Complementary and Alternative Therapies for Onychomycosis: A Systematic Review of the Clinical Evidence

Onychomycosis is a common fungal nail infection predominantly caused by dermatophytes such as Trichophyton rubrum and less commonly caused by nondermatophyte molds and yeasts [1]. Risk factors for onychomycosis development include trauma, older age, diabetes, immunosuppression, tinea pedis, psoriasis, and family history [2]. The condition is notoriously difficult to treat due to the thick nail plate barrier, high reinfection rates, growing antifungal resistance, biofilm formation, and relatively low efficacy of most antifungal agents [3-5]. While oral antifungals are the most efficacious treatment for onychomycosis, they are contraindicated in certain patient populations, and patients may desire lower risk and accessible alternatives to systemic agents [6, 7].

A variety of at-home treatments for onychomycosis have become popularized on the Internet, including Vicks VapoRub®, tea tree oil, banana peels, vinegar soaks, and Listerine® [7]. Additionally, several essential oils have shown broad-spectrum antifungal activity through in vitro studies, showing promise for a potential role in the treatment of onychomycosis [8]. Halteh et al. [9] published a study in 2015 reviewing over-the-counter and natural remedies for onychomycosis. Authors found both in vitro and clinical evidence for the use of tea tree oil, topical cough suppressants, natural coniferous resin, Ageratina pichinchensis, and ozonized sunflower oil in the treatment of onychomycosis [9]. In this systematic review, we sought to critically appraise the literature and provide an update to Halteh et al. [9] with a focus on the clinical evidence supporting the use of complementary and alternative therapy for the treatment of onychomycosis.

We searched PubMed, Embase, and Cochrane Library for studies on complementary and alternative therapies for onychomycosis published through September 24, 2021. A scoping preliminary search was conducted to identify complementary and alternative therapies with in vitro antifungal properties to be included in the search. Search syntax can be found in the online supplementary Document 1 (for all online suppl. material, see www.karger.com/doi/10.1159/000521703). No filters were used in any of the searches. The PRISMA checklist can be found in online supplementary Document 2.

We included English language clinical studies examining the efficacy of a complementary or alternative therapy in the treatment of onychomycosis. We included clinical trials, observational studies, and case reports/case series. We excluded review articles and in vitro and ex vivo studies.

The following data were extracted from each selected study: study type, study participants, fungal species identified by culture, therapeutic intervention, comparison intervention, primary outcome measures, relevant results, and adverse effects. For clinical trials, Jadad scoring was calculated to independently assess methodological quality. Trials received a score between zero (very poor) and five (rigorous) based on randomization, blinding, and participant withdrawal [10].

We received 551, 128, and 56 results for the respective searches, with a total of 735 results (Fig. 1). There were 641 unique results after duplicates were removed. Titles and abstracts were screened for inclusion and exclusion criteria. Full texts were obtained for twenty-two studies that passed initial screening. Seventeen studies were selected to be included in the review.

The selected articles studied a variety of complementary and alternative medicines for onychomycosis, including tea tree oil (n = 5), Ageratina pichinchensis (n = 3), Arthrospira maxima (n = 2), natural coniferous resin lacquer (n = 2), Vicks VapoRub (n = 2), propolis extract (n = 2), and ozonized sunflower oil (n = 1) (Table 1). Sixteen studies were clinical trials, and one was a case series. Of the clinical trials, six were open-label, single-arm, clinical trials, and five were double-blind, randomized, controlled clinical trials. The rest were variations of these two study designs. The number of study participants in clinical trials ranged from 10 to 400 participants [11-13]. Two studies included patients with a preexisting condition, one included patients with type 2 diabetes mellitus and the other included patients with HIV [14, 15].

Ten studies included data on fungal species. Of those studies, four included only dermatophyte molds [13, 16-18], while the other six included a combination of dermatophyte molds, nondermatophyte molds, and/or yeasts [15, 19-22]. Treatment courses ranged from 8 weeks to 1 year [16, 21], with the most common treatment course being 6 months. Thirteen studies measured both mycological cure and clinical cure as primary outcome measures, while four studies only measuring clinical cure [11, 14, 23]. Mycological cure was defined as a negative fungal culture and potassium hydroxide preparation. A complete cure was defined as a mycological cure and a clinical cure, most commonly meaning a 100% clear nail. All studies found that their intervention was effective to some extent. Jadad scores ranged from 0 to 5, with the mean score being 2 and the median score being 1.5 for all studies.

Due to its broad-spectrum antimicrobial properties, tea tree oil has been studied in the treatment of a variety of dermatological conditions including acne, seborrheic dermatitis, and chronic gingivitis [24]. Five studies examined the efficacy of tea tree oil in treating onychomycosis, with two of the studies treating participants with a nail oil containing vitamin E, lime, oregano, and tea tree oil [22, 25]. Mycological cure rates for onychomycosis treated with tea tree oil twice daily for 6 months were reported to be between 82 and 89%, and clinical cure rates ranged from 27 to 78.5% [20, 22, 26]. A double-blind, randomized, controlled study of 117 patients with distal subungual onychomycosis compared twice daily 100% tea tree oil versus twice daily 1% clotrimazole for 6 months [26]. Investigators found comparable mycological and clinical cure rates between the two treatment courses.

A second double-blind, randomized, controlled study of 60 patients with distal subungual onychomycosis compared an 8-week treatment course of combined 5% tea tree oil and 2% butenafine hydrochloride cream versus tea tree oil cream alone. While 80% of patients treated with the 5% tea tree oil/2% butenafine hydrochloride achieved a complete cure, no patient receiving tea tree oil alone achieved a complete cure (p < 0.0001). Authors noted that perhaps 8 weeks was not a sufficient amount of time for the tea tree oil to achieve full efficacy [16]. Two of these trials reported adverse effects to tea tree oil including dermatitis and subjective mild inflammation in 6–10% of patients using tea tree oil [16, 20]. Jadad scoring for these trials ranged from zero to four.

Ageratina pichinchensis is a plant that is utilized in traditional Mexican medicine to treat superficial fungal infections [23]. The plant extract has demonstrated in vitro antifungal activity, especially against Trichophyton species [27], and has been found to be as effective as a topical ketoconazole in the treatment of tinea pedis in clinical trials [28, 29]. There were three double-blind, randomized clinical trials from the same author examining the ability of Ageratina pichinchensis to treat onychomycosis [15, 23, 30]. All three studies treated participants with Ageratina pichinchensis extract in a nail lacquer for 6 months. Two of the studies compared Ageratina pichinchensis extract to 8% ciclopirox [15, 30], while one study compared two concentrations of Ageratina pichinchensis extract, 12.6% and 16.8%.

The two studies comparing the plant extract to ciclopirox found comparable mycological and clinical cure rates between the two agents [15, 30]. In a study of 110 healthy patients with mild-moderate onychomycosis confirmed with direct examination of fungi, mycological cure rates were reported at 59.1% and 63.8% for patients in the Ageratina pichinchensis and ciclopirox groups, respectively [30]. Clinical cure rates were reported at 71.4% and 80.9% for patients in the Ageratina pichinchensis and ciclopirox groups, respectively. In a study of 71 patients with diabetes mellitus and mild-moderate culture-confirmed onychomycosis, the cure rates were much lower for both Ageratina pichinchensis and ciclopirox, at 7.1% and 8.6%, respectively, for mycological and clinical cure [15]. Additionally, the study comparing 12.6% and 16.8% Ageratina pichinchensis extracts found that the higher concentration was significantly more effective at achieving a clinical cure in patients with onychomycosis [23]. Adverse effects of Ageratina pichinchensis extract nail lacquer included a temporary irritation of the skin surrounding the nail [15]. Of note, these three studies were received between 3 and 5 on Jadad scoring, which is higher than the average.

Arthrospira maxima is a filamentous cyanobacteria that goes under the trade name of spirulina. Spirulina is a food supplement and additive that is rich in protein, essential amino acids, minerals, and essential fatty acids [31, 32]. In vitro studies have found antimicrobial properties of Arthrospira maxima, demonstrating its efficacy against Trichophyton mentagrophytes, T. rubrum, Epidermophyton floccosum, Candida albicans, Malassezia furfur, and Propionibacterium acnes [33].

Two small studies with 10 participants each examined the efficacy of Calmagen® lotion, which contains Arthrospira maxima, in the treatment of onychomycosis. The product is only sold in Australia at this time. One open-label single-arm trial treated participants with Calmagen for 11 months and reported a clinical cure rate of 70% and partial clinical cure rate of 20% [11]. The second double-blind, randomized, controlled clinical trial compared Calmagen lotion to an inert placebo for a 12-week treatment course [13]. Authors found that patients receiving Calmagen achieved a 100% mycological cure rate and an improvement in their clinical severity score compared to the placebo group (p = 0.0008). This study was of rigorous design receiving a 5 on Jadad scoring. No adverse effects were reported from treatment in either study.

The antimicrobial resin of the Norway spruce (Picea abies) has been utilized for centuries in traditional medicine to treat skin disease [18, 34]. The resin has demonstrated in vitro activity against dermatophytes but not Candida yeasts or opportunistic fungi [35]. Two clinical trials studied the efficacy of 30% resin lacquer daily for 9 months in patients with dermatophyte nail infections. An open-label, single-arm clinical trial of 33 patients reported that 65% of culture-positive patients at study entry achieved mycological cure, 9% of all patients achieved clinical cure, and 33% of all patients achieved a partial clinical cure [17].

The second investigator-blinded, randomized, controlled clinical trial divided 73 participants into three treatment groups: 30% resin lacquer once daily for 9 months, topical 5% amorolfine lacquer once weekly for 9 months, and 250 mg of oral terbinafine once daily for 3 months [18]. At 10 months, mycological cure rates were highest among the terbinafine group at 56%, followed by the resin group at 13% and the amorolfine group at 8% (p < 0.002). A clinical cure was only obtained by patients in the terbinafine group. A partial clinical cure achieved in 30%, 28%, and 36% of patients in the resin, amorolfine, and terbinafine groups, respectively (p < 0.05). Investigators concluded that while oral terbinafine remains the gold standard for treating onychomycosis, resin lacquer and amorolfine lacquer demonstrated similar efficacy rates. The trials did not report any adverse effects to resin lacquer.

Ozonized sunflower oil has demonstrated in vitro antifungal activity against Candida yeasts and has been shown to be as effective as topical ketoconazole in the treatment of tinea pedis [36-38]. In a simple-blinded, randomized, controlled trial of 400 participants with culture-confirmed onychomycosis, investigators compared topical ozonized sunflower oil (OLEOZON®) twice daily for three months to ketoconazole cream 2% twice daily for 3 months [12]. Investigators found that more patients in the sunflower oil group achieved mycological cure compared to the ketoconazole group (90.5% vs. 13.5%; p < 0.0001). Additionally, patients in the sunflower group were less likely to relapse than the ketoconazole group at the 1-year follow-up (37.0% vs. 2.8%). The authors concluded that sunflower oil offered a safe and cost-effective alternative for the treatment of onychomycosis. However, the study received a one on Jadad scoring indicating methodological flaws, including a lack of double-blinding, description of how randomization was conducted, and discussion of patient withdrawals.

Propolis extract is a resin compound produced by honeybees with in vitro activity against Trichophyton and Candida species [39, 40]. Propolis extract was studied in a case series and an open-label single-arm study. In the case series, 3 patients with culture-confirmed onychomycosis were treated with propolis extract for 1 year [21]. One patient achieved a partial clinical cure, 1 patient achieved mycologic cure and partial clinical cure, and 1 patient achieved a complete cure. Results from an open-label single-arm trial of 16 patients revealed that 56.3% of patients achieved a complete cure, and 31.3% achieved a partial clinical cure [40]. Authors concluded that propolis extract was an effective treatment for onychomycosis and may particularly be helpful in patients with resistance to antifungal agents due its ability to penetrate biofilms [40].

Vicks VapoRub is a popular over-the-counter topical cough suppressant with anecdotal evidence for treating onychomycosis [14]. It contains three active ingredients including camphor, eucalyptus oil, and menthol which have demonstrated in vitro antifungal activity against dermatophytes and Candida species [41-44]. Two small, open-label single-arm clinical trials studied the efficacy of Vicks VapoRub for onychomycosis. The studies found that once daily use of Vicks VapoRub for 48 weeks lead to a mycological cure rate of 27.8%, clinical cure rates of 11–27.8%, partial clinical cure rates of 55.6–83%, and a complete cure rate of 22% [14, 19]. Interestingly, one study noted that all of the patients that achieved a clinical cure initially grew C. parapsilosis or T. mentagrophytes [19].

While several studies of alternative therapies for the treatment of onychomycosis have been performed, there was no single therapy with strong evidence supporting its use. Tea tree oil was the most well studied but was utilized in multiple different formulations. Many studies did not have a control group, and few studies compared the intervention to an approved topical or oral antifungal. Other study limitations include differences in study design, making it difficult to draw conclusions across study results and variations in efficacy rates for therapies that were studied by multiple authors. Ideally, only randomized controlled trials would be included; however, we included all clinical studies in order to cover a range of therapies with any clinical evidence supporting their use.

The gold standard for comparing efficacies of antifungal agents is the complete cure rate. However, a complete cure can be difficult to achieve as a chronic fungal nail infection can scar the nail and leave residual nail dystrophy [45]. Factors associated with failure to achieve a complete cure include age greater or equal to 70 years and a nail thickness greater than 2 mm [46]. Therefore, differences in the average age of participants and onychomycosis severity in the treatment group may account for some of the variation we found in cure rates between studies. The open-label single-arm trials are particularly vulnerable to this shortcoming as randomized studies will ideally balance patient characteristics between the two study groups.

Variations in cure rates have also been noted to be an issue in onychomycosis clinical trials for prescription antifungals [47-49]. Factors that have been suggested to increase consistency in onychomycosis clinical studies include excluding nails with a history of trauma, the inclusion of all toenails in studies, excluding patients with inflammatory skin diseases, and taking into account the duration of onychomycosis, nail changes caused by asymmetry, and the possibility of dermatophytoma [50]. If a patient has onychomycosis coexisting with another nail condition, such as psoriasis or trauma, antifungal agents are unlikely to achieve a clinical cure. In a patient with multiple affected nails, a clinical cure in one nail can prove effectiveness of a therapy, and lack of response in other nails may suggest a secondary cause of nail damage [50]. Study authors also suggest grouping patients by fungal pathogen [19]. Two studies noted patterns in which patients affected by certain molds or yeasts responded best to therapy [15, 19].

Onychomycosis caused by nondermatophyte molds and mixed infections are difficult to treat and may be contributing to growing antifungal resistance [51, 52]. Some nondermatophytes and Candida species have demonstrated resistance to terbinafine [50]. As complementary and alternative therapies may work through different mechanisms than prescription antifungals, they may serve as a useful adjunctive therapy to help combat antifungal resistance. Additionally, many fungal pathogens that cause onychomycosis can form biofilms, a collection of adherent microorganisms that are encased in an extracellular matrix, which are also thought to contribute to antifungal resistance [53, 54]. Azole antifungals, like fluconazole, are ineffective against C. albicans-affected nails if a biofilm is present [55]. Some complementary and alternative therapies, such as propolis extract, have demonstrated efficacy against biofilms, highlighting another potential benefit for their future use [40].

We encourage continued study of complementary and alternative therapies for onychomycosis as a method to combat rising antifungal resistance. Currently, there is not sufficient evidence to endorse complementary and alternative therapies for onychomycosis to patients. Existing studies supporting their use are limited in number, tend to be small, and of poor methodological quality. For complementary and alternative therapies to have a role as adjunctive therapy for onychomycosis, future large-scale, randomized, controlled trials are required. Additionally, future studies should compare complementary and alternative medicine to placebos and established antifungal therapies, as well as cautiously consider individual patient factors that may impact cure rates.

Ethics approval was not required since the study is a review article.

The authors have no conflicts of interest to declare.

The authors received no funding for this manuscript.

M.N. designed the study methodology and wrote the manuscript. J.M. and P.L. edited the manuscript and provided expertise on the review topic.

All data were extracted from PubMed, Embase, or Cochrane Library, which are publicly available websites. Data are available at https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1440-0960.2011.00757.x [11], https://pubmed.ncbi.nlm.nih.gov/20492527/ [12], https://pubmed.ncbi.nlm.nih.gov/28923039/ [13], https://pubmed.ncbi.nlm.nih.gov/26585031/ [14], https://pubmed.ncbi.nlm.nih.gov/32086985/ [15], https://pubmed.ncbi.nlm.nih.gov/10357864/ [16], https://pubmed.ncbi.nlm.nih.gov/23131104/ [17], https://pubmed.ncbi.nlm.nih.gov/26036329/ [18], https://pubmed.ncbi.nlm.nih.gov/21209346/ [19], https://ijppr.openresearchjournals.com/index.php/ijppr/article/view/352 [20], https://pubmed.ncbi.nlm.nih.gov/30504984/ [21], https://pubmed.ncbi.nlm.nih.gov/32021856/ [22], https://pubmed.ncbi.nlm.nih.gov/19683043/ [23], https://www.wcd2019milan-dl.org/abstract-book/assets/html/abstracts/29-nail-disorders.html [25], https://pubmed.ncbi.nlm.nih.gov/8195735/ [26], https://pubmed.ncbi.nlm.nih.gov/18671197/ [30], and https://pubmed.ncbi.nlm.nih.gov/29922236/ [40].