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Melaleuca alternifolia (Tea Tree) Oil: A Review of Antimicrobial and Other Medicinal Properties

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FULL TEXT available free from http://cmr.asm.org/content/19/1/50.full.pdf+html?sid=eccd451a-5b42-44f2-b9cc-fe6223ee045a Complementary and alternative medicines such as tea tree (melaleuca) oil have become increasingly popular in recent decades. This essential oil has been used for almost 100 years in Australia but is now available worldwide both as neat oil and as an active component in an array of products. The primary uses of tea tree oil have historically capitalized on the antiseptic and anti-inflammatory actions of the oil. This review summarizes recent developments in our understanding of the antimicrobial and anti-inflammatory activities of the oil and its components, as well as clinical efficacy. Specific mechanisms of antimicrobial and anti-inflammatory action are reviewed, and the toxicity of the oil is briefly discussed.
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10.1128/CMR.19.1.50-62.2006.
2006, 19(1):50. DOI:Clin. Microbiol. Rev.
C. F. Carson, K. A. Hammer and T. V. Riley
Medicinal Properties
Review of Antimicrobial and Other
(Tea Tree) Oil: aMelaleuca alternifolia
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CLINICAL MICROBIOLOGY REVIEWS, Jan. 2006, p. 50–62 Vol. 19, No. 1
0893-8512/06/$08.000 doi:10.1128/CMR.19.1.50–62.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Melaleuca alternifolia (Tea Tree) Oil: a Review of Antimicrobial
and Other Medicinal Properties
C. F. Carson,
1
K. A. Hammer,
1
and T. V. Riley
1,2
*
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 for
Pathology and Medical Research, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009,
2
Australia
INTRODUCTION.........................................................................................................................................................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
Many complementary and alternative medicines have en-
joyed increased popularity in recent decades. Efforts to vali-
date their use have seen their putative therapeutic properties
come under increasing scrutiny in vitro and, in some cases, in
vivo. One such product is tea tree oil (TTO), the volatile essential
oil derived mainly from the Australian native plant Melaleuca
alternifolia. Employed largely for its antimicrobial properties,
TTO is incorporated as the active ingredient in many topical
formulations used to treat cutaneous infections. It is widely avail-
able over the counter in Australia, Europe, and North America
and is marketed as a remedy for various ailments.
COMPOSITION AND CHEMISTRY
TTO is composed of terpene hydrocarbons, mainly mono-
terpenes, sesquiterpenes, and their associated alcohols. Ter-
penes are volatile, aromatic hydrocarbons and may be consid-
ered polymers of isoprene, which has the formula C
5
H
8
. Early
reports on the composition of TTO described 12 (65), 21 (3),
and 48 (142) components. The seminal paper by Brophy and
colleagues (25) examined over 800 TTO samples by gas chro-
matography and gas chromatography-mass spectrometry and
reported approximately 100 components and their ranges of
concentrations (Table 1).
TTO has a relative density of 0.885 to 0.906 (89), is only
sparingly soluble in water, and is miscible with nonpolar sol-
vents. Some of the chemical and physical properties of TTO
components are shown in Table 2.
Given the scope for batch-to-batch variation, it is fortunate
that the composition of oil sold as TTO is regulated by an
international standard for “Oil of Melaleuca—terpinen-4-ol
type,” which sets maxima and/or minima for 14 components of
the oil (89) (Table 1). Notably, the standard does not stipulate
the species of Melaleuca from which the TTO must be sourced.
Instead, it sets out physical and chemical criteria for the de-
sired chemotype. Six varieties, or chemotypes, of M. alternifolia
have been described, each producing oil with a distinct chem-
ical composition. These include a terpinen-4-ol chemotype, a
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
in commercial TTO production. Despite the inherent variabil-
ity of commercial TTO, no obvious differences in its bioactivity
either in vitro or in vivo have been noted so far. The suggestion
that oil from a particular M. alternifolia clone possesses en-
* Corresponding author. Mailing address: Microbiology and Immu-
nology (M502), School of Biomedical and Chemical Sciences, The
University of Western Australia, 35 Stirling Hwy, Crawley, Western
Australia 6009, Australia. Phone: 61 8 9346 3690. Fax: 61 8 9346 2912.
E-mail: triley@cyllene.uwa.edu.au.
50
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hanced microbicidal activity has been made (106), but the
evidence is not compelling.
The components specified by the international standard were
selected for a variety of reasons, including provenance verifi-
cation and biological activity. For example, with provenance,
the inclusion of the minor components sabinene, globulol, and
viridiflorol is potentially helpful, since it may render the for-
mulation of artificial oil from individual components difficult
or economically untenable. With biological activity, the anti-
microbial activity of TTO is attributed mainly to terpinen-4-ol,
a major component of the oil. Consequently, to optimize an-
timicrobial activity, a lower limit of 30% and no upper limit
were set for terpinen-4-ol content. Conversely, an upper limit
of 15% and no lower limit were set for 1,8-cineole, although
the rationale for this may not have been entirely sound. For
many years cineole was erroneously considered to be a skin
and mucous membrane irritant, fuelling efforts to minimize its
level 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.
PROVENANCE AND NOMENCLATURE
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
being a Maori and Samoan common name for plants in the
genus Cordyline (155). Even the term “melaleuca oil” is poten-
tially ambiguous, since several chemically distinct oils are dis-
tilled from other Melaleuca species, such as cajuput oil (also
cajeput or cajaput) from M. cajuputi and niaouli oil from M.
quinquenervia (often misidentified as M. viridiflora) (51, 98).
However, the term has been adopted by the Australian Ther-
apeutic Goods Administration as the official name for TTO.
The use of common plant names further confounds the issue.
In Australia, “tea trees” are also known as “paperbark trees,”
and collectively these terms may refer to species in the Melaleuca
or Leptospermum genera, of which there are several hundred. For
instance, common names for M. cajuputi include “swamp tea
tree” and “paperbark tea tree,” while those for M. quinquenervia
include “broad-leaved tea tree” and “broad-leaved paperbark”
(98). Many Leptospermum species are cultivated as ornamental
plants and are often mistakenly identified as the source of TTO.
In addition, the essential oils kanuka and manuka, derived from
the 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
the oil of M. alternifolia.
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
November (12, 98), and flowers are produced in loose, white to
TABLE 1. Composition of M. alternifolia (tea tree) oil
Component
Composition (%)
ISO 4730 range
a
Typical
composition
b
Terpinen-4-ol 30
c
40.1
-Terpinene 10–28 23.0
-Terpinene 5–13 10.4
1,8-Cineole 15
d
5.1
Terpinolene 1.5–5 3.1
-Cymene 0.5–12 2.9
-Pinene 1–6 2.6
-Terpineol 1.5–8 2.4
Aromadendrene Trace–7 1.5
-Cadinene Trace–8 1.3
Limonene 0.5–4 1.0
Sabinene Trace–3.5 0.2
Globulol Trace–3 0.2
Viridiflorol Trace–1.5 0.1
a
IOS 4730, International Organization for Standardization standard no. 4730
(from reference 89).
b
From reference 25.
c
No upper limit is set, although 48% has been proposed.
d
No lower limit is set.
TABLE 2. Properties of TTO components
Component Type of compound
Chemical
formula
Solubility
(ppm)
a
Log
K
OW
b
Terpinen-4-ol Monocyclic terpene
alcohol
C
10
H
18
O 1,491 3.26
-Terpinene Monocyclic terpene C
10
H
16
1.0 4.36
-Terpinene Monocyclic terpene C
10
H
16
8.2 4.25
1,8-Cineole Monocyclic terpene
alcohol
C
10
H
18
O 907 2.84
-Terpinolene Monocyclic terpene C
10
H
16
4.3 4.24
-Cymene Monocyclic terpene C
10
H
14
6.2
()--Pinene Dicyclic terpene C
10
H
16
0.57 4.44
-Terpineol Monocyclic terpene
alcohol
C
10
H
18
O 1,827 3.28
Aromadendrene Sesquiterpene C
15
H
24
-Cadinene Sesquiterpene C
15
H
24
()-Limonene Monocyclic terpene C
10
H
16
1.0 4.38
Sabinene Dicyclic monoterpene C
10
H
16
Globulol Sesquiterpene alcohol C
15
H
26
O
a
From reference 63.
b
K
ow
, octanol-water partition coefficient, from reference 62.
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creamy colored terminal spikes, which can give trees a “fluffy”
appearance (155).
COMMERCIAL PRODUCTION
The commercial TTO industry was born after the medicinal
properties of the oil were first reported by Penfold in the 1920s
(121–124) as part of a larger survey into Australian essential
oils with economic potential. During that nascent stage, TTO
was produced from natural bush stands of plants, ostensibly M.
alternifolia, that produced oil with the appropriate chemotype.
The native habitat of M. alternifolia is low-lying, swampy, sub-
tropical, coastal ground around the Clarence and Richmond
Rivers in northeastern New South Wales and southern
Queensland (142), and, unlike several other Melaleuca species,
it does not occur naturally outside Australia. The plant mate-
rial was hand cut and often distilled on the spot in makeshift,
mobile, wood-fired bush stills. The industry continued in this
fashion for several decades. Legend has it that the oil was
considered so important for its medicinal uses that Australian
soldiers were supplied oil as part of their military kits during
World War II and that bush cutters were exempt from national
service (35). However, no evidence to corroborate these ac-
counts could be found (A.-M. Conde and M. Pollard [Austra-
lian War Memorial, Canberra, Australia], personal communi-
cation). Production ebbed after World War II as demand for
the oil declined, presumably due to the development of effec-
tive antibiotics and the waning image of natural products. In-
terest in the oil was rekindled in the 1970s as part of the
general renaissance of interest in natural products. Commer-
cial plantations were established in the 1970s and 1980s, allow-
ing the industry to mechanize and produce large quantities of
a consistent product (25, 93). Today there are plantations in
Western Australia, Queensland, and New South Wales, al-
though the majority are in New South Wales around the Lis-
more region. Typically, plantations are established from seed-
lings sowed and raised in greenhouses prior to being planted
out in the field at high density. The time to first harvest varies
from 1 to 3 years, depending on the climate and rate of plant
growth. Harvesting is by a coppicing process in which the
whole plant is cut off close to ground level and chipped into
smaller fragments prior to oil extraction.
Oil Extraction
TTO is produced by steam distillation of the leaves and
terminal branches of M. alternifolia. Once condensed, the clear
to pale yellow oil is separated from the aqueous distillate. The
yield of oil is typically 1 to 2% of wet plant material weight.
Alternative extraction methods such as the use of microwave
technology have been considered, but none has been utilized
on a commercial scale.
ANTIMICROBIAL ACTIVITY IN VITRO
Of all of the properties claimed for TTO, its antimicrobial
activity has received the most attention. The earliest reported
use of the M. alternifolia plant that presumably exploited this
property was the traditional use by the Bundjalung Aborigines
of northern New South Wales. Crushed leaves of “tea trees”
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 sore
throats or skin ailments (101, 135). The oral history of Austra-
lian Aborigines also tells of healing lakes, which were lagoons
into which M. alternifolia leaves had fallen and decayed over
time (3). Use of the oil itself, as opposed to the unextracted
plant material, did not become common practice until Penfold
published the first reports of its antimicrobial activity in a
series of papers in the 1920s and 1930s. In evaluating the
antimicrobial activity of M. alternifolia oil and other oils, he
made comparisons with the disinfectant carbolic acid or phe-
nol, the gold standard of the day, in a test known as the
Rideal-Walker (RW) coefficient. The activity of TTO was com-
pared directly with that of phenol and rated as 11 times more
active (121). The RW coefficients of several TTO components
were also reported, including 3.5 for cineole and 8 for cymene
(122), 13 for linalool (123), and 13.5 for terpinen-4-ol and 16
for terpineol (121). As a result, TTO was promoted as a ther-
apeutic agent (5–7). These publications, as well as several
others (60, 70, 84, 102, 120, 124, 152), describe a range of
medicinal uses for TTO. However, in terms of the evidence
they provide for the medicinal properties of TTO, they are of
limited value, since by the standards of today the data they
provide would be considered mostly anecdotal.
In contrast, contemporary data clearly show that the broad-
spectrum activity of TTO includes antibacterial, antifungal,
antiviral, and antiprotozoal activities. Not all of the activity has
been characterized well in vitro, and in the few cases where
clinical work has been done, data are promising but thus far
inadequate.
Evaluation of the antimicrobial activity of TTO has been
impeded by its physical properties; TTO and its components
are only sparingly soluble in water (Table 2), and this limits
their miscibility in test media. Different strategies have been
used to counteract this problem, with the addition of surfac-
tants to broth and agar test media being used most widely (11,
13, 15, 31, 32, 61). Dispersion of TTO in liquid media usually
results in a turbid suspension that makes determination of end
points in susceptibility tests difficult. Occasionally dyes have
been used as visual indicators of the MIC, with mixed success
(31, 32, 40, 104).
Antibacterial Activity
The few reports of the antibacterial activity of TTO appear-
ing in the literature from the 1940s to the 1980s (11, 15, 100,
153) have been reviewed elsewhere previously (35). From the
early 1990s onwards, many reports describing the antimicrobial
activity of TTO appeared in the scientific literature. Although
there was still a degree of discrepancy between the methods
used in the different studies, the MICs reported were often
relatively similar. A broad range of bacteria have now been
tested for their susceptibilities to TTO, and some of the pub-
lished susceptibility data are summarized in Table 3. While
most bacteria are susceptible to TTO at concentrations of
1.0% or less, MICs in excess of 2% have been reported for
organisms such as commensal skin staphylococci and micro-
cocci, Enterococcus faecalis, and Pseudomonas aeruginosa (13,
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79). TTO is for the most part bactericidal in nature, although
it may be bacteriostatic at lower concentrations.
The activity of TTO against antibiotic-resistant bacteria has
attracted considerable interest, with methicillin-resistant
Staphylococcus aureus (MRSA) receiving the most attention
thus far. Since the potential to use TTO against MRSA was
first hypothesized (153), several groups have evaluated the
activity of TTO against MRSA, beginning with Carson et al.
(31), who examined 64 MRSA isolates from Australia and the
United Kingdom, including 33 mupirocin-resistant isolates.
The MICs and minimal bactericidal concentrations (MBCs)
for the Australian isolates were 0.25% and 0.5%, respectively,
while those for the United Kingdom isolates were 0.312% and
0.625%, respectively. Subsequent reports on the susceptibility of
MRSA to TTO have similarly not shown great differences com-
pared to antibiotic-sensitive organisms (39, 58, 68, 106, 115).
For the most part, antibacterial activity has been determined
using agar or broth dilution methods. However, activity has
also been demonstrated using time-kill assays (34, 48, 80, 106),
suspension tests (107), and “ex vivo”-excised human skin (108).
In addition, vaporized TTO can inhibit bacteria, including
Mycobacterium avium ATCC 4676 (105), Escherichia coli, Hae-
mophilus influenzae, Streptococcus pyogenes, and Streptococcus
pneumoniae (85). There are anecdotal reports of aerosolized
TTO reducing hospital-acquired infections (L. Bowden, Abstr.
Infect. Control Nurses Assoc. Annu. Infect. Control Conf., p.
23, 2001) but no scientific data.
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
treatment with TTO.
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 of
these effects confirm that TTO compromises the structural and
functional integrity of bacterial membranes.
The loss of viability, inhibition of glucose-dependent respi-
ration, and induction of lysis seen after TTO treatment all
occur to a greater degree with organisms in the exponential
rather than the stationary phase of growth (67; S. D. Cox, J. L.
Markham, C. M. Mann, S. G. Wyllie, J. E. Gustafson, and J. R.
Warmington, Abstr. 28th Int. Symp. Essential Oils, p. 201–213,
1997). The increased vulnerability of actively growing cells was
also apparent in the greater degree of morphological changes
seen in these cells by electron microscopy (S. D. Cox et al.
Abstr. 28th Int. Symp. Essential Oils, p. 201–213). The differ-
ences in susceptibility of bacteria in different phases of growth
suggest that targets other than the cell membrane may be
involved.
When the effects of terpinen-4-ol, -terpineol, and 1,8-cin-
eole on S. aureus were examined, none was found to induce
autolysis but all were found to cause the leakage of 260-nm-
light-absorbing material and to render cells susceptible to so-
dium chloride (34). Interestingly, the greatest effects were seen
with 1,8-cineole, a component often considered to have mar-
ginal antimicrobial activity. This raises the possibility that while
cineole may not be one of the primary antimicrobial compo-
nents, it may permeabilize bacterial membranes and facilitate
the entry of other, more active components. Little work on the
effects of TTO components on cell morphology has been re-
ported. Electron microscopy of terpinen-4-ol-treated S. aureus
cells (34) revealed lesions similar to those seen after TTO
TABLE 3. Susceptibility data for bacteria tested against
M. alternifolia oil
Bacterial species
% (vol/vol)
Reference(s)
MIC MBC
Acinetobacter baumannii 1179
Actinomyces viscosus 0.6 0.6 134
Actinomyces spp. 1 1 80
Bacillus cereus 0.3 61
Bacteroides spp. 0.06–0.5 0.06–0.12 75
Corynebacterium sp. 0.2–2 2 42, 61, 79
Enterococcus faecalis 0.5–8 8 13, 61
E. faecium (vancomycin
resistant)
0.5–1 0.5–1 115
Escherichia coli 0.08–2 0.25–4 13, 32, 67, 104
Fusobacterium nucleatum 0.6–0.6 0.25 134, 144
Klebsiella pneumoniae 0.25–0.3 0.25 61, 79
Lactobacillus spp. 1–2 2 75, 80
Micrococcus luteus 0.06–0.5 0.25–6 79
Peptostreptococcus
anaerobius
0.2–0.25 0.03–0.6 75, 134
Porphyromonas
endodentalis
0.025–0.1 0.025–0.1 80
P. gingivalis 0.11–0.25 0.13–0.6 134, 144
Prevotella spp. 0.03–0.25 0.03 75
Prevotella intermedia 0.003–0.1 0.003–0.1 80
Propionibacterium acnes 0.05–0.63 0.5 37, 61, 126
Proteus vulgaris 0.08–2 4 13, 42, 61, 104
Pseudomonas aeruginosa 1–8 2–8 13, 61, 79
Staphylococcus aureus 0.5–1.25 1–2 13, 32, 126
S. aureus (methicillin
resistant)
0.04–0.35 0.5 31, 42, 104, 115
S. epidermidis 0.45–1.25 4 42, 79, 126
S. hominis 0.5 4 79
Streptococcus pyogenes 0.12–2 0.25–4 13, 33
Veillonella spp. 0.016–1 0.03–1 80
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treatment (127), including mesosome-like structures.
Mechanism of action studies analogous to those described
above have not been conducted with P. aeruginosa. Instead,
research has concentrated on how this organism is able to
tolerate higher concentrations of TTO and/or components.
These studies have indicated that tolerance is associated with
the outer membrane by showing that when P. aeruginosa cells
are pretreated with the outer membrane permeabilizer poly-
myxin B nonapeptide or EDTA, cells become more susceptible
to the bactericidal effects of TTO, terpinen-4-ol, or -terpinene
(99, 103).
In summary, the loss of intracellular material, inability to
maintain homeostasis, and inhibition of respiration after treat-
ment with TTO and/or components are consistent with a
mechanism of action involving the loss of membrane integrity
and function.
Antifungal Activity
Comprehensive investigations of the susceptibility of fungi
to TTO have only recently been completed. Prior to this, data
were somewhat piecemeal and fragmentary. Early data were
also largely limited to Candida albicans, which was a commonly
chosen model test organism. Data now show that a range of
yeasts, dermatophytes, and other filamentous fungi are suscep-
tible to TTO (14, 42, 52, 61, 116, 128, 140) (Table 4). Although
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)
and affect sporulation (88).
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 Saccharomyces
cerevisiae (72). Medium acidification occurs largely by the ex-
pulsion of protons by the plasma membrane ATPase, which is
fuelled by ATP derived from the mitochondria. The inhibition
of this function suggests that the plasma and/or mitochondrial
membranes have been adversely affected. These results are
consistent with a proposed mechanism of antifungal action
whereby TTO causes changes or damage to the functioning of
fungal membranes. This proposed mechanism is further sup-
ported by work showing that the terpene eugenol inhibits mi-
tochondrial respiration and energy production (46).
Additional studies have shown that when cells of C. albicans
are treated with diethylstilbestrol to inhibit the plasma mem-
brane ATPase, they then have a much greater susceptibility to
TTO than do control cells (72), suggesting that the plasma
membrane ATPase has a role in protecting cells against the
destabilizing or lethal effects of TTO.
TTO inhibits the formation of germ tubes, or mycelial con-
version, in C. albicans (52, 78). Two studies have shown that
germ tube formation was completely inhibited in the presence
of 0.25 and 0.125% TTO, and it was further observed that
treatment with 0.125% TTO resulted in a trend of blastospores
changing from single or singly budding morphologies to mul-
tiply budding morphologies over the 4-h test period (78).
These cells were actively growing but were not forming germ
tubes, implying that morphogenesis is specifically inhibited,
rather than all growth being inhibited. Interestingly, the inhi-
bition of germ tube formation was shown to be reversible, since
cells were able to form germ tubes after the removal of the
TABLE 4. Susceptibility data for fungi tested against
M. alternifolia oil
Fungal species
% (vol/vol)
Reference(s)
MIC MFC
Alternaria spp. 0.016–0.12 0.06–2 74
Aspergillus flavus 0.31–0.7 2–4 61, 74, 116, 137
A. fumigatus 0.06–2 1–2 74, 148
A. niger 0.016–0.4 2–8 15, 61, 74
Blastoschizomyces
capitatus
0.25 117
Candida albicans 0.06–8 0.12–1 13, 42, 52, 59,
77, 111, 116,
117, 148
C. glabrata 0.03–8 0.12–0.5 13, 52, 59, 77,
111, 117, 148
C. parapsilosis 0.03–0.5 0.12–0.5 52, 77, 111, 117
C. tropicalis 0.12–2 0.25–0.5 52, 59, 148
Cladosporium spp. 0.008–0.12 0.12–4 74
Cryptococcus
neoformans
0.015–0.06 111
Epidermophyton
flocossum
0.008–0.7 0.12–0.25 42, 74
Fusarium spp. 0.008–0.25 0.25–2 74
Malassezia furfur 0.03–0.12 0.5–1.0 73
M. sympodialis 0.016–0.12 0.06–0.12 73
Microsporum canis 0.03–0.5 0.25–0.5 52, 74, 116
M. gypseum 0.016–0.25 0.25–0.5 52
Penicillium spp. 0.03–0.06 0.5–2 74
Rhodotorula rubra 0.06 0.5 71
Saccharomyces
cerevisiae
0.25 0.5 71
Trichophyton
mentagrophytes
0.11–0.44 0.25–0.5 52, 61, 116
T. rubrum 0.03–0.6 0.25–1 42, 52, 74, 116
T. tonsurans 0.004–0.016 0.12–0.5 74
Trichosporon spp. 0.12–0.22 0.12 71, 116
54 CARSON ET AL. CLIN.MICROBIOL.REV.
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TTO (78). However, there was a delay in germ tube formation,
indicating that TTO causes a postantifungal effect.
Antiviral Activity
The antiviral activity of TTO was first shown using tobacco
mosaic virus and tobacco plants (18). In field trials with Nico-
tiniana glutinosa, plants were sprayed with 100, 250, or 500 ppm
TTO or control solutions and were then experimentally in-
fected with tobacco mosaic virus. After 10 days, there were
significantly fewer lesions per square centimeter of leaf in
plants treated with TTO than in controls (18). Next, Schnitzler
et al. (132) examined the activity of TTO and eucalyptus oil
against herpes simplex virus (HSV). The effects of TTO were
investigated by incubating viruses with various concentrations
of TTO and then using these treated viruses to infect cell
monolayers. After 4 days, the numbers of plaques formed by
TTO-treated virus and untreated control virus were deter-
mined and compared. The concentration of TTO inhibiting
50% of plaque formation was 0.0009% for HSV type 1
(HSV-1) and 0.0008% for HSV-2, relative to controls. These
studies also showed that at the higher concentration of 0.003%,
TTO reduced HSV-1 titers by 98.2% and HSV-2 titers by
93.0%. In addition, by applying TTO at different stages in the
virus replicative cycle, TTO was shown to have the greatest
effect on free virus (prior to infection of cells), although when
TTO was applied during the adsorption period, a slight reduc-
tion in plaque formation was also seen (132). Another study
evaluated the activities of 12 essential oils, including TTO, for
activity against HSV-1 in Vero cells (110). Again, TTO was
found to exert most of its antiviral activity on free virus, with
1% oil inhibiting plaque formation completely and 0.1% TTO
reducing plaque formation by approximately 10%. Pretreat-
ment of the Vero cells prior to virus addition or posttreatment
with 0.1% TTO after viral absorption did not significantly alter
plaque formation.
Some activity against bacteriophages has also been reported,
with exposure to 50% TTO at 4°C for 24 h reducing the
number of SA and T7 plaques formed on lawns of S. aureus
and E. coli, respectively (41).
The results of these studies indicate that TTO may act
against enveloped and nonenveloped viruses, although the
range of viruses tested to date is very limited.
Antiprotozoal Activity
Two publications show that TTO has antiprotozoal activity.
TTO caused a 50% reduction in growth (compared to con-
trols) of the protozoa Leishmania major and Trypanosoma
brucei at concentrations of 403 mg/ml and 0.5 mg/ml, respec-
tively (109). Further investigation showed that terpinen-4-ol
contributed significantly to this activity. In another study, TTO
at 300 mg/ml killed all cells of Trichomonas vaginalis (151).
There is also anecdotal in vivo evidence that TTO may be
effective in treating Trichomonas vaginalis infections (120).
Antimicrobial Components of TTO
Considerable attention has been paid to which components
of TTO are responsible for the antimicrobial activity. Early
indications from RW coefficients were that much of the activity
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
same as, or slightly lower than values obtained for TTO (36, 42,
48, 71, 117, 126). However, -terpineol does not represent a
significant proportion of the oil. Additional components with
MICs similar to or lower than those of TTO include -pinene,
-pinene, and linalool (36, 71), but, similar to the case for
-terpineol, these components are present in only relatively
low amounts. Of the remaining components tested, it seems
that most possess at least some degree of antimicrobial activity
(36, 71, 126), and this is thought to correlate with the presence
of functional groups, such as alcohols, and the solubility of
the component in biological membranes (63, 138). While
some TTO components may be considered less active, none
can be considered inactive. Furthermore, methodological is-
sues have been demonstrated to have a significant influence on
assay outcomes (48, 71).
The possibility that components in TTO may have synergis-
tic or antagonistic interactions has been explored in vitro (48),
but no significant relationships were found. The possibility that
TTO may act synergistically with other essential oils, such as
lavender (38), and other essential oil components, such as
-triketones from manuka oil (43, 44), has also been investi-
gated. Given the numerous components of TTO, the scope for
such effects is enormous, and much more work is required to
examine this question.
Resistance to TTO
The question of whether true resistance to TTO can be
induced in vitro or may occur spontaneously in vivo has not
been examined systematically. Clinical resistance to TTO has
not been reported, despite the medicinal use of the oil in
Australia since the 1920s. There has been one short report of
induced in vitro resistance to TTO in S. aureus (114). Stepwise
exposure of five MRSA isolates to increasing concentrations of
TTO yielded three isolates with TTO MICs of 1% and one
isolate each with TTO MICs of 2% and 16%, respectively. All
isolates showed initial MICs of 0.25%. There has also been one
report suggesting that E. coli strains harboring mutations in the
multiple antibiotic resistance (mar) operon, so-called Mar mu-
tants, may exhibit decreased susceptibility to TTO (66). Minor
changes in TTO and -terpineol susceptibilities have also been
seen in S. aureus isolates with reduced susceptibility to house-
hold cleaners (53). However, in these last two studies the
changes in susceptibility were marginal and do not represent
strong evidence of resistance (53, 66). With regard to fungi, an
attempt to induce resistance to TTO in two clinical isolates of
Candida albicans was largely unsuccessful, with isolates failing
to grow in 2% (vol/vol) TTO after serial passage in increasing
concentrations of TTO (111).
Resistance to conventional antibiotics has not been demon-
strated to influence susceptibility to TTO, suggesting that
cross-resistance does not occur. For example, antimicrobial-
resistant isolates of S. aureus (31, 58), C. albicans and C. gla-
brata (148), P. aeruginosa (106), and Enterococcus faecium
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(106, 115) have in vitro susceptibilities to TTO that are similar
to those of nonresistant isolates.
Overall, these studies provide little evidence to suggest that
resistance to TTO will occur, either in vitro or in vivo, although
minimal data are available. It is likely that the multicomponent
nature of TTO may reduce the potential for resistance to occur
spontaneously, since multiple simultaneous mutations may be
required to overcome all of the antimicrobial actions of each of
the components. Furthermore, since TTO is known to affect
cell membranes, it presumably affects multiple properties and
functions associated with the cell membrane, similar to the
case for membrane-active biocides. This means that numerous
targets would have to adapt to overcome the effects of the oil.
Issues of potential resistance are important if TTO is to be
used more widely, particularly against antibiotic-resistant or-
ganisms.
CLINICAL EFFICACY
In parallel with the characterization of the in vitro antimi-
crobial activity of TTO, the clinical efficacy of the oil has also
been the subject of investigation. Early clinical studies attempt-
ing to characterize the clinical efficacy of TTO (60, 120, 152)
are not considered scientifically valid by today’s standards and
will therefore not be discussed further. Data from some of the
more recent clinical investigations are summarized in Table 5.
One of the first rigorous clinical studies assessed the efficacy
of 5% TTO in the treatment of acne by comparing it to 5%
benzoyl peroxide (BP) (14). The study found that both treat-
ments reduced the numbers of inflamed lesions, although BP
performed significantly better than TTO. The BP group
showed significantly less oiliness than the TTO group, whereas
the TTO group showed significantly less scaling, pruritis, and
dryness. Significantly fewer overall side effects were reported
by the TTO group (27 of 61 patients) than by the BP group (50
of 63 patients).
The efficacy of TTO in dental applications has been as-
sessed. An evaluation of the effect of a 0.2% TTO mouthwash
and two other active agents on the oral flora of 40 volunteers
suggested that TTO used once daily for 7 days could reduce the
number of mutans streptococci and the total number of oral
bacteria, compared to placebo treatment. The data also indi-
cated that these reductions were maintained for 2 weeks after
the use of mouthwash ceased (64). In another study, compar-
ison of mouthwashes containing either approximately 0.34%
TTO, 0.1% chlorhexidine, or placebo on plaque formation and
vitality, using eight volunteers (9), showed that after TTO
treatment, both plaque index and vitality did not differ from
those of subjects receiving placebo mouthwash on any day,
whereas the results for the chlorhexidine mouthwash group
differed significantly from those for the placebo group on all
days (9). Lastly, a study comparing a 2.5% TTO gel, a 0.2%
chlorhexidine gel, and a placebo gel found that although the
TTO group had significantly reduced gingival index and pap-
illary bleeding index scores, their plaque scores were actually
increased (139). These studies indicate that although TTO may
cause decreases in the levels of oral bacteria, this does not
necessarily equate to reduced plaque levels. However, TTO
may have a role in the treatment of gingivitis, and there is also
some evidence preliminary suggesting that TTO reduces the
levels of several compounds associated with halitosis (144).
Two studies have assessed the efficacy of TTO for the erad-
ication of MRSA carriage. The effectiveness of a 4% TTO
nasal ointment and a 5% TTO body wash was compared to
that of conventional treatment with mupirocin nasal ointment
and Triclosan body wash in a small pilot study (28). Of the 15
patients receiving conventional treatment, 2 were cleared and
8 remained colonized at the end of therapy; in the TTO group
of 15, 5 were cleared and 3 remained colonized. The remainder
of patients did not complete therapy. Differences in clearance
rates were not statistically significant, most likely due to the
low patient numbers. Stronger evidence for the efficacy of TTO
in decolonizing MRSA carriage comes from a recent trial in
which 236 patients were randomized to receive standard or
TTO treatment regimens (56). The standard regimen consisted
of 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
consisted of 10% TTO nasal cream applied three times a day,
5% TTO body wash applied at least once daily and 10% TTO
cream applied to skin lesions, wounds, and leg ulcers once a
day, all for 5 days. The 10% TTO cream was allowed to be used
as an alternative to the body wash. Follow-up swabs were taken
at 2 and 14 days posttreatment, with the exception of 12 pa-
tients who were lost to follow-up. Evaluation of the remaining
224 patients showed no significant differences between treat-
ment regimens, with 49% of patients receiving standard ther-
apy cleared versus 41% of patients in the TTO group.
For many years there has been considerable interest in the
possibility of using TTO in handwash formulations for use in
hospital or health care settings. It is well known that hand-
washing is an effective infection control measure and that lack
of compliance is related to increased rates of nosocomial in-
fections. The benefits of using TTO in a handwash formulation
include its antiseptic effects and increased handwashing com-
pliance. A recent handwash study using volunteers showed that
either a product containing 5% TTO and 10% alcohol or a
solution of 5% TTO in water performed significantly better
than soft soap, whereas a handwash product containing 5%
TTO did not (108).
Occasional case reports of the use of TTO have also been
published. In one, a woman self-treated successfully with a
5-day course of TTO pessaries after having been clinically
diagnosed with bacterial vaginosis (19). In a second, a combi-
nation of plant extracts of which TTO was a major component
was inserted percutaneously into bone to treat an intractable
MRSA infection of the lower tibia, which subsequently resolved
(136). This same essential oil solution has now been shown to aid
in the healing of malodorous malignant ulcers (154).
With regard to fungal infections, TTO has been clinically
evaluated for the treatment of onychomycosis (26, 143), tinea
pedis (131, 145), dandruff (130), and oral candidiasis (92, 149).
Although much has been made of the potential for TTO to be
used in the treatment of vaginal candidiasis, no clinical data
have been published. However, results from an animal (rat)
model of vaginal candidiasis support the use of TTO for the
treatment of this infection (111).
In the first of the onychomycosis trials (26), 60% of patients
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TABLE 5. Summary of clinical studies using TTO
Study population Study type
Treatment groups
(no. of evaluable patients)
Administration of
treatment
Outcomes Adverse events Reference
124 patients with mild
to moderate acne
RCT
a
, investigator
blinded
b
5% TTO gel (58), 5% benzoyl
peroxide (61)
3 mo Both significantly reduced inflamed
lesions (P 0.001) but BP better
than TTO (P 0.05); BP better at
reducing oiliness (P 0.02); less
scaling (P 0.02), pruritis
(P 0.05), dryness (P 0.001)
with TTO; treatments equivalent
for noninflamed lesions, erythema
27 (44%) in TTO group, 50 (79%)
in BP group (e.g., dryness,
stinging, burning, redness);
significantly fewer events in TTO
group (P 0.001)
14
18 patients with
recurrent herpes
labialis (cold sores)
RCT, investigator
blinded
b
6% TTO gel (9), placebo gel (9) 5 times daily Median time to reepithelization of 9
days for TTO vs 12.5 days for
placebo (not significant)
1 in TTO group (event
not stated)
30
126 patients with mild
to moderate dandruff
RCT, investigator
blinded
b
5% TTO shampoo (63), placebo
shampoo (62)
Daily for 4 wk Whole scalp lesion score significantly
improved in TTO group (41.2%)
compared to placebo group (11.2%)
(P 0.001)
3 (5%) in TTO group, 8 (13%) in
placebo group (e.g., mild burning,
stinging, itching)
130
30 hospital inpatients
colonized or infected
with MRSA
Randomized,
controlled pilot
study
4% TTO nasal ointment 5%
TTO body wash (15), 2%
mupirocin nasal ointment
Triclosan body wash (15)
Frequency not
stated, minimum
of 3 days
For TTO, 33% cleared, 20% chronic,
47% incomplete; for routine
treatment, 3% cleared, 53%
chronic, 33% incomplete
(no significant differences)
With TTO nasal ointment (no. not
stated), mild swelling of nasal
mucosa to acute burning
28
236 hospital patients
colonized with
MRSA
RCT 10% TTO cream 5% TTO
body wash (110), 2% mupirocin
nasal ointment 4% Triclosan
body wash 1% silver
sulfadiazine cream (114)
Once daily for
5 days
For TTO, 41% cleared; for routine
treatment, 49%cleared; treatment
regimens did not differ significantly
(P 0.0286); mupirocin
significantly better than TTO at
clearing nasal carriage (P 0.0001)
None 56
117 patients with
culture-positive
onychomycosis
RCT, double blind 100% TTO (64), 1%
clotrimazole (53)
Twice daily for
6mo
Full or partial resolution for 60% of
TTO and 61% of clotrimazole
patients after 6 months of therapy
(not significant; P 0.05)
5 (7.8%) in TTO group, 3 (5.7%) in
clotrimazole group (erythema,
irritation, edema)
26
60 outpatients with a
clinical diagnosis of
onychomycosis
RCT, double blind 2% butenafine hydrochloride with
5% TTO cream (40), 5% TTO
cream (20)
3 times daily for
8wk
Cure in 80% of butenafine/TTO
group and 0% of TTO group
(P 0.0001)
4 (10%) in butenafine/TTO group
(mild inflammation)
143
13 patients with AIDS
and fluconazole-
refractory oral
candidiasis
Case series Melaleuca oral solution
(15 ml) (12)
4 times daily for
2–4 wk
Clinical response rate of 67% after
4 weeks (cure in 2 patients,
improvement in 6 patients, no
response in 4 patients,
1 deterioration)
None 92
27 patients with AIDS
and fluconazole-
refractory oral
candidiasis
Open-label trial Melaleuca oral solution (15 ml)
(12), alcohol-free melaleuca
oral solution (5 ml)
c
(13)
4 times daily for
2–4 wk
Mycological and clinical response in
58% (alcohol-based solution) and
54% (alcohol-free solution) of
patients after 4 wk
8 (66.7%) in alcohol-based solution
group, 2 (15.4%) in alcohol-free
solution group (mild to moderate
burning)
149
121 patients with
clinically diagnosed
tinea pedis
RCT, double blind 10% TTO in sorbolene (37),
1% tolnaftate (33), placebo
(sorbolene) (34)
Twice daily for
4wk
Mycological cure and clinical
improvement in 46% (tolnaftate),
22% (TTO), and 9% (placebo) of
patients; tolnaftate significantly
better than placebo (P 0.003) but
not TTO (P 0.59); TTO not
different from placebo (P 0.3)
None 145
137 patients with
culture-positive
tinea pedis
RCT, double blind 25% TTO (36), 50% TTO (38),
placebo (46)
Twice daily for
4wk
Effective cure in 48% (25% TTO),
50% (50% TTO), and 13%
(placebo) of patients; TTO
significantly better than placebo
(P 0.0005)
1 (2.8%) in 25% TTO group, 3
(7.9%) in 50% TTO group
(moderate to severe dermatitis)
131
a
RCT, randomized controlled trial.
b
The distinctive odor of TTO was stated as preventing patient blinding.
c
The alcohol-free solution was more concentrated, and thus a smaller volume was used.
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treated with TTO and 61% of patients treated with 1% clo-
trimazole had full or partial resolution. There were no statis-
tically significant differences between the two treatment groups
for any parameter. The second onychomycosis trial (143) com-
pared two creams, one containing 5% TTO alone and the
other containing 5% TTO and 2% butenafine, both applied
three times daily for 8 weeks. The overall cure rate was 0% for
patients treated with 5% TTO alone, compared to 80% for
patients treated with both butenafine and TTO. Unfortunately,
butenafine alone was not evaluated. The observation that TTO
may be useful adjunct therapy for onychomycosis has been
made by Klimmek et al. (95). However, onychomycosis is con-
sidered to be largely unresponsive to topical treatment of any
kind, and a high rate of cure should therefore not be expected.
The effectiveness of TTO in treating tinea pedis has been
evaluated in two trials. In the first trial, patients were treated
with 10% TTO in sorbolene, 1% tolnaftate, or placebo (sor-
bolene) (145). At completion of treatment, patients treated
with TTO had mycological cure and clinical improvement rates
of 30% and 65%, respectively. This compares to mycological
cure rates of 21% in patients receiving placebo and 85% in
patients receiving tolnaftate. Similarly, clinical improvement
was seen in 41% of patients receiving placebo and 68% of
patients receiving tolnaftate. In a second tinea trial, the efficacy
of solutions of 25% and 50% TTO in ethanol and polyethylene
glycol was compared to treatment with placebo (vehicle) (131).
Marked clinical responses were seen in 72% and 68% of pa-
tients in the 25% and 50% TTO treatment groups, respec-
tively, compared to 39% of patients in the placebo group.
Similarly, there were mycological cures of 55% and 64% in the
25% and 50% TTO treatment groups, respectively, compared
to 31% in the placebo group. Dermatitis occurred in one pa-
tient in the 25% TTO group and in three patients in the 50%
TTO group. This led to the recommendation that 25% TTO be
considered an alternative treatment for tinea, since it was as-
sociated with fewer adverse reactions than but was just as
effective as 50% TTO. These studies highlight the importance
of considering the formulation of the TTO product when con-
ducting in vivo work, since it is likely that the sorbolene vehicle
used in the first tinea trial may have significantly compromised
the antifungal activity of the oil.
The evaluation of a 5% TTO shampoo for mild to moderate
dandruff demonstrated statistically significant improvements in
the investigator-assessed whole scalp lesion score, total area of
involvement score, and total severity score, as well as in the
patient-assessed itchiness and greasiness scores, compared to
placebo. Overall, the 5% TTO was well tolerated and appeared
to be effective in the treatment of mild to moderate dandruff.
TTO has been evaluated as a mouthwash in the treatment of
oropharyngeal candidiasis. In a case series, 13 human immu-
nodeficiency virus-positive patients who had already failed
treatment with a 14-day course of oral fluconazole were
treated with an alcohol-based TTO solution for up to 28 days
(92). After treatment, of the 12 evaluable patients, 2 were
cured, 6 were improved, 4 were unchanged, and 1 had deteri-
orated. Overall, eight patients had a clinical response and
seven had a mycological response. In subsequent work the
same TTO solution was compared with an alcohol-free TTO
solution (149). Of patients receiving the alcohol-based solu-
tion, two were cured, six improved, four were unchanged, and
one had deteriorated. Of patients receiving the alcohol-free
solution, five were cured, two improved, two were unchanged,
and one had deteriorated. Three patients were lost to fol-
low-up and were considered nonresponders.
Support for TTO possessing in vivo antiviral activity comes
from a pilot study investigating the treatment of recurrent
herpes labialis (cold sores) with a 6% TTO gel or a placebo gel
(30). Comparison of the patient groups (each containing nine
evaluable patients) at the end of the study showed that reepi-
thelialization after treatment occurred after 9 days for the
TTO group and after 12.5 days for the placebo group. Other
measures, such as duration of virus positivity by culture or
PCR, viral titers, and time to crust formation, were not signif-
icantly different, possibly due to small patient numbers. Inter-
estingly, when TTO was evaluated for its protective efficacy in
an in vivo mouse model of genital HSV type 2 infection, it did
not perform well (21). In contrast, the oil component 1,8-cineole
performed well, protecting 7 of 16 animals from disease.
There are a number of limitations to the clinical studies
described above. Several had low numbers of participants,
meaning that statistical analyses could not be performed or
differences did not reach significance. Many studies had am-
biguous and/or equivocal outcomes. Of those studies with
larger numbers of patients, few reported 95% confidence in-
tervals or relative risk values. While most studies compared the
efficacy of TTO to a placebo, many did not compare TTO to a
conventional therapy or treatment regimen, again limiting the
conclusions that could be drawn about efficacy. Several publi-
cations noted that patient blinding was compromised or im-
practicable due to the characteristic odor of TTO (14, 30, 130,
131). These studies, while perhaps conducted as double
blinded, are technically only single blinded, which is not ideal.
Perhaps most importantly, few studies have been replicated
independently. Therefore, although some of these data indi-
cate that TTO has potential as a therapeutic agent, confirma-
tory studies are required. In addition, factors such as the final
TTO concentration, product formulation, and length and fre-
quency of treatment undoubtedly influence clinical efficacy,
and these factors must be considered in future studies. The
cost-effectiveness of any potential TTO treatments must also be
considered. For example, TTO therapy may offer no cost advan-
tage over the azoles in the treatment of tinea but is probably more
economical than treatment with the allylamines.
ANTI-INFLAMMATORY ACTIVITY
Numerous recent studies now support the anecdotal evi-
dence attributing anti-inflammatory activity to TTO. In vitro
work over the last decade has demonstrated that TTO affects
a range of immune responses, both in vitro and in vivo. For
example, the water-soluble components of TTO can inhibit the
lipopolysaccharide-induced production of the inflammatory
mediators tumor necrosis factor alpha (TNF-), interleukin-1
(IL-1), and IL-10 by human peripheral blood monocytes by
approximately 50% and that of prostaglandin E
2
by about 30%
after 40 h (81). Further examination of the water-soluble frac-
tion of TTO identified terpinen-4-ol, -terpineol, and 1,8-cin-
eole as the main components, but of these, only terpinen-4-ol
was able to diminish the production of TNF-, IL-1, IL-8,
IL-10, and prostaglandin E
2
by lipopolysaccharide-activated
58 CARSON ET AL. CLIN.MICROBIOL.REV.
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monocytes. The water-soluble fraction of TTO, terpinen-4-ol,
and -terpineol also suppressed superoxide production by
agonist-stimulated monocytes but not neutrophils (22). In con-
trast, similar work found that TTO decreases the production of
reactive oxygen species by both stimulated neutrophils and
monocytes and that it also stimulates the production of reac-
tive oxygen species by nonprimed neutrophils and monocytes
(29). TTO failed to suppress the adherence reaction of neu-
trophils induced by TNF- stimulation (2) or the casein-in-
duced recruitment of neutrophils into the peritoneal cavities of
mice (1). These studies identify specific mechanisms by which
TTO may act in vivo to diminish the normal inflammatory
response. In vivo, topically applied TTO has been shown to
modulate the edema associated with the efferent phase of a
contact hypersensitivity response in mice (23) but not the de-
velopment of edema in the skin of nonsensitized mice or the
edematous response to UVB exposure. This activity was attrib-
uted primarily to terpinen-4-ol and -terpineol. When the ef-
fect of TTO on hypersensitivity reactions involving mast cell
degranulation was examined in mice, TTO and terpinen-4-ol
applied after histamine injection reduced histamine-induced
skin edema, and TTO also significantly reduced swelling in-
duced by intradermal injection of compound 48/80 (24). Hu-
man studies on histamine-induced wheal and flare provided
further evidence to support the in vitro and animal data, with
the topical application of neat TTO significantly reducing
mean wheal volume but not mean flare area (97). Erythema
and flare associated with nickel-induced contact hypersensitiv-
ity in humans are also reduced by neat TTO but not by a 5%
TTO product, product base, or macadamia oil (119). Work has
now shown that terpinen-4-ol, but not 1,8-cineole or -terpineol,
modulates the vasodilation and plasma extravasation associ-
ated with histamine-induced inflammation in humans (94).
SAFETY AND TOXICITY
Despite the progress in characterizing the antimicrobial and
anti-inflammatory properties of tea tree oil, less work has been
done on the safety and toxicity of the oil. The rationale for
continued use of the oil rests largely on the apparently safe use
of the oil for almost 80 years. Anecdotal evidence over this
time suggests that topical use is safe and that adverse events
are minor, self-limiting, and infrequent. More concrete evi-
dence such as published scientific work is scarce, and much
information remains out of the public domain in the form of
reports from company-sponsored work. The oral and dermal
toxicities of TTO are summarized briefly below.
Oral Toxicity
TTO can be toxic if ingested, as evidenced by studies with
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 rats
dosed with 1.5 g/kg TTO appeared lethargic and ataxic (D.
Kim, D. R. Cerven, S. Craig, and G. L. De George, Abstr.
Amer. Chem. Soc. 223:114, 2002). Incidences of oral poisoning
in children (55, 91, 112) and adults (57, 133) have been re-
ported. In all cases, patients responded to supportive care and
recovered without apparent sequelae. No human deaths due to
TTO have been reported in the literature.
Dermal Toxicity
TTO can cause both irritant and allergic reactions. A mean
irritancy score of 0.25 has been found for neat TTO, based on
patch testing results for 311 volunteers (10). Another study, in
which 217 patients from a dermatology clinic were patch tested
with 10% TTO, found no irritant reactions (150). Since irritant
reactions may frequently be avoided through the use of lower
concentrations of the irritant, this bolsters the case for discour-
aging the use of neat oil and promoting the use of well-formu-
lated products. Allergic reactions have been reported (54, 147),
and although a range of components have been suggested as
responsible, the most definitive work indicates that they are
caused mainly by oxidation products that occur in aged or
improperly stored oil (82). There is little scientific support for
the notion that 1,8-cineole is the major irritant in TTO. No
evidence of irritation was seen when patch testing was per-
formed on rabbits with intact and abraded skin (118), guinea
pigs (82), and humans (118, 141), including those who had
previous positive reactions to TTO (96). Rarely, topically ap-
plied tea tree oil has been reported to cause systemic effects in
domestic animals. Dermal application of approximately 120 ml
of undiluted TTO to three cats with shaved but intact skin
resulted in symptoms of hypothermia, uncoordination, dehy-
dration, and trembling and in the death of one of the cats (17).
PRODUCT FORMULATION ISSUES
The physical characteristics of TTO present certain difficul-
ties for the formulation and packaging of products. Its lipophi-
licity leads to miscibility problems in water-based products,
while its volatility means that packaging must provide an ade-
quate barrier to volatilization. Since TTO is readily absorbed
into plastics, packaging must cater to and minimize this effect.
Consideration must also be given to the properties of the
finished product. Early suggestions that the antimicrobial ac-
tivity of TTO may be compromised by organic matter came
from disk diffusion studies in which the addition of blood to
agar medium decreased zone sizes (8). This observation con-
trasts sharply with historical claims that the activity of TTO
may in fact be enhanced in the presence of organic matter such
as blood and pus. A thorough investigation of this claim com-
prehensively refuted this idea (76) and also showed that prod-
uct excipients may compromise activity.
Some work on the characteristics and behavior of TTO
within formulations has been conducted. Caboi et al. (27)
examined the potential of a monoolein/water system as a car-
rier for TTO and terpinen-4-ol. The activity of TTO products
in vitro has also been investigated (16, 77, 107). However, very
little work has been conducted in this area, and if stable,
biologically active formulations of TTO are going to be devel-
oped, much remains to be done.
CONCLUSIONS
A paradigm shift in the treatment of infectious diseases is
necessary to prevent antibiotics becoming obsolete, and where
appropriate, alternatives to antibiotics ought to be considered.
There are already several nonantibiotic approaches to the
treatment and prevention of infection, including probiotics,
VOL. 19, 2006 ACTIVITY OF M. ALTERNIFOLIA (TEA TREE) OIL 59
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phages, and phytomedicines. Alternative therapies are viewed
favorably by many patients because they are often not being
helped by conventional therapy and they believe there are
fewer detrimental side effects. In addition, many report signif-
icant improvement while taking complementary and alterna-
tive medicines. Unfortunately, the medical profession has been
slow to embrace these therapies, and good scientific data are
still scarce. However, as we approach the “postantibiotic era”
the situation is changing. A wealth of in vitro data now sup-
ports the long-held beliefs that TTO has antimicrobial and
anti-inflammatory properties. Despite some progress, there is
still a lack of clinical evidence demonstrating efficacy against
bacterial, fungal, or viral infections. Large randomized clinical
trials are now required to cement a place for TTO as a topical
medicinal agent.
ACKNOWLEDGMENTS
This review was supported in part by a grant (UWA-75A) from the
Rural Industries Research and Development Corporation.
We are grateful to Ian Southwell (Wollongbar Agricultural Institute,
NSW) for helpful discussions on oil provenance and to staff at the
Australian War Memorial (Canberra, ACT) for sharing their knowl-
edge of Australian military history and TTO.
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62 CARSON ET AL. CLIN.MICROBIOL.REV.
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... The results of the MIC reveal that the formulation has profound action on the bacterial strains. Tea tree oil (5%) had a significant effect in ameliorating the patient's acne by reducing the inflamed and non-inflamed lesions (Carson, 2006). It was reported, that exposing these organisms to MIC and MBC of tea tree oil, inhibited respiration and increased the permeability of bacterial cytoplasmic membrane by uptake of propidium iodide. ...
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The aim of this study is to determine the total phenolic content and the antioxidant potential of Peganum harmala (Zygophyllaceae), medicinal plant widely used in Algerian folk medicine. Air-dried and powdered aerial parts of Peganum harmala, harvested from the area of Tébessa (North-Eastern Algeria), were extracted by percolation using solvents with increasing polarity, successively: petroleum ether (PE), dichloromethane (DM), ethyl acetate (EA) and methanol (ME), to yield dry extracts. The capacity of the obtained extracts to inhibit the free radical 1, 1-diphenyl-2-picrylhydrazyl (DPPH) was measured according to the method of Loo et al. (2008). Total phenolic content was estimated as gallic acid equivalents per milligram of dried plant extract, according to the Folin-Ciocalteu phenol reagent method (Li et al., 2007). The ME extract showed, on the one hand, the best DPPH inhibition percentage at test-concentration, and, on the other hand, the highest yield which was 4.3, 5.6 and 15.8-fold higher than that of PE, DM and EA extracts, respectively. Its total phenolic content was 2-fold higher than that of PE, DM and EA extracts. Peganum harmala may be suggested as a new potential source of natural antioxidant via its ME extract justifying the Algerian folk medicine use of this plant. Further investigations are necessary in order to refine its antioxidant potential and to determine its phytochemical composition.
... The results of the MIC reveal that the formulation has profound action on the bacterial strains. Tea tree oil (5%) had a significant effect in ameliorating the patient's acne by reducing the inflamed and non-inflamed lesions (Carson, 2006). It was reported, that exposing these organisms to MIC and MBC of tea tree oil, inhibited respiration and increased the permeability of bacterial cytoplasmic membrane by uptake of propidium iodide. ...
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The aim of this study is to determine the phytochemical screening and the antibacterial potential of aerial parts from Pituranthos scoparius (Coss. & amp; Dur) Benth. & amp; Hook. (Apiaceae), endemic species widely used in Algerian folk medicine. Air-dried and powdered aerial parts of Pituranthos scoparius, harvested from the area of Tébessa (North-Eastern Algeria), were extracted by percolation using solvents with increasing polarity, successively: petroleum ether (PE), dichloromethane (DM), ethyl acetate (EA) and methanol (ME), to yield dry extracts. The plant aerial parts were screened for the presence of key families of phytochemicals according to the standardized methods (Dohou et al., 2003; Rizk, 1982; Razafindrambao, 1973 and Bouquet, 1972). The antibacterial activity of the obtained dried plant extracts was evaluated against selected pathogenic bacteria, using the well agar diffusion method. The phytochemical screening of the plant aerial parts highlights a variety of secondary metabolites mainly represented by flavonoïds, saponins and alcaloïds. The ME extract, on the one hand, showed against the tested pathogenic bacteria, the best antibacterial effect which was either similar or better than that of some antibiotics-controls and, on the other hand, it exhibited the highest yield which was nearly 2-fold higher than that of PE, DM and EA extracts all together. The good antibacterial effect of PE extract was relativized at view of its extraction lower-yield. The Pituranthos scoparius ME extract may be suggested as a new potential source of natural antibacterial, justifying the Algerian folk medicine use of this endemic species. Further investigations are necessary in order to refine its antibacterial potential and to determine its phytochemical composition.
... The results of the MIC reveal that the formulation has profound action on the bacterial strains. Tea tree oil (5%) had a significant effect in ameliorating the patient's acne by reducing the inflamed and non-inflamed lesions (Carson, 2006). It was reported, that exposing these organisms to MIC and MBC of tea tree oil, inhibited respiration and increased the permeability of bacterial cytoplasmic membrane by uptake of propidium iodide. ...
... broccoli), can promote oxidised dimer formation in the Prx3 protein in Jurkat T-lymphocytes and promyelocytic leukemia cells (the human HL-60 cell line) (Brown et al., 2010;Brown et al., 2008). Allyl sulphides found in garlic (Allium sativum) oil, such as diallyl disulfide (DADS) and diallyl trisulfide (DATS), and terpenoids found in tea tree (Melaleuca alternifolia) oil, such as terpinen-4-ol, have both pro-and anti-oxidant effects but their exact mechanisms of action are not fully understood [11][12][13]. Thus, the aims of the present study were to investigate the effects of garlic oil, DADS, DATS, tea tree oil and terpinen-4-ol on the in vivo redox/oligomerization state of the Prx1, 2 and 3 proteins in Jurkat-T lymphocytes and also to investigate whether the oils/compounds exerted their effects on the typical 2-Cys Prx proteins by inhibiting the activity of TrxR, the enzyme required to regenerate the reduced/thiol state of CP from its disulphide-bonded state. ...
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... 166 Tea tree oil (TTO) is a volatile oil that is used in Australia, Europe, and North America for treatment of tinea pedis. 167 In C. albicans, TTO has been shown to decrease glucose-induced acidification of media surrounding fungi and alter respiration and permeability of plasma membranes. [168][169][170] In a randomized, multicenter, double-blind trial of 117 patients with DLSO of the toenails who applied either TTO 100% or clotrimazole solution 1% twice daily for 6 months, 171 culture cure did not significantly differ between groups (18% vs 11%, respectively). ...
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... In this work, controlled release tests were carried out using tea tree oil [25][26][27][28][29][30][31][32] trapped inside the chitosan matrix containing gold nanoparticles. The tree oil can be extracted from a plant native to the Australian region called Melaleuca alternifolia by steam distillation processes of its leaves and branches [25,29]. ...
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... Melaleuca alternifolia is a well-reputed plant in traditional and folk remedies and remains of interest in modern medicine because of its prolonged historic position as a healing agent [68]. TTO consists of a mixture of~100 various components, mostly sesquiterpenes and monoterpenes, from which 1,8-cineole and terpinen-4-ol are the most active (antibacterial, analgesic, anti-inflammatory, antifungal, antiprotozoal, antiviral) [69,70]. Currently, the beneficial properties of the TTO and its constituents have been alternatively integrated into different products, including dermatological ointments and creams [14]. ...
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Context: The current epidemiological situation causes a new surge of interest to perspective antimicrobial formulations for proper skin hygiene. Aims: To evaluate in vitro and in vivo the antimicrobial activity of a novel active quadrocomplex (QC) for skin hygiene based on Melaleuca alternifolia essential oil, eucalyptol, (-)-α-bisabolol and silver citrate. In addition, to analyze the phytochemical constituents by gas chromatography-mass spectrometry (GC-MS) and to assess the skin irritant potential after regular washing. Methods: The phytochemical analysis was performed using GC-MS. The Minimum Inhibitory Concentrations (MICs) were assessed using a colony-counting method with resazurin. The type of pharmacological interaction was investigated using a modern checkerboard assay. Results: The chemical composition exhibited 18 resolved phytochemicals with the highest concentrations for (-)-α-bisabolol (32.2%) and terpinen-4-ol (31.6%) through the GC-MS analysis. QC agents showed antimicrobial activity against Gram-positive and Gram-negative strains, with MIC values ranging from 1.25 to 40.00 mg/mL. The checkerboard assay demonstrated reduced MIC values for the combinations of QC agents against all reference strains. QC showed significant inhibition of Staphylococcus aureus growth with an average efficiency of 99.91% and Candida albicans 99.94 %. In vivo, the investigation of QC showed higher immediate and prolonged efficiency compared to base formulation (p
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Microbial transformations of cyclic hydrocarbons have received much attention during the past three decades. Interest in the degradation of environmental pollutants as well as in applications of microorganisms in the catalysis of chemical reactions has stimulated research in this area. The metabolic pathways of various aromatics, cycloalkanes, and terpenes in different microorganisms have been elucidated, and the genetics of several of these routes have been clarified. The toxicity of these compounds to microorganisms is very important in the microbial degradation of hydrocarbons, but not many researchers have studied the mechanism of this toxic action. In this review, we present general ideas derived from the various reports mentioning toxic effects. Most importantly, lipophilic hydrocarbons accumulate in the membrane lipid bilayer, affecting the structural and functional properties of these membranes. As a result of accumulated hydrocarbon molecules, the membrane loses its integrity, and an increase in permeability to protons and ions has been observed in several instances. Consequently, dissipation of the proton motive force and impairment of intracellular pH homeostasis occur. In addition to the effects of lipophilic compounds on the lipid part of the membrane, proteins embedded in the membrane are affected. The effects on the membrane-embedded proteins probably result to a large extent from changes in the lipid environment; however, direct effects of lipophilic compounds on membrane proteins have also been observed. Finally, the effectiveness of changes in membrane lipid composition, modification of outer membrane lipopolysaccharide, altered cell wall constituents, and active excretion systems in reducing the membrane concentrations of lipophilic compounds is discussed. Also, the adaptations (e.g., increase in lipid ordering, change in lipid/protein ratio) that compensate for the changes in membrane structure are treated.
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Microbial transformations of cyclic hydrocarbons have received much attention during the past three decades. Interest in the degradation of environmental pollutants as well as in applications of microorganisms in the catalysis of chemical reactions has stimulated research in this area. The metabolic pathways of various aromatics, cycloalkanes, and terpenes in different microorganisms have been elucidated, and the genetics of several of these routes have been clarified. The toxicity of these compounds to microorganisms is very important in the microbial degradation of hydrocarbons, but not many researchers have studied the mechanism of this toxic action. In this review, we present general ideas derived from the various reports mentioning toxic effects. Most importantly, lipophilic hydrocarbons accumulate in the membrane lipid bilayer, affecting the structural and functional properties of these membranes. As a result of accumulated hydrocarbon molecules, the membrane loses its integrity, and an increase in permeability to protons and ions has been observed in several instances. Consequently, dissipation of the proton motive force and impairment of intracellular pH homeostasis occur. In addition to the effects of lipophilic compounds on the lipid part of the membrane, proteins embedded in the membrane are affected. The effects on the membrane-embedded proteins probably result to a large extent from changes in the lipid environment; however, direct effects of lipophilic compounds on membrane proteins have also been observed. Finally, the effectiveness of changes in membrane lipid composition, modification of outer membrane lipopolysaccharide, altered cell wall constituents, and active excretion systems in reducing the membrane concentrations of lipophilic compounds is discussed. Also, the adaptations (e.g., increase in lipid ordering, change in lipid/protein ratio) that compensate for the changes in membrane structure are treated.
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Mycoses of the foot are among the most common pedal problems encountered in podiatric medicine. Melaleuca alternifolia (tea tree) oil has a long history of antiseptic use for dermatologic conditions, including fungal infections, which is largely based on anecdotal evidence. In an in vitro study of the antifungal properties of tea tree oil, the extract proved to have an inhibitory effect on the growth of 10 clinically important fungi.
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The inhibitory effect of seven essential oils on the apical growth of hyphae of Aspergillus fumigatus was studied using a bio cell tracer by vapour contact in a sealed vessel. Based on the inhibitory pattern, these essential oils were classified into three groups. The first group, composed of citron, lavender and tea tree oils, stopped the apical growth in a loading dose of 63 mu g ml(-1) air, but allowed the regrowth of the hyphae after removal of the vapour, indicating fungistatic action. The second group, consisting of perilla and lemongrass oils, stopped the apical growth in a loading dose of 6.3 mu g ml(-1) air, and did not allow the regrowth after gaseous contact at 63 mu g ml(-1) air, indicative of fungicidal action. The third group, consisting of cinnamon bark and thyme oils, retarded the growth in a dose of 6.3 mu g ml(-1) air, stopped it in a dose of 63 mu g ml(-1) air, and incompletely suppressed regrowth of the hyphae. Gas chromatographic analysis revealed that vapours of essential oils were absorbed on fungal mycelia and agar medium most abundantly by the first group, followed by the second and third groups, reflecting the volatility of the respective groups. Suppression of the apical growth by vapour contact was ascribed to the direct deposition of essential oils on fungal mycelia, together with an indirect effect via the agar medium absorbed.
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