Olea – Olive leaf (Oleae folium)
|Latin name of the genus:||Olea|
|Latin name of herbal substance:||Oleae folium|
|Botanical name of plant:||Olea europaea l.|
|English common name of herbal substance:||Olive leaf|
Latin name of the genus: Olea
Latin name of herbal substance: Oleae folium
Botanical name of plant: Olea europaea L.
English common name of herbal substance: Olive leaf
- 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
The aim of this report is to assess available preclinical, clinical and other relevant data on Oleae folium for preparing a Community monograph. This report is based on the documentation provided by the European Medicines Agency (EMA) completed by additional searches and information taken from recent international literature on Olea europaea L., Oleae folium.
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Olea europaea L. belongs to the Oleaceae family. The name Olea europaea L. synonym with
O. officinarum CRANTZ; O. pallida SALISB applies to both the wild O. europaea ssp. sylvestris
(MILLER) ROUY (syn O. oleaster HOFFM. et LINK, O. sylvestris MILL.) and domestic (cultivated) plant which is mainly known as O. europaea ssp. sativa (HOFFM et LINK) ROUY (syn = O. europaea L. var. europaea, O. europaea ssp. sativa LOUD., O. europaea L. ssp. sativa ARCANG., O. gallica MILL.,
O. hispanica MILL., O. lancifolia MOENCH, O. sativa GATERAU). Several varieties have been recognised. More than 300 are differentiated, among which more than 150 only in Italy for oil or table- olives production (Blaschek et al. 2006).
The olive tree is an evergreen that grows to approximately
Latin Name: Olea europaea folium (Oleaceae); olive leaf (English), Feuilles d’Olivier (French), Ölbaumblätter, Olivenblätter (German), Foglie di olivo (Italian), Hojas de olivo (Spanish), folhas de oliveira (Portuguese); Olijfblad (Dutch), liść oliwki (Polish), Φύλλα Ελιάς (Greek)
O. europaea L., folium is the dried leaf of the plant containing minimum 5% of oleuropein (C25H32O13; Mr 540.5) (Ph. Eur. 2008:1878).
The leaf is simple, thick and coriaceous, lanceolate to obovate,
The leaves are harvested from cultivated trees and dried in the shade. The crude herbal drug complies with the European Pharmacopoeia monograph “Oleae folium” 01/2009:1878. The drug tastes bitter. It can be identified by its microscopic characteristics, particularly the presence of many
Constituents of olive leaves
–Iridoid monoterpenes: including among others, oleuropein
–Triterpenes: including oleanolic acid, maslinic acid etc.
–Flavonoids: luteolin, kaempferol, chrysoeriol and apigenin derivatives etc.
–Phenolic acids: cumaric acid, caffeic acid, ferulic acid, vanillic acid etc.
–Coumarins: aesculetin, scopoletin, aesculins.
Additional analytical information:
The main constituents of olive leaves are secoiridoids like oleuropein, ligstroside, I methyloleuropein, and oleoside (Gariboldi et al. 1986) as well as flavonoids (apigenin, kaempferol, luteolin, chrysoeriol) and phenolic compounds (caffeic acid, tyrosol, hydroxytytrosol) (Ross 2005).
Two new phenolic compounds were isolated from fruits of O. europaea, Hojiblanca cultivar. The first compound is the methyl acetal of the aglycone of ligstroside, while the second derivative, not yet reported in the literature, is the
The secoiridoids is a very specific group that are abundant in Oleaceas and many other plants that are produced from the secondary metabolism of terpenes as precursors of various indole alkaloids and are usually derived from the oleoside type of glucoside oleosides, which are characterised by a combination of elenolic acid and a glucosidic residue. It can be stated that these compounds proceed from the acetate/mevalonate pathway (Gariboldi et al. 1986).
Oleuropein 1, the major constituent of the secoiridoid family in the olive trees, is a complex phenol present in large quantities in olive tree leaves, in low quantities in olive oil
Triterpenes have been also isolated like maslinic acid,
Olive leaves contain around
Olive leaf extract is derived from the leaves of the olive tree. The olive leaf dry extract complies with the European Pharmacopoeia monograph “Oleae folii extractum siccum” 04/2009:2313 of European Pharmacopoeia.
Olive leaf and extracts are utilised in the complementary and alternative medicine community for its perceived ability to act as a natural pathogens killer by inhibiting the replication process of many pathogens. Olive leaf is commonly used to fight colds and flu, yeast infections, and viral infections such as the
•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.
Oleae folium is reported to be used in combinations with Rauwolfia (Holzhauer & Knobloch 1950),
Veratrum or with Viscum album.
This assessment and the monograph refers exclusively to the use of Oleae folium as a single ingredient.
Vitamin(s)1: not applicable
Mineral(s)1: not applicable
1.2. Information about products on the market in the Member States
The following information has been received on products in European Union:
Preparations: Powdered dried leaves since 1980
Pharmaceutical form: Hard capsules
Posology for oral use in adults:
Posology for oral use in adults:
(or 2 times daily
Powdered or cut leaves for oral use as herbal tea or
Powdered or cut leaves for oral use in capsules
Posology for oral use in adults: 3 times daily
Indications: Traditionally used to enhance the renal excretion of water and to support the cardiovascular system.
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
Databases: Pubmed, Medline, HealLink, Scopus were searched with the search term Olea europea L., olive leaf,
Libraries: University of Athens, Laboratory of Pharmacognosy and Chemistry of Natural Products of the University of Athens
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
The leaves of the olive tree O. europaea have been widely used in folk medicine in regions around Mediterranean Sea and the islands therein (Bouaziz and Sayadi, 2005).
Olive leaf and extracts are utilised in the complementary and alternative medicine community for its ability to act as a natural pathogens killer by inhibiting the replication process of many pathogens (Juven and Henys 1972). Olive leaf extract has been also used as a folk remedy for combating fevers and other diseases, such as malaria, while several reports have shown that it has the capacity to lower blood pressure in animals, to increase blood flow in the coronary arteries, to relieve arrhythmia and to prevent intestinal muscle spasms (Samuelson 1951; Zarzuelo 1991).
Interest in the potential benefits of extracts from the olive tree originates from two main independent historical sources. The first formal medical mention of the olive leaf, an account describing its ability to cure severe cases of fever and malaria, occurred about 150 years ago. In 1854, the Pharmaceutical Journal published a report by Daniel Hanbury. The author wrote he discovered the effective tincture in 1843 and had used it successfully. As second source appear records that, in the early 19th century,
Spanish physicians sometimes prescribed olive leaves as a “febrifuge”, and consequently, during the Spanish war of
Decades later, scientists isolated a bitter substance from the leaf and named it oleuropein. It was reported that it makes the olive tree particularly robust and resistant against insect and bacterial damage. Oleuropein is an iridoid, a structural class of chemical compounds found in plants. It is present in olive oil, throughout the olive tree, and is the bitter material that is eliminated from the olives when they are cured. In 1962, an Italian researcher reported that oleuropein lowered blood pressure in animals (Panizzi L. et al. 1960). This triggered of scientific interest in the olive leaf. Other European researchers confirmed this interesting finding. In addition, they found it could also increase blood flow in the coronary arteries, relieve arrhythmias, and prevent intestinal muscle spasms (Petkov & Manolov 1972; Juven & Henys 1972; Kubo & Matsumoto 1984). The dried or fresh leaves have been also used against malaria as antipyretic as well as diuretic.
France: “Feuille d’olivier” Olive leaf is regarded as one of the herbal drugs whose efficacy and safety has been proven by thorough literature studies and
Germany: Olive leaves have been traditionally used at least since 1976, for prevention of atherosclerosis and against hypertension (Martindale 1996). It has also been used in combination either with Rauwolfia (Holzhauer & Knobloch 1950), Veratrum or with Viscum album.
The Commission E issued a negative monograph (Blaschek et al. 2006; Blumental et al.1998).
Worldwide, the following information has been received (references available to the Rapporteur):
Arabic countries: In Unani medicine, dried plant is taken by fumigation as an abortifacient.
Argentina: Decoctions of the dried fruit and of the dried leaf are taken orally for diarrhoea and to treat respiratory and urinary tract infections.
Brazil: Herbal tea of the fresh leaves is taken orally to treat hypertension and to induce diuresis.
Bulgaria: Herbal tea of the fresh or dried leaves is taken orally to treat hypertension (Petkov 1979).
Canary Islands: An infusion prepared from the fresh or dried leaf is taken orally as hypoglycaemic agent. Leaves are taken orally as hypotensive and administered per rectum for haemorrhoids.
Cuba: Herbal tea of the fresh leaves is taken orally to treat hypertension
Greece: Hot water extract of the leaf is taken orally for high blood pressure.
Italy: Extract of the fruits essential oil is taken orally as a cholagogue and laxative and to treat renal lithiasis. It is used externally to treat sores, burns, and rheumatism. Water extract of the fruits essential oil is used externally to treat sunburns. Decoction of the fruit essential oil is taken orally as a diuretic and hypotensive. Fruit fixed oil is taken orally as a febrifuge. Infusion of the dried leaf is taken orally as a hypotensive and is used for its
Japan: Hot water extract of the dried bark is taken orally as an antipyretic, for rheumatism, as a tonic and for scrofula.
Kenya: Stem, fresh and dried twigs of O. europaea ssp. africana are used as a chewing stick.
Madeira: Infusion of leaves of O. europaea var. maderensis is taken orally as an antihypertensive.
Mexico: Decoction of dried leaves is taken orally for diabetes.
Morocco: Leaves are taken orally for stomach and intestinal disease and used as a mouth cleanser. Essential oil made from the leaves is taken orally for constipation, liver pain and tonic and applied externally for hair care.
Oman: Barks and leaves are applied externally for skin rash. The Cataplasm prepared from leaves is applied externally for ulcers.
Peru: Hot water extract of the dried bark is taken orally for urinary retention, herpes simplex, and constipation and to expel biliary calculi.
Reunion Island: Hot water extract of the dried O. europaea ssp. africana plant is taken orally for diabetes, diarrhoea, rheumatism, fever and gastroenteritis in infants.
Serbia: (former Yugoslavia) Hot water extract of the dried leaf orally for diabetes. (Ross 2005).
Spain: Infusion of the leaf is taken orally for hypertension. Extracts of the leaf is taken orally for gastrointestinal colic. Leaves are eaten for diabetes.
Tunisia: Extract of the dried leaf is taken orally for diabetes and as hypotensive.
Turkey: The fruit is used externally as a skin cleanser.
Ukraine: Hot water extract of dried plant is taken orally for bronchial asthma.
2.2. Information on traditional/current indications and specified substances/preparations
The following herbal substances and herbal preparations are on the European market for a period of at least 30 years as requested by Directive 2004/24 EC and were proposed for the monograph on traditional use.
–fresh or dried leaves Herbal preparations
–comminuted leaves for herbal tea
–powdered dried leaves,
Indications of the traditional herbal substance and preparations of Olive leaves.
Traditional herbal medicinal product according the European market overview:
–to support cardiovascular function (Germany);
–to enhance the renal excretion of urine (France);
–herbal medicinal product for the relief of functional cardiovascular complaints (Spain);
–cardiovascular system (in France and Spain).
After discussions in both MLWP and HMPC it has been acknowledged that the tradition and the pharmacologically plausible threefold mild activity (diuretic, antidiabetic,
Traditional herbal medicinal product used to promote the renal elimination of water, in mild cases of water retention.
Herbal preparations in solid dosage forms for oral use or comminuted herbal substance as herbal tea for oral use.
After the acceptance of the above referred indication, the HMPC agreed that products used for more than 35 years in Germany (liquid extract
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
Adults and elderly
–fresh or dried leaves
Up to 20 g of fresh or up to 10 g of dried olive leaves in 300 ml of water, boiled, till the water to reach 200 ml, filter. To be consumed hot twice a day (morning and evening) (Van Hellemont 1986).
–comminuted or powdered dried leaves for herbal tea (Duke 2002; Raynaud 2005).
Powdered dried leaves,
Duration of use
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
O. europaea, and its products and chemical constituents have been recognised as important components of a healthy diet because of their phenolic content (Visioli et al. 2002). The olive leaf
extract is used to enhance the immune system, as an antimicrobial, antiviral, as an antioxidant, hypoglycaemic agent and for use in cardiovascular problems (PDR for Herbal Medicines 2007).
In vitro studies
Dried leaf extracts (ethanol:water 1:1) at concentrations of 500 mg/ml, were found to be inactive in vitro against Aspergillus fumigatus, A. niger, Fusarium oxysporum, Penicillium digitatum, Rhizopus nigricans, Trichophyton mentagrophytes, Candida albicans and Saccharomyces pastorianus (Guerin & Reveillere 1985).
Activity against Mycobacterium tuberculosis (H37Rv TMC 102) of 95% ethanol extracts of O. europaea (part not specified) has been reported, using the broth culture method (Grange & Davey 1990).
Hot water extracts of olive leaf of Argentinian origin, at a concentration of 62.5 mg/ml, were found to be inactive against Staphylococcus aureus, Aspergillus niger and Escherichia coli (agar plate method) (Anesini & Perez 1993).
Hot water leaf extracts (1 mg/ml) were inactive against Salmonella typhi (Perez & Anesini 1994).
Olive leaves are known to resist insect and microbial attack, and in vitro studies have been conducted to establish the range of activity of olive leaf extracts. Olive leaf extract has been reported to be an effective antimicrobial agent against a variety of pathogens, including Salmonella typhi, Vibrio paraemoliticus and Streptococcus aureus (including
An aqueous extract of olive leaf was bactericidal against Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus (0.6% w/v), as well as bacteriostatic against
Bacillus subtilis (at 20% w/v) (Markin & Duek 2003).
In vitro antiviral activity of an olive leaf extract (not further defined) against
The virucidal activity of olive leaves is more likely to be attributed to its ability to prevent virus entry into the cells. It may be due to the interaction of olive leaf extract with Vero cell membrane and/or
Olive leaf has been reported to inhibit platelet aggregation and production of thromboxane A2 (a stimulator of platelet aggregation with vasodilatory effects) (Petroni et al. 1995).
The effects on PRP aggregation of oleuropein, another typical olive oil phenol, and of selected flavonoids (luteolin, apigenin, quercetin) were also tested and found to be much less active. On the other hand a partially characterised
Also of interest is a recent study reporting that olive leaf extract inhibited both angiotensin converting enzymes (Hansen et al. 1996).
Experiments have been conducted to demonstrate the antioxidant activity of olive leaf extracts. In rat epithelial cells stimulated with cytokines, an olive leaf polyphenol concentrate extract reduced nitrite concentration and free radical production. The effects of several natural antioxidants on nitric oxide modulation and oxidative status were determined in rat epithelial lung cells. Resveratrol and olive leaf polyphenol concentrate extract were found to be effective in reducing nitrite levels, modifying nitric oxide mRNA, and decreasing free radical production. In particular resveratrol and olive leaf polyphenol concentrate extract, may have therapeutic potential in the treatment of inflammatory diseases (Zaslaver et al. 2005).
Recently (Fleming et al. 2011) an in vitro study, kinetic measurements was performed with an 80% ethanolic extract of olive leaf and its possible inhibitory effects on xanthine oxidase, an enzyme well known for its significant contribution to the pathological process of gout. The studied standardised extract significantly inhibited the activity of xanthine oxidase. Through this study the authors suggest to provide a rational basis for the use of olive leaves against gout in Mediterranean folk medicine.
Effects on the inflammatory response
Fresh olive leaf extracts of Italian provenance were assessed in vitro for effects on the complementary system both alternative and classical pathways. Neither ethyl acetate (50 mcg/ml) nor methanol
(50 mcg/ml) extracts inhibited the alternative pathway while both inhibited the classical pathway, at IC50 >7.7 µ/ml (EtOAc) and >5.8 µ/ml (MeOH) (Pieroni et al. 1996).
The inhibitory action of the olive leaf ethanol extract on the activities of human amylases was examined in vitro. Olive leaf ethanol extract inhibited the activities of
In vivo studies
Although tradition attributes to the olive tree leaf numerous properties (febrifuge, hypoglycaemic, hypotensive, diuretic, and more) few of them have been studied experimentally.
Animal experiments studies suggest olive leaf extracts possess antiviral activity against viral haemorrhagic septicaemia rhabdovirus (VHSV) (Micol et al. 2005).
Oleuropein has been claimed in a United States patent to have potent antiviral activities against DNA and RNA viruses such as herpes mononucleosis, hepatitis virus, rotavirus, bovine rhinovirus, canine parvovirus, and feline leukaemia virus (safe and effective natural antiviral agents, the antiviral activity of a commercial extract of olive leaves O. europaea, and its major component, oleuropein, were tested against a model rhabdovirus such as the VHSV, which infects continental and sea farmed fish and a wide range of wild marine species in Europe, North America and Japan. The results presented showed the inhibitory action of both extract and oleuropein against VHSV when the virus was incubated with the agents before infecting the cells, suggesting a direct inactivation effect on VHSV infectivity by the compounds.
Antihypercholesterolaemic activity has been shown in rats given a high daily dose, administered intragastrically of 500 mg/kg of a glycerine: ethanol leaf extract for 15 days. Activity was shown both in
Besides, the hypothesis in vitro by inducing LDL oxidation with copper sulphate and
Effects on the cardiovascular system
O. europaea extracts also appear to have some interesting effects on the cardiovascular system that are unrelated to their antioxidant properties , including blood pressure lowering and
O. europaea extract of fresh leaves administered to rats in a single dose of 360 mg/kg daily showed spasmolytic activity against
European olive leaf and shoot has been administered in the rat intragastrically (i.g.) at doses of 25 mg/kg, following
The effects of a glyceroethanolic macerate of the leaves of O. europaea L. and of oleuropein on excito- conduction and on the right atrial and ventricular monophasic action potential have been studied in anaesthetised dogs using the technique of endocavitary recording. At the higher doses tested a slight increase in the sinusal cycle of the sinoatrial conduction time and of the sinus node recovery time, together with a prolongation of the atrioventricular and intraventricular conduction and an increase of the atrial and ventricular monophasic action potential duration were observed. This may be due to a decrease in the repolarisation phase 3. These electrophysiological effects indicate an inhibitory action both on the swift influx of sodium and on the slow influx of calcium, as well as a decrease in potassium conductance (Occhiuto et al. 1990).
Leaf decoctions or lyophilised extracts of fresh olive leaves
1 mg/ml (Rauwald et al. 1994).
Some of the
A special prepared olive leaf extract (EFLA 943) has been tested for its blood pressure lowering activity in rats rendered hypertensive by daily oral doses of
Effects of a commercial O. europaea leaf extract (OLE, not further specified) on isolated hearts and cultured cardiomyocytes have been investigated. Isolated rabbit hearts were perfused according to the Langendorff technique and connected to a
An early study, using ethanol leaf extracts (defatted with petrol ether) given by gastric intubation to the rabbit (dose not specified), showed a
Aqueous decoctions of Spanish olive leaf, administered i.g. to the rat at a dose of 32 mg/kg, showed hypoglycaemic activity against
(a) potentiation of
Aqueous extracts of dried olive leaves from Italy, administered i.g. to male rats in a very high dosage of 500 mg/kg, reduced the blood glucose levels of normal or
The hypoglycaemic activity of olive leaf has been demonstrated in animals. In one study the significance of supplementation of oleuropein in reducing oxidative stress and hyperglycaemia in
Studies in laboratory animals have reported mainly hypoglycaemic activity of olive leaves (Bennani- Kabchi et al. 1999; Gonzalez et al. 1992). The active constituent was reported to be oleuropein, with a potentiation of
hypocholesterolemic effect (42%) related to decreases in LDL and VLDL cholesterol. In addition, hypoglycaemic (16%) and antihyperglycemic (40%) effects were observed accompanied by a 27% decrease in insulin. Chronic treatment reduced total cholesterol (32%), LDL and VLDL cholesterol. Both treatments produced no significant reduction in plasma levels of triglycerides and HDL cholesterol. No toxic effects of this plant have been observed in usual doses
In another experimental model of diabetes, induced by streptozotocin, olive leaf failed to lower blood glucose levels or prevent glucosuria and ketonuria but it did not reduce circulating levels of liver enzymes and minimised histopathologic abnormalities in both the kidneys and liver (Onderoglu et al. 1999).
Lyophilised extracts of freeze dried Saudi Arabian leaf samples, proved active in vivo in the male rat. Given intragastrically in doses of 500, 250 and 100 mcg/animal, to rats for 14 days increased triiodothyronine (T3) levels and reduced circulating
Smooth muscle relaxant effects
In experiments demonstrating that a dried extract of olive leaf has relaxant effects on both isolated rat ileal tissue and rat tracheal segments, the effects were not altered in the presence of calcium antagonists including verapamil and nifedipine. It is possible however, that olive leaf extract alters calcium transport though an increase in the intracellular concentration of cyclic adenomonophosphate (Fehri et al. 1995)
Ethanol: water (50:50) extracts of fresh olive leaf from Brazil, administered perorally to the rats in doses of 40 ml/kg, showed diuretic activity (Ribeiro et al. 1986).
Effects on the inflammatory response
Aqueous leaf extracts from Tunisia, given intragastrically to the rat (dose unspecified), showed activity against
In vivo glutathione
Some of the
In vitro tests
A study was done to identify the major phenolic compounds present in an extract of olive leaf and estimate their antioxidant activity by their ability to scavenge the radical cation ABTS. Several structural attributes of flavonoids present in olive leaf, including
Olive leaf contains flavonoids that possess antioxidant activity, and tissue antioxidant status has been proposed as a key factor in the development of diabetic complications. This may help explaining why an orally administrated preparation of olive leaf substantially diminished tissue damage in the kidney and liver in rats with streptozotocin induced diabetes (Onderoglu et al. 1999).
Caffeic acid, luteolin and
Phenolic compounds derived from the leaves, fruits and oil of the olive tree (O. europaea L.) have long been known to have
Oleuropein and hydroxytyrosol, two phenolic compounds contained in olives and olive oil, are known to possess several biological properties, many of which may be related, partially at least, to their
antioxidant and free
Studies have shown that oleuropein possesses a wide range of pharmacologic and health promoting properties including antiarrhythmic, spasmolytic,
Olive leaf has antioxidant properties associated with phenolic constituents and oleuropein (Turner et al. 2005). Oleuropein, an antioxidant has been reported to decrease the oxidation of LDL cholesterol (Visioli et al. 1994). Oxidized LDL is the most damaging form of cholesterol and can initiate damage to arterial tissues, thereby promoting atherosclerosis.
The effects of oleuropein were studied on the electromechanical properties of isolated
A variety of antibacterial actions of oleuropein and its associated compounds have been demonstrated in vitro.
The component usually associated with olive leaf’s antimicrobial properties is oleuropein (Petkov & Manolov 1972; Juven & Henys 1972).
Fleming et al (1973) isolated six major phenolic compounds from green olives; one particular compound, possibly a hydrolysis product of oleuropein, was more active than oleuropein itself against the lactic acid bacterium Leuconostoc mesenteroides FBB 42. Later on, the oleuropein aglycone and elenolic acid were found to strongly inhibit the growth of three further species of lactic acid bacteria –
Lactobacillus plantarum, Pediococcus cerevisiae and Lactobacillus brevis (Fleming et al. 1973). Since the aglycone is composed of elenolic acid bound to
Oleuropein has also been reported to directly stimulate macrophage activation in laboratory studies (Visioli et al. 1998i). Besides, oleuropein has shown
The activity of oleuropein, a phenolic glycoside contained in olive oil, was investigated in vitro against
Mycoplasma hominis, Mycoplasma fermentans, Mycoplasma pneumoniae and Mycoplasma pirum. Oleuropein inhibited mycoplasmas at concentrations from 20 to 320 mg/l. The MICs of oleuropein to
Mycoplasma pneumoniae, Mycoplasma pirum, Mycoplasma hominis and Mycoplasma. fermentans were 160, 320, 20 and 20 mg/l, respectively (Furneri et al. 2002).
In vitro studies have demonstrated that oleuropein acts as an
The antioxidant/anticancer potential of phenolic compounds isolated from olive tree (Owen et al. 2000), as well as the in vitro cytotoxicity to human cells in culture of some phenolics from olive oil, has been reported by Babich & Visioli (2003) as well as by Hamdi & Castellon (2005); who have shown the activities of oleuropein, as an
Besides oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts (Katsiki et al. 2007).
In addition to its antibacterial actions, elenolic acid has been shown to be a potent inhibitor of a wide spectrum of viruses. Olive leaf extract has reported antiviral activity, caused by the constituent calcium elenolate, a derivative of elenolic acid (Renis 1970; Heinze et al. 1975). The isolated calcium salt of elenolic acid was tested as a
influenza A (PR8), Newcastle disease, parainfluenza 3, Coxsackie A21, encephalomyocarditis, polio 1, 2 and 3, vesicular stomatitis, Sindbis and reovirus 3 (Deering) viruses (Renis 1975; Soret 1969; Hirschman 1972). Calcium elenolate also inhibits the
The mechanism of action of the antiviral activity is reported to include:
i)ability to interfere with critical amino acid production essential for viruses
ii)ability to contain viral infection and/or spread by inactivating viruses or by preventing virus shedding, budding, or assembly at the cell membrane
iii)ability to directly penetrate infected cells and stop viral replication
iv)in the case of retroviruses, it is able to neutralise the production of reverse transcriptase and protease
v)stimulation of phagocytosis
Hypoglycaemic effect of
The triterpene oleanolic acid on the activities of human amylases was examined in vitro. It has inhibited the activities of
In vivo tests
Rabbits with induced diabetes showed a decrease in oxidative stress markers when treated with oleuropein
Petkov and Manolov (1972) observed in their investigations of the cardiovascular effects of oleuropein in animals that
(30 mg/kg intravenously) largely abolished the characteristic ECG (electrocardiogram) changes caused by Pituitrin (which diminishes coronary blood flow) in conscious rabbits, when given 1 minute after the Pituitrin injection. Lastly, found that oleuropein eliminated cardiac arrhythmia in dogs with induced hypertension for
Some of the
In vivo, studies in rats indicate that oleuropein prevents oxidative myocardial injury (Manna et al. 2004).
Herbal preparations in animal experiments in rabbit and rats found a hypotensive effect of oleuropein, possibly via direct action on smooth muscle. Oleuropeoside also may exert a vasodilatory activity.
(10 and 20 mg/ml) reduced total cholesterol and triglycerides concentrations. This is the first experimental study in vivo that suggests the possibility of using oleuropein in the treatment of ischemia (Andreadou et al. 2006).
Oleuropein is reported to have an
Patients with diabetes mellitus are likely to develop certain complication such as retinopathy, nephropathy and neuropathy as a result of oxidative stress and overwhelming free radicals. Treatment of diabetic patients with antioxidant may be of advantage in attenuating these complications. One study aimed to evaluate the significance of supplementation of oleuropein in reducing oxidative stress and hyperglycaemia in
Other clinical effects of oleuropein are the potentiation of cellular and organismal protection through the
Oleuropein has been patented in the United States for antiviral activity against viral diseases, including herpes, mononucleosis, and hepatitis (Fredrickson 2000).
Soret (1969) showed that calcium elenolate effectively reduced viral titres in vivo when given before and/or after inoculation of hamsters with myxovirus parainfluenza type 3
A bioassay guided study of triterpenoids isolated from the leaves of O. europaea from Greece, from wild African olive and from cultivar of O. europaea grown in Cape Town was reported. The experiment was undertaken since the preliminary analyses showed that the African wild olive leaves are rich in triterpenoids and contain only traces of oleuropein which is typical for European olive leaves. The anti- hypertensive, diuretic,
Laboratory experiments evaluating safety pharmacology were not fully performed. Therefore, safety parameters and the
Oleuropein is among the herbal constituents that act as
inhibition of CYPs by herbal constituents may decrease the formation of toxic metabolites and thus inhibit carcinogenesis, as CYPs play an important role in procarcinogen activation (Zhou et al. 2007).
Pharmacodynamic drug interactions of whole extracts or isolated constituents have not been reported.
ASSESSOR’S OVERALL CONCLUSIONS ON PHARMACOLOGY
Olive leaf as herbal substance and/or herbal preparation has antihypertensive, hypolipidemic and diuretic activities, mainly due to its secoiridoids constituents (oleuropein) as well as phenolic constituents (especially flavonoids). Together with their strong antioxidant activities, which contribute to resist oxidation, a supporting action to the cardiovascular system and function is assumed. Other possible pharmacodynamic actions including hypoglycaemic (in high doses), antimicrobial, antiviral, hepatic, smooth muscle relaxant as well as effects on the inflammatory response. Taken together such bioactivities help to account for some of the existing clinical effects.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Herbal substance/Herbal Preparations
No data on Olea extracts have been found or reported, while there is only the following reference on oleuropein purified from Olea extracts.
There are insufficient data in the literature to fully understand the bioavailability of polyphenols such as oleuropein, hydroxytyrosol and tyrosol. It is known that oleuropein is poorly absorbed due to its large size and planar configuration (Edgecombe et al. 2000). It is however hypothesised that since oleuropein is a glucoside, it could probably access a glucose transporter (SGLT1) found on the epithelial cells of the small intestine, permitting its entry into the cells. Conversely, it was postulated in previous investigations that the absorption of the quercetin glycoside (a similar polyphenolic) involved active sugar transporters (Singh et al. 2008).
Other studies have shown that oleuropein is rapidly absorbed after oral administration, with maximum plasma concentration occurring 2 hours after administration. Hydroxytyrosol was its most important metabolite. Both compounds are rapidly distributed and excreted in urine as glucoronides or in very low concentrations as free forms (Tan et al. 2003; Boccio et al. 2003; Vissers et al. 2002).
Assessor’s overall conclusions on pharmacokinetics
Limited data are available on pharmacokinetics. No data are available for the herbal substance or the herbal preparation and therefore no conclusion can be drawn. Only some data exist for oleuropein and its metabolites. Oleuropein is also among the herbal constituents which behave as
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Single dose toxicity
The LD50 of an extract (not specified) of olive leaf (O. europaea) was given 1300 mg/kg, i.p. in mouse; > 3000 mg/kg orally in mouse (Duke 2002; Blaschek et al. 2006), besides at 1 mg/ml, an extract of olive leaf was not toxic to human cells
Chronic oral toxicity
No information on olive leaf are available.
Petkov and Manolov (1972) gave single daily intraperitoneal doses of oleuropein to albino mice ranging from 100 to 1000 mg/kg (in solutions of 1, 5 and 10%). No toxic effects or deaths during the
Elliott et al. (1969) determined the LD50 for calcium elenolate to be 120 mg/kg in mice when given intraperitoneally, and 160 mg/kg in rats via the intraperitoneal route and 1,700 mg/kg via the oral route.
Repeated dose toxicity
Elliott et al. (1969) found calcium elenolate to be well tolerated in rats given daily oral doses of 0, 30, 100 or 300 mg/kg for 1 month. The only
No blood toxicity studies have been carried out according to available scientific literature.
No genotoxicity studies have been carried out according to available scientific literature.
No carcinogenicity studies have been carried out according to available scientific literature.
No teratogenicity studies have been carried out according to available scientific literature.
No immunotoxicity studies have been carried out according to available scientific literature.
Assessor’s overall conclusions on toxicology
There are only limited preclinical safety data for olive leaf extracts and some limited toxicological data concerning the toxicity of oleuropein and calcium elanolate mainly published in the 70’s, considered to be insufficient.
Due to the lack of data on mutagenicity, carcinogenicity and reproductive and developmental toxicity, a list entry for Oleae folium cannot be recommended.
3.4. Overall conclusions on
Olive leaf was officially used in Germany as a herbal remedy traditionally used to support cardiovascular system while in France is used for elimination functions and to help digestion. Moreover, Olive leaf is used in Spain and other European countries as a traditional remedy for more than
30 years without safety problems.
The published data with respect to the indications and preparations is limited. On the basis of existing pharmacological data mainly on Olea constituents antihypertensive, hypolipedimic and diuretic, antioxidant activities are reported. Furthermore hypoglycaemic (in high doses), antimicrobial, antiviral, smooth muscle relaxant as well as effects on the inflammatory response were described.
Some of these data support the traditional use of O. europaea and preparations thereof in the proposed indication:
Traditional herbal medicinal product used to promote the renal elimination of water, in mild cases of water retention.
The efficacy of traditional herbal medicinal products is only plausible but not proven by clinical data. The lack of genotoxicity, carcinogenicity as well as reproductive and developmental toxicity studies do not allow the establishment of a Community List Entry.
4. Clinical Data
4.1. Clinical Pharmacology
Preclinical studies have shown that olive leaf extracts and therein contained phenolic compounds as well as secoiridoids as oleuropein protect the cardiovascular system mainly through their antioxidant activity.
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
The flavonoid polyphenols in olive leaves are natural antioxidants that have a host of health beneficial effects (Visioli et al. 1998i). The active phenolic compounds in the olive leaf extract are part of the secoiridoid family, known for their capacity to scavenge H2O2. Pignatelli et al. demonstrated that following stimulation by collagen, there is a burst of hydrogen peroxide in the process of platelet activation. H2O2 activates the enzyme phospholipase C, which brings about arachidonic acid metabolism and platelet aggregation (Singh et al. 2008).
Previous studies demonstrated that oleuropein and hydroxytyrosol due to their capacity to scavenge H2O2, inhibited the respiratory burst of human neutrophils elicited by phorbol
Several polyphenols have been found in the olive leaves even though oleuropein was found to be in higher concentration. Other polyphenols like hydroxytyrosol, caffeic acid, luteolin and rutin as well as flavanol cathechin have been also determined
Assessor’s overall conclusions on pharmacodynamics
At present, the mechanism of action of olive leaf extracts cannot be considered clarified.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
Phenolic compounds such as oleuropein, phenolic acids and flavonoids are quantitatively important constituents of the whole olive leaf extract. The systemic bioavailability of them is probably relatively low and variable.
Assessor’s overall conclusions on pharmacokinetics
Data on pharmacokinetics of Oleae folium extract or relevant components are limited in humans.
4.2. Clinical Efficacy
4.2.1. Dose response studies
No pharmacokinetic or pharmacodynamic studies were performed to support the posology and daily dose proposed.
4.2.2. Clinical studies (case studies and clinical trials)
Olive leaf extract (with no further details given for the extract used) had an antihypertensive effect in patients with essential arterial hypertension. Patients were separated into two groups: first timers who had never been previously treated with hypotensive medication (n=12) and a second group who had previously benefited from some sort of
3 months that followed, the placebo was replaced with similar gel capsules, each containing 400 mg of aqueous olive leaf extract. Patients took 4 capsules daily for total dose of approximately 1.6 g olive leaf extract daily. A significant decrease in blood pressure occurred in all patients
(p < 0.001). No adverse effects were reported during treatment with olive leaf extract and patients especially noted a disappearance of gastric disturbances that they had previously experienced on beta- blockers medications. As a side note, the authors also found a small but significant decrease of glycaemia (p < 0.01) and calcium (p <0.001) in the groups (Cherif et al. 1996).
The extract EFLA®943, manufactured from the dried leaves of O. europaea L, is an ethanol (80% m/m) extract. After a patented filtration process (EFLA®Hyperpure), the crude extract was dried. The drug to extract ratio (DER) was
232 patients referred to Nephrology & Hypertension Division, Department of Internal Medicine, of Medicine, University of Indonesia, were enrolled in the study. Of them, 162 (69.8%) subjects completed the study, 16 (6.9%) dropped out from the study due to various reasons and 54 (23.3%) had no available
The primary efficacy endpoint was reduction in systolic blood pressure (SBP) from baseline to
After 8 weeks of treatment, both groups experienced a significant reduction of SBP as well as DBP from baseline; while such reductions were not significantly different between groups. Means of SBP reduction from baseline to the end of study were −11.5±8.5 and −13.7±7.6 mmHg in olive and captopril groups, respectively; and those of DBP were −4.8±5.5 and −6.4±5.2 mmHg, respectively. A
significant reduction of triglyceride level was observed in the olive group, but not in the captopril group. In conclusion, olive leaf extract, at the dosage regimen of 500 mg twice daily, was similarly effective in lowering systolic and diastolic blood pressures in subjects with
A total of 1057 adverse events were reported by 168 (94.4%) study subjects, 83 subjects (49.4%) belonged to the olive group and 85 (50.6%) to the captopril group. The majority of adverse events were tolerably mild (99.8%) and comparable between groups. The most common adverse events which contributed to more than 5% of the total events observed during the study were coughing (4.6% in olive and 7% in captopril group) and vertigo (5.9% in olive and 6.3% in captopril group). Less frequently, muscle discomfort, headache, fatigue, malaise, myalgia and muscle cramp were reported and comparable between groups, constituting less than 5% of the total events. Vertigo, muscle discomfort and headache were judged to be possibly related to both olive leaf extract and captopril. All these adverse events had resolved at the end of the study. Based on the laboratory safety evaluation, it was observed that administration of olive leaf extract to
The olive leaf extract EFLA®943, having antihypertensive actions in rats (Khayyal et al. 2002), was tested as a food supplement in an open study including 40 borderline hypertensive monozygotic twins. Twins of each pair were assigned to different groups receiving 500 or 1000 mg/day EFLA®943 for
8 weeks, or advice on a favourable lifestyle. Body weight, heart rate, blood pressure, glucose and lipids were measured fortnightly. Blood pressure changed significantly within pairs, depending on the dose, with mean systolic differences of ≤6 mmHg (500 mg vs control) and ≤13 mmHg (1000 vs 500 mg), and diastolic differences of ≤5 mmHg. After 8 weeks, mean blood pressure remained unchanged from baseline in controls (systolic/diastolic: 133 ± 5/77 ± 6 vs 135 ± 11/80 ± 7 mmHg) and the
Diuretic activity was observed in human adult patients given a leaf infusion (5 ml) or decoction (3 ml) by mouth once daily for
4.2.3. Clinical studies in special populations (e.g. elderly and children)
No information available.
4.3. Overall conclusions on clinical pharmacology and efficacy
Four existing clinical studies could support the traditional use with a mild diuretic activity as well as antihypertensive activity.
Analytically a very recent
EFLA®943 in comparison with captopril in 148 patients with
According to the published in vitro and in vivo studies as well as the existing old and not well documented, but also the two very recent clinical trials (Susalit et al. 2011;
No side effects have been reported during the use of olive leaf preparations.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
The safety profile of olive leaf extracts can be described as acceptable from the limited existing clinical studies and from its use from products on the market. The safety results obtained from the clinical studies conducted so far show that the oral use of olive leaf extracts are well tolerated by most patients. No
5.2. Patient exposure
There are limited data available on the exposure of patients (see also sections
5.3. Adverse events and serious adverse events and deaths
Pollinosis, in the form of rhinitis or bronchial asthma has been reported (PDR for Herbal Medicines 2007).
In a recent clinical trial (Susalit et al. 2011) with olive leaf extract several adverse events were reported whereof 83 (49.4%) belonged to the olive group. The majority of adverse events were tolerably mild (99.8%) and occurred less frequently than in the captopril group. The most common adverse events which contributed to more than 5% of the total events observed during the study were coughing (4.6% in olive group) and vertigo (5.9% in olive group). Less frequently, muscle discomfort and headache were reported (< 5% of the total events).
Serious adverse events and deaths
The safety profile of olive leaf extracts can be described as acceptable from the existing clinical studies (Susalit et al. 2011;
market. The safety results obtained from the clinical studies conducted so far show that the oral use of olive leaf extracts are well tolerated by most patients. The majority of adverse events were tolerably mild while the most common ones (5% of the total events observed during the studies) were coughing and vertigo (4.6% and 5.9% respectively in olive group). Less frequently, muscle discomfort and headache, were reported.
There are no reported
5.4. Laboratory findings
5.5. Safety in special populations and situations
The product is not suitable for patients with known hypersensitivity against the herbal substance, the plant family, the herbal preparation or the excipients of the final product.
Intrinsic (including elderly and children)/extrinsic factors
Olive leaf is not intended for use in children, while no restrictions are known for its use in elderly.
No drug interactions have been reported.
Use in pregnancy and lactation
Olive leaf should not be used during pregnancy and lactation as no data are available on the use in pregnancy and lactation.
No data available.
No data available.
Withdrawal and rebound
No data available.
Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
5.6. Overall conclusions on clinical safety
In the absence of data in special patient populations, Olea leaf is intended only for adults.
In the absence of data and in accordance with general medical practice, it is recommended not to use
the herbal medicinal products containing olive leaf during pregnancy and lactation. Fertility data are lacking.
The safety profile of olive leaf and olive extracts can be judged as good from the existing clinical data and from their long term use, more than 30 years, in the European market. The available literature, on pharmacological and toxicological studies, does not give reason for safety concerns.
As there is no available data on genotoxicity, carcinogenicity and reproductive toxicity on Oleae folium, the establishment of a Community List Entry is not possible for safety reasons.
6. Overall conclusions
The positive effects of olive leaf to enhance the excretion of urine and to support somehow the cardiovascular function (through its hypotensive activity) have long been recognised empirically. The use is made plausible especially by in vitro and in vivo pharmacological data. There are not many available clinical studies, using herbal preparations, containing the herbal substance of olive leaf. A very recent
After discussions in both MLWP and HMPC it has been acknowledged that the tradition and the pharmacologically plausible threefold mild activity (diuretic, hypotensive, mild anti- hypercholesterolaemic) would be considered as beneficial for the cardiovascular system (function).
Safety concerns remain with respect to a cardiovascular indication, i.e. the demarcation between mild functional complaints and organic symptoms. More serious conditions may not be easily distinguished by patients. Even after exclusion of such conditions, it should be avoided that patients may be encouraged for self treatment, where clearly medical supervision and medically supervised medication is required. The HMPC endorsed therefore only a diuretic indication.
In conclusion, olive leaf’s preparations can be accepted as traditional herbal medicinal products in the following indication:
Traditional herbal medicinal product used to promote the renal elimination of water, in mild cases of water retention.
The following herbal substances/preparations have been proposed
•fresh or dried leaves
•comminuted or powdered dried leaves for herbal tea
•powdered dried leaves.
After the acceptance of the above mentioned indication, two herbal preparations (Liquid extract
The proposed herbal substance and herbal preparations have been traditionally used for more than 30 years. Therefore, on the basis of the
In the absence of data in special patient populations, olive leaf is intended only for adults and elderly.
In the absence of data and in accordance with general medical practice, it is recommended not to use the herbal medicinal products containing olive leaf during pregnancy and lactation.
Thirty patients have been treated with water extracts of olive leaf (mainly 1,600 mg daily) from 15 days up to 12 weeks with a very good tolerability.
Another 188 patients have used ethanolic extracts of olive leaf for 8 weeks with no serious adverse effect (Susalit et al. 2011;
As there is no available data on genotoxicity, carcinogenicity and reproductive toxicity, the establishment of a Community List Entry is not possible for safety reasons.