key: cord-0734840-yqux09qp authors: Omokhua-Uyi, Aitebiremen Gift; Van Staden, Johannes title: Natural product remedies for COVID-19: A focus on safety date: 2021-03-18 journal: S Afr J Bot DOI: 10.1016/j.sajb.2021.03.012 sha: 7491417095bd65f70f255054ccdfec2131b8c832 doc_id: 734840 cord_uid: yqux09qp Infection by the novel coronavirus SARS-CoV-2 causing the coronavirus disease (COVID-19), is currently a global pandemic with nearly two million deaths to date. Though a number of vaccines have recently been approved against the virus, availability remains a big challenge, and also acceptance by most people has become a big debate. This review discusses possible/ proposed natural product remedies and some major conventional treatment options used to manage the infection and, safety concerns on the use of unproven or unapproved health products against COVID-19. An extensive literature review indicated that the influx of unproven and unapproved health products in the global market are on the rise, leading to various forms of self- medication. To this effect, there have been warnings by the United States Food and Drug Administration and the World Health Organisation against the use of such products. Conventional drugs such as remdesivir, chloroquine/hydroxychloroquine and dexamethasone are the major proposed drugs that are currently undergoing clinical trials for the management of this disease. Efforts are being made globally in the search for possible therapeutics which may be the best way to eradicating this disease. Some countries have approved the use of natural products in the management of COVID-19, despite little or no clinical evidence on their efficacy and safety. Natural products may hold a great potential in the fight against COVID-19 but without detailed clinical trials, their potency against the virus and their safe use cannot be established. To attain this goal, extensive research followed by clinical studies are needed. Collaborative efforts between researchers, clinicians, governments and traditional medicinal practitioners in the search and development of safe and effective therapeutics from natural products for the treatment of COVID-19 could be a potential option. CDC 2 2 a ch der, 2020). The SARS-CoV was transmitted from civet cats to humans with outbreak traced to Chinese market, while the MERS-CoV was believed to have been contracted by humans first in Saudi Arabi from dromedary camels who may have been infected by bats (Kan et al., 2005; Paden et al., 2018; WHO, 2019a WHO, , 2020a . The recent outbreak is the SARS-CoV-2, a novel coronavirus which causes the disease COVID-19 (Lau et al., 2020) . The first reported case was in China in December 2019. The virus was believed to have developed in bats and later in pangolins (Hassanin, 2020; Panyod et al., 2020; Zhang et al., 2020) and to have spread from a Chinese seafood marketplace (Shereen et al., 2020) . However, recent studies show a virus with 99% genomic agreement to SARS-CoV-2, suggesting that the COVID-19 virus is the result of a recombination between two different viruses. Thus, the exact origin of the virus is still uncertain (Hassanin, 2020) . The virus spreads through saliva droplets from talking and discharge from the nose and mouth of an infected person, through coughing or sneezing (CDC, 2020b) . When these droplets are aerosolized, the virus can remain viable in the air for about 3 h, suggesting possible airborne transmission (van Doremalen et al., 2020) . The presence of SARS-CoV-2 RNA have also been detected in stools and urine of infected patients (Sun et al., 2020; Wang et al., 2020a) . With more research, other possible SARS-CoV-2 routes of transmission may be discovered. Hence, alternative forms of transmission cannot be excluded when taking safety measures. Most people exposed to COVID-19 virus experience mild to moderate respiratory illness and recover without requiring special treatment (WHO, 2020b) . However, the older population and those whose immune systems have been compromised due to medical conditions such as diabetes, obesity, chronic kidney disease, cardiovascular diseases, chronic respiratory diseases (CRDs), cancers, sickle cell disease and human immunodeficiency virus -acquired immunodeficiency syndrome (HIV-AIDS) are at higher risk (CDC, 2020c; Clark et al., 2020) . People infected with COVID-19 usually start to show symptoms between 2-14 days after exposure to the virus (CDC, 2020d) . Symptoms include cough, headache, muscle or body aches, fever or chills, fatigue, shortness of breath or difficulty with breathing, new loss of taste or smell, congestion or runny nose, sore throat, nausea or vomiting and diarrhoea (CDC, 2020d) . Due to the novel nature of the virus, the list of possible symptoms is not exhaustive, and research is still ongoing. The disease progression and mortality rates of MERS and SARS cannot be compared to that of COVID-19 which has resulted in unprecedented number of deaths close to two million and placed massive pressure on the world economy (Gazeta, 2020) . The World Health Organisation (WHO) declared the COVID-19 outbreak a global pandemic (WHO, 2020c) . The information presented in this review were obtained from scientific literature databases such as Google Scholar, Science-Direct, PubMed, Scifinder, Web of Science and Scopus. Key words used include; Coronavirus, natural products, traditional, herbal preparation, toxicity, safety, World Health Organisation, Centers for Disease Control and Food and Drug Administration. More than 400 unit of literature were screened and those relevant to the aim of this review were considered. Though a number of vaccines have recently been approved against the SARS-CoV-2 virus, availability to the public remains a big challenge, and also acceptance by most people has become a big debate. In most cases, patients are given medical care or supportive therapy with oxygen and fluids to help relieve symptoms (Auwaerter, 2020; Eyvazzadeh, 2020) . Sometimes antibiotics are used to treat secondary infections (Farooq, 2020; Hassanin, 2020) . However, there are many ongoing clinical trials evaluating potential treatments. Drugs of target for the treatment of COVID-19 should be able to stop the replication of the virus SARS-CoV-2 that causes COVID-19, thereby reducing its disease-causing ability. Some of the established drugs currently under trials supported by the WHO are: remdesivir, chloroquine and hydroxychloroquine, and dexamethasone (Jean et al., 2020; Joseph, 2020; WHO, 2020e). Remdesivir is an intravenous antiviral drug which was developed during the Ebola crisis. The drug can block the replication of viruses (Jean et al., 2020; Wang et al., 2020b) . In a current study, 36 (68%) COVID-19 patients out of 53 treated with remdesivir showed clinical improvement (Grein et al., 2020) . In another study, 541 patients were treated with remdesivir while 521 received the placebo. Patients treated with remdesivir recovered faster than patients in similar conditions who received the placebo (Beigel et al., 2020) . In a multicentre trial in ten hospitals in Hubei province, China, most patients administered remdesivir for 10 days recovered faster than those administered the placebo. However, no significant advantage was recorded. Adverse events of 66% (102 out of 155) were reported in patients administered remdesivir while 64% (50 out of 70) were reported in patients who received the placebo (Wang et al., 2020c) . Currently, there is a randomized controlled clinical trial (Adaptive COVID-19 Treatment Trial 3 (ACTT 3)), evaluating the safety and efficacy of remdesivir plus the immunomodulato inte fe on β-1a (traded as Rebif) in COVID-19 patients. This trial is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). The drug shows antiviral and anti-inflammatory properties, and the type 1 interferon can inhibit SARS-CoV-2, SARS-CoV and MERS-CoV (Medscape, 2020) . Chloroquine and hydroxychloroquine are currently used to treat malaria, arthritis and lupus disease. In a study conducted by Self et al. (2020) , hospitalized patients with respiratory illness from COVID-19 that were administered hydroxychloroquine compared with placebo, did not show significant improvement clinically after 14 days. Hence authors suggested that hydroxychloroquine is not effective against COVID-19. Some other clinical trials using hydroxychloroquine in COVID-19 patients also concluded that it did not in any way prevent infections better than a placebo (Herper, 2020) . However, some clinical trials on the drug are still being conducted (Chen et al., 2020) . In May 2020, chloroquine, hydroxychloroquine and remdesivir received emergency use authorization (EUA) from the Food and Drug Administration (FDA, 2020a) to manage severe cases of COVID-19 under hospital settings. However, on June 15, 2020, the FDA revoked the emergency use authorisation of chloroquine and hydroxychloroquine in cases where clinical trials were unavailable. The main concern with these drugs was their ability to cause cardiac problems (FDA, 2020b). Current studies show dexamethasone as one of the most promising drugs for managing COVID-19. Dexamethasone is a glucocorticosteroid used in the treatment of different inflammatory conditions related to allergic disorders, skin conditions and lupus, psoriasis, ulcerative colitis, arthritis and respiratory disorders (Chemocare, 2020 . Dexamethasone is also used either alone or in combination with other drugs to treat some types of cancers or to prevent/treat cancer-related conditions (NIC, 2019). A preliminary clinical trial released by the University of Oxford, United Kingdom (UK) to the WHO on June 16, 2020, showed the effective use of dexamethasone in patients with COVID-19 under critical conditions. The treatment reduced mortality in patients on ventilators by about onethird. For patients requiring only oxygen, mortality was cut by about one-fifth (WHO, 2020e). The study, however, indicated that the positive effect was not as clear in patients with milder symptoms of the disease. A recent recovery trial conducted on 1007 hospitalised COVID-19 patients with respiratory failure that were administered a moderate dose of dexamethasone for 10 days with supplemental oxygen or mechanical ventilation, showed a reduced mortality rate. However, the same recovery trial also indicated that there might be an increased mortality rate in patients administered dexamethasone in the absence of supplementary oxygen or mechanical ventilator . Following the outcome of the above studies, it can be deduced that it might not be advisable to administer dexamethasone to patients without oxygen support or ventilator. Even though the adverse effects of this drug may be less severe, this may not be the case with COVID-19 patients with Strongyloidiasis comorbidity, a rare but fatal parasitic disease caused by nematodes mostly associated with Strongyloides stercoralis (Stauffer et al., 2020) . Therefore, proper diagnosis is very important before administering corticosteroids such as dexamethasone to patients. There is a relationship between corticosteroid therapy and strongyloidiasis with a two-to three-fold increased risk of being infected by S. stercoralis (Fardet et al., 2006) . With little knowledge available on the mechanism involved in susceptibility, it is hypothesized that this may be through its suppressive effects on some major mediators of the immune response such as eosinophils to the parasite (Fardet et al., 2006) . Such hypothesis needs to be tested through clinical studies. The use of natural products in the treatment and management of infections and diseases has a long history in human existence. Hence, it is possible that treatment for viral infections such as COVID-19 can be discovered from natural products such as plants and microorganism (Sohail et al 2011; Abdalla and McGaw, 2018) . For example, one of the proposed treatments (as explained above) for COVID-19 is chloroquine (Farooq, 2020) . Chloroquine is an antimalaria drug which is an analogue of quinine isolated from the plant extract of Cinchona officinalis L. belonging to the family Rubiaceae (Lowe, 2020) . Exploration of microorganisms such as endophytes as possible treatment for COVID-19 may also be beneficial as they are sources of treatments for other human diseases (Abdalla and McGaw, 2018). Endophytes are microorganisms, mainly bacteria and fungi, living in the intercellular and intracellular regions of healthy plant tissues without constituting any harm to the plant. These (Strobel, 2003; Hallmann et al., 2006) . Endophytes produce biologically active compounds, (Selim et al., 2018) . Although not tested, authors hypothesised that two compounds; alternariol and alternariol-(9)-methyl ether isolated from the endophytic fungi may be responsible for the antiviral activity. Extracts of endophytic fungi such as Alternaria alternata, Nigrospora sphaerica and Phialophora sp showed antiviral activity against the HSV (Manganyi and Ateba 2020). Compounds from endophytic fungi Phomopsis sp. isolated from Achyranthes bidentate Blume was reported to display promising antiviral activity against HIV-1 . Following the above reported antiviral activities, it is not unlikely that effective therapeutic may be discovered from endophytes. However, this may not be known if investigations are not carried out. For example, camphotothecin and podophyllotoxin are anticancer drugs isolated from endophytes (Puri et al., 2005 (Puri et al., , 2006 . patients (Mansour, 2020) . There is some scientific evidence supporting dietary therapy and herbal medicines as potential antiviral agents against COVID-19, as have been noticed with other viral diseases (Panyod et al., 2020). A recent review screened 55 research articles to identify active phytochemicals against coronavirus infection. Compounds such as quercetin, tryptanthrin, scutellarein, saikosaponin B2, myricetin, caffeic acid, psoralidin, isobavachalcone and griffithsin were reported to inhibit human coronavirus, serving as leads for further studies (Mani et al., 2020) . The most promising small molecules capable of inhibiting coronavirus contained a conjugated fused ring structure with the majority classified as polyphenols (Mani et al., 2020) . Theaflavin (a polyphenol) from Camellia sinensis (L.) Kuntze suppressed SARS-CoV-2 via the inhibition of RNA-dependent RNA polymerase (RdRp) activity (Lung et al., 2020) . A detailed mechanism of action and safety profile for this phytochemical will be necessary. Plantderived alkaloids such as emetine, homoharringtonine and cepharanthine are other small molecules which display broad-spectrum antiviral activities and are currently being targeted as potential therapeutics for COVID-19 . Cepharanthine inhibits SARS-CoV-2 through the suppression of agiotensin-converting enzyme 2 (ACE2) activity (Fan et al., 2020) . Other plant molecules such as 7-methoxycryptopleurine, ouabain, lycorine, silvestrol, homoharringtonine and tylophorine are also under investigation (Islam et al., 2020) . The potential of plant molecules with anti-inflammatory properties in the treatment of COVID-19 are also being considered. One example is celastrol (Nabavi et al., 2020) , a plantderived product mainly found in the Celastraceae family (Kutney et al., 1981) . Extracts from the plant family have been used traditionally in the treatment of oedema, fever and joint pain, and they have low toxicity (Allison et al., 2001) . The compound celastrol has been exploited as a source of neuroprotective agent. A collaborative screening of existing drugs against neurodegenerative diseases showed celastrol as one of the active components (Zhao et al., 2012) . The anti-inflammatory activity of this compound both in in vitro and in vivo animal models was evaluated and mechanisms of action established (Nabavi et al., 2020) . Celastrol alleviated chronic obstructive pulmonary disease in the lungs of mice . It has an anti-inflammatory pathway through the suppression of nuclear factor kappa B (NF-κB) signalling (Zhang et al., 2019) . In a study conducted on MERS-CoV and SARS-CoV infections, the inflammatory response mediated by NF-κB pathway was egulated by transmembrane serine protease 2 (TMPRSS2) levels within the airway in a TMPRSS2 knockout murine model (Iwata-Yoshikawa et al., 2019; Nabavi et al., 2020) , suggesting that the inhibition of TMPRSS2 may exert a dual effect on COVID-19, limiting viral entry by reducing the cleavage of the spike protein in ACE2 receptor mediated viral entry (Hoffmann et al., 2020; Nabavi et al., 2020) . There is a high demand for herbal products in the treatment of COVID-19 in some countries in Africa, Asia and in the United States of America, with approval by governments in some countries (Timoshyna et al., 2020) . Some scientists have suggested the repurposing of available drugs in the market for the management of COVID-19, as a fastest way to curb the spread of the disease, as many diseases share overlapping molecular pathways (Hodos et al., 2016; Ahmed et al., 2020) . The use of herbal remedies has been widely embraced in China with 91.5% of the total number of coronavirus cases nationwide using repurposed herbal products for treatment. Based on clinical observation, more than 90% efficacy was observed (Timoshyna et al., 2020) . More than 125 plant species are reported to be used in the Chinese Officinalis Cortex and Agastachis Herba. These herbal formulae were used to treat patients with mild, moderate to severe cases and in recovery. Another Chinese herbal product, Lianhua Qingwen which has been clinically proven active against influenza virus, has also been screened against the SARS-CoVs (Lv et al., 2020) . In a clinical trial, the herbal capsule reduced symptoms such as cough, fatigue, fever and shortness of breath in 63 COVID-19 patients (Lv et al., 2020) . A 91.5% recovery rate was recorded in 142 COVID-19 patients after 14 days of administering Lianhua Qingwen in a multicenter open-label randomized controlled trial, and this herbal product was confirmed to be safe (Hu et al., 2020) . As part of self-care measures, a recommendation was made by the Ministry of AYUSH, Government of India on the use of Ayurveda immune boosters against COVID-19 (Li et al., 2020; Timoshyna et al., 2020; Vellingiri et al., 2020) . Honey has also gained some attention due to its antiviral properties with reports on its ability to prevent viral replication (da Cruz et al., 2019; ClinicaTrials.gov, 2020) . With safety in focus, it is pertinent that most of these repurposed herbal formulations mentioned above with no available safety data, are properly evaluated for use in COVID-19 patients, especially those with co-morbidity. It is also very important that the mechanisms of action of these herbal formulations are known to avoid contraindications or interactions with unintended molecular targets. In the search for effective therapeutics against COVID-19 from plant products, focus should be on plant molecules that are able to interact and bind with the SARS-CoV-2 virus proteins capable of promoting viral entry, replication and infection. Researchers have suggested that any therapeutic of interest should be able to show a high affinity to binding and inhibiting the SARS-CoV-2 spike protein, main protease enzyme (Mpro) and RdRp which are associated with host attachment and viral replication, resulting in infection in the individual. This has been demonstrated through in silico studies which is a quick way to identifying potential drugs (Table 1) proteins. Among the phytochemicals evaluated, triterpenoids showed more than 50% strong interaction with the spike protein-RDB. Also, 32% of molecules that showed interesting interaction with the active site of human TMPRSS2 were flavonoids. Some of the plant molecules were seen to interact with more than one of the target proteins. For example, agathisflavone was seen to interact with RdRp and TMPRSS2, amentoflavone interacted with Mpro and spike protein, while isoginkgetin interacted with RdRp and Mpro. Through an in silico screening of the Traditional Chinese Medicine Systems Pharmacology Database (TCMSPD), compounds such as kaempferol, lignan, moupinamide, N-cisferuloyltyramine, quercetin, sugiol, tanshinone IIa, betulinic acid, dihydrotanshinone, coumaroyltyramine, cryptotanshinone, desmethoxyreserpine and dihomo-γ-linolenic acid were identified as potential leads for the development of COVID-19 treatment (Alamanou, 2020). The use of herbal remedies as complementary or alternative medicines has been widely embraced in different parts of the world such as Africa, Australia, UK and other countries in Europe, North America and Asia (Calapai, 2008; Braun et al., 2010; Anquez-Traxler, 2011; Nirmal et al., 2013) . In Africa, an estimate of 80% of the population use herbal remedies (WHO, 2002; Mahomoodally, 2013) . Herbal remedies have a global annual market of about US$60 billion (WHO, 2002; WHO, 2019b) . The international trade in medicinal plants is expected to reach US$5 trillion by 2050 (Niraml et al., 2013) . Thus, natural products have contributed immensely in the health care system globally. However, natural products may have adverse effects and must be used with caution. It is essential that the general public is aware of the risk associated with the use of unproven or uncertified products. Since the beginning of the COVID-19 pandemic, people have resorted to self-medication. The internet has been flooded with numerous products acclaimed to fight the virus. This led the United States Food and Drug Administration (FDA) to issue warnings to more than 68 firms producing and marketing these products . Some of these products are: cannabidiol, restorative botanicals, hemp products, colloidal silver, vitamins, minerals, grapefruit seed extract amongst many others ( Table 2 ). The warnings were issued as urgent measures to protect consumers from the negative effects that might result, as these products have not been proven, approved or authorised for use against COVID-19 (FDA, 2020c). For example, colloidal silver can cause serious side effects such as permanent bluish-grey discoloration on the skin (argyria) and contra-indications with antibiotics and thyroxine (NCCIH, 2017) . A previous warning on the use of colloidal silver was issued by the FDA in 1999 indicating that the product is not safe or effective for treating any disease or condition (FDA, 1999) . Kratom from Mitragyna speciose plant is another acclaimed treatment. It is used traditionally to treat diarrhoea and fatigue and as a possible treatment for pain and management of opioid withdrawal symptoms (NCCIH, 2018) . The extract is sold as a treatment for muscle pain or to suppress appetite (Mayo Clinic, 2020). Two compounds,7hydroxymitragynine and mitragynine, isolated from the leaves interacts with opioid receptors in the brain, producing sedation, pleasure, and decreased pain when administered in high doses (NCCIH, 2018) . However, no scientific evidences of its health benefits exist (NCCIH, 2018) . Side effects of kratom include increased aggression, hallucinations and delusion, nausea, constipation, irritability, anxiety, itching, difficulty in breathing, loss of appetite and weight, tremor, psychosis, seizures, liver damage and cases of fatalities (NCCIH, 2018; Mayo Clinic, 2020) . Ginseng detoxication pills which probably originated from the genus Panax, is another example of an acclaimed product in the management of COVID-19 (FDA, 2020c). The genus Panax in G eek means -all healing.‖ It is so called because it is believed to cure any kind of human disease (Kim, 2018) . Ginseng is one of the most popular herbal remedies in the global market and there are several pharmacological reports on its ginsenoside compounds (Kim, 2018) . However, the product also causes mastalgia and vaginal bleeding even when used at the recommended doses (Baldwin et al, 1986; Dunnick and Nyska, 2013) . Other side effects include lack of concentration, headaches, transient nervousness, excitation, epistaxis and allergies (Ekor, 2014) . A case of Stevens-Johnson syndrome was reported after the administration of ginseng to a patient for three days (Dega et al., 1996) . The plant products may also have carcinogenic effects in the liver and thyroid and can induce tumorigenesis in the nasal cavity (Ekor, 2014). While acknowledging the fact that traditional medicines have enormous health benefits that may be exploited as possible therapeutics for COVID-19, the WHO recently warned against the use of unproven traditional herbs in the treatment of COVID-19 (Mugabi, 2020; WHO, 2020f) . This came after a herbal drink named Baptized COVID Organics was introduced in Madagascar and acclaimed as being helpful in the treatment of COVID-19. Some African countries such as Guinea, Equatorial Guinea, Guinea-Bissau, Liberia and Tanzania purchased large quantities of this herbal drink (Mugabi, 2020) . The drink is derived from an anti-malaria plant Artemisia and mixed with other herbs. Although, the drink is acclaimed as helpful in relieving symptoms of COVID-19, there is currently no scientific proof or evidence. There is the fear of possible toxicity which may lead to adverse effects and no published safety evidence for this drink exists. A concern is that people who consume this drink may become susceptible to malaria as they may develop resistance to the drug artemisinin (Mugabi, 2020) . Several herbal formulations have got approval from the Chinese Government and three patented herbal drugs are currently being used to treat COVID-19, with no strong scientific evidence of efficacies and safety (Ang et al., 2020; Cunningham et al., 2020; Yang, 2020) . Finding an effective treatment for an ailment is important but safety is a major priority that must never be ignored. It cannot be disputed that all drugs, be it conventional, complementary or alternative, carry risks for the users (Juhn et al., 2007; Ghenadenik et al., 2012; Yang, 2020) . However, with detailed clinical studies, safe dose ranges are attained, and possible adverse effects or contra-indications are known. Such important information assists in the prescription of such therapeutics to patients. Hence, it is of utmost importance that rigorous clinical studies with safety as a major focus are carried out on herbal remedies. There is much misleading information available on the internet on the use of garlic (Allium sativum L.) against COVID-19, which has led to the increased demand of garlic (McClain, 2020; Wiesemeyer, 2020) . Although garlic has some medicinal properties, there is no evidence of its efficacy against COVID-19 (WHO, 2020g). Adverse effects which include light headedness, nausea, alteration of platelet function and coagulation, burning sensation in the gastrointestinal tract, diaphoresis, hypotension and allergy have been associated to the use of garlic (Rose et al., 1990; Borrelli et al., 2007; WebMD, 2020a) . Another example of widely spread, misleading information is the use of ginger (Zingiber officinale Rosc.) to cure COVID-19. Ginger is often included in diets to treat nausea, vomiting, diabetes, migraine, menstrual cramps and osteoarthritis (Mashhadi et al., 2013; WebMD, 2020b). The plant possesses anticancer, anti-inflammatory, antidiabetic and antioxidant properties (Mashhadi et al., 2013) . However, its cure against COVID-19 has not been established. The WHO warned in a message conveyed by the executive director of the WHO Health Emergencies Program, Michael Ryan on 3 rd April 2020 that, though, ginger can have some health benefits, no evidence on its ability to cure COVID-19 exist (Wintle, 2020) . Some side effects of ginger include heartburn, mouth irritation and diarrhoea. Although there are no reports of its contra-indication, there are concerns that ginger may interact with anticoagulants (NICCH, 2016). Hence, it is not wise to use unproven natural products with the notion that they are completely free of side effects. One of the most used herbs in Chinese and Korean traditional medicine is the Semen Armeniacae Amarum, known as apricot seed (Prunus armeniaca L.). It has a long history in controlling acute lower respiratory infections (Jin et al., 2009 ). This is one of the common herbs included in the Chinese herbal formulations against COVID-19 (Ang et al., 2020) . In vivo studies have shown its toxicity in rats, leading to fatalities (Suchard et al., 1998; Kim et al, 2012; Park et al., 2013) . This toxicity has been linked to the presence of amygdalin and hydrogen cyanide which is more concentrated in the endocarp and can cause life-threatening respiratory disorders (Park et al., 2013) . As a result, it is advised that the endocarp is removed when using it in herbal formulations (Park et al., 2013) . Hence, a strong quality control needs to be set for this herb even after clinical studies on its potency against COVID-19 is established. The inclusion of traditional medicinal practitioners in the management of health crises is an important option that should not be overlooked. In many African countries, especially in the rural areas, and among the poor, traditional medicinal practitioners are often the closest resource when it comes to health issues with an estimated 80% of the African population using herbal remedies (WHO, 2002) . Most of these traditional healers have learned a wealth of knowledge from their ancestors with regards to plant medicinal use. It is regarded as a trade which helps to sustain their livelihoods (Karunamoorthi et al., 2013; Hamilton, 2014) . These traditional healers may be aware of the negative effects that might result but do not have the capacity to follow the drug development process. Hence, a criticism of traditional healing is that, traditional healers lack a body of evidence to authenticate their practice through scientific knowledge (Mokgobi, 2014) . Having the knowledge that a natural product can cure, manage or treat an infection is not enough. With the influx of herbal remedies and increase in self-medication especially in this COVID-19 era, safe use of drugs is an issue of great public health importance. The need for extensive toxicity assessment on herbal products for safe use and protection of public health cannot be overemphasized. However, there are many challenges when it comes to the regulation of herbal medicines in different parts of the world. Because of this, there is a need for a global standard and strong regulatory policies on herbal medicines (Ekor, 2014; WHO, 2019b) . It is risky to use a drug when important parameters such as how it is absorbed, distributed, metabolized and excreted, the mechanisms of action of that drug, the safe dosage range, side effects or adverse effects that may result due to possible toxicity, and its interaction with other drugs and treatments are not known. Five major processes are involved in drug development. These include discovery and development, preclinical research, clinical research, FDA review and FDA post-market safety monitoring (FDA-CDER, 2016; FDA, 2018) . The WHO has set some basic criteria that need to be followed in herbal formulations. These processes include efficacy, safety, quality control, marketing and regulatory guidelines (Akerele, 1993; WHO Technical Report, 2018) . Drug development processes may be rigorous but seems to be the only way to develop an effective and safe therapeutic (Yang, 2020) . The safety assessment of effective therapeutics is critical for drug use. In silico methods for the assessment of drug safety has recently become a useful tool (Arvidson et al., 2008; Rahman et al., 2020) . Such method is relevant in identifying safe doses, drug interaction among others, thereby giving a quick understanding of such a drug and a quick lead for further investigation. Though dose-response relationship is usually the main focus when it comes to safety assessment, some researchers have argued that this is not enough as other parameters need to be taken into consideration, before it can be concluded that a drug is safe. According to Li, (2004) , Five key parameters to be considered are; (1) Possible toxicity due to drug-target interactions, including interactions with unintended molecular targets, or with molecular targets in unintended organs; (2) Chemical scaffolding and sidechains with safety concerns; (3) Toxicity in animals in vivo and in vitro; (4) Safety concerns due to toxification or detoxification, organ distribution, clearance and pharmacokinetic drugdrug interactions and (5) Physiological, environmental and genetic factors that may enhance a patient's susceptibility. Most of these drug development stages need to be carried out by research scientists and clinicians. Therefore, collaborative efforts are needed. For instance, traditional medicine researchers in Togo are working in collaboration with scientists to find ways for traditional medicine to be integrated into the treatment of COVID-19 (Mugabi, 2020) . Governments, especially in developing countries, have pivotal roles to play in these collaborations, such as capacity building for traditional healers and scientists alike. With the available wealth of knowledge on natural products with antiviral properties, possible safe and effective preventive agents or therapeutics against COVID-19 may be discovered through such global collaborative efforts and selfless dedication to practice. The COVID-19 pandemic has resulted in the influx of high volumes of unproven and unapproved products in the market globally and increased self-medication. A number of vaccines have recently been approved for use to curb the spread of the virus. However, availability and acceptance by some critics is a big challenge. Conventional drugs such as remdesivir, chloroquine/hydroxychloroquine and dexamethasone are the major proposed drugs that are currently under trials for the management of this disease. Repurposing of therapeutics including those of natural products already available in the market, have been advocated by researchers with some countries already approving such for treatment or management of COVID-19. Natural products are helpful in the treatment of infections, but the consumption of unproven and unapproved products is a great health risk. It is of utmost importance that proposed or repurposed natural products against the novel SARS-CoV-2 virus are well evaluated for efficacy, mechanisms of action and safety before use. Collaborative efforts between researchers, governments and traditional medicinal practitioners in the search and development of possible safe and effective therapeutics from natural products, that may be helpful in the treatment or management of COVID-19 is a good option to explore. The authors of this review declare no conflict of interest whatsoever. https://www.afro.who.int/news/who-supports-scientifically-proven-traditional-medicine. (2020) Only plant molecules with binding anergy score between -7 and -15 are reported. If you have any flu-like symptoms or confirmed to have COVID-19, take 125 mL of one tablet dissolved in 2 L of water every two hours for eight days; One tablet dissolved in 1.5 L of water to be used in nasal or mouth dispensers into the nose and deep into the throat with three squirts per application against COVID-19. -3 Aug 2020 FDA 2020c The antiviral tincture boosts immune system and strengthen the body against COVID-19 and similar diseases. -10 July 2020 Traditional Chinese Medicines (TCM) TCM Lianhua Qingwen plays an important role in fighting against COVID-19 and its capsule has been proven effective for the treatment of COVID-19; Research provides scientific evidence for Lianhua Qingwen; Combining Western medicine and TCM appear to be the best approach to treating COVID-19. -6 July 2020, 26 June 2020 FDA 2020c COVID supplement protection pack, Thymosin-Alpha, and Methylene blue capsules Improve immunity of the tissues most susceptible to COVID viral attack; Improve immune response once the virus has entered the body; Improve immune response after one experiences respiratory symptoms or fatigue; Improve immune response for those at high risk of moderateto-severe COVID disease; Methylene blue works by producing a Colloidal silver Boost immune system; Colloidal silver has been a very effective way to kill vi us It's a potent emedy fo any infection D ink the silve and even nebulize it to get it directly in the lungs and at the site of the virus; Atomized fumes through ultrasonic humidifier can be inhaled deep into the lungs which may inhibit the virus from replicating too quickly; Colloidal silver 1100 PPM Immune support protect your immune system. -14 Aug 2020, 26 May 2020, 11 May 2020, 1 April 2020, 6 March 2020 Nano silver 10 PPM (silver solution) The Nano silver 10 PPM is your totally non-toxic key to halting COVID-19 attachment, penetration, and replication, with no reason to panic about COVID-19. -15 May 2020 FDA 2020c New study reveals vitamin D may be the key to COVID-19; Severity of Immune 26 May FDA 2020c What pharmacists should know about Ginseng? 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General wellbeing 14 Adaptogens: Reduce cortisol levels and improve immune response Zinc: Reduce the severity and duration of colds, flu, infections, wounds, and many other diseases Magnesium: Assist with immune response and reduce susceptibility to vitamin D3 that may help to fight COVID-19 by reducing the incidence, severity, and risk of death from current COVID -19 Plum dragon herbs (Chinese herbs for Boast immune system in the fight against COVID -19 The authors are grateful to Dr Wendy Stirk (Research Center for Plant Growth and Prefense non-alcoholic hand and skin sanitizer Prefense hand and skin sanitizer offers an alternative to alcohol-based gels; The only product on the market today that kills germs on contact and offers continuous protection for up to 24 hours or 10 hand washings with only one application. Super silver toothpaste, super blue toothpaste, super silver wound gel and superblue silver immune gargle Boost your immune system against virus.-9 April 2020 FDA 2020c The kit gives support to the immune system and the lungs and helps get through the respiratory illnesses more quickly and more easily.