article information

Jundishapur Journal of Natural Pharmaceutical Products: Vol.17, issue 2; e120872
published online: April 20, 2022
article type: Review Article
received: November 8, 2021
revised: February 5, 2022
accepted: February 16, 2022
DOI: https://doi.org/10.5812/jjnpp-120872
Crossmark

COVID-19 Crisis, Herbal Medicines, and Natural Products - Concerns and Suggestions

authors:

avatar Seyed Mohammad Zarei ORCID 1 , * , avatar Mohsen Reza Heydari ORCID 2

Department of Pharmacognosy and Traditional Pharmacy, School of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
Educational Development Office, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, IR Iran

how to cite: Zarei S M, Heydari M R. COVID-19 Crisis, Herbal Medicines, and Natural Products - Concerns and Suggestions. Jundishapur J Nat Pharm Prod. 2022;17(2):e120872. https://doi.org/10.5812/jjnpp-120872.

Abstract

Since the outbreak of the COVID-19 pandemic in the last days of 2019 in China, medical experts and organizations worldwide have proposed guidelines for its prevention and treatment. However, despite the availability of state-of-the-art technologies, modern medicine specialists have so far not been successful in controlling it. This has led traditional medicine experts to propagate their knowledge to prevent and cure COVID-19, creating an open debate.
According to scientific literature, traditional medicine experts claim beneficial effects of herbal medicines against viral infections and their effectiveness in controlling the symptoms of respiratory disorders. Modern medicine specialists express their concerns about the quality, safety, and efficacy of herbal medicines, in addition to the risk of herb-drug interactions and the lack of randomized clinical studies.
Herbal medicines have been popular since prehistoric times, and during the COVID-19 pandemic, they are increasingly used worldwide. The lack of definite cure and the high cost of available modern medicines have also promoted the use of herbal medicines. An evidence-based approach using herbal medicines with proven antiviral activities or containing compounds providing symptomatic relief in COVID-19 can be considered for clinical studies. The interaction of herbal medicines with modern drugs should also be considered in patients taking them.
Traditional and modern medicine aim to provide effective and safe treatment and prevent COVID-19 infection. Considering the ground realities of the COVID-19 crisis and keeping in view the worldwide use of herbal medicines, in our opinion, the pros and cons of their use should be carefully weighed, and practical solutions should be considered.

1. Context

Since prehistoric times, human beings have used medicinal plants to treat and find the cure for various diseases caused by bacteria, viruses, fungi, and other microbial agents (1). With the outbreak of the COVID-19 virus in Wuhan (China) and its spread to other countries that resulted in a pandemic, the lack of standard protocol for effective treatment by modern medicine experts has resulted in attention to exploring medicinal plants for possible treatment (2). Another reason for the shift of attention toward the possible use of medicinal herbs, especially in developing countries, is the expensive cost of modern antiviral and other drugs used to treat COVID-19 (3). As herbal medicines are used worldwide, with the outbreak of COVID-19, experts of traditional medicines in different parts of the world have started using medicinal herbs to treat COVID-19. Several reports have been published claiming partially or completely successful treatment of COVID-19 by using popular medicinal plants that are edible worldwide such as turmeric, coneflower, licorice, ginger, common ivy, and onion (4-6). Due to being cheap and easily available, the use of medicinal plants may have increased for the treatment of COVID-19. However, their use has led to concerns about the lack of credible scientific evidence, toxicity, and ineffectiveness. Adequate quality control, unknown herb-drug interactions, and possible adulteration are other vital concerns in this regard. COVID-19 patients suffering from chronic disorders such as cardiovascular diseases, diabetes, psychiatric problems who take several medicines are especially considered susceptible to herb-drug interactions.

While the worldwide use of herbal medicines for the treatment of COVID-19 is gaining popularity, precautionary guidelines for their use are being published in medical journals (7-9), and public awareness in this regard has increased, many pivotal questions remain:

(1) Can herbal medicines alone really prevent, treat or cure COVID-19 infection?

(2) If natural medicinal formulations have positive effects on controlling COVID-19, are these effects limited to few popular plants such as ginger, turmeric, and onion?

(3) Can herbal medicines be used simultaneously with current COVID-19 treatment protocols?

(4) How serious are the interactions between herbal medicines and the currently available drugs used to treat COVID-19?

(5) For patients suffering from chronic diseases, how are dose adjustments made for the current drugs they are taking for COVID-19 if they also use herbal medicines?

These questions and probably many other such questions remain to be answered apparently because of a lack of collaboration and communication between the experts of modern medicine and traditional medicine worldwide. While both sides have their claims of advantages over the other side, the ground reality is that based on the popularity of herbal medicine worldwide, it can be reasonably argued that their use is also common for the treatment of COVID-19, while data about their beneficial or adverse effects are not available. On the other hand, no effective modern medicine-based treatment protocol currently exists that is accepted by experts worldwide. In this review article, we present the pros and cons, safety, and precautions of using herbal medicines for the treatment of COVID-19 in an attempt to reconcile and minimize the difference of opinion between traditional and modern medicine.

2. Methods

English articles published in recent scientific literature, especially since the start of the COVID-19 pandemic at the end of 2019, about herbal medicines, traditional medicines, and natural products and their activity against viral diseases, COVID-19, and respiratory problems were searched in Medline, Scopus, and Web of Science. Gathered articles' content was investigated accurately, and applicable data were extracted. In addition, literature published as critical reviews, commentaries, and articles mentioning concerns of modern medical experts on the safety, quality, and efficacy of herbal medicines for the treatment of COVID-19 were also searched, and relevant content was used for writing this review.

3. Approaches to the Promising Use of Herbal Medicines and Phytochemicals in COVID-19

In order to respond to the questions mentioned above regarding COVID-19 infection, we present two broad approaches that are also in agreement with the published views of experts:

The first approach is screening and developing antiviral compounds from herbal medicines currently used in traditional medicine to treat COVID-19. This can also result in a novel antiviral compound as a lead molecule. Several studies have previously reported antiviral activity in natural products, several antiviral compounds have been identified, and some of them or their related derivatives have progressed to the stage of clinical trials (10-12). However, there is currently no marketed antiviral compound originating from natural products.

In vitro and in silico antiviral activities in natural products against severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) have been reported in several studies (13-15). Developing a new single compound drug to treat COVID-19 from these natural antiviral products would be an expensive and time-consuming approach. Especially in developing countries with the low income of the general population, the cost of the new drug will be expected to be unaffordable.

The second approach is the application of currently available herbal medicine formulations to treat symptoms of COVID-19 infection. Based on the physiopathology and clinical presentation of COVID-19, herbal medicines can be used for the treatment of symptoms related to different systems, including fever, cough, malaise, dyspnea, fatigue, sputum secretion, anorexia, sneeze, rhinitis, myalgia, goosebumps, sore throat, headache, diarrhea, chest pain, rhinorrhea, palpitation, dizziness, nausea or vomiting, shivering, confusion, nasal congestion, abdominal pain, and hemoptysis (16).

4. Suggested Categories of Medical Plants for Their Use in COVID-19

Concerning the signs and symptoms of COVID-19 disease, the following categories of herbal medicines (sections 4.1 - 4.7) are suggested to be used as a supportive treatment for the management of patients (17). It is worth mentioning that most of these medicinal plants and bioactive compounds have been reported to possess multiple activities mentioned below, either in vitro or in vivo.

4.1. Antipyretic Medicinal Plants

As fever is a common symptom of COVID-19 infected patients, antipyretic drugs are used for treatment. Medicinal herb Salix spp. bark is a source of salicin glycoside, which is metabolized by hydrolase enzymes to yield salicylic acid that inhibits cyclooxygenase 1 and 2 enzymes, leading to anti-inflammatory and anti-fever activities (18). Also, studies have confirmed similar activities of some other compounds and fractions such as black pepper (containing piperine, an alkaloid) (19), fenugreek (seeds chloroform fraction and aqueous extract of leaves) (20), mango (containing mangiferin, a phenolic compound) (21), and sweet wormwood (water fraction) (22).

The use of medicinal plants for their antipyretic activities in COVID-19 infection is justified based on the in vitro and in vivo scientific data about their antipyretic activities. However, the exact concentration of medicinal plants for their antipyretic activities remains to be determined.

4.2. Medicinal Plants with Antiviral Activity

Several plants used in traditional medicine have been reported to have antiviral activities at extract, fraction, or pure compound level (23). Particularly, few plants are reported to have antiviral activity against coronavirus species causing SARS and MERS (15). Most antiviral compounds are prevalent in dietary food items such as culinary species, vegetables, nuts, fruits, and popular medicinal plants and herbal medicines. Some examples are Apiaceae family members like parsley and celery (containing psoralen, a furanocoumarin) (24), Brassicaceae family members like broccoli, brussels sprouts, and black mustard seeds (containing sinigrin, a glucosinolate) (25), strawberries, apples, spinach, Aloe vera, carrots, mulberries and tea (containing an abundant amount of myricetin, a flavonol) (26), soybean and olive oil (containing β-sitosterol, a phytosterol) (27), citrus fruits juices (containing hesperetin, a flavanone) (28), and licorice (containing glycyrrhizin, a pentacyclic saponin) (29).

These data show the broad-spectrum antiviral activity of different plants, particularly those that are edible and common in diets worldwide. Also, some studies report the antiviral activity of plants mentioned above against previous outbreaks caused by other coronaviruses and even COVID-19. It can be concluded that the inclusion of these plants in diets can enhance general antiviral immunity and play a role in the prevention and treatment of COVID-19 infection.

4.3. Anti-inflammatory Medicinal Plants

COVID-19 is associated with cytokine storms leading to severe and generalized inflammatory reactions (30). Thus, using medicinal plants with in vivo or in vitro anti-inflammatory activity can benefit patients suffering from COVID-19 (31). Typical examples are turmeric (containing curcumin, a polyphenolic compound) (32), ginger (containing 6-gingerol, a phenolic compound) (33), rosemary (containing rosmarinic acid, a phenolic acid) (32), borage (containing gamma-linolenic acid, an omega-6 polyunsaturated fatty acid) (34), evening primrose (containing linoleic acid and gamma-linolenic acid, omega-6 polyunsaturated fatty acids) (35), dog rose (containing linoleic and linolenic acid, polyunsaturated fatty acids) (36), nettle (containing quercetin, a flavonol) (37), sage (containing a phenolic acid: rosmarinic acid and a triterpene: ursolic acid) (38), and olive (containing oleocanthal, a phenolic compound) (39). Anti-inflammatory effects of traditional medicines specifically relate to their flavonoids, terpenoids, and fixed oils content that are extensively distributed in other vegetables, nuts, beans, cereals, herbal beverages, and fruits.

Inflammation plays a pivotal role in the pathogenesis of COVID-19, causing cytokine storms and increasing mortality by the widespread occurrence of the inflammatory process. Consumption of medicinal plants with anti-inflammatory compounds with novel structures can help treat COVID-19 patients or at least decrease the number of severe cases.

4.4. Immuno-stimulating Medicinal Plants

COVID-19 infection is more common and severe in immunocompromised patients (40, 41). Thus, using medicinal plants with immuno-stimulating activities, such as coneflower (containing polysaccharides, alkamides; dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutyl amide, and phenolics; cichoric acid) (42) that is a famous plant with reported immunostimulating and immunomodulating activity, can benefit such patients. Some of the marketed products of coneflower, such as Nature's Way Echinacea, Now Foods Echinacea, and Nature Made Echinacea, are commercially available. Other plants include Mongolian milkvetch (Astragalus membranaceus) (containing astragaloside IV, a triterpene saponin) (43), ginger (containing zingerone, a phenolic compound) (44), green tea (containing epigallocatechin-3-gallate, a polyphenolic compound) (45), Aloe vera (containing acemannan, a polysaccharide) (46), and ginseng (containing ginsenoside Rb1, a triterpene saponin) (47). However, the use of immunostimulant medicinal plants is contraindicated in patients suffering from autoimmune diseases or those taking immunosuppressive drugs.

In summary, plants with immuno-stimulating activities can increase the human body's resistance to pathogens and contribute to the prevention of infectious diseases. In addition, herbal products can also be used during COVID-19 to enhance immunity. However, their limitation for use in immunocompromised patients should be considered.

4.5. Antioxidant Medicinal Plants

COVID-19 infection is associated with extensive tissue damage requiring repair and recovery back to a normal functional state. Medicinal plants containing antioxidant compounds, such as flavonoids (eg, quercetin, kaempferol, apigenin, myricetin, luteolin, isorhamnetin, luteolin, chrysoeriol, hyperin, isoquercetin, rutin, hesperidin, naringenin, taxifolin, nobiletin, and hyperoside), anthocyanins (eg, cyaniding, malvidin, peonidin, delphinidin, pelargonidin, petunidin, and idaein), carotenes (eg, α-carotene, β-carotene, γ-carotene, and lycopene), and xanthophylls (eg, auroxanthin, antheraxanthin, neoxanthin, lutein, violaxanthin, zeaxanthin, and β-cryptoxanthin), can help in this process (48, 49). Commonly used edible plants like spinach, celery, parsley, apple, orange, red cabbage, blackberry, barberry, carrot, tomato, mango, and pumpkin have high antioxidant content. In addition to the above-mentioned antioxidant phytochemicals that give a specific color to plant parts, the antioxidant activity of chlorophylls as the most widespread natural pigment cannot be ignored (49). In every plant organ, a class of phytochemicals predominates others in making the plant a colorful appearance in which the main coloring agents are chlorophylls (green), flavonoids (yellow), anthocyanins (red to blue), and tetraterpenoids including carotenes and xanthophylls (yellow to red) with either conjugated double bonds or phenolic hydroxyls responsible for their free radical scavenging activity. Thus, all vegetables and fruits used in different world regions have some antioxidant activity.

According to the antioxidant potential of various phytochemicals and their widespread presence in medicinal plants, they can be used as supportive therapy to treat COVID-19. Free radical production plays a prominent role in the tissue damage caused by infectious diseases, especially when accompanied by inflammation. Thus, the antioxidant activity of medicinal plants can minimize tissue damage and promote faster recovery.

4.6. Medicinal Plants Used in Treating Respiratory Infections, Cough, and Flu

As respiratory infections are common worldwide, several medicinal plants in different traditional systems have been used for treatment. These herbal medicinal products include decongestants (eucalyptus oil, peppermint oil, and camphor) (50), bronchodilators (cocoa, coffee, tea, onion) (51, 52), demulcents and emollients (mallow, marshmallow, licorice, elder, pelargoniums) (29, 50), expectorants and mucolytics (thyme, common ivy, licorice, sage, senega, ipecac, poplar buds) (29, 50, 53, 54), anti-allergics (toothpick plant, chicory) (50, 55) and antitussives (licorice, black cumin, flax, common wormwood, cumin) (53, 54, 56).

Although COVID-19 infection involves different body systems, it is usually considered a respiratory disease and causes respiratory symptoms. The above-mentioned plants and their products can help reduce COVID-19 associated respiratory symptoms and facilitate the convalescence of patients.

4.7. Adaptogenic Medicinal Plants

Adaptogenic medicinal plants protect against stress and increase adaptability, resilience, and survival via enhancing non-specific resistance. These plants act by modulating innate and adaptive immunity, enhancing anti-inflammatory activity, neutralizing oxidative stress and repairing related damage, enhancing antiviral effects, and improving quality of life during convalescence (57). Commonly used adaptogenic plants include ginseng (containing ginsenoside Rb1, a triterpene saponin), licorice (containing glycyrrhizin, a pentacyclic saponin, liquiritin, and isoliquiritin flavonoid compounds), and ashwagandha (containing withaferin A, a steroidal lactone triterpene) (58) that can be considered in the treatment of COVID-19 infection.

Adaptogenic plants with various biological effects can increase body resistance against the COVID-19 virus, decrease the infection period, and increase the patient recovery rate. Generally, adaptogenic plants can help overcome the COVID-19 induced damage and promote recovery.

5. Concerns for the Use of Herbal Medicines in COVID-19

What is mentioned above illustrates the possible effects of natural compounds and herbal products on the treatment of COVID-19 infection. However, there are inherent issues related to the composition, preparation, and use of herbal medicines. In addition, the use of medicinal plants can lead to problems and adverse effects, mainly when used in patients with specific medical conditions (vide infra).

5.1. Quality

Several factors affect the concentration of bioactive compounds in medicinal plants, such as geographical conditions of the soil where the plant is harvested, plant species and plant parts used in treatment, harvesting time, storage condition, and processes that are routinely employed for preparation. Standardization and quality control are much more difficult and technically more time-consuming in herbal medicines than in single compound drugs. In this regard, the contamination of herbal products by heavy metals and microbes is a common problem. Medicinal plants used for sexual performance enhancement, bodybuilding, and weight loss have the highest adulteration rate (59). Considering the fear and stress caused by the COVID-19 pandemic leading to rapid demand for herbal products in a short duration of time, the quality control of herbal medicines may be further compromised.

5.2. Efficacy

Although many papers have reported positive effects of herbal medicines, due to the difficulties in quality control as mentioned above and the lack of comparison of their therapeutic effects with modern medicines, their actual efficacy remains unknown in most cases. This is true for most herbal medicines currently available on the market.

5.3. Safety

5.3.1. Adverse Effects

Contrary to popular belief, most herbal medicines have adverse effects that are also reported (60). Common examples include Ephedra preparations that cause hypertension, myocardial infarction and arrhythmia, seizure, stroke, hepatotoxicity, neurotoxicity, and transient blindness (61, 62). Another example is the risk of hepatotoxicity by pyrrolizidine alkaloids containing plants of Boraginaceae like Borago officinalis (63). Medicinal plants with mild side effects include garlic (insomnia, vomiting, heartburn, dizziness, diarrhea, tachycardia, nausea, bloating, flushing, headache, mild orthostatic hypotension, sweating, offensive body odor, and flatulence) (64), echinacea (rash, abdominal pain, angioedema, dyspnea, nausea, pruritus, rash, erythema, and urticaria) (65), St. John's wort (nausea, rash, fatigue, restlessness, and photosensitivity) (66), ginger (mild to moderate gastrointestinal side effects and sleepiness) (67), ginseng (headaches, alterations in blood pressure, diarrhea, skin irritations, and vaginal bleeding) (68), and Aloe spp. (skin irritation, hives, cramping, and diarrhea) (69). Thus, patients with COVID-19 may exacerbate their symptoms while taking some of the medicinal plants.

5.3.2. Herb-Drug Interaction

Pharmacodynamic and pharmacokinetic herbal drug interactions are common, especially in patients suffering from chronic diseases such as diabetes, hypertension, and psychiatric and neurologic disorders (70). Additionally, drugs with a narrower therapeutic index, such as anticonvulsants, anticoagulants and antiplatelets, antiarrhythmics, immunosuppressives, neuroleptics, and antidiabetics, and some antibiotics, such as vancomycin, have a higher probability of herb-drug interaction and life-threatening consequences. Common examples of herb-drug interactions include St John’s wort used as an antidepressant that has significant interactions with antiviral drugs, oral contraceptives, immunosuppressive and anti-cancer medicines leading to their reduced clinical effectiveness (71). Ginseng, used as adaptogenic, interacts with anticoagulants such as warfarin and potentiates hypoglycemic effects of antidiabetic drugs (72). Another example of herb-drug interaction is ginger that is used to treat COVID-19. It enhances the effect of anticoagulants, leading to bleeding and hypoglycemic attacks in diabetic patients taking sulfonylureas (62, 73).

5.3.3. Concerns for Particular Groups of Patients

In addition to the restricted number of clinical studies performed on herbal medicines in patients, most of such studies have been carried out on regular adult volunteers with common health conditions and patients suffering from specific conditions have been largely excluded because of ethical and scientific considerations. This has led to the lack of authentic data in specific groups, including infants and children who have not achieved maturation of physiological and metabolic pathways (74). Pregnant women are another group where the nonselective use of herbal medicines can endanger the mother and unborn baby's health by embryotoxicity, teratogenicity, and abortion (75). Furthermore, breastfeeding women's use of herbal medicines, such as, tea and other caffeine-rich materials, can affect milk production or transfer some phytochemicals to newborns (76). Additionally, elderly patients who usually use more medicines and have age-related pharmacokinetic and pharmacodynamic changes are at higher risk of adverse effects of herbal medicines, herb-drug interactions, and related consequences (77, 78). Patients undergoing a surgical operation within two weeks are another group who require more precaution (79) since herbal medicines can alter the coagulation system (ginger) (62), cardiovascular stability (Ephedra spp.) (61, 62), blood sugar control (ginger) (73), anesthesia (valerian) (80) and drug metabolism (St John’s wort) (73). All these groups of patients require special precautions compared to regular patients.

6. Randomized Clinical Trials

Several medicinal plants have undergone clinical trials for their various biological effects. These include onion, garlic, ginger, turmeric, licorice, and ginseng preparations. However, no randomized clinical trials have been reported for their effectiveness in COVID-19 treatment. Comprehensive guidelines for clinical trials on herbal medicine have long been published and are available (81). Recently, clinical trial protocols have been reported for curcumin and herbal extracts of Shunthi (Zingiber officinale, ginger), Vidanga (Embelia ribes), Yashtimadhu (Glycyrrhiza glabra, licorice), Haritaki (Terminalia chebula), Guduchi (Tinospora cordifolia), Shatavari (Asparagus racemosus), Amalaki (Emblica officinalis), and Pippali (Piper longum) (82, 83), and results are being awaited for their efficacy and safety.

7. Conclusions

Medicinal plants used in traditional medicine have a promising role in treating COVID-19. Several antiviral compounds with novel structures are found in these plants that can be considered for further research to develop new medicinal products or new lead compounds. In addition, several categories of herbal medicines can be used for reducing inflammation and tissue damage and managing associated signs and symptoms of COVID-19 patients. Herbs, including commonly used edible plants such as licorice, onion, peppermint, marshmallow, carrot, spinach, apple, orange, cabbage, barberry, tomato, and parsley, can increase the general resistance of the human body against infection and promote immunity to overcome the COVID-19 associated pathogenic process. Thus, the rational use of herbal medicines can help prevent COVID-19, decrease its severity and duration, promote tissue repair, and enhance general recovery when used alongside modern medicines. However, several areas, including the quality, safety, and efficacy of herbal medicines, their interaction with drugs, and their use in particular groups of patients, require attention. We suggest randomized clinical trials on herbal medicines before their safe and effective use in the treatment of COVID-19.

References

  • 1.

    Luo L, Yang J, Wang C, Wu J, Li Y, Zhang X, et al. Natural products for infectious microbes and diseases: An overview of sources, compounds, and chemical diversities. Sci China Life Sci. 2021:1-23. https://doi.org/10.1007/s11427-020-1959-5.

  • 2.

    Abiri R, Abdul-Hamid H, Sytar O, Abiri R, Bezerra de Almeida EJ, Sharma SK, et al. A Brief Overview of Potential Treatments for Viral Diseases Using Natural Plant Compounds: The Case of SARS-Cov. Molecules. 2021;26(13). [PubMed ID: 34202844]. [PubMed Central ID: PMC8270261]. https://doi.org/10.3390/molecules26133868.

  • 3.

    Komolafe K, Komolafe TR, Fatoki TH, Akinmoladun AC, Brai BIC, Olaleye MT, et al. Coronavirus Disease 2019 and Herbal Therapy: Pertinent Issues Relating to Toxicity and Standardization of Phytopharmaceuticals. Rev Bras Farmacogn. 2021:1-20. [PubMed ID: 33727754]. [PubMed Central ID: PMC7951132]. https://doi.org/10.1007/s43450-021-00132-x.

  • 4.

    Zhang QH, Huang HZ, Qiu M, Wu ZF, Xin ZC, Cai XF, et al. Traditional Uses, Pharmacological Effects, and Molecular Mechanisms of Licorice in Potential Therapy of COVID-19. Front Pharmacol. 2021;12:719758. [PubMed ID: 34899289]. [PubMed Central ID: PMC8661450]. https://doi.org/10.3389/fphar.2021.719758.

  • 5.

    Thota SM, Balan V, Sivaramakrishnan V. Natural products as home-based prophylactic and symptom management agents in the setting of COVID-19. Phytother Res. 2020;34(12):3148-67. [PubMed ID: 32881214]. [PubMed Central ID: PMC7461159]. https://doi.org/10.1002/ptr.6794.

  • 6.

    Silveira D, Prieto-Garcia JM, Boylan F, Estrada O, Fonseca-Bazzo YM, Jamal CM, et al. COVID-19: Is There Evidence for the Use of Herbal Medicines as Adjuvant Symptomatic Therapy? Front Pharmacol. 2020;11:581840. [PubMed ID: 33071794]. [PubMed Central ID: PMC7542597]. https://doi.org/10.3389/fphar.2020.581840.

  • 7.

    Xiong Y, Gao M, van Duijn B, Choi H, van Horssen F, Wang M. International policies and challenges on the legalization of traditional medicine/herbal medicines in the fight against COVID-19. Pharmacol Res. 2021;166:105472. [PubMed ID: 33592272]. [PubMed Central ID: PMC7882224]. https://doi.org/10.1016/j.phrs.2021.105472.

  • 8.

    Paudyal V, Sun S, Hussain R, Abutaleb MH, Hedima EW. Complementary and alternative medicines use in COVID-19: A global perspective on practice, policy and research. Res Social Adm Pharm. 2022;18(3):2524-8. [PubMed ID: 33992585]. [PubMed Central ID: PMC8116135]. https://doi.org/10.1016/j.sapharm.2021.05.004.

  • 9.

    Nordling L. Unproven herbal remedy against COVID-19 could fuel drug-resistant malaria, scientists warn. Science. 2020. https://doi.org/10.1126/science.abc6665.

  • 10.

    Butler MS. Natural products to drugs: Natural product-derived compounds in clinical trials. Nat Prod Rep. 2008;25(3):475-516. [PubMed ID: 18497896]. https://doi.org/10.1039/b514294f.

  • 11.

    Naithani R, Huma LC, Holland LE, Shukla D, McCormick DL, Mehta RG, et al. Antiviral activity of phytochemicals: A comprehensive review. Mini Rev Med Chem. 2008;8(11):1106-33. [PubMed ID: 18855727]. https://doi.org/10.2174/138955708785909943.

  • 12.

    Martinez JP, Sasse F, Bronstrup M, Diez J, Meyerhans A. Antiviral drug discovery: broad-spectrum drugs from nature. Nat Prod Rep. 2015;32(1):29-48. [PubMed ID: 25315648]. https://doi.org/10.1039/c4np00085d.

  • 13.

    Boukhatem MN, Setzer WN. Aromatic Herbs, Medicinal Plant-Derived Essential Oils, and Phytochemical Extracts as Potential Therapies for Coronaviruses: Future Perspectives. Plants (Basel). 2020;9(6). [PubMed ID: 32604842]. [PubMed Central ID: PMC7356962]. https://doi.org/10.3390/plants9060800.

  • 14.

    Chinsembu KC. Coronaviruses and Nature's Pharmacy for the Relief of Coronavirus Disease 2019. Rev Bras Farmacogn. 2020;30(5):1-19. [PubMed ID: 33041391]. [PubMed Central ID: PMC7537782]. https://doi.org/10.1007/s43450-020-00104-7.

  • 15.

    Khare P, Sahu U, Pandey SC, Samant M. Current approaches for target-specific drug discovery using natural compounds against SARS-CoV-2 infection. Virus Res. 2020;290:198169. [PubMed ID: 32979476]. [PubMed Central ID: PMC7513916]. https://doi.org/10.1016/j.virusres.2020.198169.

  • 16.

    da Rosa Mesquita R, Francelino Silva Junior LC, Santos Santana FM, Farias de Oliveira T, Campos Alcantara R, Monteiro Arnozo G, et al. Clinical manifestations of COVID-19 in the general population: Systematic review. Wien Klin Wochenschr. 2021;133(7-8):377-82. [PubMed ID: 33242148]. [PubMed Central ID: PMC7689634]. https://doi.org/10.1007/s00508-020-01760-4.

  • 17.

    Oladele JO, Ajayi EI, Oyeleke OM, Oladele OT, Olowookere BD, Adeniyi BM, et al. A systematic review on COVID-19 pandemic with special emphasis on curative potentials of Nigeria based medicinal plants. Heliyon. 2020;6(9). e04897. [PubMed ID: 32929412]. [PubMed Central ID: PMC7480258]. https://doi.org/10.1016/j.heliyon.2020.e04897.

  • 18.

    Tawfeek N, Mahmoud MF, Hamdan DI, Sobeh M, Farrag N, Wink M, et al. Phytochemistry, Pharmacology and Medicinal Uses of Plants of the Genus Salix: An Updated Review. Front Pharmacol. 2021;12:593856. [PubMed ID: 33643045]. [PubMed Central ID: PMC7908037]. https://doi.org/10.3389/fphar.2021.593856.

  • 19.

    Salehi B, Zakaria ZA, Gyawali R, Ibrahim SA, Rajkovic J, Shinwari ZK, et al. Piper Species: A Comprehensive Review on Their Phytochemistry, Biological Activities and Applications. Molecules. 2019;24(7). [PubMed ID: 30959974]. [PubMed Central ID: PMC6479398]. https://doi.org/10.3390/molecules24071364.

  • 20.

    Goyal S, Gupta N, Chatterjee S. Investigating Therapeutic Potential of Trigonella foenum-graecum L. as Our Defense Mechanism against Several Human Diseases. J Toxicol. 2016;2016:1250387. [PubMed ID: 26884758]. [PubMed Central ID: PMC4739449]. https://doi.org/10.1155/2016/1250387.

  • 21.

    Du S, Liu H, Lei T, Xie X, Wang H, He X, et al. Mangiferin: An effective therapeutic agent against several disorders (Review). Mol Med Rep. 2018;18(6):4775-86. [PubMed ID: 30280187]. https://doi.org/10.3892/mmr.2018.9529.

  • 22.

    Ekiert H, Swiatkowska J, Klin P, Rzepiela A, Szopa A. Artemisia annua - Importance in Traditional Medicine and Current State of Knowledge on the Chemistry, Biological Activity and Possible Applications. Planta Med. 2021;87(8):584-99. [PubMed ID: 33482666]. https://doi.org/10.1055/a-1345-9528.

  • 23.

    Ali SI, Sheikh WM, Rather MA, Venkatesalu V, Muzamil Bashir S, Nabi SU. Medicinal plants: Treasure for antiviral drug discovery. Phytother Res. 2021;35(7):3447-83. [PubMed ID: 33590931]. [PubMed Central ID: PMC8013762]. https://doi.org/10.1002/ptr.7039.

  • 24.

    Caboni P, Saba M, Oplos C, Aissani N, Maxia A, Menkissoglu-Spiroudi U, et al. Nematicidal activity of furanocoumarins from parsley against Meloidogyne spp. Pest Manag Sci. 2015;71(8):1099-105. [PubMed ID: 25157855]. https://doi.org/10.1002/ps.3890.

  • 25.

    Mazumder A, Dwivedi A, du Plessis J. Sinigrin and Its Therapeutic Benefits. Molecules. 2016;21(4):416. [PubMed ID: 27043505]. [PubMed Central ID: PMC6273501]. https://doi.org/10.3390/molecules21040416.

  • 26.

    Gupta G, Siddiqui MA, Khan MM, Ajmal M, Ahsan R, Rahaman MA, et al. Current Pharmacological Trends on Myricetin. Drug Res (Stuttg). 2020;70(10):448-54. [PubMed ID: 32877951]. https://doi.org/10.1055/a-1224-3625.

  • 27.

    Babu S, Jayaraman S. An update on beta-sitosterol: A potential herbal nutraceutical for diabetic management. Biomed Pharmacother. 2020;131:110702. [PubMed ID: 32882583]. https://doi.org/10.1016/j.biopha.2020.110702.

  • 28.

    Ferreira de Oliveira JMP, Santos C, Fernandes E. Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models. Phytomedicine. 2020;73:152887. [PubMed ID: 30975541]. https://doi.org/10.1016/j.phymed.2019.152887.

  • 29.

    El-Saber Batiha G, Magdy Beshbishy A, El-Mleeh A, Abdel-Daim MM, Prasad Devkota H. Traditional Uses, Bioactive Chemical Constituents, and Pharmacological and Toxicological Activities of Glycyrrhiza glabra L. (Fabaceae). Biomolecules. 2020;10(3). [PubMed ID: 32106571]. [PubMed Central ID: PMC7175350]. https://doi.org/10.3390/biom10030352.

  • 30.

    Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm' in COVID-19. J Infect. 2020;80(6):607-13. [PubMed ID: 32283152]. [PubMed Central ID: PMC7194613]. https://doi.org/10.1016/j.jinf.2020.03.037.

  • 31.

    Mehta N, Mazer-Amirshahi M, Alkindi N, Pourmand A. Pharmacotherapy in COVID-19; A narrative review for emergency providers. Am J Emerg Med. 2020;38(7):1488-93. [PubMed ID: 32336586]. [PubMed Central ID: PMC7158837]. https://doi.org/10.1016/j.ajem.2020.04.035.

  • 32.

    Ghasemian M, Owlia S, Owlia MB. Review of Anti-Inflammatory Herbal Medicines. Adv Pharmacol Sci. 2016;2016:9130979. [PubMed ID: 27247570]. [PubMed Central ID: PMC4877453]. https://doi.org/10.1155/2016/9130979.

  • 33.

    Morvaridzadeh M, Fazelian S, Agah S, Khazdouz M, Rahimlou M, Agh F, et al. Effect of ginger (Zingiber officinale) on inflammatory markers: A systematic review and meta-analysis of randomized controlled trials. Cytokine. 2020;135:155224. [PubMed ID: 32763761]. https://doi.org/10.1016/j.cyto.2020.155224.

  • 34.

    Dasgupta A. Translational inflammation. In: Actor JK, Smith KC, editors. Antiinflammatory herbal supplements. Academic Press; 2019. p. 69-91.

  • 35.

    Timoszuk M, Bielawska K, Skrzydlewska E. Evening Primrose (Oenothera biennis) Biological Activity Dependent on Chemical Composition. Antioxidants (Basel). 2018;7(8). [PubMed ID: 30110920]. [PubMed Central ID: PMC6116039]. https://doi.org/10.3390/antiox7080108.

  • 36.

    Ilyasoğlu H. Characterization of Rosehip (Rosa caninaL.) Seed and Seed Oil. Int J Food Prop. 2014;17(7):1591-8. https://doi.org/10.1080/10942912.2013.777075.

  • 37.

    Jan KN, Zarafshan K, Singh S. Stinging nettle (Urtica dioica L.): A reservoir of nutrition and bioactive components with great functional potential. J Food Meas Charact. 2016;11(2):423-33. https://doi.org/10.1007/s11694-016-9410-4.

  • 38.

    Sharma Y, Fagan J, Schaefer J, Yashaswini Sharma C. Ethnobotany, phytochemistry, cultivation and medicinal properties of Garden sage (Salvia officinalis L.). J Pharmacogn Phytochem. 2019;8:3139-48.

  • 39.

    Guo Z, Jia X, Zheng Z, Lu X, Zheng Y, Zheng B, et al. Chemical composition and nutritional function of olive (Olea europaea L.): A review. Phytochem Rev. 2017;17(5):1091-110. https://doi.org/10.1007/s11101-017-9526-0.

  • 40.

    Fung M, Babik JM. COVID-19 in Immunocompromised Hosts: What We Know So Far. Clin Infect Dis. 2021;72(2):340-50. [PubMed ID: 33501974]. [PubMed Central ID: PMC7337668]. https://doi.org/10.1093/cid/ciaa863.

  • 41.

    Martins-Chaves RR, Gomes CC, Gomez RS. Immunocompromised patients and coronavirus disease 2019: A review and recommendations for dental health care. Braz Oral Res. 2020;34. e048. [PubMed ID: 32428085]. https://doi.org/10.1590/1807-3107bor-2020.vol34.0048.

  • 42.

    Catanzaro M, Corsini E, Rosini M, Racchi M, Lanni C. Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea. Molecules. 2018;23(11). [PubMed ID: 30373170]. [PubMed Central ID: PMC6278270]. https://doi.org/10.3390/molecules23112778.

  • 43.

    Li S, Sun Y, Huang J, Wang B, Gong Y, Fang Y, et al. Anti-tumor effects and mechanisms of Astragalus membranaceus (AM) and its specific immunopotentiation: Status and prospect. J Ethnopharmacol. 2020;258:112797. [PubMed ID: 32243990]. https://doi.org/10.1016/j.jep.2020.112797.

  • 44.

    Ahmad B, Rehman MU, Amin I, Arif A, Rasool S, Bhat SA, et al. A Review on Pharmacological Properties of Zingerone (4-(4-Hydroxy-3-methoxyphenyl)-2-butanone). Sci World J. 2015;2015:816364. [PubMed ID: 26106644]. [PubMed Central ID: PMC4461790]. https://doi.org/10.1155/2015/816364.

  • 45.

    Sharma R, Sharma A, Kumari A, Kulurkar PM, Raj R, Gulati A, et al. Consumption of green tea epigallocatechin-3-gallate enhances systemic immune response, antioxidative capacity and HPA axis functions in aged male Swiss albino mice. Biogerontology. 2017;18(3):367-82. [PubMed ID: 28341876]. https://doi.org/10.1007/s10522-017-9696-6.

  • 46.

    Liu C, Cui Y, Pi F, Cheng Y, Guo Y, Qian H. Extraction, Purification, Structural Characteristics, Biological Activities and Pharmacological Applications of Acemannan, a Polysaccharide from Aloe vera: A Review. Molecules. 2019;24(8). [PubMed ID: 31010204]. [PubMed Central ID: PMC6515206]. https://doi.org/10.3390/molecules24081554.

  • 47.

    Kang N, Gao H, He L, Liu Y, Fan H, Xu Q, et al. Ginsenoside Rb1 is an immune-stimulatory agent with antiviral activity against enterovirus 71. J Ethnopharmacol. 2021;266:113401. [PubMed ID: 32980486]. https://doi.org/10.1016/j.jep.2020.113401.

  • 48.

    Dias MC, Pinto D, Silva AMS. Plant Flavonoids: Chemical Characteristics and Biological Activity. Molecules. 2021;26(17). [PubMed ID: 34500810]. [PubMed Central ID: PMC8434187]. https://doi.org/10.3390/molecules26175377.

  • 49.

    Perez-Galvez A, Viera I, Roca M. Carotenoids and Chlorophylls as Antioxidants. Antioxidants (Basel). 2020;9(6). [PubMed ID: 32526968]. [PubMed Central ID: PMC7346216]. https://doi.org/10.3390/antiox9060505.

  • 50.

    Heinrich M, Williamson EM, Gibbons S, Barnes J, Prieto-Garcia J. Fundamentals of pharmacognosy and phytotherapy E-BOOK. Elsevier Health Sciences; 2017.

  • 51.

    S. Bisen P, Emerald M. Nutritional and Therapeutic Potential of Garlic and Onion (Allium sp.). Curr Nutr Food Sci. 2016;12(3):190-9. https://doi.org/10.2174/1573401312666160608121954.

  • 52.

    Onatibia-Astibia A, Martinez-Pinilla E, Franco R. The potential of methylxanthine-based therapies in pediatric respiratory tract diseases. Respir Med. 2016;112:1-9. [PubMed ID: 26880379]. https://doi.org/10.1016/j.rmed.2016.01.022.

  • 53.

    Kuang Y, Li B, Fan J, Qiao X, Ye M. Antitussive and expectorant activities of licorice and its major compounds. Bioorg Med Chem. 2018;26(1):278-84. [PubMed ID: 29224994]. https://doi.org/10.1016/j.bmc.2017.11.046.

  • 54.

    Pastorino G, Cornara L, Soares S, Rodrigues F, Oliveira M. Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review. Phytother Res. 2018;32(12):2323-39. [PubMed ID: 30117204]. [PubMed Central ID: PMC7167772]. https://doi.org/10.1002/ptr.6178.

  • 55.

    Street RA, Sidana J, Prinsloo G. Cichorium intybus: Traditional Uses, Phytochemistry, Pharmacology, and Toxicology. Evid Based Complement Alternat Med. 2013;2013:579319. [PubMed ID: 24379887]. [PubMed Central ID: PMC3860133]. https://doi.org/10.1155/2013/579319.

  • 56.

    Saadat S, Shakeri F, Boskabady MH. Comparative Antitussive Effects of Medicinal Plants and Their Constituents. Altern Ther Health Med. 2018;24(4):36-49. [PubMed ID: 29332022].

  • 57.

    Panossian A, Brendler T. The Role of Adaptogens in Prophylaxis and Treatment of Viral Respiratory Infections. Pharmaceuticals (Basel). 2020;13(9). [PubMed ID: 32911682]. [PubMed Central ID: PMC7558817]. https://doi.org/10.3390/ph13090236.

  • 58.

    Kaur P, Makanjuola VO, Arora R, Singh B, Arora S; Robin. Immunopotentiating significance of conventionally used plant adaptogens as modulators in biochemical and molecular signalling pathways in cell mediated processes. Biomed Pharmacother. 2017;95:1815-29. [PubMed ID: 28968926]. https://doi.org/10.1016/j.biopha.2017.09.081.

  • 59.

    Rocha T, Amaral JS, Oliveira M. Adulteration of Dietary Supplements by the Illegal Addition of Synthetic Drugs: A Review. Compr Rev Food Sci Food Saf. 2016;15(1):43-62. [PubMed ID: 33371574]. https://doi.org/10.1111/1541-4337.12173.

  • 60.

    Lee JY, Jun SA, Hong SS, Ahn YC, Lee DS, Son CG. Systematic Review of Adverse Effects from Herbal Drugs Reported in Randomized Controlled Trials. Phytother Res. 2016;30(9):1412-9. [PubMed ID: 27196988]. https://doi.org/10.1002/ptr.5647.

  • 61.

    Ekor M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol. 2014;4:177. [PubMed ID: 24454289]. [PubMed Central ID: PMC3887317]. https://doi.org/10.3389/fphar.2013.00177.

  • 62.

    Kaye AD, Kucera I, Sabar R. Perioperative anesthesia clinical considerations of alternative medicines. Anesthesiol Clin North Am. 2004;22(1):125-39. [PubMed ID: 15109694]. https://doi.org/10.1016/S0889-8537(03)00113-5.

  • 63.

    Schramm S, Kohler N, Rozhon W. Pyrrolizidine Alkaloids: Biosynthesis, Biological Activities and Occurrence in Crop Plants. Molecules. 2019;24(3). [PubMed ID: 30704105]. [PubMed Central ID: PMC6385001]. https://doi.org/10.3390/molecules24030498.

  • 64.

    El-Saber Batiha G, Magdy Beshbishy A, G. Wasef L, Elewa YHA, A. Al-Sagan A, Abd El-Hack ME, et al. Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review. Nutrients. 2020;12(3). [PubMed ID: 32213941]. [PubMed Central ID: PMC7146530]. https://doi.org/10.3390/nu12030872.

  • 65.

    Manayi A, Vazirian M, Saeidnia S. Echinacea purpurea: Pharmacology, phytochemistry and analysis methods. Pharmacogn Rev. 2015;9(17):63-72. [PubMed ID: 26009695]. [PubMed Central ID: PMC4441164]. https://doi.org/10.4103/0973-7847.156353.

  • 66.

    Russo E, Scicchitano F, Whalley BJ, Mazzitello C, Ciriaco M, Esposito S, et al. Hypericum perforatum: Pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytother Res. 2014;28(5):643-55. [PubMed ID: 23897801]. https://doi.org/10.1002/ptr.5050.

  • 67.

    Toth B, Lantos T, Hegyi P, Viola R, Vasas A, Benko R, et al. Ginger (Zingiber officinale): An alternative for the prevention of postoperative nausea and vomiting. A meta-analysis. Phytomedicine. 2018;50:8-18. [PubMed ID: 30466995]. https://doi.org/10.1016/j.phymed.2018.09.007.

  • 68.

    Cambria C, Sabir S, Shorter IC. Ginseng. StatPearls Publishing; 2019.

  • 69.

    Guo X, Mei N. Aloe vera: A review of toxicity and adverse clinical effects. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2016;34(2):77-96. [PubMed ID: 26986231]. [PubMed Central ID: PMC6349368]. https://doi.org/10.1080/10590501.2016.1166826.

  • 70.

    Alissa EM. Medicinal herbs and therapeutic drugs interactions. Ther Drug Monit. 2014;36(4):413-22. [PubMed ID: 24452064]. https://doi.org/10.1097/FTD.0000000000000035.

  • 71.

    Izzo AA. Interactions between herbs and conventional drugs: Overview of the clinical data. Med Princ Pract. 2012;21(5):404-28. [PubMed ID: 22236736]. https://doi.org/10.1159/000334488.

  • 72.

    Choi MK, Song IS. Interactions of ginseng with therapeutic drugs. Arch Pharm Res. 2019;42(10):862-78. [PubMed ID: 31493264]. https://doi.org/10.1007/s12272-019-01184-3.

  • 73.

    Maideen NMP, Balasubramaniam R. Pharmacologically relevant drug interactions of sulfonylurea antidiabetics with common herbs. J HerbMed Pharmacol. 2018;7(3):200-10. https://doi.org/10.15171/jhp.2018.32.

  • 74.

    Farrington R, Musgrave I, Byard RW. Potential adverse outcomes of herbal preparation use in childhood. Acta Paediatr. 2019;108(3):419-22. [PubMed ID: 30256451]. https://doi.org/10.1111/apa.14595.

  • 75.

    Bernstein N, Akram M, Yaniv-Bachrach Z, Daniyal M. Is it safe to consume traditional medicinal plants during pregnancy? Phytother Res. 2021;35(4):1908-24. [PubMed ID: 33164294]. https://doi.org/10.1002/ptr.6935.

  • 76.

    Budzynska K, Gardner ZE, Low Dog T, Gardiner P. Complementary, holistic, and integrative medicine: Advice for clinicians on herbs and breastfeeding. Pediatr Rev. 2013;34(8):343-52. quiz 352-3. [PubMed ID: 23908361]. [PubMed Central ID: PMC4530286]. https://doi.org/10.1542/pir.34-8-343.

  • 77.

    de Souza Silva JE, Santos Souza CA, da Silva TB, Gomes IA, Brito Gde C, de Souza Araujo AA, et al. Use of herbal medicines by elderly patients: A systematic review. Arch Gerontol Geriatr. 2014;59(2):227-33. [PubMed ID: 25063588]. https://doi.org/10.1016/j.archger.2014.06.002.

  • 78.

    Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lancet. 2007;370(9582):185-91. [PubMed ID: 17630042]. https://doi.org/10.1016/S0140-6736(07)61092-7.

  • 79.

    Kleinschmidt S, Rump G, Kotter J. [Herbal medications. Possible importance for anaesthesia and intensive care medicine]. Anaesthesist. 2007;56(12):1257-66. [PubMed ID: 17898965]. https://doi.org/10.1007/s00101-007-1264-z.

  • 80.

    Dippenaar JM. Herbal and alternative medicine: The impact on anesthesia. South African J Anaesth Analg. 2015;21(1):15-20. https://doi.org/10.1080/22201181.2015.1013321.

  • 81.

    CONSORT transparent reporting of trials. Herbal Medicinal Interventions. CONSORT transparent reporting of trials; 2021, [cited 09/18/2021]. Available from: http://www.consort-statement.org/extensions?ContentWidgetId=557.

  • 82.

    Rangnekar H, Patankar S, Suryawanshi K, Soni P. Safety and efficacy of herbal extracts to restore respiratory health and improve innate immunity in COVID-19 positive patients with mild to moderate severity: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):943. [PubMed ID: 33225970]. [PubMed Central ID: PMC7680979]. https://doi.org/10.1186/s13063-020-04906-x.

  • 83.

    Hassaniazad M, Inchehsablagh BR, Kamali H, Tousi A, Eftekhar E, Jaafari MR, et al. The clinical effect of Nano micelles containing curcumin as a therapeutic supplement in patients with COVID-19 and the immune responses balance changes following treatment: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):876. [PubMed ID: 33092653]. [PubMed Central ID: PMC7578586]. https://doi.org/10.1186/s13063-020-04824-y.