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The Functional Medicine Approach to COVID-19: Additional Research on Nutraceuticals and Botanicals

Updated February 11, 2021

In this paper, we add to the list of nutraceuticals and botanicals introduced earlier in our first article, The Functional Medicine Approach to COVID-19: Virus-Specific Nutraceutical and Botanical Agents. Periodically, we will update the original list to highlight other agents that may be considered as additional treatments against SARS-CoV. Along with the original list, these agents can be considered as immunoadjuvants, protease inhibitors, ACE2 modulators, zinc ionophores, and anti-inflammatory agents. Additionally, some nutraceuticals and botanicals could potentially inhibit SARS-CoV-2 replication. Our recommendation is to use higher dosing and/or multiple agents when patient contextual factors (e.g., patient desire, pre-existing inflammation, multiple co-morbidities, higher risk, etc.) and/or therapeutic decision-making warrant such use.

Download COVID-19: Nutraceutical and Botanical Recommendations for PatientsDownload COVID-19: Nutraceutical and Botanical Recommendations for Patients

As part of the Functional Medicine approach to COVID-19, IFM has outlined the biological plausibility, mechanism of action, strength of evidence, and risk of harm for various nutraceutical and botanical agents that may have activity against SARS-CoV-2. This article is part two of a series. Click here to view part one.

BETA GLUCANS

Beta glucans are known to modulate immune activity, mostly by priming or training innate immune responses through interactions with pattern recognition receptors (PRRs)1,2 and by increasing anti-inflammatory cytokines such as IL-10.3-7 Beta glucans induce activity against viral attack.8,9 Numerous human trials have shown that beta glucans decrease cold and flu symptoms10-12 and upper respiratory tract infections compared to placebo.13-18

Intervention Beta glucans
Suggested dose 250-500 mg daily
Mechanism(s) of action against non-COVID-19 viruses Priming innate immune function19
Promoting viral eradication or inactivation8,9
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms10-18
Strength of evidence Strong
Risk of harm Minimal

MUSHROOMS

Various mushrooms species have been shown to possess broad immunomodulatory effects. They possess multiple mechanisms of action, including increasing the number of circulating B cells,5 increasing gut immunity,20 stimulating host immunity,21 activating innate immune cells,22 and increasing cytotoxic activity of NK cells.23

Intervention Various medicinal mushrooms, including Shiitake (Lentinula edodes), Lion’s Mane (Hericium erinaceus), Maitake (Grifola frondosa), Reishi (Ganoderma lucidum)
Suggested dose Varied.
Given the variety of active ingredients in mushrooms and the variability of the extraction processes, it is suggested that dosing instructions should be individualized based on research of specific mushroom genus and species.
Mechanism(s) of action against non-COVID-19 viruses Promoting viral eradication or inactivation24,25
Modulation of innate immune response26,27
Outcomes data supporting their mitigating effects on illness from other viral strains Inconclusive, due to variety of species and combinations. Consult knowledgeable healthcare provider.
Strength of evidence Limited
Risk of harm Inconclusive, due to variety of species and combinations.

LICORICE (GLYCYRRHIZA SPECIES)

Licorice (Glycyrrhiza species) has multiple mechanisms of action, including inhibition of viral replication28-30 blocking the ACE2 receptor,31 promoting the activity of Th1 cells,32 and inhibition of pro-inflammatory cytokines,33 prostaglandins, and nitric oxide production.34 The inhibition of hydrocortisone metabolism by 11 beta-HSD has also been suggested as a potential mechanism of licorice’s anti-inflammatory action.35 Licorice has been use in traditional Chinese medicine (TCM) formulations against SARS-CoV-1 and H1N1 and reviewed for its effects on SARS-CoV-2.36,37 Two positive human trials have been performed against SARS-CoV-1 using a TCM formulation containing licorice.38,39

Intervention Licorice (Glycyrrhiza glabra)
Suggested dose Licorice root standardized to glycyrrhizin. 200-400 mg daily in divided doses. Short term use: <4 weeks.
Mechanism(s) of action against non-COVID-19 viruses Promoting viral eradication or inactivation28,29,30,36,37,40,41
Favorably modulating inflammation
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms42,43
Strength of evidence Moderate
Risk of harm71, 72, 73, 74 Minimal, if short-term use (< 4 weeks)44-47

ANDROGRAPHIS PANICULATA

The leaves of Andrographis paniculata have been used in traditional Eastern medicine systems for centuries for the treatment and prevention of upper respiratory tract infections (URTI), coughs, and sinusitis.48 Systematic reviews show a consistent and clinically relevant effect when used as a single herb or in combination with other herbal preparations.49-51 Andrographis has demonstrated anti-inflammatory, antiviral, and immune-stimulatory activities and has been shown, in vitro, to be effective against avian influenza A (H9N2 and H5N1) and human influenza A H1N1 viruses.52-53 It has been shown to inhibit platelet-activating factor–mediated inflammatory responses, to reduce the expression of cyclooxygenase-2, and to have analgesic as well as antipyretic effects.54-60 In addition, Andrographis is one of many agents that acts to decrease the activity of furin protease, a necessary step in SARS-CoV-2 spike protein activation and insertion into mucosal epithelial cells.61

Intervention Andrographis (Andrographis paniculata)
Suggested dose Standardized extract (typically 30% andrographolides) 100-600 mg daily,
most often delivered in combination with other herbal preparations.
Mechanism(s) of action against non-COVID-19 viruses Inhibition of furin protease61
Priming innate immune function56
Promoting viral eradication or inactivation49
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms51,62-64
Strength of evidence Strong
Risk of harm Minimal65-67

ASTRAGALUS MEMBRANACEUS

Astragalus membranaceus has been used in traditional Chinese medicine (TCM) for centuries.68 Astragalus is well-known for its antiviral activity,69-71 for its anti-inflammatory properties,72-76 for priming the innate immune system,77-79 and for reducing NLRP3-mediated inflammation.80 In addition, the plant alkaloid swainsonine inhibits the glycosylation necessary for the SARS-CoV-2 spike protein to attach to human cells.81

Intervention Astragalus (Astragalus membranaceous)
Suggested dose Dosage range varies between 1-20 grams daily,
depending on the percentage of astragalosides and other
immunoactive polysaccharides. In China, it is usually in dried root powder form.
Mechanism(s) of action against non-COVID-19 viruses Priming innate immune function
Inhibiting glycosylation and viral binding81
Promoting viral eradication or inactivation82-86
Outcomes data supporting their mitigating effects
on illness from other viral strains
Inconclusive
Strength of evidence Conditional
Risk of harm Minimal87-89

BERBERINE

Berberine is an alkaloid that is found in the roots, rhizomes, and stem bark of various plants, including goldenseal, goldthread, and Oregon grape. Berberine has been shown to have anti-viral activity across a broad range of viral targets.90-95 Berberine also activates 5′ AMP-activated protein kinase (AMPK), 96,97 which is directly anti-inflammatory. Berberine’s anti-inflammatory effects also include suppression of inhibition of IkB kinase and downregulation of NFkB, IL-1?, and TNF?.98 Berberine also acts to lower blood glucose,99 thus helping with furin inhibition, as well as preserving ACE2 receptors, possibly through aldose reductase inhibition.

Intervention Berberine
Suggested dose 500 mg, 2-3 times daily
Mechanism(s) of action against non-COVID-19 viruses Priming innate immune function100-102
Aldose reductase inhibition103
Promoting viral eradication or inactivation92-94,104-107
Outcomes data supporting their mitigating effects on illness from other viral strains No data available
Strength of evidence Limited
Risk of harm Minimal108-112

ECHINACEA (ECHINACEA SPECIES)

Echinacea species (E. purpurea, E. angustifolia, and E. pallida) are all used for medicinal purposes. Echinacea’s immunological effects appear to be derived from a combination of constituents.113 E. purpurea has been shown to stimulate macrophage activation as well as NK cell activity in both human and animal models,114-118 and it may be linked directly to increased cytokine expression.119,120 Various Echinacea preparations have shown antiviral activity.121-123 Echinacea preparations alone have been shown to reduce the frequency, severity, and/or duration of upper respiratory tract symptoms in several trials,124-126 and various multi-herb/nutrient formulas containing Echinacea preparations have also been shown to be effective in reducing symptoms127-130

Intervention Echinacea species (E. purpurea, E. angustifolia, and E. pallida)
Suggested dose Varied.
Given the variety of active ingredients in various species and the
variability of the extraction processes, it is suggested that dosing instructions be
individualized based on research of specific Echinacea species.
Mechanism(s) of action against non-COVID-19 viruses Priming innate immune function114-120
Promoting viral eradication or inactivation121-123
Outcomes data supporting their mitigating effects on illness from other viral strains Prevention of infection131-133
Reduced duration of symptoms134,135
Strength of evidence Strong (for prevention)
Conditional (for treatment—conflicting studies)
Risk of harm Minimal132,136-8

LUTEOLIN

Luteolin is a flavonoid found in medicinal plants and many fruit and vegetables, including peppers, celery, radicchio, chicory, and lemons. Plants rich in luteolin have been used in traditional Chinese medicine for the treatment of hypertension, inflammatory disorders, and cancer.139 Recent screening studies have identified luteolin as a candidate molecule to block SARS-CoV-2 entry into the cell as well as to modulate excessive inflammatory responses.

Intervention Luteolin
Suggested dose 100-200 mg, 2-3 times daily
Mechanism(s) of action against non-COVID-19 viruses Mpro inhibition140,141
Inhibition of wild-type SARS-CoV infection142
Binding to viral S protein and furin inhibition143
Promoting viral eradication or inactivation144-146
Modulation of inflammation147
Outcomes data supporting their mitigating effects on illness from other viral strains Inconclusive
Strength of evidence Conditional
Risk of harm Minimal

Evaluative Criteria

In the recommendations above, the following criteria are used to identify strength of evidence and risk of harm.

Strength of Evidence
Risk of Harm
Strength of Evidence Conditional

Human trials with conflicting outcomes, or lack of published human trials. Must be supported by extensive historical experience of effectiveness, consensus of expert opinion, mechanistic plausibility, and compelling Functional Medicine model factors. In the absence of any one of these features, must be supported by compelling patient or clinical circumstances or contextual

Risk of Harm Minimal Risk of self-limited symptoms No risk of loss of function or corrective intervention anticipated; expected to resolve with discontinuation and observation
Strength of Evidence Limited One human study demonstrating correlation between intervention and outcome, or real world data/evidence demonstrating patient oriented outcome; Must be accompanied by compelling Functional Medicine model factors and/or patient contextual factors and mechanistic plausibility

Risk of Harm Mild Risk of self-limited symptoms. No risk of loss of function. Expected to resolve with discontinuation and minor evaluative and/or therapeutic intervention
Strength of Evidence Moderate Moderate Two independent human studies (one of which is LOE = 1 or 2) demonstrating correlation between intervention and patient oriented outcome; mechanistic plausibility required
Risk of Harm Significant Risk of temporary loss of function or quality of life Significant evaluative and/or therapeutic intervention necessary to resolve
Strength of Evidence Strong Strong Two independent human studies (both LOE = 1 or 2) demonstrating correlation between intervention and patient oriented outcome; mechanistic plausibility or one additional independent human study required
Risk of Harm Severe Risk of permanent symptoms, loss of function, quality of life, or death Long term evaluative and/or therapeutic intervention necessary to mitigate

*This resource is only intended to identify nutraceutical and botanical agents that may boost your immune system. It is not meant to recommend any treatments, nor have any of these been proven effective against COVID-19. None of these practices are intended to be used in lieu of other recommended treatments. Always consult your physician or healthcare provider prior to initiation. For up-to-date information on COVID-19, please consult the Centers for Disease Control and Prevention at www.cdc.gov.

SPECIAL THANKS
We would like to thank the IFM COVID-19 Task Force, members of the IFM staff, and consultants working with IFM for their contributions to this article.

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