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The potential of cannabidiol in the COVID‐19 pandemic: a hypothesis letter

Abstract

Identifying candidate drugs effective in the new coronavirus disease 2019 (Covid‐19) is crucial, pending a vaccine against SARS‐CoV2. We suggest the hypothesis that Cannabidiol (CBD), a non‐psychotropic phytocannabinoid, has the potential to limit the severity and progression of the disease for several reasons: 1) High‐CBD Cannabis Sativa extracts are able to downregulate the expression of the two key receptors for SARS‐CoV2 in several models of human epithelia 2) CBD exerts a wide range of immunomodulatory and anti‐inflammatory effects and it can mitigate the uncontrolled cytokine production featuring Acute Lung Injury 3) Being a PPARγ agonist, it can display a direct antiviral activity 4) PPARγ agonists are regulators of fibroblast/myofibroblast activation and can inhibit the development of pulmonary fibrosis, thus ameliorating lung function in recovered patients. We hope our hypothesis, corroborated by several preclinical evidence, will inspire further targeted studies to test CBD as a support drug against the COVID‐19 pandemic.
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doi: 10.1111/bph.15157
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Esposito Giuseppe (Orcid ID: 0000-0001-8080-8218)
The potential of cannabidiol in the COVID-19 pandemic: a hypothesis letter
Giuseppe Esposito1, Marcella Pesce2, Luisa Seguella1, Walter Sanseverino3, Jie Lu4, Chiara
Corpetti1, and Giovanni Sarnelli2*
1 Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of
Rome, Italy
2 Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples,
Italy
3 Sequentia Biotech SL, Carrer Comte D’Urgell 240 3D, Barcelona, Spain
4 Department of Human Anatomy, College of Basic Medical Sciences, China Medical
University, Shenyang City, Liaoning, China
ABSTRACT
Identifying candidate drugs effective in the new coronavirus disease 2019 (Covid-19) is
crucial, pending a vaccine against SARS-CoV2. We suggest the hypothesis that Cannabidiol
(CBD), a non-psychotropic phytocannabinoid, has the potential to limit the severity and
progression of the disease for several reasons: 1) High-CBD Cannabis Sativa extracts are able
to downregulate the expression of the two key receptors for SARS-CoV2 in several models of
human epithelia 2) CBD exerts a wide range of immunomodulatory and anti-inflammatory
effects and it can mitigate the uncontrolled cytokine production featuring Acute Lung Injury
3) Being a PPAR agonist, it can display a direct antiviral activity 4) PPAR agonists are
regulators of fibroblast/myofibroblast activation and can inhibit the development of
pulmonary fibrosis, thus ameliorating lung function in recovered patients. We hope our
hypothesis, corroborated by several preclinical evidence, will inspire further targeted studies
to test CBD as a support drug against the COVID-19 pandemic.
ABBREVIATIONS: Corona Virus Disease 2019 (COVID-19), Severe Acute Respiratory
Syndrome - Coronavirus 2 (SARS-CoV2), interleukin (IL), monocyte chemoattractant
protein (MCP)-1, cannabidiol (CBD), Angiotensin-converting enzyme 2 (ACE2),
Transmembrane Serine Protease 2 (TMPRSS2), peroxisome proliferator-activated receptor
gamma (PPAR), 5-hydroxytryptamine (5HT)-1A, transient receptor potential (TRP), Acute
Lung injury (ALI), Tumor Necrosis Factor (TNF), Macrophage Inflammatory Protein 2
(MIP-2), Food and Drug Administration (FDA), Human Immunodeficiency Virus (HIV),
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Respiratory syncytial virus (RSV), Hepatitis B virus (HBV), Hepatitis C Virus (HCV),
Cytochromes P450 (CYP450), half inhibitory concentration (IC50).
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 [Huang et al. 2020].
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
[Channappanavar et al. 2016]. 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 [Huang et al.
2020]. 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 [Wang et al 2020]. By downregulating
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ACE2 and TMPRSS2 receptors, the authors suggested high-CBD products, such as mouth
washes, as a preventative strategy in COVID-19 infection to limit SARS-CoV2 entry into
susceptible hosts. While this article puts forward the concept that cannabinoids-containing
products may serve as a preventative treatment for topical use, there is evidence suggesting
that CBD immunomodulatory activities may play a role in later stages of the disease.
We herein explore the hypothesis that systemic administration of CBD could have the
potential to limit COVID-19 disease progression and post-infectious sequelae.
Non-psychotropic phytocannabinoid CBD is 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 [Iffland and Grotenhermen, 2017]. 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 [Iffland and Grotenhermen, 2017]. CBD acts as a powerful
antioxidant acting at various receptor sites, including peroxisome proliferator-activated
receptor gamma (PPAR), 5-hydroxytryptamine (5HT)-1A, Adenosine A2, transient receptor
potential (TRP) channels receptors to directly or indirectly display a wide range of anti-
inflammatory 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 [Iffland and Grotenhermen, 2017].
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
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proinflammatory cytokines release, comparable to COVID19. By acting at adenosine A2
receptor site, CBD caused a marked amelioration of the pulmonary function [Ribeiro et al.
2015, Ribeiro et al. 2012] 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 (TNF and IL-6) and chemokines (MCP-1 and
MIP-2) released [Ribeiro et al. 2015, Ribeiro et al. 2012].
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) [O’Sullivan and Kendall, 2010]. 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 PPAR) have been identified and they have been described to regulate the expression of
genes related to lipid and glucose homeostasis and inflammatory responses.
PPAR agonism in resident alveolar macrophages significantly limits pulmonary
inflammation and promotes host recovery following respiratory viral infections [Huang et al.,
2019]. As it has been demonstrated during acute pneumonia, alveolar macrophage largely
express PPAR. PPAR 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 PPAR agonists led to reduction of morbidity
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and mortality during influenza A virus infection [Bassaganya-Riera et al. 2010]. Not
coincidentally, the opportunity of thiazolidinediones repurposing for the treatment of
COVID-19 patients has been recently suggested, based on their activity on PPAR receptors
[Carboni et al. 2020]. Nonetheless, full PPARγ agonists bear several unwanted side effects
that could limit their clinical applicability in COVID-19 infection. The use of
thiazolidinediones indeed suffered a back-box warning from the FDA given the risk of
cardiovascular complications, such as acute myocardial infarction, heart failure and stroke.
Conversely, being a weak PPARγ agonist, CBD may overcome these limitations and be
voided of these side effects [Graham et al. 2010].
Moreover, PPAR 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. Noteworthy, these experimental evidences are corroborated by recent
study showing a direct antiviral against HCV in vitro [Lowe et al. 2017].
Recent reports show that a subset of COVID-19 survivors can develop post-infectious
sequelae with persistently impaired lung function and pulmonary fibrosis [Ng et al. 2020].
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 [Milam et al. 2008]. Notably, CBD has been shown to reduce pulmonary
inflammation and fibrosis in animal models of asthma [Vuolo et al. 2018]. 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 [Millar et al. 2019] or are ongoing, especially in the field of neurological disorders
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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. According to a precautionary principle, a
possible strategy would be testing CBD therapeutic potential in COVID-19 patients (aged 18
years or older) either at an early stage of the disease to stop the cytokine storm and
development of respiratory distress, or alternatively, to evaluate its effectiveness in COVID-
19 recovered patients to prevent pulmonary fibrosis. CBD effects in vivo largely depend on
its doses and the bioavailability of its receptor targets in various pathological conditions.
Different plasmatic concentrations of CBD may be required in order to activate the distinct
pathways responsible for its multifaceted activity; indeed, subtherapeutic dosing (0.3
mg/kg/die) has been suggested to account for CBD lack of effectiveness in Crohn’s disease
[Millar et al. 2019]. In humans, CBD has been tested across a wide dosage range, varying
from <1 up to 50 mg pro kg/die depending on the trials and on the explored pathological
condition, with both in vitro and in vivo studies suggesting an immunosuppressive action at
higher concentrations or doses. Both in HIV and in post-Ebola syndrome, CBD has been
proposed as a therapeutic agent to control immune activation at the doses of 10-20 mg/kg/die
and 1.710 mg/kg/d (100 mg/die titrating up to 600 mg/die), respectively [Costiniuk et al,
2019; Reznik et al. 2016]. We suggest that CBD should be given orally starting at 100
mg/day titrating up to 300 mg/day (2.5 mg/kg/die), since this dosage did not produce relevant
adverse effects even for prolonged administrations (up to 18 weeks) in clinical trials in
humans. However, it is worth mentioning that most of the published clinical trials lack of the
effective plasmatic concentrations reached by orally-administered CBD in vivo. This has also
implications for its safety profile, since CBD acts as an in vitro inhibitor of several CYP450
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isoforms [Millar et al. 2019]. As previously underlined, drugdrug interaction studies
between CBD and anti-COVID-19 treatments are lacking; therefore, monitoring of patients
for potential drug interactions would be required. Similarly, CYP inhibitors are predicted to
increase CBD plasma concentrations and patients should be carefully monitored for adverse
effects. Nonetheless, we do not anticipate serious adverse side effects, since the proposed
dose of CBD is generally well tolerated in humans and the half inhibitory concentration
(IC50) required to inhibit the CYP450 is significantly higher to the plasmatic concentration
of CBD achieved following oral administration. Finally, regarding the possible concerns
about immunosuppression during acute infections, we believe it is important to underline that
CBD did not determine an increased mortality in acutely infected animals; rather, in
pneumococcal meningitis, animal survival was increased and TNFα concentrations decreased
at the doses of 2.5, 5 and 10 mg/kg [Barichello et al. 2012].
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.
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Figure 1. The potential of cannabidiol in SARS-CoV2 infection.
... More generally, given the hastiness with which drugs are required during sudden pandemics, it would be highly desirable to repurpose drugs already used for clinical treatments that do not require further toxicity studies. Endocannabinoid-related compounds are endogenous bioactive lipid amides with pleiotropic homeostatic properties, including immune response regulation, control of food intake, neuroprotection, and inhibition of pain and inflammation [39][40][41][42][43][44][45]. These well-known multifaceted properties, readily translatable to clinics, and the lack of unwanted side effects have already attracted the attention of the scientific community toward the repurposing of these compounds during the COVID-19 pandemic [43,[46][47][48]. ...
... Endocannabinoid-related compounds are endogenous bioactive lipid amides with pleiotropic homeostatic properties, including immune response regulation, control of food intake, neuroprotection, and inhibition of pain and inflammation [39][40][41][42][43][44][45]. These well-known multifaceted properties, readily translatable to clinics, and the lack of unwanted side effects have already attracted the attention of the scientific community toward the repurposing of these compounds during the COVID-19 pandemic [43,[46][47][48]. In particular, Oleoylethanolamide (OEA), cannabidiol, PEA, and other unsaturated fatty acids have been selected as drug candidates for potential novel strategies against COVID-19 [47,49,50]. ...
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This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT1 receptors (AT1Rs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB1 receptors (CB1Rs), modify the response to AT1R stimulation. CB1R blockade may enhance AT1R-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CB1Rs and AT1Rs induces opposite or the same effects. Second, CB1R blockade may diminish AT1R levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II—AT2 receptor system or angiotensin 1-7—Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of AT1R-CB1R heteromerization. As a therapeutic consequence, CB1R antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.
... Even with optimal viral suppression, YWH will have chronic inflammation across their life span with its associated comorbidities. If it can be demonstrated that marijuana attenuates pro-inflammatory cytokines in chronic infections such as HIV, or even COVID-19 [81], our results may have implications for management of other inflammatory conditions. ...
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Introduction Despite antiretroviral therapy (ART), people living with HIV have higher rates of non-infectious chronic diseases. These conditions are driven by relatively high levels of inflammation persisting on ART compared with uninfected individuals. Chronic inflammation also contributes to HIV persistence during ART. Cannabis when taken orally may represent a way to reduce inflammation and strengthen immune responses. Before planning large interventional studies, it is important to ensure that cannabis taken orally is safe and well tolerated in people living with HIV. We propose to conduct a pilot randomised trial to examine the safety and tolerability of cannabis oils containing tetrahydrocannabinol (THC) and cannabidiol (CBD) consumed orally in people living with HIV. We will also measure inflammatory markers, markers of HIV persistence in peripheral blood cells and changes in the gastrointestinal microbiome. Methods and analysis Twenty-six people living with HIV having undetectable viral load for at least 3 years will be randomised to receive TN-TC11LM (THC:CBD in 1:1 ratio) or TN-TC19LM (THC:CBD in 1:9 ratio) capsules daily for 12 weeks. Safety and tolerability of these capsules will be assessed through haematological, hepatic and renal blood tests, face-to-face interviews and questionnaires. Proportions of participants without any signs of significant toxicity (grades 0–2 scores on the WHO toxicity scale) and who complete the study, as well as scores on quality of life and mood will be examined using descriptive statistics. The effects on inflammatory markers, markers of peripheral blood reservoir size and effect on the composition of the gastrointestinal microbiome will be assessed before and after study completion. Ethics and dissemination This study has been approved by the Research Institute of the McGill University Health Centre. A Data Safety Monitor will review safety information at regular intervals. The final manuscript will be submitted to an open-access journal within 6 months of study completion. Trial registration number NCT03550352 .
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With the rapidly growing pandemic of COVID-19 caused by the new and challenging to treat zoonotic SARS-CoV2 coronavirus, there is an urgent need for new therapies and prevention strategies that can help curtail disease spread and reduce mortality. Inhibition of viral entry and thereby spread constitute plausible therapeutic avenues. Similar to other respiratory pathogens, SARS-CoV2 is transmitted through respiratory droplets, with potential for aerosol and contact spread. It uses receptor-mediated entry into the human host via angiotensin-converting enzyme II (ACE2) that is expressed in lung tissue, as well as oral and nasal mucosa, kidney, testes, and the gastrointestinal tract. Modulation of ACE2 levels in these gateway tissues may prove a plausible strategy for decreasing disease susceptibility. Cannabis sativa, especially one high in the anti-inflammatory cannabinoid cannabidiol (CBD), has been proposed to modulate gene expression and inflammation and harbour anti-cancer and anti-inflammatory properties. Working under the Health Canada research license, we have developed over 800 new Cannabis sativa lines and extracts and hypothesized that high-CBD C. sativa extracts may be used to modulate ACE2 expression in COVID-19 target tissues. Screening C. sativa extracts using artificial human 3D models of oral, airway, and intestinal tissues, we identified 13 high CBD C. sativa extracts that modulate ACE2 gene expression and ACE2 protein levels. Our initial data suggest that some C. sativa extract down-regulate serine protease TMPRSS2, another critical protein required for SARS-CoV2 entry into host cells. While our most effective extracts require further large-scale validation, our study is crucial for the future analysis of the effects of medical cannabis on COVID-19. The extracts of our most successful and novel high CBD C. sativa lines, pending further investigation, may become a useful and safe addition to the treatment of COVID-19 as an adjunct therapy. They can be used to develop easy-to-use preventative treatments in the form of mouthwash and throat gargle products for both clinical and at-home use. Such products ought to be tested for their potential to decrease viral entry via the oral mucosa. Given the current dire and rapidly evolving epidemiological situation, every possible therapeutic opportunity and avenue must be considered.
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Viral hepatitis B (HBV) and hepatitis C (HCV) pose a major health problem globally and if untreated, both viruses lead to severe liver damage resulting in liver cirrhosis and cancer. While HBV has a vaccine, HCV has none at the moment. The risk of drug resistance, combined with the high cost of current therapies, makes it a necessity for cost-effective therapeutics to be discovered and developed. The recent surge in interest in Medical Cannabis has led to interest in evaluating and validating the therapeutic potentials of Cannabis and its metabolites against various diseases including viruses. Preliminary screening of cannabidiol (CBD) revealed that CBD is active against HCV but not against HBV in vitro. CBD inhibited HCV replication by 86.4% at a single concentration of 10 μM with EC50 of 3.163 μM in a dose-response assay. These findings suggest that CBD could be further developed and used therapeutically against HCV. Summary: Cannabidiol exhibited in vitro activity against viral hepatitis C. Abbreviations Used: CB2: Cannabis receptor 2, CBD: Cannabidiol, DNA: Deoxyribonucleic acid, HBV: Hepatitis B virus, HCV: Hepatitis C virus, HIV/AIDS: Human immunodeficiency virus/acquired immune deficiency syndrome, HSC: Hepatic stellate cells, MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Htetrazolium, PCR: Polymerase chain reaction.