Manuka essential oil

Manuka essential oil

Manuka oil also known as Leptospermum scoparium oil, is an essential oil derived from the foliage, bark and seeds of Leptospermum scoparium or Manuka myrtle, a plant that has been used by the indigenous populations of New Zealand and Australia as topical preparations for wounds, cuts, sores and skin diseases and as inhalations for colds and fevers 1. Leptospermum scoparium is also known as Manuka myrtle, New Zealand teatree, broom tea-tree, or just tea tree that is native to south-east Australia and New Zealand 2. Manuka oil has an aromatic odor that is produced by a steam distillation process from plants harvested mostly in the autumn, summer and spring, with a yield ranging from 0.2–1%, depending on seasonal and geographical factors 3. Manuka oil is generally distilled using leaves and young stems, although the oil has also been produced from the seeds 4. Manuka oil is mainly composed of monoterpenes, sesquiterpenes, and triketones 5. The triketones in Manuka oil make the oil unique, attributing to its potent antibacterial activity against Gram-positive bacteria, including antibiotic-resistant strains 6. Manuka oil has been extensively used in traditional medicinal preparations particularly in New Zealand and Australia and its individual fractions, particularly β-triketone constituents, exhibit many bioactive properties. Yet its application in clinical medicine remains under explored. In contrast to Tea Tree oil, there is limited evidence on the efficacy and safety of Manuka oil in terms of geographic origin, parts of the plant used, dilutions and variation among formulations 1. The mechanisms of action exerted by topical application of Manuka oil are general to those of essential oils.

Manuka oil is currently listed as a complementary medicine by Therapeutic Goods Administration (TGA, an Australian equivalent of the FDA) in the forms of balm and cream for skin applications. Manuka oil is also used as a bioactive ingredient in various cosmetic products and herbal medicines. Manuka oil is an active ingredient in the Therapeutic Goods Administration-listed product Kiwiherb Herbal Throat Spray, which contains a mixture of Echinacea purpurea (6%), honey (7%), Manuka oil (1 µL/mL), Macropiper excelsum var. excelsum (7%), propolis tincture (0.09 µg/mL and Thymus vulgaris (5%). The formulation is accepted in Australia by TGA for oral administration to reduce or relieve cold, cough, dry throat, mild throat inflammation, itchy throat and pharyngitis 7.

Figure 1. Manuka myrtle

Leptospermum scoparium

Footnote: Manuka grows abundantly throughout New Zealand and has been a part of traditional Maori medicine for a variety of applications. The bark of Manuka tree has been used for the treatment of skin diseases, as a sedative and as a mouthwash. The leaves are boiled in water for treating colds or crushed and applied to ease itching and scabs, while the leaves have been used as tea, as a febrifuge and for pain relief. The seeds were used for treating dysentery and diarrhea 8.

Manuka oil properties

A large number of studies have examined the constituents of Manuka oil, which vary depending on the source of the oil 4 as well as the plant chemotype and season of collection 9. Overall, 100 components were identified from 16 commercial samples of Manuka oil, of which 51 components made up 95% of the content 4. The major components of commercially available Manuka oils are reported to be leptospermone (0.8–19.4%), calamenene (2.5–18.5%), δ-cadinene (0.9–6.9%), cadina-1,4-diene (0.1–5.9%), flavesone (0.7–5.8%), cadina-3,5-diene (3.0–10.0%), α-copaene (4.3–6.5%) and α-selinene (1.3–5.0%) (see Table 1). Chemotypes found in the East Coast of the North Island of New Zealand tend to contain higher levels of β-triketones than oil sourced from other regions 9. The compartmentalization of β-triketones and grandiflorone within oil glands inside Manuka leaves may defend the plants against Manuka’s herbicidal activity 10. There are also some types of Leptospermum scoparium that are high in α-pinene (21.5%) 9, though the majority of plants possess lower levels of this monoterpene (0.6–11%) 11.

Higher levels of triketones known to have strong antibacterial properties were predominant in samples from the East Cape population. Higher levels of the monoterpenes, α- and β-pinene, were present in the Northland populations 12. Beta-triketones (β-triketones) have been found to have strong antibacterial and antifungal properties on their own, along with natural herbicidal efficacy 13. The main β-triketones found in steam distilled, East Cape Manuka oil are leptospermone, isoleptospermone, flavesone and smaller amounts of grandiflorone. Samples from Leptospermum scoparium grown in Australia had higher monoterpene levels and almost no triketones compared to those from New Zealand 12. Manuka oil from New Zealand was shown to have low concentrations of monoterpenes in comparison to Kanuka oil (75% α-pinene) and negligible amounts of terpinen-4-ol and 1,8-cineole predominant in Australian tea tree oil 4. In general, Manuka oils from different geographic locations around New Zealand can be simplified into 3 basic chemo-type groups based on the ratio of the monoterpenes:sesquiterpenes:ß-triketones 14. These include triketone-rich in the East Cape (marketed as Manex), monoterpene-, linalool- and eudesmol-rch in Nelson (Kaiteriteri) and monoterpene- and pinene rich in Canterbury 15. A varied chemotype in Manuka grown in South Africa in comparison to New Zealand-grown was shown by van Vurren 16. The age of the plant also plays a role in the nature of the essential oil, with higher sesquiterpene content in young plants and a mixed amount of monoterpenes and sesquiterpenes in mature ones 15.

The lack of consistency in constituents is a common problem with natural extracts and a source of inconsistency in medicinal properties 17. Though Manuka oil is listed under the New Zealand Inventory of chemicals (CAS 219828- 87-2), ECHA (CAS 223749-44-8) and EINECS (425-630-7), further research into regulation, standardization and characterization of the medicinal properties from varying origins is required.

Table 1. Chemical composition of Manuka oil and known properties of each component

ComponentPercentage in Commercial CompositionsKnown PropertiesReference
α-pineneUp to 21.5%Reported to have antibiotic resistance modulation, anticoagulant, antitumor, antimicrobial, antimalarial, antioxidant, anti-inflammatory, anti-Leishmania, and analgesic effects in association with other essential oils.12
Leptospermone0.8–19.4%Herbicidal; antibacterial: treatment with 5–20 mg/disc of concentrate was effective against foodborne bacteria: Listeria monocytogenes, Staphylococcus aureus and Staphylococcus intermedius and three Gram-negative bacteria: Salmonella typhimurium, Shigella flexneri and Shigella sonnei18
Calamenene2.5–18.5%Major constituent of mānuka oil; contributes to insecticidal, antiseptic, bactericidal, analgesic and anti-inflammatory properties.
Antibacterial effect against S. aureus and MRSA was shown.
19
δ-cadinene0.9–6.9%Pesticidal effects against mosquito have been shown for constituents isolated from Kadsura heteroclita leaf oil.20
Cadina-1,4-diene0.1–5.9%Not reported
Cadina-3,5-diene3.0–10.0%Not reported
Flavesone0.7–5.8%Antiviral properties.21
α-copaene4.3–6.5%Enhances mating in male Mediterranean fruit flies; Lures for trapping Redbay ambrosia beetle (Xyleborus glabratus).22
α-selinene1.3–5.0%Insecticidal: retarding the growth of mosquito larvae.19
α-terpineol1–2%Antifungal effects; preservative for the postharvest storage of grapes and other fruits; has been shown to suppress the production of inflammatory mediators when sourced from Tea tree oil.23
Terpinene-4-ol0.8–1.4%Spasmolytic activity; anti-inflammatory properties have been characterized in constituent isolated from Melaleuca alternifolia.24

Manuka essential oil benefits

Manuka oil scientific data, prominently from in vitro (test tube) studies, demonstrated a broad spectrum of antibacterial, antifungal, anti-parasitic/insecticidal, anti-inflammatory, antiviral and spasmolytic activity. Manuka oil was also known to contain substantial amount of antioxidant compounds that can protect cell components from the harmful action of free radicals 25.

Antibacterial activity

The antibacterial activity of Manuka oil is the most characterized, being effective against both Gram-positive and Gram-negative bacteria (see Table 2). These effects are variable depending on the type and source of Manuka oil, with fractions containing triketone constituents seeming particularly active 11. The antibacterial activity of Manuka oil is relatively more pronounced against Gram positive bacteria than Gram negative bacteria (Table 2). The exact mechanism of the antibacterial effects in Gram positive bacteria are unknown but cell lysis of Gram-positive cells suggests disruption of the bacterial cell membrane is an important component of the mechanism 1. Treatment with 1.5% (v/v) of Manuka oil for 4 hours induced morphological changes and cell lysis in methicillin-resistant Staphylococcus aureus (MRSA), while treatment with a high dose (3% v/v) completely disrupted the cells 26. The β-triketone content are suggested to be responsible for this activity 27. In contrast, treatment with Manuka oil against Gram negative bacteria, such as E. coli, caused mild alterations in morphology at low doses and higher concentrations (6% v/v) were required for antibacterial effects 26. The basis of the difference is unknown but this may be due to limited diffusion across the lipopolysaccharide-based capsule covering the outer membrane of Gram negative bacteria 26.

Table 2. Manuka oil antibacterial activity

OrganismMethod of Analysis%(vol/vol) (µg/mL)RelevanceReference
# Minimum Inhibitory Concentration (MIC)* Minimum Bactericidal Concentration (MBC)
Gram positive bacteria
Atopobium vaginae Broth microdilution0.0010.001Vaginal infections, pre-term birth and neonatal infections28
Bacillus subtilis Broth microdilution0.030.5Intestinal bacteria26
Bacteroides vulgatus Broth microdilution0.0010.001Vaginal infections, pre-term birth and neonatal infections28
Lactobacillus plantarum Broth microdilution12.5Not reportedOral probiotic29
H2O2-producing lactobacilli and non H2O2-producing lactobacilliBroth microdilution0.0750.075Vaginal bacteria28
Listeria monocytogenes Two-fold serial dilution0.414Not reportedFoodborne pathogen30
Gardnerella vaginalis Broth microdilution0.0010.001Vaginal infections, pre-term birth and neonatal infections28
Propionibacterium acnes ATCC 11827Broth microdilution0.055Not reportedAcne31
Propionibacterium acnes Broth microdilution0.2110.25Acne32
Staphylococcus aureus Two‘-fold serial dilution0.535Not reportedFoodborne pathogen30
Staphylococcus aureus strainsTwo-fold serial dilution0.513Not reportedMultiple clinical manifestations in humans33
Methicillin-resistant Staphylococcus aureus (MRSA)Broth microdilution0.031Skin infections, pneumonia, sepsis, surgical site infections26
Streptococcus agalactiae Broth microdilution0.0010.001Meningitis; sepsis28
Staphylococcus epidermidis ATCC 2223Broth microdilution1.4Not reportedAcne31
Staphylococcus intermediusBroth microdilution0.0581Not reportedFoodborne pathogen30
Streptococcus sobrinusBroth microdilution0.048Not reportedOral pathogen33
Streptococcus sobrinus 671596-well liquid culture microdilution0.130.25Oral pathogen34
Streptococcus sobrinus B1396-well liquid culture microdilution0.250.25Oral pathogen
Streptococcus mutans JC296-well liquid culture microdilution0.250.25Oral pathogen
Streptococcus mutans ATCC 25175Two-fold microdilution6.2Not reportedOral pathogen; dental caries29
Vancomycin-resistant Enterococcus faecalis (VRE)Broth microdilution0.0064Not reportedSepsis; infection of open wounds35
Gram negative bacteria
Actinobacillus actinomycetemcomitans (now known as Aggregatibacter actinomycetemcomitans) strains Y4, ATCC 29523, 29524, 33384 96-well liquid culture microdilution0.030.13Oral pathogen34
Escherichia coli (E. coli)
Broth microdilution>4>4Intestinal bacteria; opportunistic pathogen26
E. coli antibiotic and multidrug resistant strainsTwo-fold microdilution1–42–4Hospital-based infections36
Fusobacterium nucleatum ATCC 25586 strainsBroth microdilution0.030.03Periodontal disease; dental caries36
Helicobacter pylori (H. pylori) Broth microdilutionNot reported0.4Gastritis, gastric ulcers and gastric cancer37
Klebsiella pneumoniae spp. antibiotics and multidrug resistant isolatesMicrodilution2–42–8Hospital-based infections; opportunistic pathogen36
Porphyromonas gingivalis ATCC 33277, W50 and Su6396-well liquid culture microdilution0.030.06Oral pathogen34
Porphyromonas gingivalis ATCC 5397796-well liquid culture microdilution0.030.03Oral pathogen34
Pseudomonas aeruginosa antibiotic and multidrug resistant isolatesTwo-fold microdilution≥8≥8Burn wound infections, sepsis36
Proteus mirabilis Two-fold microdilution1–42–8Hospital based infections
Salmonella typhimurium Two-fold serial dilution0.00236Not reportedFoodborne bacteria30
Shigella flexneriTwo-fold serial dilution0.00653Foodborne bacteria30
Shigella sonneiTwo-fold serial dilution0.00697Foodborne bacteria30
Serratia marcescens Broth microdilution≥4≥4Opportunistic pathogen26

Footnote: * MIC = Minimum inhibitory concentration: minimum dose required to inhibit growth of bacteria; # MBC = Minimum bactericidal concentration: minimum dose required to kill bacteria

Gram Positive bacteria

The efficacy of Manuka oil is both dose- and time-dependent. Treatment with a 10% solution of Manuka oil in DMSO was equally effective as the same concentration of Kanuka oil against Staphylococcus aureus, Staphylococcus sobrinus and Staphylococcus mutans (Minimum Inhibitory Concentration [MIC] = 0.048% (480 µg/mL); the highest dilution at which no growth was observed) (Table 2) 33. A time to kill assay against the same strains showed 100% inhibition on treatment with either 10% Manuka oil or Kanuka oil required as low as 5 seconds and as high as 900 seconds 38. Another study determined the MIC value ranging between 0.13–0.25% against Streptococcus sobrinus strains and 0.25% against Streptococcus mutans 34. Higher concentrations of essential oils are reported in the case of other antibacterial medicinal products against the same oral pathogens—tea tree (1%), eucalyptus (1%), lavender (>1%) and rosemary (>1%) (Table 2) 34.

Manuka oil exhibits strong bacteriostatic effects against different strains of Staphylococcus, including antibiotic-resistant strains (Table 2). Treatment with 2% (v/v) Manuka oil, kanuka oil or triketones in Tween 80 had limited bactericidal effects at 240 minutes post-treatment (using death a kinetics assay) 16. Manuka oil has also exhibited strong activity against different strains of Staphylococcus pseudintermedius, often contributory to skin and ear infections in dogs 39. These included methicillin-resistant strains, with MICs being around 2% (v/v) for both resistant- and antibiotic-sensitive isolates 40. Inhibition of Staphylococcus pseudintermedius biofilm formation was also reported in the same study 39. Exposure of various strains of Staphylococcus aureus to subinhibitory concentrations of Manuka oil has also been found to significantly inhibit their ability to produce enterotoxins, an effect not observed after treatment with oregano and marjoram essential oils 41.

Activity against Staphylococcus epidermidis and Propionibacterium acnes, pathogenic bacteria responsible for acne in humans, has also been reported 31. Interestingly, this study also found Manuka oil to show the highest likelihood amongst a range of different essential oil combinations, of being involved in synergist interactions against Staphylococcus epidermidis 31. Kim et al. 42 and Wu 32 have shown reduction in acne and bactericidal effects (MIC = 0.211% w/v or 2.11 mg/mL; MBC = 0.25% w/v or 2.5 mg/mL) of Manuka oil against Propionibacterium acnes respectively.

Impressive effects of Manuka oil have been found against pathogenic bacteria associated with biosolid soil contamination, with significant growth inhibition of Clostridium perfringens and Listeria monocytogenes 43. The EC50 = 0.07% and 23.3% (environmental effect concentration is the dose required to reduce pathogen growth by 50%) for C. perfringens and L. monocytogenes, respectively, on treatment with concentrated Manuka leaf extract for 24 hours 43.

Specific components or fractions of Manuka oil, such as leptospermone (and its derivatives, grandiflorone and myrigalone A), have also been identified to possess antibacterial activity 35. Leptospermone had the strongest inhibitory effect against foodborne Gram positive bacteria, such as Listeria monocytogenes, Staphylococcus aureus and Staphylococcus intermedius (Table 2), using both dilution assay and agar diffusion assay (≥30 mm inhibition zone on treatment with 1 and 2 mg/disc) 44. Leptospermone and its derivative 1,2,3-cyclohexanetrione-1,3-dioxime had strong inhibitory effects against intestinal bacteria, Clostridium difficle and Clostridium perfringens (inhibitory zone ranged between 20 and >30 mm on treatment with 2 or 5 mg/disc) 44. The derivative 1,2,3-cyclohexanetrione-1,3-dioxime had a strong inhibitory effect against Bifidobacterium breve and Bifidobacterium longum (≥30 mm inhibition zone on treatment with 5 mg/disc) but leptospermum had no effect on these strains. Neither fractions were effective against Lactobacillus casei, a non-pathogenic probiotic 44.

Two other components of typical Manuka oil, grandiflorone (MIC = up to 0.0032% or 32 μg/mL) and myrigalone A (MIC = 0.0064% or 64 μg/mL), have also been identified as active against vancomycin-resistant Enterococcus faecalis (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) and may therefore provide potential treatments for infection with these bacterial species 35.

Gram Negative bacteria

A comprehensive study of the effects of 60 different essential oils on the growth of Helicobacter pylori (H. pylori) found Manuka oil to be the seventh most effective antibacterial when diluted in propylene glycol (500 µg/mL after 1 h and 40 µg/mL after 24 hour) 37. Manuka oil derived from the North Island of New Zealand displayed significant antibacterial activity against 20/20 Listeria monocytogenes strains, whereas more so than that of Manuka oil from the South Island was effective against (0/20 Listeria monocytogenes strains) 24. Higher levels of β-triketones found in chemotypes growing in the North Island of New Zealand, are likely to be contributory to these differences 9.

Investigation of the growth inhibitory effect of an oil from Manuka seeds against Escherichia coli (E. coli) showed it to be ineffective according to Jeong et al. (2009) while it was effective for Prosser et al. (2014). Based on calorimetric growth experiments using E. coli K12 C600, Jeong et al. 44 showed that treatment with different doses of Manuka oil dissolved in Tween 80 (up to 4% v/v) had a dose-dependent effect in reducing bacterial growth but was not as effective as treatment with Tea tree oil (Melaleuca alternifolia oil) 45. On the other hand, Prosser et al. 43 showed treatment with a very high dose of concentrated Manuka oil inhibited the growth of E. coli 0157 (EC50 = 27.8%). Similar doses were required to inhibit the growth of Salmonella typhimurium. In comparison, treatment with 0.597% of concentrated Manuka oil was sufficient to retard the growth of Campylobacter jejuni 43. This study proposed the potential applications to improve polluted soils and adjacent waterways, through planting Manuka or including Manuka oil when biosolids are applied to the soil to help prevent bacterial contamination 46.

Manuka-derived leptospermone has strong antibacterial activity against Gram negative foodborne bacterial pathogens, Salmonella typhimurium, Shigella flexneri and Shigella sonnei, with MICs ranging from 23.6 to 69.7 μg/mL 30. These data suggest that leptospermone may be useful clinically or as a natural food preservative, as it is able to inhibit the growth of harmful gut and foodborne bacteria while displaying no significant effect on beneficial bacterial species 30.

Activity against various Gram negative, antibiotic-resistant bacterial isolates from dogs with otitis externa, has also been reported recently for Manuka. These included both antibiotic-sensitive and multidrug-resistant clinical isolates of Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae spp. pneumoniae and Proteus mirabilis 36. MIC and MBC values (minimum bactericidal concentrations) of Manuka oil alone were ≥1% v/v and ≥2%, respectively 36.

Manuka oil was the most effective against periodontopathic bacteria in comparison to tea tree oil, eucalyptus oil, lavandula oil and romarinus oil. Manuka oil was effective at very low concentration (MIC = 0.03%) against the oral pathogens Aggregatibacter actinomycetemcomitans (MBC = 0.13%), P. gingivalis (MBC = 0.06; 0.03 for ATCC 53977) and Fusobacterium nucleatum (MBC = 0.03%). By comparison, higher MIC values very observed for other antibacterial essential oils such as tea tree (0.06–0.5%), eucalyptus (0.13–0.5%), lavender (0.25–1.0%) and rosemary (0.5–1.0%) against the same oral pathogens 34.

Antifungal activity

A summary of the antifungal effects of Manuka oil is given in Table 3. Although the exact mechanism of action is unknown. When the fungi were exposed to Manuka oil as a fumigant, the inhibition rate was 50% against Phytophthora cactorum and 62% against Fusarium circinatum; however, no inhibition was observed against Cryphonectria parasitica 47.

The effect of Manuka oil on Aspergillus niger, Aspergillus ochraceus and Fusarium culmorum was assessed in another study, which found wide variation in the antifungal activity depending on the source of Manuka oil; the Manuka oil sample from the South Island of New Zealand had greater antifungal activity against Aspergillus ochraceus and Fusarium culmorum than Manuka oil from the North Island 24. The fungicidal activity of Manuka oil was assessed for a series of human fungal species, Malassezia furfur, Trichosporon mucoides, Candida albicans and Candida tropicalis, with a MIC of 1.56% for Malassezia furfur and Trichosporon mucoides and 3.13% for both Candida species 38. Good activity against Candida species was also reported in a subsequent study 48.

Table 3. Antifungal activity of Mānuka oil

Organism* Minimum Inhibitory Concentration (MIC) (% v/v)# Minimum Fungicidal Concentration (MFC) (% v/v)RelevanceReference
Malassezia furfur 1.56Not reportedPityriasis versicolor and Pityrosporum folliculitis38
Trichosporon mucoides 1.56Not reportedOpportunistic pathogen
Candida albicans 3.13Not reportedOpportunistic pathogen
Candida tropicalis 3.13Not reportedOpportunistic pathogen
Candida albicans 0.0150.015Candida vulvovaginitis infections28
Candida glabrata 0.010.01Vaginal candidiasis

Footnote: * MIC = Minimum inhibitory concentration; # MFC = Minimum Fungicidal concentration. Both values were determined using microdilution assays

Antiparasitic and insecticidal activity

Several studies have examined the antiparasitic activity of Manuka oil, for parasites with significant impact on plants, humans and animals (see Table 4). The primary animal parasites under investigation have been poultry red mites (Dermanyssus gallinae), while the primary human parasites investigated have been scabies (Sarcoptes scabei), house dust mites (Dermatophagoides farina and Dermatophagoides pteronyssinus), stored product mites (Tyrophagus putrescentiae) and mosquitos (Aedes aegypti). The adsorption of the active ingredients in Manuka oil are suggested to cause fumigant and/or contact toxicity in the parasites. Contact and fumigation assays are generally used to determine the antiparasitic efficacy of essential oils. The compound efficacy would therefore depend on their lipophilic nature, viscosity and vapor pressure. In contact bioassays, lipophilic and viscous compounds are commonly more effective as they penetrate the cuticle layer of the arthropod. In fumigation bioassays, the toxic compounds are inhaled via the respiratory system and are dependent on the vapor pressure exerted by the compound 49.

A study of the effect of Manuka oil on different life stages of poultry red mites (Dermanyssus gallinae) suggests it is effective against both adult and juvenile mites but that it is not ovicidal for this parasite 50. A study of the effect of Manuka oil on poultry red mites (Dermanyssus gallinae) found the lethal concentration required to kill 50% of the parasites (LC50) during a 24-hour period in a contact bioassay was ~0.05 mg/cm³ and 0.03 mg/cm³ 50. Manuka oil displayed a repelling effect on >75% of poultry red mites (Dermanyssus gallinae) for up to 4 days after treatment of the mites contained in the Y-tube of an olfactometer and exposed to either fresh air in one arm of the Y-tube or air containing the volatile components of each essential oil in the other arm 51.

The effect of Manuka oil on a poultry beetle (Tenebrio molitor), a beneficial insect in a poultry system, was assessed along with a non-target organism. In this case, the Manuka oil had no significant effect on beetle mortality compared to the control (~15% vs. ~5%, respectively) 52. Similar results for poultry beetle (Tenebrio molitor) exposure to Manuka oil were observed in another study 51. In contrast, exposure of brine shrimp (Artemia salina, an organism commonly used in toxicity testing) to Manuka oil revealed a 90% mortality rate after exposure to ~0.05 mg/cm³, the same concentration as the LC50 for poultry red mites (Dermanyssus gallinae) 51, indicating potential use of Manuka oil as a general acaricide may need careful consideration regarding the effect on non-target organisms.

Manuka seed oil appears to be effective against house dust mites (Dermatophagoides farina and Dermatophagoides pteronyssinus) and stored product mites (Tyrophagus putrescentiae), with a LD50 (dose required to kill half the members of a tested population after a specified test duration) values of 0.54, 0.67 and 1.21 µg/cm², respectively, against the stated parasites; these values are 11.5–68.7 times more effective than DEET (N,N-diethyl-3-methylbenzamide), a common chemical treatment to control these mites 53. Further analysis of the major components of Manuka seed oil indicated the main triketone, leptospermone, to be the most active component of Manuka oil in this study, with LD50 values of 0.07–0.15 ug/cm² against house dust mites (Dermatophagoides farina and Dermatophagoides pteronyssinus) and stored product mites (Tyrophagus putrescentiae); these values represent 92.6–530.3 times the toxicity of DEET against the same organisms 53.

A study of the effects of essential oils on human scabies mites (Sarcoptes scabei) found Manuka oil to be moderately effective against scabies mites (Sarcoptes scabei), with median lethal times of 30 minutes (± 7.5 minutes) after direct contact with a 10% Manuka oil solution in paraffin oil 54. Vapor phase toxicity of Manuka oil was determined via fumigation assay, where mites were exposed to a filter paper treated with Manuka oil and mortality was checked every 5 minutes. Median lethal time for undiluted Manuka oil was 23 minutes (± 8.7 minutes) 54.

Insecticidal activity for Manuka oil has also been reported against Drosophila suzukii, a fruit fly pest which is a serious economic threat to soft summer fruit. Manuka oil’s LD50 for contact toxicity was 0.60 μg/mL for males and 1.10 for females. Triketone components were shown to be contributory to these insecticidal effects 55.

Manuka oil has also been used as a lure to attract Xyleborus glabratus (Redbay ambrosia beetle), an exotic wood-borer that transmits the fungal agent (Raffaelea lauricola) responsible for laurel wilt, which has had a severe impact on forest ecosystems in South-East United States 56.

Screening of essential oils for their toxicity against Aedes aegypti (L.) larvae found that Manuka oil containing calamenene and leptospermone as dominant constituents, exhibited strong larvicidal effects. This suggests potential applications for Manuka oil in mosquito vector control. These effects were enhanced when Manuka oil was combined with carvacrol or oregano oil 57 and with an emulsion made using amylose-N-1-hexadecylammonium chloride 19.

Table 4. Manuka oil antiparasitic or insecticidal effect

OrganismMethodLethal EffectClinical SignificanceReference
Acaricidal activity
Dermanyssus gallinae Contact assayLC50: 0.02 to 0.03, LC90:0.05 to 0.07
LD99: 0.10 mg/cm²
Poultry red mite58
D. farinae Fabricated disc methodLD50: 0.54 μg/cm²House dust mite53
D. pteronyssinus LD50: 0.67 μg/cm²House dust mite
Tyrophagus putrescentiae LD50: 1.21 μg/cm2Stored product mite
Sarcoptes scabei Contact assayLT50: 60 min for 5% solution
LT50: 30 min for 10% solution
Human scabies mites54
Drosophila suzukii Contact assay0.60 μg/mL for males and 1.10 for femalesFruit fly pest55
Aedes aegypti (Linnaeus) larvaeLarvicidal bioassayLC90: 66.62Malaria19
Repellent effects
Dermanyssus gallinae (De Geer) Fumigant assay80–84%Poultry red mite52
Dermanyssus gallinae Fumigant assay80.00%Poultry red mite59
Sarcoptes scabei Fumigant assay80.00%Human scabies mites54

Footnotes:

  • LC50 (Lethal Concentration 50%) or LD50 (Lethal Dose 50%) is the dose or the estimated air concentration of a substance administered via inhalation at which 50% of the animals will be expected to die.
  • LT50 is the median Lethal Time (time until death) after exposure of an organism to a toxic substance or stressful condition.

Antiviral activity

Herpes simplex viruses can cause cold sores (usually Herpes simplex virus type 1, HSV-1) or genital herpes (usually Herpes simplex virus type 2, HSV-2) and both can become chronic and recurrent infections sometimes resistant to antiviral drugs 60. Pre-treatment with a β-triketone-rich Manuka oil has been reported to exhibit inhibitory effects on Herpes simplex virus type 1 (HSV-1) and Herpes simplex virus type 2 (HSV-2) 61. RC-37 cells (monkey kidney cells) or the Herpes simplex viruses were pre-treated with Manuka oil for one hour followed by inoculation. Pre-treatment of the Herpes simplex virus with Manuka oil significantly inhibited plaque formation in comparison to pre-treatment of the cells alone 21. The IC50 against HSV-1 was 0.96 µg/mL (0.0001% v/v) and that for HSV-2 was 0.587 μg/mL (0.00006% v/v) 21. IC50 also known as the half maximal inhibitory concentration, is a quantitative measure that indicates how much of a particular inhibitory substance (e.g. Manuka oil) is needed to inhibit, in vitro (in test tube), a given biological process or biological component by 50%. The biological component could be an enzyme, cell, cell receptor or microorganism. Pre-treatment of host cells before viral infection reduced replication of HSV-1 by 41%. Treatment with flavesone and leptospermone alone, two characteristic triketone constituents of Manuka oil, had similar effects 21. Another study reported pre-treatment of acyclovir-resistant isolates of HSV-1 and HSV-2 with 0.001% Manuka oil reduced the infectivity of the viruses by >99% 62. The absence of viral inhibition in pre-treated cells suggests that the oil is likely to exert a direct antiviral effect on HSV before or during adsorption onto the host cells 62.

Spasmolytic activity

Smooth muscle spasmolytic activity has been reported for Manuka oil in experiments on guinea pig ileum showing a dose-dependent inhibitory effect of Manuka oil on smooth muscle contractions 63. A subsequent study of the components of Manuka oil showed α-terpineol and terpinene-4-ol both produce strong spasmolytic activity in guinea pig ileum, while in contrast, α- and γ-terpinenes displayed spasmolytic activity after an initial spasmogenic action 24. A post-synaptic mechanism affecting cAMP to alter potassium channels in the muscle was suggested by the authors as the possible mode of action 24. This activity was absent in kanuka oil and neither Manuka or kanuka oil used cGMP nor behave like potassium channel openers as seen in Melaleuca oil or tea tree oil.

Manuka oil and its components were also reported to increase muscle tone in skeletal muscle, evaluating its absorption in chick biventer muscle and rat phrenic nerve diaphragm preparations 24. In contrast, both Manuka oil and tea tree oil (Melaleuca oil) decreased uterine muscle contractions 24. Application of either oils showed a decrease in tension (via inhibition of twitch response on stimulating the skeletal muscle nerve) and a weighty increase in resting tone (indicating contracture) when the muscle was stimulated either directly or via the phrenic nerve. the components α-terpineol, α-terpinene and terpinene-4-ol showing a similar, significant decrease in the force of contractions 24. The study suggests the use of these oils for aromatherapy, where they would aid as relaxants for those suffering from stress and anxiety. While these studies involved relatively high doses of a limited number of Manuka oil samples, whose origins and chemotypes were not well characterized, to isolated tissues in vitro 24. The researchers highlighted caution against the use of Manuka oil as a relaxant during childbirth may be detrimental to the birthing process and should therefore be avoided in this situation 24. This suggestion was based on similar properties exhibited by tea tree oil and other essential oils 64.

Anti-inflammatory effects

Experiments to assess the anti-inflammatory potential of Manuka oil found that THP-1 cells stimulated with lipopolysaccharide (LPS) and co-treated with 0.1–10% Manuka oil had significantly reduced release of TNF-α but there was no significant effect on the release of IL-4 38. This study found no cellular toxicity at an oil concentration of 10%, which contrasts with the results discussed in the toxicity section earlier. The diluent used in the study by Chen et al. 38 was not specified and this discrepancy could be a result of diluting the lipophilic Manuka oil in aqueous cell culture media. Lis-Balchin et al. (2000) also showed the antioxidant effects of Manuka oil from the North- and South-islands of New Zealand were more consistent in comparison to kanuka oil 24.

Photo-protective effects

The sunlight ultraviolet (UV) radiation is the primary environmental factor causing skin damage and consequently premature aging. Kwon et al. 57 evaluated Manuka oil (from Coast Biologicals Ltd., Auckland, New Zealand) for its effects against photoaging in UV-B-irradiated hairless mice. After 8 weeks of exposure to UVB radiation, mice that were treated topically with 10% Manuka oil experienced a reduction in typical UVB-related skin changes, such as skin thickening, appearance of wrinkles and loss of skin collagen 57. These effects were associated with inhibition of loss of collagen fibers, reduction of epidermal hyperplasia, suppressed production of proinflammatory cytokines (IL-1β and TNF-α) and reduced macrophage infiltration, suggesting Manuka oil can inhibit UVB-associated inflammation in skin 57.

A nanoemulsion (particle size of 11.93 µm) containing Manuka oil (10% by weight) as the main component along with a Vitamin C derivative (ascorbyl tetraisopalmitate; 2% to 10% by weight) has been used in cosmetic formulations, including skin creams, lotions, essences and cosmetic powders 65. The versatile formulation is effective as a whitening, anti-inflammatory agent and for wrinkle improvement 65. Treatment for 9 weeks with the Manuka oil + Vitamin C derivative nanoemulsion in SKH-1 Hairless Mice exposed to artificial photoaging using UV-B irradiation showed increased thickness of the skin within 6 to 8 weeks post-treatment while the control showed no change 65.

Manuka oil uses

Manuka essential oil has been used as a traditional medicine in New Zealand and Australia to treat wounds, fever, and pain 66. Currently, Manuka oil commercial application is in skin care and as antiaging product. A recent report indicated that manuka oil possesses a strong antibacterial activity against Propionibacterium acnes, which suggests that Manuka oil could be effective against acne 67.

Manuka oil is currently listed as a complementary medicine by Therapeutic Goods Administration (TGA, an Australian equivalent of the FDA) in the forms of balm and cream for skin applications. Manuka oil is also used as a bioactive ingredient in various cosmetic products and herbal medicines. Manuka oil is an active ingredient in the Therapeutic Goods Administration-listed product Kiwiherb Herbal Throat Spray, which contains a mixture of Echinacea purpurea (6%), honey (7%), Manuka oil (1 µL/mL), Macropiper excelsum var. excelsum (7%), propolis tincture (0.09 µg/mL and Thymus vulgaris (5%). The formulation is accepted in Australia by TGA for oral administration to reduce or relieve cold, cough, dry throat, mild throat inflammation, itchy throat and pharyngitis 7.

Manuka oil side effects and toxicity

Manuka oil, like other essential oils, has been classified as safe and tolerable for human use 1. However, the lack of clinical trials means there is limited data to inform dosing practices and toxicology profiles. The in vitro (test tube) toxicity of Manuka oil and its main constituent, leptospermone, tended to vary with cell lines, concentrations tested and method of analysis. Higher cytotoxicity was observed on treatment with Manuka oil in comparison to leptospermone alone 1. This suggests additional components of Manuka oil that makes it more toxic to cell lines. A study of Manuka oil in human umbilical vein endothelial cells found treatment with a concentration of 0.2% of Manuka oil reduced cell viability by ~30% 34. Given Manuka oil is lipophilic and cannot be diluted in aqueous cell culture media 68, it is possible the actual concentration of Manuka oil in contact with the human umbilical vein endothelial cells cultures was significantly less than assumed.

No signs of toxicity were observed on treatment with 10% active aqueous or oily phase of the cosmetic formulation for Campo Manuka Oil Extract in fibroblast cells. In vitro organogenesis assay (Living Dermal Matrix), a toxicity assay that closely mimics the effect of a substance on human skin, consists of skin cells in a 3D-construct made of collagen. The Living Dermal Matrix test proved Campo Manuka oil to be non-irritant with 99.4% cell viability after treatment with an undiluted sample in comparison to 100% propylene glycol (73%; a non-irritant) and 100% morpholine (6%; a moderate irritant) 69.

Unpublished data showed gel formulations containing >10% Manuka oil did not induce acute skin sensitivity in mice (unpublished data Phytomed Medicinal Herbs Ltd.). LD50 also known as the median lethal dose, refers to an estimate of the amount of poison that, under control conditions, will be a lethal dose to 50% of a large number of test animals of a particular species. LD50 value is expressed in milligrams of the substance being tested per kilogram of animal body weight (mg/kg). Acute toxicity was not observed (LD50 = 4612 g/kg body weight) in mice after single oral administration of varying doses (500 mg/kg to 5000 mg/kg body weight) of a patented formulation containing a mix of Leptospermum scoparium and Kunzea ericoides essential oils. The same formulation did not induce erythema or edema 3 and 7 days after a skin irritation test in epilated rabbits treated with 0.5 g of the product. Absence of percutaneous irritation was also demonstrated after treatment with 0.1 mL of 10% emulsion of the combined oil product onto the eyes of rabbits treated up to 7 days 70.

Product safety report on MELORA Manuka oil (<5%) according to the European Chemical Agency Regulation 1223/2009 detailed high skin tolerance and good cosmetic acceptability of the product 3. The formulation has a relatively high content of β-triketones, such as flavesone, isoleptospermone, leptospermone and grandiflorone. Acute toxicities based on the routes of administration were LD50 = 1061 mg/kg body weight and LD50 > 2000 mg/kg body weight for oral and dermal administration, respectively 3. No irritation was noted on testing the formulation on rabbit eye mucous membranes. There was no skin sensitization or genetic toxicity after a micronucleus test in TK6 Human lymphoblastoid cells and bacterial reverse mutation test in Salmonella typhimurium and E. coli. It is intended for external use, could cause irritations in the eye on direct contact and a patch test is suggested before use 3.

The safety evaluations for Campo Manuka Oil Extract (10% concentrate in water or ceramide) formulation according to the European Chemical Agency regulations described that the oil was non-toxic for dermal use and was edible in small quantities (oral LD50 = >9000 mg/kg body weight) after testing in rats. The formulation was classified as a non-irritant based on tests in vivo (in animal) and in healthy human subjects. Patch tests in 50 healthy human subjects at doses from 0.5% to 100% showed satisfactory tolerance with no significant irritation reactions 69. The irritation potential of a 10% solution of Manuka oil was tested on the chorio-allantoic membrane of chicken egg, using the Eyetex assay and Skintex assay. All three tests deemed the formulation as non-irritant. The product did not have any comedogenic effect on the skin, indicating that the product does not clog pores and is well tolerated on the skin 69.

Manuka oil sample pre-registered by the European Chemical Agency (EC Number: 434-370-3) was found to have LD50 of 1.061 mg/kg body weight for oral administration and LD50 >2000 mg/kg body weight. Low scores for redness and swelling were determined for skin irritation and eye irritation tests in vivo.

References
  1. Mathew, C., Tesfaye, W., Rasmussen, P., Peterson, G. M., Bartholomaeus, A., Sharma, M., & Thomas, J. (2020). Mānuka Oil-A Review of Antimicrobial and Other Medicinal Properties. Pharmaceuticals (Basel, Switzerland), 13(11), 343. https://doi.org/10.3390/ph13110343
  2. Leptospermum scoparium. http://www.plantsoftheworldonline.org/taxon/urn:lsid:ipni.org:names:597505-1
  3. Melora . Cosmetic Product Safety Report: MELORA™ Mānuka Oil. Melora; Dublin, Ireland: 2017.
  4. Christoph F., Kubeczka K.-H., Stahl-Biskup E. The Composition of Commercial Manuka Oils from New Zealand. J. Essent. Oil Res. 1999;11:705–710. doi: 10.1080/10412905.1999.9712001
  5. Christoph F., Kubeczka K.H., Stahl-Biskup E. The composition of commercial manuka oils from New Zealand. J. Essent. Oil Res. 1999;11:705–710. doi: 10.1080/10412905.1999.9712001
  6. Van Klink J.W., Larsen L., Perry N.B., Weavers R.T., Cook G.M., Bremer P.J., MacKenzie A.D., Kirikae T. Triketones active against antibiotic-resistant bacteria: Synthesis, structure-activity relationships, and mode of action. Bioorg. Med. Chem. 2005;13:6651–6662. doi: 10.1016/j.bmc.2005.07.045
  7. Kiwiherb Herbal Throat Spray (ARTG ID 337576). https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=6CECA70A7F830F60CA258582004305C6&agid=(PrintDetailsPublic)&actionid=1
  8. Māori medicine. https://www.tepapa.govt.nz/discover-collections/read-watch-play/maori/maori-medicine
  9. Douglas M.H., Van Klink J.W., Smallfield B.M., Perry N.B., Anderson R.E., Johnstone P., Weavers R.T. Essential oils from New Zealand manuka: Triketone and other chemotypes of Leptospermum scoparium. Phytochemistry. 2004;65:1255–1264. doi: 10.1016/j.phytochem.2004.03.019
  10. Killeen D.P., Van Klink J.W., Smallfield B.M., Gordon K.C., Perry N.B. Herbicidal β-triketones are compartmentalized in leaves of Leptospermumspecies: Localization by Raman microscopy and rapid screening. New Phytol. 2015;205:339–349. doi: 10.1111/nph.12970
  11. Porter N.G., Wilkins A.L. Chemical, physical and antimicrobial properties of essential oils of Leptospermum scoparium and Kunzea ericoides. Phytochemistry. 1999;50:407–415. doi: 10.1016/S0031-9422(98)00548-2
  12. Perry N.B., Brennan N.J., Van Klink J.W., Harris W., Douglas M.H., McGimpsey J.A., Smallfield B.M., Anderson R.E. Essential oils from New Zealand manuka and kanuka: Chemotaxonomy of Leptospermum. Phytochemistry. 1997;44:1485–1494. doi: 10.1016/S0031-9422(96)00743-1
  13. Douglas MH, van Klink JW, Smallfield BM, Perry NB, Anderson RE, Johnstone P, Weavers RT. Essential oils from New Zealand manuka: triketone and other chemotypes of Leptospermum scoparium. Phytochemistry. 2004 May;65(9):1255-64. doi: 10.1016/j.phytochem.2004.03.019
  14. Manuka Oil Beta Troketones. Manuka Essential Oil. http://www.mbtk.org.nz/what-msstk/manuka-essential-oil
  15. Porter N.G., Smale P.E., Nelson M.A., Hay A.J., Van Klink J.W., Dean C.M. Variability in essential oil chemistry and plant morphology within aLeptospermum scopariumpopulation. N. Z. J. Bot. 1998;36:125–133. doi: 10.1080/0028825X.1998.9512551
  16. Christoph F., Kaulfers P.-M., Stahl-Biskup E. A Comparative Study of the in vitro Antimicrobial Activity of Tea Tree Oils s.l. with Special Reference to the Activity of β-Triketones. Planta Med. 2000;66:556–560. doi: 10.1055/s-2000-8604
  17. Bent S. Herbal Medicine in the United States: Review of Efficacy, Safety, and Regulation: Grand Rounds at University of California, San Francisco Medical Center. J. Gen. Intern. Med. 2008;23:854–859. doi: 10.1007/s11606-008-0632-y
  18. Dayan F.E., Howell J.L., Marais J.P., Ferreira D., Koivunen M. Manuka Oil, A Natural Herbicide with Preemergence Activity. Weed Sci. 2011;59:464–469. doi: 10.1614/WS-D-11-00043.1
  19. Muturi E.J., Selling G.W., Doll K.M., Hay W.T., Ramirez J.L. Leptospermum scoparium essential oil is a promising source of mosquito larvicide and its toxicity is enhanced by a biobased emulsifier. PLoS ONE. 2020;15:e229076. doi: 10.1371/journal.pone.0229076
  20. Govindarajan M., Rajeswary M., Benelli G. δ-Cadinene, Calarene and δ-4-Carene from Kadsura heteroclita Essential Oil as Novel Larvicides Against Malaria, Dengue and Filariasis Mosquitoes. Comb. Chem. High Throughput Screen. 2016;19:565–571. doi: 10.2174/1386207319666160506123520
  21. Reichling J., Koch C., Stahl-Biskup E., Sojka C., Schnitzler P. Virucidal Activity of a β-Triketone-Rich Essential Oil ofLeptospermum scoparium (Manuka Oil) Against HSV-1 and HSV-2 in Cell Culture. Planta Med. 2005;71:1123–1127. doi: 10.1055/s-2005-873175
  22. Hanula J.L., Mayfield A.E., III, Reid L.S., Horn S. Influence of trap distance from a source population and multiple traps on captures and attack densities of the redbay ambrosia beetle (Coleoptera: Curculionidae: Scolytinae) J. Econol. Entomol. 2016;109:1196–1204. doi: 10.1093/jee/tow068
  23. Kong Q., Zhang L., An P., Qi J., Yu X., Lu J., Ren X. Antifungal mechanisms of α-terpineol and terpene-4-alcohol as the critical components of Melaleuca alternifolia oil in the inhibition of rot disease caused by Aspergillus ochraceus in postharvest grapes. J. Appl. Microbiol. 2019;126:1161–1174. doi: 10.1111/jam.14193
  24. Lis-Balchin M., Hart S.L., Deans S.G. Pharmacological and antimicrobial studies on different tea-tree oils (Melaleuca alternifolia, Leptospermum scoparium or Manuka and Kunzea ericoides or Kanuka), originating in Australia and New Zealand. Phytotherapy Res. 2000;14:623–629. doi: 10.1002/1099-1573(200012)14:8<623::AID-PTR763>3.0.CO;2-Z
  25. Lis-Balchin M, Hart SL, Deans SG. Pharmacological and antimicrobial studies on different tea-tree oils (Melaleuca alternifolia, Leptospermum scoparium or Manuka and Kunzea ericoides or Kanuka), originating in Australia and New Zealand. Phytotherapy Research. 2000;14(8):623–629.
  26. Alnaimat S., Wainwright M., Jaber S., Amasha R. Mechanism of the Antibacterial Action of (Leptospermum scoparium) Oil on Methicillin-resistant Staphylococcus aureus (MRSA)and E. coli); Proceedings of the 2nd Mediterranean Symposium on Medicinal and Aromatic Plants (MESMAP-2); Antalya, Turkey. 22–25 April 2015.
  27. Christoph F, Kaulfers PM, Stahl-Biskup E. A comparative study of the in vitro antimicrobial activity of tea tree oils s.l. with special reference to the activity of beta-triketones. Planta Med. 2000 Aug;66(6):556-60. doi: 10.1055/s-2000-8604
  28. Schwiertz A., Duttke C., Hild J., Müller H.J. In vitro activity of essential oils on microorganisms isolated from vaginal infections. Int. J. Aromatherapy. 2006;16:169–174. doi: 10.1016/j.ijat.2006.09.005
  29. Filoche S.K., Soma K., Sissons C.H. Antimicrobial effects of essential oils in combination with chlorhexidine digluconate. Oral Microbiol. Immunol. 2005;20:221–225. doi: 10.1111/j.1399-302X.2005.00216.x
  30. Jeong E.Y., Lee M.J., Lee H.S. Antimicrobial activities of leptospermone isolated from Leptospermum scoparium seeds and structure-activity relationships of its derivatives against foodborne bacteria. Food Sci. Biotechnol. 2018;27:1541–1547. doi: 10.1007/s10068-018-0391-4
  31. Orchard A., Van Vuuren S., Viljoen A.M., Kamatou G.P.P. The in vitro antimicrobial evaluation of commercial essential oils and their combinations against acne. Int. J. Cosmet. Sci. 2018;40:226–243. doi: 10.1111/ics.12456
  32. Wu Q., Wu Q. Master’s Thesis. Massey University; Auckland, New Zealand: Jun, 2011. Antimicrobial Effect of Manuka Honey and Kanuka Honey Alone and in Combination with the Bioactives Against the Growth of Propionibacterium Acnes ATCC 6919
  33. Fratini F., Mancini S., Turchi B., Friscia E., Pistelli L., Giusti G., Cerri D. A novel interpretation of the Fractional Inhibitory Concentration Index: The case Origanum vulgare L. and Leptospermum scoparium J.R. et G. Forst essential oils against Staphylococcus aureus strains. Microbiol. Res. 2017;195:11–17. doi: 10.1016/j.micres.2016.11.005
  34. Takarada K., Kimizuka R., Takahashi N., Honma K., Okuda K., Kato T. A comparison of the antibacterial efficacies of essential oils against oral pathogens. Oral Microbiol. Immunol. 2004;19:61–64. doi: 10.1046/j.0902-0055.2003.00111.x
  35. Killeen D.P., Larsen L., Dayan F.E., Gordon K.C., Perry N.B., Van Klink J.W. Nortriketones: Antimicrobial Trimethylated Acylphloroglucinols from Mānuka (Leptospermum scoparium) J. Nat. Prod. 2016;79:564–569. doi: 10.1021/acs.jnatprod.5b00968
  36. Song S., Hyun J., Kang J.H., Hwang C.Y. In vitro antibacterial activity of the manuka essential oil from Leptospermum scoparium combined with Tris-EDTA against Gram-negative bacterial isolates from dogs with otitis externa. Veter Dermatol. 2020;31:81. doi: 10.1111/vde.12807
  37. Bergonzelli G., Donnicola D., Porta N., Corthésy-TheulazI E. Essential Oils as Components of a Diet-Based Approach to Management of Helicobacter Infection. Antimicrob. Agents Chemother. 2003;47:3240–3246. doi: 10.1128/AAC.47.10.3240-3246.2003
  38. Chen C.C., Yan S.H., Yen M.Y., Wu P.F., Liao W.T., Huang T.S., Wen Z.H., Wang H.M.D. Investigations of kanuka and manuka essential oils for in vitro treatment of disease and cellular inflammation caused by infectious microorganisms. J. Microbiol. Immunol. Infect. 2016;49:104–111. doi: 10.1016/j.jmii.2013.12.009
  39. Song C.Y., Nam E.H., Park S.H., Hwang C.Y. In vitroefficacy of the essential oil fromLeptospermum scoparium(manuka) on antimicrobial susceptibility and biofilm formation in Staphylococcus pseudintermedius isolates from dogs. Veter Dermatol. 2013;24:404. doi: 10.1111/vde.12045
  40. Song C.Y., Nam E.H., Park S.H., Hwang C.Y. In vitroefficacy of the essential oil fromLeptospermum scoparium(manuka) on antimicrobial susceptibility and biofilm formation inStaphylococcus pseudintermediusisolates from dogs. Veter Dermatol. 2013;24:404. doi: 10.1111/vde.12045
  41. Turchi B., Mancini S., Pistelli L., Najar B., Fratini F. Sub-inhibitory concentration of essential oils induces antibiotic resistance in Staphylococcus aureus. Nat. Prod. Res. 2019;33:1509–1513. doi: 10.1080/14786419.2017.1419237
  42. Kim H., Lee H., Lee J., Joo C., Choe T. The effects of antimicrobial properties of manuka oil and improvement of acne. J. Korean Soc. Cosmetol. 2011;17:245–256.
  43. Prosser J., Anderson C., Horswell J., Speir T. Can manuka (Leptospermum scoparium) antimicrobial properties be utilised in the remediation of pathogen contaminated land? Soil Biol. Biochem. 2014;75:167–174. doi: 10.1016/j.soilbio.2014.04.003
  44. Jeong E.Y., Jeon J.H., Kim H.W., Kim M.G., Lee H.S. Antimicrobial activity of leptospermone and its derivatives against human intestinal bacteria. Food Chem. 2009;115:1401–1404. doi: 10.1016/j.foodchem.2009.01.086
  45. Schmolz E., Doebner R., Auste R., Daum R., Welge G., Lamprecht I. Bioenergetic investigations on tea-tree and related essential oils. Thermochim. Acta. 1999;337:71–81. doi: 10.1016/S0040-6031(99)00231-2
  46. Prosser J., Woods R., Horswell J., Robinson B. The potential in-situ antimicrobial ability of Myrtaceae plant species on pathogens in soil. Soil Biol. Biochem. 2016;96:1–3. doi: 10.1016/j.soilbio.2015.12.007
  47. Lee Y.S., Kim J., Lee S.G., Oh E., Shin S.C., Park I.K. Effects of plant essential oils and components from Oriental sweetgum (Liquidambar orientalis) on growth and morphogenesis of three phytopathogenic fungi. Pestic. Biochem. Physiol. 2009;93:138–143. doi: 10.1016/j.pestbp.2009.02.002
  48. Elisa B., Aldo A., Ludovica G., Viviana P., Debora B., Massa N., Giorgia N., Elisa G. Chemical composition and antimycotic activity of six essential oils (cumin, fennel, manuka, sweet orange, cedar and juniper) against different Candida spp. Nat. Prod. Res. 2019;11:6. doi: 10.1080/14786419.2019.1696327
  49. Gonzalez-Audino P., Picollo M.I., Gallardo A., Toloza A., Vassena C., Cueto G.M. Comparative toxicity of oxygenated monoterpenoids in experimental hydroalcoholic lotions to permethrin-resistant adult head lice. Arch. Dermatol. Res. 2010;303:361–366. doi: 10.1007/s00403-010-1110-z
  50. George D.R., Sparagano O.A.E., Port G., Okello E., Shiel R.S., Guy J.H. Environmental interactions with the toxicity of plant essential oils to the poultry red miteDermanyssus gallinae. Med. Veter Entomol. 2010;24:1–8. doi: 10.1111/j.1365-2915.2009.00855.x
  51. George D.R., Sparagano O.A.E., Port G., Okello E., Shiel R.S., Guy J.H. Toxicity of plant essential oils to different life stages of the poultry red mite, Dermanyssus gallinae, and non-target invertebrates. Med. Veter Entomol. 2010;24:9–15. doi: 10.1111/j.1365-2915.2009.00856.x
  52. George D.R., Sparagano O.A.E., Port G., Okello E., Shiel R., Guy J. Repellence of plant essential oils to Dermanyssus gallinae and toxicity to the non-target invertebrate Tenebrio molitor. Veter Parasitol. 2009;162:129–134. doi: 10.1016/j.vetpar.2009.02.009
  53. Jeong E.Y., Kim M.G., Lee H.S. Acaricidal activity of triketone analogues derived fromLeptospermum scopariumoil against house-dust and stored-food mites. Pest Manag. Sci. 2009;65:327–331. doi: 10.1002/ps.1684
  54. Fang F., Candy K., Melloul E., Bernigaud C., Chai L., Darmon C., Durand R., Botterel F., Chosidow O., Izri A., et al. In vitro activity of ten essential oils against Sarcoptes scabiei. Parasites Vectors. 2016;9:1–7. doi: 10.1186/s13071-016-1889-3
  55. Park C.G., Jang M., Shin E., Kim J. Myrtaceae Plant Essential Oils and their β-Triketone Components as Insecticides against Drosophila suzukii. Molecules. 2017;22:1050. doi: 10.3390/molecules22071050
  56. Hanula J.L., Sullivan B.T., Wakarchuk D. Variation in Manuka Oil Lure Efficacy for CapturingXyleborus glabratus (Coleoptera: Curculionidae: Scolytinae), and Cubeb Oil as an Alternative Attractant. Environ. Entomol. 2013;42:333–340. doi: 10.1603/EN12337
  57. Kwon, O. S., Jung, S. H., & Yang, B. S. (2013). Topical Administration of Manuka Oil Prevents UV-B Irradiation-Induced Cutaneous Photoaging in Mice. Evidence-based complementary and alternative medicine : eCAM, 2013, 930857. https://doi.org/10.1155/2013/930857
  58. George D.R., Sparagano O.A.E., Port G., Okello E., Shiel R.S., Guy J.H. Environmental interactions with the toxicity of plant essential oils to the poultry red mite Dermanyssus gallinae. Med. Veter Entomol. 2010;24:1–8. doi: 10.1111/j.1365-2915.2009.00855.x
  59. Seyedalikhani S., Esperschuetz J., Dickinson N., Hofmann R., Breitmeyer J., Horswell J., Robinson B. Biowastes to augment the essential oil production of Leptospermum scoparium and Kunzea robusta in low-fertility soil. Plant Physiol. Biochem. 2019;137:213–221. doi: 10.1016/j.plaphy.2019.02.008
  60. Looker K.J., Garnett G.P. A systematic review of the epidemiology and interaction of herpes simplex virus types 1 and 2. Sex. Transm. Infect. 2005;81:103–107. doi: 10.1136/sti.2004.012039
  61. Astani A., Reichling J., Schnitzler P. Screening for Antiviral Activities of Isolated Compounds from Essential Oils. Evid. Based Complement. Altern. Med. 2011;2011:1–8. doi: 10.1093/ecam/nep187
  62. Schnitzler P. Essential Oils for the Treatment of Herpes Simplex Virus Infections. Chemotherapy. 2019;64:1–7. doi: 10.1159/000501062
  63. Lis-Balchin M., Hart S.L. An Investigation of the Actions of the Essential oils of Manuka (Leptospermum scoparium) and Kanuka (Kunzea ericoides), Myrtaceae on Guinea-pig Smooth Muscle. J. Pharm. Pharmacol. 1998;50:809–811. doi: 10.1111/j.2042-7158.1998.tb07144.x
  64. Lis-Balchin M. Essential oils and ’aromatherapy’: Their modern role in healing. J. R. Soc. Health. 1997;117:324–329. doi: 10.1177/146642409711700511
  65. Park M.-I., Lee B.-J., Lee S.W., Tag H., Soonkyu J. Vitamin C Derivative and Manuka Oil Surface Treated Composite Powder for Skin-Whitening and Wrinkle-Care. Patent KR101639615B1. 2016 Jul 15
  66. Maddocks-Jennings W., Wilkinson J., Shillington D.P., Cavanagh H. A fresh look at manuka and kanuka essential oils from New Zealand. Int. J. Aromather. 2005;15:141–146. doi: 10.1016/j.ijat.2005.07.003
  67. Kim HS, Lee HY, Lee JN, Joo CG, Choe TB. The effects of antimicrobial properties of manuka oil and improvement of acne. Journal of the Korean Society of Cosmetology. 2011;17(2):245–256.
  68. Schnitzler P., Wiesenhofer K., Reichling J. Comparative study on the cytotoxicity of different Myrtaceae essential oils on cultured vero and RC-37 cells. Die Pharm. 2008;63:830–835.
  69. Campo Research PTE Ltd. Manuka Oil Extract Leptospermum Scoparium. Campo Research PTE Ltd.; Singapore: 2015.
  70. Yoo J.-G., Han M., Hong N. External Preparation for Antibacterial, Anti-Inflammatory and Skin Protection Containing Manuka Oil as a Main Ingredient. Patent KR19990016741A. 2003 May 12
Health Jade