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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.
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.
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.
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.
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
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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.
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Treating pneumonia with medical marijuana is complicated. Not only can the effects of it vary depending on the type of pneumonia you have, but it is also known to cause pneumonia in people who are long-term marijuana smokers. Cannabis smoke does not appear to increase the risk of developing chronic obstructive pulmonary disease (COPD) or lung cancer . However, it is associated with symptoms of chronic bronchitis ( 8 ).
According to a 2015 expert panel review of the literature “It is unclear whether cannabis is associated with an increased risk of pneumonia. Some case series and studies in immunocompromised patients have noted a link, but no definitive studies have been done. Some effects of smoked cannabis could predispose to pneumonia ( 8 ).”
The use of Δ9-tetrahydrocannabinol (THC) suppresses macrophages, a type of immune cell, and their functionality in alveoli which are little air sacs that connect to the bronchioles and bronchi (where air enters the lungs) (8). Alveoli are important because it’s the portion of the lung where your blood cells exchange carbon dioxide for fresh oxygen. THC also causes the ciliated, or hair-like bronchial tissues to be replaced by hyperplastic mucus-secreting bronchial cells. This is related to increased phlegm and the cough smokers develop.
Cannabis begins its influence on the body through the activation of the endocannabinoid system (ECS), which is made up of fat-based neurotransmitters that the body self produces. Through the activation of cannabinoid receptors in the body, the cannabinoids found in cannabis, such as THC and cannabidiol (CBD) , can increase or decrease neurotransmitters in the body, allowing for immune modulation, pain reduction, and other physiological effects.
An evidence brief from the Michael G. DeGroote Centre for Medicinal Cannabis Research on the lungs and cannabis notes that THC activates the endocannabinoid anandamide (AEA), which binds to CB1 receptors in the lungs, causing the bronchial muscles, or upper lung to relax (17). This can help open up the airways into the lungs, but if THC is ingested and the airways are already relaxed, patients may experience bronchospasms which restrict the airways. It is thought that acute use helps relax the bronchial muscles, but long-term cannabis use actually constricts the lungs’ ability to take in air.
For more information on how the endocannabinoid system works, please see our page on endocannabinoids here .
Cannabis Use and Pneumonia
Using medical cannabis while you have pneumonia can have different effects depending on a variety of factors. If you are a long-term cigarette or cannabis smoker, despite the evidence above about how cannabis can help open airways, it most likely will cause you to have a harder time breathing while you have pneumonia.
Marijuana smoking or cigarette smoking can cause you to experience the following: increased coughing, increased mucus production, possible allergy to any contaminants, and increased risk for infection (23).
It is important to note that research supports that these issues can improve after smoking has stopped, so these changes are not necessarily permanent unless you are suffering from chronic lung disease or other cardiopulmonary complications (8 ). If you continue to suffer from the above symptoms after quitting and it has been several months, please reach out to your health care provider to determine why you are having continued shortness of breath or other breathing issues.
Vaping and edibles offer more efficient and less irritating methods of delivery while avoiding potentially hazardous free radicals and carbon monoxide from combustion. In general, inhalational methods are best avoided in patients with pneumonia or lung issues (8).
In general, medical marijuana has the following positive health effects:
- Temporarily increase bronchodilation (17)
- Reduce chronic pain
- Reduce inflammation
- Temporarily increases lung capacity
Treating Pneumonia with Medical Cannabis
Treating pneumonia with medical cannabis is not recommended by smoking or inhaling it because it can irritate the lungs, throat, and airways, and actually increase your risk for developing pneumonia over time (17). Smoking cannabis, like tobacco smoke, increases your risk of damage to your lungs over time. It can also increase your body’s risk of health problems and infections such as pneumonia through its ability to modulate your immune system.
Through modulating your immune system, cannabis helps decrease chronic pain and inflammation by slowing down immune cell responses in B/T lymphocytes and macrophages, as well as altering the presence of cytokines (17). This may be great for people who have chronic inflammatory conditions such as autoimmune diseases and arthritis to slow the body’s attack on healthy tissue, but it can increase your risk for infection.
Smoking and Pneumonia: Notes to Consider
It is important to note that cannabis can sometimes contain bacteria and fungus that may also increase your risk of infection when inhaling cannabis, particularly if you have another chronic condition that lowers your immune system’s ability to fight off infections or are taking immunity-modifying medications (17).
It is also unlikely, but possible, to be allergic to any contaminants like Aspergillus and Penicillium mold present on contaminated cannabis (17)(8). This is also noteworthy for persons with predisposing asthma or cystic fibrosis . All the more reason for everyone to double-check the lab quality of your cannabis before purchasing or consuming it.
Understanding the Different Types of Pneumonia
There are four main types of pneumonia; they are grouped by what is causing the infection. Healthcare providers may also further divide pneumonia into two groups: community-acquired vs healthcare-associated pneumonia, depending on the probable source of infection (2). This helps providers determine appropriate management and treatment per guidelines from the Center for Disease Control & Prevention (CDC) and other professional societies (4 ) . There are also many subtypes of each of the four main kinds that include new diagnoses like pneumonia caused by COVID-19 infection.
The four main types include:
Bacterial pneumonia can be caused by a variety of different types of bacteria. It usually happens when the body has been weakened by illness, poor nutrition, or an impaired immune system. It is typically caused by pneumococci bacteria that are also responsible for ear infections, sinus infections, sepsis , and meningitis ( 24). You may also have an increased risk of pneumonia if you abuse alcohol or smoke cigarettes or cannabis (18). Certain medical conditions, immune-reducing medications, and even surgery can also increase the risk of bacterial or other pneumonia.
Viral types of pneumonia are caused by viruses as opposed to bacteria. Influenza causes about one-third of viral pneumonia infections (18). If you suspect you have viral pneumonia, it is important to rest and take care of yourself because it can develop into bacterial pneumonia.
Breathing, pain, or any issues that worsen or fail to improve should be medically evaluated to rule out other potentially serious conditions. This is especially important in a COVID-19 world, and also emphasizes the need for vaccinations.
There are now safe and effective vaccinations for COVID-19 readily available in the US that prevent COVID pneumonia, hospitalization, and severe disease (9). Additionally, there are existing vaccines recommended by the CDC to prevent bacterial pneumonia in children under 2 and persons over 65 (5). Antibiotics are not recommended for viral pneumonia, only bacterial ones. Speak to your provider if you have any health concerns or questions about vaccines.
Also known as “walking pneumonia,” Mycoplasma pneumoniae bacteria can cause damage to the lining of the respiratory system and is considered contagious if you are in close contact with someone who has it (25). Outbreaks of walking pneumonia are common in crowded places like schools, dormitories, military barracks, nursing homes, and hospitals.
These types of pneumonia are harder to diagnose through standard bacterial identification methods. They also can cause slightly different symptoms, appear differently in chest x-rays, or respond to antibiotics differently than the more typical types of pneumonia (26). Some atypical types can be caused by the following bacteria:
- Chlamydia pneumoniae – This is a type of bacteria that causes respiratory infections in children, that usually leads to mild pneumonia or bronchitis (3). Some people may be infected by this bacteria and have mild or no symptoms. Sometimes it is also referred to as Chlamydophila pneumoniae.
- Chlamydia psittaci – Also known as psittacosis, this bacteria is known for infecting birds, but it can sometimes be passed to people (27). It is important to follow good precautions while cleaning and handling birdcages to help avoid this infection. It can cause a mild respiratory illness or pneumonia in people.
- Legionella pneumophila – Legionnaires’ disease is a very serious type of pneumonia to be infected with. It is caused by swallowing or inhaling small water droplets that contain legionella (28). Legionella occurs naturally in lakes and streams, but it becomes a health concern when it grows and spreads in building water systems, air conditioners, and hot tubs that are not properly maintained. According to the CDC, 1 out of 10 people with Legionnaire’s will die from it.
Research on Pneumonia and Cannabis Use
According to a report given at the 2020 CHEST Conference, COPD patients saw a 37.6% reduction in the odds of dying in the hospital in patients with cannabis use (29). In addition, the same COPD patients had an 11.8% lower risk of developing pneumonia.
Another recent study evaluated cannabis use with the risk of pneumonia in men with human immunodeficiency virus (HIV) that came with similar results as above. This study checked in with patients at regular six-month intervals over the course of 30 years. Self-reported cannabis smoking daily or weekly did not increase the risk for pneumonia in the control group that included participants without HIV (30). Patients with HIV saw a small increase in the risk of pneumonia, which researchers thought had to do with this group’s compromised immune system combined with the immune-suppressing effects of THC.
Note: Veriheal does not intend to give this as professional medical advice. Do not attempt to self-diagnose, or prescribe treatment based on the information provided on this page. Always consult a physician before making any decision on the treatment of a medical condition.