Harnessing the Power of Plants: SARS-CoV 2 (COVID-19)

Amanda McKinney, MD; Andrea Holmes, PhD

SARS CoV-2 (COVID-19) is a global health concern with worldwide mortality increasing daily. There is a race by researchers and medical practitioners to find new therapeutic agents but success has so far been elusive. Given the extended timeline to a vaccine or new therapeutics, it’s time to re-acquaint ourselves with the plants that have been used as medicine for centuries

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Traditional herbal medicines consisting of plant-derived substances with minimal or no industrial processing are getting significant attention in global health debates. During the SARS outbreaks in China in 2008, traditional herbal medicine played a prominent role in the strategy to contain and treat the disease. (Hsu CH, et al. 2008) We should be doing the same now.

Those of us who practice Lifestyle Medicine are well acquainted with the power of whole-food, plant-predominant diets to prevent and, oftentimes, reverse chronic disease. However, the treatment of acute and infectious diseases has remained solidly within the sphere of conventional Western medicine and its reductionist approach...a lengthy process including isolation of one molecule (oftentimes from a plant source) synthesizing the molecule in a lab, testing of the molecule in vitro followed by in vivo testing, ultimately leading to a drug that can be used to fight an infection or reduce inflammation, etc.

While the application of reductionism in modern biomedical research and practice has resulted in some utterly amazing feats, reductionism alone is not only inadequate but has created some collateral damage. Reducing complex biological or medical phenomena into their individual components, improves the chances of identifying a single cause in order to devise a cure. However, this eliminates the value of the complexities of whole plants and the entourage effect. “The entourage effect refers to the synergistic effects of the multiple compounds present in whole organisms, which may potentiate clinical efficacy while attenuating side effects. In opposition to this view, mainstream pharmacology is adamant about the need to use purified substances, presumably more specific and safe.” (Williamson,2001)

This reductionist approach is also inappropriate for rapidly mutating organisms and oftentimes results in resistance of these germs to the drugs meant to fight them. The classic example is resistance to penicillin of bacteria such as MRSA (Methicillin-Resistant Staph Aureus) which became clinically relevant after penicillin became widely distributed. Bacteria have a remarkable ability to respond to a wide array of environmental threats, including the presence of antibiotics that represent an existential threat. (Munita and Arias, 2016)

The same is true for certain viruses. Single-stranded RNA viruses, like influenza and the novel coronavirus causing COVID-19, mutate much faster than other types of viruses. (Sanjuán and Domingo-Calap, 2016) This faster mutation rate makes it nearly impossible to create a highly effective vaccine. Influenza vaccines are an excellent example. According to the CDC, “...flu vaccination reduces the risk of flu illness by between 40% and 60% among the overall population during seasons when most circulating flu viruses are well-matched to the flu vaccine.” (CDC, 2020)

Likewise, the rapidity of mutation results in resistance to antiviral drugs which is now endemic. It’s now known that a majority of the Influenza A Virus (IAV) subtypes circulating globally are resistant to one class of drugs (adamantanes), making these drugs essentially obsolete. (Hussain, et al. 2017)

Another class of drugs, the neuraminidase inhibitors (NAI’s) are suffering the same fate. In the 2008-2009 flu season, 90% of globally circulating IAV H1N1 subtypes were resistant to the NAI, oseltamivir, with the exception of the H1N1 strain that caused the 2009 “swine flu” pandemic. (Hussain, et al. 2017) However, by the 2018-2019 flu season, a 23% resistance rate to oseltamivir had emerged in those infected with a mutated form of swine flu. These patients were also more likely to die from the infection. (Behillil, et al. 2019) Given some of its structural similarities, it is reasonable to believe that this novel coronavirus, will share similar characteristics.

The triad of vaccines, antiviral drugs, and surveillance is the mainstay for dealing with viral infections and the current global pandemic is no exception. However, the argument has been made that the current approach to antiviral medications is insufficient. An alternative, and potentially more effective, approach to medical treatments that can shorten the course and lessen the severity of viral infections is phytomedicine (phyto=plant), inclusive of traditional herbal and indigenous medicine.

Phytomedicine utilizes whole plant extracts in combination. Whole plant extracts work differently in the body and there are often synergies between different whole plant extracts that make them more effective at lower doses. It’s much like the analogy of eating an apple. Everyone knows apples are good for you but many will debate why apples are good for you. Some will say it is because apples have vitamin C while others will say it’s because they have fiber. Rather, the answer is, apples are good for you because they have vitamin C and fiber and a whole host of other phytochemicals that work together in concert to support health. It’s also been well documented that taking a fiber or vitamin C supplement does not provide the same benefits as eating an apple. The supporting evidence of the synergies in phytomedicine is also accumulating in the medical and scientific literature. (Yang, et al. 2014) Using whole plant extracts, in combination, helps address antimicrobial resistance as plants have different compounds that impact distinct pathways of microbial binding and replication, ‘attacking’ the microbe in a mulit-faceted way. This creates therapeutic options in the face of novel microbial infections as well as known and endemic antimicrobial resistant infections. (Gupta and Birdi, 2017)

Which Plants and Why?

After much research, Dr. Holmes and I came up with two herbal tinctures that we believe have the potential to shorten the course and severity of viral infections, specifically COVID-19. Critics will ask where the randomized, placebo controlled trials are that make us think this is even a possibility. We have two. In a randomized study of elderberry for influenza A and B treatment, 60 patients (aged 18-54 years) suffering from influenza-like symptoms for 48 hours or less received 15 ml of elderberry or placebo syrup four times a day for 5 days. Symptoms were relieved on average 4 days earlier and use of rescue medication was significantly less in those receiving elderberry extract compared with placebo. (Zakay-Rones, et al. 2004) The second is a randomized, placebo controlled study from 2008 which found that those infected with SARS who received Natural Herbal Medicine recovered, as indicated by chest x-ray, from their infection 4.5 days faster on average than those who received a placebo. (Hsu CH, et al. 2008)

Specifics about each herb and why it was chosen follows. This work is based on a study of the scientific and medical literature and inspired by the herbalist Stephan Harrod Buhner, author of “Herbal Antivirals”.

Tincture #1: Antiviral

Scutellaria baicalensis (Chinese skullcap)-

Scutellaria baicalensis is a traditional Chinese medicinal herb that has been used for centuries. It is well documented as having antiviral activity against a multitude of viruses and low toxicity. (Chen, et al. 2011) (Wang, et al. 2018) (Błach-Olszewska, 2008) (Chu, et al. 2007) (Gao and Chen, 2008) (Nayak, et al. 2014)(Li, et al. 2015)

Isatis indigotica (Woad Root)

Woad root has been used for the prevention of influenza for hundreds of years in many Asian countries. (Su, et al. 2016) It has also been shown to have anti-SARS activity with an excellent safety profile. (Lin, et al. 2005) (AHPA, 2013)

Glycyrrhiza glabra (Licorice)

Ancient Chinese, Indian and Grecian manuscripts all report the use of Glycyrrhiza species for use in viral respiratory tract infections and hepatitis. Studies also reveal antiviral activity against several viruses including SARS-related coronavirus. (Fiore, et al. 2008) Glycyrrhiza glabra (licorice) constituents work similarly to NAIs, inhibiting viral replication. (Grienke, et al. 2014) Licorice is typically safe but should be used with caution and supervision for those with certain chronic health conditions and in those who are pregnant. (AHPA, 2013) Short term use is typically very safe. Houttuynia cordata -

Houttuynia cordata (HC) is conventionally used to treat pneumonia in the Traditional Chinese Medicine (TCM) tradition and has direct inhibitory activity against herpes simplex virus type 1 (HSV-1), influenza virus, and human immunodeficiency virus type 1 (HIV-1). (Salehi B, etl al 2018) During the SARS-CoV epidemic in late 2002 to mid 2003, Chinese scientists shortlisted HC to help address the SARS problem. Like woad root, HC reduces replication of SARS-CoV, the coronavirus that caused the 2003 outbreak in China. No toxicity has been noted with its use even at high levels. (Lau, et al. 2008) It should be avoided in pregnancy due to its ability to induce menstrual periods but in cases of life-threatening infection, its use is warranted. (Buhner, 2013)

Ceanothus americanus (Red Root)-

Betulinic acid, the primary constituent extract of red root, is another broad spectrum antiviral (Aiken and HoChen, 2005) (Visalli, et al 2015) (Pavlova, et al. 2015) with no side or adverse effects noted in the scientific or traditional literature. (AHPA, 2013)

Lingusticum porteri (Osha)

Osha is primarily added for taste however it does have significant anti-inflammatory properties. (Nguyen, et al. 2017) No side or adverse effects have been identified in the scientific or traditional literature. (AHPA, 2013)

Cinchona officinalis (Cinchona bark) -

Cinchona or Peruvian bark contains several beneficial compounds. The most well-known, quinine, has been used for centuries in the treatment of malaria. (Permin, 2016) However, in an attempt to identify novel drug therapeutics for Dengue virus (DENV) infection, quinine and three other FDA approved drugs (aminolevullic acid, azelaic acid, mitoxantrone hydrochloride) were evaluated for their ability to inhibit DENV replication. Quinine outperformed them all. (Malakar, et al. 2018)

Chloroquine, or synthetic quinine, was discovered in 1934 and inhibits replication of several viruses including coronaviruses. (Yang, et al. 2004) While it is speculated that chloroquine/hydroxychloroquine might be of some use for the clinical management of SARS (Savarino, et al. 2003), current recommendations from the FDA caution against use of hydroxychloroquine or chloroquine outside the hospital setting given the cardiac complications that have arisen in trials evaluating their use in SARS CoV-2 (COVID-19). (FDA, 2020) A Brazilian trial was halted due to deaths related to cardiac dysrhythmias in patients receiving the higher dose of the drug (12 grams over 10 days vs 2.7 grams over 5 days). (Bowler, 2020) It’s important to note that the amount of quinine in this tincture is small in comparison. Cinchona bark is approximately 5% quinine by weight. In the course of a viral illness, a patient would consume approximately 120 ml of tincture containing a total of 170 mg of quinine administered over 3-4 days orally.

Symptoms of “cinchonism” due to overdose of the compound quinine include headache, nausea, disturbed vision, tinnitus, delirium, abdominal pain and diarrhea. However, if the standard dose of 1-4 g daily is not exceeded, there are typically no concerns with its use. (AHPA, 2013)

Tincture#2: Cytokine Reduction

With a virus like the one that causes SARS-CoV-2 (COVID-19), fighting the virus isn’t always enough. In the severe cases that result in respiratory complications requiring intubation, the infected are faced with needing to fight their own immune systems as well. SARS-CoV-2 uses a ACE-2 receptor to gain entry into cells that possess these receptors. This includes the cells of the lung. Licorice and Chinese skullcap block this attachment to varying degrees however once attachment occurs, inflammation can ensue that results in fluid accumulating in the lungs.

While inflammation is a normal response to a viral or bacterial infection, an excessive inflammatory response or “cytokine storm” can be deadly. The term cytokine is a generic term for a substance released by an immune cell in response to a stimulus and is part of an inflammatory response. The cytokine storm, as seen in SARS-CoV-2 infections, is best exemplified by severe lung infections. These localized responses can spill over into the system circulation, resulting in sepsis, as defined by persistent and dangerous low blood pressure, low or high body temperature, low or high white blood cell counts and often low platelets, which can lead to spontaneous bleeding. (Tisoncik, et al. 2012)

A common consequence is acute lung injury (ALI) which can progress into its more severe form, acute respiratory distress syndrome (ARDS), as seen with SARS-CoV and influenza virus infections, with death occurring 9-20% of the time. (Diamond, et al. 2020) (Tisoncik, et al. 2012)

Fourteen cytokines have been confirmed in severe acute respiratory syndrome (SARS) patients. In a study of SARS patients, these cytokines were documented during active infection. Additionally, several of these cytokines were significantly higher in those who died from the infection than in those who survived. (Huang, et al, 2005) This leads us to believe that reducing the cytokine response...regulating the inflammatory response...can potentially prevent these severe cases (requiring intubation or leading to death) from occurring.

Corticosteroids, like prednisone, may be of some benefit in controlling the inflammatory response but may also cause uncontrolled suppression of the immune system that can lead to a secondary bacterial pneumonia. (Yang and Jiang, 2009) Thus, a more nuanced approach to moderating the immune response is required. Likewise, the pneumonia associated with COVID-19 is insidious. Front-line physicians are reporting that infected patients are presenting to emergency departments with advanced pneumonia on x-ray and dangerous hypoxia (oxygen saturation as low as 50%) with no feelings of shortness of breath. These patients decompensate quickly but have had viral symptoms such as cough and fever for as long as a week before seeking treatment. (Levitan, 2020) Therefore, it’s critical that treatment begin at the onset of viral symptoms to avoid this treacherous course.

This information led us to the second tincture of 3 herbs and a cannabinoid extract with properties that have the potential to dampen a cytokine storm. Information about each herb and why it was chosen follows.

Angelica sinensis (Danggui)

In studies of mice with sepsis, Danggui, Danshen, and Green tea were able to rescue affected mice from lethal sepsis even when the first doses were given 24 hours after the onset of sepsis. This indicates that these herbs are potential therapeutic agents. (Zhu, et al. 2008) (Wang, et al. 2006) (Wang, et al. 2004) No significant adverse effects of Danggui use have been reported in the traditional Chinese medical literature.

Salvia miltiorrhiza (Danshen)

Salvia miltiorrhiza (SM) or Danshen, is used in treatment of various systemic and surgical infections in Chinese hospitals. See above. No toxicity has been noted in animal studies even at high doses for 14 days however it must be used with caution in situations where there is bleeding or if the patient is on a blood thinning medication. (AHPA 2013)

Pueraria montana var. Lobata OR Pueraria thunbergiana Benth. (Kudzu)

Kudzu, or Japanese arrowroot, is known as “the vine that ate the South”. Both its root and flower have been used for herbal medicine in Asia for centuries. Kudzu roots have been shown to contain large amounts of beneficial constituents that possess anti-inflammatory activity. (Eom, et al. 2018; Son, et al. 2019).

A study from March of this year (2020) found that four kudzu leaf extracts all have active activity against COVID-19 with one, gallic acid, exhibiting the strongest activity. Gallic acid was also far more active than the standard drugs remdesivir and chloroquine. (Kahn, et al. 2020) Kudzu has no known adverse or side effects but should be used with caution in those taking blood thinning drugs (anticoagulants or anti-platelet drugs) (AHPA 2013)

Cannabidiol (CBD)

While whole plant extracts are preferred, federal and state regulations make utilization of whole plant cannabis (hemp) extracts difficult. As such, utilizing non-psychotropic isolates of cannabinoid products is more practical.

There is now recent and consistent proof that cannabinoids are responsible for a decrease in the expression of multiple pro-inflammatory cytokines. (Dinu, et al. 2020) Recent studies have also shown a series of beneficial actions of cannabinoids in sepsis. (Ruiz-Valdepeñas, et al. 2011)

CBD has been shown to have a very favorable safety profile. (Iffland K, Grotenhermen F 2017)

Conclusion

The COVID-19 global pandemic has exposed the weaknesses of our current approach to dealing with communicable viral diseases, especially those that are novel and rapidly mutating. It’s likely that a vaccine is many, many months on the horizon and quality surveillance and testing has been, in many places, lackluster. Given the lack of effective therapeutic agents and the safety profile of whole plant extracts used in combination, it is our opinion that the efficacy of these medicinals should occur in a clinical setting immediately.

These herbs are readily available and inexpensive. Additionally, the beauty of whole plant extracts is that, even if some plants are not available, other plants can often be interchanged or omitted altogether. Costly, high-tech labs are also not required as the equipment required to tincture is also readily available. This means that a minimal amount of training, repurposing of a commercial kitchen or lab, and local sourcing of plants can help address the crisis at a local or regional level without relying on far away companies and disrupted supply chains.

While there are some limitations to this approach and while these medicinals will not CURE anyone, there is potential to shorten the course and lessen the severity of the disease, helping to prevent overwhelming the healthcare system. This is exactly what remdesivir apparently does. If we can do this with locally produced and sourced plant medicines accessible by the public at the onset of symptoms, there is potential to have a significant impact on the course of the pandemic.

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