [6,7]. CBD acts as a powerful antioxidant acting at
various receptor sites, including peroxisome proliferator-activated
receptor gamma (PPARγ), 5-hydroxytryptamine (5HT)-1A, Adenosine A2,
transient receptor potential (TRP) channels receptors to directly or
indirectly display a wide range of antinflammatory and immunomodulatory
effects. A complete review of CBD receptor targets is beyond the purpose
of the present article and the readers are invited refer to more
extensive review on this subject [5].
Such pleiotropic pharmacological activity has been tested in various
pathological conditions, including respiratory diseases resembling
COVID19-induced respiratory distress. Acute Lung injury (ALI) refers to
a characteristic form of parenchymal lung disease, featured by bilateral
pulmonary infiltrates, alveolar-capillary vasculitis with neutrophil
infiltration and proinflammatory cytokines release, comparable to
COVID19. By acting at adenosine A2 receptor site, CBD caused a marked
amelioration of the pulmonary function [8,9] as a consequence of the
significantly decreased lung resistance and elastance due to the
reduction of leukocyte migration into the lung, accompanied to a marked
inhibition of both pro-inflammatory cytokines (TNFα and IL-6) and
chemokines (MCP-1 and MIP-2) released [8,9].
Although limited to interesting preclinical studies, scattered evidence
also points towards a possible use of CBD in viral infections. Indeed,
several plant-derived compounds have evolved to display antiviral
activity, including many phenol-based compounds, such as terpenoids.
CBD and other cannabinoids exert their activity through the interaction
with the nuclear peroxisome proliferator-activated receptors (PPARs)
[10]. The PPARs belong to the family of nuclear hormone receptors
and their activity is regulated by steroids and lipid metabolites. Three
different PPAR isoforms (PPARα, PPARβ, also called δ, and PPARγ) have
been identified and they have been described to regulate the expression
of genes related to lipid and glucose homeostasis and inflammatory
responses.
PPARγ agonism in resident alveolar macrophages significantly limits
pulmonary inflammation and promotes host recovery following respiratory
viral infections [11]. As it has been demonstrated during acute
pneumonia, alveolar macrophage largely express PPARγ. Such increase has
been also detected in pathological conditions similar to COVID-19
infection, such as Middle East Respiratory Syndrome (MERS) [12].
PPARγ activation is also responsible for the control of cytokine
over-secretion with consequent amelioration of the tissue damage. It is
therefore likely that in addition to directly determining an improvement
in lung dynamics, CBD could significantly counteract the onset of the
cytokine storm from resident macrophages. Interestingly, prophylactic or
therapeutic administration of PPARγ agonists led to reduction of
morbidity and mortality during influenza A virus infection [13].
Moreover, PPARγ agonists may directly inhibit viral replication by
different human viruses such as Human Immunodeficiency Virus,
Respiratory syncytial virus, Hepatitis B Virus and Hepatitis C Virus
[14,15]. Noteworthy, these experimental evidences are corroborated
by recent study showing a direct antiviral against HCV in vitro
[16].
Recent reports show that a subset of COVID-19 survivors can develop
post-infectious sequelae with persistently impaired lung function and
pulmonary fibrosis [17]. PPAR-γ receptors represent a potential
therapeutic target in fibrotic lung diseases, given their ability of
regulating fibroblast/myofibroblast activation and collagen secretion in
murine models [18]. Notably, CBD has been shown to reduce pulmonary
inflammation and fibrosis in animal models of asthma [19].
It is therefore conceivable to speculate that, being a PPAR-γ receptor
agonist, CBD can potentially limit the onset of late-onset pulmonary
fibrosis in COVID19-recovered patients.
Although CBD is a relatively safe molecule for humans and different
trials have been conducted [20] or are ongoing, especially in the
field of neurological disorders therapy; there are currently no
evidences about the efficacy and relative toxicity of CBD in COVID19.
Even if CBD was (incorrectly in our opinion) considered as a mere
therapeutic supplement, there is still lack of data regarding the
relative toxicity profile in co-administration with other drugs in the
current anti-COVID19 protocols. A possible strategy would be testing CBD
therapeutic potential in COVID19 patients, according to a precautionary
principle, at an early stage of the disease or alternatively, to
evaluate its effectiveness in COVID-19 recovered patients.
The COVID19 pandemic is testing the planet. The off-label use of readily
available therapeutics able to limit the severity of the disease must be
scrupulously scrutinized, pending a vaccine against SARS- CoV2. In
keeping with this, we consider CBD a promise candidate drug to bet on,
based on the encouraging preclinical studies and its relative safety
profile in humans (figure 1) . Further evidence will be needed
to confirm its beneficial activities and turn CBD into a useful addition
to the treatment of COVID-19.