Antiparasitic Activity of TTO and Its Components Against Medically Important Ectoparasites: a Systematic Review Solomon Abrha, M.Sc1, Wubshet Tesfaye, Phd1, Julia K

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Antiparasitic activity of TTO and its components against medically important ectoparasites: a systematic review Solomon Abrha, M.Sc1, Wubshet Tesfaye, PhD1, Julia K. Christenson, MNutrDiet1, Christine F. Carson, PhD2, *Jackson Thomas, PhD1 1Faculty of Health, University of Canberra, Bruce, Canberra, Australian Capital Territory, Australia. 2UWA School of Biomedical Sciences, The University of Western Australia, 35 Stirling Highway, Western Australia, Australia * Corresponding author: Jackson Thomas (PhD) Study design Introduction In vitro (n=24) In vitro/clinical (n=4) • Ectoparasites are pathogens that can infect the skin and cause pain, In vivo (n=1) discomfort, and disease. In vivo/clinical (n=1) Non-RCTs (n=21) Ectoparasites studied • Essential oils (EOs) have been used for centuries for ectoparasitic Publication language RCTs (n=12) Demodex mites (n=35) English (n=61) infestation treatment because of their antiparasitic, antibacterial, Scabies mites (n=5) Mandarin (n=3) and/or anti-inflammatory properties. House dust mites (n=6) Head lice (n=16) • Only a few of EOs produce broad activity against a wide range of Study setting Fleas (n=4) parasites, and tea tree oil (TTO), the EO obtained from Melaleuca Europe (n=19) Chigger mites, Sand fleas & Bed Asia (n=18) bugs (n=0) alternifolia, is one of these rare EOs with potent and broad North America (n=12) Key findings antiparasitic properties. Australia & New Zealand (n=11) Africa (n=2) Treatment outcome for TTO and its components (1- Study aim 100%) Quality assessment • To assess preclinical and clinical studies investigating the Preclinical efficacy: (Good quality) Lethal effect within 5 mins-3hrs antiparasitic activity of TTO and its components against Demodex In vitro & In vivo (65%) Adverse events (AEs, n=18) mites, scabies mites, house dust mites, chigger mites, lice, fleas, and RCTs (58%) No AEs (n=9) Clinical efficacy: Cure rate of 20- Non-RCTs (80%) Mild to Moderate skin irritation (n=9) bed bugs. 100% Methods Strength and Limitations Databases and search strategy Strength • Record searched from the following sources in any language from • To our knowledge, this is the first systematic review to comprehensively inception to 07 June 2021. summarise all the preclinical and clinical studies exploring the antiparasitic activity of TTO and its components against mites, lice, and fleas. Databases and other sources Keywords

CENTRAL, Cochrane Library, “tea tree oil” OR “Melaleuca alternifolia oil” LILACS, MEDLINE, PubMed, Limitations ScienceDirect, SciELO , Scopus, & Web of Science parasites OR “ectoparasitic infestations” OR mites • Heterogeneity in the study designs, evaluation methods, outcome measures, OR “mite infestations” OR scabies OR blepharitis and study periods precluded a meta-analysis. Australian Tea Tree Industry OR Pyroglyphidae OR Trombiculidae OR Association (ATTIA), Google & Pediculus OR “lice infestations” OR Phthirapteran • Most of the included clinical studies are non-RCTs, limiting the quality of Google Scholar & Included papers’ OR flea OR “flea infestations” OR Siphonaptera reported findings. OR Tunga OR tungiasis OR “bed bugs” reference lists • In vitro studies, the difference in sources of TTO and the use of TTO with Methodological quality assessments different contents of the main active components could have impacted the study results. Quality assessment tools used in this review ToxRTool (Toxicological data Preclinical (in vitro & in vivo) reliability assessment tool) studies Conclusions Joanna Briggs Institute (JBI) tools Quasi-experimental, cohort, case series, & case studies • The findings of this review reveal TTO and its components as the Jadad scoring scale Randomised controlled trials promising treatment option for ectoparasitic infestations caused by mites, (RCTs) lice, and fleas. Results • The compelling in vitro activity of TTO against ectoparasites noted in this review seems to have translated well to the clinical environment. 483 records identified from database 18 additional records identified searching through other sources • Still, further large-scale and high-quality RCTs can provide insight into a comparative advantage over the promising Demodex, head lice, and scabies

200 duplicates excluded interventions. • We found no study investigating TTO and its components against bed bugs, 301 records screened by title and abstract chigger mites, and sand fleas. Given their promising activity against similar ectoparasites, this review alerts researchers to explore the potential use of 221 non-relevant records excluded TTO and its components as an alternative treatment for these parasites. 80 full-text articles assessed for eligibility

18 records excluded References 8 on veterinary ectoparasites 2 wrong study design 1. Barker SC, Altman PM. A randomised, assessor blind, parallel group comparative efficacy trial of three products 1 wrong intervention for the treatment of head lice in children--melaleuca oil and lavender oil, pyrethrins and piperonyl butoxide, and a 1 wrong outcome "suffocation" product. BMC Dermatol 2010; 10: 6 1 wrong patient population 2. Carson CF, Hammer KA, Riley TV. Melaleuca alternifolia (tea tree) oil: a review of antimicrobial and other 1 no full text access medicinal properties. Clin Microbiol Rev 2006; 19(1): 50-62 4 duplicates 3. Ergun SB, Saribas GS, Yarayici S, et al. Comparison of effficacy and safety of two tea tree oil-based formulations in patients with chronic blepharitis: A double-blinded randomized clinical trial. Ocul Immunol Inflamm 2020; 28(6): 888-97. 62 studies included in the review 4. Walton SF, Myerscough MR, Currie BJ. Studies in vitro on the relative efficacy of current acaricides for Sarcoptes scabiei var. hominis. Trans R Soc Trop Med Hyg 2000; 94(1): 92-6.

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