Coronavirus disease-2019 (COVID-19), caused by Severe Acute Respiratory Syndrome coronoavirus-2
(SARS-CoV2) has emerged as a global pandemic, which was first reported in Wuhan, China.
Recent reports have suggested that acute infection is associated with a cytokine superstorm,
which contributes to the symptoms of fever, cough, muscle pain and in severe cases
bilateral interstitial pneumonia characterized by ground glass opacity and focal chest
infiltrates that can be visualized on computerized tomography scans (Rothan and Byrareddy,
2020). Currently, there are no effective antiviral drugs or vaccines against SARS-CoV2.
In the recent issue of BBI, Zhang et al. (Zhang et al., 2020) thoroughly summarized
the current status of potential therapeutic strategies for COVID-19. One of them,
anti-IL6 receptor (Tocilizumab) antibody, resulted in clearance of lung consolidation
and recovery in 90% of the 21 treated patients (Fu et al., 2020). Although promising,
it has also produced adverse effects like pancreatitis and hypertriglyceridemia (Morrison
et al., 2020), which make it imperative to explore effective alternative anti-inflammatory
strategies. Here, we intend to highlight the potential effects of cannabinoids, in
particular, the non-psychotropic cannabidiol (CBD), that has shown beneficial anti-inflammatory
effects in pre-clinical models of various chronic inflammatory diseases and is FDA
approved for seizure reduction in children with intractable epilepsy (Nichols and
Kaplan, 2020).
Similar to Δ9-tetrahydrocannabinol (Δ9-THC), the most studied cannabinoid, CBD decreased
lung inflammation in a murine model of acute lung injury potentially through the inhibition
of proinflammatory cytokine production by immune cells and suppressing exuberant immune
responses (Vuolo et al., 2019). CBD can inhibit the production of proinflammatory
cytokines like interleukin (IL)-2, IL-6, IL-1α and β, interferon gamma, inducible
protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α,
and tumor necrosis factor-α (Nichols and Kaplan, 2020) (Figure 1
) that have been associated with SARS-CoV2 induced multi-organ pathology and mortality.
In a murine model of chronic asthma, CBD reduced proinflammatory cytokine production,
airway inflammation and fibrosis (Vuolo et al., 2019). Moreover, CBD can effectively
inhibit the JAK-STAT pathway including the production and action of type I interferons
without leading to addiction, alterations in heart rate or blood pressure and adverse
effects on the gastrointestinal tract and cognition (Nichols and Kaplan, 2020). In
simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs), we reported THC
mediated attenuation of IFN stimulated gene expression in the intestine (Kumar et
al., 2019). Similar to CBD, chronic THC administration blocked inflammation induced
fibrosis in lymph nodes of chronically SIV-infected RMs (Kumar et al., 2019). Unlike
THC, CBD has a high margin of safety and is well tolerated pharmacologically even
after treatments of up to 1500 mg/day for two weeks in both animals and humans (Nichols
and Kaplan, 2020), which suggests its feasibility to reduce SARS-CoV2 induced lung
inflammation/pathology and disease severity.
Figure 1
Potential mechanisms associated with cannabinoid mediated suppression of SARS-CoV-2
induced lung inflammation and fibrosis. ROS- Reactive oxygen species, IL- Interleukin;
IFN- Interferon; MIP- Macrophage inhibitory protein; MCP- Monocyte chemotactic protein;
ER-Endoplasmic reticulum.
The many uncertainties associated with the COVID-19 pandemic such as status of the
economy, employment and loss of connection can fuel depression, fear and anxiety.
CBD has shown promise as an alternative therapy for the clinical management of anxiety
disorders (Nichols and Kaplan, 2020). Based on its anxiolytic and anti-depressant
properties, it has been suggested CBD could be used to improve the mental and somatic
health of patients suffering from anxiety and emotional stress after recovering from
Ebola disease (Reznik et al., 2016). Like Ebola, patients recovering from COVID-19
may experience various psychological and social stressors that may be triggered by
residual chronic inflammation and autoimmune reactions. Therefore, randomized clinical
trials to test the efficacy of CBD on alleviating anxiety and fear associated with
COVID-19 infection and its consequences on people’s physical, social and psychological
well-being may be beneficial in the future. Additionally, severely ill COVID-19 patients
exhibited neurological symptoms like cerebrovascular disease, headache and disturbed
consciousness (Reviewed in (Wu et al., 2020)). Brain edema, neuronal degeneration
and presence of SARS-CoV2 in the cerebrospinal fluid (CSF) were confirmed at autopsy
(Wu et al., 2020). Therefore, longitudinal CSF sampling using non-human primate (NHP)
studies may help clarify whether and when SARS-CoV2 invades the brain, and if this
happens, does it result in neuroinflammation and more importantly, whether cannabinoids
can modulate these events (Kumar et al., 2019).
Being a negative allosteric modulator of the cannabinoid receptor-1, CBD can counter
the psychotropic effects of THC when co-administered with THC (Nichols and Kaplan,
2020). Although, Remdesivir reduced the mortality rate of seriously ill COVID-19 patients
needing invasive ventilation (Zhang et al., 2020), similar studies in rhesus macaques
revealed minimal subpleural inflammatory cellular infiltrates in the lungs of clinically
recovered Remdesivir treated RMs at necropsy (Williamson et al., 2020). This suggests
persistence of inflammation and may partly explain the 20-30% reduction in lung function
in COVID-19 patients after recovery, which if left unresolved may lead to pulmonary
fibrosis. Therefore, these findings support the investigation of cannabinoids as a
plausible option to be added as an adjunct to Remdesivir or any new antivirals on
SARS-CoV2 induced lung inflammation.
This work was supported by the National Institutes of Health Award Numbers R01DA042524,
R01DA050169 and R56DE026930 to MM, and OD011104 formerly RR00164. The content is solely
the responsibility of the authors and does not necessarily represent the official
views of the NIH.