This systematic review included full original articles obtained through PubMed, Scopus, and Cochrane. During this search, original studies meeting the defined criteria were identified. Boolean operators such as “OR” and “AND” were used to expand the exploration within each concept and refine the results, respectively. Medical Subject Headings (MeSH) terms were also applied and the detailed search terms are outlined in Table 1. Furthermore, the original study published from 2019 to 2023 was used regarding clinical trials of herbal medicines with a randomized controlled method in English and the study subject was human. There were also study articles that did not clearly state the intervention, such as book chapters, article abstracts only, conference reports, reviews, posters, and discussion results. The articles identified for inclusion were screened and the findings were discussed to reach consensus. The procedure for selecting study articles is shown in Figure 1.

Subjects involved in the studies that were included in this systematic review were patients with positive reverse transcription polymerase chain reaction (RT-PCR) test for COVID-19, who had mild or moderate symptoms. Inclusion criteria included patients >18 years of age, and there were no gender restrictions. Patients with severe symptoms were excluded from this study.

The studies included in this analysis evaluated the efficacy of herbal medicines based on specific outcomes such as LOS, NCR and NCT. The LOS for inpatients with COVID-19 refers to the duration of time that individuals diagnosed with COVID-19 spend in hospital care, from admission to discharge (Wen et al., 2022). NCT for inpatients with COVID-19 refers to the duration it takes for a patient to transition from testing positive for the virus to testing negative (Bob-Manuel et al., 2021). Meanwhile, NCR refers to the proportion of patients who transition from testing positive for the virus to testing negative within a certain timeframe (Hu et al., 2020).

IRL and NW screened all relevant articles by evaluating their titles and abstracts. The full articles deemed suitable were reviewed and approved by IRL. Data extraction was conducted utilizing a review matrix created with Microsoft Excel and included author names, the active compound, country, sample size, patient characteristics, design study and outcomes (LOS, NCT and NCR). The risk of bias was conducted utilizing the Jadad score, which focused on three main guidelines for evaluating articles: randomization, double blinding, and the description of withdrawals and dropouts. Five questions need to be answered within a 10-min timeframe: Was the study described as randomized (using terms like random, randomly, or randomization)? Was the method for generating the randomization sequence adequately described and suitable? Was the study identified as double-blind? Was the method of double blinding adequately described and appropriate? Was there a description provided for withdrawals and dropouts?

The Jadad score was chosen for the systematic review because of its advantage in providing a simple yet systematic assessment of the methodological quality of clinical studies. The tool focuses on three main elements: randomization, double blinding, and missing data reports, which are considered important indicators in evaluating the quality of a study. With a clear and standardized approach, the Jadad score allows researchers to directly compare the methodological quality of different studies, making it possible to make a more objective assessment of the evidence. In addition, the simplicity of the tool also facilitates its implementation in systematic analyses involving a large number of studies. (Jadad et al., 1996; Olivo et al., 2008).

The 5 herbs in the inclusion criteria gave positive results where the LOS in the test group was better than the control and showed significant differences (Karimi et al., 2021; Xu et al., 2021; Tavakoli et al., 2022; Varnasseri et al., 2022; Chen et al., 2023). Meanwhile, the standard care used for each herbal medicine was adjusted to the value of each country. The duration of administration ranged from 7 days for Persian Medicine Herbal (PM Herbal) and Jingyin Granules (JY granules), 10 days for Phyllanthus emblica (Amla), and 14 days for Persian Barley Water (PBW) and Reduning Injection. A summary of the results for the efficacy of herbal medicines on LOS outcomes is provided in Table 2 and Figure 2.

Several studies use NCR and NCT outcomes to determine the efficacy of herbal medicines. However, some only use one of the NCR or NCT outcomes. For Lianhuaqingwen Capsules (LH capsules), JY granules and Kovir capsule used NCR and NCT outcomes simultaneously. For LH capsules, the results showed no significant differences in the control and test groups for NCR and NCT parameters (Hu et al., 2021). Similarly, in the Kovir capsule, where the results showed no significant difference in the NCR or NCT parameters (Loc et al., 2022). JY granules showed good results, significantly increasing NCR and also decreasing the average of NCT (Chen et al., 2023).

Studies that only use NCR parameters to determine the efficacy of therapy is Amla. There was no significant difference between the control and test groups (Varnasseri et al., 2022). Herbs that use NCT as a parameter of therapeutic outcome are Reduning Injection and Hua Shi Bai Du Granule (Q-14 granule). Reduning Injection shows good therapeutic results where the herb can significantly reduce NCT (Xu et al., 2021). Meanwhile, the herbal Q-14 granule did not significantly differ in NCT parameters (Liu et al., 2021). The duration of herbal administration for these patients is 7, 10, and 14 days. A summary of the results for the efficacy of herbal medicines on NCT and NCR outcomes is provided in Table 3 and Figures 3, 4.

Quality assessment of the included studies is a critical step in evaluating the reliability and validity of research results. One of the commonly used methods to conduct such an assessment is by using the Jadad score. The Jadad score is a tool used to assess the methodological quality of clinical studies. The total value of the Jadad score ranges from 0 to 5, where higher values indicate higher methodological quality (Jadad et al., 1996). There were no complete scores in the reviewed studies. Two studies had the highest score of 4 (Loc et al., 2022; Varnasseri et al., 2022). The studies fully described the randomization and blinding methods used but did not explain the description of withdrawal/dropout. Meanwhile, a study by Chen et al., 2019 had the lowest Jadad score of 1, because it did not use randomization and blinding methods but a prospective cohort study (Chen et al., 2023). However, we still included this study in the review because it fell within the inclusion criteria. Two other studies did not use blinding methods and did not explain the description of withdrawal/dropout so they had a Jadad score of 2 (Karimi et al., 2021; Tavakoli et al., 2022). Three studies used a single-blind method and did not explain the description of withdrawal/dropout and therefore had a Jadad score of 3 (Hu et al., 2021; Liu et al., 2021; Xu et al., 2021). Table 4 provides an overview of the quality assessment by Jadad score.

The pandemic has triggered intensive studies to obtain effective therapies for the disease. In addition, herbal medicines have also become the focus of attention as an alternative treatment (Demeke et al., 2021). Various medicinal plants have been investigated for their potential antiviral, anti-inflammatory, and immunomodulatory effects assisting the treatment of COVID-19 (Latarissa et al., 2021; Lim et al., 2021). The mechanism of herbal medicines for COVID-19 related to antiviral, anti-inflammatory and immunomodulatory is shown in Figure 5.

LOS is a parameter often used in clinical trials to determine the efficacy of a drug, and COVID-19 is no exception. Understanding the prognosis can be facilitated by examining the LOS (Alimohamadi et al., 2022). The 5 herbs showed significant differences in reducing LOS in COVID-19 patients. The main mechanisms are antiviral, anti-inflammatory, and immunomodulatory. Other mechanisms to accelerate the healing of patients which are seen from LOS parameters used as an antifever, bronchodilator, and antiasthma features, strengthen the body, and invigorate the lungs (Karimi et al., 2021). These mechanisms support providing improvements in the clinical condition of patients, specifically in cases seen from LOS parameters.

PM Herbal is a system of medicine in the world that dates back 7,000 years with formulations that are beneficial for several viral and bacterial infections and respiratory diseases (Soleymani and Zargaran, 2018; Walsh, 2021). The results of the PM Herbal clinical trial to fight COVID-19 were evidenced by a significant difference in the decrease in LOS for the intervention group and the control group (3,291 days vs. 6,468 days) (Karimi et al., 2021). This is also supported by research showing that the compounds contained in PM Herbal are proven to fight several viruses such as influenza virus, Echovirus type 11, adenovirus, respiratory syncytial virus and coronavirus (Balzarini et al., 1992; Utsunomiya et al., 1997; Liu et al., 2004; Kumaki et al., 2011; Lazreg et al., 2011; Karimi et al., 2020).

PBW is a herb originating from Iran and has long been used as an antitussive, for flu, bronchitis, body pain, fever, and other respiratory symptoms (Kapadia, 2006; De Natale and Pollio, 2007). These effects result from the combination of vitamins, dietary fibers, unsaturated fatty acids, mineral elements, and antioxidants found in PBW (Jo et al., 2020). Its good efficacy against SARS-CoV-2 was also proven by an in vitro study where the ricin-based peptide from PBW was able to inhibit Mpro with the half-maximal inhibitory concentration (IC50) of 0.52 nM (Kashyap et al., 2022). Mpro is a cysteine protease that plays an important role in viral RNA replication and transcription (Liu et al., 2020). This in vitro study is in line with the results of clinical trials that can reduce patient LOS (Tavakoli et al., 2022).

The JY granules comprise various components that exhibit inhibitory effects on SARS-CoV-2. For instance, Radix glycyrrhizae is included to directly suppress SARS-CoV-2 by acting on the IL-6/signal transducers and activators of the transduction-3 (STAT3) pathway (Luo et al., 2022). In addition, Flos lonicera and its effective ingredients can also reduce the main protease activity of the new coronavirus (Gu et al., 2022). JY granules is an antiviral herbal product that has been used for more than 40 years in China to treat various respiratory problems such as fever, sore throat and cough (Wang et al., 2020). JY granules is known to have antiviral activity that has been proven in vitro and in vivo against the influenza virus (Wang et al., 2021b).

The antiviral activity of Reduning Injection, specifically for treating pneumonia, is also a potential treatment for COVID-19. Reduning Injection is used for indications of nausea, colds, fever, cough, yellow sputum, and upper respiratory tract infections (Zhang et al., 2013; Cao et al., 2020; Chen et al., 2020; Xie et al., 2020). Several studies have also proven that Ieduning Injection has effects as antipyretic, antiviral, and anti-inflammatory (Cao et al., 2020; Xie et al., 2020). Besides pneumonia, the activity of Reduning Injection against viruses is also proven by its efficacy against H1N1 A influenza (Chen et al., 2020).

The antiviral effect of Amla has been investigated to treat several diseases caused by viruses such as herpes simplex and those causing disorders in the reproductive and respiratory system (Xiang et al., 2011; Arjin et al., 2020). In addition, Amla also has therapeutic effects such as analgesic, antipyretic, anti-spasmolytic, expectorant, and antitussive. This can reduce the symptoms of patients affected by COVID-19 (Perianayagam et al., 2004; Krishnaveni and Mirunalini, 2010; Goel et al., 2014). In addition, Amla also showed antiviral potential against coxsackie virus B3 (CVB3) at concentrations of 7.8 μg/mL, 11.0 μg/mL, and 21.8 μg/mL. These results indicate that the highly oxygenated bisabolene sesquiterpenoid glycoside phyllaemblicins compounds found in Amla have potential against the Hepatitis B virus (Lv et al., 2015). The compound glochicoccinoside D which was also obtained from Amla has antiviral potential against influenza A virus strain H3N2 and hand, foot, mouth virus (enterovirus) EV71 (Perera et al., 2021).

NCT and NCR in COVID-19 are strongly related to disease progression and clinical outcomes in patients (Yang et al., 2021) There are only 2 herbs that show good therapeutic results in terms of NCT or NCR outcomes, namely, JY granules and Reduning Injection.

Other herbs showed results on NCT or NCR outcomes that were insignificantly different. However, improved results in NCT and NCR parameters are reported within the treatment group as opposed to the control without statistical significance. In certain clinical trials, a broader array of parameters such as symptom recovery, the mean increase in oxygen saturation (SpO2) level, reduction in the percentage of lung inclusion on CT, and improvement in CRP test results were considered. NCT/NCR parameter did not show a significant difference between the control and test groups.

Herbal medicines have been an important part of traditional medicine practices in the community for centuries. Their use has empirically proven their benefits in overcoming various health problems. However, to increase the trust and validity of using herbal medicines, clinical studies have been conducted to scientifically validate their effectiveness. The summarized results of these clinical trials can be an important reference in developing phytopharmaceuticals, which are medicinal products derived from plant ingredients. Thus, the combination of empirical knowledge and scientific evidence from clinical studies can provide a strong basis for the use of herbal plants as a reliable therapeutic alternative in modern medicine. The strength of this study summarizes all clinical trials on herbal medicines using the randomized controlled trial method with specific outcomes. This review is exclusively a systematic review in nature and lacks statistical analysis, preventing a definitive conclusion regarding which herbs are most effective in terms of LOS, NCT, and NCR outcomes.

In addition, there are several potential biases and study heterogeneity that need to be considered in this systematic review. First, the variability of herbal medicine formulations can be a source of heterogeneity between studies. Various herbal medicines can have different compositions, both in active ingredients and concentrations, which can affect study results (Wang et al., 2023). Second, the method of administration of herbal medicines may also vary between studies, including dosage, frequency of administration, and mode of ingestion (e.g., oral, topical, or inhalation). These differences may affect the rate of absorption, distribution, metabolism, and excretion of herbs in the body, as well as the observed treatment outcomes (Sun et al., 2019). Third, heterogeneity in the patient population, such as differences in age, gender, premenopausal health conditions, history of chronic diseases, and use of other medications, may affect the response to herbal medicines. Studies that include demographically or clinically diverse populations may lead to heterogeneous results that are difficult to synthesize directly. These biases may affect the validity and reliability of the study results and may affect the interpretation and conclusions drawn in the systematic review.

Study on herbal medicines related to COVID-19 is conducted as a supplementary therapy and the cases in several countries are currently increasing. The study provides an overview of beneficial herbal medicines with good effects on patients. In the future, a comprehensive systematic review/meta-analysis should be carried out with certain outcomes to compare herbal medicines that provide the best therapeutic results. In addition, the safety aspects of each herbal medicine must be thoroughly analyzed and this consideration becomes crucial in selecting a therapy for COVID-19, specifically in patients with comorbidities.