Cautions and Opportunities for Botanicals in COVID-19 Patients: A Comment on the Position of the French Agency for Food,Environmental and Occupational Health & Safety

Abstract

Introduction

The COVID-19 pandemic is a global health crisis caused by SARS-CoV-2 and >700 trials are running worldwide (https://www.covid-trials.org/) in an attempt to identify effective drugs to prevent the infection, eradicate the virus, and manage disease complications. Research has also involved medicinal herbs, due to their possible antiviral or symptomatic role, although their use in clinical practice is often influenced by tradition and characterized by self-medication. In this regard, the authors believe that the possible administration of medicinal herbs should be discussed, especially for patients suffering from emerging, poorly known, and potentially severe diseases such as COVID-19. Within this field of study, the ultimate objective of the scientific community should be to identify all appropriate clinical uses and potential risks of botanicals, to avoid dangerous interactions with drugs and, at the same time, to outline a list of evidence-based indications (and contraindications) of medicinal herbs in any stage of the disease.

Therefore, adequate communication and dissemination of reliable information are important both for the general population and for health care professionals. As such, the recent effort of the French “National Agency for Food Safety, Environmental and Occupational Health” (ANSES) has been appreciated to raise awareness about the need for caution regarding potentially inappropriate and risky uses of botanicals in COVID-19 patients.¹ However, in the authors' opinion, it is essential that actual risks are adequately assessed and not inflated nor overestimated, since botanicals may still offer a range of valuable therapeutic options to study in depth.

The study aims to briefly discuss this issue to prompt further research on the topic, in the perspective of eventually formulating a list of evidence-based effective and safe uses of botanicals for COVID-19 patients.

First Consideration

The position article issued by the ANSES discourages patients from using herbal supplements by declaring that botanicals could interfere with viral entry through an upregulation of the angiotensin-converting enzyme 2 (ACE2) receptor. This hypothesis has been previously raised for nonsteroidal anti-inflammatory drugs (NSAIDs), since ibuprofen can increase the expression of ACE2 receptors used by SARS-CoV-2 to penetrate into cells.² Therefore, it has been suggested that ibuprofen can worsen the patient's symptoms during COVID-19 by indirectly promoting the viral entry into cells. However, the European Medicines Agency, the World Health Organization, and the United States Food & Drug Administration have reported that scientific evidence associating the use of NSAIDs with any worsening of COVID-19 symptoms lacks to date.

Actually, some plants with an anti-inflammatory activity mentioned in the ANSES document belong to traditional long-standing medicinal systems and are also used in modern medicine. Moreover, these plants do not include ibuprofen-like substances in their composition, but pharmacologically different bioactive molecules (e.g., coumarins, polyphenols, and triterpenes), which do not act as enhancers of ACE2 receptor expression.^3,4 In addition, active components of medicinal plants have always been considered an important source of clinical therapeutics, with a multitarget pharmacologic activity ascribed to their great chemical diversity.⁵

Second Consideration

The ANSES experts state that another reason not to use botanicals is the substantial lack of information regarding their specific composition. Today, these concerns, although legit in some cases, can be generally misleading, since pharmaceutical companies can produce high-quality, adequately controlled, standardized, and well-characterized herbal preparations, following recommendations reported in official Pharmacopoeias. As such, many herbal preparations are today available not only as traditional remedies, but also as standard medicines or galenic preparations.

Third Consideration

The ANSES's document states that substances with an activity on the immune system could amplify the inflammatory response and become responsible for the worsening of COVID-19.¹ In particular, among all inflammatory mediators and cytokines, some authors have underscored the association between high interleukin (IL)-6 levels and poor clinical outcomes in patients with COVID-19, thus hypothesizing new pharmacologic approaches involving this pathway.

Conversely, many botanicals capable of eliciting a nonspecific stimulation of the immune system can have, at the same time, anti-inflammatory and antioxidant effects.

For example, Echinacea spp. extracts, probably the most popular botanicals of this category, can be useful for the prevention of upper respiratory tract infections in adults and children, and are characterized by a multicomponent composition, with many substances pharmacologically acting all together in a synergistic way through different mechanisms of action.⁵ Their main active ingredients are polyphenols, polysaccharides, and alkamides with immunomodulatory and anti-inflammatory activities.

Astragalus membranaceus, a typical medicinal plant of Traditional Chinese Medicine (TCM), used as an immunostimulant remedy, can induce a dose-dependent inhibition of several inflammatory factors, including IL-6.⁶ Curcuma longa can also inhibit the release of phlogistic mediators such as IL-6, and has an antifibrotic activity, which makes it a possible candidate to be studied in post-COVID-19 patients who develop pulmonary fibrosis.⁵

Uncaria tomentosa, traditionally used for the prevention of infectious diseases and cancer, contains compounds such as alkaloids, terpenes, flavonoids, and glycosides of the quinovic acid, which share not only immunostimulant properties, but also anti-inflammatory, antiviral, antioxidant, and protective effects on the central nervous, cardiovascular, and respiratory systems. In addition, isorhynchophylline, a tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla, has showed anti-inflammatory and antioxidant effects on murine alveolar macrophages through inhibition of the TLR4/NF-κB/NLRP3 inflammasome pathway. However, data about IL production and U. tomentosa administration show the importance of further clinical research: in fact, an increase of IL-1 and IL-6 levels has been observed in mice infected with Listeria monocytogenes and treated with extracts of U. tomentosa. ⁷

Similarly to synthetic drugs that stimulate the immune system, these botanicals are not to be used in patients with autoimmune disorders, to avoid possible relapses or disease worsening, as well as in COVID-19 patients during the acute phase of the illness. However, they may have role in the disease prevention, or in the stressful situation faced by many COVID-19 patients, who are forced to very long quarantines even after full clinical recovery due to a persistent positivity of the nasal swab test: in these cases, botanicals may be useful to promote viral clearance.

Fourth Consideration

Some plants with anti-inflammatory properties can be used in early disease stages. Medicinal herbs rich in polyphenols and characterized by an antiviral activity (Andrographis paniculata, Pelargonium sidoides, Sambucus nigra, etc.) appear eligible for further studies to find effective remedies against SARS-CoV-2 infection, as they have an interesting combination of antimicrobial and anti-inflammatory properties, thus being capable of improving the patient's phlogistic symptoms and potentially inhibiting the viral replication at the same time.^4,8 The usefulness of such plants has also been underscored by systematic reviews investigating their clinical efficacy and safety.^8,9

Therefore, based on scientific evidence and empirical tradition, it is possible to hypothesize a potential role of some plants during the evolution of the disease from prevention to rehabilitation,¹⁰ with some consequent recommendations (Table 1).^10,11

Table 1.

Recommendations for the Use of Some Plants or Derivatives During COVID-19 Evolution

Phase disease	Treatment	Medicinal plants	Therapeutic effects
Healthy subjects^a	Home therapy	Echinacea spp.	Immunomodulator
Healthy subjects^a	Home therapy	Echinacea spp.	Prevention of upper respiratory tract infections
Initial stages	Home therapy	Pelargonium sidoides	Anti-inflammatory
Initial stages	Home therapy	Pelargonium sidoides	Antiviral
Severe pulmonary or systemic complications	Clinical trials	Colchicine	Anti-inflammatory
Severe pulmonary or systemic complications	Clinical trials	TCM	Antiviral
Post-COVID^b	Home therapy	Astragalus membranaceus	Immunomodulator
			Anti-inflammatory
			Antifibrotic
		Curcuma longa	Anti-inflammatory
			Antioxidant
			Antifibrotic

Exposed to the risk of contracting viral infections, such as physicians and health workers, but also children, elderly people, and patients with risk factors (diabetes, hypertension, cardiovascular or respiratory diseases, and cancer).

Risk of long-term complications such as pulmonary fibrosis, as well as cardiologic or neurologic sequelae.

COVID, coronavirus disease; TCM, Traditional Chinese Medicine.

Perspectives

During the cytokine burst of COVID-19, any self-prescribed use of botanicals should be avoided, especially if medicinal herbs with immunostimulant properties are considered. In this inflammatory phase of the disease, botanicals with potentially beneficial effects could be safely included as complementary therapies only within the frame of rigorous and adequately controlled clinical trials. Beside colchicine, bioactive substances capable of reducing the production of ILs and leukotrienes can be found in Boswellia serrata and in Glycyrrhiza glabra, a medicinal plant widely used in TCM with some evidence of efficacy for the integrative management of hepatitis B, HIV, and others viral infectious diseases. Furthermore, glycyrrhizin, a saponin extracted from licorice, has also demonstrated an interesting anti-SARS-CoV activity in laboratory experiments.¹²

Several flavonoids (e.g., hesperidin, luteolin, quercetin, kaempferol, and baicalin) can interfere with the activation of NOD-like receptor, pyrin domain-containing 3 inflammasome and may modulate the inflammatory response to SARS β-coronaviruses. In particular, hesperidin and other citrus flavonoids can inhibit the interaction between the S protein of SARS-CoV 2 and the ACE2 receptor in a dose-dependent manner, thus being interesting targets for future studies.¹³ In addition, it can be useful to further investigate the preventive role of some botanicals, not only to find new strategies to limit other outbreaks of the disease, but also to mitigate fears and psychologic distress spread across the population during this pandemic. Recent findings also indicate that ginseng supplementation may improve the response to influenza vaccination, thus being an interesting option to study as an adjuvant for a future vaccine against SARS-CoV-2.¹⁴

Conclusions

In conclusion, as suggested by available scientific evidence, the authors think that botanicals can have a role in the prevention and early symptomatic treatment of viral respiratory infections, and their rational administration may also become a complementary therapy for COVID-19 and post-COVID-19 patients. During the course of the disease, supervision is necessary to tailor phytotherapy prescriptions according to the patient's and the illness characteristics, as well as to minimize any risk of adverse interactions between herbs and other drugs. Further research on the topic is recommended to gather evidence on the efficacy and safety of botanicals in COVID-19.

References

Anses: French Agency for Food, Environmental and Occupational Health & Safety. ANSES warns against taking food supplements that could lower the body's immune response. Online document at: https://www.anses.fr/fr/system/files/NUT2020SA0045.pdf, accessed May 28, 2020 .

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