With the worldwide death toll from the coronavirus rising exponentially, The Lancet drew attention to “accumulating evidence” that indicates “patients with severe COVID-19 might have a cytokine storm syndrome.”
Characterized by intense immune overreaction in the lungs, this little understood syndrome can sicken and kill infected individuals. Respiratory distress is the leading cause of mortality in COVID-19 cases. The critically ill who survive intensive care may suffer long term lung damage, resulting in functional impairment and reduced quality of life.
Science Daily reports that a hyper-inflammatory cytokine storm, involving a surge of immune cells gone haywire, was likely the primary cause of death in several viral outbreaks, including the 1918-20 “Spanish flu” pandemic (which killed more than 50 million people) and, more recently, the H1N1 swine flu and the so-called bird flu.
In cases of acute, viral-induced pulmonary distress, cytokine-storm-targeted therapy would seem to make sense. But treatment with corticosteroids is not a great option because it can exacerbate COVID-19-associated lung injury. “However,” as The Lancet emphasizes, “in hyperinflammation, immunosuppression is likely to be beneficial.”
COULD CANNABIS CALM A CYTOKINE STORM?
Several laboratory studies indicate that cannabinoid compounds – in particular, cannabidiol (CBD) and tetrahydrocannabinol (THC) – are immunosuppressant. This would explain why medical cannabis is beneficial for people with autoimmune diseases and chronic inflammation.
Which begs the question: Could cannabis calm a cytokine storm?
The short answer is we don’t know. There’s a lot that we still don’t understand about cannabis and the immune system.
For many years, scientific inquiry in the United States has been handcuffed by cannabis prohibition, and the federal government continues to thwart research that could shed light on the therapeutic use of cannabis and whole plant CBD-rich oil extracts. The federal stranglehold on cannabis research is the main reason why we know so little about CBD’s clinical potential as an antiviral remedy.
Cannabis prohibition is exacerbating the current crisis in other ways, as well, as we discuss later in this article. For now, let’s turn our attention back to cytokines and cannabinoids.
CBD acts as a potent anti-inflammatory, reducing cytokine production and inhibiting immune cell function.
WHAT ARE CYTOKINES?
Secreted by immune cells, cytokines are a group of proteins that regulate inflammatory responses to disease and infection. There are both pro-inflammatory and anti-inflammatory cytokines.
Overproduction or excess secretion of pro-inflammatory messenger molecules can trigger a dangerous cytokine storm and other aberrant conditions. A cytokine known as tumor necrosis factor alpha (TNFa), for example, is produced in excess in rheumatoid arthritis, a painful, autoimmune disease that afflicts 1.3 million Americans.
The interaction between cytokines, immune cells, and the endogenous cannabinoid system plays an important role in neuroinflammation and neurodegeneration.
It’s well documented that stimulation of the CB2 cannabinoid receptor by THC and its endogenous counterparts can suppress inflammation. Cannabinoid receptor signaling confers therapeutic effects by downregulating inflammatory cytokine expression.
CBD FOR VIRAL INFECTIONS?
Could CBD be a viable candidate for reducing mortality in critically ill patients infected with COVID-19? A couple of dozen websites are already proclaiming that CBD has antiviral applications, as if this was an established medical fact.
Actually, thus far there is only “fragmentary evidence” that points to “possible use of CBD in viral infections,” according to a team of British and Italian scientists who recently addressed this issue in the online journal Cannabis and Cannabinoid Research. The authors referenced an in vitro study, which suggested that CBD had a direct antiviral effect against the Hepatitis C virus. But other than a single preclinical study involving Hep C, there is scant scientific evidence supporting the alleged antiviral properties of CBD.
The authors cited another study, which found that CBD reduced neuroinflammation in a virus-induced animal model of multiple sclerosis. But they acknowledge that this could have more to do with CBD’s efficacy as an anti-inflammatory compound rather than direct antiviral activity. Similarly, anecdotal accounts of using cannabidiol to treat viral infections, such as shingles and Herpes, “are plausible on the basis of the anti-inflammatory and analgesic properties of CBD,” the scientists acknowledged, without asserting an intrinsic antiviral effect.
CBD is currently undergoing clinical trials in Israel as a treatment for graft-versus-host disease (GVHD), a potentially fatal condition (with a mortality rate exceeding 80 percent) caused by systemic immune rejection of an organ or bone marrow transplant. Thus far, the results are encouraging. GHVD and COVID-19 fatalities both involve extreme immune overreactions, but there’s a crucial difference: GVHD is not triggered by a virus. And CBD has never been tested as a remedy for a viral-induced cytokine storm.
Many therapeutic applications of CBD and THC are related to their anti-inflammatory prowess. But that’s not the whole story. The interplay between cannabinoids and the immune system is complex, adaptive, and bidirectional.
In certain situations, cannabinoids can potentiate immune activity. A 2014 study by Louisiana State University scientists demonstrated that regular cannabis use can increase white blood cell counts in immune deficiency disorders such as HIV, suggesting a proinfammatory, immune-boosting effect. That’s the exact opposite of what’s needed to mitigate a viral-induced cytokine storm.
Given the conflicting data on the impact of cannabinioids on immune function, medical scientists are reevaluating their ideas about inflammation and immunosuppression. As Mary Biles reported for Project CBD: “A new wave of research and mounting anecdotal evidence points towards cannabinoids having an adaptive, immunomodulating effect, rather than just suppressing immune activity.”
The ability of cannabinoids to both suppress and enhance immune function lends credence to the notion that the endocannabinoid system is involved in bidirectional immunomodulation, keeping inflammation in check under healthy conditions but enabling an inflammatory response when needed to fight infection.
Dr. Garcia de Palau, a Spanish cannabis clinician, sums it up this way: “I believe [cannabis] is immunosuppressive when there is a hyper-immune response, but otherwise it regulates and corrects the immune system. In fact, you could say it functions like the endocannabinoid system, bringing equilibrium to the organism.”
A CALL FOR SOLIDARITY
What does this mean, practically speaking, for those who are using CBD or cannabis during the COVID-19 pandemic? Will consuming small amounts of CBD or cannabis as a preventive measure help to strengthen our immune resistance, or could it make us more susceptible to the corona virus? Only a relatively small percentage of people with COVID-19 experience a life-threatening cytokine storm, but if one is infected (without showing severe symptoms) could CBD increase the risk of serious disease progression? Would CBD have any impact at all?
The International Association for Cannabinoid Medicine (IACM), based in Germany, issued a statement on the COVID-19 pandemic and the use of cannabinoids, noting that some laboratory studies suggest that cannabinoids may have antiviral effects. “However,” according to the IACM, “there is no evidence that individual cannabinoids – such as CBD, CBG or THC – or cannabis preparations protect against infection … or could be used to treat COVID-19, the disease produced by this virus.”
But the IACM also emphasizes “there is no evidence that the use of cannabinoids could increase the risk of viral infection.”
Project CBD, a U.S. ambassador of the IACM, endorses the association’s call for “solidarity during this time, especially with those who are particularly at risk from such an infection.” Don’t share “false information that is circulating on the Internet,” the IACM implores. “Help contain the spread of the virus by following government and health authority guidelines.”
There have been reports of people stockpiling cannabis products obtained from licensed dispensaries and delivery services in U.S. states where cannabis is legal for therapeutic and/or adult use. Several state governments have followed California’s lead by declaring that cannabis businesses are essential services that can stay open, while the pandemic prompted lockdowns and closures in hard-hit areas.
But cannabis remains illegal under federal law, and cannabis prohibition is making a terrible situation even worse. The pandemic has magnified the damage wrought by U.S. drug policy, which continues to stymie scientific inquiry and impede medical advances by blocking therapeutic-oriented cannabis research. Consequently, we don’t have clear answers to key questions about cannabinoids and viral infections at a time of dire need.
COVID-19 & CANNABIS PROHIBITION
Cannabis prohibition is also introducing needless public health risks in other areas. Because of the plant’s criminal status at a federal level, banks are prohibited from opening accounts and issuing credit cards to cannabis businesses. Even legitimate, state-licensed companies are forced to operate on a cash-only basis, a practice that puts frontline dispensary staff, other industry workers, and state tax collectors at risk. Handling cash can be dangerous during the pandemic.
According to The New England Journal of Medicine, the corona virus “is stable for several hours to days in aerosols and on surfaces.” That includes paper money and coins, according to Dr. Sanjay Maggirwar, chair of the George Washington University School of Medicine’s department of microbiology, immunology and tropical medicine. “Certainly with the coronavirus, cash handling is a concern,” he told CBS MoneyWatch.
As with restrictions on research, this practice is entirely unnecessary and could easily be remedied with swift legislative action on the part of Congress.
DRUG WAR PRISONERS
U.S. prisons are poised to become hotbeds for COVID-19. Overcrowding, poor nutrition, toxic stress, and an aging prison population put incarcerated individuals at exceptionally high risk. Moreover, as the BBC notes: “Handcuffed people cannot cover their mouths when they cough or sneeze, sinks [in prisons and jails] often lack soap, and hand sanitizer is considered contraband due to its alcohol content.”
The war on drugs is a major cause of overcrowded U.S. prisons, which have been condemned by international human rights organizations. A 2016 report from the Brennan Center for Justice concluded that nearly 40 percent of imprisoned Americans are behind bars with no compelling public safety reason.
The Last Prisoner Project estimates that 40,000 nonviolent cannabis convicts are sequestered in state and federal penal institutions, and they’re doing time because of something that is no longer illegal in many states. The group is advocating for the swift release of all cannabis prisoners and any inmates who are over 65 or who have an underlying health condition.
“Prison health is public health by definition,” says The Lancet. “With an estimated 30 million people released from custody each year globally, prisons are a vector for community transmission that will disproportionately impact marginalized communities.”
Proponents of criminal justice reform maintain that reducing prison populations should be an immediate priority if we are to slow the spread of a highly infectious disease, which, unlike the prisoners themselves, can’t be contained within prison walls.
Martin A. Lee is the Director of Project CBD and author of Smoke Signals: A Social History of Marijuana—Medical, Recreational and Scientific. Tiffany Devitt is President of Care By Design, a Division of CannaCraft.
- Biles, Mary. Cannabis and the Immune System. Project CBD. May 18, 2019. https://www.projectcbd.org/science/cannabis-and-immune-system
- Das UN. Can Bioactive Lipids Augment Anti-cancer Action of Immunotherapy and Prevent Cytokine Storm? Arch Med Res. 2019 Aug;50(6):342-349. doi: 10.1016/j.arcmed.2019.10.004. Epub 2019 Oct 31. Review. PubMed PMID: 31677539.
- IACM: Statement of the Board on current corona virus pandemic and the use of cannabinoids, March 25, 2020. http://www.cannabis-med.org/english/bulletin/ww_en_db_cannabis_artikel.p…
- Jean-Gilles L, Gran B, Constantinescu CS. Interaction between cytokines, cannabinoids and the nervous system. Immunobiology. 2010 Aug;215(8):606-10. doi: 10.1016/j.imbio.2009.12.006. Epub 2010 Jan 4. Review. PubMed PMID: 20153076.
- Kaplan BL, Springs AE, Kaminski NE. The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT). Biochem Pharmacol. 2008 Sep 15;76(6):726-37. doi: 10.1016/j.bcp.2008.06.022. Epub 2008 Jul 8. PubMed PMID: 18656454; PubMed Central PMCID: PMC2748879.
- Kinner SA, Young JT, Snow K, Southalan L, Lopez-Acuña D, Ferreira-Borges C, O’Moore É. Prisons and custodial settings are part of a comprehensive response to COVID-19.Lancet Public Health. 2020 Mar 17;. doi: 10.1016/S2468-2667(20)30058-X. [Epub ahead of print] PubMed PMID: 32197116.
- Klein TW, Lane B, Newton CA, Friedman H. The cannabinoid system and cytokine network. Proc Soc Exp Biol Med. 2000 Oct;225(1):1-8. doi: 10.1046/j.1525-1373.2000.22501.x. Review. PubMed PMID: 10998193.
- Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, Friedman H. The cannabinoid system and immune modulation. J Leukoc Biol. 2003 Oct;74(4):486-96. doi: 10.1189/jlb.0303101. Epub 2003 Jul 1. Review. PubMed PMID: 12960289.
- Lee, Martin A. ICRS 2018: CBD Shines in Leiden. Project CBD. Aug 15, 2018. https://www.projectcbd.org/science/icrs-2018-cbd-shines-leiden-part-1
- Lowe HI, Toyang NJ, McLaughlin W. Potential of Cannabidiol for the Treatment of Viral Hepatitis. Pharmacognosy Res. 2017 Jan-Mar;9(1):116-118. doi: 10.4103/0974-8490.199780. PubMed PMID: 28250664; PubMed Central PMCID: PMC5330095.
- Mecha M, Feliú A, Iñigo PM, Mestre L, Carrillo-Salinas FJ, Guaza C. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis. 2013 Nov;59:141-50. doi: 10.1016/j.nbd.2013.06.016. Epub 2013 Jul 11. PubMed PMID: 23851307.
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 16;. doi: 10.1016/S0140-6736(20)30628-0. [Epub ahead of print] PubMed PMID: 32192578.
- Molina PE, Amedee AM, LeCapitaine NJ, Zabaleta J, Mohan M, Winsauer PJ, Vande Stouwe C, McGoey RR, Auten MW, LaMotte L, Chandra LC, Birke LL. Modulation of gut-specific mechanisms by chronic δ (9)-tetrahydrocannabinol administration in male rhesus macaques infected with simian immunodeficiency virus: a systems biology analysis. AIDS Res Hum Retroviruses. 2014 Jun;30(6):567-78. doi: 10.1089/aid.2013.0182. Epub 2014 Feb 7. PubMed PMID: 24400995.
- Reiss CS. Cannabinoids and Viral Infections. Pharmaceuticals (Basel). 2010 Jun 1;3(6):1873-1886. doi: 10.3390/ph3061873. PubMed PMID: 20634917; PubMed Central PMCID: PMC2903762.
- Scripps Research Institute. “Deadly immune ‘storm’ caused by emergent flu infections.” ScienceDaily, 27 February 2014. www.sciencedaily.com/releases/2014/02/140227142250.htm.
- Tagne, AM, Pacchetti B, Sodergren M, Cosentino M, and Marino F. Cannabidiol for Viral Disease: Hype or Hope? Cannabis and Cannabinoid Research. Jan 15, 2020 ahead of print. http://doi.org/10.1089/can.2019.0060
- Teijaro JR, Walsh KB, Rice S, Rosen HM. Oldstone BA. Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection. Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1400593111
- van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, Tamin A, Harcourt JL, Thornburg NJ, Gerber SI, Lloyd-Smith JO, de Wit E, Munster VJ. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020 Mar 17;. doi: 10.1056/NEJMc2004973. [Epub ahead of print] PubMed PMID: 32182409.
- Vuolo F, Petronilho F, Sonai B, Ritter C, Hallak JE, Zuardi AW, Crippa JA, Dal-Pizzol F. Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma. Mediators Inflamm. 2015;2015:538670. doi: 10.1155/2015/538670. Epub 2015 May 25. PubMed PMID: 26101464; PubMed Central PMCID: PMC4458548.