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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 (