Skip to main content
Cannabis and Cannabinoid Research logoLink to Cannabis and Cannabinoid Research
. 2022 Oct 12;7(5):582–590. doi: 10.1089/can.2022.0018

Cannabinoids as Emergent Therapy Against COVID-19

Joseph McGrail 1, Lucía Martín-Banderas 1, Matilde Durán-Lobato 1,*
PMCID: PMC9587773  PMID: 35512732

Abstract

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS-Cov-2), was identified for the first time in late 2019 in China, resulting in a global pandemic of massive impact. Despite a fast development and implementation of vaccination strategies, and the scouting of several pharmacological treatments, alternative effective treatments are still needed. In this regard, cannabinoids represent a promising approach because they have been proven to exhibit several immunomodulatory, anti-inflammatory, and antiviral properties in COVID-19 disease models and related pathological conditions. This mini-review aims at providing a practical brief overview of the potential applications of cannabinoids so far identified for the treatment and prevention of COVID-19, finally considering key aspects related to their technological and clinical implementation.

Keywords: COVID-19, acute respiratory distress syndrome, cytokine storm, antiviral, cannabinoid

Introduction

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appeared in late 2019 in China, leading to a global pandemic of massive impact.1 Several treatments have been investigated, including interferon (IFN)-α and antiviral drugs such as remdesivir.2 Vaccines were designed to fight off the virus, including novel formulations such as mRNA-based vaccines that have been proven highly efficient and safe.3 Notwithstanding, owing to the scale of the pandemic and the evolving characteristics of the virus, alternative and effective treatments still need to be considered.

Cannabinoids have been explored as potential pharmaceutical treatments against a wide range of pathologies including inflammatory diseases and cardiovascular disorders.4,5 Their effects are mainly owing to the activation of CB1 and CB2.5 Of interest, specific CB2 activation was found to lead to a higher controlled release of proinflammatory cytokines, useful in conditions that cause airway inflammation and fibrosis, such as asthma,4,6 and subsequently COVID-19.7 More specifically, cannabinoids have been recently shown to alleviate the symptoms associated to severe cases of COVID-19 through several mechanisms8–10 and have been attributed to antiviral activity.9–11

This mini-review aims at providing a practical brief overview of the potential applications of cannabinoids so far identified for the treatment and prevention of COVID-19, finally considering key aspects related to their technological and clinical implementation.

Potential Applications of Cannabinoids in COVID-19

Recently identified pharmacological properties of cannabinoids with high interest in the context of COVID-19 are summarized and discussed in the following sections.

Downregulation of angiotensin-converting enzyme 2 and TMPRSS2 (prophylaxis)

The infection mechanism of SARS-CoV-2 involves the priming of spike (S) proteins by host cell proteases, which leads to the fusion of the viral and cellular membranes. Specifically, the process takes place upon interaction of the S protein with angiotensin-converting enzyme 2 (ACE2) receptors and transmembrane serine proteases (TMPRSS2).12

In this context, a potential application of cannabidiol (CBD) as prophylaxis has been considered. CBD has been reported to downregulate ACE2 and TMPRSS2.13 More specifically, CBD reduced ACE2 expression in an alveolar epithelial cells (A549),8 indicating a potential hampering effect on SARS-CoV-2 infection. Mouthwashes with high concentrations of CBD were proposed as prophylaxis.10

Peroxisome proliferator-activated receptors-γ activation

Peroxisome proliferator-activated receptors (PPARs) are a large family of nuclear receptors/transcription factors, which modify the transcription of target genes upon activation.14 Particularly, the activation of PPAR-γ leads to reduced pulmonary inflammation, subsequently related to a faster recovery in viral respiratory infections such as influenza.15 Thus, PPAR-γ activation could be considered a potential pharmacological target in severe cases of COVID-19.1

Moreover, a significant number of patients surviving COVID-19 present unresolved decreased lung capacity and pulmonary fibrosis.10 Pulmonary fibrosis is categorized as an alteration in fibroblast phenotypes causing a disproportionate accumulation of extracellular matrix. Of interest, in vitro experiments showed that the activation of PPAR-γ in lung fibroblasts led to an inhibition of a proliferative response.16

CBD has been attributed to PPAR-γ agonist activity, potentially useful for limiting excessive lung inflammation, decreasing in turn the mortality rate of COVID-19 and associated sequelae. In fact, CBD led to reduced lung inflammation and a lower rate of fibrosis in mice with induced allergic asthma.4

Furthermore, CBD has been described as a weak agonist.10 Thus, CBD could prevent secondary effects associated with full PPAR-γ agonist, such as higher risk of cardiovascular complications, including stroke and heart failure.17 Thus, CBD would represent an interesting approach against COVID-19 pulmonary inflammation and fibrosis with minimized side effects.

Prevention of the cytokine storm and acute respiratory distress syndrome

The cytokine storm is a disproportionate release of inflammatory cytokines as a response of the human body upon exposure to a biological or chemical agent,18 and constitute a key factor in the development of the acute respiratory distress syndrome (ARDS).9 ARDS arises from excessive activation of the immune system and may result in respiratory and multiorgan failure, leading to death. Of importance, COVID-19 disease stems from the development of ARDS.19 Several strategies involving the use of cannabinoids as a means of preventing and treating the cytokine storm, and therefore ARDS, have been identified.

Downregulation of the expression of inflammation-related genes

Cannabinoids have been attributed to the capacity to downregulate the expression of inflammation-related genes. The effect of several cannabis extracts on the expression of genes encoding interleukins and proinflammatory cytokines with a significant role in the development of ARDS and associated mortality of COVID-19 was evaluated in ultraviolet-exposed artificial skin.20 A correlation between Δ-9-tetrahydrocannabinol (Δ9-THC) concentration and the downregulated expression of several genes was found (Fig. 1).

FIG. 1.

FIG. 1.

Graphic displaying analysis of global gene expression profiling of artificial human 3D skin EpiDermFT™ exposed to UV and treated with different Cannabis sativa extracts (15 μL of 60 mg/mL extract solutions in DMSO). Extracts 4, 6, 8, 13, and 14 highly downregulated genes such as proinflammatory interleukins and cytokine, C-C motif chemokines, and C-X-C subfamily cytokines that play a role in ARDS. Extract 12 upregulated the genes and extract 15 did not modify gene expression. Reproduced from Kovalchuk et al.20 Extracts composition in % of cannabinoids: extract 4, 10.69% THC, 0.55% CBD, 0.10% CBGA, 0.05% CBN; extract 6, 3.28% THC, 7.44% CBD, 1.07% CBGA, 0.03% CBN; extract 8, 10.34% THC, 0.10% CBD, 0.15% CBGA, 0.02% CBN; extract 12, 13.74% THC, 0.57% CBD, 0.29% CBGA, 0.04% CBN; extract 13, 12.24% THC, 0.38% CBD, 0.12% CBGA, 0.04% CBN; extract 14, 14.09% THC, 0.35% CBD, 0.07% CBGA, 0.11% CBN; extract 15, 10.34% THC, 0.29% CBD, 0.07% CBGA, 0.11% CBN. ARDS, acute respiratory distress syndrome; CBD, cannabidiol; CBGA, cannabigerolic acid; CBN, cannabinol; DMSO, dimethyl sulfoxide; THC, tetrahydrocannabinol; UV, ultraviolet.

Although these effects should be confirmed in a SARS-CoV-2 inflammation tissue model, the similarities in the mechanisms of inflammation and fibrosis with the assayed tissue model20 support the potential usefulness of cannabinoids in this regard.

Increase of immunoregulatory cells regulatory T cells and myeloid-derived suppressor cells

The potential effects of cannabinoids against the cytokine storm are also related to regulatory T cells (Tregs) and myeloid-derived suppressor cells (MSDCs).19 Tregs regulate T cell anti-inflammatory properties.21 MSDCs are attributed to a role in suppressing and controlling the inflammatory response.22 The activity of both these types of cells has been associated to autoimmune disorders, and recent studies revealed a potential related pharmacological effect of cannabinoids.19

For instance, CBD led to far milder symptoms in mice induced with experimental autoimmune encephalomyelitis (EAE) compared with control subjects.22 This was attributed to an observed profound increase of MSDC in CBD-treated mice and, subsequently, a vast reduction in T cell proliferation. This hypothesis was further confirmed when MSDC depletion reversed the positive effects of CBD treatment.22

Moreover, several findings highlighted the capacity of cannabinoids to induce Tregs.19 Cell cultures from an organ graph rejection model treated with a CB2 selective agonist, O-1996, presented a far higher amount of Tregs and interleukin (IL)-10 than their control counterparts.21 Furthermore, IL-10 was associated with reduced proliferation of T cells and increase of Tregs. Cannabinoids were therefore stated as stimulators for the production of IL-10 and Tregs.21

Overall, the anti-inflammatory effects of cannabinoids related to Tregs and MSDC levels could be also exploited as treatment of COVID-19, pending clinical evaluation.

Decrease of infiltrating MNCs

Mononuclear cells (MNCs) play an important role in inflammation processes, including the cytokine storm associated with COVID-19. For instance, a lower number of MNCs and T cells in the lungs are expected to provide COVID-19 patients with a lower chance of suffering ARDS.19 Of interest, Δ9-THC was found to stimulate apoptosis in MNCs infiltrating the lungs of an inflammation mice model. The expression of a variety of genes related to apoptosis was increased.23 Of note, Δ9-THC also induced apoptosis of activated T cells.19

Increased expression of apelin

Apelin is an endogenous multifunctional ligand that interacts with a G-protein-coupled receptor known as apelin receptor. Subsequently, the apelinergic system is activated, which results in a suppression of several molecules involved in the immune system, including inflammatory cytokines,24 which has led to consider apelin a potential target in COVID-19.

Subsequently, CBD was tested in an ARDS mice model.24 Histological evaluation (Fig. 2) revealed that CBD avoided the inflammation, fibrosis, and pulmonary edema observed in nontreated animals, and led to a higher presence of apelin and reduced amount of IL-6. Of note, tissue appearance and apelin levels from treated animals were similar to non-ARDS-induced animals. Overall, these observations highlighted the potential usefulness of CBD in the onset of ARDS in COVID-19.24

FIG. 2.

FIG. 2.

Microscopy images from Masson's trichrome analysis of lung tissues displayed that post-intranasal administration of elevated dosage of poly (I:C) led to elevated devastation of the lung tissue, pulmonary edema, hypertrophy and fibrosis, whereas CBD treatment helped maintain the original state, represented in control image (images on the left). Immunofluorescence analysis revealed that CBD contributed to maintain normal apelin levels compared with poly (I:C)-treated tissue, and reduced the amount of IL-6, a proinflammatory cytokine (images on the right) (red: apelin; green: IL-6; DAPI: cell nuclei). Dosing; control group: intranasal, once daily administration of sterile saline for three consecutive days; poly (I:C) group: intranasal, once daily administration of poly (I:C) (100 μg in 50 μL in sterile saline) for three consecutive days to mimic ARDS; poly (I:C) + CBD group: intranasal, once daily administration of poly I:C (100 μg in 50 μL in sterile saline) for three consecutive days, with i.p. administration of CBD (5 mg/kg body weight), first dose 2 h after the second poly (I:C) treatment and every other day for a total of three doses. Reproduced from Salles et al.24 DAPI, 4′,6-diamidino-2-phenylindole; IL-6, interleukin-6.

Regulation of miRNA expression and histone modifications

Regarding epigenetics, cannabinoids also play a role in regulating the expression of miRNA and histone modifications in immune cells,19 representing another pathway for reducing the inflammation caused by the cytokine storm.

miRNAs are known as noncoding RNA, and regulate the immune response through their direct binding to specific sequences of specific mRNAs, leading to their disintegration.25 CBD treatment in mice with EAE downregulated an elevated number of miRNAs linked to inflammatory effects, and upregulated several miRNAs associated with anti-inflammatory properties,26 leading to reduced severity of EAE symptoms.

In addition, CBD influenced histone modification in CD4+ T from EAE-bearing mice, leading to reduced inflammation.26 Specifically, CBD led to reduced coverage of H3K27me3, inducing transcription activation in genes related to anti-inflammatory interleukins, IL-4, IL-5 and IL-13, and also led to increased coverage of H3K4me3, leading to transcription suppression in the same genes, overall leading to an increased expression of these anti-inflammatory cytokines.26

Microbiota protection

COVID-19 patients present significant alterations in gut microbiota, resulting in an excessive amount of potentially pathogenic bacteria and reduced symbionts, some of the latter associated with anti-inflammatory properties and downregulation of ACE2, gateway for SARS-CoV-2 cell internalization.27 Overall, this dysbiosis has been associated with a higher predisposition to SARS-Cov-2 infection and worse disease prognosis.

Cannabinoids displayed an interesting effect on microbiota. Δ9-THC and CBD were found to elevate the amount of short fatty chain acids (SFCAs) in the organism, which are metabolites manufactured by the gut microbiome with several roles in the immune system.28 For instance, SFCAs decreased the formation of proinflammatory Th17 and elevated the number of Treg cells in a murine model of multiple sclerosis as inflammatory disease.29 This effect could be of use in inflammatory diseases, especially when associated with altered microbiota, such as COVID-19.

Effects on COVID-19 models: blocking of SARS-Cov-2 replication and anti-inflammatory effects

Recent research9 analyzed the cannabinoid mechanism of interference in SARS-CoV-2 replication, with focus on SARS-CoV-2 Mpro. SARS-CoV-2 Mpro is a protease that cleaves translated RNA viral polyproteins, resulting in 12 nonstructural proteins with an important role in the replication process. Therefore, SARS-CoV-2 Mpro is considered the most convenient molecular target to block coronavirus replication.

In vitro analysis (Fig. 3) indicated a highly effective antiviral activity of CBD and Δ9-THC, with half maximal inhibitory concentration (IC50) values of 7.91 and 10.25 μM, respectively.9 Of note, in terms of IC50, CBD outperformed chloroquine, remdesivir, and lopinavir, drugs currently used in the treatment of COVID-19.30 Moreover, cannabidiolic acid and cannabigerolic acid were recently discovered to block infection of the original live SARS-CoV-2 virus and variants of concern, including the B.1.1.7 and B.1.351, on account of their affinity to the S protein.11

FIG. 3.

FIG. 3.

Graphics presenting the DCR analysis of three control drugs (chloroquine, remdesivir, and lopinavir) and five different cannabinoids: Δ9-THCA, Δ9-THC, CBN, CBDA, and CBD. Infection ratios and cell numbers were quantified by immunostaining of viral N protein and staining of cell nuclei, followed by confocal microscopy analysis and image mining with in-house software. Blue circles represent the inhibitory concentrations against SARS-CoV-2 infection. Red squares represent cell viability, allowing to measure potential toxicity. IC50 was used to compare the effectiveness of the SARS-CoV-2 inhibition. Δ9-THC and CBD stood out on account of their low IC50. Reproduced from Raj et al.9 Δ9-THC, Δ9-tetrahydrocannabinol; Δ9-THCA, Δ9-tetrahydrocannabinolic acid; CBDA, cannabidiolic acid; DCR, dose–response curve; IC50, half maximal inhibitory concentration; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Further recent studies shed light on the capacity of CBD to interfere in its replication. Specifically, CBD has been reported to enhance the innate immune ability of cells to respond to the presence of viral genes; HEK293 cells modified to express ORF8, OR10, or M protein from SARS-CoV-2 presented increased apoptosis and expression of interferon (IFN)-γ, IFN-λ1 and IFN-λ2/3, and 2′-5′-oligoadenylate synthetase proteins when treated with this cannabinoid.31 In addition, both CBD and its metabolite 7-OH-CBD have been reported to inhibit SARS-CoV-2 replication through activation of the IRE1α RNAse endoplasmic reticulum stress response and subsequent activation of RIG-I and IFNs, overall leading to reduced viral titers in lungs and nasal trubinates from mice infected with the virus.32

In addition, the anti-inflammatory effects of cannabinoids over immune response markers associated with COVID-19 were evaluated.8 A Cannabis sativa extract rich in CBD (FCBD) assayed in epithelial lung cancer cells A549 led to a decreased secretion of proinflammatory cytokines IL-6 and IL-8 (Fig. 4), which are the major cytokines involved in the COVID-19 cytokine storm. Furthermore, other proinflammatory cytokines, including CCL2 and CCL7, were decreased as well.8 Of interest, the same cytokines were decreased in the artificial human 3D skin model previously mentioned.20

FIG. 4.

FIG. 4.

(a, b) Graphic presenting the levels of IL-6 (a) and IL-8 (b) in the epithelial lung cancer cell line A549. Cells were treated with TNF-α (300 ng/mL) to increase interleukin concentration, and subsequently treated with different C. sativa extracts (5 μg/mL) to analyze their effect on IL levels. From left to right, bars represent: control: cells treated with solvent (vehicle) control (0.5% v/v methanol); TNF-α: cells treated with TNF-α + solvent control treatment (negative control); Dex: cells treated with TNF-α + dexamethasone (4 μg/mL) (positive control); Arbel-crude: cells treated with TNF-α + crude extract of C. sativa strain Arbel; ArbelFCBD: cells treated with TNF-α + CBD rich fraction of extract of C. sativa strain Arbel; ArbelFTHC: cells treated with TNF-α + THC rich fraction of extract of C. sativa strain Arbel. (c, d) Dose–effect curves representing the decrease of IL-6 and IL-8 levels when A549 cells were exposed to FCBD (concentration in μg/mL) (93.5% CBD +6.1% CBG +0.4% THCV). (e, f) Dose–effect curves representing decreased concentration of IL-6 and IL-8 when A549 cells were exposed to FCBD:std, FCBD:std being a combination of phytocannabinoids in the same ratios found in FCBD without other chemical compounds. Reproduced from Anil et al.8 FCBD, CBD-rich fraction; FCBD:std, standardized CBD fraction; THCV, Tetrahydrocannabivarin; TNF-α, tumor necrosis factor α.

Furthermore, recent research reported that the PPAR-γ agonist CBD activity over Caco-2 cells, a culture model of intestinal epithelium, considered an alternative site for SARS-Cov-2 infection and replication, prevented the epithelial damage and hyper-inflammation induced by its S protein through suppression of a TLR4/NLRP3/Caspase-1 signaling pathway.33 Specifically, CBD treatment of Caco-2 cells challenged with the S protein led to reduced proinflammatory markers, inhibition of proinflammatory cytokines, and restoration of permeability (increased expression of tight junction proteins and restoration of transepithelial electrical resistance), overall yielding a powerful inhibition of S protein enterotoxicity in vitro.

Finally, CBD has also been proposed as treatment adjuvant in concomitant administration with remdesivir. The cannabinoid displayed capacity to inhibit the metabolism of this antiviral drug in human liver microsomes, increasing its half-life by fourfold, and outperforming a standard inhibitor by twofold. A combined treatment is expected to achieve higher remdesivir concentrations in the lungs by reducing its premature systemic metabolism.34

Conclusions and Future Prospects

Several potential applications of cannabinoids have been recently identified for COVID-19 treatment and prophylaxis, based on their immunomodulatory and anti-inflammatory properties and capacity to reduce viral replication.

Nonetheless, several concerns arise regarding the actual value of the studies reported as well as their clinical translation. To be noted, several of the identified mechanisms of action would need further characterization and also specific evaluation in COVID-19 models. In addition, an in vivo proof-of-concept is still lacking for most of the proposed applications.

Finally, the translation of in vivo results in small animal models to humans is conditioned by the dose of cannabinoid needed to reach the therapeutic target, subsequently determining the dose of cannabinoid to be administered, as well as interspecies differences. For instance, the active doses used in the studies referenced in this work ranged from 5 to 20 mg/kg body weight in mice, which would correspond to 0.4–1.62 mg/kg body weight in humans, according to Food and Drug Administration (FDA) criteria for conversion into human equivalent dose.

However, active doses of cannabinoids assayed in recent clinical trials also range from 5 to 20 mg/kg in humans. In this context, the unfavorable physicochemical and biopharmaceutical properties of cannabinoids must be considered. On the one hand, the poor stability and solubility of cannabinoids typically lead to inadequate bioavailability values. On the other hand, cannabinoids unspecific biodistribution, along with their capacity to interact with several receptors, the latter being widely distributed in the organism, frequently result in side effects, even including psychotropic effects.

Ultimately, only a limited fraction of the dose used is estimated to reach the therapeutic target, with a significant risk of adverse effects. Of note, the recent clinical trial on CBD for COVID-19 patients (NCT04467918) previously referenced used an oral 300 mg/day dose of CBD (5 mg/kg), resulting in no alteration of the clinical evolution of COVID-19 along with the observation of mild and transient side effects, and leading to consider the need of higher doses.

Overall, the issues related to cannabinoids unfavorable properties remain a common challenge regardless of the disease of interest. Because increasing the administered dose may not be the most convenient alternative, given the potential associated costs and increased side effects, technological tools have been increasingly considered for a wide range of applications. Initially, a local modality of administration is expected to help minimize the extent of drug reaching off-side targets. Furthermore, advanced technological tools, including microspheres and nanocarriers, with the capacity to optimize cannabinoid delivery to the desired location, are enabling advances reaching clinical evaluation and the therapeutic market.

In the specific case of COVID-19, pulmonary administration would be an especially convenient alternative to be considered for cannabinoid-based therapies. In addition, the success reported by cannabinoid-based drug delivery systems for several syndromes offer a promising alternative to boost the clinical development in this arena.

Overall, cannabinoids offer a great pharmacological potential in the management of COVID-19, but their successful implementation as actual treatment will rely on further pharmacological evaluation along with the implementation of drug delivery tools. It is to be hoped that the scientific evidence so far reported on cannabinoids effects along with the possibilities offered by drug delivery systems will entice the development of valuable therapies in this area.

Abbreviations Used

Δ9-THC

Δ9-tetrahydrocannabinol

Δ9-THCA

Δ9-tetrahydrocannabinolic acid

ACE2

angiotensin-converting enzyme 2

ARDS

acute respiratory distress syndrome

CBD

cannabidiol

CBDA

cannabidiolic acid

CBGA

cannabigerolic acid

CBN

cannabinol

COVID-19

coronavirus disease 2019

DAPI

4′,6-diamidino-2-phenylindole

DCR

dose–response curve

DMSO

dimethyl sulfoxide

EAE

experimental autoimmune encephalomyelitis

ER

endoplasmic reticulum

FCBD

CBD rich fraction

FCBD:std

standardized CBD fraction

IC50

half maximal inhibitory concentration

IL-6

interleukin-6

IFN

interferon

MS

multiple sclerosis

MSDC

myeloid-derived suppressor cells

PPAR

peroxisome proliferator-activated receptors

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

SFCAs

short fatty chain acids

TEER

transepithelial electrical resistance

THC

tetrahydrocannabinol

THCV

tetrahydrocannabivarin

TMPRSS2

transmembrane serine proteases

TNF-α

tumor necrosis factor α

Tregs

regulatory T cells

UV

ultraviolet

Author Disclosure Statement

No competing financial interests exist.

Funding Information

M.D.-L. acknowledges a postdoctoral contract granted by “VI Plan Propio” from the University of Seville (USE-19533-Y).

Cite this article as: McGrail J, Martín-Banderas L, Durán-Lobato M (2022) Cannabinoids as emergent therapy against COVID-19, Cannabis and Cannabinoid Research 7:5, 582–590, DOI: 10.1089/can.2022.0018.

References

  • 1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:10223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Shereen MA, Khan S, Kazmi A, et al. COVID-19 infection: origin, transmission, and characteristics of human coronaviruses. J Adv Res. 2020;24:91–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384:403–416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Vuolo F, Abreu SC, Michels M, et al. Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma. Eur J Pharmacol. 2019;843:251–259. [DOI] [PubMed] [Google Scholar]
  • 5. Berman P, Futoran K, Lewitus GM, et al. A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in Cannabis. Sci Rep. 2018;8:14280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Galiègue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232:54–61. [DOI] [PubMed] [Google Scholar]
  • 7. Crippa JAS, Pacheco JC, Zuardi AW, et al. Cannabidiol for COVID-19 patients with mild to moderate symptoms (CANDIDATE study): a randomized, double-blind, placebo-controlled clinical trial. Cannabis Cannabinoid Res. 2021. [Online ahead of print], DOI: 10.1089/can.2021.0093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Anil SM, Shalev N, Vinayaka AC, et al. Cannabis compounds exhibit anti-inflammatory activity in vitro in COVID-19-related inflammation in lung epithelial cells and pro-inflammatory activity in macrophages. Sci Rep. 2021;11:1462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Raj V, Park JG, Cho KH, et al. Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches. Int J Biol Macromol. 2021;168:474–485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Esposito G, Pesce M, Seguella L, et al. The potential of cannabidiol in the COVID-19 pandemic. Br J Pharmacol. 2020;177:4967–4970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. van Breemen RB, Muchiri RN, Bates TA, et al. Cannabinoids block cellular entry of SARS-CoV-2 and the emerging variants. J Nat Prod. 2022;85:176–184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Wang B, Kovalchuk A, Li D, et al. In search of preventive strategies: novel high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues. Aging (Albany NY). 2020;12:22425–22444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. O'Sullivan SE, Kendall DA. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology. 2010;215:611–616. [DOI] [PubMed] [Google Scholar]
  • 15. Huang S, Goplen NP, Zhu B, et al. Macrophage PPAR-γ suppresses long-term lung fibrotic sequelae following acute influenza infection. PLoS One. 2019;14:e0223430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Milam JE, Keshamouni VG, Phan SH, et al. PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008;294:L891–L901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Graham DJ, Ouellet-Hellstrom R, Macurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA. 2010;304:411–418. [DOI] [PubMed] [Google Scholar]
  • 18. Dzobo K, Chiririwa H, Dandara C, et al. Coronavirus disease-2019 treatment strategies targeting interleukin-6 signaling and herbal medicine. Omi A J Integr Biol. 2021;25:13–22. [DOI] [PubMed] [Google Scholar]
  • 19. Nagarkatti P, Miranda K, Nagarkatti M. Use of cannabinoids to treat acute respiratory distress syndrome and cytokine storm associated with coronavirus disease-2019. Front Pharmacol. 2020;11:589438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Kovalchuk A, Wang B, Li D, et al. Fighting the storm: could novel anti-Tnfα and anti-Il-6 C. Sativa cultivars tame cytokine storm in COVID-19? Aging (Albany NY). 2021;13:1571–1590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Robinson RH, Meissler JJ, Fan X, et al. A CB2-selective cannabinoid suppresses T-cell activities and increases Tregs and IL-10. J Neuroimmune Pharmacol. 2015;10:318–332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Elliott DM, Singh N, Nagarkatti M, et al. Cannabidiol attenuates experimental autoimmune encephalomyelitis model of multiple sclerosis through induction of myeloid-derived suppressor cells. Front Immunol. 2018;9:1782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Mohammed A, Alghetaa HFK, Miranda K, et al. Δ9-tetrahydrocannabinol prevents mortality from acute respiratory distress syndrome through the induction of apoptosis in immune cells, leading to cytokine storm suppression. Int J Mol Sci. 2020;21:1–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Salles ÉL, Khodadadi H, Jarrahi A, et al. Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome. J Cell Mol Med. 2020;24:12869–12872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Mohammed A, Alghetaa H, Sultan M, et al. Administration of Δ9-tetrahydrocannabinol (THC) post-staphylococcal enterotoxin B exposure protects mice from acute respiratory distress syndrome and toxicity. Front Pharmacol. 2020;11:893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Yang X, Bam M, Nagarkatti PS, et al. Cannabidiol regulates gene expression in encephalitogenic T cells using histone methylation and noncoding RNA during experimental autoimmune encephalomyelitis. Sci Rep. 2019;9:15780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Zuo T, Zhang F, Lui GCY, et al. Alterations in Gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology. 2020;159:944..e–955.e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Venegas DP, De La Fuente MK, Landskron G, et al. Short chain fatty acids (SCFAs)mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019;10:277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Al-Ghezi ZZ, Busbee PB, Alghetaa H, et al. Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome. Brain Behav Immun. 2019;82:25–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Jeon S, Ko M, Lee J, et al. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrob Agents Chemother. 2020;64:e00819–e00820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Fernandes MF, Chan JZ, Hung CCJ, et al. Effect of cannabidiol on apoptosis and cellular interferon and interferon-stimulated gene responses to the SARS-CoV-2 genes ORF8, ORF10 and M protein. BioRxiv. 2022;2:2022..01.11.475901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Chi Nguyen L, Yang D, Nicolaescu V, et al. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Sci Adv. 2022;8:6110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Corpetti C, Del Re A, Seguella L, et al. Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1 signaling suppression in Caco-2 cell line. Phyther Res. 2021;35:6893–6903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Saraswat A, Vartak R, Patki M, et al. Cannabidiol inhibits in vitro human liver microsomal metabolism of remdesivir: a promising adjuvant for COVID-19 treatment. Cannabis Cannabinoid Res. 2021:1–11 [Online ahead of print], DOI: 10.1089/can.2021.0109. [DOI] [PubMed] [Google Scholar]

Articles from Cannabis and Cannabinoid Research are provided here courtesy of Mary Ann Liebert, Inc.

RESOURCES