Camellia – Green tea (Camelliae sinensis non fermentatum folium)
|Latin name of the genus:||Camellia|
|Latin name of herbal substance:||Camelliae sinensis non fermentatum folium|
|Botanical name of plant:||Camellia sinensis (l.) kuntze|
|English common name of herbal substance:||Green tea|
Latin name of the genus: Camellia
Latin name of herbal substance: Camelliae sinensis non fermentatum folium
Botanical name of plant: Camellia sinensis (L.) Kuntze
English common name of herbal substance: Green tea
- 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
Green tea leaf (Camelliae sinensis non fermentatum, folium) consists of whole or cut young, unfermented, rapidly hot dried leaf of Camellia sinensis (L.) Kuntze and its cultivated varieties. It contains not less than 2.0% of caffeine (C8H10N4O2, Mr 194,2) (dried drug) (French Pharmacopoeia, 2010).
The fresh leaves of Camellia sinensis (L.) Kuntze (Fam. Theaceae), also known as Thea sinensis L., are processed in a manner designated to prevent the enzymatic oxidation of catechins. The enzymes are inactivated by heat (steam or
• Herbal preparation(s) included in monograph:
•Comminuted herbal substance for herbal teas
•Powdered herbal substance not included in monograph:
•Dry extract, purified (DER
•Dry extract, decaffeinated (DER 6:1 to 10:1, solvents such as alcohol, methanol, acetone, or water or mixtures of these solvents). It contains not less than 60.0 percent of polyphenols, calculated as
Constituents (%, dried drug)
Gruenwald et al., 2004; Balentine et al., 1997; Ferrara et al., 2001; Peterson et al., 2005; Sharma et al., 2007; Chacko et al., 2010 Wang and Ho, 2009; Tsao, 2010:
Methylxanthines: caffeine (2.5 to 4.2%), theophylline
Flavonols: quercetin, kaempferol, myricetin mainly as
Flavones: apigenin, luteolin as
Phenolic acids: including among others, chlorogenic acid, gallic acid, theogallin
Amino acids: 19 amino acids, amongst which theanine
Terpene saponins (theafolia saponins): aglycones including among others, barringtogenol C, R1- barringenol
Polysaccharides (13 %)
The effect of climatic conditions on green tea composition was investigated: variations of theanine and other amino acids (isoleucine, leucine, valine, alanine, threonine, glutamine), quinic acid, EC, EGC, EGCG and caffeine level are reported (Lee et al., 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.
This assessment refers only to Camelliae sinensis non fermentatum folium.
1.2 Information about products on the market in the Member States
Preparations: powdered herbal substance
Preparations on the market: Registered product, 1986
Pharmaceutical form: capsules, hard, 250 mg
Therapeutic indication: adjuvant treatment of weight control diets
Posology: 2 capsules 3 times daily
Preparations: powdered herbal substance
Preparations on the market: registered product, 2006
Pharmaceutical form: tablets, 465 mg
Therapeutic indication: adjuvant treatment of weight control diets
Posology: 2 tablets twice a day
Preparations: powdered herbal substance
Preparations on the market: authorised product, 1986
Pharmaceutical form: capsules, hard, 390 mg
Therapeutic indication: traditionally used in functional asthenia; traditionally used as an adjuvant of slimming diets
Posology: 1 capsule 3 times daily (up to 5 capsules daily if necessary)
Germany (marketing authorisation)
Preparations: purified dry extract from Camelliae sinensis non fermentata folia
Pharmaceutical form: ointment
Therapeutic indication and posology: cutaneous treatment of external genital and perianal warts (condylomata acuminata) in immunocompetent patients from the age of 18 years, up to 0.5 cm string of ointment (=250 mg) 3 times daily (1 g ointment contains 100 mg purified dry extract) Preparations: purified dry extract from Camelliae sinensis non fermentata folia
Preparations on the market: authorised product, 07.09.2011
Pharmaceutical form: ointment
Therapeutic indication and posology: cutaneous treatment of external genital and perianal warts (condylomata acuminata) in immunocompetent patients from the age of 18 years, up to 0.5 cm string of ointment (250 mg) 3 times daily (1 g ointment contains 100 mg purified dry extract)
Risks (adverse drug effects, literature):
The following undesirable effects have been observed and reported during treatment with purified dry extract from Camelliae sinensis non fermentata folia, with the following frequencies:
General disorders and administration site conditions:
Very common (≥1/10): Local reactions at the application site like erythema, pruritus, irritation/burning, pain, ulcer, oedema, induration and vesicles
Common (≥1/100 to <1/10): Local reactions at the application site like exfoliation, discharge, bleeding and swelling;
Uncommon (≥1/1,000 to ≤100): Local reactions at the application site like discolouration, discomfort, dryness, erosion, fissure, hyperaesthesia, anaesthesia, scar, nodule, dermatitis, hypersensitivity, local necrosis, papules, and eczema
Blood and lymphatic system disorders:
Common (≥1/100 to <1/10): lymphadenitis, lymphadenopathy
Infections and Infestations:
Uncommon (≥1/1,000 to ≤100): application site infection, application site pustules, herpes simplex, infection, pyoderma, staphylococcal infection, urethritis, vaginal candidiasis, vulvovaginitis and vulvitis
Renal and urinary disorders:
Uncommon (≥1/1,000 to ≤100): dysuria, micturition urgency, pollakisuria and urethral meatus stenosis
Reproductive system and breast disorders: Common (≥1/100 to <1/10): phimosis
Uncommon (≥1/1,000 to ≤100): balanitis, dyspareunia, and vaginal discharge
Skin and subcutaneous tissue disorders:
Uncommon (≥1/1,000 to ≤100): Rash and papular rash
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.
Despite green tea is widely used, just a few herbal preparations has been marketed so far in EU.
1.2. Search and assessment methodology
Databases: Scopus, Medline, PubMed
Search terms: Green tea, Camellia sinensis folium
Libraries: Carol Davila University of Medicine and Pharmacy, Faculty of Pharmacy, Bucharest
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
According to Gardner et al., 2007, tea is the most consumed beverage in the world after water. Green tea is most commonly used in Asia, especially in Japan and China. It was introduced in Europe as beverage by the Dutch East India Company around 1610. The tea initially imported into Europe was green tea. Green Tea (Thea viridis,) (Camelia viridis) was included in Culpeper’s Complete Herbal (1880) as diuretic, stomachic and useful in headache. The stimulant action on nervous system is mentioned as a side effect.
In ‘Precis de Matiere Medicale’, tea (Thea sinensis Sims sin. Camellia Thea Link.) is introduced as the only important, from the medical point of view, representative of the Camelliaceae. Details on preparation and sources of tea are included. As therapeutical indications, the external use as solution with astringent properties and the internal use (infusion, 4 – 10 g per 100 ml water) as tonic and digestive, mild diuretic in arthritis, diaphoretic and general stimulant (with no distinction between green and black tea) are listed (Leurier et al, 1946).
Used first during the Song Dynasty
In Handbuch der Pharmacognosie a short history of green tea in Japan and the description of traditional method of preparation are also included (Tschirch, 1923).
Taking into account the historical use of Camellia sinensis and the information about products on the market in the Member States the requirements of at least 30 years in medicinal use and at least
15 years of use in the Community as requested by Directive 2004/24/EC for qualification as traditional herbal medicinal product are fulfilled for the herbal substance and herbal preparations specified in the monograph (comminuted and powdered herbal substance) in the proposed indications.
No proposals can be made for the two dry extracts listed as herbal preparations.
No information on products in Europe containing a decaffeinated dry extract described in USP34- NF29S2, Dietary Supplements have been found.
The purified dry extract, DER
2.2. Information on traditional/current indications and specified substances/preparations
According to Culpeper, “Green Tea (Thea viridis, Camellia viridis) is diuretic, and carries an agreeable roughness with it into the stomach, which gently astringes the fibres of that organ, and gives such a tone as is necessary for a good digestion: the Bohea is softening and nutritious, and proper in all inward decays. Strong tea is prejudicial to weak nerves, but is salutary for violent headache and sickness occasioned by inebriation (Culpeper, 1880).
According to Gruenwald et al. (2004) green tea is used internally for stomach disorders, migraine, symptoms of fatigue, vomiting and diarrhea when taken as a beverage (unproven use). It can be used to increase performance (stimulant effect). Due to caffeine content, the drug has a centrally stimulating, antidepressant and diuretic effect. The inotropic positive effect, stimulating effect on gastric acid secretion, glycolysis and lipolysis are also reported (Gruenwald et al., 2004).
Chinese medicine uses green tea to treat migraine, nausea, diarrhoea resulting from malaria and digestion problems. It is also used as a cancer preventive (Gruenwald et al., 2004).
Leung(1980) in Duke (1983) reports the use of tea for neuralgic headaches.
In India, tea preparations are traditionally used for diarrhea, loss of appetite, hyperdipsia, migraine, cardiac pain, fever and fatigue (Gruenwald et al., 2004).
Duke and Wain (1981) in Duke, J.A. (1983) report that the traditional use as analgesic, antidote, astringent, cardiotonic, carminative,
In Potter’s Herbal Cyclopaedia the following medicinal uses of tea are reported: stimulant and diuretic due to caffeine content, astringent due to polyphenols with shown results in diarrhoea. The effectiveness of green tea extract treatment in weight loss is cited. (Williamson, 2003)
Khare C.P. (2007) indicates the stimulant, diuretic and astringent action of tea. Hypocholesterolaemic and hypoglycaemic activity of green tea are also included. Leaves are good appetizer, stomachic, diaphoretic, diuretic, detergent and resolvent; as well as useful in thirst, hemicrania, pain in the heart, piles, and inflammations. Young leaves and the alkaloid caffeine contained in it are astringent, stimulant and diuretic. Caffeine is extensively used in modern practice and is of great value in migraine, hemicrania, neuralgia and other nervous affections. Tannins contained in the leaves are astringent. Tea catechols improve capillaries and small blood vessels function. It is also used against poliomyelitis, rheumatism and infection of respiratory organs and radiation diseases. (Bokhtear, 2011)
Uses as food:
As a stimulant drink in form of infusions, of
As food supplements in solid form, or as a drink in many cases on the basis of dried green tea extracts. (EFSA, 2009)
Information from literature:
Whole or comminuted herbal substance for herbal preparation,
Preparation: boiling water is poured over a heaped teaspoon of leaf tea, a level teaspoon of crushed leaves or a tea bag and left to steep for
Daily dosage: a daily dose of
The indication proposed by
Traditional herbal medicinal product for relief of fatigue and sensation of weakness.
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
A 180 ml serving (6 ounces) of tea contains approximately 60 mg of caffeine, compared with approximately 100 mg of caffeine in a 180 ml serving of freshly brewed coffee. Black, green, and oolong tea beverages contain about the same amount of caffeine when prepared using the same amount of leaves. The amount of caffeine in tea beverage is determined by the brewing conditions of time, temperature, leaf size, and amount of tea. (Balentine et al., 1997)
Doses corresponding to 300 mg caffeine (5 cups of tea as a beverage) are reported as the maximum accepted daily intake. (Gruenwald et al., 2004)
According to Gruenwald a daily dose of
Health Canada, in a 2010 information update, recommends that healthy adults do not exceed 400 mg of caffeine per day. According to the same source, a serving size of green tea (237 ml) contains approximately 30 mg of caffeine.
Posology based on information received from the Member States (France, Spain): Adjuvant treatment of weight control diets and functional asthenia: 1,170 to 1,950 mg of powdered herbal substance daily (corresponding to approximately 35 – 80 mg of caffeine).
Posology based on information received from the Member States (France) and Gruenwald et al. (2004):
Adults and elderly:
Herbal substance, powdered: 390 mg 3 to 5 times daily
The use in children and adolescents under 18 years of age is not recommended (see section 4.4 ‘Special warnings and precautions for use’)
Duration of use:
No information available.
Taking into account the indication, the proposed duration of use is 1 week.
If the symptoms persist longer than 1 week during the use of the herbal medicinal product, a doctor or a qualified health care practitioner should be consulted.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Oral administration of 0.6% green tea (6 mg tea solids/ml) or 0.04% caffeine (0.4 mg/ml; equivalent to the amount of caffeine in 0.6% green tea) as the sole source of drinking fluid to
administration of 0.6% decaffeinated green tea (6 mg tea solids/ml) for 15 weeks increased locomotor activity by 9% (p <0.05). The small increase in locomotor activity observed in mice treated with decaffeinated green tea may have resulted from the small amounts of caffeine still remaining in the decaffeinated green tea solutions (0.047 mg/ml). (Michna, 2003)
Singal (2005, abstract only) investigated the protective effect of green tea extract
Caffeine is a mild stimulant, and this is the main basis of the use of green tea. Some of the pharmacodynamic properties of green tea may be interpreted on the basis of its caffeine content. Caffeine itself is sometimes given concomitantly with other analgesics to produce stronger and quicker
The mild stimulant effect of green tea on the central nervous system, due to the amount in caffeine, was further demonstrated in vivo.
The ability of tea catechins to act as a free radical scavenger, measured by standard reduction potential proved to be lower that of
Standard reduction potential for tea catechins, tea polyphenols and other physiological antioxidants- according to Balentine (1997).
Table1. Redox Potentials of Catechins, Gallocatechins, Quercetin,and Rutin.
Tea polyphenols may also inhibit the formation of reactive oxygen species by inhibiting the enzymes, like xanthine oxidase.
Aucamp et al. (1997) reported the inhibition of xanthine oxidase by five tea catechins. The Ki values (µM) were 303.95 for C, 20.48 for EC, 10.66 for EGC 2.86 for ECG and 0.76 for EGCG. The Ki of EGCG was almost similar to the one of allopurinol (0.30), exerciting the most potent effect.
Lin et al. (2000) investigated in cultured human leukemia cells
xanthine oxidase activity. Theaflavins and EGCG inhibit xanthine oxidase,TF3 acting as a competitive inhibitor and is the most potent inhibitor among these compounds. EGCG and theaflavins have potent inhibitory effects (>50%) on phorbol myristate acetate (PMA)
Gallic acid, EGC and EGCG can inhibit lipopolysaccharide- induced iNOS gene expression and iNOS activity in cultured macrophages. iNOS activity in lipopolysaccharide- activated macrophages treated with EGCG (5 and 10 mM) for
Long et al. (2000) indicated that addition of 1 mM of EGC, EGCG or quercetin to commonly used cell culture media leads to generation of substantial amounts of hydrogen peroxide .
Administration of tea and catechins has been reported to prevent or attenuate decreases in antioxidant enzyme activities in a number of animal models of oxidative stress.
In hypercholesterolemic rabbits, green tea extract (GTE) and black tea extract administration in their drinking water (3 g/l) increased plasma α- tocopherol concentrations after 8 and 17 weeks of tea
administration, but not after 21 weeks. GTE contained 28.5% (w/w) catechins including EGCG (10%) and EGC (7%), ECG (5%) and EC (4%), while black tea extract contained approximately 6% catechins, 1.2% theaflavins, 2% flavonols and thearubigens. The total plasma antioxidant capacity was not affected by green or black tea administration over the
Yuan et al., 2006 examined the effect of EGCG on
Augustyniak et al., 2005 (only abstract available) investigated the influence of green tea on the liver antioxidant potential of different aged rats chronically intoxicated with ethanol. The ethanol diet caused a significant decrease in activity of antioxidant enzymes (SOD, catalase), while administration
of green tea (7 g/l) to
Agarwal et al., 1993 (only abstract available) observed that oral feeding of 0.2% GTE (w/v) for
30 days to
Effects on glucose tolerance and insulin sensitivity
Wu et al., 2004 examined whether GTE has an effect on glucose tolerance and insulin sensitivity in
In addition, Potenza,et al., 2007 observed that spontaneously hypertensive rats, which are often used as a genetic model of the metabolic syndrome, fed a diet supplemented with 200 mg EGCG/ kg/day for 3 weeks, insulin sensitivity was increased.
Wolfram et al., 2005 (only abstract available) investigated the antidiabetic effects of a highly purified extract containing 94% EGCG, 5% and 3% ECG in rodent models of type 2 diabetes mellitus and H4IIE rat hepatoma cells. Dietary supplementation with 0.25%, 0.5%, and 1% EGCG for 2 weeks resulted in reductions of glucose levels in
Metabolic effects including effect on body weight
Richard,et al., 2009 investigated if regular decaffeinated green tea intake (as drinking fluid), for 6 weeks could modulate body weight in an experimental model of obesity (male
significantly slowed their rate of weight gain, as compared with control group (fed with buffer alone). This effect is apparent after only 1 week of supplementation (p<0.05). No significant difference was recorded between C57BL/6J lean mice administrated decaffeinated green tea and the control group. Decaffeinated green tea consumption by ob/ob mice was also associated with significantly lower cholesterolemia, triglyceridemia, and adiponectin concentration. Fecal lipids did not change significantly throughout the experiment.
Kim et al., 2009 (only abstract available) further examined the efficacy of GTE in the
Bose et al., 2008 studied the effects of EGCG, on
In another experiment conducted by the same authors (Bose et al., 2008) on
Wolfram,et al., 2006 investigated the effect of GTE (90% EGCG), on
Ito, 2008 investigated the effect of tea extract (1 and 5 g/l in the drinking fluid) administered for 3 weeks in male Wistar rats fed a
decreased body weight compared with the
Yang et al., 2001 compared the effects of
Kao et al., 2000 showed that intraperitoneal injection of EGCG (>98% pure), but not other catechins- EC, EGC, and
Lean and obese male Zucker rats injected intraperitoneally with
Lu et al., 2001 showed that oral administration of green tea, black tea (6 mg tea solids/ml), decaffeinated green tea plus caffeine, decaffeinated black tea plus caffeine, or caffeine alone to normal
Murase et al., 2006 investigated the effects of 15 weeks intake of GTE (that contain EGCG (41%), EGC (23%), ECG (12%), EC (9%), GC (7%), caffeine( 0.1%) in combination with regular exercise on the development of obesity in C57BL/6 mice. The authors compared body weight, adipose tissue mass, plasma parameters and
Murase et al., 2005 investigated the effects of
exhaustion in mice fed 0.5% GTE were 30% higher than in
Kao et al., 2000 observed that EGCG (purity > 98%), at dose of 85 mg/kg body weigth, administered intraperitoneally significantly reduced food intake in
The data on weight loss is inconsistent,not all the studies suggested a positive correlationand seems to be an adaptative response, sometimes reversible, in some cases is related with reduction of food intake, or with the administration of high doses of extracts or isolated compounds (EGCG), which are not relevant for oral human intake. The rodents’ diets contain very high concentrations of fat
A decaffeinated methanolic extract of Camellia sinensis leaves (composition not investigated) showed in vitro antimicrobial properties against 111 bacteria, comprising 2 genera of Gram positive and
7 genera of Gram negative bacteria. Most of the strains were inhibited by the extract at
The antibacterial activity was also confirmed in vivo in mice by the same authors. When it was given to Swiss strain of white mice at different dosages (30 or 60 μg/mouse), it significantly protect (p<0.001) the animals challenged with Salmonella typhimurium (Bandyopadhyay et al., 2005)
In mice infected with Mycobacterium tuberculosis, oral administration of GTE (that contains approximately 70% catechins constituted by ECGC (45.05%), ECG (23.60%), EC (1.11%) and EG (0.02%) at dose of 10 mg/100 g body weight for 7 days attenuated decreases in erythrocyte GSH concentrations caused by the infection, and decreases in erythrocyte SOD activity (Guleria et al., 2002).
Dental Caries Prevention
Otake et al., 1991 (only abstract available) found that compared to other catechins EGCG and ECG were more active, 167 mg/l of EGCG caused 91% inhibition of glucosyltransferase activity of S. mutans
Xu et al., 2011 found that ECGC inhibited growth of S. mutans planktonic cells at an MIC of
31.25 μg/ml and a minimal bactericidal concentration of EGCG at
S. mutans adherence to
Significantly lower caries scores were observed in specific pathogen free rats infected with S. mutans
There are several reviews regading the protective effects of GTE and its catechins, especially EGCG against chemical carcinogens (Yang et al., 2002, 2009; Ju et al., 2007). According to Yang et al., 2009, there are more than 133 published studies since 1991 on this topic (Table 2).
Table 2. Inhibitory effects of tea and tea constituents in animal models*
Inhibition of lung tumorigenesis by green tea, black tea and their constituents has been demonstrated in different animal models, including those induced by tobacco smoke related chemical carcinogens such as
Inhibitory effects of tea against tumorigenesis in the digestive tract have been shown in 27 out of 33 studies (Ju et al., 2007). The inhibitory effects of tea and tea polyphenols on intestinal tumorigenesis in mice have been consistently observed in different studies (Yin et al., 1994; Orner et al., 2003; Suganuma et al., 2001; Ju et al., 2005).
Ju et al., 2005 showed that administration of EGCG at
Hao et al., 2007 observed that in ApcMin/+ mice, green tea standardized extract (0.12% in diet) decreased intestinal tumor multiplicity by 70.5%, but ECG (0.08% in drinking fluid) had no significant inhibitory effect.
There are also some studies on the effect of tea on prostate cancer, according to Ju et al.(2007). Gupta et al., 2001 reported that oral infusion of the polyphenolic fraction isolated from green tea (0.1% as drinking fluid) significantly inhibited tumor incidence and burden in the prostate as well as
metastases to distant sites in an autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP). model.
Adhami et al., 2004 found that this treatment decrease
The cytotoxicity of green tea components was tested in rat hepatocytes in vitro and turned out to be highest with EGCG and to decline in the following order: EGCG > propylgallate > ECG > EGC > EC (Galati et al., 2006).
In vitro studies by Schmidt et al., 2005 showed that high concentrations
In vivo– see Chapter 3.3. Toxicological data
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Chen et al. 1997 investigated the absorption of EGCG, EGC and EC in rats after administration of decaffeinated green tea dry aquoeus extract that contained 73, 68, and 27 mg/g of EGCG, EGC and EC, respectively. After intragastric administration of the extract (200 mg/kg), bioavailability of EGCG was low in rats (1.6%) in comparison to 31.2% for EC and 13.7% for EGC.
Swezey et al., 2003 (only abstract available) also investigated the absorption of radiolabelled EGCG (administered orally in single dose, 250 mg/kg) in beagle dogs. This study found that approximately 20% of EGCG is absorbed systemically in beagle dogs, which is higher compared with in rats.
Zhang et al., 2004 showed that EC, EGC, ECG and EGCG have a limited transepithelial absorption across small intestine by
Kim et al., 2000 investigated the kinetics of EC, EGC and EGCG following repeated oral administration of a GTE in male
A comparison of total and free plasma catechin concentrations showed that EC and EGC were mostly available in their conjugated forms. Over the
Zhu et al., 2001 investigated the distribution of EC, ECG and EGCG in male
This extract contained 5% EC, 13% ECG, and 50% EGCG (ratio: 1: 2.6: 10 (w/w)). The extract was administered as single dose of 50, 100, 200 and 300 mg/kg. A
The maximum plasma levels of the three catechins differed, but corresponded relatively to their respective amount in the dosing formulation.
Kim et al., 2000 studied in female A/J mice the distribution of EC, EGC and EGCG. A polyphenol preparation containing 86, 76, and 590 mg/g EC, EGC, and EGCg (ratio approximately 1: 0.9: 6.9) was administered at 0.6% (w/v) in water ad libidum for a period of up to 12 days. The catechin levels were generally higher in the lung when compared to the liver. In the lung, EGCG levels were considerably higher than EGC and EC levels. EGC and EC concentrations in the lung exceeded those observed in plasma. In the liver, EGC levels were slightly higher than EGCG levels and higher than EC levels. EGC distributes more to the lung and liver than EGCG.
Suganuma et al., 1998 evaluated the distribution of
Lambert et al., 2003 also investigated the distribution of EGCG following a single intragastic (163,8 μmol/kg) and an intravenous dose (21.8 μmol/kg) of EGCG in male
intestine, lung, and liver. Lowest levels were observed in the prostate and the spleen with about 10- and
Chen et al., 1997, investigated the distribution of EC, EGC and EGCG in rat tissue following intravenous administration of a GTE. This catechin extract contained 27, 68, and 73 mg/g EC, EGC and EGCG (ratio 1:2.5:2.7). After intravenous dose of 25 mg/kg the highest level of EGCG was observed in the intestine. The lung, kidney, and liver were between 4- and 16- fold less exposed to EGCG than the intestine. Exposure in the liver was about
In general, the metabolism of catechins follows the same pathway in mice, rats and humans. The difference between the species was only observed with regard to quantitative differences between individual metabolites.
The main biotransformation pathways of EGCG are
Zhu et al., 2001 and Lu et al., 2003 showed that in vitro
Meng et al., 2002 identified in vivo four mono- and
Four different monomethylated EGCG derivatives were found by Kida et al., 2000, in bile fluid of rats, in addition to
Kohri et al., 2001 revealed that the metabolism of catechins by intestinal bacteria involves cleavage of the
Suganuma, 1998 observed that the excretion of EGCG occurred in the mice predominantly via faeces. Only about 0.6% of the administered EGCG is excreted via the urine. In rats, 32% and 35% of the EGCG dose was excreted via the urine and faeces within 72 hours. (Kohri, 2001)
Kohri et al., 2001 also showed that after intravenous administration of
Kim et al., 2000 studied the excretion of EC, EGC and EGCG after oral administration of a green tea extract in male
Zhu et al., 2001 investigated the excretion of EC, ECG and EGCG following intravenous adminsitration of a decaffeinated extract of catechins from Camellia sinensis in male
Wang et al., 1988 investigated in vitro the inhibition of rat liver microsomal cytochrome P450 activity by isolated catechins. Purified catechins inhibited hydroxylase, deethylase and
Huynh et al., 2002 confirmed the above findings. EGCG inhibited CYP2B1 activity at 0.1 mM and 0.25 mM by 26% and 31.6%.
Goodin et al., 2003 investigated the effect of catechins on the activity and the levels of CYP450 isoforms in the liver of
Embola et al., 2001 observed increased levels of a glucuronidated metabolite of
Lu et al., 2003 investigated in vitro the inhibition of COMT by catechins and their metabolites. ECG, EGCG was about
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
There are available toxicological data on herbal preparations but also on isolated constituents. Caffeine toxicityespecially its reproductive and developmental toxicity, has been assessed extensively by Brent et al, 2011. The authors concluded that in rodents caffeine does not increase the risk of embryonic death even at high dosages (exceeding 30 mg/kg/day) that produce toxic effects in parental animals.
Single dose toxicity
The acute oral LD50 of ECGC in mice has been reported to be 1390 mg/kg and intraperitoneal LD50 is 195mg/kg (Hara, 2001). Polyphenons (extracts with a mixture of catechins) have even higher LD50, suggesting extremely low toxicity of these. (Table 3.)
Table 3. Acute Toxicity of Tea Catechins
Repeat dose toxicity
Chan et al., 2010 evaluated the toxicity of GTE in male and female F344/NTac rats and B6C3F1 mice treated with 0, 62.5, 125, 250, 500, or 1,000 mg/kg extract in
Sakamoto et al., 2001 investigated in a
Johnson et al., 2001 (only abstract available) mentioned a
was observed in both genders in the highest dose group. Body weight gain, feed consumption, relative and absolute weight of the spleen and thymus were reduced
In the same abstract (Johnson, 2001) is mentioned also a
(4 animals/sex and group) treated orally with the same polyphenol fraction by capsules in doses of 0, 60, 200 or 600 mg/kg/day, corresponding to 0, 32, 107, or 320 mg EGCG/kg/day. A NOEL of ≥ 600 mg/kg/day (320 mg EGCG/kg/day) was determined by the authors.
Bun et al., 2006 (only abstract available) examined the serological parameters of liver function (ALT, AST, alkaline phosphatase, glutamyl transferase, total bilirubin) in a
Isolated constituents (EGCG)
Isbrucker et al., 2006 examined the effect of EGCG in a
500 mg/kg/day was derived from the study for the EGCG preparation, corresponding to 460 mg EGCG /kg/day. (Isbrucker et al., 2006)
Groups of 4 male and 4 female fasting beagles, which had been given no food for at least 15 hours, were given EGCG (80% purity) at doses of 0, 50, 150 or 500 mg/kg/day (referred to the pure substance 0, 40, 120 or 400 mg EGCG/kg/day) in capsules for 13 weeks. EGCG was isolated from the initial hot water extract of Camellia sinensis leaves with ethyl acetate and subjected to chromatographic separation followed by spray drying.
was observed. From the study the authors derived a NOAEL of 40 mg EGCG/kg/day (Isbrucker et al. 2006).
According to a published abstract by McCormick et al., 1999;
The mutagenic potential of a decaffeinated green tea dry extract (containing 51.4% EGCG and other catechins) was assessed in a range of established in vitro and in vivo test models such as Ames test, mouse lymphoma cell assay, micronucleus assay in mice and Big Blue transgenic mouse mutation assay. It was assessed in Ames test using Salmonella typhimurium (strains
Clastogenic activity of the same decaffeinated GTE was assessed in L5178Y tk+/- mouse lymphoma cell assay. Mutations in the tk locus were evaluated in cells exposed to green tea preparation, with and without S9 activation for 4 h. The study was conducted according to OECD 476 Guideline. Six concentrations of green tea preparation were tested and positive MMS (methyl methansufonate) and EMS (ethyl methansufonate) controls as well as sterile water as vehicle control were also included. In the absence of S9 activation, the results were equivocal (the statistically significant increases in mutation frequency was observed only in one experiment). With S9 activation, a statistically significant increase of mutation frequency was observed in both experiments starting from 205 µg/ml (Chang et al., 2003).
The green tea decaffeinated extract is well characterized but the manufacturing process includes multiple steps of purification, therefore the extrapolation of data to the herbal tea is not recommended.
A micronucleus assay was carried out on
300 mg/kg) and vehicle control were also included. Two sampling time were considered (after 24 h and
48 h). Under the conditions employed, there was no significant increase in the frequency ofmicronucleated polychromatic erythrocytes (Chang et al., 2003).
Gene mutations were assessed in B6C3F1 Big Blue lacI transgenic mouse. Animals were treated 28 days with GTE, administered by gavage at dose levels of 500, 1000 and 2000 mg/kg/day. A positive control (urethane 50 mg/kg/day) was also included. Thetissues selected were liver, lung and spleen. There was no significant increases in the frequency of lacI mutantions in all tissues tested.(Chang et al., 2003).
Isolated constituents (EGCG)
The mutagenic potential of EGCG
Clastogenic activity of EGCG (77% purity) was assessed in L5178Y tk+/- mouse lymphoma cell assay. Mutations in the tk locus were evaluated in cells exposed to EGCG, with and without S9 activation for 3h and 24 h. The study was conducted according to OECD 476 Guideline. Five concentrations of EGCG were tested and positive NQO and MMS controls as well as vehicle control were also included. In the absence of S9 activation, no increase of mutation frequency compared with control was noticed, at concentrations up to 100µg/ml EGCG. With S9 activation, a statistically significant increase of mutation frequency was observed starting from 125 µg/ml EGCG (equivalent to 210 µM). So, EGCG was clastogenic in the murine cells (Isbrucker et al., 2006).
A micronucleus assay was carried out on NMRI mice (5 males and 5 females per group) to establish the potential of EGCG to cause chromosomal aberrations. The assay was carried out using oral single doses of EGCG (91.9% purity) of 500, 1000 or 2000 mg/kg. Positive control demethylbenzanthracene (DMBA) and vehicle control were also included. Under the conditions employed, there was no significant increase in the frequency of micronucleated polychromatic erythrocytes (Isbrucker et al., 2006).
Administration in diet to
Micronucleus assay was also conducted in Wistar rats (5 males and 5 females per group), treated intravenous with EGCG (92.6% purity) with doses of 15, 25 nd 50 mg/kg/day on two consecutive days. EGCG did not increased frequency of micronucleated polychromatic erythrocytes.
In an oral gavage carcinogenicity study, a green tea preparation (catechins
The effects of dietary administration of GTE (that contains 91.2% catechins [GC 1.4%, EGC 17.6%, EC 5.8%, EGCG 53.9% and ECG 12.5% (w/w)]) were examined using a
model. Groups of 15 F344 male rats were initially treated with a single i.p. administration of 100 mg/kg body weight
The International Agency of Research in Cancer (IARC) listed in 1991 green tea in group 3, meaning that is not classifiable as to its carcinogenicity to humans.
Reproduction and developmental toxicity Herbal preparation
Isolated constituents (EGCG)
EGCG (purity >91%) was administered to pregnant rats during organogenesis and development. Feeding pregnant rats diets supplemented at 1400, 4200 of 14,000 ppm during organogenesis was
3.4 Overall conclusions on
Although a large variety of pharmacological effects have been reported for green tea and its constituents, for the proposed traditional oral use in functional asthenia, published data are limited. Nevertheless, it is sufficient to support the indication, taking into account the significant concentration of caffeine in herbal substance and the
Regarding the use as adjuvant treatment in control of weight, the studies were conducted mainly on extracts or isolated compounds. The weight loss in animals is inconsistent and looks like an adaptative response, sometimes reversible. In some cases it is connected with reduction of food intake or with high doses administration of extracts or isolated compounds, which are not realistic for oral human use. The animal diets tested contained very high concentrations of fat
Other pharmacological studies provide only a theoretical background for the protective effects of green tea.
The bioavailability of green tea and its compounds in animals and humans is low, and the biotransformation is similar.
Several data regarding
With exception of mouse lymphoma cell assay, the other in vitro and in vivo studies on the mutagenic potential of decaffeinated GTE or EGCG have not shown any evidence of mutagenic activity.
Although that Ames test was negative, this was performed with a decaffeinated extract, taking into account that the manufacturing process to obtain the extract includes multiple steps of purification the extrapolation of these data to herbal tea is not recommended. These data can not support the inclusion to the Community list.
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
There are several human pharmacokinetic studies performed by different investigators.
Yang et al., 1998 investigated in 18 volunteers the kinetics after oral administration of beverage containing decaffeinated GTE (1.5, 3.0, or 4.5 g) after overnight fasting. The plasma concentrations of EGCG, EGC, and EC reached peak levels between 1.5 and 2.5 h and declined to undetectable levels after 24 h. When the dose of green tea was increased from 1.5 to 3.0 g, the maximum plasma concentrations and the areas under the curve of EGCG, EGC, and EC increased 2.5- to
Catechins significantly differ in their pharmacokinetic profile. The catechins had been isolated from green tea by methanol, ethyl acetate and chloroform solvent extraction, and subsequently purified by column chromatography on Sephadex
water and final freeze drying and stored at
5.0 EGC µmol/L EGC. Very limited interconversion fromECG to epicatechin or EGCG to EGC occurred, indicating that degallation is not required for uptake. Up to 13.6% of the ingested EGC (partly methylated) was excreted in the urine, while ECG or EGCG were not detected. (van Amelsvoort et al., 2001).
After ingestion of 1.2 g of decaffeinated GTE (88 mg EGCG, 82 mg EGC and 33 mg ECG ) in healthy volunteers, the plasmatic levels at 1 h were
Natsume et al., 2003 identified following three metabolites in human blood and urine after oral administration of EC:
Chow et al., 2001 investigated the systemic bioavailability of green tea catechins after oral
Same authors also investigated the systemic availability of green tea catechins after 4 weeks of oral administration of EGCG capsules (200 mg EGCG/capsule) and GTE capsules (200 mg EGCG, 37 mg EGC, 31 mg EC/capsule). Eight healthy subjects were assigned per dose level to receive one of the five doses for 4 weeks (800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG and GTE once/day, 400 mg EGCG and GTE twice/day or placebo once/day). There was more than 60% increase in the AUC of EGCG after 4 weeks of administration at a dosing schedule of 800 mg one daily. No significant changes were observed in the kinetics of EGCG after repeated treatment at a regimen of 400 mg twice daily. EGCG was present mostly in free form (92%) in the systemic circulation. (Chow et al., 2003)
Henning et al., 2004 observed that plasmatic levels of EGCG were increased when is administered as extract, compared with consumption as green tea, even that the absorption is delayed in the first case.
Lee et al., 2002 investigated the pharmacokinetic parameters of EGCG, EGC and EC after single oral dose administration of green tea or decaffeinated green tea (20 mg tea solids/kg) or EGCG (2 mg/kg) to eight subjects. The plasma concentration time curves of the EGCG, EGC, and EC were fitted in a one compartment model. The maximum plasma concentrations of EGCG, EGC, and EC in the three
repeated experiments with green tea were 77.9±22.2, 223.4±35.2, and 124.03±7.86 ng/ml, respectively. The time needed to reach the peak concentrations was in the range of
No linear association between caffeine consumption and incident hypertension was found. Even though habitual consumption was not associated with an increased risk of hypertension, consumption of caffeinated beverages is associated with it. Further research to elucidate the role of caffeinated beverages in hypertension is warranted (Winkelmayer et al., 2005).
4.2. Clinical Efficacy
4.2.1. Dose response studies
No data available
4.2.2. Clinical studies (case studies and clinical trials)
Non controlled clinical study
After ingestion of a soft drink containing GTE enriched with
Controlled clinical studies
The effect of a combination of GTE and
In a randomised,
Another study investigated the effect of a combination of 97 mg
The stimulatory activity of the green tea should be corroborated by its caffeine content. Concerning this, many studies confirm caffeine’s ability to enhance mood and alertness (Kaplan et al., 1997; Lorist and Tops, 2003), awareness, attention, and reaction time (Cysneiros et al., 2007).
Non controlled clinical study
Ota et al., 2005 showed positive results in young Japanese men consuming a green tea catechins beverage (570 mg catechins and 40 mg caffeine) as part of an exercise program (90 min/week) for 8 weeks. Fat oxidation was increased in the green tea catechins group under both exercising and sedentary conditions as compared to a placebo.
Hill et al., 2007 failed to show differences in abdominal fat in overweight and obese Caucasian women consuming 300 mg/day EGCG (without caffeine) as part of a
Dullo et al., 1999 investigated the effect of GTE (containing 50 mg caffeine and 90 mg EGCG) in 24
p<0.001) without any change in urinary nitrogen. Treatment with caffeine in amounts equivalent to those found in the GTE had no effect on EE and respiratory quotient nor on urinary nitrogen.
Controlled clinical studies
Nagao et al., 2005 investigated the effect of catechins on body fat reduction and the relation between oxidized LDL and body fat variables in healthy Japanese men. After a
Positive findings were reported by Maki et al., 2009 who compared the effects of a
Belza et al., 2007 investigated the effect of three different food ingredients: tyrosine, GTE and caffeine on resting metabolic rate and haemodynamics, on ad libitum energy intake (EI) and appetite in
20 healthy, normal weight men (age: 23.7±2.6 years). Subjects participated in a
500 mg GTE, 400 mg tyrosine, 50 mg caffeine, or placebo, and were separated by more than
Venables et al., 2008 reported that in healthy Caucasian men that ingested three capsules of GTE (890 mg total catechins and 366 mg EGCG/capsule) in the
Auvichayapat et al., 2008 (only abstract available) investigated in a randomized, controlled trial the effects of GTE (141 mg total catechins and 87 mg caffeine) on weight reduction in obese Thai population (60 obese subjects with BMI > 25 kg/m2). All subjects consumed a Thai diet containing 3 meals (8373.6 kJ/day) for 12 weeks. Body weight, BMI, body composition, resting energy
expenditure, and substrate oxidation were measured at baseline, and during weeks 4, 8, and 12 of the study. Serum levels of leptin and urine VMA (vanil mandelic acid) were measured at baseline and during the 12th week. Comparing the two groups, differences in weight loss were 2.70, 5.10, and
3.3 kg during the 4th, 8th, and 12th weeks of the study, respectively. At the 8th and 12th weeks of the study, body weight loss was significantly different (p<0.05). At the 8th week, the difference in resting energy expenditure was 183.38 kJ/day (p<0.001), the difference in the respiratory quotient was 0.02 (p<0.05), and no significant differences existed in satiety score, food intake, or physical activity. Urine VMA was significantly different in the 12 th week of the study (p<0.05).
Hursel et al., 2009 conducted a randomized,
80 overweight and moderately obese subjects [BMI: 29.6±2.0 in kg/ m2] with a habitually low caffeine intake. A
± 2.0%, body weight (<0.001). During the WM phase, WM, resting energy expenditure, and
The effect of a mixture of green tea and guarana extracts containing a fixed dose of caffeine and variable doses of EGCG on
Hursel et al., 2009
Coronary Heart Disease (CHD)
Nakachi et al., 2000 assessed in a prospective cohort study the effect of green tea consumption on 8,552 Japanese citizens for a period of 12 years and reported a significant reduction in risk of death from CHD mortality among men (RR = 0.58; 95% CI[confidence interval]:
Peters et al., 2001 provided a
Arts et al., 2001 evaluated the association between catechin intake and the incidence of mortality from ischemic heart disease and stroke in the Zutphen Elderly Study, a prospective cohort study of 806 men aged
In the prospective Rotterdam Study conducted on 3,454 adults, 55 years of age or older and
Sasazuki et al., 2000 (only abstract available) investigated the relation between tea consumption and severity of coronary atherosclerosis in 512 Japanese patients (men and women) over 30 years of age and reported a protective effect of tea consumption in men, but not in women. In the men subgroup (n=262) significant stenosis ORs was 0.5 (95% CI:
Hooper et al., 2008 evaluated in a
Kuriyama et al., 2006 (only abstract available) investigated the correlation between green tea consumption and mortality due to cardiovascular disease in Japan. The Ohsaki National Health Insurance Cohort Study, a
cardiovascular disease and 1,134 participants died of cancer. Green tea consumption was inversely associated with mortality due to all causes and due to cardiovascular disease. The inverse association with
Liang et al., 2009 studied the connection on tea consumption and ischemic stroke risk in a case– control study conducted in southern China from 2007 to 2008. A total of 374 patients with incident ischemic stroke and 464 control subjects (mean age: 69 years) were recruited. A significant decrease in ischemic stroke risk was observed for drinking at least one cup of tea weekly (p=0.015) when compared with infrequent or nondrinkers, the risk reduction being largest by drinking one to 2 cups of green or oolong tea daily. Significant inverse
Arab et al., 2009 published a
1 cup/ day (absolute risk reduction, 0.79 CI: 0.73 – 0.85).
In a prospective epidemiological study Yang et al., 2004 studied the relation between tea drinking and risk of hypertension in 1,507 Taiwanese men and women aged >20 years with no history of hypertension. Six hundred subjects (39.8%) were habitual tea drinkers, defined by tea consumption of 120 ml per day or more for more than one year. Of these subjects 96.3% were green or oolong tea drinkers and 4.8% added milk to their tea. Compared with
Iso et al., 2006 describe a retrospective cohort study that included a total of 17,413 persons (6,727 men and 10,686 women, with age between 40 to 65 years old), all of them had no history of type 2 diabetes, cardiovascular disease, or cancer at the baseline lifestyle survey. During the
frequently drank green tea and coffee (6 cups of green tea per day and 3 cups of coffee per day) were 0.67 (95% CI, 0.47 to 0.94) and 0.58 (95% CI, 0.37 to 0.90), respectively, compared with those who
drank less than 1 cup per week. Total caffeine intake from beverages was associated with a 33% reduced risk for diabetes. These inverse associations were more pronounced in women and in overweight men.
Hsu et al., 2011 examined the effect of a decaffeinated GTE on obese individuals with type 2 diabetes. The subjects were randomly assigned to either receive 1,500 mg of a decaffeinated GTE (providing a daily dose of 856 mg EGCG) or placebo daily for 16 weeks.
65 years with BMI> 25 kg/m2 and type 2 diabetes for more than one year, completed this study. Homeostasis model assessment for insulin resistance
Effect on cholesterol
Singh et al., 2011 investigated the effects of green tea supplementation on the lipid profile of hypercholesterolemic subjects (23 males and 7 females of age between
In a randomised,
In another parallel comparison trial, 45 volunteers (aged
Similarly in a
The effect of a
consumed placebo capsules. Main outcome measures were mean percentage changes in
± 1.1% (p = 0.01), 2.3% ± 2.1% (p = 0.27), and 2.6% ± 3.5% (p = 0.47), respectively, in the tea extract group. The mean levels of total C,
Protection against oxidative damage
In a controlled human intervention study, a total of 143 heavy smokers (aged
Several reviews were made regarding the protective effects of green tea consumption against cancer incidence (Boehm et al., 2009; Tsubono et al., 2001) but the results of epidemiological studies were inconclusive.
Authors concluded that is insufficient and conflicting evidence to give any firm recommendations regarding green tea consumption for cancer prevention.
Dental Caries Prevention
4.2.3. Clinical studies in special populations (e.g. elderly and children)
No data available.
4.3. Overall conclusions on clinical pharmacology and efficacy
The positive effects of preparations containing green tea against symptoms of fatigue and sensation of weakness are supported by the published data on green tea extracts (Dimpfel et al., 2007; Parker, 2011)
The stimulatory activity of the green tea should be corroborated with its caffeine content. Taking into account that the minimum content in leaves is at least 2.0%, the maximum daily dose proposed in the monograph (11 g of leaves) contains at least 220 mg caffeine. At this dose caffeine exhibits its pharmacological effects in humans.
Other studies support different other effects (especially protective actions) but can not be connected with the traditional use of green tea.
The efficacy of green tea extracts on weight loss is small, inconsistent and no persistent effects were demonstrated. The
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
Spain reported that in 2003, a product consisting of 375 mg of dry extract of Camelia sinensis (DER 4- 8:1) extraction solvent: ethanol, 25% of catechins as EGCG, was withdrawn from the market due to hepatic adverse reactions.
There are some measurements taken by ANSM (French Health Products Safety Agency) on 7 April 2003 regarding the market authorization of a phytotherapeutical drug, recommended as adjuvant to
tea (weak hydroalcoholic extract, aqueous extract and leaf powder) authorised in France (ANSM, 2003)
5.2. Patient exposure
Daily intake of green tea infusion or food supplements containing green tea components is reported by EFSA (European Food Safety Authority). According to EFSA the mean value for the consumption of green tea infusions is 362 g/person/day and the 95thpercentile is 1,097 g/person/day (EFSA, 2009). Referring to the catechin contents, the mean value corresponds to
Exposure with green tea components from food supplements may vary considerably (EFSA, 2009). Doses corresponding to 300 mg caffeine (5 cups of tea as a beverage) are reported in PDR 2004 as the maximum accepted daily intake.
The clinical trials reviewed by Nawrot et al.,2003 indicate that for the healthy adult population moderate caffeine intake (less than 400 mg caffeine per day, equivalent to 6.5 mg/kg bw/day for a
5.3. Adverse events and serious adverse events and deaths
Chow et al., 2003 investigated the safety of green tea polyphenols after 4 weeks of daily oral. administration of EGCG, or a defined decaffeinated green tea polyphenol mixture (PTE). Healthy participants were randomly assigned to receive one of the five treatments for 4 weeks: 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as PTE once/day, 400 mg EGCG as PTE twice/day, or a placebo once/day (8 subjects/group). Adverse events reported during the
Molinari et al., 2006 reported a case of a previously healthy
Some time later,
Bonkovsky et al., 2006 reported a
Another case report from a
Other cases from 2 Member States have been reported regarding the safety of GTE. Taking into account that, in some cases, cofounders were identified and these adverse reactions were not observed on clinical trials, it is questionable to extrapolate these data on all herbal preparations containing green tea as the subjects reported a consumption of high daily doses of green tea for mainly weight loss purposes. The standardised GTE (25% catechins,
Mycrocytic anemia in infants consuming an average of 250 ml of green tea/day have been reported, which may be due to impaired iron metabolism (Gruenwald et al., 2004)
5.4. Laboratory findings
No data available
5.5. Safety in special populations and situations
The potentiation of the action of psychoanaleptic drugs and
Drug interactions related withcaffeine intake: Monoamine oxidase (inhibitors, (furazolidone, procarbazine and selegiline) and concomitant intake of large amounts of caffeine may produce dangerous cardiac arrhythmias or severe hypertension because of the sympathomimetic side effects of caffeine; concurrent use with small amounts of caffeine may produce tachycardia and mild increase in blood pressure.(Thomson Micromedex, 2007)
The reabsorption of alkaline drugs can be delayed because of chemical binding with the tannins in tea (Gruenwald et al., 2004)
Green tea extract containing EGCG 4.52%, ECG 1.39%, EGC 2.57 added in meat at concentration of 0.1 mM reduced the
Special patient population
No data on the use in children and adolescents are available, therefore green tea leaves can only be intended for adults and elderly. The Community herbal monograph states that the use in children and adolescents under 18 years of age is not recommended, with a
Fertility, pregnancy and lactation
The safe use of green tea for pregnant women is addressed in relation to its main constituents (i.e. caffeine and polyphenols).
Caffeine crosses the placenta and is distributed in breast milk.
In Martindale, 2011 it is concluded that due to the limitations in reviewed studies a firm conclusion on the association between caffeine intake and miscarriage can not be drawn. Data on other adverse effects such as preterm birth and congenital malformations were found inconclusive.
UK Food Standards Agency, NHS Heathcare professionals but also the American college of Obstetricians and Gynecologists have recommended that pregnant women should limit their caffeine intake to less than 200 mg of caffeine per day. At this level, caffeine does not appear to be a major contributing factor in miscarriage or preterm birth (ACOG, 2010)
Caffeine is approved by the American Academy of Paediatrics for use by breastfeeding mothers, but is restricted to less than 300 mg/day whilst breastfeeding (Liston, 1998)
Even that the folic acid deficiency is well known to be associated with high incidence of neural tube defects (including spina bifida) the correlation between neural tube defects and tea consumption is unproved. This correlation was investigated only for high consumption of tea, and only in a few epidemiological studies
Other studies (Shiraishi et al., 2010) demonstrated that consumption of high amounts of green tea or oolong tea is associated with low circulating folate levels.
Developmental studies in rats did not reveal any fetal malformations after administration of a GTE or isolated compound.
In the absence of strong evidence requiring specific warnings and sufficient safety data, it is recommended, in accordance with general medical practice, not to use the herbal medicinal products containing green tea or at least to avoid large quantities of green tea during pregnancy and lactation (Gruenwald et al., 2004)
Overdosage (quantities corresponding to more than 300 mg caffeine or 5 cups of tea as a beverage) can lead to restlessness, termor, and elevated reflex excitability. The first signs of poisoning are vomiting and abdominal spasm (Gruenwald et al., 2004)
No information on green tea preparations in the literature search was found
Due to a possible caffeine tolerance development also addressed in literature (Martindale, 2011) and in other Community monograph on herbal products containing caffeine, the duration of use is limited toone week.
Effects on ability to drive or operate machinery or impairment of mental ability
No data in the literature search.
5.4. Overall conclusions on clinical safety
The potentiation of the action of psychoanaleptic drugs and
Taking into account the daily intake of green tea infusion as beverage reported by EFSA and the traditional use over a long period, green tea is considered to be safe, when it is used in the specified conditions.
Green tea dried extracts were involved in some cases of hepatotoxicity and gave reason for safety concerns. Hepatotoxicity is related with high doses of herbal preparations (elevated percentages of caffeine
Considering the low bioavailability of EGCG and the real concentrations in green tea leaves, the actual risk for the use of green tea seems to be low.
Due to the lack of data confirming safety, the use in pregnancy, lactation, children and adolescents is not recommended.
6. Overall conclusions
Green tea has been used in traditional medicine for centuries in Asia and at least for 100 years in Europe. The herbal substance is described in French Pharmacopoeia.
The positive effects of green tea for symptoms of fatigue have been recognized since centuries empirically while this use is plausible also by the existing in vitro and in vivo pharmacological data.
Sufficient data are available to develop a Community monograph on the traditional use of Camellia sinensis (L.) Kuntze, non fermentatum folium. The indications are suitable for
Traditional herbal medicinal product for relief of fatigue and sensation of weakness.
Taking into account its traditional use over a long period of time and the assessed scientific data, green tea is considered to be safe, when use in the specified conditions.
Green tea dried extracts were involved in some cases of hepatotoxicity and gave reason for safety concerns. Hepatotoxicity is related with high doses of such preparations consumed for different reasons than the proposed indication in the monograph (mainly for weight loss) and with the cytotoxicity of EGCG exhibited at these levels. Taking into account that in some cases cofounders were identified and these adverse reactions were not observed in clinical trials, it is questionable to extrapolate these data on all herbal preparations containing green tea. Considering the low bioavailability of EGCG and the real concentrations in green tea leaves, actual risk for the use of green tea in proposed daily doses seems to be low.
In the absence of sufficient data, the medicinal use of green tea is intended only for adults and should not be taken in children and adolescents under 18 years of age.
The use of the traditional herbal medicinal products is not recommended during pregnancy and lactation in the absence of available data.
The minimum required data on mutagenicity (Ames test) are available for herbal preparations of green tea leaves. Unfortunately these data can not be extrapolated to herbal substance, taking into account that the GTE used for such tests is purified.
As there are no adequate data on genotoxicity, carcinogenicity and reproductive toxicity of green tea leaves, it is not possible, due to safety concerns, to establish a Community List Entry.