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

Updated May 20, 2020

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 anati-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-10.3,4,5,6,7 Beta glucans induce activity against viral attack.8,9 Numerous human trials have shown that beta glucans decrease cold and flu symptoms10,11,12 and upper respiratory tract infections compared to placebo.13,14,15,16,17,18,19

Intervention Beta glucans
Suggested dose 250-500 mg daily
Mechanism(s) of action against non-COVID-19 viruses Priming innate immune function20 Promoting viral eradication or inactivation8,9
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms 10,11,12,13,14,15,16,17,18,19
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,21 increasing gut immunity,22 stimulating host immunity,23 activating innate immune cells,24 and increasing cytotoxic activity of NK cells.25

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 inactivation26,27
Modulation of innate immune response28,29
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.

CHINESE SKULLCAP (SCUTELLARIA BAICALENSIS)

Chinese skullcap (Scutellaria baicalensis) has been used for centuries in Traditional Chinese Medicine (TCM). In various human trials, participants who took TCM formulations containing Chinese skullcap showed statistically significant decreases in viral infection rates compared to controls.30 Chinese skullcap has anti-inflammatory, antioxidant, antibacterial, and antiviral effects.31,32,33 It has been shown to increase immune surveillance and downregulate NLRP3 inflammasomes,34 IL-6, and TNF-alpha.35

Intervention Chinese skullcap (Scutellaria baicalensis)
Suggested dose 750–1,500 mg daily standardized to flavonoids, baicalin, or baicalein.
Given the variability of standardization, it is suggested that dosing instructions should be based on research of specific standardized extracts.
Mechanism(s) of action against non-COVID-19 viruses Priming innate immune function36,41,42
Promoting viral eradication or inactivation36-41
Favorably modulating pulmonary inflammation38,41,43,44,45,46,47,48
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms49
Strength of evidence Limited
Risk of harm Minimal, though combination product showed significant hepatotoxicity.50,51,52,53,54

LICORICE (GLYCYRRHIZA SPECIES)

Licorice (Glycyrrhiza species) has multiple mechanisms of action, including inhibition of viral replication55,56,57 blocking the ACE2 receptor,58 promoting the activity of Th1 cells,59 and inhibition of pro-inflammatory cytokines,60 prostaglandins, and nitric oxide production.61 The inhibition of hydrocortisone metabolism by 11 beta-HSD has also been suggested as a potential mechanism of licorice’s anti-inflammatory action.62 Licorice has been use in traditional Chinese medicine (TCM) formulations against SARS-CoV-1 and H1N1 and reviewed for its effects on SARS-CoV-2.63,64 Two positive human trials have been performed against SARS-CoV-1 using a TCM formulation containing licorice.65,66

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 inactivation29,54,55,56,62,65,66
Favorably modulating inflammation
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms69,70
Strength of evidence Moderate
Risk of harm71, 72, 73, 74 Minimal, if short-term use (< 4 weeks) 69,70,71,72

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.73 Systematic reviews show a consistent and clinically relevant effect when used as a single herb or in combination with other herbal preparations.74,75,76Andrographis 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.77,78 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.79,80,81,82,83,84,85 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.86

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 protease86
Priming innate immune function81
Promoting viral eradication or inactivation74
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms76,87,88,89
Strength of evidence Strong
Risk of harm Minimal90,91,92

ASTRAGALUS MEMBRANACEUS

Astragalus membranaceus has been used in traditional Chinese medicine (TCM) for centuries.93Astragalus is well-known for its antiviral activity,94,95,96 for its anti-inflammatory properties,97,98,99,100,101 for priming the innate immune system,102,103,104 and for reducing NLRP3-mediated inflammation.105 In addition, the plant alkaloid swainsonine inhibits the glycosylation necessary for the SARS-CoV-2 spike protein to attach to human cells.106

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 binding106
Promoting viral eradication or inactivation107,108,109,110,111
Outcomes data supporting their mitigating effects
on illness from other viral strains
Inconclusive
Strength of evidence Conditional
Risk of harm Minimal 112,113,114

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.115,116,117,118,119,120Berberine also activates 5′ AMP-activated protein kinase (AMPK),121,122 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?.123 Berberine also acts to lower blood glucose,124 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 function125,126,127
Aldose reductase inhibition128
Promoting viral eradication or inactivation117,118,119,129,130,131,132
Outcomes data supporting their mitigating effects on illness from other viral strains No data available
Strength of evidence Limited
Risk of harm Minimal133,134,135,136,137

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.138 E. purpurea has been shown to stimulate macrophage activation as well as NK cell activity in both human and animal modelsand it may be linked directly to increased cytokine expression.144,145Various Echinacea preparations have shown antiviral activity.146,147,148Echinacea preparations alone have been shown to reduce the frequency, severity, and/or duration of upper respiratory tract symptoms in several trials,149,150,151and various multi-herb/nutrient formulas containing Echinacea preparations have also been shown to be effective in reducing symptoms.152,153,154,155

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 function139,140,141,142,143,144,145
Promoting viral eradication or inactivation146,147,148
Outcomes data supporting their mitigating effects on illness from other viral strains Prevention of infection156,157,158
Reduced duration of symptoms159,160
Strength of evidence Strong (for prevention)
Conditional (for treatment—conflicting studies)
Risk of harm Minimal157,161,162,163

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.164Recent 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 inhibition165,166
Inhibition of wild-type SARS-CoV infection167
Binding to viral S protein and furin inhibition168
Promoting viral eradication or inactivation169,170,171
Modulation of inflammation 172
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 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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