By Anastasia Agapouda

Leptospermum scoparium or Manuka, as it is commonly known, is the most widespread and important indigenous shrub in New Zealand (Stephens, Molan, Clarkson, 2005). It is also known as the “New Zealand tea tree’’ or, by the native Maori, as “kahikatoa’’ (Old, N, 2013). It can also be found on mainland Australia from New South Wales to western Victoria and in Tasmania (Stephens, Molan, Clarkson, 2005) and if you are interested in this unique plant you can always find it in the Mecklenburgh Square Garden. The human perspective of this plant has changed over the years and currently Manuka is appreciated for the antibacterial and anti-viral properties of its essential oil. Leptospermum scoparium J.R.Forst. & G.Forst. belongs to the Myrtaceae, all of whose species are woody and contain essential oils (Old N, 2013). The name Leptospermum is derived from the Greek words leptos=slender and sperma=seed, while scoparium comes from the Greek word scoupa=broom (Peytavi, 2010). Manuka is an evergreen shrub or small tree which usually grows to 2 metres tall but occasionally reaches 4 metres, while 8 metres is the maximum height it can reach. Its bark is close and firm with young stems carrying silky hairs. The leaves can vary in size and shape but are usually elliptical (oval and pointed) and leathery, with curved margins (Stephens, Molan, Clarkson, 2005). Its flowers are usually large and white but rarely pink or red, with brown centres and are seen in blossom between March and September in the UK. (Old N, 2013).

Manuka has the advantage of being able to grow in a variety of soils and conditions from sea level to alpine areas. It thrives in infertile and well-drained soils that are considered unsuitable for the growth of other plants. It can also tolerate soils with low or high moisture levels, strong winds and even salt sprays. It is interesting how it survives in extreme conditions. For example, its root is able to survive 272 days of continuous flooding. Its ability to survive and grow in so many different environments could explain the great variability within the genus; 83 species of Leptospermum have been observed, varying both morphologically and in chemical composition. The plant seems to have the ability of adjusting phenotypically to different environments (Stephens, Molan, Clarkson, 2005).

Manuka’s role within the ecosystem

Manuka is economically and ecologically important to New Zealand. The environment of New Zealand has undergone many disturbances, from fires to clearance for pasture establishment by settlers. Those conditions led to low-nutrient level areas and set the perfect circumstances for the flourishing of Manuka. Being fast growing and producing great amounts of seeds, Manuka not only thrives in such conditions, but also constitutes the woody pioneer which is necessary for the development of a forest (Derraik, 2008). For this reason Manuka is often used in many reforestation projects. In addition, its foliage intercepts a considerable amount of rainfall (up to 50%) during a storm, controlling soil erosion (Stephens, Molan, Clarkson, 2005).

Despite Manuka’s beneficial contribution to the vegetation of New Zealand, it was initially considered a harmful weed in the 1900s and its eradication was a widespread goal among farmers (Derraik, 2008). However, the human perception of the plant changed completely after the acknowledgement of its medicinal uses.

Historical and modern uses

Most evidence for the traditional uses of Manuka relates to the indigenous people of New Zealand, the Maori. Leptospermum scoparium was used for a range of ailments, from skin conditions to dysentery and fever.

Leaves: The Maori used to boil the leaves of the plant and make a decoction which was used for urinary complaints, cold relief and dysentery (Brooker, Cooper, 1961).
Bark: The bark was thought to have sedative properties when chewed and was used in cases of insomnia and anxiety (Old N, 2013). Preparations of the bark were also rubbed on painful joints and appeared to relieve inflammation. The inner bark was boiled and used as a mouthwash.
Gum: Pia Manuka, the white gum obtained from the plant, was used in order to cure constipation in suckling babies. It was also given to adults to alleviate cough and to restore burns and scalds (Brooker, Cooper, 1961).
Essential oil: The oil distilled from the leaves of the plant was used both internally to cure constipation and externally as an anti-inflammatory agent (Old N, 2013).

European contact with the Maoris began with the arrival of Captain James Cook in New Zealand in 1769. He observed and recorded the uses of Manuka and he dispensed the knowledge on New Zealand flora, in Europe (Brooker, Cooper, 1961). Cook named Manuka “tea tree”* because he and his men used the leaves to make a tea substitute (Derraik, 2008). Later, Captain Cook used Manuka infusions to combat scurvy (Derraik, 2008). He also recorded that decoctions from the leaves were emetic (induced vomiting) in strong doses. Finally, both European settlers and Maoris used Manuka wood as a firewood and for the manufacture of weapons and tools (Derraik, 2008). Currently, the use of the essential oil of Manuka is widespread due to its antimicrobial, anti-virus and relaxing properties, as well as in household disinfectant products and in skincare products. Manuka honey, which is produced from the plant’s pollen, is also widespread on the market and has been tested for its antimicrobial and wound-healing effects (Old N, 2013).

*The name tea tree has been used for a wide range of often very different species, see for example the (Australian) Melaleuca alternifolia (Maiden & Betche) Cheel (Myrtaceae – myrtle family)

Phytochemistry

Studies on the phytochemistry of Leptospermum scoparium have focused on its essential oil due to its antimicrobial activity. The essential oil is produced via steam distillation, mostly from the leaves of the plant. It has been found to contain three major groups of components: monoterpenes are present at low levels (around 3%), sesquiterpene hydrocarbons comprise the dominant class (>60%) and the pharmacologically active triketones amount to 20-22% (Porter, Wilkins, 1999). Sesquiterpenes and monoterpenes belong to a larger class of secondary metabolites called terpenes and they play an important role in plant physiology. Triketones, with leptospermone, isoleptospermone and flavesone being the most abundant and pharmacologically active, are responsible for the antibacterial effects of Manuka oil (Christoph, Kubeczka, 1999). The great infraspecific variability that exists in Leptospermum scoparium species also reflects on the composition of the essential oil. There are differences in consistency of the oil between different areas. For example, the essential oil from the Australian Manuka has little to no triketone content and its antimicrobial activity is limited. There are three major geographical chemotypes of Manuka oil:

1) the high α-pinene chemotype in the North,
2) the high triketone chemotype on the East Cape and
3) a chemotype containing a mixture of sesquiterpenes on the North and South islands of New Zealand.

The desired high-triketone chemotype is localized almost exclusively on the East Cape of New Zealand (Douglas, van Klink, Smallfield, 2004). Manuka oil is often compared and confused with the oil from the Australian Melaleuca alternifolia (tea tree) oil because they both have antibacterial properties but the high content of triketones is what differentiates Manuka oil from other Myrtaceous oils (Porter, Wilkins, 1999). Standardization of Manuka oils to triketone content could allow discrimination between pure and mixed (or adulterated) oils.

Some methylated and methoxylated flavonoids (flavan-3-one derivatives) have been isolated from extracts of external parts of the plant and have been tested for pharmacological activity (Häberlein, Tschiersch, 1998). Flavonoids are secondary plant metabolites that have great antioxidant properties.

Scientific evidence and in vitro studies

Manuka oil as an antibacterial:

Most studies on the essential oil of Leptospermum scoparium focus on its antibacterial effects, especially against Gram positive bacteria. A lot of research teams aimed to test the antibacterial properties which are related to β-triketone content and leptospermone in particular. All tests below were conducted using the method of paper disc agar diffusion (consisting of cultivation of a pathogen on a plate with nutrients and then adding of the antibacterial agent to check the inhibition of the microbe). Jeong EY, Jeon J. and Kim H., examined in vitro in 2009 the activity of Manuka oil, distilled from the seeds of the plant, against intestinal bacteria. It was found that it strongly inhibited the growth of Clostridium difficile and Clostridium perfringens at the concentration of 5 mg/disc without affecting the natural intestinal flora. In contrast, it did not have any effect on Escherichia coli.

The antibacterial activity is also highlighted by Harkenthal, Reichling, Geiss and Saller (1999). They compared the antimicrobial potency of Manuka oil with that of Australian Tea tree oil (TTO) and found that Manuka oil is more potent than TTO against gram positive bacteria. The minimum inhibitory concentration of Manuka oil was 0.12%. It was also effective against some antibiotic-resistant Staphylococcus species.

The findings of Harkenthal et al. were in agreement with those of van Klink, Larsen and Perry in 2005. This team showed that β-triketones (leptospermone, isoleptospermone and flavesone) are highly active against gram-positive bacteria. β-triketones were also found to be effective against methicillin-resistant Staphylococcus aureus and against multidrug-resistant Mycobacterium tuberculosis at concentrations of 65-125 μg/ml per agar disc. They also found that triketones act by breaking through the cytoplasmic membrane. This could explain why triketones are not active against Gram-negative bacteria, which have an outer membrane which protects the cytoplasmic membrane. The disadvantage of triketones is that they target both bacteria and mammalian cells. This lack of selectivity could lead to toxicity.

The results of these studies indicate that Manuka oils with high β-triketone content have some efficacy against bacteria. This could help combat the emerging problem of multidrug-resistance developed by bacteria. Testing those findings in vivo and even in clinical trials would be a challenge for future research.

Manuka oil against Herpes virus:

Herpes simplex virus (HSV) is a human pathogen which produces epidermal lesions mostly in and around the oral cavity. HSV type 1 is responsible for epidermal lesions and HSV type 2 responsible for genital lesions. The team of Reichling and Koch (2005) tested in vitro the anti-infective effects of Manuka oil against both types of Herpes virus by measuring the reduction of plaque formation (toxic factor caused by the virus). They showed that the essential oil reduced considerably the plaque formation (by 99.5% for HSV1 and 98.9% for HSV2) at non-cytotoxic concentrations. The main components responsible for the anti-viral activity are leptospermone and flavesone. Manuka oil inactivates HSV before it enters the cell and it may act by binding to viral proteins which enable the penetration of host cell. The research team also proved that Manuka oil is a much more potent anti-herpes agent than tea tree or eucalyptus oil, but less potent than acyclovir (a common treatment for Herpes infection). The topical use of Manuka oil could give a solution to patients who are often infected with the virus.

Manuka oil against photoaging:

Ultraviolet (UV) radiation is one of the major factors that causes skin damage and photoaging. Kwon S., Jung S. and Yang B. (2013) examined the effects of Manuka oil in combating photoaging in mice. They showed that topical application of Manuka oil at a concentration of 10% inhibited wrinkle formation, epidermal hyperplasia (skin thickening) and prevented loss of fiber collagen in the skin. It was found that Manuka oil inhibited the expression of MMPs, the genes responsible for elimination of collagen fibres. Loss of fibres of collagen is what causes wrinkles in the skin. The team also showed that a 10% solution of Manuka oil suppresses UV-induced inflammation of the skin by inhibiting the production of the inflammation-causing cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). It also inhibited the increase of macrophages by 75.3%.

Manuka oil as a household disinfectant:

House-dust and stored food can contain mites which are the principle cause of allergic diseases to human, from asthma to atopic dermatitis. Jeong Y., Kim M. and Lee H. (2009) examined the acaricidal (i.e. against mites) effects of Manuka oil and compared the results with commonly used synthetic chemicals (benzyl benzoate and DEET). Manuka was found to be 68.7 , 27.2 and 11.5 times more effective than the commonly used DEET against Dermatophagoides farina, Dermatophagoides pteronyssinus and Tyrophagus putrescentiae respectively. These results were based on LD50 value which is the amount of substance required to kill 50% of the population of bacteria. The active component responsible for the activity is again leptospermone and it might act by affecting the biological activity of the mites.

Manuka oil as a relaxant:

The essential oil of Leptospermum scoparium is used by many aromatherapists for its muscle relaxing properties. There is some evidence for these effects of Manuka oil, but they have not been confirmed by clinical trials in humans. Lis-Balchin M., Hart S. and Deans S. (2000) tested the muscle relaxing properties ex vivo (guinea-pig ileum, skeletal muscle, rat nerve diaphragm and rat uterus). Manuka oil exerted a strong spasmolytic effect in the guinea-pig ileum and also caused a decrease in tension and a delayed increase in resting tone on the phrenic nerve diaphragm. Also, a decrease in tension on the skeletal muscle was found but not as strong as the effect of the Australian tea tree oil. Manuka also decreased the force on the uterine muscle and the frequency of the naturally occurring contractions. These findings indicate that Manuka oil has some activity as a relaxant but the same actions were also shown by clary sage, dill, fennel, frankincense and nutmeg. It seems that cyclic adenosine monophosphate (cAMP) may play a role in the mechanism of action (Lis-balchin, Hart, Deans, 2000). cAMP is a messenger involved in many biological processes.

Cautions-Interactions

As discussed earlier, Manuka oil exerts a strong spasmolytic effect and may affect the contractions of the uterus. Internal and external use should be avoided both during pregnancy and lactation because it could be harmful for the mother and the child (Lis-Balchin, Hart, Deans, 2000).

In an in vitro study, Manuka oil demonstrated moderate toxic effects in cell cultures with the non-toxic dose (28.8 μg/ml) being close to the toxic dose (38.4 μg/ml) but again, there are no clinical data on the toxicity in animals or in humans (Reichling, Koch, 2005). Essential oils can be irritating, especially for the internal mucosal membranes. In addition, due to the variation in the composition of the oil, the quality cannot always be assured.

The ketonic fraction of the essential oil (triketones) showed interactions with some antibiotics which are often used in community settings, in particular synergy was found with bacitracin, cefadroxil, cephradin and meropenem. Synergy is the interaction of two or more medicinal agents and causes an increase in the effects of one or both of the drugs. Antagonism is the opposite of synergy and it was found between Manuka oil and the fluoroquinolones: ofloxacin and enoxacin (Kim, Rhee, 1999). Fluoroquinolones are broad-spectrum antibiotics often prescribed for genitourinary infections. The concomitant use of Manuka oil (internally and externally) and of the antibiotics above should be avoided.

Leptospermum scoparium contains lipophilic flavonoids which were shown to have high binding affinity to the benzodiazepine receptors in vitro. There is a competition between those flavonoids and benzodiazepines for the benzodiazepine binding sites, so Manuka oil or plant preparations and benzodiazepines should not be used at the same time (Häberlein, Tschiersch, Schäfer, 1994).

Closing thoughts

Manuka is a fascinating plant both for its ecological value and for its ethnopharmacological uses that triggered most of the recent research. Of course, there is scope for further research on other uses of Manuka plant parts and oil described by the indigenous Maori and the first settlers and also on the toxicity and mechanism of action in vivo. Manuka oil has shown some promising effects but only better clinical evidence and in vivo experiments will be a sound verification of pharmacological effects, efficacy and safety. When in vitro studies are being conducted we have to keep in mind that only extract concentrations of <50 μg/ml and compound concentrations of <5 μM are meaningful (Gertsch, 2009). Another important factor is that compounds and extracts behave differently in an in vitro system and within a living organism due to the factors of absorption and distribution in the body which affect the bioavailability of a drug (Butterweck, Nahrstedt, 2012). So due to the lack of in vivo experiments, preparations from Leptospermum scoparium cannot be considered as medicines but as supplementary constituents used to reinforce the activity of conventional medicinal products or used in cosmetic products and aromatherapy.

Commercial development of the essential oil has led to a range of “over the counter’’ products produced in New Zealand and exported to markets all over the world. As of 2016, there are no registered (THR) Manuka medical products on the UK market. Leptospermum scoparium has been planted on a large scale on the British Isles as a garden plant and it is also abundant in gardens in Ireland (Stephens, Molan, Clarkson, 2005). So, it is always a nice opportunity to see this unique and beautiful plant at Mecklenburgh Square Garden.

Disclaimer

In this essay we do not to advise or recommend herbs for medicinal or health use. This information is intended for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products)

© Anastasia Agapouda
Msc student (2015-2016)
Research Cluster Biodiversity and Medicines
Centre for Pharmacognosy and Phytotherapy
UCL School of Pharmacy, Univ. London
29 – 39 Brunswick Sq
London WC1N 1AX

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