CLINICAL MICROBIOLOGY REVIEWS, Jan. 2006, p. 50–62
0893-8512/06/$08.00ϩ0 doi:10.1128/CMR.19.1.50–62.2006Copyright 2006, American Society for Microbiology. All Rights Reserved. Melaleuca alternifolia (Tea Tree) Oil: a Review of Antimicrobial
C. F. Carson,1 K. A. Hammer,1 and T. V. Riley1,2*
Discipline of Microbiology, School of Biomedical and Chemical Sciences, The University of Western Australia, 35 Stirling Hwy,Crawley, Western Australia 6009,1 and Division of Microbiology and Infectious Diseases, Western Australian Centre forPathology and Medical Research, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009,2 AustraliaINTRODUCTION .50 COMPOSITION AND CHEMISTRY .50 PROVENANCE AND NOMENCLATURE .51 COMMERCIAL PRODUCTION .52 Oil Extraction.52 ANTIMICROBIAL ACTIVITY IN VITRO .52 Antibacterial Activity.52 Mechanism of antibacterial action.53 Antifungal Activity .54 Mechanism of antifungal action .54 Antiviral Activity .55 Antiprotozoal Activity.55 Antimicrobial Components of TTO.55 Resistance to TTO .55 CLINICAL EFFICACY.56 ANTI-INFLAMMATORY ACTIVITY.58 SAFETY AND TOXICITY .59 Oral Toxicity.59 Dermal Toxicity.59 PRODUCT FORMULATION ISSUES .59 CONCLUSIONS .59 ACKNOWLEDGMENTS .60 REFERENCES .60 INTRODUCTION
and 48 (142) components. The seminal paper by Brophy andcolleagues (25) examined over 800 TTO samples by gas chro-
Many complementary and alternative medicines have en-
matography and gas chromatography-mass spectrometry and
joyed increased popularity in recent decades. Efforts to vali-
reported approximately 100 components and their ranges of
date their use have seen their putative therapeutic properties
come under increasing scrutiny in vitro and, in some cases, in
TTO has a relative density of 0.885 to 0.906 (89), is only
vivo. One such product is tea tree oil (TTO), the volatile essential
sparingly soluble in water, and is miscible with nonpolar sol-
oil derived mainly from the Australian native plant Melaleuca
vents. Some of the chemical and physical properties of TTO
alternifolia. Employed largely for its antimicrobial properties,
TTO is incorporated as the active ingredient in many topical
Given the scope for batch-to-batch variation, it is fortunate
formulations used to treat cutaneous infections. It is widely avail-
that the composition of oil sold as TTO is regulated by an
able over the counter in Australia, Europe, and North America
international standard for “Oil of Melaleuca—terpinen-4-ol
and is marketed as a remedy for various ailments.
type,” which sets maxima and/or minima for 14 components ofthe oil (89) (Table 1). Notably, the standard does not stipulate
COMPOSITION AND CHEMISTRY
the species of Melaleuca from which the TTO must be sourced.
TTO is composed of terpene hydrocarbons, mainly mono-
Instead, it sets out physical and chemical criteria for the de-
terpenes, sesquiterpenes, and their associated alcohols. Ter-
sired chemotype. Six varieties, or chemotypes, of M. alternifolia
penes are volatile, aromatic hydrocarbons and may be consid-
have been described, each producing oil with a distinct chem-
ered polymers of isoprene, which has the formula C H . Early
ical composition. These include a terpinen-4-ol chemotype, a
reports on the composition of TTO described 12 (65), 21 (3),
terpinolene chemotype, and four 1,8-cineole chemotypes (83). The terpinen-4-ol chemotype typically contains levels of terpi-nen-4-ol of between 30 to 40% (83) and is the chemotype used
* Corresponding author. Mailing address: Microbiology and Immu-
in commercial TTO production. Despite the inherent variabil-
nology (M502), School of Biomedical and Chemical Sciences, The
ity of commercial TTO, no obvious differences in its bioactivity
University of Western Australia, 35 Stirling Hwy, Crawley, Western
either in vitro or in vivo have been noted so far. The suggestion
Australia 6009, Australia. Phone: 61 8 9346 3690. Fax: 61 8 9346 2912. E-mail: email@example.com.
that oil from a particular M. alternifolia clone possesses en-
ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL
TABLE 1. Composition of M. alternifolia (tea tree) oil
and mucous membrane irritant, fuelling efforts to minimize itslevel in TTO. This reputation was based on historical anec-
dotal evidence and uncorroborated statements (20, 55, 98, 126,
153, 156–158), and repetition of this suggestion appears to
have consolidated the myth. Recent data, as discussed later in
this review, do not indicate that 1,8-cineole is an irritant. Al-
though minimization of 1,8-cineole content on the basis of
reducing adverse reactions is not warranted, it remains an
important consideration since 1,8-cineole levels are usually
inversely proportional to the levels of terpinen-4-ol (25), one of
the main antimicrobial components of TTO (36, 48, 71, 126).
The composition of TTO may change considerably during stor-
age, with -cymene levels increasing and ␣- and ␥-terpinene levels
declining (25). Light, heat, exposure to air, and moisture all affect
oil stability, and TTO should be stored in dark, cool, dry condi-
tions, preferably in a vessel that contains little air. a IOS 4730, International Organization for Standardization standard no. 4730
PROVENANCE AND NOMENCLATURE c No upper limit is set, although 48% has been proposed. d No lower limit is set.
The provenance of TTO is not always clear from its common
name or those of its sources. It is known by a number of
synonyms, including “melaleuca oil” and “ti tree oil,” the latter
hanced microbicidal activity has been made (106), but the
being a Maori and Samoan common name for plants in the
genus Cordyline (155). Even the term “melaleuca oil” is poten-
The components specified by the international standard were
tially ambiguous, since several chemically distinct oils are dis-
selected for a variety of reasons, including provenance verifi-
tilled from other Melaleuca species, such as cajuput oil (also
cation and biological activity. For example, with provenance,
cajeput or cajaput) from M. cajuputi and niaouli oil from M.
the inclusion of the minor components sabinene, globulol, and
quinquenervia (often misidentified as M. viridiflora) (51, 98).
viridiflorol is potentially helpful, since it may render the for-
However, the term has been adopted by the Australian Ther-
mulation of artificial oil from individual components difficult
apeutic Goods Administration as the official name for TTO.
or economically untenable. With biological activity, the anti-
The use of common plant names further confounds the issue.
microbial activity of TTO is attributed mainly to terpinen-4-ol,
In Australia, “tea trees” are also known as “paperbark trees,”
a major component of the oil. Consequently, to optimize an-
and collectively these terms may refer to species in the Melaleuca
timicrobial activity, a lower limit of 30% and no upper limit
or Leptospermum genera, of which there are several hundred. For
were set for terpinen-4-ol content. Conversely, an upper limit
instance, common names for M. cajuputi include “swamp tea
of 15% and no lower limit were set for 1,8-cineole, although
tree” and “paperbark tea tree,” while those for M. quinquenervia
the rationale for this may not have been entirely sound. For
include “broad-leaved tea tree” and “broad-leaved paperbark”
many years cineole was erroneously considered to be a skin
(98). Many Leptospermum species are cultivated as ornamentalplants and are often mistakenly identified as the source of TTO. In addition, the essential oils kanuka and manuka, derived fromthe New Zealand plants Kunzea ericoides and Leptospermum sco-parium, respectively, are referred to as New Zealand TTOs (42)
although they are very different in composition from Australian
TTO (125). In this review article, the term TTO will refer only to
As explained above, the international standard for TTO
does not specify which Melaleuca species must be used to
produce oil. Rather it sets out the requirements for an oil
chemotype. Oils that meet the requirements of the standard
have been distilled from Melaleuca species other than M. al-ternifolia, including M. dissitiflora, M. linariifolia, and M. unci-nata (113). However, in practice, commercial TTO is produced
from M. alternifolia (Maiden and Betche) Cheel. The
Melaleuca genus belongs to the Myrtaceae family and contains
approximately 230 species, almost all of which are native to
Australia (51). When left to grow naturally, M. alternifolia
grows to a tree reaching heights of approximately 5 to 8 meters
(45). Trees older than 3 years typically flower in October and
b Kow, octanol-water partition coefficient, from reference 62.
November (12, 98), and flowers are produced in loose, white to
creamy colored terminal spikes, which can give trees a “fluffy”
were inhaled to treat coughs and colds or were sprinkled on
wounds, after which a poultice was applied (135). In addition,tea tree leaves were soaked to make an infusion to treat sorethroats or skin ailments (101, 135). The oral history of Austra-
lian Aborigines also tells of healing lakes, which were lagoons
The commercial TTO industry was born after the medicinal
into which M. alternifolia leaves had fallen and decayed over
properties of the oil were first reported by Penfold in the 1920s
time (3). Use of the oil itself, as opposed to the unextracted
(121–124) as part of a larger survey into Australian essential
plant material, did not become common practice until Penfold
oils with economic potential. During that nascent stage, TTO
published the first reports of its antimicrobial activity in a
was produced from natural bush stands of plants, ostensibly M.
series of papers in the 1920s and 1930s. In evaluating the
alternifolia, that produced oil with the appropriate chemotype.
antimicrobial activity of M. alternifolia oil and other oils, he
The native habitat of M. alternifolia is low-lying, swampy, sub-
made comparisons with the disinfectant carbolic acid or phe-
tropical, coastal ground around the Clarence and Richmond
nol, the gold standard of the day, in a test known as the
Rivers in northeastern New South Wales and southern
Rideal-Walker (RW) coefficient. The activity of TTO was com-
Queensland (142), and, unlike several other Melaleuca species,
pared directly with that of phenol and rated as 11 times more
it does not occur naturally outside Australia. The plant mate-
active (121). The RW coefficients of several TTO components
rial was hand cut and often distilled on the spot in makeshift,
were also reported, including 3.5 for cineole and 8 for cymene
mobile, wood-fired bush stills. The industry continued in this
(122), 13 for linalool (123), and 13.5 for terpinen-4-ol and 16
fashion for several decades. Legend has it that the oil was
for terpineol (121). As a result, TTO was promoted as a ther-
considered so important for its medicinal uses that Australian
apeutic agent (5–7). These publications, as well as several
soldiers were supplied oil as part of their military kits during
others (60, 70, 84, 102, 120, 124, 152), describe a range of
World War II and that bush cutters were exempt from national
medicinal uses for TTO. However, in terms of the evidence
service (35). However, no evidence to corroborate these ac-
they provide for the medicinal properties of TTO, they are of
counts could be found (A.-M. Conde and M. Pollard [Austra-
limited value, since by the standards of today the data they
lian War Memorial, Canberra, Australia], personal communi-
provide would be considered mostly anecdotal.
cation). Production ebbed after World War II as demand for
In contrast, contemporary data clearly show that the broad-
the oil declined, presumably due to the development of effec-
spectrum activity of TTO includes antibacterial, antifungal,
tive antibiotics and the waning image of natural products. In-
antiviral, and antiprotozoal activities. Not all of the activity has
terest in the oil was rekindled in the 1970s as part of the
been characterized well in vitro, and in the few cases where
general renaissance of interest in natural products. Commer-
clinical work has been done, data are promising but thus far
cial plantations were established in the 1970s and 1980s, allow-
ing the industry to mechanize and produce large quantities of
Evaluation of the antimicrobial activity of TTO has been
a consistent product (25, 93). Today there are plantations in
impeded by its physical properties; TTO and its components
Western Australia, Queensland, and New South Wales, al-
are only sparingly soluble in water (Table 2), and this limits
though the majority are in New South Wales around the Lis-
their miscibility in test media. Different strategies have been
more region. Typically, plantations are established from seed-
used to counteract this problem, with the addition of surfac-
lings sowed and raised in greenhouses prior to being planted
tants to broth and agar test media being used most widely (11,
out in the field at high density. The time to first harvest varies
13, 15, 31, 32, 61). Dispersion of TTO in liquid media usually
from 1 to 3 years, depending on the climate and rate of plant
results in a turbid suspension that makes determination of end
growth. Harvesting is by a coppicing process in which the
points in susceptibility tests difficult. Occasionally dyes have
whole plant is cut off close to ground level and chipped into
been used as visual indicators of the MIC, with mixed success
smaller fragments prior to oil extraction. Oil Extraction Antibacterial Activity
TTO is produced by steam distillation of the leaves and
terminal branches of M. alternifolia. Once condensed, the clear
The few reports of the antibacterial activity of TTO appear-
to pale yellow oil is separated from the aqueous distillate. The
ing in the literature from the 1940s to the 1980s (11, 15, 100,
yield of oil is typically 1 to 2% of wet plant material weight.
153) have been reviewed elsewhere previously (35). From the
Alternative extraction methods such as the use of microwave
early 1990s onwards, many reports describing the antimicrobial
technology have been considered, but none has been utilized
activity of TTO appeared in the scientific literature. Although
there was still a degree of discrepancy between the methodsused in the different studies, the MICs reported were oftenrelatively similar. A broad range of bacteria have now been
ANTIMICROBIAL ACTIVITY IN VITRO
tested for their susceptibilities to TTO, and some of the pub-
Of all of the properties claimed for TTO, its antimicrobial
lished susceptibility data are summarized in Table 3. While
activity has received the most attention. The earliest reported
most bacteria are susceptible to TTO at concentrations of
use of the M. alternifolia plant that presumably exploited this
1.0% or less, MICs in excess of 2% have been reported for
property was the traditional use by the Bundjalung Aborigines
organisms such as commensal skin staphylococci and micro-
of northern New South Wales. Crushed leaves of “tea trees”
cocci, Enterococcus faecalis, and Pseudomonas aeruginosa (13,
ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL
TABLE 3. Susceptibility data for bacteria tested against
Mechanism of antibacterial action. The mechanism of action
of TTO against bacteria has now been partly elucidated. Prior to
the availability of data, assumptions about its mechanism of ac-
tion were made on the basis of its hydrocarbon structure and
attendant lipophilicity. Since hydrocarbons partition preferen-
tially into biological membranes and disrupt their vital functions
(138), TTO and its components were also presumed to behave in
this manner. This premise is further supported by data showing
that TTO permeabilizes model liposomal systems (49). In previ-
ous work with hydrocarbons not found in TTO (90, 146a) and
with terpenes found at low concentrations in TTO (4, 146), lysis
and the loss of membrane integrity and function manifested by
the leakage of ions and the inhibition of respiration were dem-
onstrated. Treatment of S. aureus with TTO resulted in the leak-
age of potassium ions (49, 69) and 260-nm-light-absorbing mate-
rials (34) and inhibited respiration (49). Treatment with TTO also
sensitized S. aureus cells to sodium chloride (34) and produced
morphological changes apparent under electron microscopy
(127). However, no significant lysis of whole cells was observed
spectrophotometrically (34) or by electron microscopy (127). Fur-
thermore, no cytoplasmic membrane damage could be detected
using the lactate dehydrogenase release assay (127), and only
modest uptake of propidium iodide was observed (50) after
In E. coli, detrimental effects on potassium homeostasis (47),
glucose-dependent respiration (47), morphology (67), and abil-
ity to exclude propidium iodide (50) have been observed. A
modest loss of 280-nm-light-absorbing material has also been
reported (50). In contrast to the absence of whole-cell lysis
seen in S. aureus treated with TTO, lysis occurs in E. coli
treated with TTO (67), and this effect is exacerbated by co-
treatment with EDTA (C. Carson, unpublished data). All ofthese effects confirm that TTO compromises the structural and
79). TTO is for the most part bactericidal in nature, although
functional integrity of bacterial membranes.
it may be bacteriostatic at lower concentrations.
The loss of viability, inhibition of glucose-dependent respi-
The activity of TTO against antibiotic-resistant bacteria has
ration, and induction of lysis seen after TTO treatment all
attracted considerable interest, with methicillin-resistant
occur to a greater degree with organisms in the exponential
Staphylococcus aureus (MRSA) receiving the most attention
rather than the stationary phase of growth (67; S. D. Cox, J. L.
thus far. Since the potential to use TTO against MRSA was
Markham, C. M. Mann, S. G. Wyllie, J. E. Gustafson, and J. R.
first hypothesized (153), several groups have evaluated the
Warmington, Abstr. 28th Int. Symp. Essential Oils, p. 201–213,
activity of TTO against MRSA, beginning with Carson et al.
1997). The increased vulnerability of actively growing cells was
(31), who examined 64 MRSA isolates from Australia and the
also apparent in the greater degree of morphological changes
United Kingdom, including 33 mupirocin-resistant isolates.
seen in these cells by electron microscopy (S. D. Cox et al.
The MICs and minimal bactericidal concentrations (MBCs)
Abstr. 28th Int. Symp. Essential Oils, p. 201–213). The differ-
for the Australian isolates were 0.25% and 0.5%, respectively,
ences in susceptibility of bacteria in different phases of growth
while those for the United Kingdom isolates were 0.312% and
suggest that targets other than the cell membrane may be
0.625%, respectively. Subsequent reports on the susceptibility of
MRSA to TTO have similarly not shown great differences com-
When the effects of terpinen-4-ol, ␣-terpineol, and 1,8-cin-
pared to antibiotic-sensitive organisms (39, 58, 68, 106, 115).
eole on S. aureus were examined, none was found to induce
For the most part, antibacterial activity has been determined
autolysis but all were found to cause the leakage of 260-nm-
using agar or broth dilution methods. However, activity has
light-absorbing material and to render cells susceptible to so-
also been demonstrated using time-kill assays (34, 48, 80, 106),
dium chloride (34). Interestingly, the greatest effects were seen
suspension tests (107), and “ex vivo”-excised human skin (108).
with 1,8-cineole, a component often considered to have mar-
In addition, vaporized TTO can inhibit bacteria, including
ginal antimicrobial activity. This raises the possibility that while
Mycobacterium avium ATCC 4676 (105), Escherichia coli, Hae-
cineole may not be one of the primary antimicrobial compo-
mophilus influenzae, Streptococcus pyogenes, and Streptococcus
nents, it may permeabilize bacterial membranes and facilitate
pneumoniae (85). There are anecdotal reports of aerosolized
the entry of other, more active components. Little work on the
TTO reducing hospital-acquired infections (L. Bowden, Abstr.
effects of TTO components on cell morphology has been re-
Infect. Control Nurses Assoc. Annu. Infect. Control Conf., p.
ported. Electron microscopy of terpinen-4-ol-treated S. aureus
cells (34) revealed lesions similar to those seen after TTO
TABLE 4. Susceptibility data for fungi tested against
test methods differ, MICs generally range between 0.03 and
0.5%, and fungicidal concentrations generally range from 0.12
to 2%. The notable exception is Aspergillus niger, with minimal
fungicidal concentrations (MFCs) of as high as 8% reported
for this organism (74). However, these assays were performed
with fungal conidia, which are known to be relatively impervi-
ous to chemical agents. Subsequent assays have shown that
germinated conidia are significantly more susceptible to TTO
than nongerminated conidia (74), suggesting that the intact
conidial wall confers considerable protection. TTO vapors
have also been demonstrated to inhibit fungal growth (86, 87)
Mechanism of antifungal action. Studies investigating the
mechanism(s) of antifungal action have focused almost exclu-
sively on C. albicans. Similar to results found for bacteria, TTO
also alters the permeability of C. albicans cells. The treatment
of C. albicans with 0.25% TTO resulted in the uptake of pro-
pidium iodide after 30 min (50), and after 6 h significant
staining with methylene blue and loss of 260-nm-light-absorb-
ing materials had occurred (72). TTO also alters the perme-
ability of Candida glabrata (72). Further research demonstrat-
ing that the membrane fluidity of C. albicans cells treated with
0.25% TTO is significantly increased confirms that the oil sub-
stantially alters the membrane properties of C. albicans (72).
TTO also inhibits respiration in C. albicans in a dose-depen-
dent manner (49). Respiration was inhibited by approximately
95% after treatment with 1.0% TTO and by approximately
40% after treatment with 0.25% TTO. The respiration rate of
Fusarium solani is inhibited by 50% at a concentration of
0.023% TTO (88). TTO also inhibits glucose-induced medium
acidification by C. albicans, C. glabrata, and Saccharomycescerevisiae (72). Medium acidification occurs largely by the ex-pulsion of protons by the plasma membrane ATPase, which is
treatment (127), including mesosome-like structures.
fuelled by ATP derived from the mitochondria. The inhibition
Mechanism of action studies analogous to those described
of this function suggests that the plasma and/or mitochondrial
above have not been conducted with P. aeruginosa. Instead,
membranes have been adversely affected. These results are
research has concentrated on how this organism is able to
consistent with a proposed mechanism of antifungal action
tolerate higher concentrations of TTO and/or components.
whereby TTO causes changes or damage to the functioning of
These studies have indicated that tolerance is associated with
fungal membranes. This proposed mechanism is further sup-
the outer membrane by showing that when P. aeruginosa cells
ported by work showing that the terpene eugenol inhibits mi-
are pretreated with the outer membrane permeabilizer poly-
tochondrial respiration and energy production (46).
myxin B nonapeptide or EDTA, cells become more susceptible
Additional studies have shown that when cells of C. albicans
to the bactericidal effects of TTO, terpinen-4-ol, or ␥-terpinene
are treated with diethylstilbestrol to inhibit the plasma mem-
brane ATPase, they then have a much greater susceptibility to
In summary, the loss of intracellular material, inability to
TTO than do control cells (72), suggesting that the plasma
maintain homeostasis, and inhibition of respiration after treat-
membrane ATPase has a role in protecting cells against the
ment with TTO and/or components are consistent with a
destabilizing or lethal effects of TTO.
mechanism of action involving the loss of membrane integrity
TTO inhibits the formation of germ tubes, or mycelial con-
version, in C. albicans (52, 78). Two studies have shown thatgerm tube formation was completely inhibited in the presenceof 0.25 and 0.125% TTO, and it was further observed that
treatment with 0.125% TTO resulted in a trend of blastospores
Comprehensive investigations of the susceptibility of fungi
changing from single or singly budding morphologies to mul-
to TTO have only recently been completed. Prior to this, data
tiply budding morphologies over the 4-h test period (78).
were somewhat piecemeal and fragmentary. Early data were
These cells were actively growing but were not forming germ
also largely limited to Candida albicans, which was a commonly
tubes, implying that morphogenesis is specifically inhibited,
chosen model test organism. Data now show that a range of
rather than all growth being inhibited. Interestingly, the inhi-
yeasts, dermatophytes, and other filamentous fungi are suscep-
bition of germ tube formation was shown to be reversible, since
tible to TTO (14, 42, 52, 61, 116, 128, 140) (Table 4). Although
cells were able to form germ tubes after the removal of the
ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL
TTO (78). However, there was a delay in germ tube formation,
indications from RW coefficients were that much of the activity
indicating that TTO causes a postantifungal effect.
could be attributed to terpinen-4-ol and ␣-terpineol (121). Data available today confirm that these two components con-tribute substantially to the oil’s antibacterial and antifungal
activities, with MICs and MBCs or MFCs that are generally the
The antiviral activity of TTO was first shown using tobacco
same as, or slightly lower than values obtained for TTO (36, 42,
mosaic virus and tobacco plants (18). In field trials with Nico-
48, 71, 117, 126). However, ␣-terpineol does not represent a
tiniana glutinosa, plants were sprayed with 100, 250, or 500 ppm
significant proportion of the oil. Additional components with
TTO or control solutions and were then experimentally in-
MICs similar to or lower than those of TTO include ␣-pinene,
fected with tobacco mosaic virus. After 10 days, there were
␤-pinene, and linalool (36, 71), but, similar to the case for
significantly fewer lesions per square centimeter of leaf in
␣-terpineol, these components are present in only relatively
plants treated with TTO than in controls (18). Next, Schnitzler
low amounts. Of the remaining components tested, it seems
et al. (132) examined the activity of TTO and eucalyptus oil
that most possess at least some degree of antimicrobial activity
against herpes simplex virus (HSV). The effects of TTO were
(36, 71, 126), and this is thought to correlate with the presence
investigated by incubating viruses with various concentrations
of functional groups, such as alcohols, and the solubility of
of TTO and then using these treated viruses to infect cell
the component in biological membranes (63, 138). While
monolayers. After 4 days, the numbers of plaques formed by
some TTO components may be considered less active, none
TTO-treated virus and untreated control virus were deter-
can be considered inactive. Furthermore, methodological is-
mined and compared. The concentration of TTO inhibiting
sues have been demonstrated to have a significant influence on
50% of plaque formation was 0.0009% for HSV type 1
(HSV-1) and 0.0008% for HSV-2, relative to controls. These
The possibility that components in TTO may have synergis-
studies also showed that at the higher concentration of 0.003%,
tic or antagonistic interactions has been explored in vitro (48),
TTO reduced HSV-1 titers by 98.2% and HSV-2 titers by
but no significant relationships were found. The possibility that
93.0%. In addition, by applying TTO at different stages in the
TTO may act synergistically with other essential oils, such as
virus replicative cycle, TTO was shown to have the greatest
lavender (38), and other essential oil components, such as
effect on free virus (prior to infection of cells), although when
␤-triketones from manuka oil (43, 44), has also been investi-
TTO was applied during the adsorption period, a slight reduc-
gated. Given the numerous components of TTO, the scope for
tion in plaque formation was also seen (132). Another study
such effects is enormous, and much more work is required to
evaluated the activities of 12 essential oils, including TTO, for
activity against HSV-1 in Vero cells (110). Again, TTO wasfound to exert most of its antiviral activity on free virus, with
1% oil inhibiting plaque formation completely and 0.1% TTO
Resistance to TTO
reducing plaque formation by approximately 10%. Pretreat-ment of the Vero cells prior to virus addition or posttreatment
The question of whether true resistance to TTO can be
with 0.1% TTO after viral absorption did not significantly alter
induced in vitro or may occur spontaneously in vivo has not
been examined systematically. Clinical resistance to TTO has
Some activity against bacteriophages has also been reported,
not been reported, despite the medicinal use of the oil in
with exposure to 50% TTO at 4°C for 24 h reducing the
Australia since the 1920s. There has been one short report of
number of SA and T7 plaques formed on lawns of S. aureus
induced in vitro resistance to TTO in S. aureus (114). Stepwise
and E. coli, respectively (41).
exposure of five MRSA isolates to increasing concentrations of
The results of these studies indicate that TTO may act
TTO yielded three isolates with TTO MICs of 1% and one
against enveloped and nonenveloped viruses, although the
isolate each with TTO MICs of 2% and 16%, respectively. All
range of viruses tested to date is very limited.
isolates showed initial MICs of 0.25%. There has also been onereport suggesting that E. coli strains harboring mutations in themultiple antibiotic resistance (mar) operon, so-called Mar mu-
tants, may exhibit decreased susceptibility to TTO (66). Minor
Two publications show that TTO has antiprotozoal activity.
changes in TTO and ␣-terpineol susceptibilities have also been
TTO caused a 50% reduction in growth (compared to con-
seen in S. aureus isolates with reduced susceptibility to house-
trols) of the protozoa Leishmania major and Trypanosoma
hold cleaners (53). However, in these last two studies the
brucei at concentrations of 403 mg/ml and 0.5 mg/ml, respec-
changes in susceptibility were marginal and do not represent
tively (109). Further investigation showed that terpinen-4-ol
strong evidence of resistance (53, 66). With regard to fungi, an
contributed significantly to this activity. In another study, TTO
attempt to induce resistance to TTO in two clinical isolates of
at 300 mg/ml killed all cells of Trichomonas vaginalis (151). Candida albicans was largely unsuccessful, with isolates failing
There is also anecdotal in vivo evidence that TTO may be
to grow in 2% (vol/vol) TTO after serial passage in increasing
effective in treating Trichomonas vaginalis infections (120).
Resistance to conventional antibiotics has not been demon-
strated to influence susceptibility to TTO, suggesting that
Antimicrobial Components of TTO
cross-resistance does not occur. For example, antimicrobial-
Considerable attention has been paid to which components
resistant isolates of S. aureus (31, 58), C. albicans and C. gla-
of TTO are responsible for the antimicrobial activity. Early
brata (148), P. aeruginosa (106), and Enterococcus faecium
(106, 115) have in vitro susceptibilities to TTO that are similar
some evidence preliminary suggesting that TTO reduces the
levels of several compounds associated with halitosis (144).
Overall, these studies provide little evidence to suggest that
Two studies have assessed the efficacy of TTO for the erad-
resistance to TTO will occur, either in vitro or in vivo, although
ication of MRSA carriage. The effectiveness of a 4% TTO
minimal data are available. It is likely that the multicomponent
nasal ointment and a 5% TTO body wash was compared to
nature of TTO may reduce the potential for resistance to occur
that of conventional treatment with mupirocin nasal ointment
spontaneously, since multiple simultaneous mutations may be
and Triclosan body wash in a small pilot study (28). Of the 15
required to overcome all of the antimicrobial actions of each of
patients receiving conventional treatment, 2 were cleared and
the components. Furthermore, since TTO is known to affect
8 remained colonized at the end of therapy; in the TTO group
cell membranes, it presumably affects multiple properties and
of 15, 5 were cleared and 3 remained colonized. The remainder
functions associated with the cell membrane, similar to the
of patients did not complete therapy. Differences in clearance
case for membrane-active biocides. This means that numerous
rates were not statistically significant, most likely due to the
targets would have to adapt to overcome the effects of the oil.
low patient numbers. Stronger evidence for the efficacy of TTO
Issues of potential resistance are important if TTO is to be
in decolonizing MRSA carriage comes from a recent trial in
used more widely, particularly against antibiotic-resistant or-
which 236 patients were randomized to receive standard or
TTO treatment regimens (56). The standard regimen consistedof 2% mupirocin nasal ointment applied three times a day, 4%chlorhexidine gluconate soap applied at least once a day, and
1% silver sulfadiazine cream applied to skin lesions, wounds,and leg ulcers once a day, all for 5 days. The TTO regimen
In parallel with the characterization of the in vitro antimi-
consisted of 10% TTO nasal cream applied three times a day,
crobial activity of TTO, the clinical efficacy of the oil has also
5% TTO body wash applied at least once daily and 10% TTO
been the subject of investigation. Early clinical studies attempt-
cream applied to skin lesions, wounds, and leg ulcers once a
ing to characterize the clinical efficacy of TTO (60, 120, 152)
day, all for 5 days. The 10% TTO cream was allowed to be used
are not considered scientifically valid by today’s standards and
as an alternative to the body wash. Follow-up swabs were taken
will therefore not be discussed further. Data from some of the
at 2 and 14 days posttreatment, with the exception of 12 pa-
more recent clinical investigations are summarized in Table 5.
tients who were lost to follow-up. Evaluation of the remaining
One of the first rigorous clinical studies assessed the efficacy
224 patients showed no significant differences between treat-
of 5% TTO in the treatment of acne by comparing it to 5%
ment regimens, with 49% of patients receiving standard ther-
benzoyl peroxide (BP) (14). The study found that both treat-
apy cleared versus 41% of patients in the TTO group.
ments reduced the numbers of inflamed lesions, although BP
For many years there has been considerable interest in the
performed significantly better than TTO. The BP group
possibility of using TTO in handwash formulations for use in
showed significantly less oiliness than the TTO group, whereas
hospital or health care settings. It is well known that hand-
the TTO group showed significantly less scaling, pruritis, and
washing is an effective infection control measure and that lack
dryness. Significantly fewer overall side effects were reported
of compliance is related to increased rates of nosocomial in-
by the TTO group (27 of 61 patients) than by the BP group (50
fections. The benefits of using TTO in a handwash formulation
include its antiseptic effects and increased handwashing com-
The efficacy of TTO in dental applications has been as-
pliance. A recent handwash study using volunteers showed that
sessed. An evaluation of the effect of a 0.2% TTO mouthwash
either a product containing 5% TTO and 10% alcohol or a
and two other active agents on the oral flora of 40 volunteers
solution of 5% TTO in water performed significantly better
suggested that TTO used once daily for 7 days could reduce the
than soft soap, whereas a handwash product containing 5%
number of mutans streptococci and the total number of oral
bacteria, compared to placebo treatment. The data also indi-
Occasional case reports of the use of TTO have also been
cated that these reductions were maintained for 2 weeks after
published. In one, a woman self-treated successfully with a
the use of mouthwash ceased (64). In another study, compar-
5-day course of TTO pessaries after having been clinically
ison of mouthwashes containing either approximately 0.34%
diagnosed with bacterial vaginosis (19). In a second, a combi-
TTO, 0.1% chlorhexidine, or placebo on plaque formation and
nation of plant extracts of which TTO was a major component
vitality, using eight volunteers (9), showed that after TTO
was inserted percutaneously into bone to treat an intractable
treatment, both plaque index and vitality did not differ from
MRSA infection of the lower tibia, which subsequently resolved
those of subjects receiving placebo mouthwash on any day,
(136). This same essential oil solution has now been shown to aid
whereas the results for the chlorhexidine mouthwash group
in the healing of malodorous malignant ulcers (154).
differed significantly from those for the placebo group on all
With regard to fungal infections, TTO has been clinically
days (9). Lastly, a study comparing a 2.5% TTO gel, a 0.2%
evaluated for the treatment of onychomycosis (26, 143), tinea
chlorhexidine gel, and a placebo gel found that although the
pedis (131, 145), dandruff (130), and oral candidiasis (92, 149).
TTO group had significantly reduced gingival index and pap-
Although much has been made of the potential for TTO to be
illary bleeding index scores, their plaque scores were actually
used in the treatment of vaginal candidiasis, no clinical data
increased (139). These studies indicate that although TTO may
have been published. However, results from an animal (rat)
cause decreases in the levels of oral bacteria, this does not
model of vaginal candidiasis support the use of TTO for the
necessarily equate to reduced plaque levels. However, TTO
may have a role in the treatment of gingivitis, and there is also
In the first of the onychomycosis trials (26), 60% of patients
ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL
treated with TTO and 61% of patients treated with 1% clo-
one had deteriorated. Of patients receiving the alcohol-free
trimazole had full or partial resolution. There were no statis-
solution, five were cured, two improved, two were unchanged,
tically significant differences between the two treatment groups
and one had deteriorated. Three patients were lost to fol-
for any parameter. The second onychomycosis trial (143) com-
low-up and were considered nonresponders.
pared two creams, one containing 5% TTO alone and the
Support for TTO possessing in vivo antiviral activity comes
other containing 5% TTO and 2% butenafine, both applied
from a pilot study investigating the treatment of recurrent
three times daily for 8 weeks. The overall cure rate was 0% for
herpes labialis (cold sores) with a 6% TTO gel or a placebo gel
patients treated with 5% TTO alone, compared to 80% for
(30). Comparison of the patient groups (each containing nine
patients treated with both butenafine and TTO. Unfortunately,
evaluable patients) at the end of the study showed that reepi-
butenafine alone was not evaluated. The observation that TTO
thelialization after treatment occurred after 9 days for the
may be useful adjunct therapy for onychomycosis has been
TTO group and after 12.5 days for the placebo group. Other
made by Klimmek et al. (95). However, onychomycosis is con-
measures, such as duration of virus positivity by culture or
sidered to be largely unresponsive to topical treatment of any
PCR, viral titers, and time to crust formation, were not signif-
kind, and a high rate of cure should therefore not be expected.
icantly different, possibly due to small patient numbers. Inter-
The effectiveness of TTO in treating tinea pedis has been
estingly, when TTO was evaluated for its protective efficacy in
evaluated in two trials. In the first trial, patients were treated
an in vivo mouse model of genital HSV type 2 infection, it did
with 10% TTO in sorbolene, 1% tolnaftate, or placebo (sor-
not perform well (21). In contrast, the oil component 1,8-cineole
bolene) (145). At completion of treatment, patients treated
performed well, protecting 7 of 16 animals from disease.
with TTO had mycological cure and clinical improvement rates
There are a number of limitations to the clinical studies
of 30% and 65%, respectively. This compares to mycological
described above. Several had low numbers of participants,
cure rates of 21% in patients receiving placebo and 85% in
meaning that statistical analyses could not be performed or
patients receiving tolnaftate. Similarly, clinical improvement
differences did not reach significance. Many studies had am-
was seen in 41% of patients receiving placebo and 68% of
biguous and/or equivocal outcomes. Of those studies with
patients receiving tolnaftate. In a second tinea trial, the efficacy
larger numbers of patients, few reported 95% confidence in-
of solutions of 25% and 50% TTO in ethanol and polyethylene
tervals or relative risk values. While most studies compared the
glycol was compared to treatment with placebo (vehicle) (131).
efficacy of TTO to a placebo, many did not compare TTO to a
Marked clinical responses were seen in 72% and 68% of pa-
conventional therapy or treatment regimen, again limiting the
tients in the 25% and 50% TTO treatment groups, respec-
conclusions that could be drawn about efficacy. Several publi-
tively, compared to 39% of patients in the placebo group.
cations noted that patient blinding was compromised or im-
Similarly, there were mycological cures of 55% and 64% in the
practicable due to the characteristic odor of TTO (14, 30, 130,
25% and 50% TTO treatment groups, respectively, compared
131). These studies, while perhaps conducted as double
to 31% in the placebo group. Dermatitis occurred in one pa-
blinded, are technically only single blinded, which is not ideal.
tient in the 25% TTO group and in three patients in the 50%
Perhaps most importantly, few studies have been replicated
TTO group. This led to the recommendation that 25% TTO be
independently. Therefore, although some of these data indi-
considered an alternative treatment for tinea, since it was as-
cate that TTO has potential as a therapeutic agent, confirma-
sociated with fewer adverse reactions than but was just as
tory studies are required. In addition, factors such as the final
effective as 50% TTO. These studies highlight the importance
TTO concentration, product formulation, and length and fre-
of considering the formulation of the TTO product when con-
quency of treatment undoubtedly influence clinical efficacy,
ducting in vivo work, since it is likely that the sorbolene vehicle
and these factors must be considered in future studies. The
used in the first tinea trial may have significantly compromised
cost-effectiveness of any potential TTO treatments must also be
considered. For example, TTO therapy may offer no cost advan-
The evaluation of a 5% TTO shampoo for mild to moderate
tage over the azoles in the treatment of tinea but is probably more
dandruff demonstrated statistically significant improvements in
economical than treatment with the allylamines.
the investigator-assessed whole scalp lesion score, total area ofinvolvement score, and total severity score, as well as in the
patient-assessed itchiness and greasiness scores, compared toplacebo. Overall, the 5% TTO was well tolerated and appeared
Numerous recent studies now support the anecdotal evi-
to be effective in the treatment of mild to moderate dandruff.
dence attributing anti-inflammatory activity to TTO. In vitro
TTO has been evaluated as a mouthwash in the treatment of
work over the last decade has demonstrated that TTO affects
oropharyngeal candidiasis. In a case series, 13 human immu-
a range of immune responses, both in vitro and in vivo. For
nodeficiency virus-positive patients who had already failed
example, the water-soluble components of TTO can inhibit the
treatment with a 14-day course of oral fluconazole were
lipopolysaccharide-induced production of the inflammatory
treated with an alcohol-based TTO solution for up to 28 days
mediators tumor necrosis factor alpha (TNF-␣), interleukin-1␤
(92). After treatment, of the 12 evaluable patients, 2 were
(IL-1␤), and IL-10 by human peripheral blood monocytes by
cured, 6 were improved, 4 were unchanged, and 1 had deteri-
approximately 50% and that of prostaglandin E by about 30%
orated. Overall, eight patients had a clinical response and
after 40 h (81). Further examination of the water-soluble frac-
seven had a mycological response. In subsequent work the
tion of TTO identified terpinen-4-ol, ␣-terpineol, and 1,8-cin-
same TTO solution was compared with an alcohol-free TTO
eole as the main components, but of these, only terpinen-4-ol
solution (149). Of patients receiving the alcohol-based solu-
was able to diminish the production of TNF-␣, IL-1␤, IL-8,
tion, two were cured, six improved, four were unchanged, and
IL-10, and prostaglandin E by lipopolysaccharide-activated
ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL
monocytes. The water-soluble fraction of TTO, terpinen-4-ol,
and ␣-terpineol also suppressed superoxide production byagonist-stimulated monocytes but not neutrophils (22). In con-
TTO can cause both irritant and allergic reactions. A mean
trast, similar work found that TTO decreases the production of
irritancy score of 0.25 has been found for neat TTO, based on
reactive oxygen species by both stimulated neutrophils and
patch testing results for 311 volunteers (10). Another study, in
monocytes and that it also stimulates the production of reac-
which 217 patients from a dermatology clinic were patch tested
tive oxygen species by nonprimed neutrophils and monocytes
with 10% TTO, found no irritant reactions (150). Since irritant
(29). TTO failed to suppress the adherence reaction of neu-
reactions may frequently be avoided through the use of lower
trophils induced by TNF-␣ stimulation (2) or the casein-in-
concentrations of the irritant, this bolsters the case for discour-
duced recruitment of neutrophils into the peritoneal cavities of
aging the use of neat oil and promoting the use of well-formu-
mice (1). These studies identify specific mechanisms by which
lated products. Allergic reactions have been reported (54, 147),
TTO may act in vivo to diminish the normal inflammatory
and although a range of components have been suggested as
response. In vivo, topically applied TTO has been shown to
responsible, the most definitive work indicates that they are
modulate the edema associated with the efferent phase of a
caused mainly by oxidation products that occur in aged or
contact hypersensitivity response in mice (23) but not the de-
improperly stored oil (82). There is little scientific support for
velopment of edema in the skin of nonsensitized mice or the
the notion that 1,8-cineole is the major irritant in TTO. No
edematous response to UVB exposure. This activity was attrib-
evidence of irritation was seen when patch testing was per-
uted primarily to terpinen-4-ol and ␣-terpineol. When the ef-
formed on rabbits with intact and abraded skin (118), guinea
fect of TTO on hypersensitivity reactions involving mast cell
pigs (82), and humans (118, 141), including those who had
degranulation was examined in mice, TTO and terpinen-4-ol
previous positive reactions to TTO (96). Rarely, topically ap-
applied after histamine injection reduced histamine-induced
plied tea tree oil has been reported to cause systemic effects in
skin edema, and TTO also significantly reduced swelling in-
domestic animals. Dermal application of approximately 120 ml
duced by intradermal injection of compound 48/80 (24). Hu-
of undiluted TTO to three cats with shaved but intact skin
man studies on histamine-induced wheal and flare provided
resulted in symptoms of hypothermia, uncoordination, dehy-
further evidence to support the in vitro and animal data, with
dration, and trembling and in the death of one of the cats (17).
the topical application of neat TTO significantly reducingmean wheal volume but not mean flare area (97). Erythema
PRODUCT FORMULATION ISSUES
and flare associated with nickel-induced contact hypersensitiv-ity in humans are also reduced by neat TTO but not by a 5%
The physical characteristics of TTO present certain difficul-
TTO product, product base, or macadamia oil (119). Work has
ties for the formulation and packaging of products. Its lipophi-
now shown that terpinen-4-ol, but not 1,8-cineole or ␣-terpineol,
licity leads to miscibility problems in water-based products,
modulates the vasodilation and plasma extravasation associ-
while its volatility means that packaging must provide an ade-
ated with histamine-induced inflammation in humans (94).
quate barrier to volatilization. Since TTO is readily absorbedinto plastics, packaging must cater to and minimize this effect. Consideration must also be given to the properties of the
SAFETY AND TOXICITY
finished product. Early suggestions that the antimicrobial ac-
Despite the progress in characterizing the antimicrobial and
tivity of TTO may be compromised by organic matter came
anti-inflammatory properties of tea tree oil, less work has been
from disk diffusion studies in which the addition of blood to
done on the safety and toxicity of the oil. The rationale for
agar medium decreased zone sizes (8). This observation con-
continued use of the oil rests largely on the apparently safe use
trasts sharply with historical claims that the activity of TTO
of the oil for almost 80 years. Anecdotal evidence over this
may in fact be enhanced in the presence of organic matter such
time suggests that topical use is safe and that adverse events
as blood and pus. A thorough investigation of this claim com-
are minor, self-limiting, and infrequent. More concrete evi-
prehensively refuted this idea (76) and also showed that prod-
dence such as published scientific work is scarce, and much
uct excipients may compromise activity.
information remains out of the public domain in the form of
Some work on the characteristics and behavior of TTO
reports from company-sponsored work. The oral and dermal
within formulations has been conducted. Caboi et al. (27)
toxicities of TTO are summarized briefly below.
examined the potential of a monoolein/water system as a car-rier for TTO and terpinen-4-ol. The activity of TTO productsin vitro has also been investigated (16, 77, 107). However, very
little work has been conducted in this area, and if stable,
TTO can be toxic if ingested, as evidenced by studies with
biologically active formulations of TTO are going to be devel-
animals and from cases of human poisoning. The 50% lethal
dose for TTO in a rat model is 1.9 to 2.6 ml/kg (129), and ratsdosed with Յ1.5 g/kg TTO appeared lethargic and ataxic (D. CONCLUSIONS
Kim, D. R. Cerven, S. Craig, and G. L. De George, Abstr. Amer. Chem. Soc. 223:114, 2002). Incidences of oral poisoning
A paradigm shift in the treatment of infectious diseases is
in children (55, 91, 112) and adults (57, 133) have been re-
necessary to prevent antibiotics becoming obsolete, and where
ported. In all cases, patients responded to supportive care and
appropriate, alternatives to antibiotics ought to be considered.
recovered without apparent sequelae. No human deaths due to
There are already several nonantibiotic approaches to the
TTO have been reported in the literature.
treatment and prevention of infection, including probiotics,
phages, and phytomedicines. Alternative therapies are viewed
22. Brand, C., A. Ferrante, R. H. Prager, T. V. Riley, C. F. Carson, J. J.
favorably by many patients because they are often not being
Finlay-Jones, and P. H. Hart. 2001. The water soluble-components of the essential oil of Melaleuca alternifolia (tea tree oil) suppress the production
helped by conventional therapy and they believe there are
of superoxide by human monocytes, but not neutrophils, activated in vitro.
fewer detrimental side effects. In addition, many report signif-
Inflamm. Res. 50:213–219.
23. Brand, C., M. A. Grimbaldeston, J. R. Gamble, J. Drew, J. J. Finlay-Jones,
icant improvement while taking complementary and alterna-
and P. H. Hart. 2002. Tea tree oil reduces the swelling associated with the
tive medicines. Unfortunately, the medical profession has been
efferent phase of a contact hypersensitivity response. Inflamm. Res. 51:236–
slow to embrace these therapies, and good scientific data are
24. Brand, C., S. L. Townley, J. J. Finlay-Jones, and P. H. Hart. 2002. Tea tree
still scarce. However, as we approach the “postantibiotic era”
oil reduces histamine-induced oedema in murine ears. Inflamm. Res. 51:
the situation is changing. A wealth of in vitro data now sup-
ports the long-held beliefs that TTO has antimicrobial and
25. Brophy, J. J., N. W. Davies, I. A. Southwell, I. A. Stiff, and L. R. Williams.
1989. Gas chromatographic quality control for oil of Melaleuca terpinen-
anti-inflammatory properties. Despite some progress, there is
4-ol type (Australian tea tree). J. Agric. Food Chem. 37:1330–1335.
still a lack of clinical evidence demonstrating efficacy against
26. Buck, D. S., D. M. Nidorf, and J. G. Addino. 1994. Comparison of two
bacterial, fungal, or viral infections. Large randomized clinical
topical preparations for the treatment of onychomycosis: Melaleuca alter- nifolia (tea tree) oil and clotrimazole. J. Fam. Pract. 38:601–605.
trials are now required to cement a place for TTO as a topical
27. Caboi, F., S. Murgia, M. Monduzzi, and P. Lazzari. 2002. NMR investiga-
tion on Melaleuca alternifolia essential oil dispersed in the monoolein aque- ous system: phase behavior and dynamics. Langmuir 18:7916–7922.
28. Caelli, M., J. Porteous, C. F. Carson, R. Heller, and T. V. Riley. 2000. Tea ACKNOWLEDGMENTS
tree oil as an alternative topical decolonization agent for methicillin-resis-
This review was supported in part by a grant (UWA-75A) from the
tant Staphylococcus aureus. J. Hosp. Infect. 46:236–237.
29. Caldefie-Che´zet, F., M. Guerry, J. C. Chalchat, C. Fusillier, M. P. Vasson,
Rural Industries Research and Development Corporation. and J. Guillot. 2004. Anti-inflammatory effects of Melaleuca alternifolia
We are grateful to Ian Southwell (Wollongbar Agricultural Institute,
essential oil on human polymorphonuclear neutrophils and monocytes.
NSW) for helpful discussions on oil provenance and to staff at the
Free Rad. Res. 38:805–811.
Australian War Memorial (Canberra, ACT) for sharing their knowl-
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Oral ketamine/midazolam is superior to intramuscular meperidine, promethazine, and chlorpromazine for pediatric cardiac catheterization. Authors:Auden SM, Sobczcyk WL, Solinger RE, Goldsmith, LJ Anesthesia & Analgesia . 90(2):299-305, 2000 Feb. Reviewer(s): Joseph P. Cravero, MD, Dartmouth-Hithcock Medical Center Abstract: An IM combination of meperidine, promethazine, and c