Table 1.

Clinical trials investigating natural therapies against onychomycosis.

Study	Patients and Treatment	Outcomes	Treatment Comparisons and Adverse Events (AE)
Buck et al. 1994 [34] Randomised, double-blind trial	117 pts with DLSO. Tea tree oil (TTO) 100% (n = 64) Clotrimazole (CL) 1% solution (n = 53) Applied twice daily for 6 months	Mycologic cure TTO 18% Clinical assessment TTO 60% Patient assessment TTO 56% Mycologic cure CL 11% Clinical assessment CL 61% Patient assessment CL 55%	No statistical differences between treatments Most common AE were erythema and irritation (7.8% TTO)
Syed et al. 1999 [35] Randomised, double-blind, placebo-controlled trial	60 pts with DLSO Butenafine hydrochloride (BH) 2% and TTO 5% cream (n = 40) Tea tree oil 5% cream (n = 20) Applied three times daily for 8 weeks, with nails debrided between weeks 4 and 6. Final follow up at 36 weeks	Complete cure BH + TTO 80% Complete cure TTO 0%	BH + TTO was statistically superior (p < 0.0001), and mean time to complete healing was 29 weeks No AE in TTO group. Mild skin inflammation in 4/40 pts in active BH + TTO group
Auvinen et al. 2015 [30] Prospective, randomised, controlled, investigator-blinded trial	73 pts with toenail onychomycosisNatural Coniferous Resin (NCR) lacquer (n = 23) Applied once daily for 9 months Amorolfine (A) 5% lacquer (n= 25) Applied once weekly for 9 months Oral terbinafine (T) 250 mg (n= 25) Taken once daily for 3 months	Mycologic cure NCR 13% Partial cure NCR 30% Complete cure NCR 0% Mycologic cure A 8% Partial cure A 28% Complete cure A 0% Mycologic cure T 56% Partial cure T 36% Complete cure T 16%	At 10 months follow up, oral T was significantly superior to NCR and A in terms of mycologic cure and clinical outcomeNo AE in NCR or A groups. 2 pts with diarrhoea and rash in T group
Romero-Cerecero et al. 2008 [27] Randomised, controlled, double-blind trial	110 pts with toenail onychomycosis Ageratina pichinchensis (AP) 10% lacquer (n = 55) Ciclopirox (CL) 8% lacquer (n = 55) Applied once every three days for 4 weeks, twice a week for 4 weeks, then once a week for 16 weeks. Lacquer removed weekly	Clinical effectiveness AP 71.1% Mycologic cure AP 59.1% Treatment compliance 95.9% Clinical effectiveness CL 80.9% Mycologic cure CL 63.8% Treatment compliance 100%	No statistical difference between treatments No severe AE reported
Romero-Cerecero et al. 2009 [28] Randomised double-blind trial	122 pts with DLSO AP 12.6% lacquer (n = 62) AP 16.8% lacquer (n = 60) Applied once daily for 6 months	Clinical effectiveness/complete cure 12.6% AP 67.2% Clinical effectiveness/complete cure 16.8% AP 79.1% (no clinical manifestation in toenails, considered healthy)	The 16.8% AP lacquer formulation possessed a higher effectiveness than the 12.6% AP lacquer formulation (p = 0.01)No AE reported
Menéndez et al. 2011 [36] Randomised, controlled, single-blind trial	400 pts with onychomycosis OLEOZON®, ozonized sunflower oil * (OSO) (n = 200) Ketoconazole cream (KC) 2% (n = 200) Applied twice daily for 3 months, with filing and massage of affected nails upon treatment application	Complete cure OSO 90.5% Improvement OSO 9.5% Complete cure KC 13.5% Improvement KC 27.5%	After 3 months, OSO was more effective compared to KC (p < 0.00001) At 1 year follow up, relapse had occurred in 2.8% of cured pts in OSO group and 37.0% of cured pts in KC groupNo AE reported
Parekh et al. 2017 [37] Randomized, placebo-controlled, double-blind, parallel trial	28 pts with severe tinea (n = 18) or onychomycosis (n = 10) Calmagen® * cream or lotion (C) (n = 14) Placebo (P) (n = 14) Applied for 12 weeks	Mycologic cure C (13/14) 92.8% Clinical cure C (14/14) 100% Mycologic cure P (0/14) 0% Clinical cure P (0/14) 0%	There was a significant difference in mycologic cure rate between both arms (p < 0.0001) No AE reported

DLSO = Distal lateral subungual onychomycosis; pts = patients; * with active ingredient AMYCOT^®, a bioactive extract derived from Arthospira maxima (Spirulina); adapted from studies reviewed by Halteh et al. [19].