Medicinal and Aromatic Plants—Industrial Profiles


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IOLOGICAL ACTIVITY
181
very effective in enhancing the penetration of other compounds through the skin (Williams
and Barry 1991), and thus its restriction to very low levels may reduce the clinical
effectiveness of the oil.
Effect of Aging
p-Cymene, limited by the ISO standard to a maximum of 12% of the oil composition,
generally represents less than 5% of freshly distilled tea tree oil, but has been reported to
increase in oils as they age, due to oxidation of hydrocarbon components, mainly 
α- and γ-
terpinenes. The rate and extent of these oxidation reactions varies among oils, but appears
to relate more to the surface area of the oil exposed to the air, than to storage temperature or
colour of glass of the storage bottle (Southwell 1993). Table 5 shows the change with aging
of the levels of six of the major components of a tea tree oil sample in our laboratory.
Oxidation of 
α- and γ-terpinenes has occurred and p-cymene content has increased from
2.78% to 15.06%, with no significant changes in the concentration of terpinen-4-ol or 1,8-
cineole. Associated with these changes was a decrease in MIC values; that is, the oil became
more active with aging, an effect also reported by Lassak and McCarthy (1983) in some
oils.
Williams and Lusunzi (1994) have reported oils from Melaleuca dissitiflora with terpinen-
4-ol concentrations above 40% and p-cymene at concentrations up to 16% and their data
indicates that such oils possess greater antimicrobial activity than standard tea tree oil.
When these authors tested individual components by the disc diffusion method, both terpinen-
4-ol and p-cymene showed significant activity, with p-cymene giving larger zones than
terpinen-4-ol against some of the test organisms. The authors concluded that p-cymene was
correlated with the high level of antimicrobial activity. Penfold and Grant (1925) reported a
Rideal-Walker coefficient of 8 for a fraction containing p-cymene, and stated that it acted as
a synergist when added to other terpenes.
These results suggest that an increase in p-cymene in aged tea tree oil might explain the
observed increase in bioactivity. However, addition of p-cymene to standard tea tree oil to
give final concentrations up to 15% did not reduce MIC values (Mann and Markham 1997).
In addition, when tested individuallyp-cymene showed no significant activity in either disc
Table 5 Composition changes in aged tea tree
oil measured by gas chromotagraphy
Copyright © 1999 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint,
part of The Gordon and Breach Publishing Group.

JULIE L.MARKHAM
182
or MIC assays, a result supported by the work of Carson and Riley (1995). Other reports
have indicated that 
α- and γ-terpinene possess comparable or greater activity than p-cymene
(Deans and Svoboda 1989; Carson and Riley 1995). These results contradict the idea that
the increase in p-cymene alone is responsible for the increased activity and further work is
required to establish the correlation between changes in chemical composition as a result of
aging and changes in antimicrobial activity.
TESTING OF EFFICACY IN CLINICAL TRIALS
The toxicity of tea tree oil precludes its use internally, but the broad spectrum antimicrobial
activity of tea tree oil suggests a variety of external applications, and records of clinical
use date from 1930. The oil is claimed to have antiinflammatory and mild anaesthetic
properties, and a recent study has reported that terpinen-4-ol and 
α-terpinene, two of the
components of tea tree oil, exhibited a topical antiinflammatory effect in rats (Pongprayoon
et al. 1997). This long history of use suggests the efficacy and safety of the oil as an
antiseptic and the laboratory data outlined in the previous sections of this review supports
its antimicrobial properties. However, as highlighted by Cowen (1974), there are many
factors which affect antimicrobial efficacy and, unless these are very well understood for
each organism, optimum formulation determined by laboratory tests does not always
correlate with optimal effectiveness in vivo. In addition, interactions, which may be either
synergistic or antagonistic, can occur between components and thus it is not sufficient to
assume that a product will be effective simply because it contains an ingredient known to
be active. This section reviews the published reports of clinical testing of tea tree oil and
of products containing tea tree oil; reports are grouped according to the type of infection
under investigation.
Bacterial Infections of the Skin
A number of infections of the hair follicles and sebaceous glands, such as pimples, acne
vulgaris and furunculosis (boils and abcesses) are caused by bacteria, including S. aureus,
Streptococcus spp. and Propionibacterium acnes. These organisms are sensitive to tea tree
oil in laboratory tests (see previous sections) and there have been a number of studies carried
out to determine their efficacy in clinical situations.
Feinblatt (1960) discusses the unique property of oils containing terpene derivatives of
benzene of penetrating to the subcutaneous layers by mixing with sebaceous secretions and
reports the use of such an oil in the treatment of 25 cases of furunculosis (boils). Undiluted
‘cajeput-type’ oil from Melaleuca alternifolia was used to paint the infected area two to
three times daily, and patients were examined on alternate days. The study included ten
untreated controls: five of the controls had similar symptoms at the end of the eight-day
study, while the boils of five worsened and were finally incised. Only one of the twenty-five
patients treated with the Melaleuca oil required incision, and in 15 cases the boil site had
completely cleared in eight days. A reduction in symptoms was recorded for the remaining
nine participants. Three patients reported slight temporary stinging following application
of the oil, but no toxic effects were reported.
Copyright © 1999 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint,
part of The Gordon and Breach Publishing Group.

IOLOGICAL ACTIVITY 183
Whilst this study provides evidence of the efficacy of tea tree oil in the treatment of
furunculosis, the author does not specify the chemical composition of the oil used and it is
possible that the oil was a high cineole (eucalyptol) variety. This highlights the importance
of specifying the chemical composition of oils used in all studies if comparisons are to be
drawn between them, or if the work is to support applications for registration of oils or
products containing them.
Bélaiche (1985b) reports the efficacy of the oil in the treatment of two cases of impetigo
(one caused by Staphylococcus and the other by Streptococcus) and three cases of acne
caused by Staphylococcus spp. Improvement was reported in all cases, but the lack of
untreated controls and the small numbers limit the conclusions which can be drawn. In
addition, the test oil does not meet the specification of the current ISO standard because of
the high concentration of p-cymene (16.4%).
A more rigorous study was carried out by Bassett et al. (1990) to examine the efficacy of
a tea tree oil preparation in the treatment of acne vulgaris, a multifactorial disorder, common
especially among teenagers. The bacterium, Propionibacterium acnes, which has been
implicated as one of the causative factors, is sensitive to tea tree oil in in vitro tests (
Table 2
).
Bassett et al. (1990) report MIC values of 0.75% or less for 90% of strains tested, while
Carson and Riley (1994) report lower values. As a result, the oil has been incorporated in a
number of commercially available facewash and pimple gel preparations, generally at
concentrations in the range of 0.5–4.0% (w/w or w/v).
Bassett et al. (1990) report the results of a single-blind, randomised clinical trial on 124
patients with mild to moderate acne. The efficacy of a 5% tea-tree oil gel was compared to
a 5% benzoyl peroxide lotion in terms of its ability to reduce the number of inflamed and
non-inflamed lesions over the three-month treatment period. Oiliness, erythema, scaling,
pruritis and dryness were also assessed as a measure of skin tolerance.
The results showed that the number of both inflamed and non-inflamed lesions was
significantly reduced in both groups, with benzoyl peroxide having a more rapid onset of
action. Benzoyl peroxide was significantly more effective than tea-tree oil in reducing
inflamed lesions (P<0.001 at three months); however, there was, no significant difference
between the two protocols in the reduction of non-inflamed lesions. Of the two preparations,
tea tree oil was better tolerated than benzoyl peroxide, with fewer reports of side-effects
such as skin scaling, pruritis and dryness.
The above study has been criticised because of the lack of a control or placebo group to
which the test groups can be compared, and further trials, including a placebo group are
needed to confirm the findings of the study. The study was considered single-blind by the
authors, because, although neither group was informed of the preparation being used, it was
reported that it was not possible to disguise the characteristic smell of tea tree oil. This will
remain an issue in all future clinical trials of products containing tea tree oil as the active
ingredient.
Tea Tree Oil in the Treatment of Fungal Infections of the Skin and Nails
Fungal infections of the skin and nails tend to be persistent, irritating infections with a high
rate of recurrence. Treatment may be oral or topical and is frequently required for many
months, as penetration of the drugs to the site of the infection is poor. Side-effects are
Copyright © 1999 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint,
part of The Gordon and Breach Publishing Group.

JULIE L.MARKHAM
184
relatively common, particularly with drugs administered orally. Hence alternative treatments
are desirable.
Infections include tinea pedis (also known as athlete’s foot), tinea (or pityriasis) versicolor,
paronychia (infection of the tissue surrounding the nails) and onychomycosis (infection of
the nail). The causative organisms vary from case to case and site to site, but the most
common causative organisms are the dermatophytes Trichophyton rubrum, Trichophyton
mentagrophytes, Epidermophyton floccosum and Microsporum canis and the yeast, Candida
albicans.
Walker (1972) has reported the effectiveness of tea tree oil in sixty patients over a six-
year period. Undiluted oil, a 40% solution of tea tree oil with 13% isopropyl alcohol and an
ointment containing 8% oil were used to treat a variety of foot ailments. Treatment was
applied for periods ranging from one week to up to two-and-a-half years, and a clearing of
both infection and symptoms is reported in 63.7% of cases and improvement in symptoms
in a further 33.3% of patients. The symptoms which were reported to have been reduced
included bromidrosis (foul-smelling secretions), inflammation associated with corns,
calluses, bunions and hammertoes, scaling of nails in onychomycosis and symptoms and
degree of recurrence of tinea pedis.
Bélaiche (1985b) also reports the effectiveness of tea tree oil in resolving infection of
toe-nails in eight cases, with improvement of symptoms in six of these cases. However,
both these reports should be considered anecdotal as they are studies of individual cases
and do not include controls or comparisons to other treatments.
Double-blind, randomised clinical trials have been carried out by Buck et al. (1994) and
Tong  et al. (1992). The former study compares the effectiveness of twice daily topical
application of undiluted tea tree oil to that of 1% clotrimazole in the treatment of
onychomycosis. Outcomes were measured at one, three and six months by culture, clinical
assessment and the patient’s subjective assessment. There were no significant differences
between the two treatments by any of the above criteria. A full or partial recovery was
achieved in approximately 60% of patients in both groups, with less than 20% in either
group becoming culture negative at the end of the test period. This study is limited by the
lack of inclusion of an untreated control group, but the authors do compare their results to
those of studies of other antifungal agents. Cure rates compare favourably with agents such
as ciclopiroxolamine, but the two agents tested were both less effective than others including
naftitine hydrochloride gel and amorolfine.
The effectiveness of tea tree oil as an antiinflammatory agent is also supported by the
work of Tong et al. (1992). These authors compare the effectiveness of a sorbolene cream
containing 10% tea tree oil to a commercially available tolnafate 1% cream over a four
week test period. The study included a control group who were treated with sorbolene
cream only. At the end of the study, all three groups had reduced symptoms, but the tea
tree and tolnafate groups were significantly better than the placebo group. However, only
30% of the tea tree group had negative culture compared to 21% of the placebo group and
85% of the tolnafate group. It is possible that changes to the tea tree formulation might
result in enhanced mycocidal activity, but there is no published data on the kill rate of tea
tree oil on the fungi responsible for these infections. This is an area which requires further
study.
Copyright © 1999 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint,
part of The Gordon and Breach Publishing Group.

IOLOGICAL ACTIVITY
185
Infections of the Genitourinary System
Although Humphrey (1930) suggested the suitability of tea tree oil for treatment of vaginal
infections, the first report in the literature of its effectiveness in treating such infections is
that of Pena (1962). He reported clinical cure following treatment of 130 cases of vaginal
infections, due mostly to Trichomonas (116 cases) and Candida albicans (4 cases). The
treatment regime involved douching with a 0.4% solution of Melaleuca alternifolia oil and
insertion of tampons saturated with a 20–40% solution of the oil. This treatment was reported
to be as effective as use of standard antitrichomonal suppositories, and without side-effects
of irritation and burning.
Twenty-eight chronic cases of vaginal infection caused by Candida albicans were treated
by nightly insertion of a pessary containing 20mg of tea tree oil for a period of three months
(Belaiche 1985b). Infection and symptoms were alleviated in 21 cases, with an improvement
in symptoms, but persistence of the yeast, in a further three cases. The author also comments
that the preparation was well tolerated by all but one of the participants who withdrew from
the study early in the first week. Barnes (1990) also reports the alleviation of symptoms of
vaginal irritation and burning in a number of women following treatment with a tea tree
cream and/or douche. The women in this report all had chronic conditions which had not
responded to conventional treatments. Once again, the evidence which suggests that tea tree
oil is useful both for its antimicrobial activity and its soothing and pain-relieving effects, is
anecdotal, and appropriately designed and controlled clinical trials are needed to establish
a sound basis for the marketing of therapeutically useful vaginal products.
AGRICULTURAL APPLICATIONS OF TEA TREE OIL
The role of essential oils within the plants producing them, is primarily one of defence of
the plant from attack by other organisms. It is possible that tea tree oil will find many
marketable applications in agriculture through exploitation and expansion of this natural
function. Essential oils would have the advantage over synthetic chemicals, such as those
currently used to control post-harvest pathogens, of being more acceptable both
environmentally and to the consumer. Potential applications include control agents of plant
pathogens, insect repellants and antifeedants and insecticides. Terpinen-4-ol, the major
ingredient of tea tree oil, has been shown to be very active as a repellant of the yellow-fever
mosquito, Aedes aegyptii (Hwang et al. 1985). Bishop and Thornton (1997) demonstrated
the ability of tea tree oil to inhibit hyphal growth of fifteen common fungal post-harvest
pathogens. Whilst direct contact was more effective, the oil also demonstrated significant
antifungal activity in the vapour phase, a characteristic which suggests the possibility of its
use as a fumigant for stored crops.
There are very few reports of field trials testing the efficacy of tea tree oil in the control
of fungal or viral pathogens of economically important crops. A 1% aqueous solution of tea
tree oil was reported to control powdery mildew of greenhouse-grown cucurbits caused by
the fungus Sphaerotheca fuliginea (Olsen et al. 1988). In another study, it was reported that
Nicotiana glutinosa plants sprayed with 100, 250 and 500 ppm of tea tree oil in distilled
water prior to inoculation with the Tobacco Mosaic Virus showed significantly fewer lesions
than control plants for 10 days following inoculation (Bishop 1995). Neither of these studies
Copyright © 1999 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint,
part of The Gordon and Breach Publishing Group.

JULIE L.MARKHAM
186
distinguish between microbial inactivation and inhibition of infection through changes to
the host plant, and, hence, conclusions cannot be drawn about the mechanism of action.
However, these studies indicate the potential of tea tree oil in the treatment of a variety of
plant diseases.
OTHER APPLICATIONS OF TEA TREE OIL
The range of possibilities for products containing tea tree oil as an active ingredient is vast.
The uses reported in the literature are as diverse as its use as an additive in an aerosol system
used for cleansing of air conditioning systems (Ryan 1990), its potential for addition to
laundry detergents as an acaricidal agent to destroy mites in bedding and clothing (McDonald
and Tovey 1993) and its use in burn preparations for its properties of soothing the damaged
tissue, rapid healing, prevention of infection and pain relief (Price 1989).
The literature indicates an interest in the role of plant volatile oils as antioxidants (Deans
and Waterman 1993). Essential oils have been shown to act as hepatoprotective agents in
aging mammals and to have a positive effect upon docohexanoic acid levels in aging rodent
retinas. In a recent study, essential oils of geranium, monarda, nutmeg, oregano and thyme,
which contain a number of monoterpenes also present in tea tree oil, demonstrated extensive
antioxidant capacities at final concentrations of 0.75 ppm to 100ppm (Dorman et al. 1995).
Once the active ingredients in the oils have been elucidated, the potential of tea tree oil as an
antioxidant can be assessed.
CONCLUSION
Tea tree oil has a well-established reputation, supported by laboratory data, as an effective,
well-tolerated, broad spectrum antimicrobial which possesses a number of advantages over
its synthetic counterparts. Results of a limited number of clinical trials have been promising,
but further clinical testing, both of standard oils of known chemical composition and of
formulated products, is required to enable tea tree oil to broaden its acceptance in the
marketplace. Although its antimicrobial activity is well established, little is understood about
the way in which it acts on microbial cells. A more rational approach to breeding programs
and to the incorporation of tea tree oil in formulated products will be possible once the
mode of action of tea tree oil against a range of microbial cell types is elucidated.
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part of The Gordon and Breach Publishing Group.

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