Oral candidiasis is an opportunistic infection of the oral mucosa caused by an overgrowth of Candida strains, influenced by systemic and local factors (Contaldo, 2023). Oral candidiasis is common among the very young and the elderly. About 5%–7% of infants experience oral candidiasis. In patients with AIDS, the prevalence is estimated to range from 9% to 31%, while it is nearly 20% among cancer patients (Patil et al., 2015). Patients with severe oral candidiasis often experience symptoms such as a burning sensation, altered taste, pain, and discomfort that may affect eating ability and subsequently impaired quality of life (Hu et al., 2023).

The current treatment for oral candidiasis includes both topical and systemic antifungal agents (Hu et al., 2023). Topical antifungals are typically recommended for mild cases. In contrast, systemic antifungal therapy is indicated in immunocompromised patients or those at risk of disseminated candidiasis (El-Ansary and El-Ansary, 2023; Hu et al., 2023). Four main categories of antifungal agents are commonly used: polyenes, azoles, echinocandins, and flucytosine (Al Aboody and Mickymaray, 2020; Ordaya et al., 2023). The antifungal that are most frequently utilized are categorized as either polyenes or azoles. The usual dosage for these antifungals is 2–4 times per day for 2–4 weeks. Although the recommended duration of treatment is 2–4 weeks, treatment for oral candidiasis should last at least 2 weeks (Alajbeg et al., 2021).

The global rise in antifungal resistance has escalated the demand for alternative, safe, and effective therapies. Fungi like Candida are developing resistance to conventional antifungals (e.g., azoles, polyenes, echinocandins) (Alfadil et al., 2024; Hu et al., 2023). While Candida albicans isolates generally remain susceptible to fluconazole, non-albicans Candida species exhibit variable susceptibility to antifungal agents (Ordaya et al., 2023). Although nystatin remains one of the most commonly used antifungal agents for topical and oral applications, its prolonged use is limited by concerns related to toxicity, the potential for resistance development, and high recurrence rates. (Anwar et al., 2023). Nystatin, a polyene, is associated with significant toxicity, particularly nephrotoxicity, which limits its clinical use (dos Santos and Branquinha, 2024). Additionally, treatment with nystatin often requires an extended duration of 14–28 days or longer, with occasional adverse effects such as nausea, diarrhea, and loss of appetite (Hu et al., 2023).

Limitations in the efficacy and safety of conventional antifungal agents have led to increased interest in alternative therapeutic strategies that aim to reduce toxicity and improve clinical outcomes. (Contaldo, 2023). While botanical treatments can offer therapeutic benefits, they also come with toxicity risks, especially when misused, at high doses, or alongside conventional medications. Research has explored the potential of discovering new antifungal agents from crude plant extracts, studying botanical medicines like Psidium guajava L., Piper betle L., Schefflera leucantha R. Vig., Andrographis paniculata (Burm.f.) Wall. ex Nees, Garcinia atroviridis Griff. ex T. Anderson, Morus alba L., Garcinia mangostana L., Carthamus tinctorius L., Camellia sinensis (L.) Kuntze, Aegle marmelos (L.) Corrêa, and Rhinacanthus nasutus (L.) Kurz (Suwanmanee et al., 2014; Jeenkeawpieam et al., 2021).

There are only a few systematic studies directly compare botanical antifungals to conventional antifungals under the same clinical conditions. To address this gap, this study aims to conduct a systematic review and meta-analysis to assess the efficacy of botanical antifungals compared to conventional antifungals for treating oral candidiasis. Importantly, many systematic reviews only evaluate either botanical or conventional antifungals, while this study proposes a pairwise comparison of their efficacy. Additionally, many botanical antifungal reviews are narrative or qualitative in nature; including a meta-analysis brings quantitative strength and objectivity to the discussion. The findings of this research will contribute to a deeper understanding of the role of botanical antifungals in the management of oral candidiasis. Furthermore, the results are expected to provide valuable insights and practical recommendations for integrating diverse botanical antifungal agents into therapeutic protocols for oral candidiasis.

This systematic review follows the PRISMA 2020 statement: an updated guideline for reporting systematic review guidelines (Page et al., 2021). The protocol was registered in PROSPERO with an ID of CRD42024589391.

Oral candidiasis is the most common opportunistic infection of the oral cavity, primarily caused by fungi from the Candida genus, particularly C. albicans (Alajbeg et al., 2021). The success of oral candidiasis treatment largely depends on administering appropriate antifungals (Sharma, 2019). However, the emerging resistance to antifungal drugs poses serious challenges in managing these infections (Murtaza et al., 2015). Therefore, the development of novel drugs and alternative therapies, including those derived from medicinal plants, has become imperative for the effective treatment of oral candidiasis (Leite et al., 2014). These botanical antifungals offer various mechanisms of action, are biocompatible, and have a lower environmental impact. However, they face challenges in standardization, regulatory approval, clinical validation, and large-scale manufacturing. According to our comprehensive literature search conducted up to June 2024, this systematic review represents the first to undertake a comparative analysis of several botanical and conventional antifungal agents. A total of ten studies meeting the established inclusion criteria were incorporated. The findings indicate that botanical antifungals predominantly demonstrate efficacy that is comparable to or exceeds that of conventional antifungal treatments in the resolution of lesions associated with oral candidiasis. To compare the efficacy of botanical and conventional antifungals, lesion improvements were grouped based on treatment duration (≤15 days and >15 days) to calculate the prevalence of lesion improvement. The treatment durations of ≤15 days and >15 days were determined according to the methods outlined in the reviewed studies, which aligns with clinical practice guidelines for managing oral candidiasis with topical treatments, typically ranging from 7 to 14 days (Quindós et al., 2019).

Overall, the clinical significance is evident in the improvement of lesions treated with botanical antifungals, demonstrating that they can serve as an alternative to conventional antifungal treatments. Three studies demonstrated higher efficacy for botanical antifungals than conventional antifungals. The study by Munkhbat et al. (2023) demonstrated that a mean healing period of 3–5 days was observed in 60% of patients with Akhizunber preparation, while in the Povidone iodine group, all patients recovered in 6–10 days (Munkhbat et al., 2023). The study by Wright et al. (2009) demonstrated that C. × limon (L.) Osbeck and C. citratus (DC.) Stapf had better clinical success than gentian violet in treating oral candidiasis in an HIV population (Wright et al., 2009). Furthermore, Amanlou et al. (2006) study indicated that Z. multiflora Boiss. gel reduced the surface erythema of the palate more efficiently than miconazole (Amanlou et al., 2006).

Five studies demonstrated comparable efficacy in improving lesions associated with oral candidiasis. The study by de Araújo et al. (2021) demonstrated that mouthwash and spray of C. zeylanicum Blume leaves and nystatin promoted significant clinical improvement of denture-related candidiasis (de Araújo et al., 2021). Tatapudi et al. (2021) study also demonstrated complete resolution of the lesion of denture stomatitis with clotrimazole and C. longa L. ointment. However, when both groups were analyzed, it was not statistically significant (P = 0.765) (Tatapudi et al., 2021). Moreover, the study by Ghorbani et al. (2018) demonstrated significant decrease in the mean length and width of lesions in the C. sinensis (L.) Kuntze group (P < 0.001), as well as significant decrease in the mean length (P = 0.001) and width (P = 0.004) of lesions in nystatin group, but no statistically significant difference between the two groups in terms of the mean length (P = 0.179) and width (P = 0.390) of lesions (Ghorbani et al., 2018). Furthermore, the Tay et al. (2014) study demonstrated that the severity of denture stomatitis diminished over the evaluation periods, with no significant differences between U. tomentosa (Willd. ex Schult.) DC., miconazole, and placebo (P > 0.05) (Tay et al., 2014). Lastly, the study by Pinelli et al. (2013) demonstrated that the efficacy of R. communis L. was similar to that of the treatment with miconazole (Pinelli et al., 2013).

Meanwhile, two other studies demonstrated that conventional antifungals were more effective at improving lesions in the treatment of oral candidiasis. Bakhshi et al. (2012) found that the reduction in the width of erythema was more pronounced in the nystatin group compared to the A. sativum L. extract group (Bakhshi et al., 2012). Similarly, de Souza Vasconcelos et al. (2003) reported that miconazole produced better clinical results than P. granatum L., with this difference being statistically significant (P < 0.01) (de Souza Vasconcelos et al., 2003).

Essential oils are rich sources of phytoactive molecules and are gaining popularity because of their safety, wide potential applications, and significant consumer acceptance (Gupta and Poluri, 2022). Essential oils have extensive biological activity. They are rich mixtures of chemical metabolites belonging to different chemical families, including terpenes, terpenoids, aldehydes, phenols, alcohols, ethers, esters, ketones, and other aromatic and aliphatic constituents with low molecular weights (Gupta and Poluri, 2022; Biernasiuk et al., 2023). Chemical characterization of many essential oils typically reveals that two to three primary metabolites are present in relatively high concentrations (20%–70%), with other elements found in trace amounts (Biernasiuk et al., 2023).

The antimicrobial mechanisms of essential oils are complex and influenced by their chemical composition and the concentration of key individual metabolites (Biernasiuk et al., 2023). In a previous study, essential oils were observed to have anti-Candida activity, with the metabolites possibly acting on cell membranes (de Araújo et al., 2021). Some reports revealed that constituents of essential oils mixture can cause cell membrane damage, influence many other cellular activities, including energy production, may be linked to reduced membrane potentials, the disruption of proton pumps, and the depletion of the adenosine triphosphate, the coagulation of cell content, cytoplasm leakage, and finally cell apoptosis or necrosis, leading to cell death (Biernasiuk et al., 2023).

Our meta-analysis demonstrated that botanical antifungals are as effective as conventional antifungals in improving lesions associated with oral candidiasis. This finding is consistent with many studies comparing the efficacy of botanical and conventional antifungals. The diversity of botanical drugs provides a wide range of essential biologically active molecules with enormous potential antifungal properties, such as phenols, tannins, terpenoids, and alkaloids (Hsu et al., 2021). Polyphenols could be classified as phenolic acids, lignin, flavonoids, and tannins (Silva-Beltran et al., 2023).

This study included ten botanical antifungals derived from thirteen different botanical drugs, alongside five conventional antifungal agents. The botanical antifungal included were Akhizunber preparation (A. asiatica Serg., J. sabina L., and B. crassifolia (L.) Fritsch), C. zeylanicum Blume, C. longa L., C. sinensis (L.) Kuntze, U. tomentosa (Willd. ex Schult.) DC., R. communis L., A. sativum L., C. × limon (L.) Osbeck, C. citratus (DC.) Stapf, Z. multiflora Boiss., and P. granatum L. The studies included these botanical drugs because of their biologically active chemical metabolites, such as terpenes, terpenoids, polyphenols (flavonoids and tannins), and alkaloids (de Araújo et al., 2021; Tatapudi et al., 2021; Ghorbani et al., 2018; Tay et al., 2014; Pinelli et al., 2013; Alajbeg et al., 2021; Silva-Beltran et al., 2023; Boncan et al., 2020; Konuk and Ergüden, 2020; Yang et al., 2020; Manso et al., 2022; Shahzad et al., 2014; Dorsaz et al., 2017).

Botanical-derived molecules often target multiple cellular pathways. Terpenes are the most diverse and abundant phytoactive molecules with potent antimicrobial applications. Terpenes are known to modulate ergosterol content in a fungal cell membrane differentially (Gupta and Poluri, 2022). Boncan et al. (2020) also reported that terpenes generate oxidative stress and activate associated cellular response pathways. The increased reactive oxygen species have altered mitochondrial membrane potential, increased Ca²⁺ influx, and cytochrome c flow toward cytosol from mitochondria (Boncan et al., 2020). An optimum level of Ca²⁺ ion is crucial for mitochondrial functioning or ATP production, and any irregularity in its balance leads to apoptosis (Gupta and Poluri, 2022). Terpenoids, the main metabolites of plant volatiles and essential oils, are a large class of natural products exhibiting various biological activities (Konuk and Ergüden, 2020). Terpenoids (isoprenoids) are terpenes containing an oxygen moiety and additional structural rearrangements (Boncan et al., 2020). Raut et al. (2020) found that menthol showed significant biofilm inhibitory activity when studying the effects of plant-derived terpenoids on C. albicans (Yang et al., 2020). Phenolic terpenoids disrupt cell membrane integrity and cause leakage of ions, resulting in cell death (Konuk and Ergüden, 2020). Polyphenols are metabolites derived from different parts of plants that contain one or more phenolic groups (Manso et al., 2022). They are macromolecular structures containing phenolic hydroxyl rings (Shahzad et al., 2014). They have many human health benefits, including antioxidant, anti-inflammatory, antibacterial, and antifungal. Studies have reported that plant extracts rich in polyphenols can inhibit the growth of pathogenic fungi (Manso et al., 2022). The polyphenol mechanisms of action could contribute to inhibiting the efflux pump, cell membrane, ergosterol synthesis, and cell wall or produce biofilm damage and reactive oxygen species effect (Silva-Beltran et al., 2023). Shahzad et al. (2014) demonstrated that polyphenols from curcumin and pyrogallol were the most active, inhibiting growth and biofilm formation of C. albicans via suppression of genes responsible for adhesion and hyphal growth (Shahzad et al., 2014). Another essential secondary metabolite is alkaloids, which have diverse pharmacological activities. Alkaloids are classified as true alkaloids, protoalkaloids, and pseudoalkaloids. Their mechanism of action is related to membrane permeabilization, inhibition of DNA and RNA, protein synthesis, ergosterol synthesis, and increasing the generation of reactive oxygen species (Silva-Beltran et al., 2023). A study by Dorsaz et al. (2017) showed that the effect of tomatidine isolate of S. tuberosum L. alters the regulation of genetics in the ergosterol biosynthesis of C. albicans, C. krusei, and Saccharomyces cerevisiae cells (Dorsaz et al., 2017).

Medicinal plants contain chemical metabolites that may operate singly or combine to heal diseases and improve health (Pammi et al., 2023). Some botanical drugs have various biological activities, including antimicrobial and anti-inflammatory activities, which may be associated with their antioxidant activity (Mahlo et al., 2016). Antioxidants reduce oxidative stress in cells and are, therefore, helpful in treating many human diseases (Pammi et al., 2023). Plants with antioxidant properties mainly contain phenols and flavonoids. Flavonoids play essential roles in preventing diseases associated with oxidative stress (Nwozoa et al., 2023). This metabolite reduces inflammation stress by enhancing the release of systemic mediators, cytokines, and chemokines to induce cellular infiltration, resolve inflammatory responses, and reestablish tissue coordination Gonfa et al., 2023).

Meanwhile, conventional antifungals included povidone iodine, nystatin, clotrimazole, miconazole, and gentian violet (de Souza Vasconcelos et al., 2003; Munkhbat et al., 2023; de Araújo et al., 2021; Tatapudi et al., 2021; Pinelli et al., 2013; Tay et al., 2014; Bakhshi et al., 2012; Wright et al., 2009; Amanlou et al., 2006; Ghorbani et al., 2018) Topical antifungal drugs available include nystatin, miconazole, clotrimazole, and ketoconazole (Taylor et al., 2024). Topical therapy using nystatin and miconazole is still the primary recommended treatment for oral candidiasis due to its high efficacy, low cost, and low side effects (Quindós et al., 2019). Nystatin oral suspension (100000 units/mL) is used in 5 mL orally four times daily (swished for several minutes then swallowed) Taylor et al., 2024). Meanwhile, various topical formulations of miconazole, including buccal tablets, chewing gum, oral gel, and lacquer, have been used to treat oral candidiasis (Zhang et al., 2016). Clotrimazole troches are used at 10 mg orally five times daily (dissolved over 20 min) (Taylor et al., 2024). Both polyenes (nystatin) and azoles (clotrimazole and miconazole) affect fungal plasma membranes by disrupting the synthesis and placement of ergosterol (Contaldo, 2023). Polyenes disrupt ergosterol production, crucial for cell membrane integrity, and can hinder fungal adherence to epithelial cells (Alajbeg et al., 2021). Azoles work by inhibiting the fungal enzyme cytochrome P450 14α-lanosterol demethylase. This leads to the accumulation of toxic methylated intermediates, which disrupt the function of the fungal cell membrane and inhibit its growth (Costa-de-Oliveira and Rodrigues, 2020). Gentian violet is effective against numerous types of pathogenic yeast, such as Candida, and has been used in aqueous solutions at 1%–10% concentrations (Kondo et al., 2012). Gentian violet killed C. albicans at high concentrations but inhibited its virulence by inhibiting adhesion and germ tube production at subinhibitory doses (Hassan et al., 2022). Povidone-iodine is considered to have the broadest spectrum of antimicrobial action, showing efficacy against Gram-positive and Gram-negative bacteria, bacterial spores, fungi, protozoa, and several viruses (Munkhbat et al., 2023). Persistence of effect has also been demonstrated in a study that assessed 1% povidone-iodine as a preprocedural antibacterial agent in individuals with varying degrees of oral hygiene. Povidone-iodine has also shown rapid activity against Candida in vitro, ranging between 10 and 120 s from contact to kill time (Kanagalingam et al., 2015).

Candida levels were also evaluated as an additional outcome. The results demonstrated that only eight out of 10 studies reviewed also included an in vitro examination. Two studies demonstrated higher efficacy for conventional antifungals in reducing the Candida levels. These studies used nystatin and clotrimazole as conventional antifungals (de Araújo et al., 2021; Tatapudi et al., 2021). Meanwhile, the other six studies demonstrated comparable results in reducing Candida levels using botanical and conventional antifungals (Munkhbat et al., 2023; Amanlou et al., 2006; Ghorbani et al., 2018; Tay et al., 2014; Pinelli et al., 2013; de Souza Vasconcelos et al., 2003). Polyenes are usually fungicidal, and azoles are fungistatic for Candida at therapeutic doses. The main mechanisms of antifungal action involve altering the membrane or the fungal cell wall by inhibiting molecules essential for these (Quindós et al., 2019). As mentioned, this mechanism is the same as that of the chemical metabolite in botanical antifungals used to eliminate Candida.

To our knowledge, this is the first pairwise comparison of the clinical efficacy that supports the use of botanical antifungals to treat oral candidiasis. This meta-analysis with a random-effect model showed significant heterogeneity (I² = 84.17%), suggesting the need to address this variability with subgroup analysis. Potential sources of heterogeneity in our analysis may arise from several factors related to the studies included. First, we were unable to obtain information about the extraction methods used for the botanical antifungals in the original studies, such as whether they employed aqueous, ethanolic, or other solvent-based extractions. This lack of data could influence the concentration and bioavailability of the active metabolites. Second, there were significant differences in dosages and forms of administration, such as mouth rinses, gels, and lozenges. These variations may impact the local drug concentration and overall treatment efficacy. Finally, the duration of interventions was not standardized across the studies, which might have affected treatment outcomes. These methodological and intervention-related differences could all contribute to the observed heterogeneity. However, the limited number of studies (n = 10) hindered the ability to conduct meaningful subgroup or meta-regression analyses. Further clinical studies should adhere to standardized guidelines for the treatment of oral candidiasis. It is also essential to expand research to include other types of oral candidiasis beyond denture stomatitis. This broader approach will help enhance our understanding and improve treatment options for various forms of oral candidiasis. Additionally, comprehensive studies can provide valuable insights into the efficacy of different antifungal agents and their mechanisms of action in diverse populations.

In conclusion, this review has thoroughly assessed the efficacy of botanical antifungals for treating oral candidiasis based on clinical trials, providing evidence of their potential as alternative or adjunctive treatments. The results indicate that nearly all botanical antifungals effectively treat oral candidiasis. Due to a specific research question, this study included small sample sizes. Additionally, the significant variation in the botanical antifungals used limits the ability to generate strong clinical recommendations.