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Commentary: Use of Cannabinoids to Treat Acute Respiratory Distress Syndrome and Cytokine Storm Associated With Coronavirus Disease-2019 CBD products abound, in all kinds of forms. Despite marketing claims, there’s no proof they’ll help lung disease. Learn the facts on CBD and where research stands. Researchers are recommending more research into how cannabis-derived CBD might help treat dangerous lung inflammation from the novel coronavirus. The authors detailed the evidence for how cannabis’ anti-inflammatory powers may help in this month’s issue of Brain, Behavior, and Immunity.

Commentary: Use of Cannabinoids to Treat Acute Respiratory Distress Syndrome and Cytokine Storm Associated With Coronavirus Disease-2019

We read with great interest the recent opinion by Nagarkatti et al. (2020), highlighting a potential role of cannabinoids in the treatment of acute respiratory distress syndrome (ARDS) associated with COVID-19. In particular, based on their previous studies evaluating the effect of THC in ARDS animal models, they focused the attention on the cannabinoid receptors targeting to control the hyperimmune response in severe COVID-19. Although cannabinoids and CBD in particular show an interesting potential, important issues concerning this therapeutics must be considered.

In recent months, the pressing need for effective treatments to counteract the spread of the COVID-19 pandemic dictated the development of new therapeutic approaches to handle or possibly prevent the complications of SARS-CoV-2 infections as a worldwide priority. Clinical profiles of COVID-19 patients range from asymptomatic infection to severe pneumonia with multisystem failure, the leading cause of mortality. In patients with severe disease, the occurrence of cytokine storm and a state of hyperinflammation led to acute respiratory distress syndrome (ARDS) (Lotfi and Rezaei, 2020). As Nagarkatti and colleagues (2020) highlighted, the potential use of cannabinoids in COVID-19 has been suggested for their immunomodulatory and anti-inflammatory properties, but not for the direct antiviral activity. Several authors focused the attention on the nonpsychoactive CBD as adjuvant in SARS-CoV-2 therapy. Recently, for the first time, it has been reported that CBD is able to reduce pro-inflammatory cytokine levels ameliorating symptoms of ARDS induced in a murine model (Khodadadi et al., 2020). Moreover, CBD seems to down-regulate the expression of ACE2 and TMPRSS2, two receptors exploited by SARS-CoV-2 to enter the cells (Wang et al., 2020). However, further studies to support CBD-mediated regulation of ACE2 and TMPRSS2 are needed.

Despite the encouraging potential of CBD, in our opinion, the first issue to consider is that, to date, there are no clinical data about the optimal anti-inflammatory dose and regimen of CBD in patients. Our knowledge about CBD use in patients comes mainly from few clinical studies evaluating the safety and efficacy of CBD as oral solution in the treatment of serious seizure disorders. The results from these studies highlighted that in comparison with other drugs employed for the treatment of seizure disorders, CBD has an overall safe profile, generally showing mild/moderate adverse effects (AEs). However, although with a low incidence, serious CBD AEs were registered (Brown and Winterstein, 2019; Huestis et al., 2019; Chesney et al., 2020; Dos Santos et al., 2020), some of which deserve particular caution in COVID-19 patients. The CBD-mediated impairment of immune response increases the risk of pneumonia or viral infection. Thus, particular attention must be paid for patients receiving immunosuppressive therapy, as some SARS-CoV-2 patients (Brown and Winterstein, 2019). Most importantly, it was observed that increased transaminases levels (ALT and AST) and hepatic injuries occur in CBD-treated patients who are chronically exposed to antiepileptic drugs, probably due to the multiple drug–drug interactions of CBD (Brown and Winterstein, 2019; Dos Santos et al., 2020).

CBD influences the principal enzymes (e.g., CYP450-3A4, -2C19, and UGTs) responsible for biotransformation of a wide range of drugs, thus potentially having impact on their pharmacokinetics and pharmacodynamics (Brown and Winterstein, 2019). The hypothetic drug–drug interactions of THC and CBD with the drugs currently used in therapeutic protocols for COVID-19, mainly antiviral and immunosuppressive drugs, have been analyzed (Land et al., 2020). However, the clinical profiles of frail patients infected by COVID-19 must be considered. Nowadays, the majority of patients included in CBD clinical trials are children or young adults. ARDS arises in severe COVID-19, and it is now clear that advanced age and several comorbidities including diabetes, hypertension, obesity and cardiovascular diseases are associated with disease severity, and predispose to a worse prognosis (Lotfi and Rezaei, 2020). This implies that with high probability, the COVID-19 patients with ARDS are under chronic therapies to treat their comorbidities. In this frame, we need to take into account the potential interaction of CBD with therapeutics like antiplatelet, antiarrhythmic, antihypertensive, or lipid-lowering drugs like statins, some of which are metabolized by CYP450 and/or UGTs (Brown and Winterstein, 2019), to avoid the worsening of liver and kidney injuries in COVID-19 patients (Lotfi and Rezaei, 2020).

Last but not least, it is reported that to exert their action, some cannabinoids require membrane lipid rafts integrity (Sarnataro et al., 2006), where cannabinoid receptors are localized. To produce its proapoptotic effect in murine primary microglial cells, CBD induces a lipid rafts coalescence, an event specifically reverted by the cholesterol-depleting agent methyl-β-cyclodextrin (Wu et al., 2012), suggesting the key role of lipid rafts in CBD signaling. Even if the anti-inflammatory action of CBD seems to be cannabinoid receptor independent and considering that ACE2 receptor reside into lipid rafts, further investigations are needed to evaluate the potential impact of CBD on SARS-CoV-2–host cell interaction.

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The current global emergency dictates the identification of therapeutics suitable to counteract the COVID-19 infection. CBD shows an interesting potential, but it is clear that further studies are required to corroborate this hypothesis, encompassing a clinical evaluation of risks and benefits of CBD use in SARS-CoV-2 patients.

Author Contributions

MP and DF designed the General Commentary and drafted the manuscript; CP contributed to the preparation of the manuscript; MB and PG critically revised the manuscript for intellectual content and provided the funding source.

Funding

This study was partially supported by Regione Campania—Italy (POR Campania FESR 2014-2020—ASSE I 2020, grant to MB and PG). CP was supported by a PhD Program in Drug Discovery and Development-Department of Pharmacy, the University of Salerno.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Brown, J., and Winterstein, A. (2019). Potential adverse drug events and drug-drug interactions with medical and consumer cannabidiol (CBD) use. Jcm 8 (7), 989. doi:10.3390/jcm8070989

Chesney, E., Oliver, D., Green, A., Sovi, S., Wilson, J., Englund, A., et al. (2020). Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacol. 45, 1799–1806. doi:10.1038/s41386-020-0667-2

Dos Santos, R. G., Guimarães, F. S., Crippa, J. A. S., Hallak, J. E. C., Rossi, G. N., Rocha, J. M., et al. (2020). Serious adverse effects of cannabidiol (CBD): a review of randomized controlled trials. Expert Opin. Drug Metab. Toxicol. 16 (6), 517–526. doi:10.1080/17425255.2020.1754793

Huestis, M. A., Solimini, R., Pichini, S., Pacifici, R., Carlier, J., and Busardò, F. P. (2019). Cannabidiol adverse effects and toxicity. Cn 17 (10), 974–989. doi:10.2174/1570159X17666190603171901

Khodadadi, H., Salles, É. L., Jarrahi, A., Chibane, F., Costigliola, V., Yu, J. C., et al. (2020). Cannabidiol modulates cytokine storm in acute respiratory distress syndrome induced by simulated viral infection using synthetic RNA. Cannabis cannabinoid Res. 5 (3), 197–201. doi:10.1089/can.2020.0043

Land, M. H., MacNair, L., Thomas, B. F., Peters, E. N., and Bonn-Miller, M. O. (2020). Letter to the editor: possible drug-drug interactions between cannabinoids and candidate COVID-19 drugs. Cannabis Cannabinoid Res. 5, 340. doi:10.1089/can.2020.0054

Lotfi, M., and Rezaei, N. (2020). SARS-CoV-2: a comprehensive review from pathogenicity of the virus to clinical consequences. J. Med. Virol. 92 (10), 1864–1874. doi:10.1002/jmv.26123

Nagarkatti, P., Miranda, K., and Nagarkatti, M. (2020). Use of cannabinoids to treat acute respiratory distress syndrome and cytokine storm associated with Coronavirus disease-2019. Front. Pharmacol. 11, 589438. doi:10.3389/fphar.2020.589438

Sarnataro, D., Pisanti, S., Santoro, A., Gazzerro, P., Malfitano, A. M., Laezza, C., et al. (2006). The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Mol. Pharmacol. 70 (4), 1298–1306. doi:10.1124/mol.106.025601

Wang, B., Kovalchuk, A., Li, D., Rodriguez-Juarez, R., Ilnytskyy, Y., Kovalchuk, I., et al. (2020). In search of preventative strategies: novel high-CBD cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues. Aging 12 (22), 22425–22444. doi:10.18632/aging.202225

Wu, H.-Y., Goble, K., Mecha, M., Wang, C.-C., Huang, C.-H., Guaza, C., et al. (2012). Cannabidiol-induced apoptosis in murine microglial cells through lipid raft. Glia 60 (7), 1182–1190. doi:10.1002/glia.22345

Keywords: cannabinoids, cannabidiol, SARS–CoV–2, COVID–19, pneumonia, ARDS

Citation: Bifulco M, Fiore D, Piscopo C, Gazzerro P and Proto MC (2021) Commentary: Use of Cannabinoids to Treat Acute Respiratory Distress Syndrome and Cytokine Storm Associated With Coronavirus Disease-2019. Front. Pharmacol. 12:631646. doi: 10.3389/fphar.2021.631646

Received: 20 November 2020; Accepted: 03 February 2021;
Published: 12 April 2021.

Stefania Tacconelli, University of Studies G. d’Annunzio Chieti and Pescara, Italy

Cristina Maccallini, University of Studies G. d’Annunzio Chieti and Pescara, Italy
Luciano De Petrocellis, Consiglio Nazionale delle Ricerche (CNR), Italy

Copyright © 2021 Bifulco, Fiore, Piscopo, Gazzerro and Proto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

CBD Oil and Lung Disease

You’ve likely noticed that CBD products crowd the alternative-remedy market these days. CBD, or cannabidiol, is a compound found in the cannabis plant that comes in all kinds of forms, from tablets to tea. Many of these products make claims of health benefits that can’t be shown to be true.

So, what, if anything, can CBD do for lung disease?

Claims Not Backed or Debunked by Science

David Mannino, MD, a pulmonologist in Lexington, KY, and the medical director and co-founder of the COPD Foundation, says the question is common. The answer is not that easy.

“These are questions we get a lot,” Mannino says. “There’s a whole cottage industry around CBD, not dissimilar from snake oil, purported to do everything with very little evidence.” Like dietary supplements, these products can pretty much claim anything. But studies haven’t shown results on humans that CBD can help lung disease.

But there’s nothing out there yet to say CBD doesn’t help, either, Mannino says.

CBD has, at most, a trace amount — no more than .03% — of THC, or tetrahydrocannabinol, the psychoactive substance in marijuana that triggers the “high” and other brain responses. Lots of products boast CBD as an active ingredient: over-the-counter pills and capsules; oils and tinctures (meaning it’s dissolved in alcohol instead of oil); foods and drinks; oil for vaping; and even topical types you put on your skin, nails, and even in your hair. Right now, it’s illegal to market CBD by adding it to a food or labeling it as a dietary supplement. Some online stores try anyway.

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At the same time, pure hemp seed oil, which comes from a different part of the hemp plant, and other hemp products don’t have CBD or THC. The FDA says they’re safe. But CBD/hemp oil combos exist and blur the lines even more.

Animal Testing Shows Some Positive Results

Because CBD comes from hemp, researchers might be able to study its possible benefits more widely. Few studies have been done to date. Of that small number, not enough of them researched humans to say if it can help lung disease or not.

Some positive results have come from animal studies. A 2015 study on guinea pigs showed CBD helped open up the bronchial passages. Some researchers believe it’s possible it could help people with COPD breathe easier and keep blood oxygen levels from falling, too. And a 2014 study on mice with damaged lungs showed CBD helped lower inflammation and improved lung function.

One of the few reports on CBD involving a person is a case report of an 81-year-old man with lung cancer whose tumor shrunk greatly when he regularly took CBD oil drops for a short time. Meanwhile, a 2020 pilot study using human cells and CBD oil to test possible COPD connections confirmed earlier studies that showed CBD might support your body’s anti-inflammatory and immune responses.

For now, the limited CBD research means there’s no info either about its long-term effects on the body or how it works with other drugs, and there is reason to be cautious with some medications, such as blood thinners.

Labels Don’t Tell the Whole Story

The hemp plant itself is legal from a federal standpoint. To date, though, the FDA has only approved one cannabidiol product, an oral prescription drug called Epidiolex to treat seizures caused by two rare, serious forms of epilepsy. Because CBD safety guidelines haven’t been decided for other uses, the FDA stresses taking the substance can be risky.

The strength levels of CBD in OTC products can change from product to product even throughout the same brand. Some don’t have any CBD in them at all. And sometimes they really do have THC, which brings its own risk and possible side effects as with marijuana, especially if the user doesn’t know they’ve taken it. These include anxiety, aggression, and paranoia.

CBD doesn’t usually cause a lot of side effects at first. But it’s possible you’ll have diarrhea, low appetite, sleepiness, and fatigue. So check with your doctor before adding CBD to your treatment.

Since CBD product quality is unknown and unregulated, it can be hard to tell what’s legit. A Penn Medicine study of 84 “CBD oil” products from 31 different online companies found nearly 70% were mislabeled. Some said they had more CBD than they advertised, while others had less. There also have been reports that cannabinoid products like CBD have been tainted with microbes, pesticides, or other foreign substances.

Still, it’s possible that one day CBD will be found to have science-proven benefits for people with lung disease.

“There are a lot of people who use CBD and swear by it, in the absence of evidence,” Mannino says. “However, if they believe it helps, then perhaps it can. There’s fully no data that’s clear that it doesn’t do anything.”

Show Sources

David Mannino, MD, director, Pulmonary Epidemiology Research Laboratory, University of Kentucky, Lexington; medical director, COPD Foundation.

Lung Health Institute: “Can CBD Cure My Lung Disease?”

National Center for Complementary and Integrative Health: “Cannabis (Marijuana) and Cannabinoids: What You Need To Know.”

FDA: “What You Need to Know (And What We’re Working to Find Out) About Products Containing Cannabis or Cannabis-derived Compounds, Including CBD,” “Hemp Ingredients /Dietary Supplements/ Conventional Food,” “FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy.”

Mayo Clinic: “Clinicians’ Guide to Cannabidiol and Hemp Oils,” “What Are the Benefits of CBD — and is it Safe To Use?”

The Journal of Pharmacology and Experimental Therapeutics: “The Effect of Phytocannabinoids on Airway Hyper-Responsiveness, Airway Inflammation, and Cough.”

Sage Open Medical Case Reports: “Striking lung cancer response to self-administration of cannabidiol: A case report and literature review.”

Journal of Cannabis Research: “Effects of cannabis oil extract on immune response gene expression in human small airway epithelial cells (HSAEpC): implications for chronic obstructive pulmonary disease (COPD).”

Journal of Clinical Medicine Research: “The Impact of Cannabidiol on Psychiatric and Medical Conditions.”

Penn Medicine: “Penn Study Shows Nearly 70 Percent of Cannabidiol Extracts Sold Online Are Mislabeled.”

Cannabis May Reduce Deadly COVID-19 Lung Inflammation: Researchers Explain Why

Researchers are studying cannabis’ potential as an adjunct treatment for COVID-19.

As COVID-19 cases continue to rise, researchers have started to look for solutions in an unlikely place – the cannabis plant. Cannabis’ active compounds have a number of properties that make it appealing as a potential adjunct treatment for infections from the novel coronavirus, and recently scientists have begun looking at its potential for reducing susceptibility to the disease, and even discussed whether it could be used as an antiviral medication.

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This month, researchers from the University of Nebraska and the Texas Biomedical Research Institute are recommending more research into how cannabis-derived CBD might help treat dangerous lung inflammation from the novel coronavirus. The authors detailed the evidence for how cannabis’ anti-inflammatory powers may help in a peer reviewed article in this month’s issue of Brain, Behavior, and Immunity.

In the article, researchers explain that “recent reports have suggested that acute infection is associated with a cytokine superstorm, which contributes to the symptoms of fever, cough, muscle pain.” These extreme instances of inflammation can lead to severe pneumonia which clog up the lungs, make breathing difficult or impossible. So, one of the important strategies that scientists are studying in the fight against COVID-19 is reducing inflammation.

In particular, researchers are looking at drugs which reduce IL-6 cytokine activity. In a recent study, one such drug, Tocilizumab, was able to clear out patients’ lungs, and resulted in recovery for 90% of the patients treated. Unfortunately, it also produced serious negative side effects like inflammation of the pancreas and hypertriglyceridemia (a risk factor for coronary artery disease). This has led researchers to continue the search for anti-inflammatory strategies – preferably ones that aren’t as harsh on these already critically ill patients.

Cannabis can be smoked in its raw form, or infused into tinctures like this one.

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That’s where cannabis comes in. The authors explain that several cannabinoids in the cannabis plant have anti-inflammatory properties. In particular, they point to CBD as the most likely candidate for treating COVID-19 related inflammation. CBD has shown serious anti-inflammatory properties in previous studies, it doesn’t create the disorienting psychotropic effects associated with cannabis’ most common chemical THC, and it has already been approved by the FDA as safe for children with intractable epilepsy. If successful at reducing inflammation for COVID-19 patients, it could be a safer alternative to other anti-inflammatory options.

Why do researchers believe CBD can help with COVID-19, specifically?

For one thing, the authors explain that previous research has shown that CBD can reduce a number of pro-inflammatory cytokines including IL-6, the one reduced by other drugs being studied for COVID-19. CBD was also shown to reduce interleukin (IL)-2, IL-1α and β, interferon gamma, inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α – all of which are associated with the pathology of severe cases of COVID-19. In addition to reducing these pro-inflammatory cytokines, CBD has also been shown to increase the production of interferons, a type of signaling protein that activates immune cells and prevents viruses from replicating.

Previous research also supports the idea that CBD can specifically reduce lung inflammation. In an animal study on asthma, CBD was able to reduce production of proinflammatory cytokine production, actually reducing airway inflammation. In the same study CBD also reduced pulmonary fibrosis – a condition where lung tissue becomes damaged and scarred, thickening lung tissue and making breathing more difficult. This is important, because COVID-19 can also leave patients with serious pulmonary fibrosis.

The authors also note that CBD isn’t the only cannabinoid that shows promise as an anti-inflammatory medicine. THC has also shown powerful anti-inflammatory results, but it’s less well tolerated than CBD, with common symptoms like disorientation, anxiety, and increased heart rate. Research on CBD, on the other hand, shows it to be safe and well-tolerated with dosing as high as 1500 mg a day, for a period of up to two weeks. The authors explain that this “suggests its feasibility to reduce SARS-CoV2 induced lung inflammation/ pathology and disease severity.”

NEW YORK, NEW YORK – MAY 05: A sign placed outside a CBD store in Murray Hill during the coronavirus . [+] pandemic on May 5, 2020 in New York City. (Photo by Noam Galai/Getty Images)

While negative side effects are minimal with CBD, the article’s authors point out that CBD may have a side benefit for patients with the disease – reduced anxiety. “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” they explain, pointing out that the increased inflammation in COVID-19 may also trigger increased levels of anxiety. But CBD has shown serious promise for the management of anxiety, and may help reduce these challenging levels of stress.

No peer reviewed studies to date show that cannabis or its compounds can help with COVID-19 specifically, but the authors of this article say the evidence suggesting that it may help is worth further investigation. They recommend that scientists begin studies to investigate whether CBD can be used to reduce inflammation and anxiety in COVID-19 cases, as an adjunct to antiviral medications.

While this doesn’t suggest cannabis should be considered a cure or treatment of COVID-19 on its own, it does suggest that it may have potential to help bring down inflammation and reduce anxiety in those suffering from the disease. But until more studies are done, this is just a well-supported theory. Direct experimentation is needed to bring us real answers.

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