Efficacy and Safety of Add-On Plant-Based Drugs for COVID-19 Patients: A Review of the Randomized Control Trials

Figures & data

Figure 1 The cell cycle of SARS‐CoV‐2 in humans.

Figure 2 Flow chart diagram of the review process.

Table 1 Characteristics of the Study

Ref.	Sample Size	Gender	Clinical Conditions	Name of Plant (Active Compound); Product Name; Dose	Standard Drug (SD)	Design of the Study	Length of Therapy (Days)	Efficacy or Clinical Outcomes	Safety Evaluation	Adverse Effect
	(Patients)*	Male (%)
Shanker et al^Citation14	62	69	Mild or moderate severity	Andrographis paniculata standard extract (andrographolide, neo-andrographolide, 14-deoxy-11,12-didehydroandrographolide, and andrograpanin); CIM-MEG19 (contains 150 mg A. paniculata extract/tablet)	SD = NSAIDs, antibiotics, antacids, and supplements	Intervention Group (n=38): SD + add-on therapy A. paniculata extract dosage 300 mg twice/day Control Group: SD + Redemsivir (n=24) and SD + Favipiravir (n=13)	14	Reduction of ESR, LDH, CRP, and D-dimer and an increase of IL-6 in the Intervention Group (p ≤ 0.05)	Analysis of blood biochemical parameters (total protein, albumin, globulin, bilirubin, SGOT, SGPT, alkaline phosphatase, urea, and creatinine) before and after add-on intervention	No AE or SAE was observed in the Intervention Group. Five SAEs occurred in the Control Group
Adel Mehraban et al^Citation15	108	51.90	Mild or moderate severity	Viola odorata L (hydroquinone, gallic acid, resorcinol, pyrocatechol, catechin, and caffeic acid); Banafsheh syrup; 10 mL (contains V. odorata dried flower 1.5 g) three times/day	SD = acetaminophen or other NSAIDs for myalgia, bromhexine or dextromethorphan for cough, dimenhydrinate for nausea and vomiting, and replacement of water and electrolytes for diarrhea	Intervention Group (n=54): SD + add-on therapy V. odorata dried flower dosage 1.5 g in 10 mL syrup three times a day Control Group (n=54): standard antivirus if needed + placebo syrup	7	Faster recovery and a significant decrease in severity scores: cough (P = 0.025), myalgia (P = 0.036), headache (P = 0.037), and diarrhea (P = 0.044) in the Intervention Group	Analysis of blood biochemical parameters (WBC, neutrophil percentage, lymphocyte percentage, RBC, HGB, platelets count, CRP, ESR), oxygen saturation, pulse rate, and BP before and after add-on intervention. Vital signs (body temperature, heart rate, respiratory rate, and blood pressure) and laboratory tests (complete blood count and CRP) were assessed. Any AEs were recorded via phone call during the study and through history-taking and physical examination at the final visit.	No AE or SAE was observed in both groups. AE was monitored daily based on Common Terminology Criteria for Adverse Events (CTCAE) ver. 5
Chitre et al^Citation17	175	69.8	Moderate plus at least one respiratory symptom (nasal congestion, sore throat, cough, breathing difficulty); and at least one constitutional symptom (aches/pains, fatigue, headache, chills, or sweats). Patients were confirmed positive with Delta or B.1.617 variant.	Ashwagandha (Withania somnifera), Boswellia carterii, Zingiber officinale, and Curcuma longa; BV-4051; 2 tablets twice/day	SD = Redemsivir	Intervention Group (n=89): SD + add-on therapy (dosage 1776 mg of BV-4051 twice/day after meals) Control Group (n=86): SD + placebo	14	Alleviation of fever in the Intervention Group on day-4th = 34% compared to the Control Group = 16.9%, a reduction in the duration of illness, and a decrease in IL-6, ERS, and LDH in the Intervention Group on day-14th. An increase of TNF-alpha was observed in both groups.	Safety was assessed by monitoring and recording all adverse events (AEs), regular physical examinations, hematology, chemistry, and 12-lead-electrocardiograms.	Moderate AEs (increase in LDH=1.5%, CRP=1.5%, and TNF=1.0%) were reported. These AEs were observed in 13 patients, 4 were in the Intervention Group and 9 were in the Control Group, but resolved during the study period, and were considered not related to the product
Hasanpour et al^Citation18	50	70	Mild or moderate severity	Ferula foetida (oleo‐gum) (butyl propenyl disulfide and methylthiopropyl 1‐propenyl disulfide) Covexir; 1 capsule (260 mg of F. foetida oleo‐gum) twice a day	SD = Azithromycin 500 mg once daily, hydroxychloroquine 200 mg twice daily for 5 days, and acetaminophen 500 mg tablets were used as standard care of treatment	Intervention Group (n=30): SD + F. foetida oleo-gum add-on therapy (dosage 260 mg twice a day) Control Group (n=20): Antivirus + placebo	7	An improvement in the clinical presentations (cough, shortness of breath, myalgia, anorexia, anosmia, and sense of taste) of patients in the Intervention Group was observed. A 27.01% reduction in CRP level in the Intervention Group, with no significant difference compared to the Control Group (p > 0.05)	An infectious disease specialist and a nurse visited and scored the patients’ clinical manifestations in the baseline (day-0) and the follow‐up sessions (day-3 and day-7) were performed by a nurse.	No specific AEs were observed in the Intervention Group. Gastrointestinal complications such as bloating and nausea were merely recorded in a few patients
Damle et al^Citation19	95	48	Mild or moderate severity and the presence of co-morbidity like diabetes and hypertension	Andrographis paniculata, Centella asiatica, Withania somnifera; ATRICOV 452 (dosage 1 g) three times/day	SD for mild severity patients = Favipiravir 1800 mg day-1 continued with Favipiravir 500 mg day-2 to day-7; SD for moderate severity patients = Oseltamivir 75 mg 1-0-1 for 5 days	Intervention Group (n=48): SD + ATRICOV 452 (dosage 1 g) three times/day Control Group (n=47): SD + placebo three times/day	14	In the Intervention (ATRICOV 452) Group and the Control Group (placebo), symptoms resolved in 100% of patients by day-15. An improvement in the levels of CRP, leucocyte count, NLR, D-dimer, PCT, LDH, and IL-6	The levels of CRP, leucocyte count, NLR, D-dimer, PCT, LDH, and IL-6 were measured as indicators of recovery	No AE. All organ system was normal in function.
Hawkins et al^Citation25	40	0	Post-COVID-19	Thymus vulgaris, Citrus sinensis, Eugenia caryophyllus, Boswellia carterii (essential oils); Longevity; 4 drops for 10 minutes inhalation, twice/day	N/A	Intervention Group (n=20): 4 drops of essential oils, inhaled, twice/day Control Group (n=20): 4 drops of a placebo, inhaled, twice/day	14	Significantly lower fatigue (p=0.002)	N/A	One participant in the Intervention Group reported experiencing headaches and withdrew on day 13; no other AE was observed
Shakeeb et al^Citation20	64	N/A	Mild or moderate severity; detected positive no more than 24 h	Elettaria cardamomum, Salvia Rosmarinus, Piper nigrum (1,8-cineole); Recovereez Forte; 500 mg, three times/day	SD = Oral Prednisolone in tapered dosage for 10 days, 100 mg × 3 times for the first 3 days, 100 mg × 2 times for the next 3 days, and 100 mg × 1 time for the last 4 days	Intervention Group (n=32): SD + Recovereez Forte 500 mg, three times/day Control Group (n=0.32): SD	10	Negative from COVID-19 at the fifth day (37.5%), with recovery from symptoms such as fever, cough, sore throat, and breathlessness compared to the control group by day 5.	Monitoring changes in the vital markers (liver function, renal function, serum electrolyte)	There were no patients in the Recovereez Forte group who dropped out owing to major side effects. Patients taking Recovereez Forte had minor gastrointestinal side effects such as gastroesophageal reflux. There were no negative changes in vital markers (liver function, renal function, serum electrolyte) during the study
Singh et al^Citation21	74	64.9	Mild or moderate severity	Alstonia scholaris R. Br., Picrorhiza kurroa Royle ex. Benth, Swertia chirata Pexbex. Karst, Caesalpinia crista; AYUSH-64; two tablets (500 mg each) three times/day	SD = Acetaminophen 500 mg SOS, Cetirizine 10 mg OD, Vitamin C 500 mg BD, and Azithromycin 500 mg OD (for 5 days)	Intervention Group (n=40): SD + Ayush-64 Control Group (n=40): SD	30	Reduced the levels IL-6 and d-dimer (p = 0.007), higher decrease in CRP level, LDH, serum ferritin and HRCT chest score compare to control group	Monitoring changes in the vital markers (liver function, renal function, serum electrolyte)	No AE. None of the participants required invasive or non-invasive oxygen therapy or developed complications
Ebrahimi et al^Citation22	30	67	Mild or moderate severity; respiratory symptoms (including dyspnea, chest pain, or discomfort); oral temperature > 38°C and SpO2 < 93%	Pumpkin seed oil (Squalene); injection of 5 mg SQ microemulsion twice/day	SD = 150 mg chloroquine (equivalent to 250 mg chloroquine phosphate), two tablets on the first day and one tablet every 12 h for a total of 10 days, or 400 mg hydroxychloroquine on the first day and then one tablet every 12 h for 10 days and Lopinavir/Ritonavir (200/50) every 12 h for 10–14 days and heparin 5000IU subcutaneous TDS (for body mass index [BMI] ≥ 40, 7500 IU SC TDS) or Enoxaparin 40 mg SC once a day (for BMI ≥ 40, 40 mg SC BID) and Oxygen therapy	Intervention Group (n=15): SD + Pumpkin seed oil (Squalene); injection of 5 mg SQ microemulsion twice/day for 6 days Control Group (n=15):	7	There was a significant difference between 2 groups in the need for oxygen therapy s after 7 days of treatment (p = 0.020); no fever at least for 2 days (p = 0.025); Cough alleviation (p = 0.010); improvement in chest CT scan (p = 0.033)	All participants were monitored for adverse events including anaphylaxis, ALT or AST elevation more than 2.5‐fold beyond the normal upper limit, total bilirubin elevation more than 1.5‐fold beyond the normal upper limit, acute pancreatitis, and diarrhea.	No clinical or laboratory adverse effects were observed within 7 days of admission
Devpura et al^Citation23	95	81	No or mild severity	Tinospora cordifolia, Withania somnifera, Ocimum sanctum; tablet 500 mg, twice/day	Placebo (tablets with identical looks and feels, composed of wheat flour as a major ingredient along with excipients and binders)	Intervention Group (n=45): Oral administrations of 1 g of Tinospora cordifolia and 2 g of traditional herbal-mineral formulation and 0.5 g each of Withania somnifera and Ocimum sanctum) twice per day for 7 days Control Group (n=50): Placebo	7	Reduced the time to recovery; decreased serum levels of hs-CRP and pro-inflammatory markers, IL-6 and TNF-α	Safety profile outcome was studied.	N/A
Shohan et al^Citation24	60	56.7	Severe; Non-ICU admission; uninterrupted O2 therapy supported by reservoir bags; arterial blood O2 saturation under 93%	Quercetin; 1000 mg once/day	Remdesivir: First day 200 mg (IV injection); Second to fifth day: 100 mg (IV injections daily); Favipiravir: First day: 3200 mg (1600 mg PO BD); Second to fifth day: 1200 mg (600 mg PO BD); Vitamin. D: 1000 IU daily; MgSO4: 250 mg orally twice a day (based on serum Mg level); Famotidine: 40 mg oral daily; Zinc sulfate: 30 mg daily; Vitamin C: 500–1000 mg daily; Dexamethasone: 8 mg daily IV injection	Intervention Group (n=30): SD + Quercetin 1000 mg, once/day Control Group (n=30): SD	7	Reduced the hospitalization period; more effective decreased serum levels of q-CRP (p=0.004), LDH (p=0.032), and ALP (p=0.002) in the intervention group	Not mentioned in the study	AE related to SD
Taghavi et al^Citation16	141	49	Comply with the latest version of The Scientific Committee of the National Staff for COVID-19 Disease Management	Allium sativum (thiosulfate (allicin), S-allyl cysteine sulfoxide (alliin), ajoenes, vinyldithiin, and diallyl sulfide); Gallecina; 1 capsule 90 mg three times/day	Remdesivir at a 200-mg loading dose as an intravenous infusion on day 1 of hospitalization, followed by a maximum maintenance dose of 100 mg/day from day 2 to 5; subcutaneous enoxaparin 40 mg daily, oral bromhexine syrup 5 mL thrice daily, oral multivitamin syrup 5 mL daily, oral zinc sulfate syrup 10 mg daily, and oral acetaminophen tablets 500 mg every 6 hours as needed	Intervention Group (n=101): Control Group (n=95): SD + placebo	5	The clinical status distribution on day-6 and at discharge was not statistically significant between the 2 groups. On the day of discharge, the degree of body temperature significantly differed between the Intervention Group (36.92°C) and the Control Group (36.98°C) (P = 0.04). The CRP level on the day of discharge was below the normal range (<7 mg/L) in both groups, making it clinically non-significant.	Safety profile outcome was studied.	GI side effects were documented in 20% of patients in the Intervention Group when compared with 12% of patients in both groups starting from day-1 and day-2. The most frequent complications were abdominal pain, nausea, vomiting, and diarrhea. Although the distribution of GI complications did not differ significantly between the 2 groups (P = 0.12), GI complications in the Intervention Group were approximately double when compared with those in the Control Group.

Note: *Participants who completed the study.

Abbreviations: SD, standard drugs; NSAIDs, non-steroid anti-inflamation drugs; AE, adverse events; SAE, severe adverse events.

Table 2 Efficacy of the Plant-Based Add-On Therapy on the Inflammatory Responses in Patients with COVID-19

Name of the Plant (Trade Name of the Drug)	Analysis of the Chemical Constituents	Reference	Before Add-On Intervention			After Add-On Intervention
			IL-6 in pg/mL	CRP in mg/L	D-Dimer in ng/mL	IL-6 in pg/mL	CRP in mg/L	D-Dimer in ng/mL
A. paniculata (CIM-MEG19 tablet)	Andrographolide Neo-andrographolide 14-deoxy-11,12-di-dehydro andrographolide Andrograpanin	Shanker et al (2023)^Citation14	7.13 ± 2.33	21.5 ± 41.5	188 ± 51.8	+21.88%	−53.58%	−22.04%
V. odorata (Banafsheh syrup)	Hydroquinone Gallic acid Resorcinol Pyrocatechol Catechin Caffeic acid	Adel Mehraban et al (2023)^Citation15	N/A	19.09 + 12.89	N/A	N/A	−2.57%	N/A
W. somnifera, B. carterii, Z. officinale, C. longa (BV-4051 tablet)	N/A	Chitre et al (2022)^Citation17	N/A	N/A	N/A	N/A	+1.5%	N/A
F. foetida (Covexir capsule)	Butyl propenyl disulfide Methylthiopropyl 1‐propenyl disulfide	Hasanpour et al (2022)^Citation18	N/A	N/A	N/A	N/A	−27.01%	N/A
A. paniculata, C. asiatica, W. somnifera (ATRICOV 452 capsule)	N/A	Damle et al (2022)^Citation19	N/A	N/A	N/A	Decrease	Decrease	Decrease
E. cardamom, S. rosmarinus, P. nigrum (Recovereez Forte)	N/A	Shakeeb et al (2022)^Citation20	N/A	N/A	N/A	Increase	Increase	N/A
A. scholaris, P. kurroa, S. chirata, C. crista (AYUSH-64)	N/A	Singh et al (2022)^Citation21	5.8	5.0	0.35 + 0.21	−18.97%	−26.00%	−40.00%
T. cordifolia, W. somnifera, O. sanctum (Ayurvedic Medicine)	N/A	Devpura et al (2021)^Citation23	N/A	N/A	N/A	Decrease	Decrease	Decrease
N/A	Quercetin	Shohan et al (2022)^Citation24	27 + 8	66.9 + 23.9	872 + 452	−33.33%	−68.01%	−41.17%
A. sativum	N/A	Taghavi et al (2023)^Citation16	N/A	13.7	N/A	N/A	−62.55%	N/A

Notes: “-” value decreases after the intervention; “+” value increases after the intervention.

Figure 3 Proposed add-on phytotherapy algorithm for COVID-19 patients.

Shanker K, Rangnekar H, Wele A, et al. A randomized controlled pilot study of add-on therapy of CIM-MEG19 (standardized Andrographis paniculata formulation) in mild to moderate COVID-19. Phytomedicine Plus Int J Phyther Phytopharm. 2023;3(1):100398. doi:10.1016/j.phyplu.2022.100398

 PubMedGoogle Scholar

Adel Mehraban MS, Shirzad M, Taghizadeh Kashani L M, et al. Efficacy and safety of add-on Viola odorata L. in the treatment of COVID-19: a randomized double-blind controlled trial. J Ethnopharmacol. 2023;304:116058. doi:10.1016/j.jep.2022.116058

 PubMed Web of Science ®Google Scholar

Chitre D, Nadkarni S, Jagtap N, et al. Phase III randomized clinical trial of BV-4051, an Ayurvedic polyherbal formulation in moderate SARS-CoV-2 infections and its impact on inflammatory biomarkers. Phytother Res. 2023;37(4):1232–1241. doi:10.1002/ptr.7683

 PubMed Web of Science ®Google Scholar

Hasanpour M, Safari H, Mohammadpour AH, et al. Efficacy of Covexir® (Ferula foetida oleo-gum) treatment in symptomatic improvement of patients with mild to moderate COVID-19: a randomized, double-blind, placebo-controlled trial. Phytother Res. 2022;36(12):4504–4515. doi:10.1002/ptr.7567

 PubMed Web of Science ®Google Scholar

Damle L, Damle H, Br B. Plant formulation ATRICOV 452 in improving the level of COVID-19 specific inflammatory markers in patients. Contemp Clin Trials Commun. 2022;28:100961. doi:10.1016/j.conctc.2022.100961

 PubMed Web of Science ®Google Scholar

Hawkins J, Hires C, Keenan L, Dunne E. Aromatherapy blend of thyme, Orange, clove bud, and frankincense boosts energy levels in post-COVID-19 female patients: a randomized, double-blinded, placebo controlled clinical trial. Complement Ther Med. 2022;67:102823. doi:10.1016/j.ctim.2022.102823

 PubMed Web of Science ®Google Scholar

Shakeeb N, Varkey P, Hynse A, Mandlecha A. Anti-inflammatory response of cardamom extract and prediction of therapeutic window in COVID-19 patients by assessing inflammatory markers using RT-PCR. Inflammopharmacology. 2022;30(3):883–894. doi:10.1007/s10787-022-00951-x

 PubMed Web of Science ®Google Scholar

Singh H, Srivastava S, Yadav B, et al. AYUSH-64 as an adjunct to standard care in mild to moderate COVID-19: an open-label randomized controlled trial in Chandigarh, India. Complement Ther Med. 2022;66:102814. doi:10.1016/j.ctim.2022.102814

 PubMed Web of Science ®Google Scholar

Ebrahimi M, Farhadian N, Amiri AR, Hataminia F, Soflaei SS, Karimi M. Evaluating the efficacy of extracted squalene from seed oil in the form of microemulsion for the treatment of COVID-19: a clinical study. J Med Virol. 2022;94(1):119–130. doi:10.1002/jmv.27273

 PubMed Web of Science ®Google Scholar

Devpura G, Tomar BS, Nathiya D, et al. Randomized placebo-controlled pilot clinical trial on the efficacy of ayurvedic treatment regime on COVID-19 positive patients. Phytomedicine. 2021;84:153494. doi:10.1016/j.phymed.2021.153494

 PubMed Web of Science ®Google Scholar

Shohan M, Nashibi R, Mahmoudian-Sani M-R, et al. The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: a randomized controlled trial. Eur J Pharmacol. 2022;914:174615. doi:10.1016/j.ejphar.2021.174615

 PubMed Web of Science ®Google Scholar

Taghavi MR, Tavanaei Tamanaei T, Oghazian MB, et al. Effectiveness of Fortified Garlic Extract Oral Capsules as Adjuvant Therapy in Hospitalized Patients with Coronavirus Disease 2019: a Triple-Blind Randomized Controlled Clinical Trial. Curr Ther Res Clin Exp. 2023;98:100699. doi:10.1016/j.curtheres.2023.100699

 PubMed Web of Science ®Google Scholar