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

Introduction

The outbreak of COVID-19 has been a global concern for more than three years. This pandemic has deeply affected the health sector. It is a highly contagious severe acute respiratory syndrome that eventually attacks and damages many organs. It was reported in the last 28 days (13 March to 9 April 2023) the incidence of 3 million new cases and approximately 23,000 deaths, mostly in the South-East Asia and Eastern Mediterranean regions. ¹ The new Omicron variant, which is called Arcturus XBB.1.16, migrates from infecting mainly lungs and nervous tissue to the upper airways.²

COVID-19 patients show diverse clinical presentations ranging from asymptomatic, and mild to severe symptoms. Accumulating evidence suggests that comorbidities in SARS-CoV-2-infected individuals contribute to exacerbated outcomes, heightened symptom severity, and potentially elevated mortality risk.^3–5

The virus, SARS-CoV-2, is an enveloped virus of spherical shape with a single-stranded RNA genome in the nucleus. It uses ACE2 to invade the human body (Figure 1) and the cellular protease TMPRSS2 for its spike (S) protein priming (proteolytic separation of the S1 and S2 subunits).⁶

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

Infections are instigated by the attachment of transmembrane S glycoprotein to the peptidase domain of human ACE2.^7,8 The virus enters the target cells by binding the surface unit of the S protein (S1) to ACE 2. Viral fusion is primed by TMPRSS2 and the active S protein of SARS‐CoV‐2. The pH-dependent cysteine protease cathepsin L activates the S protein for fusion within the endosomal membrane. Mpro is a non-structural cysteine protease of SARS-CoV-2 that plays a role in the replication and transcription of the virus. RdRp (RNA-dependent RNA polymerase) is a non-structural protein of SARS-CoV-2 that works as a catalyst in the translation of viral RNA. SARS-CoV-2 uses an RdRp complex for the replication of their genome and for the transcription of their genes.^9,10

At a time of worldwide anxiety, it is imperative to find long-term solutions to prevent the transmission of such pandemics, therefore, many studies have been focused on how to enhance the role of the immune system. The immune system can be classified into two functional categories: (1) the innate (non-specific) immune system and (2) the adaptive (specific or acquired) immune system. The immune system’s architecture is organized into multiple layers, providing defenses at several levels. The skin serves as the primary and most evident barrier against infection. Physiological factors, such as body temperature and pH, also contribute to creating inhospitable environments for foreign organisms. Upon successful pathogen entry, the innate and/or adaptive immune systems become active. Both systems encompass a diverse array of cells and molecules that engage in intricate interactions to detect and eliminate pathogens. Detection and elimination rely on chemical bonding, where immune cell surfaces are adorned with various receptors. Some of these receptors bind to pathogens, while others interact with other immune cells or molecules, facilitating the complex signaling networks that underlie immune responses.^11,12 In a healthy organism, the immune system preserves internal homeostasis. The functionality and efficiency of the immune system are modulated by diverse exogenous and endogenous factors, leading to either immunosuppression or immunostimulant. Agents capable of normalizing or modulating pathophysiological processes are classified as immunomodulators.^12,13

Many studies have reported the potency of medicinal plants in enhancing the function of the immune system to combat virus infection, however, no study reported on the safety of randomized control trials of plant extracts for patients with COVID-19. In this review, the efficacy and safety of add-on plant-based drugs for COVID-19 patients are discussed. Randomized controlled trials or clinical trials were chosen because they are prospective studies that evaluate the effectiveness of therapy. Before performing the trials, the researchers have to attentively choose the population, what interventions to be compared, and the outcomes of interest. Through this review, readers will get insights into the results, outcomes, and benefits of using add-on plant-based therapy particularly plants with immunomodulatory activity for COVID-19 patients.

Materials and Methods

This review was based on the articles indexed in the PubMed and Cochrane Library databases, published during 2020–2023. The search was done using the keywords: (immune system AND flavonoids OR plants AND covid19 patients) AND (controlled trial” OR “randomized controlled trial” OR “randomized controlled trial” OR RCT[filter]). Inclusion criteria were limited to original articles written in English, plant-based drugs, accessible full texts, and randomized control trials or human studies. In vivo/in vitro/in silico studies, non-plant-based, or incomplete studies, were excluded. The titles and the abstracts of the articles included were further screened for their relevance to the topic of this study. Additional relevant studies were obtained from the citations in the selected articles. The detailed flowchart of the article searches and the results obtained are depicted in Figure 2.

Figure 2 Flow chart diagram of the review process.

Results

Of the 163 articles identified, 12 studies were reckoned to meet the eligibility criteria and these articles were included for analysis (depicted in Figure 2). Out of 12 studies, 11 studies are conducted in COVID-19 patients^14–24 and 1 study is conducted in post-COVID-19 patients.²⁵ There are 22 varieties of plants involved as add-on therapy for COVID-19 patients. These plants were Andrographis paniculata (Acanthaceae) in the dosage form of 150 mg extract in methylcellulose coated tablets (300 mg 3 times/day), Viola odorata (Violaceae) 1.5 g dried flower extract in 10 mL syrup (1.5 g 3 times/day), Withania somnifera (Solanaceae), Zingiber officinale (Zingiberaceae), Curcuma longa (Zingiberaceae), Ferula foetida (Apiaceae) 260 mg oleo‐gum in tablets (260 mg twice/day), Centella asiatica (Apiaceae), Thymus vulgaris (Lamiaceae), Citrus sinensis (Rutaceae), Eugenia caryophyllus (Myrtaceae), Boswellia carterii (Burseraceae), Elettaria cardamomum (Zingiberaceae), Salvia rosmarinus (Lamiaceae), Piper nigrum (Piperaceae), Alstonia scholaris (Apocynaceae), Picrorhiza kurroa (Plantaginaceae), Swertia chirata (Gentianaceae), Caesalpinia crista (Fabaceae or Leguminosae), Cucurbita maxima (Cucurbitaceae) 5 mg squalene in microemulsion injection (5 mg twice/day), Tinospora cordifolia (Menispermaceae), Ocimum sanctum (Lamiaceae), and Allium sativum (Amaryllidaceae) 90 mg (three times/day). The number of trials, sample sizes, standard drugs used, clinical outcomes, and the adverse events for each included plant are tabulated in Table 1.

Table 1 Characteristics of the Study

The articles analyzed were published from 2020 to 2023. The total number of participants involved was 1042 COVID-19 patients, with the majority of the patients being male gender (56.83%). The duration of the studies ranged from 5 to 30 days. However, one study included in this review was performed on 40 post-COVID-19 female patients.

The studies used standard-of-care drugs, eg, a combination of NSAIDs (acetaminophen 500 mg)^{14–16,18,21} or SAIDs (prednisolone),²⁰ antibiotics (azithromycin 500 mg),^18,21 chloroquine or hydroxychloroquine,^18,22 H1R antagonists (cetirizine 10 mg for allergy or dimenhydrinate for nausea),^15,21 anticoagulants (enoxaparin 40 mg),^16,22 antitussive (bromhexine or dextromethorphan),^15,16 antacids or H2R antagonists (famotidine),²⁴ and supplements (Vitamin C 500 mg). The antiviral drugs used were remdesivir (in general) or favipiravir (for mild severity symptoms) or oseltamivir (for moderate severity symptoms) or a combination of lopinavir/ritonavir. Most of the studies reported a reduction of symptoms or faster recovery and a decrease in inflammatory responses (IL-6, C-reactive protein, and D-dimer) in the Intervention Group (plant-based add-on therapy) compared to the Control Group. Moreover, 6 studies indicated the safety of the add-on plant-based therapy as proven by no AEs observed in the Intervention Group patients.

Efficacy

All twelve reviewed studies reported the efficacy of the plant-based add-on therapy (Table 1). Efficacy was evaluated by measuring the levels of inflammatory responses, either IL-6 or C-reactive protein or D-dimer or all (10 articles), and/or the hospitalization period (5 articles), and/or the severity of the symptoms, eg, cough, myalgia, fever, sore throat, fatigue (7 articles). Not all studies showed their data, some of them only reported general qualitative statements, eg, an improvement in inflammatory responses or a significant decrease in inflammatory markers.

The efficacy data of the plant-based add-on therapy for COVID-19 patients in this review were obtained by comparing the changes (calculated in %) in IL-6, CRP, and D-dimer levels (Table 2) before and after the intervention.

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

It is interesting to find out that the aerial part of Andrographis paniculata plants (CIM-MEG19 tablet) has shown the best efficacy as an add-on therapy for COVID-19 patients.^14,19 This drug showed a statistically significant (p < 0.05) reduction in CRP (53.58%) and D-dimer (22.04%) levels as well as the ESR (erythrocyte sedimentation rate). However, an increase in IL-6 (21.88%) was observed, although in general, the patients in the Intervention Group showed no AEs or SAEs.¹⁴ A. paniculata was also studied in a combination with other plants (ATRICOV 452 capsule) and resulted in a decrease of IL-6, CRP, and D-dimer levels.¹⁹

Moreover, the bulb of garlic (Allium sativum) was studied as an add-on therapy in reducing CRP in mild-severity hospitalized patients with COVID-19. Although the result was not clinically significant compared to that of the placebo group, the add-on therapy using A. sativum could reduce 62.55% CRP level compared to the baseline. However, this plant has caused GI discomfort in 20% of the patients.¹⁶

A study in post-COVID-19 patients was included in this review because the term post-COVID-19 syndrome has recently procured global recognition among scientific communities. The pathogenesis of post-COVID syndrome involves multiple mechanisms that result in various clinical manifestations.²⁶ The post-COVID-19 patients were given 10 minutes of inhalation of essential oils containing a mixture of Thymus vulgaris, Citrus sinensis, Eugenia caryophyllus, and Boswellia carterii (essential oils) twice per day for 14 days, which resulted in a significant decrease in fatigue in the Intervention Group. Nevertheless, one participant in the Intervention Group reported experiencing headaches and withdrew on day-13. No other AE was observed.²⁵

Safety

The safety of the add-on therapy was evaluated in 10 of the 12 studies, by analyzing the hematologic parameters (WBC, neutrophil percentage, lymphocyte percentage, RBC, hemoglobin, platelets count) and/or blood biochemical parameters (total protein, albumin, globulin, bilirubin, SGOT, SGPT, alkaline phosphatase, urea, and creatinine), and/or inflammatory biomarkers (ESR, LDH, CRP, and D-dimer), and/or physical examination (oxygen saturation, pulse rate, and BP), and/or by monitoring the AEs, before and after add-on intervention. The most frequently reported side effects are mild GI discomfort (bloating and nausea) and headache. None of the studies reported severe side effects. All studies confirmed the safety of the add-on therapy.

Discussion

SARS-CoV-2 infection rapidly stimulates CD4⁺T lymphocyte cells to become pathogenic T helper (Th)1 cells and produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6. Eventually, it invigorates inflammatory factors engendering a cascade of interactions and cytokine storm.³ C-reactive protein (CRP) and IL-6 were appointed as markers to determine the severity of COVID-19. An elevation of IL-6 indicated the worsening of the disease, while a decrease indicated the effectiveness of therapy.²⁷

IL-6, a cytokine featuring pleiotropic activity, works by stimulating the production of acute-phase proteins, eg, CRP, and blocking the production of albumin. IL-6 also contributes a part to the acquired immune response by activating immunoglobulin production and T-cells generation. IL-6 stimulates the differentiation or proliferation of various non-immune cells; thus, discontinued production of IL-6 governs the instigation of various diseases.²⁸

CRP is a pentameric protein produced in the mitochondria of hepatocytes. The level of this protein increases in correlation with inflammation. CRP is released when oxidative stress due to the presence of reactive oxygen species which opens the mitochondrial permeability transition pore. CRP is primarily induced by the IL-6 action on the gene controlling the CRP transcription process.²⁹ The normal level of CRP is < 10 mg/L; however, it elevates rapidly within 6–8 hours and reaches its maximum in 48 hours from the onset of inflammation.³⁰ The level of blood CRP has been reported to range from 20 to 50 mg/L in patients with COVID‐19.^31,32

Immunomodulator Activity of the Plants

Several studies reported that most of the medicinal plants used in the treatment of COVID-19 have similar mechanisms, including the regulation of apoptosis and immune response.^33–35 For example, a clinical study proposed that standardized A. paniculata extract had increased both T and T helper cells, and significantly increased IFN-γ, IL-4, and decreased IL-2 at day-30 in participants with absolute lymphocyte counts of 1000–3000 cells/mm³. There were no treatment-related adverse effects following standardized A. paniculata extract intake for 30 days.³⁵ In a multicenter randomized open‐label trial involving adult patients hospitalized with mild to moderate COVID‐19, an injection containing 9‐dehydro‐17‐hydro‐andrographolide and sodium 9‐dehydro‐17‐hydro‐andrographolide‐19‐yl sulfate (popularly known as Xiyanping injection) was proven a safe and effective in accelerating symptom resolution (eg, fever and cough) and rapid SARS‐CoV‐2 clearance.³⁶

Andrographolide, the main active compound A. paniculate, are reported to exhibit various pharmacological activities including immunostimulator, antiviral, antibacterial, and anti-inflammation.^37,38 Andrographolide was proven could inhibit the function of hepatitis C virus NS3-4A serine protease, a protein essential for RNA replication and signal transduction.^39,40 In addition, an in silico study concluded that andrographolide, a major diterpenoid lactone of Andrographis paniculata, was confirmed to effectively prevent the fusion of SARS-CoV-2 to hACE2 by breaking the salt bridge in hotspot-353 and occupying the site where the virus binds (Lys353 and Asp38).⁷ Moreover, andrographolide could inhibit the inflammatory cytokines in LPS-induced RAW264.7 cells by blocking the NF-kappaB/MAPK signaling pathway,⁴¹ thus this diterpenoid lactone may reduce the occurrence of cytokine storms in COVID-19 patients.

A previous study investigated the immunomodulatory effect of W. somnifera (Ashwagandha) extract, revealed that after the 30-day period, participants in the intervention group showed a significant increase (p < 0.05) in immunoglobulins (IgA, IgM, IgG, IgG2, IgG3, and IgG4), cytokines (IFN-γ, IL4), and T-helper 1 (Th1) cytokines, CD4+ and CD8+ T cell counts, and natural killer NK cells, whereas, in the placebo group, these cells showed a significant decrease (p < 0.05) and no alteration in the levels of immunoglobulins and cytokines (p > 0.05).⁴²

Herbal-Drug Interactions

Herbal-drug interactions are frequently observed, particularly in patients with chronic conditions, such as diabetes, hypertension, and psychiatric or neurological disorders, and therapy using medications with narrow therapeutic index, including anticonvulsants, anticoagulants, antiplatelet agents, antiarrhythmics, immunosuppressants, neuroleptics, antidiabetic drugs, and specific antibiotics like vancomycin.^43,44

Standard-of-Care in the management of COVID-19 comprises various antiviral agents, such as remdesivir, favipiravir, and oseltamivir, alongside the extensive employment of antibacterial medications, antitussives, expectorants, and supportive care, which increase the potential of herbal-drug interactions. Although the clinical study review in this article assessed the safety profile of herbal therapies, none addressed the potential interactions between the herbal compounds and other drugs employed in the studies.

It is widely acknowledged that pharmacokinetic and pharmacodynamic interactions represent the two fundamental categories of drug interactions observed in clinical settings. Most of these interactions are associated with the role of principal drug-metabolizing enzymes or/and drug transporters, including cytochrome P450 (CYP450) enzymes and/or P-glycoprotein (P-gp). An in vitro CYP450 study in human liver microsomes indicated that remdesivir possesses a moderate inhibition towards CYP3A4, CYP2C8, and CYP2D6, while W. somnifera had no inhibitory effect alone or in combination with remdesivir. Thus, W. somnifera was considered safe to be co-administered with the substrates of CYP3A4, CYP2C8, and CYP2D6. However, caution is warranted in prescribing AYUSH-64, a polyherbal formulation, along with CYP2C8 substrate drugs.⁴⁵

Although we cannot find other studies reporting the herbal-drug interaction related to those employed in the clinical study, several studies had reported justifiable findings. A recent study disclosed that an injection prepared from andrographolides, the major active components of A. paniculata (Burm. f.) had affected the pharmacokinetics of lopinavir/ritonavir through strong noncompetitive inhibition of CYP3A4 in a time-dependent manner.⁴⁶ Hence, extreme caution needs to be taken when A. paniculata, as a parenteral dosage form, is co-administrated with lopinavir/ritonavir for COVID-19 treatment.

Taken together, we propose an add-on phytotherapy algorithm for COVID-19 patients using A. paniculata as a single add-on therapy or in combination with other plants possessing antioxidant or immunomodulatory activity (depicted in Figure 3).

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

Conclusion

The efficacy of plant-based add-on therapy for patients with COVID-19, in general, was evaluated by measuring the levels of inflammatory responses, and/or the hospitalization period, and/or the severity of the symptoms, eg, cough, myalgia, fever, sore throat, fatigue. The most effective and safest plant-based drugs for COVID-19 patients are A. paniculata as a single component in pharmaceutical dosage form or in combination with W. somnifera and C. asiatica or with T. cordifolia and O. sanctum. The safety of the plant-based add-on therapy has been confirmed and proven by no occurrence of AEs or mild GI discomfort. Caution and therapy drug monitoring is needed if A. paniculata is to be administered in combination with lopinavir/ritonavir because a strong noncompetitive inhibition of CYP3A4 may occur thus altering the pharmacokinetics of the antivirals.