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Preface

This Practical Guide is part of Forever Healthy's "Maximizing Health" initiative that seeks to holistically review the world's leading medical knowledge on various health-related topics and turn it into actionable information.

Motivation

Antivirals with a broad spectrum of action and immunomodulators that improve host resilience are crucial to overcoming novel viral infections. As of yet, there aren't any evidence-based or clinically proven treatments or vaccines available for COVID-19.

However, numerous compounds, including natural antivirals and natural immunomodulators, have been suggested for both prevention and treatment. Unfortunately, the scientific evidence behind these recommendations is most often not provided, making the decision whether to use a certain compound virtually impossible.

In light of the current COVID-19 outbreak, we review the scientific, empirical, and clinical evidence of proposed natural compounds that could potentially help prevent infection or reduce the severity of symptoms.

Methods

A search for recommendations of natural antivirals and immune-boosting compounds with possible relevance to COVID-19 was conducted using online resources of the leading integrative medical, naturopathic, and functional medicine associations in order to gather a list of compounds for further assessment.

Evidence for or against each compound was then collected through PubMed searches using the following terms <compound name> AND (antiviral OR coronavirus OR COVID-19 OR SARS).

In cases where supporting or refuting evidence was not found, consultations with experts and of association-specific supporting literature were carried out.

Finally, substances were categorized and a list of recommendations of compounds that have shown beneficial immunomodulatory actions, clinical efficacy, safety, and potentially specific effects on SARS-CoV-2 was created. 

Summary of the Results 

We identified 50 natural substances and mixtures recommended for preventing infection with SARS-CoV-2 or lessening the severity of symptoms of COVID-19. As there hasn't been enough time for the scientific community to conduct clinical trials on the effects of any of the compounds on SARS-CoV-2, we chose to recommend substances with established safety that have shown strong antiviral/immunomodulatory effects in previously conducted clinical trials or clinical practice.

This resulted in a final recommendation for 8 natural compounds, 4 that have shown activity against other coronaviruses and that have strong immunomodulatory effects (see Recommended based on scientific literature) along with 4 further compounds that have traditionally been used for prevention/treatment of viral infections with a long record of efficacy and safety (see Recommended based on clinical practice). 

Additionally, we found there is some supporting evidence for 23 more substances, discussed in the Potentially useful section.

7 of the reviewed compounds are basic building blocks of the immune system and we have grouped them under Recommended basic supplementation. 

We excluded the remaining 12 substances based on a lack of scientific or clinical literature supporting antiviral use or because of safety considerations (see Not recommended). 

Impatient readers may choose to skip directly to the Summary Table for the final list of recommended compounds and doses. 

Recommended based on scientific literature 

There are natural antivirals that have demonstrated similar or higher efficacy than existing antiviral pharmaceuticals in clinical trials, with fewer complications and adverse effects (Nabeshima et al., 2012; Rausch et al., 2015). 

The four compounds recommended in this section have been extensively studied in both clinical and preclinical trials. They have demonstrated high levels of antiviral activity against several respiratory viruses, including coronaviruses, and have additionally been shown to have good safety profiles. 

Elderberry Extract

Elderberry (Sambucus nigra) is a species of flowering plants in the genus Adoxaceae that has had an important role in herbal medicine in North American, European, and West Asian countries. The berries have traditionally been used for cold and flu symptoms (Hawkins et al., 2018). Consumption of elderberries has been shown to increase plasma concentrations of anthocyanins, chemicals that boost immune function and exhibit antiviral effects (Hawkins et al., 2018). Elderberries also contain a variety of nutrients ranging from various vitamins (A, B1, B2, B6, B9, C, and E), trace elements such as Cu, Zn, Fe and minerals such as K, Ca and Mg to phytochemicals such as carotenoids, phytosterols and polyphenols (Tiralongo et al., 2016). 

Although nothing is yet known about its effect on SARS-CoV-2, elderberry has been shown to inhibit a type of coronavirus that causes bronchitis in chickens (Chen et al., 2014). It also inactivates two other types of enveloped viruses and therefore, has potential as an antiviral for SARS-CoV-2.

Clinical studies have shown the beneficial effects of elderberry extract on upper respiratory tract infections, influenza, and HIV. A randomized control trial (RCT) (n=312) reported a lower incidence of colds, reduced severity of symptoms and quicker recovery (4.75 days vs. 6.88 days) in the group taking an elderberry supplement (Tiralongo et al., 2016). Two smaller RCTs (n=23, 60) that used elderberry to treat influenza also reported a significant improvement of symptoms that occurred 4 days earlier than in the control group (Zakay-Rones et al., 1995; Zakay-Rones et al., 2004). A meta-analysis (n=180) found that elderberry was effective in reducing the duration of upper respiratory symptoms, particularly those due to influenza compared to a control group (Hawkins et al., 2018). A case study of a patient with HIV reported that elderberry + olive leaf extract exhibited a viral load decrease from 17,000 to 4,000 (Konlee, 1998). 

In vitro, elderberry has been shown to inhibit several types of bacteria (Krawitz et al., 2011; Chatterjee, 2004; Hearst et al., 2010; Arjoon et al., 2012; Mohammadsadeghi et al., 2013; Rodino et al., 2015). It is thought that resistance to it is unlikely to ever develop and it may even have potential as a hospital disinfectant (Wermig-Morgan, 2020). Its antibacterial properties may also be useful in the prevention of secondary complications such as bacterial pneumonia.

In preclinical studies, elderberry has been shown to inhibit many strains of influenza (Zakay-Rones et al., 1995; Karimi et al., 2014; Kinoshita et al., 2012; Roschek et al., 2009), as well as HIV (Fink et al., 2009). The in vivo effect against influenza in mice was even greater than the in vitro effect (Kinoshita et al., 2012). 

Additionally, elderberry has shown immunomodulatory effects including activation and enhancement of the immune system in some cases, and inhibition of pro-inflammatory pathways in others. There is some concern that it could cause a cytokine storm based on the results of one ex vivo study (Barak et al., 2001) but later studies contradicted those results and showed a dampening effect on the production of cytokines (Barak et al., 2002; Wermig-Morgan, 2020). 

Given elderberry's ability to strongly activate the immune system, it appears most effective in the prevention or early stage of infections.

Curcumin

Curcumin is the major bioactive substance found in the rhizome of Curcuma longa, a member of the ginger family (Zingiberaceae) that grows natively in India and Southeast Asia. Curcumin has long been used in traditional Chinese and Indian medicine. It has excellent tolerability with no toxicity even at high oral doses of up to 12 g/day (Praditya et al., 2019). However, curcumin has extremely poor bioavailability, leading to low serum concentrations. Several formulations to improve its bioavailability have been developed (cancermind.com). High-dose curcumin has also been given intravenously in two phase I trials (n=70) without serious side effects (biospace.com).

Curcumin was amongst a group of phytochemicals identified that potentially target the main protease of SARS-CoV-2 to inhibit viral replication (Khaerunnisa et al., 2020). It has also been shown to modulate the NLRP3 inflammasome, a component of the innate immune response that can cause an uncontrolled release of pro-inflammatory cytokines (Tőzsér et al., 2016). Intravenously administered curcumin has been shown to suppress IL-6 by 83%, TNF-a by 77% and IL-1 beta by 85% (biospace.com).

In vitro, curcumin exhibited anti-SARS-CoV activity by inhibiting replication and the SARS-CoV 3CL protease (Wen et al., 2007). Treatment with curcumin has also been shown to affect ACE gene expression in mice (Fazal et al., 2015; Pang et al., 2015) which may have relevance since SARS-CoV-2 uses ACE2 receptors to enter cells. 

Curcumin has also shown antiviral activity towards numerous other viruses in preclinical studies as seen in the table below:

Table 1 - Antiviral Activity of Curcumin

Similar to elderberry, curcumin has also been shown to have antibacterial activities against Staphylococcus (Bhawana et al., 2011; Krausz et al., 2015; Liu & Huang, 2012) and Streptococcus (Song et al., 2012; Li et al., 2018; Betts et al., 2016), both of which are common causes of secondary complications of viral pneumonia.

Echinacea 

Echinacea is a genus of nine herbaceous flowering plants in the daisy family (Asteraceae; Compositae), commonly called coneflowers, that originate from North America. Three species of Echinacea, namely E. purpurea, E. angustifolia, and E. pallida, have been used in folk medicine for centuries as a treatment for colds, coughs, bronchitis, and flu. Preparations of Echinacea are available in the form of extracts, tinctures, teas, and sprays, derived from various parts of one or more of three species of Echinacea. 

In a paper that is currently under peer review, echinacea was found to inhibit several types of coronaviruses, including SARS-CoV-1, leading the authors to conclude it may be an effective prophylactic against SARS-CoV-2 (Signer et al., 2020).

A meta-analysis of clinical trials (n=2458) found that the use of echinacea extracts is associated with a risk reduction for recurrent respiratory infections of 35% (Schapowal et al., 2015). The effect was even greater in highly susceptible individuals where it halved the risk of recurrent respiratory infections. Additionally, complications that commonly follow respiratory infections such as pneumonia, otitis media/externa, and tonsillitis/pharyngitis were also 50% less frequent. Ethanolic extracts from echinacea appeared to have superior effects compared with pressed juices (Schapowal et al., 2015). 

In vitro, echinacea has shown antiviral effects towards many viruses including influenza A and B, herpes simplex virus (HSV)-1 and -2, coronaviruses, RSV, and rhinoviruses (Wacker & Hilbig, 1978; Binns et al., 2002; Vimalanathan et al., 2005; Hudson et al., 2005; Schneider et al., 2009). In rhinovirus-infected human bronchial and lung epithelial cell lines, echinacea was able to inhibit the secretion of more than 30 different cytokines (Hudson & Vimalanathan, 2011).

Recent detailed studies with the standardized preparation Echinaforce (comprised of ethanol extracts of E. purpurea, 95% aerial parts plus 5% roots) showed that this preparation was very active as a virucidal agent against viruses with envelopes. Echinacea appears to be active during initial contact with the virus via interactions with hemagglutinase and neuraminidase and also during transmission of the virus from infected cells while it is less active intracellularly (Hudson & Vimalanathan, 2011).

A further benefit is that the use of echinacea is less likely to produce resistant viral strains (in contrast to preparations like Tamiflu) (Hudson & Vimalanathan, 2011). 

Quercetin

Quercetin is a flavonol, one of the six subclasses of flavonoid compounds and is widely distributed in plants. It is found in a variety of foods including apples, berries, Brassica vegetables, capers, grapes, onions, shallots, tea, and tomatoes, as well as many seeds, nuts, flowers, barks, and leaves. Additionally, it is contained in the medicinal products Ginkgo biloba, Hypericum perforatum, and Sambucus canadensis. Most research on quercetin and its derivatives has focused on their use as potential therapeutic agents against chronic and inflammatory diseases.

In vitro, quercetin exhibited antiviral activity against SARS-CoV with very low cytotoxicity (Yi et al., 2004; Nguyen et al., 2012; Ryu et al., 2010). A recent, not yet peer-reviewed study also found that quercetin was a likely inhibitor of the SARS-CoV-2 main protease (Khaerunnisa et al., 2020). It has also been shown to modulate the NLRP3 inflammasome, a component of the innate immune response that can cause an uncontrolled release of pro-inflammatory cytokines (Tőzsér et al., 2016). 

Quercetin will be tested over the next four months in clinical trials. Quercetin produced by the Swiss company Quercegen Pharmaceuticals will be used as the researchers believe it is the purest available quercetin (mcgilltribune.com).

Recent studies have demonstrated that quercetin has antiviral activity against a wide variety of viruses, including influenza, Chikungunya, Epstein-Barr, hepatitis C, Mayaro and ebola (Qiu et al., 2016). The mechanism of action is as of yet unknown but, it has been proposed that quercetin and its derivatives affect a step in the viral entry process (Qiu et al., 2016). 

Quercetin also possesses strong anti-inflammatory capacities as shown in several in vitro studies. It is known to possess both mast cell stabilizing and gastrointestinal cytoprotective activity and can have modulatory, biphasic and regulatory effects on inflammation (Li et al., 2016). However, likely due to low bioavailability, the results in human studies have been less impressive (Li et al., 2016). 

Recommended based on longstanding clinical practice 

 

Several studies have reported on the use of traditional Chinese medicine (TCM) herbal preparations in the prevention of SARS and H1N1 influenza (Luo et al., 2019). In these studies, none of the study participants (all high-risk, front line medical workers) who took the TCM herbal preparations contracted SARS and the infection rate of H1N1 influenza in the TCM group was also 64% lower than in the non-TCM group. In response to the emergence of COVID-19, 23 provinces in China issued preventative TCM programs.

Anthroposophic and homeopathic clinics and hospitals also have a long history of clinical experience in treating infections with extremely limited use of antibiotics and largely without the use of antipyretics (Munda et al., 2007; Geyer et al., 2013). During the Spanish Flu pandemic, homeopathic hospitals had a dramatically lower mortality rate than conventional hospitals (Dewey, 1921; Jahn, 2014).

Although still widely disputed, there is scientific evidence (including at least 43 double-blind RCTs) demonstrating that homeopathy is both effective and safe (facultyofhomeopathy.org). With regard to respiratory viral illnesses, an RCT (n=445) reported that homeopathic medication reduced the frequency of colds and flu-like illnesses in children (Siqueira et al., 2016). Homeopathic remedies have also shown in vitro action against HSV, RSV, influenza, adenoviruses, parainfluenza, rhinovirus, and coxsackie viruses (Glatthaar-Saalmüller et al., 2007).

Given the long-standing clinical evidence of efficacy and safety, we chose to recommend the following TCM and diluted substances:

Fang Ji Huang Qi Tang

Fang-Ji-Huang-Qi-Tang has a long history of clinical use in traditional Chinese medicine and is composed of six medicinal herbs, three of which have been shown, in vitro, to exhibit antiviral activity against coronaviruses. 

• Radix Stephania tetrandra

• Radix Astragali

• Radix Glycyrrhizae

• Rhizoma Zingiberis

• Fructus Ziziphi jujubae

• Rhizoma Atractylodis macrocephalae

Stephania tetrandra

Stephania Tetrandra is a major source of the bis-benzylisoquinoline alkaloids tetrandrine (TET), fangchinoline (FAN), and cepharanthine (CEP). TET, FAN, and CEP significantly inhibited virus-induced cell death at an early stage of virus infection and dramatically suppressed the replication of HCoV-OC43 in vitro. They also inhibited viral spike (S) and nucleocapsid (N) protein expression and reduced the host inflammatory response compared to control (Kim et al., 2019). In addition, no cytotoxicity was caused by the compounds within the effective ranges. S. tetandra has also been shown to inhibit the differentiation of proinflammatory subsets of T helper cells, both in vitro and in vivo, in rodents (Zou et al., 2019). 

Astragalus

Astragalus (Astragalus membranaceus) is the most commonly used herb in the TCM-based preventative programs for COVID-19 (Luo et al., 2019). Polysaccharides are one of the major active ingredients in A. membranaceus. In vitro, A. membranaceus significantly reduced the replication of avian infectious bronchitis virus and reduced mRNA levels of the cytokines IL-1B, IL-6, IL-8 and TNF-α (Zhang et al., 2018). It has also been shown to have immunoregulatory and anti-inflammatory activities, including the induction of T-cell activation, regulation of effector/regulatory T-cell balance, enhancement of CD45 phosphatase activity, and inhibition of pro-inflammatory cytokines and the NF-kB pathway (Qi et al., 2017; Xie et al., 2015).

Licorice root

Licorice root (Radix Glycyrrhizae) contains several triterpene saponins. Glycyrrhizin is the major component, with a concentration varying between 1% and 9%, depending on the species, geographical location and methods of extraction (Fiore et al., 2008). Licorice root was shown to be a potent inhibitor of SARS-CoV replication in vitro. In addition to inhibition of virus replication, glycyrrhizin also inhibited adsorption and penetration of the virus—early steps of the replicative cycle (Cinatl et al., 2003). Glycyrrhizin has been used to treat patients with HIV-1, and chronic hepatitis B and C viruses (Cinatl et al., 2003). In mice, strong positive effects against influenza and encephalitic viruses have also been reported (Fiore et al., 2008). 

Latent infection with Kaposi sarcoma-associated herpesvirus in B lymphocytes can be overcome by glycyrrhizic acid (Curreli et al., 2005). In vitro, licorice has shown inhibitory effects on herpes, influenza, hepatitis, JEV, HIV viruses (Fiore et al., 2008). Components from licorice have also been shown to activate macrophages and increase nitric oxide production in vitro (Nose et al., 1998).

Ginger root, Jujube red dates, and Atractylodis macrocephalae

Ginger root (Rhizoma zingiberis) has the actions of warming the lung to resolve retained fluid, warming the spleen and regulating water metabolism. Compounds in ginger also increase levels of antioxidant enzymes (SOD and GP) and exhibit effects against influenza A (Wang et al., 2006). Jujube red dates (Fructus Ziziphi Jujubae) tonify qi and the spleen, nourish the blood and induce tranquilization (tcmwiki.com). Rhizoma Atractylodis macrocephalae helps regulate the function of the gastrointestinal system, strengthens the body, boosts immunity, protects the liver and gallbladder functions, regulates blood sugar, promotes urination, and has anti-oxidative, anti-blood-clotting, and anti-cancer effects. It also releases involuntary muscular spasms (shen-nong.com).

Shuang-Huang-Lian Oral Liquid

Shuang-Huang-Lian (SHL) oral liquid is a formula that was devised in the 1960s to treat a variety of infections. It is comprised of the alcohol-water extracts of three herbs:

• Lonicera japonica

• Scutellaria baicalensis

• Forsythia suspensa
  
  
  

Researchers at the Shanghai Institute of Drugs and Wuhan Virus Institute reported that the Chinese medicine SHL oral liquid inhibits SARS-CoV-2, at least in vitro (jqknews.com). There is currently a clinical trial underway in China to test its efficiency (Yang et al., 2020).

A systematic review reported that SHL injection showed a better effect than common antibiotics on helping relieve some symptoms, such as fever, cough, sore throat, and nasal congestion and discharge and decrease the course of acute upper respiratory tract infections (Zhang et al., 2013). SHL has also been shown to inhibit the replication of H5N1 influenza in vitro and alleviate lung injury in mice infected with influenza (Tang et al., 2018). 

In vitro, SHL significantly reduced the transcriptional and translational levels of iNOS and COX-2, production of NO and prostaglandin E2. It also suppressed inflammatory cytokine production including TNF-α, IL-1β, and IL-6. In parallel with the anti-inflammatory activity, SHL also suppressed LPS-induced intracellular total ROS levels by weakening NADPH oxidase activity, enhancing SOD activity and increasing GSH content and was shown to directly scavenge OH and O2(-) (Gao et al., 2014).

Japanese honeysuckle

Japanese honeysuckle (Lonicera japonica) is rich in chlorogenic acid, a compound that has been shown to act as a neuraminidase blocker to inhibit influenza A virus both in cellular and animal models (Ding et al., 2017). 

Chinese skullcap

Chinese skullcap (Scutellaria baicalensis) extracts and compounds exhibit broadspectrum anti-viral activities against HIV, influenza virus, dengue, hepatitis B, and human T-cell lymphotropic virus type 1 (Wang et al., 2018). 

Weeping forsythia

Weeping forsythia (Forsythia suspensa) is known for its high saponin content and is used to treat various inflammatory symptoms, such as carbuncles or abscesses associated with swelling, common cold, and fever (Bae et al., 2019). It has been shown to inhibit influenza A in vitro (Bae et al., 2019). Forsythoside A, its major bioactive compound, reduced the viral titers of different influenza virus subtypes in cell cultures and increased the survival rate of the mice in an in vivo influenza virus infection model (Law et al., 2017). 

Meteoreisen globuli velati

Meteoreisen is a remedy composed of three potentized mineral substances that are used in anthroposophic medicine:

• phosphorus (D5)

• quartz (D11)

• meteoric iron (D11)

Meteoreisen has been used prophylactically against influenza and colds for many years with success. The Vademecum of Anthroposophic Medicines reports that patients are markedly less susceptible to influenza-like infections, even within institutions.

Phosphorus

Highly dilute phosphorus has been shown to affect the infection of macrophages by parasites, the acute production of RANTES, and to cause an increase in lysosome activity, associated with cell preservation or reduced apoptosis (Naigi et al., 2019). In rats with Chagas disease, treatment with phosphorus 13C modulated the secretion of IFN-γ and TNF-α and was associated with a 52% decrease in inflammatory foci in cardiac tissue (Ferreira et al., 2017).

Silica

Highly dilute silica has been shown to aid in wound healing in mice, by accelerating the rate of repair. Greater effects were seen with higher dilutions of silica (Oberbaum, 1997). A case series (n=25) reported that silica exerted positive effects in the treatment of tubercular lymphadenitis (Chand et al., 2011).

Iron

Highly dilute meteoric iron has been used successfully as a treatment for pleuropneumonia (Girke, 1996). An iron-containing dilute remedy was also used with success in an observational study (n=251) of flu-like illness. In 62,9 % of the treated patients, an improvement of symptoms was observed within the first three days. In total, 234 of 251 patients (93,2 %) were free of symptoms or significantly improved after one week of treatment. The efficacy and tolerance were assessed as very good and good respectively by physicians (88,4% and 98,8% respectively) as well as by patients (86,9 % and 97,2 % respectively) (Rother & Steigerwald, 2007). Highly dilute iron has also been shown to affect hemoglobin levels (Jadhav et al., 2019), which may be relevant in SARS-CoV-2 infection. 

Arsenicum album C30

Arsenicum album C30 is one of the classic homeopathic remedies for flu-like illnesses. Arsenicum was the most widely prescribed remedy in India during the swine flu epidemic (Mathie et al., 2013) and is recommended by the Indian government ministry of AYUSH as a possible prophylactic for COVID-19 (indiatimes.com) based on the symptomatology of the disease as reported in the Lancet. The "symptom picture" for this remedy includes anxiety, fatigue, weakness, GI symptoms, dry cough with frothy mucus, intense fever, and headache (homeopathyworks.com). 

There is clinical evidence of a positive effect on serious viral infections. An RCT (n=612) reported that highly dilute Arsenicum album had a positive effect on the treatment outcome in children with viral encephalitis, with an NNT of only 6.6 and a relative risk reduction of 51% of the endpoint of mortality/neurovegetative state (Oberai et al., 2017).

In vivo, arsenicum has been shown to inhibit parasite replication in malaria-infected mice by 70% (Lira-Salazar et al., 2006).

In vitro, homeopathic dilutions of arsenicum have also been shown to have therapeutic effects in arsenic poisoned leukocytes (Ive et al., 2012). Arsenicum album also has antibacterial effects, exhibiting a 100% inhibition of all the Gram-negative and Gram-positive bacteria tested, regardless of the dilution used, and its activity was identical to the tetracycline used as a positive control (Almaguer-Flores & González-Alva, 2018). 

Potentially Useful 

The  23 compounds in this section have shown strong immunomodulatory and or anti-viral activity but there is either little evidence of an effect against coronaviruses, limited clinical studies or inadequate information available on the safety profile.   

Horse chestnut

Horse chestnut (Aesculus hippocastanum L.) trees are native to the Balkan Peninsula but are grown worldwide. Historically, horse chestnut seed extract was used for joint pain, bladder and gastrointestinal problems, fever, and leg cramps. Today, people use horse chestnut extract as a dietary supplement for chronic venous insufficiency (when the veins of the lower leg are unable to send blood back toward the heart), hemorrhoids, and swelling after surgery (nccih.nih.gov). The use of seed extracts is most common and the main bioactive component is escin (Michelini et al., 2018). 

Escin was identified in a screening study as having activity against SARS-CoV-1 (Wu et al., 2004). It has also shown antiviral activity against several other enveloped viruses in vitro (Michelini et al., 2018). 

Andrographis

Andrographis (Andrographis paniculata) is a herbaceous plant in the family Acanthaceae, native to Indian and Sri Lanka. It is sometimes called the "Indian Echinacea" because it provides many of the same benefits (Arora et al., 2010). 

An in silico study that screened 78 known antivirals against 20 SARS-CoV-2 targets identified A. paniculata as a potentially useful herb for the treatment of COVID-19 (Wu et al., 2020).

Several double-blind RCTs reported that andrographis was effective in reducing the symptoms of upper respiratory tract infections (Saxena et al., 2010; Gabrielian et al., 2002; Caceres et al., 1999; Melchior et al., 2000). A trial that compared andrographis with both echinacea and standard treatment, found a superior effect on cold symptoms with andrographis (Spasov et al., 2004) and a clinical trial comparing amantadine and andrographis in the treatment of influenza found that andrographis showed superior effects (Kulichenko et al.,2003).

Female ginseng

Female ginseng (Angelica sinensis) is a well-known Chinese herbal medicine, that has been used as a tonic and hematopoietic agent for the treatment of gynecological disease for thousands of years (Kataki & Kakoti, 2015). Recent research has shown that the polysaccharides in A. sinensis are the major bioactive components (Jin et al., 2012). 

It has been shown to exert numerous effects on the immune system including an increased proliferation of spleen cells, macrophages, and T cells, improved gene expression, and increased production of IL-2 and IFN-y (Yang et al., 2006). The sulfated polysaccharide (APS-1) from A. sinensis has been shown to inhibit virus replication and increase the reduced thymus/body weight index caused by murine leukemia virus infection (Yang et al., 2012). A. sinensis extract has also been shown to rescue mice from lethal sepsis (Wang et al., 2006). 

Cordyceps 

Cordyceps (Cordyceps sinensis), the Chinese caterpillar fungus or Dong Chong Xia Cao has been used in China for >700 years, mainly as a tonic for nourishing the lungs and kidneys. A recent systematic review and meta-analysis (n=1238) found that it improved lung function in COPD without any serious adverse effects (Yu et al., 2019).

Several research groups have reported that cordycepin has antiviral activity against a number of viruses including influenza virus (Mahy et al., 1973), HIV (Muller et al., 1991), murine leukemia virus (Lonai et al., 1974), and Epstein–Barr virus (EBV) (Ryu et al., 2014). It has also been shown to inhibit HIV-1 in vitro (Zhu et al., 2016). Increasing evidence shows that cordyceps is a bidirectional modulator with both potentiating and suppressive effects on the immune system through the regulation of innate and adaptive immunity (Lin & Li, 2011). 

Epigallocatechin gallate

Epigallocatechin gallate (EGCG), found in green tea, has been shown to modulate the NLRP3 inflammasome (Wang et al., 2019), potentially target the COVID-19 main protease (Mpro) reducing viral replication (ifm.org), and to prevent influenza in healthcare workers (Matsumoto et al., 2011).

In vitro, green tea extract was shown to inactivate the influenza virus A/Puerto Rico/8/34 (H1N1). The results suggested that the virucidal activity of green tea extract is mediated by oxidative crosslinking of catechins to the viral proteins and the change of physical properties of viral membranes (Lee et al., 2018).

Garlic 

Garlic (Allium sativum) has been used for hundreds of years to treat fungal, parasitic, and viral infections. It has been shown to possess antiviral activity against influenza B virus, HSV-1 (Tsai et al., 1985), cytomegalovirus (CMV) (Guo et al., 1993), parainfluenza virus, rhinovirus (Subhose et al., 2005).

A double-blind RCT on healthy participants (n = 120), between 21 and 50 y of age, that consumed aged garlic extract (AGE) or placebo 90 d during the cold and flu season reported that after 45 d of AGE consumption, γδ-T and NK cells proliferated better and were more activated than cells from the placebo group. After 90 d, the AGE group showed reduced cold and flu severity, with a reduction in the number of symptoms, the number of days participants functioned suboptimally, and the number of work/school days missed (Percival et al., 2016). 

Hesperidin

Hesperidin is a citrus flavanone that has, amongst its numerous other activities, been identified as a likely compound to inhibit SARS-CoV-2 based on in silico studies (Chen et al., 2020). It also dose-dependently inhibited the cleavage activity of an important protease in SARS-CoV-1 (Lin et al., 2005). 

Hesperidin has both antioxidant and anti-inflammatory properties and despite its low bioavailability, recent clinical trials support its use as a low-cost therapy with a general lack of side effects (Barreca et al., 2017). It has shown antibacterial action against H. pylori (Barreca et al., 2017) and demonstrated immunomodulatory actions in rats by enhancing interferon (IFN)-γ production and modifying the lymphocyte composition (Camps-Bossacoma et al., 2017).

Hesperidin has also efficacy in improving influenza-induced lung injury in a dose-dependent manner in rats by decreasing the number of immune cells and concentrations of cytokines. However, it neither inhibited virus replication nor rescued infected pulmonary microvascular endothelial cells (Ding et al., 2018).

Hesperidin did not show any inhibitory activity against dengue virus (Zandi et al., 2011) and had no effect on the infectivity of HSV-1, polio-virus type 1, parainfluenza virus type 3 (Pf-3), or RSV, in vitro (Kaul et al., 1985).

Korean red ginseng

Korean red ginseng (the root of Panax ginseng) is one of the most popular medicinal plants used in traditional medicine in East Asian countries. Korean Red Ginseng (KRG) is heat-processed ginseng developed by the repeated steaming and air-drying of fresh ginseng. Compared with fresh ginseng, KRG has been shown to possess greater pharmacological activities and stability because of changes that occur in its chemical constituents during the steaming process (Kyungtaek et al., 2016). Ginsenosides are considered the major bioactive compounds (Kyungtaek et al., 2016).

Studies have demonstrated the immunomodulatory and antiviral effects of red ginseng against RSV, influenza, HIV, HSV, hepatitis A virus (HAV), Hepatitis B virus (HBV), norovirus, rotavirus, enterovirus, and coxsackievirus through multiple mechanisms (Kyungtaek et al., 2016).

Red ginseng extract (RGE) has been shown to have an immunomodulatory effect during RSV infection by balancing Th1 and Th2 immune responses, thus protecting the host from severe pulmonary inflammation (Kyungtaek et al., 2016). RGE also decreased human epithelial cells cell death and viral replication and inhibited the production of proinflammatory cytokines in vitro. RGE treatment has been shown to improve clinical outcomes in mice infected by RSV by preventing weight loss and increasing viral clearance and IFN-γ production in bronchoalveolar lavage cells in mice (Kyungtaek et al., 2016). 

RGE treatment improved the viability of multiple cell types infected with H1N1 influenza and decreased virus-induced cytokine secretion and reactive oxygen species (ROS) production (Kyungtaek et al., 2016). In vivo, RGE orally administered to mice or ferrets prior to viral infection showed antiviral effects against all tested strains of influenza (Kyungtaek et al., 2016). 

RGE treatment alone or in combination with highly active antiretroviral therapy (HAART) showed significant anti-HIV effects in several clinical trials (Kyungtaek et al., 2016). 

Mice administered 200 mg/kg or 400 mg/kg of RGE orally for 10 days and infected with HSV-1 were more resistant to both vaginal and systemic infection, shown by a decrease in clinical severity and an increase in survival rate and viral clearance (Kyungtaek et al., 2016).

Melatonin

Melatonin is a secretory product of the pineal gland that has numerous immune effects. It is also synthesized in the lymphoid organs and there are high-affinity membrane melatonin receptors as well as nuclear binding sites in circulating white blood cells, spleen cells, and thymocytes. 

Melatonin activates both innate and adaptive immune responses and has properties as an inflammatory regulator. It differentially modulates pro-inflammatory enzymes and mediators and can also contribute to the attenuation of the immune response. It acts as a free radical scavenger and stimulates several antioxidant enzymes including GPx, CAT, and SOD. In addition to stimulating cytokines, it also directly stimulates phagocytes, NK cells, and lymphocytes and modulates apoptosis and autophagy (Boga et al., 2012).

A drug repurposing study for COVID-19 based on computational analysis selected melatonin as a possible therapy (Zhou et al., 2020). 

Clinically, positive effects of melatonin treatment have been reported in newborns with sepsis, and in preterm/newborn infants with respiratory distress syndrome (Silvestri & Rossi, 2013). 

In vivo, melatonin administration has been shown to markedly reduce acute lung oxidative injury in RSV-infected mice (Silvestri & Rossi, 2013). Melatonin administration was also reported to have positive effects on multiple strains of viruses causing encephalitis, with reductions in mortality, morbidity and decreased viral loads (Silvestri & Rossi, 2013).

Monolaurin

Monolaurin is the monoglyceride of lauric acid, believed to be responsible for the antiviral effects of coconut. Medium-chain fatty acids are broken down into fatty acids and monoglycerides that can kill or inactivate pathogenic microorganisms in the body. The mechanism of action attributed to monolaurin is that of solubilizing the lipids and phospholipids in the envelope causing the disintegration of the membrane (Arora et al., 2010). There is also evidence that it interferes with signal transduction and viral assembly and maturation (Projan et al., 1994).

A clinical study for treating patients with COVID-19 using monolaurin has been proposed by a group of researchers in the Philippines and coconut oil consumption proposed as a prophylactic measure (icp.org).

Oregano oil

Oregano oil (Origanum vulgare) comes from the leaves and shoots of the oregano plant. The main antimicrobial component of oregano oil is carvacrol. The carvacrol content of oregano oil may be as high as 85%, depending on its geographical origin (Gilling et al., 2014).

The suggestion that oregano oil may be active against SARS-CoV-2 is based on in vitro study (ljaz, 2003) showing that a component of oregano oil had antiviral effects on a strain of human coronavirus. Oregano oil has also shown antiviral effects against HSV, murine norovirus and Newcastle disease virus (Gilling et al., 2014). However, it didn't have any inhibitory effect on influenza (Sökmen et al. 2004). 

Origanum vulgare oil has demonstrated strong antibacterial effects in vitro, with minimum inhibitory concentrations up to 64 times lower than those of ethyl alcohol on Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa (Man et al., 2019).

Palmitoylethanolamide 

Palmitoylethanolamide (PEA) is an anti-inflammatory palmitic acid derivative that interfaces with the endocannabinoid system. 6 clinical trials with a total of nearly 4000 patients and volunteers have shown PEA’s effectiveness and safety for the treatment of influenza and colds (Hesselink et al., 2013). PEA has also been extensively tested in a great variety of animal models for a number of other indications, such as central and peripheral neuropathic pain, pain in osteoarthritis, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease, irritable bowel disease, interstitial cystitis, and other visceral pain states. 

There are multiple mechanisms of action associated with PEA, from inhibition of TNF-alpha and NF-kB to mast cell stabilization. In influenza, it is thought that PEA works by attenuating the potentially fatal cytokine storm (Hesselink et al., 2013).

Japanese knotweed

Japanese knotweed (Polygonum cuspidatum), is a herbaceous perennial plant that grows in Asia and North America. In TCM it is used to suppress cough, promote blood circulation, dispel stasis, expel wind and dampness and dissipate phlegm (Zhang et al., 2013). 

The main active ingredients are emodin and resveratrol. It also contains quercetin. It has shown antiviral effects against HBV, HIV (Zhang et al., 2013), influenza (Lin et al., 2015), EBV (Yiu et al., 2014), and coxsackieviruses (Liu et al., 2013). It has also been shown to modulate the immune system, inhibiting the expression of inflammatory-associated genes (Zhang et al., 2013).

Pyrrosia lingua

Pyrrosia lingua, also called Tongue Fern or Shi Wei in Pinyin, is a less commonly used Chinese herb. The leaves are mainly used in medicine. It is used to treat acute and chronic nephritis, pyelonephritis, cystitis, urethritis, urinary stones, bronchial asthma, and lung-heat induced cough (chineseherbshealing.com). 

It has shown moderate action against HSV (Zheng, 1990) and SARS-CoV-1 in vitro (Li et al., 2005). 

Red spider lily

Red spider lily (Lycoris radiata) is a plant in the amaryllis family, Amaryllidaceae, subfamily Amaryllidoideae that originates from China, Korea, and Nepal. 

L. radiata extract was identified as the most active substance against SARS-CoV-1 in a screen made of 200 TCM plants (Li et al., 2005). Four alkaloids from L. radiata were found to exhibit anti-influenza activities following virus entry into cells (He et al., 2012). 

Reishi

Reishi (Ganoderma lucidum) is an oriental fungus that has a long history of use for promoting health and longevity in many Asian countries (Wachtel-Galor, 2011).

Some small clinical studies have reported beneficial effects of Ganoderma lucidum intake (Wachtel-Galor, 2011). A dried hot water extract of G. lucidum taken orally was used as the sole treatment for postherpetic (varicella-zoster virus) neuralgia in 4 elderly patients. This treatment dramatically decreased pain and promoted the healing of lesions, without any toxicity even at very high doses. In another study, a mixture of G. lucidum with other herbs improved recovery time in patients with herpes genitalis (n = 15) and herpes labialis (n = 13).

In vitro, G. lucidum has shown inhibitory effects on HSV-1, HSV-2, and vesicular stomatitis virus (VSV). It is thought that G. lucidum inhibits viral replication by interfering with early events of viral adsorption (Wachtel-Galor, 2011). 

Some triterpenes from G. lucidum showed an inhibitory effect against HIV-1 via effects on protease activity (Wachtel-Galor, 2011). In another study, a compound isolated from G. lucidum demonstrated inhibitory effects on the replication of the HBV (Wachtel-Galor, 2011).

Resveratrol

Resveratrol (RVT) is a naturally occurring polyphenol stilbene found mostly in fermented grapes, mulberry, red wine, and peanuts. It has been shown to modulate the NLRP3 inflammasome (Tyzsér & Benko, 2016) and to have in vitro activity against MERS-CoV (Lin et al., 2017).

The antiviral mechanisms and effects of RVT have been widely studied in numerous viruses including influenza virus, hepatitis C virus, RSV, varicella-zoster virus, EBV, HSV, HIV, African swine fever virus, enterovirus, human metapneumonia virus, and duck enteritis virus. In almost all of these studies, RVT showed a remarkable reduction of viral infection with the exception of hepatitis C, where disease progression was worsened following the administration of RVT (Abba et al., 2015).  

Chinese rhubarb

Chinese rhubarb (Rheum officinale) has a long history of use in TCM. The major bioactive compounds in rhubarb are sennosides, anthraquinones, stilbenes, glucose gallates, naphthalenes, and catechins (Xiong et al., 2011). 

One of the major anthraquinones, emodin, was shown to inhibit the interaction of the SARS-CoV Spike protein and ACE in SARS-CoV (Ho et al., 2007; Yang et al., 2020). It is included in some of the currently recommended TCM prophylactic programs (Yang et al., 2020). 

Extract of rhubarb has also been shown to prevent the process of HSV attachment and penetration in vitro at a comparable level to acyclovir (Xiong et al., 2011). Emodin demonstrated potent inhibitory activities against coxsackie B5 and RSV in vitro but it couldn't directly inactivate the viruses or block their absorption to cells (Liu et al., 2015). 

Rhodiola

Rhodiola (Rhodiola rosea) is a member of the family Crassulaceae and is a perennial plant that grows at high altitudes in parts of Asia, Europe, and Canada. Several active compounds have been identified, mostly from the rhizome (Khanna et al., 2017). 

An active component, luteolin, was shown to exhibit antiviral effects against SARS-CoV-1 in vitro (Yi et al., 2004).

In a mouse model of sepsis, Rhodiola was shown to have potent anti-inflammatory effects (Khanna et al., 2017). It also exhibited antiviral effects against Dengue, Coxsackie, and hepatitis C viruses. It did not, however, show any effect against infectious bronchitis virus (a coronavirus) (Khanna et al., 2017). 

Star anise 

Star anise (Illicium verum) is an evergreen, medium-sized tree with star-shaped fruit, that is widely distributed throughout southwestern parts Asia. In addition to its use as a spice, it has been used in TCM and Ayurveda and is widely known for its antiviral effects. It is the source of the precursor molecule, shikimic acid, used in the manufacture of oseltamivir (Tamiflu) (Patra et al., 2020). 

Illicium species have also been shown to inhibit HSV (Astani et al., 2009), HIV, Hepatitis B, Coxsackievirus B3, and influenza virus A (H3N2), in vitro (Patra et al., 2020). 

Sweet wormwood

Sweet wormwood (Artemisia annua) is an aromatic, herbaceous plant native to Asia that produces a range of complex terpenoids in its trichomes, amongst which artemisinin is of special interest for the treatment of a range of pathologies.

Extract from A. annua was identified as moderately effective against SARS-CoV in an in vitro screen made up of 200 TCM plants (Li et al., 2005). 

Most of the research of A. annua's antiviral effect has been on double-stranded DNA viruses. The in vitro and in vivo evidence for the activity of artemisinin and its derivatives against DNA viruses of the Herpesviridae and Hepadnaviridae families such as CMV, human herpesvirus 6, HSV 1 and 2, Epstein-Barr virus and Hepatitis B virus is high. The evidence is weaker for Polyomaviruses and papillomaviruses and weaker or no inhibitory activity in vitro has been reported for RNA viruses (HIV, hepatitis C, influenza (Efferth, 2018). 

Indian gooseberry 

Indian gooseberry (Phyllanthus emblica) is a deciduous tree of the Euphorbiaceae family, also known as Amla in Hindi.

A methanol extract of the fruit has been shown to have a potent inhibitory action against HIV-1 reverse transcriptase. It has also been used against hepatitis A and B and influenza B. In vitro studies have shown activity against influenza, enteroviruses, human papillomaviruses, and HSV (Xiang et al., 2011). 

It has also shown immunomodulating and cytoprotective effects in lymphocytes (Sai Ram et al., 2001). 

Wellmune

Wellmune is a baker's yeast beta-glucan. Bakers yeast beta-glucan is a naturally occurring polysaccharide derived from the cell wall of baker's yeast (Saccharomyces cerevisiae) (Cox, 2017). Wellmune is collected by gut immune cells and processed by macrophages into a biologically active form that binds to neutrophils. It increases chemotaxis and enhances complement-mediated killing of nonself cells (Cox, 2017).

A double-blind RCT concluded that daily oral beta 1,3/1,6 glucan may protect against upper respiratory tract infections (URTI) and reduce the duration of URTI symptoms once infected in older people. This may be linked to effects on innate immune function (Fuller et al., 2017). Numerous other studies have shown positive effects on immune function (Cox, 2017).

Recommended Basic Supplementation 

Vitamin D

Vitamin D is a group of fat-soluble secosteroids with multiple biological effects. There is compelling evidence of an association between low Vitamin D and a variety of viral infections in observational studies (Teymoori‐Rad et al., 2018). The underlying mechanisms are only beginning to be clarified.

Vitamin D is involved with the induction of antimicrobial peptides such as LL37 and human beta-defensin that play an important role in innate immune defense against intracellular pathogens. It also has an important immunomodulatory function through suppression of inflammatory cytokine production and differential effects on lymphocytes. Additionally, it interacts with key viral factors and induces autophagy and apoptosis (Teymoori‐Rad et al., 2018).

A meta-analysis (n=11,321) reported that vitamin D supplementation prevented upper respiratory infections (Martineau et al., 2019). 

Zinc

Zinc is the second most abundant trace metal in the human body and is a structural component of ca. 750 transcription factors and catalytic component of 2000 enzymes (Read et al., 2019). The global prevalence of zinc deficiency is estimated to be about 20%. 

Zinc possesses antiviral properties against several viruses in vitro, including SARS-CoV (Read et al., 2019). Zinc appears to inhibit viral proteases and polymerases as well as physical processes such as viral attachment and uncoating (Read et al., 2019). It also exerts immunomodulatory effects on cytokine secretion and potency and receptor binding. 

Clinical studies are primarily limited to rhinovirus infection, the majority of which used zinc lozenges at varying concentrations, leading to variability in results (Read et al., 2019). High doses of ionic zinc have been shown to reduce the duration of colds by 42% (Read et al., 2019). Year-long zinc supplementation in elderly subjects resulted in a dramatic reduction in infection incidence and plasma oxidative stress markers (Read et al., 2019).

Probiotics

Probiotics have been shown to significantly influence the immune system in several ways (Frei et al., 2015). Probiotics can induce retinoic acid metabolism, a crucial immunomodulatory activity of antigen-presenting cells (Frei et al., 2015). Additionally, bacterial cell wall components and metabolites have been associated with immunomodulatory effects on dendritic cells. A Cochrane review found that probiotics were better than placebo in reducing the number of episodes, mean duration of an episode and antibiotic use associated with upper respiratory tract infections (Hao et al., 2015).

Bifidobacterium lactis HN019 is a well-characterized probiotic strain with documented effects in the area of immune system modulation (Sanders, 2006). A recent systematic review on healthy elderly adults reported that B. lactis HN019 supplementation was highly efficacious in increasing PMN phagocytic capacity and moderately efficacious in increasing NK cell tumoricidal activity (Miller et al., 2017). 

Lactobacillus gasseri is a type of probiotic that is found in the lower reproductive tract of healthy women. A group of Korean researchers recently identified that L. gasseri interferes in the acquisition of purine, an energy source required by SARS-CoV-2 (koreabiomed.com).

Oral administration of L. gasseri SBT2055 has also been shown to induce IgA production and number in Peyer's patches. IgA plays an important role in hose defense against mucosally transmitted pathogens (Frei et al., 2015).

NAC

N-Acetyl Cysteine (NAC) is a widely used glutathione (GSH) precursor with well-documented pharmacokinetic and safety profiles (Fraternale et al., 2006). It can inhibit the activation and nuclear translocation of NFkB and is a precursor of cysteine, which is itself, a substrate for GSH synthesis and an inhibitor of NFkB (Fraternale et al., 2006). NAC is also FDA-approved as an inhalation formulation for a wide range of pulmonary conditions. NAC (in combination with heparin) is being currently being tested in a COVID-19 clinical trial (biospace.com).

A clinical trial of preventative NAC treatment in mostly elderly subjects was well tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. N-acetylcysteine did not prevent H1N1 virus influenza infection but significantly reduced the incidence of clinically apparent disease (De Flora, 1997). 

NAC has also been shown to improve dengue virus-associated clinical manifestations, including leucopenia and thrombocytopenia, liver injury and hepatocyte apoptosis. It also significantly reduced virus reproduction in the liver of mice through the induction of antiviral responses via interferon signaling and helped to maintain antioxidant enzymes and redox balance (Sreekanth et al., 2019). 

NAC significantly alleviated myocardial injury caused by coxsackievirus in mice by suppressing viral replication and inhibiting viral proteases and the inflammatory response (Wang et al., 2019).

NAC reduced influenza-induced cytopathogenic effects (CPEs), virus-induced apoptosis, infectious viral yields, production of pro-inflammatory molecules and reduced monocyte migration in vitro (Geiler et al., 2010). NAC has also been shown to inhibit RSV (Li et al., 2017), HIV and HSV (Fraternale et al., 2006).

Selenium

Selenium (Se) is an essential micronutrient that has several important functions involving the immune system. The biological effects of Se are mainly exerted by its incorporation into selenoproteins, that are then involved in both the innate and adaptive immune system (Huang et al., 2012). In addition to enhancing immunity, Se also has immunomodulatory effects. On a cellular level, Se influences various leukocyte functions. 

Se levels may influence the virulence of RNA viruses (Huang et al., 2012). Data from human studies on whether Se supplementation in HIV positive individuals can reduce mortality and morbidity are inconclusive but there is in vitro evidence that Se supplementation reduces HIV pathogenesis (Huang et al., 2012). Studies that have compared the effect of influenza on Se deficient, adequate and supplemented mice demonstrate the importance of Se for viral clearance and recovery (Huang et al., 2012).

Vitamin A

Vitamin A is a micronutrient with functions including maintenance of vision and integrity of epithelial and mucosal tissues, growth and immune functions (Huang et al., 2018). Immune system organs require constant dietary intake to maintain vitamin A concentrations (Huang et al., 2018). Vitamin A deficiency has been shown to lead to defects in both T cell-mediated and antibody-mediated immune responses (Huang et al., 2018).

Vitamin A plays a crucial role in the regulation of the differentiation, maturation, and function of the cells of the innate immune system (Huang et al., 2018). Vitamin A inhibits the measles virus by up-regulating elements of the innate immune response in uninfected cells, protecting them against infection during future rounds of viral replication (Zhang et Liu, 2020).

In chickens fed a diet marginally deficient in vitamin A, infection with a type of coronavirus that causes bronchitis was more pronounced (Zhang et Liu, 2020). 

Vitamin C

Vitamin C is a water-soluble micronutrient that supports immune function. Reduced levels of vitamin C in patients with pneumonia have been reported in multiple studies (Hemila, 2011) and clinical trials have reported a significantly lower incidence of pneumonia with vitamin C supplementation (Zhang et Liu, 2020). Vitamin C improves chemotaxis, enhances neutrophil phagocytosis and oxidative killing and supports lymphocyte proliferation and function (Biancatelli et al., 2020). It also increases the production of a/b IFN and downregulates the production of inflammatory cytokines (Biancatelli et al., 2020).

Vitamin C has been shown to inhibit EBV, CMV, many types of herpes viruses, poliovirus, Venezuelan equine encephalitis, human lymphotrophic virus, HIV, parvovirus and rabies virus in vitro (Biancatelli et al., 2020). In mice, there was a dose-dependent reduction in mortality from influenza with vitamin C and the lungs showed reduced injury (Biancatelli et al., 2020). 

High-dose vitamin C is currently in clinical trials in intensive care COVID-19 patients (nutraingredients.com). 

Not Recommended 

For the remaining 12 substances, we were unable to identify sufficient in vivo or clinical evidence of antiviral or immunomodulatory effects, or in some cases, evidence of safety in humans.  

Japanese evergreen spicebush

Japanese evergreen spicebush (Lindera aggregata) is a herb used in TCM made from the roots of L. aggregata, a plant species in the family Lauraceae. It is also commonly known as radix lindera or evergreen lindera. 

Basic uses and indications include abdominal pain and bloating, chest discomfort, dyspnea due to circulation of vital energy in the wrong direction, deficient and cold urinary bladder, enuresis, frequent urination, hernia, and dysmenorrhea. The recommended dosage is from 3 to 9 grams in decoction (chineseherbshealing.com). 

It was found to have in vitro activity against SARS-CoV (Li et al., 2005). 

This herb is not often used in isolation and we were unable to identify any in vivo studies supporting its use as an antiviral or immune enhancer. 

Kaempferol

Kaempferol (KP) is a natural flavonol, a class of flavonoids, found in many fruits vegetables and herbs.

It was reported that KP had in vitro activity against a protease of SARS-CoV (Schwarz et al., 2014). However, a more recent study has shown that it is ineffective for this purpose (Jo et al., 2019).

Additionally, the oral absorption of KP is poor and KP reduces the bioavailability of iron and folic acid. It is unknown whether KP is toxic in supplemental doses and requires further investigation (Ren et al, 2019). 

Naringenin

Naringenin is a flavonoid belonging to the flavanones subclass. It is widely distributed in citrus fruits. It has shown a dose-dependent inhibitory effect against dengue, chikungunya and Hepatitis C in vitro. It is also an immunomodulator, acting as a post-translational inhibitor of TNF-a and Il-6, iNOS, NF-kB, and COX-2. It was shown to reduce oxidative stress and lung injury in rats. In vitro, it was shown to increase B cell proliferation and NK activity (Salehi, 2019).

Naringenin is poorly absorbed. Very few clinical studies have been carried out (Salehi, 2019). In a screen of potentially active flavonoids, naringenin was not found to significantly inhibit SARS-CoV-2 (Jo et al., 2020).

Propolis

Propolis is a natural resinous mixture produced by honey bees from substances collected from parts of plants, buds, and exudates.

The pharmacological activity of the components of propolis has been studied in several viruses including influenza virus, HIV, adenovirus, HSV (Schnitzler et al., 2009), and coronavirus (Debiaggi et al., 1990). The effects appear greatest in herpesviruses and propolis has shown superior effects in clinical trials for HSV 1 and 2 compared with acyclovir (Jautová et al., 2018; Vynograd et al., 2000). However, the effect on the other types of viruses is limited and did not affect viral infectivity (Debiaggi et al., 1990). 

We were unable to identify any evidence that it may have activity against SARS-CoV-2.

Boswellia

Boswellia, also known as Indian frankincense, is a herbal extract taken from the Boswellia serrata tree.

Boswellia extract inhibited HSV-1 through the modulation of the NF-κB and p38 MAPK pathway (Goswami et al., 2018). It also inhibited chikungunya and vesicular stomatitis viruses in vitro (von Rhein et al., 2016).

We were unable to identify any clinical evidence that it has antiviral effects.

Olive leaf extract

Olive leaf extract (OLE) contains phenolic compounds, specifically oleuropein, that have demonstrated antimicrobial, antioxidant, and anti-inflammatory activity. Oleuropein and derivatives such as elenolic acid have been shown to be effective in in vitro and animal studies against retroviruses, coxsackieviruses, influenza, and parainfluenza (Roxas & Jurenka, 2011). 

An RCT reported that OLE supplementation did not significantly reduce upper respiratory tract infection incidence, but did decrease duration in high school athletes (Somerville et al., 2019)

There is little clinical evidence overall and nothing related to coronaviruses.

Colloidal silver

Colloidal silver consists of tiny silver particles in a liquid and has been used historically as one of the first "antibiotics" (Morrill et al., 2013). Silver is a common constituent of medical prostheses and has been used to control postoperative infections and in the treatment of burns (Morrill et al., 2013).

In vitro studies show strong bactericidal effects on multiple species of bacteria (Morrill et al., 2013). However, it was ineffective at inhibiting the replication or spread of the viruses tested (Morrill et al., 2013). 

We were unable to identify any evidence that it has antiviral effects.

Serrapeptase

Serrapeptase is an enzyme isolated from bacteria found in silkworms.

Serrapeptase may be effective at reducing the risk of bacterial infections by destroying or inhibiting the formation of bacterial biofilms (Selan et al., 2015). It has been shown to increase the effectiveness of antibiotics (Sannino et al., 2013).

We were unable to identify any evidence that it has antiviral effects.

Rosmaranic acid

Rosmarinic acid (RA) is a polyphenolic compound widely found in the plant kingdom, most in medicinal plants (Nunes et al., 2015). It has been shown that oral supplementation with RA can be effective in the treatment of seasonal allergic rhinoconjunctivitis, due to inhibition of the inflammatory response and antioxidant effects. 

RA was shown to have some antiviral effect on HSV in vitro (Nolkemper et al., 2006). It inhibits the replication of HBV in vitro (Tsukamoto et al., 2018), enterovirus in vitro (Chen et al., 2017) in vivo (Lin et al., 2019), lung injury due to influenza (Liu et al., 2017), and Japanese encephalitis in mice (Swarup et al., 2007). 

A molecular docking study for new agents for SARS-CoV-2 that screened RA did not place it near the top of the list (Yan et al., 2020). 

We were unable to identify any clinical evidence that it has antiviral effects.

Barberry

Barberry (B. vulgaris) is a shrub in the genus Berberis found in North America, Europe and Asia that is both used medicinally and consumed as a food product (Kalmarzi et al., 2019). Berberine, one of the main bioactive compounds, has been shown to reduce inflammatory cytokines in mice and in vitro, in human pulmonary cells. It also inhibited the expression of COX2 and shifted the immune response from a Th1 to a Th2 response (Kalmarzi et al., 2019). 

We were unable to identify any evidence that it has antiviral effects.

Apigenin

Apigenin is one of the most widespread flavonoids in plants and belongs to the flavone sub-class (Salehi et al., 2019). 

Apigenin reportedly has antiviral activity (Tapas et al., 2008) and is known to decrease levels of IL-6 in vitro (Salehi et al., 2019). 

We were unable to identify any clinical evidence that it has antiviral effects.

Apigenin did not show a high-efficiency in inhibiting SARS-CoV compared with other flavones (Ryu et al., 2010).

Lysine

Lysine is an amino acid that may be protective against the symptoms of HSV. Lysine is an analog of Arginine, which is considered a nutrient to HSV and promotes replication, and the presence of lysine can stop the virus from replicating (Griffith et al., 1981). Prophylactic oral lysine supplementation reportedly decreased the frequency of flareups but the benefits dissipated within a week or two of stopping the lysine supplementation (Thein et al., 1984).

We were unable to identify any evidence that it has a positive effect on any virus other than HSV. 

Additionally, lysine may increase the risk of high viral load in HIV as an in vitro study showed an increase in the copies of HIV-RNA in lysine-supplemented samples (Butorov, 2014).

Summary Table 

A brief summary of the 8 recommended antivirals/immunomodulators and 7 compounds recommended for basic supplementation.