Citrus – Bergamot oil (Citri bergamia aetheroleum)
|Latin name of the genus:||Citrus|
|Latin name of herbal substance:||Citri bergamia aetheroleum|
|Botanical name of plant:||Citrus bergamia risso & poiteau.|
|English common name of herbal substance:||Bergamot oil|
Latin name of the genus: Citrus
Latin name of herbal substance: Citri bergamia aetheroleum
Botanical name of plant: Citrus bergamia Risso & Poiteau.
English common name of herbal substance: Bergamot oil
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- 3.4. Overall conclusions on non-clinical data
- 4. Clinical Data
- 4.1. Clinical Pharmacology
- 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.2. Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2. Clinical studies (case studies and clinical trials)
- 4.2.3. Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 6. Overall conclusions
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Citrus bergamia Risso et Poiteau belongs to the family Rutaceae, subfamily Esperidea. Trees grow to a height of 5 metres, with big dark green ovate leaves similar to those of lemon, fragrant star shaped white flowers and round yellow fruits.
The plant is native to tropical Asia but also found in Europe, for instance in Calabria, Italy. It grows also in Morocco, Iran and Ivory Coast (Di Donna et al. 2009). The trees are also cultivated on Kefalonia Island (Greece, Vlachata region) at the same latitude as in Reggio Calabria (Melliou et al. 2009) as well as in Sicily.
The plant appeared in Southern Italy before 1700 and it is believed that Christopher Columbus brought it from the Canary Islands to Italy.
C. bergamia is defined as a hybrid of bitter orange (Citrus aurantium L.) and lemon (Citrus limon L.) Burm. Fil., by some authors, or of C. aurantium L. and Citrus aurantifolia (Christm.) Swing. by others (Moufida et al. 2003). It is mainly cultivated for its essential oils that are obtained by rasping and cold pressing the fruit peel.
Bergamot is the common name of the fruit (Citrus bergamia Risso et Poiteau) and it has been believed that the name derives from the Italian city of Bergamo, placed in Lombardy, where the essential oil could have been first sold; however, this belief seems to be totally unfounded and due to the fruit and city names assonance.
The fruit peel is smooth and thin, whereas the pulp is slightly
Essential oil and juice are the preparations generally obtained from Citrus bergamia. Their chemical content has been extensively studied.
The juice obtained from the endocarp after essential oils extraction has been for a long time considered, also because of its bitter taste, just a secondary and discarded product of the essential oil production. For its organoleptic properties, bergamot juice has not reached the popularity of other citrus juices in the daily diet, but it is used to fortify fruit juice in place of synthetic additives (Di Donna et al. 2009).
Bergamot juice, as well as its peel, has attracted some attention because of its remarkable content of flavonoids. It contains different classes of flavonoids (e.g. flavanones and flavones) that can exert beneficial effects on human health (Gattuso et al. 2006).
Bergamot essential oil (BEO) is a greenish or
BEO is included in the official Pharmacopoeias of various countries. According to the Farmacopea Ufficiale Italiana (12th Ed.), BEO is obtained by cold pressing of the epicarp and, partly, of the mesocarp of the fresh fruit. Percentages of more characteristic components are reported in the Table 1.
Table 1. Percentage of single chemical components in Bergamot essential oil (Bergamotto essenza, Farmacopea Ufficiale Italiana 12th Ed.).
BEO comprises a volatile
The quality and quantity of the
The vacuum distillation of bergamot peels furnishes a
The most abundant compounds found in the volatile fraction are the monoterpene hydrocarbons limonene,
The characteristic flavour and pharmacological properties of Citrus oils are mainly provided by the oxygenated compounds, which consist of alcohols, aldehydes, and esters, such as linalool, citral and linalool acetate, respectively. Linalyl acetate is considered the main constituent of the cold pressed BEO of the rind. Other important constituents are
Oxygenated compounds, namely linalool and linalyl acetate, mark the flavour notes of BEO, whereas the hydrocarbon fraction does not have a fundamental role in determining the olfactory character of BEO. As compared with other citrus oils, bergamot oil is marked by a lower amount of limonene (25.6- 53.0%) and higher amounts of linalool
Equal to other Citrus peels, Bermagot peel still contains other exploitable components in addition to BEO, such as pectins and flavonoids. The flavonoid profile of the peel consists of Citrus characteristic flavanone rutinosides and neohesperosides derived from naringenin, eriodictyol and hesperetin. In addition, a number of minor flavanone and flavone glycosides, not found in orange and lemon peels, have been identified (Mandalari et al. 2006).
BEO is widely used by the cosmetic industries (e.g. in perfumes, soaps, body and sun tanning lotions) for its intense fragrance and freshness, being main ingredient of
BEO is not an alimentary product as such, but it is also widely used in food and confectionery industries as flavouring for liqueurs, teas, toffees, candies, ice creams, and soft drinks. It is also well- known for its use to flavour Earl Grey tea. In the pharmaceutical industries BEO is used as a flavouring for some medicinal products and as a cicatrizing agent, for its antiseptic and antibacterial proprieties while it is also used in aromatherapy (Costa et al. 2010, Martindale 2010).
•Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
1.2. Information about products on the market in the Member States
Regulatory status overview
MA: Marketing Authorisation TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
1.3. Search and assessment methodology
This assessment report reviews the scientific literature data available for Citrus bergamia from the Italian Pharmacopoeia monograph, from PubMed, internet, Medline as well as available information on products marketed in the European Community, including pharmaceutical forms, indications, posology and methods of administration.
The keywords “Citrus bergamia”, “bergamot”, “bergapten” in all text fields were used and the electronic databases were searched till the end of July 2011.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
BEO has been used in Italian folk medicine since 1725, primarily for fever and worms. BEO has been used for mouth, skin, respiratory and urinary tract infections, gonococcal infections, leucorrhoea, vaginal pruritis. It has been also used for tonsillitis and sore throat. In 1804 Francesco Calabrò published a collection of folk remedies reporting for the first time that the topical use of BEO is considered to have wound healing effects (Pendino 1998).
In Hungary, a registered “healing product” in form of ointment containing a mixture of herbal preparations, including BEO, has been on the market since 2008 for mitigation of symptoms (erythema, infiltration, parakeratosis, urticaria) and for nursing of dry, pealing, squamosus skin in the mild or moderate psoriasis.
Promising research is continuing on the antibacterial, antifungal, and antioxidant properties of constituents in BEO.
Most recently, the interest in the ability of BEO to protect neurons from excitotoxicity has triggered an ongoing surge in neuroscience research.
BEO used for aromatherapy is known to be on the market in Bulgaria and in Italy.
2.2. Information on traditional/current indications and specified substances/preparations
For its antiseptic and antibacterial proprieties, BEO has been used in the folk medicine as antiseptic, to facilitate wound healing and as anthelminthic (www.bergamottoconsorzio.it). It has been included in some preparations for upper
BEO has been used in Italy since the beginning of 1900 for its disinfectant activity and as antiseptic for the skin. Bergamot essential oil
a)Liquid antiseptic for medical uses, local infections, personal hygiene
b)Solid disinfectant for daily hygiene
c)Ointment for disinfection of nasal cavities and mouth
d)Preparation intended to be converted into vapour for the treatment of respiratory diseases
Currently in preparations for cutaneous use the
Likewise other essential oils, BEO is widely used in aromatherapy, and has recently received renewed popularity to improve mood and mild symptoms of
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
R.M. Gattefosse (1932) reports the traditional use of BEO as follows:
a)Liquid antiseptic for medical uses, local infections, personal hygiene
Add sodium sulforicinate
Twenty g of the preparation in one litre of water.
b)Solid disinfectant for daily hygiene
Reduce to powder and mix all ingredients. Dose for disinfection: 10 g to be dissolved in water before use.
c)Ointment for disinfection of nasal cavities and mouth
d) Preparation for vaporization and inhalation for the treatment of respiratory diseases
Pour in a bowl of hot water and inhale the vapour generated.
No information on posology in the traditional use for inhalation is available.
The following posology was used in a clinical study in which BEO inhalation resulted as a method of relaxation: after dilution of the essential oil with distilled water 1:75, the mist is dispensed through a vaporizer placed approximately 60 cm away for 15 minutes for a single administration a day (Peng et al. 2009).
It has been reported that BEO exhibited antifungal activity against some dermatophytes and antibacterial activity against Campylobacter jejuni, Escherichia coli O157, Listeria monocytogenes, Bacillus cereus and Staphylococcus aureus (Karaca et al. 2007).
The in vitro activity of three BEO (essential oil,
Candida spp. (Candida albicans, n 5 20; Candida glabrata, n 5 13; Candida krusei, n 5 4; Candida tropicalis, n 5 2; Candida parapsilosis, n 5 1), associated with symptomatic and asymptomatic vulvovaginal candidiasis, was determined using a modification of the NCCLS
In another study, the activities of BEO,
Results showed a MICs (v/v) of all fungi ranged from 0.156% to 2.5% for the essential oil, from 0.02% to 2.5% for the distilled BEO, and from 0.08% to 1.25% for the
It was concluded that data from this study indicate that BEO is active in vitro against several common species of dermatophytes, suggesting its potential use for topical treatment of dermatophytoses (Sanguinetti et al. 2007).
The effectiveness of oil and vapours of bergamot and its components against common foodborne pathogens was investigated. The disc diffusion method was used to screen oil and vapours against
Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, Escherichia coli O157 and
Campylobacter jejuni. The survival of each species, demonstrated to be susceptible in the in vitro studies, was tested on cabbage leaf for 60 s by direct contact and on chicken skin for 10 min by direct contact and 24 h by vapour. The results indicate that BEO was inhibitory and citral and linalool mimicked its effect (P > 0.001). Citral and linalool vapours produced 6 log reductions in L. monocytogenes, S. aureus and B. cereus populations on cabbage leaf after
It was concluded that BEO was effective and linalool the most effective
Some of the components of BEO, limonene, linalool, linalyl acetate and
A study was carried out to investigate the effect of BEO (1.0%, 2.5% and 5.0% w/w) administered to rats on both
attenuated HPA axis activity by reducing the corticosterone response to stress (Saiyudthong & Marsden 2010).
The effects of BEO on the release of amino acid neurotransmitters in rat hippocampus have been studied by in vivo microdialysis and by in vitro superfusion of isolated nerve terminals. The BEO fractions employed are as follows: (1) BEO
The effects of BEO and its fractions on excitotoxic neuronal damage have been investigated in vitro. The study was performed in human
In another study, performed by the same group of researchers, in vitro in human
The effects of BEO on brain damage caused by permanent focal cerebral ischemia in rat have been investigated. BEO
Microdialysis showed that BEO (0.5 ml/kg) did not affect basal amino acid levels, whereas it significantly reduced excitatory amino acid, namely aspartate and glutamate, efflux in the frontoparietal cortex typically observed following MCAo. Western blotting experiments demonstrated that these early effects were associated, 24 h after permanent MCAo, to a significant increase in the phosphorylation and activity of the prosurvival kinase, Akt. Indeed, BEO significantly enhanced the phosphorylation of the deleterious downstream kinase,
The effects of BEO injected into the plantar surface of the hindpaw in the capsaicin test have been investigated in vivo in mice. The intraplantar injection of capsaicin produced an intense and
In another study both linalool and linalyl acetate, injected into the hindpaw, showed a significant reduction of nociceptive response, which was much more potent than BEO. Intraperitoneal and intraplantar pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly
reversed BEO- and
BEO was investigated for its hepatoprotective effect on carbon
Chloroform bergamot fruit extracts and chemical standards corresponding to the main constituents detected were assayed for their capacity to increase erythroid differentiation of K562 cells and expression of
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Citrus bergamia essential oil has been investigated for its biological and pharmacological activities.
BEO possesses analgesic,
Campylobacter jejuni, Escherichia coli O157, Listeria monocytogenes, Bacillus cereus and
BEO possesses anxiolitic and neuroprotective activity and attenuates HPA axis activity by reducing the corticosterone response to stress. Both essential oil and juice seem to have hypolipidemic effects.
The use of the essential oils in aromatherapy to improve mood, mild symptoms of disorders such as
Recently data have been gathered demonstrating that BEO is endowed with specific and reproducible effects on the CNS of rat. For systemic administration of increasing doses (100, 250 or 500 μl/kg, given intraperitoneally) BEO causes a
These effects have been attributed to components of the volatile fraction of the BEO other than bergapten.
Pharmacological properties of bergapten
After UVA irradiation,
In the absence of UVA irradiation, biological effects such as inhibition of melatonin catabolism and blocking of potassium channels have been shown (Forlot 2000).
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
In human volunteers the pharmacokinetics of single oral dose of
No pharmacokinetic data exist for the BEO.
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
No single/repeat dose toxicity, reproductive and developmental toxicity or local tolerance studies have been performed.
BEO causes phototoxic reactions and
BEO is a widely used aromatic (fragrance) ingredient in cosmetics that may be applied on
To identify phototoxic effects, several fragrances (included BEO) were evaluated in vitro with a photohaemolysis test using suspensions of human erythrocytes exposed to radiation sources rich in ultraviolet (UV) A or B in the presence of the test compounds. Haemolysis was measured by reading the absorbance values, and photohaemolysis was calculated as a percentage of total haemolysis. Moderate phototoxic effects were induced by UVA in the presence of seven fragrances (benzyl alcohol, bergamot oil, costus root oil,
The genotoxic potential of bergapten
By using bergamot peel (BP) ethanolic extracts, an
Each BP extract was dissolved in dimethyl sulfoxide (DMSO) and tested in triplicate. Their genotoxic activity was evaluated in comparison to that of the
The two BP extracts, used at doses up to 50 μg/assay, exhibit no genotoxic effect, also when undergoing enzymatic metabolisation. According to the authors this demonstrates that the BP extracts tested do not produce DNA lesions by blocking DNA synthesis and leading to SOS system induction. A lack of genotoxic effects due to bioactivation of the compounds in BP extracts used was confirmed by HPLC analyses, which showed identical chemical profiles for the extracts before and following exposure to the S9 mix (Trombetta et al. 2010).
Psoralen photoadducts have been measured in native DNA, bacterial cells, and in eukaryotic cells such as yeast, hamster cells, mouse cells, and human cells. In order to determine the genotoxic potential of bergapten, the genetic effects of
Most essential oils have been found to be cytotoxic without being mutagenic. However, some of their constituents may be considered as secondary carcinogens after metabolic activation. Psoralen, found in BEO, can induce skin cancer after formation of covalent DNA adducts under ultraviolet A or solar light (Bakkali et al. 2008).
3.4. Overall conclusions on
Citrus bergamia essential oil has been investigated for its biological and pharmacological activities. Bergamot essential oil possesses analgesic,
BEO possesses also anxiolytic and neuroprotective activities. Both bergamot essential oil and juice seem to cause hypolipidemic effects.
The toxicological properties of Citrus bergamia have not been adequately studied.
Mainly due to the presence of psoralens (e.g.
The genotoxic and mutagenic potential of BEO cannot be considered appropriately tested.
4. Clinical Data
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No data available.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No data available.
4.2. Clinical Efficacy
4.2.1. Dose response studies
No dose response studies available.
4.2.2. Clinical studies (case studies and clinical trials)
A study an
Participants were randomly allocated to one of four study groups including (1) a music group, (2) an aroma group, (3) a combined music and aroma group, and (4) a control group. Participants in the music group were asked to listen to preselected soft music for 15 minutes, and those in the aroma group were asked to inhale Citrus bergamia essential oil vapour generated from an ultrasonic atomizer for 15 minutes.
The essential oil was diluted 1:75 with distilled water, and the mist was dispensed through an ultrasonic atomizer placed approximately 60 cm away from the participant. BEO was an extract from the peel of bergamot orange (Citrus aurantium spp. bergamia). The combined music and aroma participants were given both music and essential oil for 15 minutes.
The outcome measure involved heart rate variability (HRV) indices measured before and after the intervention. The low frequency (LF) and high frequency (HF) components of the HRV were used to quantify modulation of the sympathetic and parasympathetic branches of the autonomic nervous system.
The percentage changes of normalised LF (p = 0.003), normalised HF (p = 0.001), and the ratio of LF to HF (p = 0.001) were significantly different among the four groups. Percentage change of normalised LF and HF were significantly different between the control group and the music group. For the percentage change of the ratio of LF to HF, the negative change in the music group, the aroma group, and the combined group was significantly different from that of the increase in the control group.
In addition, no significant differences were found in the percentage changes in systolic blood pressure, diastolic blood pressure, and mean heart rate in the four groups.
The Author concluded that listening to soft music and inhaling Citrus bergamia essential oil was found to be an effective method of relaxation, as indicated by a shift of the autonomic balance toward parasympathetic activity in young healthy individuals (Peng et al. 2009).
4.2.3. Clinical studies in special populations (e.g. elderly and children)
Though often lifesaving, stem cell transplantation (SCT) is a period of great distress for both child and parent. A
Patients were assessed at the time of recruitment, prior to infusion, upon infusion completion, and one hour
Children and adolescents in the treatment group, experienced greater anxiety (p = 0.05) and nausea (p = 0.03) one hour
It was concluded that the trial did not report a benefit of inhalation aromatherapy for reducing anxiety, nausea, or pain when added to standard supportive care, however, it provides the first experimental data on testing BEO among children and adolescents (undergoing stem cell infusion) (Ndao et al. 2010).
This study did not show any advantage using BEO in anxiety, nausea, and pain of 37 paediatric patients with malignant and
4.3. Overall conclusions on clinical pharmacology and efficacy
Inhaling Citrus bergamia essential oil together with listening soft music was shown to be an effective method of relaxation, in an
In conclusion, there are no sufficient data for the clinical use of bergamot essential oil for any indication.
5. Clinical Safety/Pharmacovigilance
5.1.Overview of toxicological/safety data from clinical trials in humans
No data available.
5.3. Adverse events and serious adverse events and deaths
Freund, in 1916, was the first to describe a series of four cases of intense pigmentation in irregular areas after the use of Eau de Cologne followed by exposure to sunshine. He observed the same
phenomenon after experimental use of bergamot oil, one of the perfumes of Eau de Cologne. Rosenthal first used the term “Berlocque dermatitis” because of the form of the resulting pigmentation (Oppenheim 1947).
Hyperpigmentation of the neck, face, arms, or trunk in areas of light exposure have been attributed to psoralens in BEO derived from the peel of Citrus bergamia fruit. Cases have become much rarer since the introduction of artificial bergamot oil and the use of
BEO possesses photosensitive and melanogenic properties because of the presence of furocoumarins, primarily bergapten
The cases of two patients have been described with localised and disseminated bullous phototoxic skin reactions developing within 48 to 72 hours after exposure to bergamot aromatherapy oil and subsequent ultraviolet exposure. The first case was of a woman that had used a bergamot aromatherapy oil preparation 3 days earlier and subsequently stayed outdoors for several hours on a sunny day. In the second case, a woman has visited a sauna 2 days previously where she was exposed to a bergamot aromatherapy oil preparation; after she was exposed to UVA radiation in an adjacent tanning cure. The skin lesions developed gradually within 48 to 72 hours. In both cases the patients have not used in parallel other creams and/or medications (Kaddu et al. 2001).
Essential oil in Earl Grey tea
Earl Grey tea is composed of black tea and the BEO. Adverse effects of bergamot oil in this patient were explained by the potential effects of bergapten as a largely selective axolemmal potassium channel blocker, reducing potassium permeability at the nodes of Ranvier in a
5.4. Laboratory findings
No data available.
5.5. Safety in special populations and situations
No data available.
5.6. Overall conclusions on clinical safety
BEO possesses photosensitive and melanogenic properties because of the presence of furocoumarins, especially bergapten
Even though the oil has been used extensively for many years, there are only a few reports of phototoxic reactions to bergamot aromatherapy oil, which are related to the contact with nebulized BEO only, because furocoumarins are not volatile. Localised and disseminated bullous phototoxic skin reactions developing within 48 to 72 hours after exposure to bergamot aromatherapy oil and subsequent ultraviolet exposure have been reported.
Since BEO could act as photosensitiser, it is generally suggested to avoid sun exposure in the hours following inhalation when
As a general precaution the use of
Safety during pregnancy and lactation has not been established. In the absence of sufficient data, the use during pregnancy and lactation is not recommended.
It has been reported that the presence of BEO in Earl Grey tea, when consumed in excess (more than 1 l per day) may induce reversible effects such as muscle cramps, fasciculation, paraesthesias and blurred vision.
6. Overall conclusions
Citrus bergamia essential oil, known also with the common name of bergamot oil (BEO), is traditionally used in folk medicine in particular in Italy. BEO in magisterial, handicraft and homemade preparations for cutaneous use, as an antiseptic for the disinfection of skin and as an aid in healing of minor wounds, has a long tradition of use in Italy that can be dated back since more than 30 years.
BEO is generally well tolerated, but it could act as photosensitiser, due to the presence of furocoumarins, mainly bergapten
However, adequate information on strength and posology used in these traditional preparations is not available and therefore a traditional use monograph cannot be established, due to the lack of sufficient data: the requirement laid down in Article 16a(1)(b) of Directive 2001/83/EC that the herbal substance or herbal preparation is “exclusively for administration in accordance with a specified strength and posology” is not fulfilled.
Recent literature data suggest that Citrus bergamia essential oil could be used by inhalation (aromatherapy) for the relief of mild symptoms of mental stress. However, this use is not substantiated by information on
No single preparation medicinal product is authorised in the European Community and