Evaluation of botanicals as potential COVID-19 symptoms terminator

Table 1 Antiviral effects of plants on respiratory viruses

Plant name	Preparation	Susceptible viruses	Ref.
Allium sativum (Garlic)	Aqueous extracts	Influenza A (H9N2)	Rasool et al[53], 2017
	Extract	Infectious bronchitis virus	Mohajer Shojai et al[54], 2016
	Ethanolic extract	Influenza A (H1N1)	Chavan et al[55], 2016
	Garlic oil	Influenza A (H1N1)	Choi[56], 2018
	Fresh extract	Influenza A (H1N1)	Mehrbod et al[57], 2013
	Aqueous extract	Adenovirus (ADV3 and ADV41)	Chen et al[58], 2011
Aloe vera (Aloe)	Aloe anthraquinones and several derivatives (3-O-tetraacetoglupiranosil)	Influenza A	Borges-Argáez et al[59], 2019
	Aloe-emodin	Influenza A	Li et al[60], 2014
Astragalus mongholicus (Astragalus)	Astragalus polysaccharides	Avian infectious bronchitis virus	Zhang et al[61], 2018
	Astragalus polysaccharide	Influenza A (H9N2)	Kallon et al[62], 2013
Camellia sinensis (Green tea)	Catechins -EGCG	Adenovirus	Weber et al[63], 2003
	Catechin	Influenza A	Kuzuhara et al[64], 2009
	Catechins	Influenza A (H5N1)	Liu et al[65], 2012
	Polyphenols	Influenza A; Influenza B	Yang et al[66], 2014
Curcuma longa (Turmeric)	Curcumin	Influenza A virus	Chen et al[67], 2013
			Dai et al[68], 2018
	Curcumin	Influenza A (H1N1, H6N1)	Chen et al[69], 2010
	Curcumin	RSV	Obata et al[70], 2013
Echinacea purpurea (Purple coneflower)	E. purpurea fresh herb and root tinctures	Influenza	Vimalanathan et al[71], 2013
	Standardized E. purpurea extract	Influenza A (H5N1, H7N7, H1N1)	Pleschka et al[72], 2009
	Standardized E. purpurea extract	Rhinoviruses, RSV	Hudson et al[73], 2011
Eucalyptus globulus (Eucalyptus)	Essential oil- vapor phase	Influenza	Vimalanathan et al[74], 2014
Ginkgo biloba (Ginkgo)	Leaf extract	Influenza A (H1N1, H3N2)	Haruyama et al[75], 2013
Glycyrrhiza sp. (Licorice)	Water extract of licorice (Glycyrrhiza uralensis)	RSV	Feng Yeh et al[76], 2013
	Glycyrrhizic acid derivatives	SARS-CoV	Hoever et al[77], 2005
	Extract of Glycyrrhiza inflata	Influenza A (H1N1)	Dao et al[78], 2011
	Glycyrrhizin	Influenza A	Wolkerstorfer et al[79], 2009
	Glycyrrhizin	Influenza A (H5N1)	Michaelis et al[80], 2010
Lepidium meyenii (Maca)	Extracted with methanol	Influenza A; Influenza B	Del Valle Mendoza et al[81], 2014
Melaleuca alternifolia (Tea tree)	Tea tree oil	Influenza A (H1N1)	Garozzo et al[82], 2011
	Aerosol and vapor of tea tree oil	Influenza A (H11N9)	Usachev et al[83], 2013
	Tea tree oil	Influenza A (H11N9)	Pyankov et al[84], 2012
Melissa officinalis (Lemon balm)	Essential oil	Influenza A (H9N2)	Pourghanbari et al[85], 2016
	Extract	Avian infectious bronchitis	Lelešius et al[86], 2019
Mentha piperita (Peppermint)	Ethanol extract	RSV	Li et al[87], 2017
	Extract	Avian infectious bronchitis	Lelešius et al[86], 2019
Nigella sativa (Black cumin)	Ethanol extracts of	Influenza A (H5N1)	Dorra et al[88], 2019
	Ethanol extracts of	Influenza A (H9N2)	Umar et al[89], 2016
	Extract	Coronavirus	Ulasli et al[90], 2014
Panax ginseng (Ginseng)	Root of plant Panax ginseng	RSV	Lee et al[91], 2014
	Panax Korean red ginseng extract	RSV	Lee et al[92], 2014
	Red ginseng extract and polysaccharide and saponin fractions	Influenza A (H1N1)	Yin et al[93], 2013
	Korean red ginseng extract	Influenza A (H1N1, H3N2)	Yoo et al[94], 2012
Pelargonium sidoides (Pelargonium)	Pelargonium sidoides radix extract EPs® 7630	Rhinovirus	Roth et al[95], 2019
	EPs® 7630	Respiratory viruses	Michaelis et al[96], 2011
	EPs® 7630	Influenza A (H1N1, H3N2)	Theisen et al[97], 2012
Sambucus nigra (Black elder)	Extract	Infectious bronchitis virus	Chen et al[98], 2014
	Standardized elderberry liquid extract	Influenza A; Influenza B	Krawitz et al[99], 2011
	Concentrated juice of elderberry	Influenza A	Kinoshita et al[100], 2012
	Elderberry flavonoids	Influenza A (H1N1)	Roschek et al[101], 2009
Scutellaria baicalensis (Chinese skullcap)	Chemical constituents	Influenza A (H1N1)	Ji et al[102], 2015
	Baicalin	SARS-CoV	Chen et al[103], 2004
Torreya nucifera (Japanese nutmeg yew)	Ethanol extract	SARS-CoV	Ryu et al[104], 2010
Thymus vulgaris (Thyme)	Essential oil- liquid phase	Influenza	Vimalanathan et al[74], 2014
	Extract	Avian infectious bronchitis	Lelešius et al[86], 2019
Withania somnifera (Ashwagandha)	Withaferin A	Influenza A (H1N1)	Cai et al[105], 2015
Zingiber officinalis (Ginger)	Aqueous extracts	Influenza A (H9N2)	Rasool et al[53], 2017
	Ethanol extracts	Influenza A- (H5N1)	Dorra et al[88], 2019
	Fresh ginger	RSV	Chang et al[106], 2013

Influenza A strains: H1N1, H3N2, H5N1, H6N1, H7N7, H9N2, H11N9; RSV: Respiratory syncytial virus; H1N1: Influenza A; SARS-CoV: Severe acute respiratory syndrome coronavirus.

Table 2 Human clinical studies showing the effect of plants on respiratory infections

Plant	Disease state	Participant	Dosage	Study design	Results
Aged garlic extract[107]	Cold andflu illness	120 healthy subjects, 2 groups (21-50 yr)	4 capsules/d (2.56 g); 90 d	Double-blind, randomized, placebo-controlled parallel intervention	Increase in γδ-T cell and NK cell. Reduction in cold and flu severity; decrease in symptom days
E. purpurea and E. angustifolia root[108]	New-onset common cold	719 patients, 4 parallel groups (12-80 yr)	First 24 h: Equivalent of 10.2 g of root. Next 4 d: 5.1 g	Randomized, controlled trial	Disease duration and severity are not statistically significantly changed
Echinacea purpurea alcohol extract (Echinaforce®)[109]	Common cold	755 healthy subjects, 2 groups (≥ 18 yr)	Illness prevention: 3 × 0.9 mL. Acute stages of colds: 5 × 0.9 mL	Randomized, double-blind, placebo-controlled trial	Reduction of the total number of cold episodes, cumulated episode days, and pain-killer medicated episodes. Inhibited virally confirmed colds and especially prevented enveloped virus infections. Maximal effects on recurrent infections. Prophylactic intake of E. purpurea over a period of 4 mo to provide a positive risk/benefit ratio
Echinacea root extract[110]	Respiratory symptoms	175 adults, 2 groups (18–65 yr)	Tablets: 112.5 mg E. purpurea 6:1 extract (equivalent to 675 mg dry root) and 150 mg E. angustifolia 4:1 extract (equivalent to 600 mg dry root) 3 × 1 tablet, if required: 3 × 2 tablets	Randomized, double blind, placebo-controlled trial	Lower respiratory symptom scores. Preventive effect against the development of respiratory symptoms during travel, including long-haul flights
Green tea catechins and theanine[111]	Influenza	200 healthcare workers, 2 groups	Capsules: Green tea catechins (378 mg/d) and theanine (210 mg/d). 5 m	Randomized, double-blind, placebo-controlled trial	Lower incidence of influenza infection in the catechin/theanine group
Ivy leaf extract[112]	Acute or chronic bronchial inflammatory disease	9657 patients (5181 children)	Ivy leaves extract [drug-to-extract ratio: 5-7.5:1; extraction solvent: ethanol 30% (w/w)]. 0–5 yr: 3 × 2.5 mL; 6–12 yr: 3 × 5 mL; 12 yr and adults: 3 × 5–7.5 mL. 7 d	Prospective, open, multicenter post marketing study	Healing or improvement in 95% of symptoms. Effective and well tolerated
Ivy extract (Hedelix®)[113]	Acute respiratory catarrh and/or chronic recidivating inflammatory bronchial disease	268 children, 2 groups (syrup and drops groups) (0-12 yr)	0-1 yr: 1 × 2.5 mL syrup or 3 × 5 drops, 1-4 yr: 3 × 2.5 mL syrup or 3 × 16 drops, 4-10 yr: 4 × 2.5 mL syrup or 3 × 21 drops, 10-12 yr: 3 × 5 mL syrup or 3 × 31 drops. 14 d	Independent open, non-interventional studies	Effective and safe treatment of cough. Reduction in symptoms (especially rhinitis, cough and viscous mucus)
Ivy leaves dry extract (Prospan ®)[114]	Bronchial asthma	30 children (suffering from partial or uncontrolled mild persistent allergic asthma despite long-term treatment with 400 μg budesonide equivalent), 2 groups (6–11 yr)	2 × 5 mL (corresponding to 70 mg extract) 28–30 d	Randomized, double blind, placebo-controlled, cross-over study	Improvement of MEF75-25, MEF25 and VC
Korean red ginseng extract[115]	Influenza-like illness	100 healthy adults, 2 groups (30-70 yr)	9 capsules/d. 3 m	Placebo-controlled trial	Reduced the incidence of influenza-like illness
Modified ginseng extracts (GS-3K8 and GINST)[116]	Acute respiratory illness	45 healthy applicants, 3 groups (39-65 yr)	Capsules: 500 mg; 6 capsules/d; 8 wk	Randomized, double-blind, placebo-controlled pilot study	Reduction in acute respiratory illness development and symptom duration
Panax quinquefolius extract CVT-E002[117]	Acute respiratory illness and Chronic Lymphocytic Leukemia	293 patients, 2 groups (≥ 18 yr)	2 × 200 mg extract. 3 m	Randomized, double-blind, placebo-controlled study	Reduction intense acute respiratory illness and moderately-severe sore throat. Increased antibody responses.
Panax ginseng[118]	Chronic obstructive pulmonary disease	14 participants, 2 groups (57–73 yr)	2 × 200 mg 4 wk	Clinical trial protocol and pilot study	One participant in P. ginseng group reported events of sore throat, cough and fever
Panax ginseng root extract[119]	Chronic obstructive pulmonary disease	168 participants, 2 groups	2 × 100 mg capsules. 24 wk	Randomized, multi-center, double-blind, placebo controlled	Reduction in symptoms
Pelargonium sidoides extract EPs® 7630[120]	Chronic obstructive pulmonary disease	199 adults, 2 groups (18 yr and older)	30 drops. 24 wk	Randomized, double-blind, placebo-controlled, parallel group trial	Improvement in HRQoL (health-related quality-of-life) and PRO (Patient-reported outcomes)
Pelargonium sidoides extract EPs® 7630[121]	Acute bronchitis	220 patients (1-18 yr)	1-6 yr: 3 × 10 drops; 6–12 yr: 3 × 20 drops; 12-18 yr: 3 × 30 drops; 7 d	Randomized, double-blind, placebo-controlled clinical trial	Reduction in the total score of bronchitis-specific symptoms (especially cough and rales at auscultation)
Pelargonium sidoides extract EPs® 7630[122]	Upper respiratory tract infections	28 children with a diagnosed transient hypogammaglobulinemia of infancy (1-5 yr)	3 × 10 drops; 7 d	Randomized, placebo controlled, prospective, monocentric pilot study	Increased appetite. Reduction of nasal congestion
Pelargonium sidoides root extract EPs® 7630[123]	Upper respiratory tract- asthma attacks	61 children (1–14 yr)	1–5 yr: 3 × 10 drops; 6–12 yr: 3 × 20 drops; 12 yr and above: 3 × 30 drops; 5 d	Randomized, placebo controlled	Reduction the severity of symptoms (especially cough and nasal congestion). Shortening of the duration of upper respiratory viral infections. Reduction asthma attack frequency
Pelargonium sidoides preparation EPs® 7630[124]	Acute non-streptococcal tonsillopharyngitis	126 children, 2 groups (6–10 yr)	3 × 20 drops. 6 d	Double-blind, placebo-controlled clinical trial	Decrease in tonsillitis severity score compared to placebo in the EPs® 7630 group after 4 d of treatment
Pelargonium sidoides extract EPs® 7630[125]	Common cold	207 adults (18-55 yr)	SD: 3 × 30 drops; HD: 3 × 60 drops; 10 d	Prospective, double-blind, parallel-group, placebo-controlled, phase 3, 2 parts, 2-arm, clinical trial	After 10 d, clinical treatment in 90.4% of the active drug group. Reduction the severity of symptoms and short the duration of the disease. Higher full recovery rates or greater recovery for HD treatment on day 5
Sambucus nigra extract[126]	Influenza	64 patients (16-60 yr)	Lozenge: 175 mg extract; 4 lozenges/d; 2 d	Randomized, double-blind, placebo-controlled, pilot clinical trials	Significant improvement in most symptoms within 24 h (fever, headache, muscle aches and nasal congestion). Significant improvement in all investigated symptoms within 48 h (cough and mucus discharge)
Sambucus nigra extract[127]	Respiratory health	312 adults, 2 groups	Capsules: 300 mg. Before travel: 2 capsules/d. During travel and after arrival: 3 capsules/d. 14 d	Randomized, double-blind placebo-controlled clinical trial	Reduction of cold duration and severity in air travelers. Low symptom score

SD: Standard dose; HD: High dose.

Table 3 Plants that can have an impact on coronavirus disease 2019 symptoms

Plant name	Effects	Ref.
Allium sativum (Garlic)	Analgesic	Dehghani et al[128], 2018
	Anti-inflammatory	Arreola et al[129], 2015
	Anti-platelet	Hiyasat et al[130], 2009
	Heart protection	Sultana et al[131], 2016
	Hepatic protection	Aprioku et al[132], 2017
	Improving GI function	Chen et al[133], 2018
	Renal protection	Seckiner et al[134], 2014
Curcuma longa (Turmeric)	Analgesic	Henrotin et al[135], 2020
		Eke-Okoro et al[136], 2018
	Antiemetic	Liu et al[137], 2018
	Antifatigue	Huang et al[138], 2015
	Anti-inflammatory	Shimizu et al[139], 2019
	Antifibrotic	Gouda et al[140], 2019
	Antipyretic	Haider et al[141], 2013
	Bronchodilator	Ram et al[142], 2003
	GI protection	Haider et al[141], 2013
		Dulbecco and Savarino[143], 2013
	Hepatic protection	Dulbecco and Savarino[143], 2013
Glycyrrhiza glabra (Licorice)	Antitussives	Nosalova et al[144], 2013
		Kuang et al[145], 2018
	Anti-inflammatory	Kao et al[146], 2010
	Respiratory system protection	Shi et al[147], 2011
Nigella sativa (Black cumin)	Analgesic	Rushmi et al[148], 2017
	Anticoagulant	Muralidharan-Chari et al[149], 2016
	Antihistaminic	Ansari et al[150], 2010
		Alsamarai et al[151], 2014
	Anti-inflammatory	Majdalawieh and Fayyad[152], 2015
		Mahdavi et al[153], 2016
	Bronchodilation	Boskabady et al[154], 2010
		Salem et al[155], 2017
Panax ginseng (Ginseng)	Adaptogenic	Ratan et al[156], 2021
Pelargonium sidoides (Pelargonium)	Antitussives	Bao et al[157], 2015
	Secretolytic activity	Bao et al[157], 2015
Scutellaria baicalensis (Chinese skullcap)	Antiemetic	Aung et al[158], 2005
	Anti-inflammatory	Hong et al[159], 2013
	GI protection	Mehendale et al[160], 2007
		Cui et al[161], 2021
	Hepatic protection	Thanh et al[162], 2015
	Neuroprotective	Dai et al[163], 2013
	Regulation of histamine release-Anti allergic	Bui et al[164], 2017
Thymus vulgaris (Thyme)	Analgesic	Laub[165], 2018
		Salmalian et al[166], 2014
	Anticoagulant	Okazaki et al[167], 2002
	Anti-inflammatory	Habashy et al[168], 2018
Withania somnifera (Ashwagandha)	Adaptogenic	Salve et al[169], 2019
	Analgesic	Murthy et al[170], 2019
	Anticoagulant, antithrombotic	Ku et al[171], 2014
	Anti-inflammatory	Gupta and Singh[172], 2014
	Antitussives	Nosalova et al[144], 2013
	Stress-relieving	Lopresti et al[173], 2019
Zingiber officinale (Ginger)	Analgesic	Maghbooli et al[174], 2014
		Bartels et al[175], 2015
	Antiemetic	Tóth et al[176], 2018
	Anti-inflammatory	Khan et al[177], 2015
	Antiplatelet, antithrombotic	Lee et al[178], 2017
	Antitussives	Bera et al[179], 2016
	GI protection	Nanjundaiah et al[180], 2011
	Hepatic protection	Ajith et al[181], 2007
	Nephroprotective	Ajith et al[182], 2007

Table 4 Angiotensin-converting enzyme inhibitor plant

Plants	The compound under study	Results	Ref.
Ammoides verticillata essential oil	Isothymol	SARS-CoV-2/ACE2 inhibition	Abdelli et al[183], 2021
Allium sativum essential oil	Organosulfur compounds (99.4% of its essential oil)	SARS-CoV-2/ACE2 inhibition. Garlic essential oil can prevent protein maturation of the virus and the spread of infection	Thuy et al[184], 2020
Apium graveolens	Apigenin	Kidneys of spontaneous hypertensive rats/Regulation in ACE2 expression	Sui et al[185], 2010
Camellia sinensis	Black tea; Dark tea; Green tea; Oolong tea; White tea	ACE inhibition: Green < oolong < white < black < dark teas	Dong et al[186], 2011
Citrus aurantium	Hesperetin. Scutellarin. Nicotianamine. Glycyrrhizin. Baicalin	SARS-CoV-2/Connecting to ACE2 and blocking the SARS-CoV-2 input	Chen and Du[187], 2020
Erigeron breviscapus
Glycine max
Glycyrrhiza radix
Scutellaria baicalensis
Geranium and lemon essential oils	Citronellol and limonene	SARS-CoV-2/ACE2 inhibition	Senthil Kumar et al[188], 2020
Ginseng Glycyrrhiza uralensis	Ginsenoside Rg6; Ginsenoside F1; Monoammonium glycyrrhizinate; Glycyrrhizic acid methyl ester	SARS-CoV-2/ACE2 kinase inhibition	Zi et al[189], 2020
Glycine max (soybean)	Nicotianamine	ACE2 inhibition	Takahashi et al[190], 2015
Glycyrrhiza glabra	Glycyrrhizic acid	SARS-CoV-2/Glycyrrhizic acid disrupts the connection of the virus with the ACE2 receptor at the entry level	Sinha et al[43], 2021
Hibiscus sabdariffa anthocyanins	Delphinidin- and cyanidin-3-O-sambubiosides	ACE inhibition	Ojeda et al[191], 2010
Linum usitatissimum (Flaxseed)	Secoisolariciresinol diglucoside	ACE inhibition	Prasad et al[192], 2013
Melaleuca cajuputi essential oil	Components (70.9% of the oil)	SARS-CoV-2/ACE2 and PDB6LU7 proteins inhibition	My et al[193], 2020
Nicotiana benthamiana	Recombinant ACE2-Fc fusion protein produced from N. benthamiana	SARS-CoV-2/Strong binding to the RBD of SARS-CoV-2 and inhibition	Siriwattananon et al[194], 2020
Withania somnifera	Withanone	SARS-CoV-2/Docking to the connector interface of the AEC2-RBD complex	Balkrishna et al[51], 2020

ACE: Angiotensin-converting enzyme; RBD: Receptor binding domain; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ACE2: Angiotensin-converting enzyme-2.