COVID-19: Is There Evidence for the Use of Herbal Medicines as Adjuvant Symptomatic Therapy?

¹Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil
²School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom
³School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
⁴Biophysics and Biochemistry Center, Venezuelan Institute of Scientific Research, Caracas, Venezuela
⁵Center of Health Sciences, Federal University of Espirito Santo, Vitória, Brazil
⁶Faculty of Pharmacy, Medical University of Bialystok, Bialystok, Poland
⁷Pharmacognosy and Phytotherapy, School of Pharmacy, University College of London, London, United Kingdom

Background: Current recommendations for the self-management of SARS-Cov-2 disease (COVID-19) include self-isolation, rest, hydration, and the use of NSAID in case of high fever only. It is expected that many patients will add other symptomatic/adjuvant treatments, such as herbal medicines.

Aims: To provide a benefits/risks assessment of selected herbal medicines traditionally indicated for “respiratory diseases” within the current frame of the COVID-19 pandemic as an adjuvant treatment.

Method: The plant selection was primarily based on species listed by the WHO and EMA, but some other herbal remedies were considered due to their widespread use in respiratory conditions. Preclinical and clinical data on their efficacy and safety were collected from authoritative sources. The target population were adults with early and mild flu symptoms without underlying conditions. These were evaluated according to a modified PrOACT-URL method with paracetamol, ibuprofen, and codeine as reference drugs. The benefits/risks balance of the treatments was classified as positive, promising, negative, and unknown.

Results: A total of 39 herbal medicines were identified as very likely to appeal to the COVID-19 patient. According to our method, the benefits/risks assessment of the herbal medicines was found to be positive in 5 cases (Althaea officinalis, Commiphora molmol, Glycyrrhiza glabra, Hedera helix, and Sambucus nigra), promising in 12 cases (Allium sativum, Andrographis paniculata, Echinacea angustifolia, Echinacea purpurea, Eucalyptus globulus essential oil, Justicia pectoralis, Magnolia officinalis, Mikania glomerata, Pelargonium sidoides, Pimpinella anisum, Salix sp, Zingiber officinale), and unknown for the rest. On the same grounds, only ibuprofen resulted promising, but we could not find compelling evidence to endorse the use of paracetamol and/or codeine.

Conclusions: Our work suggests that several herbal medicines have safety margins superior to those of reference drugs and enough levels of evidence to start a clinical discussion about their potential use as adjuvants in the treatment of early/mild common flu in otherwise healthy adults within the context of COVID-19. While these herbal medicines will not cure or prevent the flu, they may both improve general patient well-being and offer them an opportunity to personalize the therapeutic approaches.

Introduction

The outbreak of Coronavirus SARS-Cov-2 disease (COVID-19) in Wuhan (China) in late 2019 and its Worldwide spread has caused hundreds of thousands of deaths so far. As of July 2020, the disease seems to be mostly affecting Europe and the Americas. Most people infected with the COVID-19 virus will experience mild to moderate respiratory illness and recover without requiring special treatment. Older people and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness (WHO, 2020a). Teens and adults without underlying medical conditions are asked to self-manage their symptoms in isolation with a minimum of drugs (paracetamol, if fever is high) and lifestyle adjustments (increased rest and hydration). However, most of the current guidelines do not specifically advise on how to treat cough, one of the main symptoms, which, apart from being very debilitating, contributes to the spread of the virus.

There is not yet any evidence-based specific therapy for COVID-19, and the real efficacy and safety of current therapeutic approaches will need further scrutiny when enough multi-site clinical data become available. The examples of ibuprofen and hydroxychloroquine illustrate how clinical protocols may include and/or exclude drugs in their therapeutic approaches based on limited evidence (Kim et al., 2020; Sodhi and Etminan, 2020; Taccone et al., 2020; Torjesen, 2020). Predictably, patients will largely try to increase their well-being at least by self-administering cough suppressing medication (natural or not) plus natural medication or supplements to combat cold/flu symptoms. These are readily accessible both in retail commerce and community pharmacies. In Europe, there are several herbal medicines registered under the European Directive 24/2004 for self-prescription (EU, 2004). Their labeling establishes that these medicines are indicated for the treatment of common cold and flu symptoms based on traditional use only. We agree in that COVID-19 is not the common flu, but the WHO definition is clear in that it is a mild, self-limiting condition and, therefore, fitting the boundaries of self-prescription, moreover if the patients have not been tested for the virus (WHO, 2020a). In that sense, there is a need to clarify the real potential and safety profile of herbal medicines to scientifically substantiate future recommendations on their benefits and risks of use them. Therefore, the impetus of this work is twofold. First, it intends to highlight which species may provide a more rational phytotherapeutic choice to the disease and second to showcase which plants can be a clinically compatible option as adjuvant therapy for the self-management of common cold/flu symptoms by otherwise healthy adults within the context of the COVID-19 pandemic.

Clinical Background

Early COVID-19 symptoms include fever, dry cough, and dyspnea, among other similar ones to other viral respiratory diseases such as common flu (Rothan and Byrareddy, 2020). Therefore, the diagnosis of COVID-19 based on anamnesis remains problematic. In general, the incubation period is around 15 days, but the reported range is 0 to 24 days (Bai et al., 2020). SARS-Cov-2 presents a strong transmission capacity (Zheng et al., 2020). To complicate matters further, there is a significant number of asymptomatic patients (up to 60%) who unknowingly contribute to the spread of the disease (Gao et al., 2020; Kronbichler et al., 2020).

The clinical spectrum of the infection goes from mild upper respiratory tract illness to the so-called ‘severe acute respiratory syndrome’: respiratory failure, shock, and multiple organ failure (Bai et al., 2020; Zhou et al., 2020); and may be accompanied by fatigue, headache, diarrhea, and lymphopenia (Rothan and Byrareddy, 2020), and high incidence of cardiovascular symptoms (Zheng et al., 2020). Older people and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop severe illness (WHO, 2020a).

The precise pathology of the disease is not yet clear, but seems to include a systemic pro-inflammatory response, inducing hemodynamic changes and, consequently, a predisposition to ischemia and thrombosis (Tang et al., 2020; Zheng et al., 2020; Zhou et al., 2020). A hallmark of the disease is the “cytokine storm”, a massive cytokine and chemokine release due to an uncontrolled dysregulation of the host immune defense that causes loss of function of multiple organs (Catanzaro et al., 2020).

Preventative and Therapeutic Approaches

Due to the emergence of the propagation of the disease, Health Systems have become overloaded, even having sufficient diagnostic capacity and hospital facilities to handle such an outbreak. In the most vulnerable regions, the COVID-19 epidemic effectively paralyzes health systems at the expense of primary health care (Velavan and Meyer, 2020). Some measures, such as lock-down of communities, social distancing, and quarantine-type for those suspected to be infected can, at least in part, slow the COVID-19 spread (Heymann and Shindo, 2020) and, so, enable the health systems to cope. However, these measures are palliative, and people tend to ignore them after a few days of isolation, mainly those in disadvantaged and vulnerable communities.

Importantly, at this stage, we are starting to build up an evidence-base for the best strategy to treat, mitigate, and prevent the diseases. Currently, none of the approaches used is evidence-based.

In the worldwide search for a response to the COVID-19 pandemic, news about “alternative remedies against COVID” have been disseminated (ANSES, 2020; Nordling, 2020). As of July 2020, the evidence-base for such treatments is often limited if not non-existent. However, often strong, unsubstantiated claims are made about the pros and cons of herbal medicines, which will also result both in false hopes or strong fears of those at risk or ill with COVID-19 (Brennen et al., 2020; Guastalegname and Vallone, 2020; Thorp, 2020).

While some preparations have been claimed to be specifically active, some commonly used medicinal plants are assessed here, especially those on the WHO list of selected medicinal plants, as adjuvant treatments. For example, Hensel et al. (2020), in their recent work, state that extracts prepared with Echinacea species (Asteraceae) have an important role with the immune system due to their alkylamide interacting with the cannabinoid receptors (Hensel et al., 2020). Additionally, curcumin, the main constituent in Curcuma longa L. (Zingiberaceae), is suggested as a potential clinical option for the treatment of SARS-CoV-2 infection, due to its action in several steps of a viral infection such as protease inhibition, cellular signalling pathways modulation, among others (Zahedipour et al., 2020)

In another paper (Panyod et al., 2020), 11 medicinal plants were discussed concerning their in vitro antiviral activity using different models. Two species (Allium sativum L. and Zingiber officinale Roscoe) mentioned in this study that had their in vitro potential and immune capacity assessed, were also included in our study. Moreover, in an elegant evidence-based analysis, eighteen phytotherapeutic preparations were mentioned as having some role in the clinical management of viral respiratory diseases, showing different levels of immunological response (Portella et al., 2020). Four plants mentioned in that report [Echinacea purpurea (L.) Moench, Glycyrrhiza glabra L., Sambucus nigra L., and Scutellaria baicalensis Georgi] were also included in our study.

The rationale used in our study was to include, mostly, species known in the Americas and Europe and those already more widely available for the management of respiratory conditions (Blumenthal, 2003; Edwards et al., 2015; Anheyer et al., 2018; Langeder et al., 2020), mainly regarding the symptoms (cough, pain, fever). We recognize that patients suffering from COVID-19 are likely to seek such herbal medications. Complementing other papers published on medicinal plants and their potential to be used for COVID-19, we focused on the therapeutic potential of 39 species, the limitations for their use, and their possible risks. It must be strongly emphasized that this is not an assessment of any mainline treatment for COVID-19 with such herbal medicines. The focus is on assessing their potential as adjuvant therapies to COVID-19. Although the listed herbal drugs included herein have been used for a long time, the evidence level of their action in the relief of mild respiratory symptoms varies, and they are pointed out here.

The Frame of the Problem

● Apart from a handful of antiviral drugs with limited efficacy, there is only symptomatic therapy for influenza.

● There is no specific therapy for COVID-19.

● There are several herbal medicines recognized by various Health Authorities for the treatment of flu, its symptoms, and other respiratory disorders.

● Health authorities in Europe and the Americas have warned the population against taking any natural/herbal medicines/supplements. They sustain this advice on theoretical potential effects on the immune system due to unspecific anti-inflammatory effects in early stages, facilitating the infection as well as potential immunostimulation, contributing to the aggravation of the “cytokines storm”. As of today, there is no clinical backup for such strong recommendations other than trying to prevent unspecific herb-drug interactions should the patient need emergency care.

● There is a significant OTC use for these herbal medicines, and a realistic prospect is that patients will self-administer them to increase their well-being.

Aims

To apply a decision-making framework to provide a benefits/risks assessment for selected herbal medicines traditionally indicated for “respiratory diseases” within the current frame of the COVID-19 pandemic.

Methods

For a treatment to be recommended as adjuvant therapy for respiratory diseases in the context of COVID-19, we here determine that the treatment is effective and that its expected benefits outweigh its potential risks to patients. Briefly, this assessment is informed by the body of evidence about each treatment’s safety and efficacy retrieved in a literature search. This assessment is also informed by a number of other factors, including the severity of the underlying condition and how well patients’ medical needs are addressed by currently available therapies (“reference drugs”). The decision also reflects current applicable laws, regulations, and healthcare recommendations, taking into consideration the uncertainty associated with COVID-19.

Selection of Herbal Medicines

A search was conducted, considering herbal medicines traditionally used to relieve cold and flu symptoms. The criterion used to limit the investigation, and to grant minimal evidence of efficacy was that the species, linked to the chosen indications, must be listed at least in one of the following organizations: World Health Organization Monographs (WHO); European Medicines Agency (EMA); European Scientific Cooperative on Phytotherapy; ANVISA (Brazilian Pharmacopoea, Brazilian Pharmacopoea Herbal Medicines Formulary, Brazilian Pharmacopoea Herbal Medicines Mementum), Ministry of Health of Chile, Ministry of Health of Cuba, Ministry of Health of Colombia, and Government of Canada. Several South American Countries use the Brazilian Pharmacopeia documents as a reference, so they are also covered within this search. Based on these documents, a list of target species was prepared to establish a search of clinical evidence for the given indication. We refer to these as “herbal medicines” as they are endorsed by Scientific and/or Regulatory committees.

We also included some species which are not listed in monographs based on their significant widespread use in the self-management of respiratory diseases. Some of them are also linked to food uses. We refer to these as “herbal remedies”.

We did not consider species that have given rise to major safety concerns (such as Ephedra sp.) and species which are only indicated for relieving mucous phlegm. Furthermore, we do not assess multi-herbal preparations.

Decision-Making Framework

To assist our decision-making and/or the benefits/risks assessment of herbal medicines, we adopted some of the procedures described in many qualitative or semi-quantitative guidelines to conduct a benefit-risk assessment (PROTECT, 2020). They consist of a step-by-step approach to follow for good decision-making practice and to increase transparency. Descriptive frameworks are usually general, and most of the time, reiterate common sense. Our framework is inspired by the PrOACT-URL method (EMA, 2011c).

The main decision-making elements that we considered for this work are:

A. Frame the problem. The appearance of early/mild respiratory symptoms during the pandemic including fever, cough, catarrh, aches, and pains, nasal congestion, runny nose, sore throat, cough, sneezing (= Condition) in adults otherwise healthy (= Target Population). The patient did not have a test or was negative for COVID-19, but continues at risk of infection (= Uncertainty). The patient uses herbal medicines alone or with drugs (= Treatment, main or adjuvant). The patient experiences relief of upper respiratory symptoms within 1-2 weeks (= Favorable effect). The treatment interferes with hospital/emergency treatment in case of severe acute respiratory syndrome (Unfavorable effects).

B. Set criteria for Favorable/Unfavorable effects. We followed the “General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine-World Health Organization” for clinical evidence (WHO, 2000) (Table 1). We agreed on six key criteria for safety (Table 2).

C. Consider options to be evaluated against the treatment. Currently available over-the-counter (OTC) medications endorsed by health authorities are non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, naproxen, etc.), antipyretics (acetaminophen/paracetamol), and cough medicines (dextromethorphan, codeine, etc.). They may be taken as monotherapy or alternating therapies. Therefore, one of each category (ibuprofen, paracetamol, and codeine) was chosen to be evaluated based on the same criterion.

D. Assess the balance between favorable and unfavorable effects and the associated uncertainty. All possible combinations of clinical and safety grades lead to four possible results: “positive”, “promising”, “negative”, and “unknown”. The last two categories allowed for the inclusion of two different degrees of uncertainty (Table 3).

E. Recommendation. See conclusions.

TABLE 1

Table 1 Grading criteria for clinical evidence of the treatments.

TABLE 2

Table 2 Grading criteria for safety level of the treatments and its evidence.

TABLE 3

Table 3 Benefits/Risks Decision Consensus Criteria.

Retrieval of Evidence and Grading

In the second step, we assessed the existing clinical evidence and safety data of all shortlisted herbal medicines and remedies through a bibliographic search, including PubMed, Web Of Science, and other available sources, using the terms “<plant name>” AND cough OR flu OR cold. Also, Cochrane, Drug.com, governmental agencies (EMA, ANSES, and others) were used.

All possible combinations of clinical and safety grades lead to four possible results: “positive”, “promising”, “negative”, and “unknown”. The last two categories allowed for the inclusion of two different degrees of uncertainty. Table 3 shows how the consensus criteria were translated into a preliminary benefits/risks assessment.

We are aware that for many herbal drug preparations, preclinical evidence exists, and this is not considered in this assessment since it cannot be translated directly into clinical practice. However, such estimation might be of relevance to unveil potential mechanisms of action only so in that case this information was included.

Results

Options to Be Evaluated Against the Criteria

Based on the defined parameters, three recommended drugs for early symptoms of COVID-19 – codeine, ibuprofen, and paracetamol – were evaluated.

Ibuprofen

Indications in the context of respiratory conditions. Fever, pain, inflammation.

Posology. Up to 2,400 mg a day in doses not bigger than 400 mg every 6 h.

Preclinical evidence. In vitro and in vivo studies showed evidence of antipyretic and mild analgesic activities (Rainsford, 2015).

Clinical evidence. In a review on the effects of non-steroidal anti-inflammatory drugs (NSAIDs) for treating pain or respiratory symptoms (e.g., cough associated with the common cold), the conclusion was NSAIDs are somewhat effective in relieving the discomfort caused by cold. However, there is no clear evidence of their effect in easing respiratory symptoms. Therefore, the balance of benefits and risks needs to be considered when using NSAIDs for colds (Kim et al., 2013). There is an ongoing clinical trial in the UK with COVID-19 patients receiving a liquid ibuprofen formulation on top of standard care (ClinicalTrials.gov, 2020). Overall, the clinical evidence is High.

Safety. Side effects of ibuprofen include anemia, decreased hemoglobin, eosinophilia, hemorrhage, vomiting, and hypertension. Other side effects include upper gastrointestinal hemorrhage, upper gastrointestinal tract ulcers, dizziness, and dyspepsia. A comprehensive list of very common (10% or more) to common (1% to 10%) adverse effects include nausea (up to 57%), vomiting (up to 22%), flatulence (up to 16%), diarrhea (up to 10%); epigastric pain, heartburn, abdominal distress, indigestion, dyspepsia, abdominal discomfort, constipation, abdominal cramps/pain, fullness of GI tract, bloating, GI hemorrhage, melena (1% to 10%) (Drugs.Com, 2020a). However, regarding COVID-19 patients, there is not enough evidence supporting the potential harmful effects (Sodhi and Etminan, 2020). Overall, safety is Medium.

Specific warnings and precautions of use. Ibuprofen may cause severe cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may be increased in patients with cardiovascular disease or risk factors for cardiovascular disease. Ibuprofen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. NSAIDs can also cause an increased risk of serious gastrointestinal adverse events, especially in the elderly, including bleeding, ulceration, and perforation of the stomach or intestines, which can also be fatal (McGettigan and Henry, 2011).

Overall assessment. According to well-established use, ibuprofen may be useful in the symptomatic relief of respiratory conditions by reducing fever and aches. However, there is only a relatively low number of clinical studies, and meta-analyses do not provide consistent evidence that ibuprofen is effective in reducing symptoms and duration and prevention of the common cold. Overall, the clinical evidence is High. Ibuprofen may have antiplatelet activities; its safety may be considered Medium.

Codeine

Indications in the context of respiratory conditions. Cough.

Posology. Up to 360 mg a day in doses not bigger than 60 mg every 4 h.

Preclinical evidence. Some in vitro, ex vivo, and in vivo studies show evidence of anti-cough activity (Ohi et al., 2007; Cui et al., 2019).

Clinical evidence. Although codeine is widely used as antitussive, the clinical evidence supporting this action is controversial. A study, involving 91 adults presenting cough associated with acute upper respiratory tract infection, showed codeine statistically had the same effect than vehicle (syrup) in controlling cough (Eccles et al., 1992). Overall, the clinical evidence is Low.

Safety. Commonly reported side effects of codeine include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation. Other possible effects include bronchospasm, laryngospasm, respiratory depression; heartbeat irregularities, blood pressure changes, syncope, itching, facial swelling, pruritus, urticaria, histamine release; dry mouth, loss of appetite, nausea, vomiting, paralytic ileus, toxic megacolon, anorexia, stomach cramps; miosis, blurred or double vision; euphoria, dysphoria, unusual dreams, hallucinations, insomnia, anxiety (0.1% to 1%); respiratory arrest, dyspnea; flushing, hypotension, palpitations, circulatory depression, shock, cardiac arrest, circulatory depression, bradycardia, tachycardia, edema (Drugs.com, 2019). Overall, safety is Low.

Specific warnings and precautions of use. Death due to respiratory depression has been reported in children (Friedrichsdorf et al., 2013; Tobias et al., 2016). Moreover, codeine can lead to opioid misuse, abuse, and addiction (Casati et al., 2012).

Overall assessment. According to established use, codeine may be useful in the symptomatic relief of cough. However, clinical studies and meta-analyses do not provide consistent evidence that codeine is effective in treating cough. Overall, the clinical evidence is Low. Due to the severe side effects, codeine safety may be considered Low.

Paracetamol

Indications in the context of respiratory conditions. Fever, pain.

Posology. Up to 4 g a day in dose not bigger than 1 g every 6 h.

Preclinical evidence. Numerous in vitro and in vivo studies show evidence of antipyretic and mild analgesic activities (Graham et al., 2013).

Clinical evidence. Paracetamol (acetaminophen) did not show any efficacy in flu, according to a clinical trial involving 80 patients (Jefferies et al., 2016). In a systematic review, the authors concluded that the data did not provide sufficient evidence to inform practice regarding the use of acetaminophen for common cold in adults (Li S. et al., 2013). Overall, the clinical evidence is Low.

Safety. Paracetamol (acetaminophen) is hepatotoxic (Athersuch et al., 2018), and several side effects have been reported (Ishitsuka et al., 2020), such as nausea (up to 34%), vomiting (up to 15%); abdominal pain, diarrhea, constipation, dyspepsia and enlarged abdomen (1% to 10%); anemia, postoperative hemorrhage (1% to 10%); rash, pruritus (1% to 10%); dyspnea, abnormal breath sounds, pulmonary edema, hypoxia, pleural effusion, stridor, wheezing, coughing (1% to 10%); cardiovascular effects (1% to 10%): peripheral edema, hypertension, hypotension, tachycardia, chest pain; metabolic alterations (1% to 10%): hypokalemia, hyperglycemia; headache, dizziness (1% to 10%). Other side effects: dystonia; muscle spasms, trismus (1% to 10%); insomnia, anxiety (1% to 10%); oliguria (1% to 10%); pyrexia, fatigue (1% to 10%) (Drugs.com, 2020b). There are reported cases of deaths in flu patients taking paracetamol (Stevenson et al., 2001). Overall, the safety evidence is Low.

Specific warnings and precautions of use. Not indicated in cases of liver disease and alcoholism (Drugs.com, 2020b).

Overall assessment. According to a well-established use, paracetamol may be useful in the symptomatic relief of respiratory conditions by reducing fever and aches (although a relatively low number of clinical studies and meta-analyses do not provide consistent evidence that paracetamol can reduce symptoms and duration), and prevention of the common cold. The clinical evidence may be considered Low or at best Medium. It is known to be hepatotoxic, and a frequent incidence of respiratory adverse effects may justify serious concerns and a safety rating of Low.

Assess the Relative Importance of the Decision Maker’s Risk Attitude Towards Herbal Substance

Risk is inherent to any therapeutic intervention (herbal or not). The level of risk of herbal interventions in adults experiencing common flu symptoms without underlying conditions is very low. According to WHO, COVID-19 is self-limiting and mild in this segment of the population (WHO, 2020a). However, we took extra care in integrating current health authorities’ advice with current clinical evidence to emit our assessment.

Scientific and Clinical Data of Current Herbal Therapy Referred to as Useful to Relieve Symptoms Related to Respiratory Conditions (Cold/Flu)

General warning: allergic reactions and gastrointestinal (GI) disturbances are common adverse effects in all medicines and apply to herbal ones. Their use in pregnancy and lactation, babies, children, and the elderly, as well as patients with known severe conditions, is to be individually assessed by a registered healthcare professional.

The recommendations made here are for medicinal products regulated by national authorities to ensure their quality and safety. Other products may be unsafe due to contamination, adulteration, and the presence of naturally occurring toxins in levels above those permitted.

Allium sativum L. – Amaryllidaceae (Bulbs, Powder)

Indications in the context of respiratory conditions. Allium sativum is indicated for respiratory disease, namely cold and cough (CUBA, 2014; EMA, 2017b), and other symptoms related to influenza (BRASIL, 2011). Other related indications of garlic preparations (fresh, garlic powder) included diaphoretic, antiseptic, bacteriostatic, and antiviral effects. It is also used to treat chronic bronchitis and recurrent upper respiratory tract infections (EMA, 2017b; El-Saber Batiha et al., 2020b).

Traditional indications. Allium sativum has been traditionally used for alleviation of symptoms of the common cold in adults and children over 12 years. Indeed, garlic is considered as a traditional herbal medicinal product used for the relief of cold symptoms. Moreover, the British Herbal Pharmacopoeia considers that garlic products are indicated for recurrent colds and whooping cough (BHMA, 1983).

Chemical composition. Sulfur compounds (allicin, mercaptan, allyl methyl thiosulphinate, allyl methyl trisulphide, diallyl disulfide, diallyl trisulfide, S-allyl cysteine sulphoxide, and others), glucosides (sativoside B1, proto-degalactotigonin), amino acids (alanine, arginine, aspartic acid, asparagine, histidine, proline, alanine, valine), monoterpenoids (citral, geraniol, alfa and beta-phellandrene and other), peptides, minerals, flavonoids, and vitamins (Lanzotti, 2006; Omar and Al-Wabel, 2010). In the presence of the enzyme alliinase, alliin will be converted to allicin (1 mg alliin to be equivalent to 0.45 mg of allicin). Allicin is also the precursor of other non-volatile products such as ajoenes or oligo- and polysulphides (ESCOP, 2003a; Kovarovič et al., 2019).

Posology (based on traditional uses). Fresh garlic: 2.0–4.0 g average daily dosage (EMA, 2017b). However, it is preferable to use a commercial preparation with defined composition and an adequate dose.

Preclinical evidence. This herbal medicine has been experimentally proven to have antiviral activity. Among the viruses which are sensitive to garlic extracts, are the Human Cytomegalovirus (HCMV), Influenza B virus, Herpes simplex virus type 1, Herpes simplex virus type 2, vesicular stomatitis virus, Parainfluenza virus type 3, Vaccinia virus, and human Rhinovirus type 2 (Tsai et al., 1985; Mikaili et al., 2013). Allicin-containing supplements can prevent attacks by the common cold virus.

Clinical evidence. There is no clinical data to support garlic in the treatment of upper respiratory infections, only in the prevention and treatment of symptoms of the common cold (Josling, 2001). Regarding the prevention or treatment of the common cold, a Cochrane meta-analysis concludes that there is insufficient clinical evidence (Lissiman et al., 2014); the sole study retained for the analysis showed fewer days of illness in the garlic group compared with the placebo group (Josling, 2001). Another trial suggested that consuming the aged garlic extract could reduce the severity of cold symptoms reported (Nantz et al., 2012). Overall, the clinical evidence is High for cold.

Safety. Garlic preparations are generally considered to be safe (EMA, 2016a). However, patients taking anticoagulation and/or antiplatelet therapy should use garlic preparations with caution because they may increase bleeding times (EMA, 2017b). Overall, safety is Medium.

Specific warnings and precautions of use. Patients should avoid concomitant use with anti-platelet drugs.

Overall assessment. Although Allium sativum preparations have been used to relieve cold symptoms since ancient times, there is no evidence this herbal medicine can relieve flu symptoms. Whether it may indirectly provide anti-inflammatory and soothing effects on the upper respiratory tract remains to be seen. The clinical evidence may be considered High. Even though garlic is known to have potential antiplatelet effects, overall, it can be considered presenting Medium safety, due to products with less than 0.6% allicin content do not appear to have any such effects (Scharbert et al., 2007).

Althaea officinalis L. – Malvaceae (Roots, Leaves)

Indications in the context of respiratory conditions. Althaea officinalis is indicated for respiratory disease symptoms, namely dry, irritable coughs, and irritations of oral and pharyngeal mucosa (EMA, 2016c).

Chemical composition. Mucilage polysaccharides, such as galacturonorhamnans (rhamnogalacturonan), arabinans, glucans, arabinoglucans, mainly of acidic polysaccharides; flavonoids (e.g., isoscutellarein, hypolaetin, kaempferol and luteolin derivatives); phenolic acids; coumarin (scopoletin); tannins (ESCOP, 2019; Kianitalaei et al., 2019).

Posology (based on traditional uses). 0.5–5.0 g in 150 ml of water as a macerate, three times daily (EMA, 2016c). Marshmallow root’s syrup is also a commonly used preparation in a daily dose of 2.0-8.0 ml (ESCOP, 2019; Kianitalaei et al., 2019).

Preclinical evidence. This herbal medicine has been experimentally proven for respiratory disease symptom, namely, cough. The aqueous extract of marshmallow roots inhibited the tracheobronchial smooth muscle contractions in rats in a dose-dependent manner (Alani et al., 2015). The antitussive effects of oral rhamnogalacturonan (50 mg/kg) were evaluated against mechanically induced cough reflux in both sexes of non-anesthetized cats. The polysaccharide significantly reduced the number of efforts, cough frequency, and intensity of cough attacks from laryngopharyngeal and tracheobronchial areas (Nosalova et al., 2005). The antitussive effects of oral syrup and the polysaccharide were tested against mechanically induced cough of non-anesthetized cats in comparison with non-narcotic antitussives (Nosal’ova et al., 1992).

Clinical evidence. Althaea officinalis preparations have been trialed clinically for respiratory disease, and the following symptom was evaluated: cough. In a randomized clinical study, 63 adults suffering from dry cough associated with angiotensin-converting enzyme inhibitors ingested 20 drops, three times per day, of either a marshmallow root preparations or a placebo, for four weeks. The severity of the cough in the marshmallow group was significantly reduced (Rouhi and Ganji, 2007). In one clinical trial on 822 patients with dry cough associated with pharyngeal irritation, the efficacy, tolerability, and satisfaction of A. officinalis root aqueous extract in the form of lozenges and syrup was evaluated. Althaea officinalis root aqueous extract improved the symptoms of dry cough within 10 min with very good tolerability. There were only three minor adverse events in the syrup group (Fink et al., 2017). Overall, the clinical evidence is High for cough.

Safety. No toxicity was reported at the indicated doses (EMA, 2016b). Overall, safety is High.

Specific warnings and precautions of use. The absorption of other drugs taken simultaneously may be retarded due to the presence of mucilage. As a precautionary measure, all preparations with A. officinalis should not be taken 30 min to 1 h before or after intake of other drugs/minerals/vitamins. The macerate should be used immediately after preparation (EMA, 2016b).

Overall assessment. Althaea officinalis preparations can suppress cough and diminish irritation through anti-inflammatory and soothing effects on the respiratory tract. Its traditional use as cold therapy in the context of upper respiratory conditions is not backed up by robust clinical data, but the evidence allows us to infer a potential use in the relief of early symptoms of COVID-19. The clinical evidence may be considered High, and as no severe concerns are reported for this herbal medicine, it can be rated as High safety.

Andrographis paniculata (Burm.f.) Nees – Acanthaceae (Leaves, Aerial Parts)

Indications in the context of respiratory conditions: Andrographis paniculata is indicated for respiratory disease, namely common cold, influenza type, and other upper respiratory tract infections, cough, and fever (WHO, 2002). It is often included in multi-herbal preparations, which are not assessed here [aside from the combination with Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.].

Chemical composition. Relevant secondary metabolites are diterpenes like andrographic acid, their glucosides (deoxyandrographolide-19β-D-glucoside) and dimers (bis-andrographolides A, B, C, and D) and labdane diterpenoids like andrographolide, neoandrographolide; flavonoids (methoxylated flavones, flavanones, chalcones); steroids (β-sitosterol (Koteswara Rao et al., 2004; Akbar, 2011; Dai et al., 2019; Hanh et al., 2020). Andrographolides are considered the active metabolites and chemical markers of this species.

Posology (based on traditional uses). 1–3 g as a decoction, three times daily (WHO, 2002). However, it is preferable to use a commercial preparation with defined composition and an adequate dose.

Preclinical evidence. This herbal medicine has been experimentally proven for respiratory disease, based on a mouse-model for influenza (an adapted H1N1 strain PR8A/PR/8/34). Treatment with andrographolide decreased the virus loads and the expression of the inflammatory cytokines. Also, diminished lung pathology and overall survival rate (Ding et al., 2017). Anti-inﬂammatory and immunomodulatory properties of the extract of A. paniculata and andrographolide have been linked to the increasing proliferation of lymphocytes and the production of IL-2 and inhibition of the tumor cell proliferation immune system (Rajagopal et al., 2003; Kumar et al., 2004). Also, diminished lung pathology and overall survival rate (Ding et al., 2017). Neoandrographolide has in vivo anti-inflammatory effects (Panossian et al., 2002). Andrographolide and a standardized registered fixed combination of A. paniculata extract SHA-10 and E. senticosus extract SHE-3 showed an in vitro effect on the activation and proliferation of immune-competent cells as well on the production of key cytokines and immune activation markers (Dai et al., 2019; Kim et al., 2019). A range of anti-inflammatory effects has been reported on diverse disease targets for A. paniculata and key constituents (Dai et al., 2019; Kim et al., 2019).

Clinical evidence. This herbal medicine has been trialed clinically for cold symptoms. Three systematic reviews pointed to the beneficial effects and safety of Andrographis for relieving symptoms of acute respiratory tract infections and shortening time to the symptom (Kligler et al., 2006; Akbar, 2011). The most recent study included 33 randomized controlled trials (RCT) with 7175 patients. The results indicated that compared to usual care, a shortening of the duration of symptoms including cough, sore throat, and sick leave/time to resolution was observed. Concerns were raised due to the low quality of many studies and their heterogeneity (Hu et al., 2017; Hu et al., 2018). Overall, the clinical evidence is High for cold and cough.

Safety. An assessment report of EMA concludes that while ‘there is a clear effect on some CYP isoenzymes, the available acute, and reproductive toxicity and genotoxicity data support the safety of Andrographis’ (EMA, 2014a). On the other hand, the Australian Therapeutic Goods Administration (TGA) highlighted the potential risks of severe allergic reactions (TGA, 2015), which, however, seems to be of very limited clinical concern. There are some preclinical indications of immunomodulatory activities of unknown implications for the COVID-19 cytokines storm. Overall, safety is Medium.

Specific warnings and precautions of use. Allergic reactions may be of concern (TGA, 2015).

Overall assessment. Andrographis may be useful in the symptomatic relief of respiratory symptoms, especially in terms of alleviating the symptoms of uncomplicated upper respiratory tract infections. Its traditional use as cold therapy in the context of upper respiratory conditions is not backed up by robust clinical data, but the evidences allow to infer a potential use in the relief of early symptoms of COVID-19. The clinical evidence may be considered High, and as although no severe concerns are reported, this herbal medicine may exert immunomodulatory activities so can be cautiously rated as Medium safety.

Commiphora molmol Engle [syn. Commiphora myrrha (T.Nees) Engl.] and Other Commiphora sp. – Burseraceae (Air-Dried Oleo-Gum Resin Exudate)

Indication in the context of respiratory conditions. Commiphora molmol is indicated symptoms of respiratory disease, namely mild inflammation of pharyngeal mucosa (WHO, 2007). Other related symptoms are cough, anti-inflammatory (Akbar, 2020); supportive treatment for tonsillitis (WHO, 2007; Barnes et al., 2012; ESCOP, 2014).

Chemical composition. Sesquiterpenes (furanoeudesma1,3-diene and lindestrene as the major components) (Marongiu et al., 2005).

Posology (based on traditional uses). It is preferable to use a commercial preparation with a defined composition, such as a tincture (0.5–5 ml in 150 ml of water for rinsing or gargling three times daily) (WHO, 2007).

Preclinical evidence. This herbal medicine has not been experimentally proven for symptoms of respiratory disease. Although C. molmol has been used as a remedy since ancient times (Akbar, 2020), so far, only a few studies on anti-inflammatory or antinociceptive action can be found. An ethanol extract from the resin (at the doses of 100 mg/kg and 200 mg/kg, p.o.) presented analgesic and anti-inflammatory activities in mice. In the swelling paw test, the effect of the extract (100 mg/kg, p.o.) was similar to indomethacin (10 mg/kg, i.p.) (Su et al., 2011).

Clinical evidence. Commiphora molmol preparations have not been trialed clinically for respiratory disease, only for inflammation. A standardized extract of C. molmol (curzerene 17.93%, furanoeudesma-1,3-diene 27.44%, lindestrene 9.08%) was evaluated about the anti-nociceptive effect. The volunteers (89 men and 95 women), presenting headache, fever-dependent pain, joint pain, muscle aches, lower back pain, or menstrual cramps, received extract (200 mg or 400 mg), or placebo, for 20 days. According to this RCT, the extract presented a similar effect to some frequently used drugs, such as diclofenac, ibuprofen, and paracetamol, although requiring a longer time of use (20 days). In the male group, the extract, at the dose of 400 mg, the effect was significant against all the symptoms. For the female group, the extract was effective against low back pain and fever-dependent pain at the doses of 200 mg/day. Furthermore, no side effect was reported by any of the volunteers (Germano et al., 2017). Overall the clinical evidence is High for pain associated with fever.

Safety. The safety of C. molmol is well established. There are no known safety concerns from non-clinical or clinical data (EMA, 2011d; EMA, 2018b). Overall, safety is High.

Specific warnings and precautions of use. Due to a uterine stimulant effect (Vafaei et al., 2020), products containing C. momol resin should be avoided in pregnancy and lactation (EMA, 2011d). The concomitant use of C. molmol with theophylline or cyclosporine A should be avoided (Al-Jenoobi et al., 2015a; Al-Jenoobi et al., 2015b; EMA, 2018a).

Overall assessment. Commiphora molmol preparations seem to have a supportive effect as antinociceptive and thus be useful in the relief of respiratory symptoms. However, its effect is evident only after a few weeks, thus exceeding the normal, uncomplicated evolution of COVID-19. The clinical evidence may be considered High. As no severe concerns are reported, this herbal medicine safety can be rated as High.