Eleutherococcus – Eleutherococcus (Eleutherococci radix)
|Latin name of the genus:||Eleutherococcus|
|Latin name of herbal substance:||Eleutherococci radix|
|Botanical name of plant:||Eleutherococcus senticosus (rupr. et maxim.) maxim.|
|English common name of herbal substance:||Eleutherococcus|
Latin name of the genus: Eleutherococcus
Latin name of herbal substance: Eleutherococci radix
Botanical name of plant: Eleutherococcus senticosus (Rupr. et Maxim.) Maxim.
English common name of herbal substance: Eleutherococcus
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Eleutherococcus root (Eleutherococci root) is a dried, whole or cut underground organs of Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. with a content of a minimum 0.08% for the sum of eleutheroside B and eleutheroside E (European Pharmacopoeiea, 2013).
The correct binomial botanic name is Eleutherococcus senticosus (Rupr. et Maxim.) Maxim., syn. Acanthopanax senticosus (Rupr. et Maxim.) Harms. Eleutherococcus was formerly known as Acanthopanax senticosus (Rupr. et Maxim.) Harms and this name is still widely used by Chinese scientists (Li et al., 2005; Frodin, 2006).
The first English name, created in the USA for Eleutherococcus, was “Eleuthero” (Baranov, 1979). “Siberian Ginseng” has been used in the USA as a second name since 1971, but the name has been banned by the Ginseng Labelling Act of 2002 (Farnsworth et al., 1986; Israelsen, 1993). Fifteen names that are based on the abbreviated Latin generic name “Eleuthero” are currently used in various EU official languages; in 4 languages variants from name “Siberian Ginseng”, in 4 languages – variants from “Russian root” or “Russian ginseng root”, and in German and in Hungarian variants from
“Taiga root” – “Taigawurzel” and “tajga gyökér” are used.
In this assessment report the names “Eleutherococcus” or latin “Eleutherococcus senticosus” are used although both synonyms may be found in the original articles.
Although over 35 compounds have been identified from the Eleutherococcus root, the search for active substances is not finished yet. Eleutherococcus senticosus is characterised by the
The main constituents are:
−phenyl propane compounds: eleutheroside B (or syringin) – 0.5% (Ovodov et al., 1967), chlorogenic acid – up to 0.3% (Deyama et al., 2001), coniferyl aldehyde and its glucoside (Deyama et al., 2001), caffeic acid derivates (Wagner et al., 1982; Liu et al. 2012a);
1967; Deyama et al., 2001),
(Ovodov et al., 1967) ,
al., 2001) and its
−triterpensaponines: daucosterol (eleutheroside A), β
−polysaccharides (heteroglycans and eleutherans) (Fang et al., 1985; Wagner et al., 1984; Wagner et al., 1985; Shen et al., 1991).
Other constituents comprise steroids, carbohydrates and essential oil 0.8% (Barnes et al., 2007).
−Comminuted herbal substance
−Powdered herbal substance
−Liquid extract (DER 1:1, extraction solvent ethanol
−Dry extract (DER
−Dry extract (DER
−Dry aqueous extract (DER
−Tincture (ratio of herbal substance to extraction solvent 1:5, extraction solvent ethanol 40% v/v)
−Liquid extract (DER 1:11), extraction solvent sweet wine
−Liquid extract (DER 1:20), extraction solvent sweet wine
•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.
Eleutherococcus root and extracts are used in combinations with other herbal substances/herbal preparations (e.g. Rhodiola rosea L., root; Leuzea carthamoides (Willd.) D.C., root; Schizandra chinensis (Turcz.) Baill., fructus Andrographis paniculata, herba etc.). Such combinations have not been assessed. This assessment report refers exclusively to Eleutherococcus root and preparations thereof.
1.2. Information about products on the market in the Member States
Regulatory status overview
MA: Marketing Authorisation TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
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 and other sources used to research available pharmaceutical,
−Articles and references retrieved from data bases: PubMed, Toxline. Search terms:
Eleutherococcus, Acanthopanax, Syringin, Siberian Ginseng
−Libraries: EMA library, University of Latvia, Rigas Stradinu University, The State Agency of Medicines of Latvia.
−Handbooks, textbooks and Pharmacopoeias
For the first
This assessment report is based on the summary of the most relevant scientific literature which includes more than 300 articles. Hundreds of other articles related to research work are summarised in various monographs and reviews (Aicher et al., 2006, 2012; Barnes et al., 2007, Bleakney, 2008; Blumenthal et al., 1998; Brekhman, 1968a; Brekhman & Kirillov 1968b; Collisson, 1991; Dardymov, 1976a; Duke, 1985; Duke et al., 2002; Farnsworth et al., 1985; Gardner et al., 2013; Halstead et al., 1984; Huang et al., 2011a; Mills et al., 2005; Phillipson et al., 1984; Sonnenborn et al., 1993; WHO , 2002; ESCOP, 2009; Panossian, 2003; Panossian & Wagner,2005; Panossian et al., 2013b, Wagner et al., 1994, Wagner, 1995; Williams, 1993). These texts were also used in preparing this assessment report.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
References are going back at least until 1960 (Brekhman, 1960). There are pharmacological and clinical studies and reviews published in medical, pharmacological Journals, starting from 1957. In 1962 an Eleutherococcus root extract was approved by the former Soviet Union Pharmacological Committee for clinical use as a “stimulant”. In 1966 Eleutherococcus root was recommended for use in the Soviet space program (Belay et al., 1966). In 1968 Brekhman published the first book on the subject entitled “Eleutherococcus”. After that, results of many tests which have been performed in Russia have been verified by researchers all over the world (Fulder, 1980).
In fact Eleutherococcus root has been used in medicine for many decades. Eleutherococcus root is in medicinal use in France (Pharm. Franc, 10), in Germany (Aicher et al., 2006, 2012), in Russia (Ross Ph XI, Mashkowsky, 1997), in the United Kingdom (British Herbal Pharmacopoeia, 1999) and in China (Chen & Chen, 2004; Tang et al., 1992).
Since the first article was published by Brekhman in 1960, over 1,000 articles have appeared. The following reviews of studies performed in the former Soviet Union are available: Grinewicz, 1966; Brekhman, 1968a; Dardymov, 1976a; Halstead et al., 1984; Farnsworth et al., 1985; Sokolov, 2000. European traditional uses are summarised in the following monographs, reviews and handbooks: Betti, 2002; Collisson, 1991; Duke et al., 2002; Blumenthal et al., 1998; Sonnenborn et al., 1993; WHO, 2002; Mills et al., 2005; Barnes et al., 2007; Bleakney, 2008; ESCOP, 2009; Aicher et al., 2006, 2012; Huang et al., 2011a; Gardner et al., 2013; Panossian et al., 2013b; Wichtl, 2009; Willuhn, 2003; Alternative Medicine Review, 2006; Schilcher, 2008; Hänsel, 1980; Meyer, 2011; Panossian et al., 2009a, Panossian & Wikman, 2009b.
Preparations from Eleutherococcus root, including powdered root, have been in medicinal use in Germany prior to January 1978 when corresponding medicinal products were notified to the German agency.
Eleutherococcus root is now widely offered in pharmacies, health food stores and as food supplements in the United States, Canada and in Europe, though not always as a product that conforms to pharmacopoeial requirements (Barna, 1985; Awang, 1996).
Eleutherococcus root is known in Chinese traditional medicine as
The following information about products currently on the market was obtained from the Member States following a new request in May 2013.
Contraindication: Arterial hypertension
Combination product: Eleutherococcus senticosus extractum root, 7.2 mg corresponding to 120 mg dry root, tablets (since 1997) – combination product with Andrographis paniculata herba. Posology – 4 tablets 3 times daily. Not to be used for more than
Assessor’s overall conclusion on the traditional medicinal use
Based on the information found in literature and information provided by Member States, a period of at least 30 years of medical use as requested by Directive 2004/24EC for qualification as a traditional herbal medicinal product is documented for the preparations included in the monograph and in the list entry.
2.2. Information on traditional/current indications and specified substances/preparations
The following indications have been reported in literature for Eleutherococcus root:
−As a tonic in case of decreased performance such as fatigue and sensation of weakness, exhaustion, tiredness and loss of concentration (Brekhman, 1968a; Halstead et al., 1984; Duke, 1985; Aicher et al., 2006, 2012; Blumenthal et al., 1998; Mashkowsky, 1997, Szolomicki et al., 2000; ESCOP, 2009; Hartz et al., 2004);
−As a prophylactic and restorative tonic for enhancement of mental and physical position for functional asthenia, strengthening and normalizing, as well as convalescence (Zotova, 1966; Batin et al., 1981; Berdyshev, 1977; Farnsworth et al., 1985; Asano et al., 1986b; Turbina et al., 1986; Wagner et al., 1992; Obolentseva et al., 1988; Blumenthal et al., 1998; Goulet et al., 2005; ESCOP, 2009);
−As adaptogen, to increase body resistance to such stressful exposures as heat, cold, physical exhaustion, viruses, bacteria, chemicals, extreme working conditions, noise, pollution (Baburin, 1966a, 1966b; Berdyshev, 1977; Brekhman & Mayansky, 1965a; Brekhman, 1965b; 1966, 1968a, 1977, 1980, 1982b; Schezin et al., 1977, 1981; Demin, 1977; Gagarin, 1977; Galanova, 1977; Kalashnikov, 1977, 1986; Bulanov et al., 1981; Lindendbraten et al., 1981; Shornikov et al., 1981a, 1981b; Wikman, 1981; Marochko et al., 1982; Sosnova et al., 1984; Sosnova, 1986; Shadrin et al., 1986; Collisson, 1991; Dowling et al., 1996; Azizov, 1997; Bucci, 2000; Glatthaar- Saalmüller et al., 2001; Arushanyan et al., 2003;).
−Eleutherococcus root was commonly used in Russia in oncology hospital departments to increase the tolerance of the patients to the adverse effects of chemotherapy and radiation therapy (Gvamichava et al., 1966; Kupin et al., 1986a, 1986b).
From the market overview the following indications and respective herbal preparations were identified:
−As a tonic for invigoration in fatigue and impairment, in decreasing capability and power of concentration: powdered herbal substance; dry extract
−Herbal medicinal product traditionally used to improve general condition. The product is a traditional herbal medicinal product for use in specified indications exclusively based on long- standing use: extract (1:20); sweet wine, aromatic with Absinthii herba; dry extract
−Traditional herbal medicinal product for symptoms of asthenia such as fatigue and weakness: powdered herbal substance.
−Herbal medicinal product against tiredness and in periods of reconvalescence: powdered herbal substance.
−Traditionally used in functional asthenia: powdered herbal substance.
−Traditional herbal medicinal product for symptoms of asthenia such as fatigue and weakness: liquid extract (1:1; ethanol 40% (v/v)).
−Traditional herbal medicinal product used as adaptogen in case of decreased performance such as fatigue and sensation of weakness. The indications are based solely on experience and use during a long period of time: Dry extract (corresponding to
For more detailed information please see section: Information about products on the market in the Member States.
Based on the available literature and the information provided by Member States on traditional use, the following indication is recommended:
Traditional herbal medicinal product for symptoms of asthenia such as fatigue and weakness. The product is a traditional herbal medicinal product for use in specified indications exclusively based upon
The requirements of medicinal use in these indications for at least 30 years (including at least 15 years within the EU) according to Directive 2004/24/EC is considered fulfilled for the following preparations:
1)Comminuted herbal substance
2)Powdered herbal substance
3)Liquid extract (DER 1:1, extraction solvent ethanol
4)Dry extract (DER
5)Dry extract (DER
6)Dry aqueous extract (DER
7)Tincture (ratio of herbal substance to extraction solvent 1:5, extraction solvent ethanol 40% v/v)
8)Liquid extract (DER 1:11), extraction solvent sweet wine
9)Liquid extract (DER 1:20), extraction solvent sweet wine
Liquid extract DER 1:20, extraction solvent: sweet wine aromatised with Absinthii herba contains Absinthii herba as flavouring to gain a bitter taste; therefore Absinthii herba is not mentioned in the preparation description in the monograph. 100 ml of sweet wine contains 49.4 mg Absinthii herba; the finished product contains 0.049% Absinthii herba (corresponding to 16 mg Absinthii herba at the maximum recommended daily dose of 33 g extract).
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
Overview of the dosage reported in literature:
The dosages used in studies to determine the prophylactic use of the Eleutherococcus root fluid extract ranged from as little as 0.5 ml every other day to as much as 22 ml per day. In experiments with healthy persons,
16.0 ml of the extract (p.o.). The usual dose employed ranged from 0.5 to 6.0 ml, given one to three times a day for a period of up to 35 days. Additional courses of Eleutherococcus root extract therapy were sometimes employed up to a series of eight courses. At the end of each course there has been a rest period of two to three weeks, during this period no extract was administered.
It is reported that patients should start on a low dose, i.e. 500 mg of powdered root, or its equivalent, three times a day; if no effect has been noted after two weeks, the dose can be increased to 1 g (Collison, 1991).
Other posologies that were reported in literature are:
German Commission E Monographs (Blumenthal et al., 1998; original monograph published in 1971)
Duration of use: generally up to 3 months. A repeated course is feasible.
Herbal medicines. A guide for Health Care Professionals (Newall et al., 1966, Barnes et al., 2007)
Daily dosage: dry root
British herbal compendium (Bradley, 1992)
Handbook of Medicinal Herbs (Duke et al., 2002)
Duration of use: up to 60 days
2002 – Daily dosage:
The essential guide to herbal safety (Mills et al., 2005)
Duration of use: The recommended regime for healthy people as an adaptogen is a course of 6 weeks followed by a 2 week break. This regime can be repeated for as long as necessary. For the treatment of specific illnesses, continous use is preferable
Duration of use: if symptoms persist or worsen after one month, medical advice should be sought
Hagers Handbuch (Aicher et al., 2006)
Duration of use:
On the basis the literature and information provided by Member States the following posology is proposed for adolescents over 12 years of age, adults and elderly:
−Comminuted herbal substance:
−Powdered herbal substance:
−Dry extracts (ethanol
−Dry aqueous extract
−Liquid extract (DER 1:11), extraction solvent sweet wine: 30 ml (31 g), corresponds to 2.7 g dried root
−Liquid extract (DER 1:20), extraction solvent sweet wine:
The daily dose can be taken in one to three doses.
Duration of use
Some authors recommend that Eleutherococcus root should not to be taken for more than 2 months. For chronic conditions such as fatigue, preparations have been used for three months. Most authors recommend that, if a course is repeated, the next course should start after a
In a more recent study, the effect did not persist after 4 weeks of use (Cicero et al., 2004).
Traditional herbal medicinal products can only be accepted if they can be used without medical advice or diagnosis. The symptoms, should they persist for more than 2 weeks, might be a signal for a serious disease that needs medical advice. The HMPC decided therefore to limit the duration of use to 2 month and to refer the patient to medical advice after 2 weeks in case of persistent symptoms.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Reference is made to the HMPC reflection paper on the adaptogenic concept (EMEA/HMPC/102655/2007).
Pharmacological studies in connection with the term “adaptogen”.
The concept of “adaptogens” is not
The heterogenicity of pharmacological studies relates to the general concept that Eleutherococcus root is expected to increase unspecific resistance to various “stressors”. Eleutherococcus root is often described as having a “stimulating and tonic effect” on the body. Stimulating action refers to the ability of medicinal substances to increase the work capacity of the organism after a single dose of the preparation. The tonic effect of a substance refers to the results obtained after prolonged doses of the medicament. This effect is reported to be manifested by an increase in work capacity, not only during the time period that the substance is being used, but for a sustained period of time thereafter (Dardymov, 1966, 1972a, 1982). Many pharmacological studies have been published on experiments that were designed to demonstrate the “adaptogenic” or “normalising” effects of Eleutherococcus root extracts (prepared with ethanol/water) in animals exposed to a variety of adverse conditions (stress, immobilisation, chemical challenge, etc.), and to elucidate the mechanism for these effects (Farnsworth et al., 1985). In more recent research, adaptogens are defined as metabolic regulators which increase the ability of an organism to adapt to environmental stressors and prevent damage to the organism by such stressors (Panossian et al., 1999b).
Pharmacological data regarding the herbal substance and herbal preparation
Pharmacological data from combinations
Panossian et al., 2009a: Experiments were carried out with BALB/c mice taking
Panossian et al., 2012; found that adaptogens like the combination
Zhang et al., 2012 showed that the combination of Scutellaria baicalensis and Eleutheroccus senticosus may be able to significantly block allergic
The actions of Eleutherococcus root may be partially explained by its
Eleutherococcus ethanolic extract have been shown to exhibit cytoprotective effects in vitro and antagonistic effects against different toxins in experimental animals (Brekhman Dardymov, 1969b; Anetai et al., 1987; Monakhov, 1965; Sakharova et al., 1985). Lymphocytes treated in vitro with lyophilised extract showed a wide spectrum of immunostimulating activity (activation of Tea, TEt and
An ethanolic fluid extract was shown to induce the production
A solution containing 0.98 g of an ethanolic extract of eleutherococcus per 5 ml increased phagocytosis of Candida albicans by human granulocytes and monocytes at concentrations between 0.0078 mg/ml and 3.14 mg/ml by 18%. In vitro transformation of granulocytes was not induced (Wildfeuer et al., 1994).
An ethanolic extract derived from the roots of Eleutherococcus senticosus (0.98 g in 5ml solution) was found to influence markedly the cytokine synthesis of activated whole blood cultures of ten healthy volunteers. Whereas the synthesis of Rantes was increased over a wide range of concentrations, the release of
Yi et al., 2001; have investigated the effect of Eleutherococcus senticosus root on
Jeong et al., 2001; investigated the effect of cell cultured Eleutherococcus (aqueous extract) by oral administration in mast
Wikman, 1980; has reported experiments performed in 1963 and 1965 by Pichurina and Bronnikov who investigated the protective action of Eleutherococcus root towards infections and other harmful influences. In one experiment rabbits were contaminated with a cultivation of dysentery microbes (Shigella flexneri, 109 microbes per rabbit). One hour before the test, one group had been given 0.1 ml of Eleutherococcus root extract per 20 g of body weight. The control group remained untreated.
Intraperitoneal administration of an ethanolic extract containing mainly eleutherosides В and D to mice at daily dose of 18 mg/animal for 1 week increased the cytostatic activity of natural killer cells by about 200%. It appeared that the eleutherosides stimulated macrophagal
Li et al., 2013a; investigated effect of 10% Eleutherococcus senticosus aqueous extracts (root or fruit) on Drosophila gut immunity and concluded that eleutherococcus improved improved the survival rate, attenuated the death of intestinal epithelial cells, promoted the expression of antimicrobial peptide genes, and decreased the formation of melanotic masses, it has a protective effect on Drosophila gut immunity and stress response, and may contribute to the prevention of inflammatory diseases induced by pathogenic and toxic.
Chen et al., 2008; investigated the antioxidant properties of 3 adaptogen extracts – Rhodiola rosea, Eleutherococcus senticosus (not specified extract) and Emblica officinalis. Extracts were investigated by screening their ability to scavenge singlet oxygen, hypochlorite and hydrogen peroxide by using chemilumiscent analysis. Furthermore, their ferric reduction /antioxidant power, iron chelating potential and protein thiol protective effect were also determined in order to determine whether these is also capable of preventing oxidative stress induced complications. Eleutheroccus showed the best potential for hypochlorite scavenging. It was concluded that antioxidant potential was proportional to the respective polyphenol content.
To determine whether heat environmental stress (HES) affects the livers of rats, it was investigated in
also examined the effects of Eleutherococcus senticosus aqueos extract (3 fold extraction) on the gene expression profile in rats subjected to heat environmental stress relative to rats that did not receive Eleutherococcus. HES induced changes in gene expression transcript profiles, including those related to fatty acid synthase activity, oxidoreductase activity and lipid peroxidation (LPO). Authors observed dramatically increased malondialdehyde (MDA) levels after HES, which indicates that HES caused LPO through the regulation of oxidative stress and
Liang et al., 2009; investigated the effect of Eleutherococcus senticosus saponins on the oxidative damage induced by hydrogen peroxide (H2O2) in cardiomyocytes. Treatment with Eleutherococcus saponins (600 mg/l) prior to H2O2 exposure increased cell viability, lessened the cardiomyocyte morphological change, and inhibited augmentation of lactate dehydrogenase activity in culture media and of the cellular malondialdehyde content. Furthermore, the activities of superoxide dismutase (89.55 +/- 6.93 U/mg), glutathione peroxidase (845.87 +/- 63.76 mU/mg), catalase (93.07 +/- 10.40 U/mg) and the content of reductive glutathione (8.91 +/- 1.06 µmol/mg) of cardiomyocytes were raised (P < 0.05). Taken together, the results of the study implicate that Eleutherococcus saponins protect cardiomyocytes against
Antioxidant effects have been studied by Mikaelyan in intact rats by injecting mixture of Eleutheroccus glycosides. The authors concluded that Eleutherococcus suppresses the intensity of of the induced peroxide oxidation of lipids and lowers the level of background lipoperoxides in the blood, plasma, heart, liver and brain. Simultaneously, Eleutherococcus decreases the expenditure of the endogenic antioxidant vitamin E, increasing its content in the tissues, also suppresses the activity of the enzymes which remove and prevent the formation of lipoperoxides (Mikaelyan et al., 1986).
Lin & Huang, 2000; studied the antioxidant activity of the Eleutherococcus crude extract and the hepatoprotective activities on CCl4 or
Hong et al., 2009; studied effects of an aqueos extract from cultured Eleutherococcus senticosus cells on the antioxidative defence system, oxidative stress and cell membrane fluidity in the liver Type 2 diabetes in the mouse as an animal which is genetically prone to develop insulin resistance and obesity/diabetes. The mice were orally administered extract (0.5 g/kg body weight) once a day for 12 weeks. The authors concluded that the extract strengthened the antioxidative defense system with an increased activity of antioxidant enzymes such as superoxide dismuthase, glutathione peroxidase and catalase, as well reduced the accumulation of reactive oxygen species such as superoxide radical and H2O2, which decrease the generation of oxidative damage substances, such as thiobarbituric acid reactive substances and lipofuscin, increase the membrane fluidity lowered by oxidative damage.
Wang et al., 2010; evaluated different doses (75 mg/kg, 150 mg/kg and 300 mg/kg) of an aqueous extract of Eleutherococcus senticosus for the antioxidant activity against oxidative stress in mice induced by
oxidised glutathione (GSH/GSSG) in serum and liver homogenates. Medium and high doses of Eleutherococcus senticosus extract also elevated the gene expression of
Stress protective and
Antistress properties and an antifatigue effect of the drug have been described by Kaznachejev, 1977; Kirillov, 1977; Baranov, 1982; Farnsworth et al., 1985; Gvamichava et al., 1966; Dalinger, 1966a.
There are studies that demonstrate that Eleutherococcus root extract counteracts the effect of different noxious substances or agents. Positive results have been described in application of Eleutherococcus root for reducing toxicity of biological toxins, physical factors, chemical compounds, including drugs, and ionising radiation as well as for its ability to increase human’s resistance (Maianskii, 1962; Voskresensky, 1977; Voskresensky et al., 1986; Yonezawa et al., 1989; Collisson, 1991; Rukavishnikova, 2010).
It has been reported (Elkin, 1970) that Eleutherococcus root extract shortens the duration of the sleep induced in mice by hexobarbital, chloralhydrate, sodium barbital and ether. Brekhman, 1982b reported that Eleutherococcus extract raises the sensitivity threshold of test animals to narcotics (ether, chloralhydrate or sodium barbital) and to ethanol. A median lethal dose of 35% ethanol for mice was doubled as a result of single administration of Eleutherococcus root, while the prophylactic use of Eleutherococcus root for a period of 30 days caused a
It has been found that intraperitoneal injection of Eleutherococcus root in irradiated
Kirillov & Dardymov 1966; has reported that Eleutherococcus root given daily to rats under various types of stress normalised the weights of the thyroid and adrenal glands (usually shrunken by stress) and eliminated any evidence of stress upon the functions of these glands. It has been proposed (Panossian et al., 2007) that nitric oxide and cortisol may be used as appropriate stress markers that can be employed in the evaluation of the
The total eleutherosides had no effect on oxygen utilisation by rat liver mitochondria with succinate, glutamate, or tetramethylphenyl substrates but did increase oxygen uptake in whole rat liver homogenates (Dardymov & Khasina, 1972d).
Glucocorticoids are major mediators of the stress response and directly suppress the natural killer (NK) activity. Thus, the response for body the stress is complex, involving metabolic, inflammatory, neuroendocrine, and immunological aspects. It has been speculated that the extracts of Eleutherococcus may have
In support of reports of the glucocorticoidlike effects in vivo for Eleutherococcus, an other study has shown that a 30% ethanol extract of Eleutherococcus roots bind to the estrogen receptor in rat uterus, mineralocorticoid, and glucocorticoid receptors in rat kidney in vitro, but not to the androgen receptor in rat kidney (Pearce et al., 1982). Intraperitoneal administration of an aqueous extract of Eleutherococcus root to rats (3 mg/kg body weight) caused a significant increase in corticosterone levels 3 hours after injection, whereas adrenocorticotropic hormone levels remained unchanged (Winterhoff et al., 1993a, 1993b). Nitrogen metabolism in normal and stressed rats has been reported to be normalised by s.c. 1 ml/kg Eleutherococcus extract (Feoktistova, 1966; Revina, 1966; Sal’nik, 1966). Anisimov et al., 1972 tested the effect of compounds isolated from Araliaceae family plants on the biosynthesis of protein in vitro.
Kimura et al., 2004; compared the effects of water extracts of Eleutherococcus senticosus bark on the swimming time, natural killer and blood corticosterone level using forced swimming stressed mice.
It was concluded that eleutheroside E may contribute to the
Fujikawa et al., 1996; have studied protective effects of aqueous or butanol extracts of Eleutherococcus from Hokkaido and its components on gastric ulcer in restrained cold water stressed rats. In the test with the extract prepared with hot water the result from a single oral administration (extract 50, 100 and 500 mg/kg per day dissolved in 1 ml distilled) water did not show any protective effect on gastric ulcer, but the protective effect was observed in a
It was investigated the effect of the hydroalcoholic extract of the stem bark of Eleutherococcus senticosus on the neuronal activation patterns of
Extracts of Eleutherococcus senticosus (contains 2.1% Eleutherosides B+E) and Rhodiola rosea increased the mean lifespan of the nematode C. elegans in a
Huang et al., 2011c; tried to ascertain the
Zhang et al., 2010; investigated the
Rhim et al., 2007; investigated the effects of Eleutherococcus senticosus on the time to exhaustion by treadmill exercise and on serotonin
TPH expression. Eleutherococcus senticosus was effective as caffeine for increasing the exhaustion time in treadmill running and for reducing the
Shakhmatov et al., 2010; investigated changes in the hemostasis system of rats during extreme exercises. It has been observed that a single
Tohda et al., 2008; investigated the effects of Eleutherococcus senticosus methanol and water extracts on the regeneration of neurites and the reconstruction of synapses in rat cultured cortical neurons damaged by amyloid beta
Bai et al., 2011; has published a similar study where a comprehensive evaluation of constituents was conducted to explore active components from Eleutherococcus senticosus which can protect against neuritic atrophy induced by amyloid β
Jin et al., 2013; examined the mechanism of Eleutherococcus senticosus (ethylacetate fraction from aqueos extract of fruits) activity in antineuroinflammatory and neuroprotective processes.
The neuroprotective effects of a water extract of Eleutherococcus senticosus were investigated in transient middle cerebral artery occlusion (MCAo, 90 min occlusion, 24 h reperfusion) of Sprague- Dawley rats. The infarct volume was significantly reduced by 36.6% after the peritoneal injection of extract (100 mg [sol ]kg) compared with the control. In the immunohistochemical study, the extract markedly inhibited both
Bocharov et al., 2008; in his review article reports that phytoadaptogens (Eleutherococcus senticosus amoung them) take part in protecting brain neurons from various injuries. The ability of phytoadaptogens to have influence on neurodegenerative mechanisms at Parkinson’s disease is discussed. The authors conclude that phytoadaptogens should be proposed for study or use as therapeutic modulators in neurodegenerative disorders including Parkinson’s disease.
Chen et al., 2011b; observed that Eleutherococcus saponins could enhance the viability of spinal motor neurons and have protective effects on hypoxic neurons.
Liu et al., 2012b; studied the neuroprotective effect of an extract of Eleutheroccus senticosus against
Li et al., 2013; who had summarised herbal medicines with
Eleutherococcus senticosus extracts are reported to inhibit the growth of a variety of viruses, bacteria and fungi. An ethanolic fluid extract inhibited the replication of human rhinovirus, respiratory syncytial virus and influenza A virus in cell cultures (Wacker & Eilmes, 1978; Wacker, 1983; Wacker et al., 1986).
The EC50 of the liquid extract was a 1/120 dilution in the case of rhinovirus and influenza A virus and 1/2240 in the case of respiratory syncytial virus. The effect of the fluid extract was affected neither by
heat stress nor by conversion to a dry extract preparation
When Eleutherococcus root liquid ethanolic extract (100 µg, after removal of ethanol) and a suspension of vesicular stomatitis virus were simultaneously introduced into mouse fibroblast culture, the growth of virus was not inhibited (Wacker & Eilmes, 1978). However, when the extract was introduced into the mouse fibroblast culture before contact with the virus, the cells became resistant to the virus. The duration of this effect, however, was only about 6 hours.
Parenteral administration of a 33% ethanolic extract of the Eleutherococcus root for 15 days prior to induced infection (dose not specified) increased the resistance of mice and rabbits to listeriosis, an infection caused by Listeria monocytogenes, capable of producing meningitis in man and animals (Cherkashin, 1966, 1968). However, administration of the extract simultaneously with the bacteria increased the severity of the infection (Cherkashin, 1966).
The antiviral activity of an Eleutherococcus root ethanolic fluid extract was evaluated in experimental influenza infection. The virus and the extract were simultaneously administered intranasally to mice. The titre of influenza virus in the lungs of the animals was recorded over 6 days. On the 5th and the 6th day after infection marked virus titres were measured in the lungs of control animals, whereas no virus titre was found in the animals treated with Eleutherococcus root extract (Protasova et al., 1986).
Jung et al., 2007; investigated the inhibitory effects of Eleutherococcus senticosus on the expression of inducible nitric oxide synthase (iNOS) and
The study by Yamazaki et al.,2007 was undertaken to analyse effects of 3 active compounds isolated from the stem bark of Eleutherococcus senticosus:
Lin et al., 2008a; investigated the inhibitory effect of the stem bark dry aqueous extract of Eleutherococcus senticosus on the production of superoxide anion and hydrogen peroxide in mouse peritoneal macrophages in vitro and in vivo. Exposure of mouse peritoneal macrophages to Eleutherococcus senticosus extract significantly suppressed superoxide anion production induced by zymosan in a
Lin et al., 2008b; examined the effects of Eleutherococcus senticosus dry aqueous extract on nitric oxide (NO) production and inducible iNOS gene expression in LPS plus
Soo et al., 2012; examined the
Eleutherococcus senticosus (dry ethanolic extract, standartised to Eleutheroside A 0.486%±0.046%) protected delayed neuronal death in the CA1 region of the hippocampus against global cerebral ischemia in rats with the recovery of spatial memory, which can be considered as the normal functioning of the hippocampus. It was concluded that regarding the immunohistochemical study, the effect of Eleutherococcus senticosus may be attributable to its
Smalinskiene et al., 2009; investigated the effects of the Eleutherococcus senticosus liquid extract on the accumulation of Cd(2+) in liver and on the mitotic and apoptotic activity of liver cells after chronic intoxication by Cd(2+). Laboratory mice were given to drink solutions of different Cd2+ and ES concentrations for 8 weeks. Cd2+ concentration in mouse liver was detected using atomic absorption spectroscopy. Mitotic and apoptotic activity of liver cells was expressed as an estimated number of mitotic and apoptotic cells in randomly selected reference areas in a histological slide. Eleutherococcus senticosus combined with CdCl2 leads to a significant decrease of cadmium concentration in the blood and liver of experimental mice. Eleutherococcus senticosus decreased the
Experimental studies were conducted on 4 groups of animals, each containing 20 rats: (1) intact animals (control); (2) the animals given inhaled nitric oxide at a concentration of 4.3 mg/m3 for 6 min;
(3) those were prophylactically administered amtizole (40 mg/kg 30 min before inhalation of nitric oxide with further
To evaluate the
According to the authors, these results demonstrate that Eleutherococcus senticosus stem bark ethanol extract is an effective treatment for insulin resistance and hepatic steatosis in ob/ob mice by decreasing hepatic lipid synthesis (Park et al., 2006).
The use of an aqueous extract of Eleutherococcus in combination with either cytarabine or
A pretreatment with Eleutherococcus senticosus extract (1 ml/kg per os during 8 days) prevented the
Chronic treatment by Eleutherococcus senticosus elevated the ventricular fibrillation threshold in rats with postinfarction cardiosclerosis (Maslov et al., 2009).
Jin et al., 2013; studied the
Glycose lowering effects
The eleutherosides are reported to potentiate the effect of insulin on glucose consumption in vitro, using the rat diaphragm (Dardymov & Khasina, 1972c).
It was investigated whether Eleutherococcus senticosus extract (dried aqueous extract) has a glucose absorption inhibitory action. The effects of Eleutherococcus on
Kwan et al., 2004; investigated the vasorelaxant effect of the aqueous extract of the roots of Eleutherococcus senticosus using several in vitro vascular rings prepared from dog carotid artery, rat aorta and rat mesenteric artery. Eleutherococcus extract
Pharmacological data regarding isolated constituents
Several studies on pharmacology of purified compounds from Eleutherococcus root have been carried out so far (Fang et al., 1985; Wagner, 1985; Anisimov et al., 1972;
Anisimov et al., 1972 have informed about the results of the investigation of the influence of triterpenes (eleutherosides I and M) and phenol glycosides (eleutherosides B, B1 and E) of Eleutherococcus senticosus on the early embryogenesis of the sea urchin. It was shown that the eleutherosides I and M at concentrations of 0.5 and 1000 μg/ml respectively hinder cleavage of sea urchin eggs with a successive lysis of the blastomeres. Eleutherosides B, B1 and E at concentrations ranging from 1 to 100 μg/ml do not influence cell division in the course of the first 6 hours of development.
Eleutheroside B (Syringin)
Song et al., 2010; investigated the therapeutic effect of syringin on adjuvant arthritis (AA) in rats and its mechanisms. The secondary inflammation of induced AA rats appeared on the 14th day; syringin and tripterygium glycosides (TG) were given by intragastric administration for 16 days from the 14th day. Treatment of AA rats with syringin and TG from the 22th day significantly attenuated the secondary hind paw swelling, as well as relieved the pain response and the polyarthritic symptoms of the whole body as compared with that of the AA model group. The suppressed lymphocyte proliferation and
Gong et al., 2013; investigated the effects and underlying mechanisms of syringin on LPS and D- galactosamine
Plasma glucose decreased was observed in a
Niu et al., 2007; employed
Niu et al., 2008 showed the ability of syringin to enhance glucose utilization and lower plasma glucose level in rats suffering from insulin deficiency.
Stress protective activity
Huang et al., 2011d investigated the effect of Eleutheroside E on cognitive performances and biochemical parameters of
Ahn et al., 2013; investigated the effect of Eleutheroside E containing Eleutherococcus senticosus extracts, as well as Eleutheroside E on hyperglycemia and insulin resistance in db/db mice. Eleutheroside E increased the
hepatic glucose metabolism by upregulating glycolysis and downregulating gluconeogenesis in obese type 2 diabetic mice. These data suggest that Eleutheroside E mediates the hyperglycemic effects of Eleutherococcus by regulating insulin signaling and glucose utilisation.
Polysaccharides fractions with molecular weigths in the range of 25 000 to 500 000 isolated from the alkaline aqueous extract of Eleutherococcus senticosus were given intraperitoneally to mice at
10 mg/kg. According to granulocytes and carbon clearance tests showed significant immunostimulating activities (Wagner et al., 1984, 1985). The effects were attributed to polysaccharides contained in the Eleutherococcus drug. The crude polysaccharide mixture and the heteroxylan stimulated phagocytosis in in vitro and in vivo tests (Wagner et al., 1984; Fang et al., 1985). In addition, according to Wagner et al., 1985, two polysaccharides in the root have been shown to display immunopotentiating activity (in phagocytosis), and immunoadjuvant activity (in B lymphocytes). Intraperitoneal administration of a polysaccharide fraction isolated from an aqueous root extract (10 mg/kg body weight) had exposed an immunostimulant activity in mice, as demonstrated by the colloidal carbon clearance test (Wagner et al., 1984).
Using C57BL mice as a model, continued daily injections of 100 mg/kg of PES significantly increased the PFC counts when evaluated on the fifth day. The
In more recent studies (Chen et al., 2011a) a
Polysaccharide (ASP) from the roots of Eleutherococcus senticosus was evaluated as an adjuvant with metformin for antidiabetic therapy in
Antioxidant, cardioprotective activity
Liang et al., 2010; investigated the effect of Acanthopanax senticosides B (a monomer of Eleutherococcus saponins) on oxidative damage induced by hydrogen peroxide (H2O2) of cardiomyocytes. Results demonstrated that Acanthopanax senticosides B (400 microg/ml and 200 microg/ml) can protect cells against oxidative injury of H2O2 (100 microM). Furthermore, the
activities of superoxide dismutase (SOD), glutathione peroxidase, catalase and the content of reduced glutathione (GSH) of cardiomyocytes were also raised by Acanthopanax senticosides B. Taken together, the study implicated that Acanthopanax senticosides B protects cardiomyocytes against
Choi, et al., 2006; studied the protective effect of a 30 kDa glycoprotein
Takahashi et al., 2010; investigated the effect of Eleutherococus senticosus aqueous extract on intestinal drug transporter
uptake was significantly decreased. On the other hand, K (m) and K (d) for rhodamine 123 and Gly- Sar uptake were not affected. Further investigations were conducted to clarify the effect of Eleutherococcus extract addition on
Nagai et al., 2009; investigated in vitro the effects of 18 herbal extracts (Eleutherococcus extract among them) on SULT1A3 (phase II detoxifying enzyme of xenobiotics predominantly expressed in the intestinal epithelium) activity and the possibility of interaction between medicinal drugs and herbal extracts. The authors examined the inhibitory potencies of herbal extracts (in concentrations 10, 100, 1000 µg/ml) on the sulfation of dopamine, a typical substrate of SULT1A3, and ritodrine, a b 2 stimulant, by human recombinant SULT1A3. It was concluded that eleutherococcus extract did not inhibit SULT1A3 activity and thus should not increase the bioavailability of drugs for which the function of SULT1A3 at the intestinal epithelium is
Data about a combination
Hovhannisiyan et al., 2006 found that the concomitant application of Kan Jang (a standardised fixed combination of extracts from Andrographis paniculata and Eleutherococcus senticosus) and warfarin in rats did not produce significant effects on the pharmacokinetics of warfarin, and practically no effect on its pharmacodynamics.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
The absorbtion and elimination of
In a subsequent study investigated the distribution of
75 minutes. High levels of labelled eleutheroside B were also found in the pancreas and medium levels in the hyphophysis, adrenals and spleen. Whereas elimination from the spleen was rapid, a more complex relationship was observed in the hypophysis and adrenals. In the hypophysis, the level of radioactivity after 30 minutes feel by 50% within 2 hours but then increased, reaching the initial level again within 4 hours. Adrenal glands also showed a tendency towards accumulation between 2 and
4 hours (ESCOP, 2009).
Ma et al., 2013; performed the pharmacokinetic study of Eleutheroside B and Eleutheroside E after oral administration at single dose of the single substances and an aqueous extract of Eleutherococcus senticosus as well as intravenous injection the single substances in healthy rats. A fast absorption process was found after oral administration of an aqueous extract from Eleutherococcus senticosus and single substances, respectively. The mean values of Tmax were 0.45 ± 0.112 h for single substances and 0.583 ± 0.144 h for an aqueous extract, respectively. The elimination
administration at a single of Eleutheroside B and Eleutheroside E. Pharmacokinetic parameters revealed differences in the plasma between oral administration of an aqueous extract from Eleutherococcus senticosus and single substances. The AUC0−t of Eleutheroside B after oral administration of an aqueous extract of Eleutherococcus senticosus was found significantly elevated (P = 0.034) compared with oral administration of single substances. In additional, AUC0−t and AUC0−∞ of Eleutheroside E were significantly increased (P = 0.009 for AUC0−t and P = 0.011 for AUC0−∞) by oral administration of an aqueous extract of Eleutherococcus senticosus, compared with oral administration of single substances. No significant difference was observed in Cmax of Eleutheroside B and Eleutheroside E in rat plasma for an aqueous extract of Eleutherococcus senticosus and single substances. Moreover, enterohepatic circulation was found in Eleutheroside E after oral administration an aqueous extract of Eleutherococcus senticosus (Ma et al., 2013).
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
The toxicity of Eleutherococcus extracts is reported to be extremely low (Brekhman & Dardymov 1969b; Curtze, 1980; Vogt, 1981; Halstead et al., 1984; Farnsworth et al., 1985; Baldwin et al., 1986; Hirosue et al., 1986; Sonnenborn et al., 1993, Gardner et al., 2013). In clinical investigations of more than 20,000 patients and test persons no signs of acute toxicity have been observed (Fulder, 1980).
The oral acute LD50 of powdered Eleutherococcus in mice is reported to be in the range of about
30 g/kg (Brekhman, 1968a; Farnsworth et al., 1985). The oral LD50 value of the 33% ethanolic extract was about 14.5 g/kg body weight in mice (Brekhman, 1961, 1968a; Farnsworth et al., 1985). Toxic effects at very high dosages (sedation, ataxia, tremor, or vomiting) are thought to be more readily due to the alcohol content of the extract than to a toxic effect of the Eleutherococcus compounds themselves (Curtze, 1980). Medon et al., 1981 reported that a single dose of 3 g
Eleutherococcus extract prepared by repeated extraction at 80°C with either ethanol or water were administered to rats at up to 400 mg/kg body weigth per day for
After treatment of rats with an aqueous extract from Eleutherococcus (containing 0.6% of eleutheroside B and 1% of eleutheroside E) orally at 100 mg/kg and 500 mg/kg body weight or intraperitoneally at 3 mg/kg daily for 5 weeks no changes were observed in body weight or organ weigths (Winterhoff et al., 1993a).
No toxic effects were observed in rats received 10 mg/kg daily of an ethanolic extract of Eleutherococcus for 2 months (Dardymov et al., 1972 d, Davydov & Krikorian, 2000).
Rats administered 5 ml/kg daily of ethanolic extract of Eleutherococcus for 320 days showed no adverse reactions (Gardner et al., 2013).
Preparations of the Eleutherococcus are reported to be
In in vitro experiments, using the AMES assay with Salmonella typhimurium strains TA 100 and TA 98 and in the micronucleus test in mice, no mutagenic potential of Eleutherococcus root aqueous and ethanolic extracts has been found. An ethanolic extract up to 1 g/kg body weight and an aqueous extract at up to 1 g/kg were used (Hirosue et al., 1986).
A “desmutagenic effect” has been observed in Drosophila (Sakharova et al., 1985, 1986).
Studies of carcinogenicity that would allow a reliable assessment have not been performed. In rats no carcinogenic potential of Eleutherococcus root was detected (Hirosue et al., 1986). Anticancer effects were noted in experimental animals with transplanted tumours (Monakhov, 1965, 1967, Sakharova, et al., 1985, 1986; Stukov, 1965, 1966, 1967).
Reproductive and Developmental Toxicity
No teratogenic or other effects have been observed in studies on pregnant animals (Brekhman et al., 1982a; Brekhman, 1982b). Dardymov et al., 1972d reported the absence of teratogenic effects in offspring from male and female Wistar rats given 10 mg/kg of total eleutherosides from Eleutherococcus root daily for 16 days.
Gordeichuk et al., 1986, 1993 have studied preventive administration of Eleutherococcus root extract during prenatal and
Curtze, 1980 reported that teratogenicity studies on rats (13.5 ml of the fluid extract per kilogram body weight during the sixth to fifteenth day of pregnancy) did not reveal any negative effects on dams or foetuses.
3.4. Overall conclusions on
Numerous studies on extracts and isolated constituents of Eleutherococcus root have been conducted in vitro and in animal models. Immunomodulating, antioxidant, stress protective,
The results of pharmacological investigations of Eleutherococcus have been summarised by Dardymov
&Khasina, 1993. The authors postulate multiple effects on the human body, which involve:
−the action on the effects of hormones and their mediators, including changes in the contents of cyclic nucleotides and prostaglandins.
Limited data on pharmacokinetics are available on isolated compound Eleutheroside B after intraperitoneal injection; on Eleutherosides B and E after oral administration, as well on aqueous extract after oral administration and intravenous injection. Available in vitro study on interactions indicates some inhibitory effects by Eleutherococcus on activity of intestinal drug transporter (P- glycoprotein), however clinical relevance of this finding is not clear and no final conclusions can be drawn at the moment.
Data from toxicity studies
Eleutherococcus root aqueous and ethanolic extracts in AMES assay test with Salmonella typhimurium strains TA 100 and TA 98 and in the micronucleus test in mice showed a negative outcome. Although there is one of the strains of Salmonella typhimurium lacking in the published AMES test, the negative outcome in
In conclusion, results from pharmacological studies support the medicinal use of Eleutherococcus as adaptogen and make plausible the use for symptoms of asthenia such as fatigue and weakness.The oral administration of Eleutherococcus root preparations can be regarded as safe under the conditions of use that are described in the monograph/list entry. Preparations of of Eleutherococcus root have been used in humans for many decades without any indication of serious risks.
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
Resistance to stress, adaptogenic potential
The main activity that is expected from an adaptogen is to enable an organism to adapt to and cope with unfavourable conditions, such as physical and psychological stress, infections, environmental pollutants, radiation and extreme climatic conditions. Numerous pharmacological studies, designed to measure the adaptogenic effects of Eleutherococcus root, have been performed in Soviet Union during the 1960s and 1970s (reviewed in Farnsworth et al., 1985: Afanasiev et al., 1973; Baburin, 1966a, 1966b, Baburin et al., 1970a, Baburin & Polonsky, 1970b, 1972; Belonosov et al., 1966, Berdyshev, 1970, 1977; Blokhin, 1966; Brandis & Pilovitskava., 1966a, 1966b; Dalinger, 1966a, 1966b; Egorov & Baburin, 1966; Gagarin, 1977; Golikov, 1966a, 1966b; Novozhilov & Sil’chenko , 1985, Oleynichenko, 1966). For more information see section 4.2.2.
Facchinetti et al., 2002; performed a study where 45 healhty volunteers (males and females) were subjected to the Stroop
with Eleutherococcus (preparation and dosage not stated) or placebo for 30 days in a randomised, double blind design. Stress reactivity was measured as increases in systolic and diastolic blood pressure as well as in heart rate. Measurements were performed before, during and after testing. In both genders heart rate response to the stress test decreased after Eleutherococcus treatment, but not after placebo. In females systolic blood pressure also decreased in the Eleutherococcus group and remained unchanged after placebo. Authors concluded that the study demonstrated that treatment with Eleutheroccus senticosus is able to reduce cardiovascular responses to stress in healthy young volunteers while placebo was ineffective (ESCOP, 2009).
In a more recent study Lee et al., 2008 examined the effects of Eleutherococcus senticosus supplementation on serum lipid profiles, biomarkers of oxidative stress, and lymphocyte DNA damage in postmenopausal women. Forty postmenopausal women, ages
6 months of intervention; however, the reductions were not significant in either group. Protein- carbonyl levels and lymphocyte DNA damage decreased significantly (p<0.001 and p<0.05, respectively) after 6 months of Eleutherococcus senticosus supplementation. The authors suggest that Eleutherococcus senticosus supplementation may have beneficial effects against oxidative stress and improve serum lipid profiles without subsequent side effects.
Shakhmatov et al., 2011; performed a study with Eleutherococcus liquid ethanolic extract in healthy young persons with different degrees of physical training. During study persons were impacted with exposure to a stress (a single physical exercise). It caused unidirectional hypercoagulative shifts and activation of anticoagulant and fibrinolytic blood systems. It was shown that changes of the untrained individuals’ haemostatic parameters could be adjusted with preliminary administration of adaptogen – Eleutherococcus liquid ethanolic extract (1:1),
In vitro and ex vivo studies suggest an increase in leukocyte, cytotoxix
extract had a significant increase in the total number of immunocompetent cells (P<0.0001), including lymphocytes (predominantly
ESCOP, 2009; cites a study (Elkin,1986) where stimulation of phagocytosis was investigated in
14 healthy volunteers who received orally 2 ml of a fluid extract of Eleutherococcus daily for 7 days, while 10 other volunteers received placebo. Blood samples for lymphocyte determination were taken before administration of the extract, on day 7 and
Kolomievsky, 1986, studied reactions in 147 cardiologic patients with hypertension, coronary heart disease and atherosclerosis induced by 30 drops of Eleutherococcus root fluid extract over
The influence of a fluid ethanolic extract was investigated on 35 healthy volunteers who received orally 75 drops of a fluid extract daily for 30 days, while 15 volunteers received pressed juice of Echinacea over the same period. The percentage of lymphocytes with spontaneous blastic transformation and phytohaemagglutinin
Effects on psychomotor performance, cognitive function and physical performance
The influence of an Eleutherococcus fluid extract on physical performance was investigated in 35 healthy volunteers following daily oral administration of 75 drops for 30 days. The study was
Effects on the psychophysical one and the cognitive efficiency were examined in a
Arushanyan et al., 2009 studied the effect of Eleutherococcus root on various psyschophysiological parameters depending on their chrontype and day time in healhy humans. It was reported that acute administration of liquid ethanolic extract (20 drops) significantly improves aural memory volume, decreases reactive anxiety and shortens individual minute. These effects were dependent on the daytime (morning verus evening) and the individual chronotype (circadian features) of each volunteer. Statistically significant efects were observed in mornings for evening people and in evenings for morning people.
The effect on experimentally induced vestibular dizziness was investigated in a controlled study involving 40 male healthy volunteers (25 had good vestibulary stability and 15 decreased vestibular stability). They were treated with 4 ml of a fluid extract 40
Eleutherococcus is reported to enhance vision and hearing. Stschichenkov, 1963, performed 60 trials to determine the influence of Eleutherococcus root on adaptation in darkness and acuteness of vision; Tikhomirova, 1977, analysed vision in seamen given adaptogens during
(Sosnova , 1969) determined the effect of Eleutherococcus root on the colour discrimination function in persons with normal trichromatic vision and the effect of for raising the level of the color discrimination function in railroad engineers (Sosnova & Bykova, 1976).
Sosnova et al., 1984 investigated to effect of Eleutherococcus root in women performing visual control during a regime involving working with
In another experiment Sosnova et al., 1986 has examined also a visual performance in a placebo- controlled study involving the group of healthy 232 volunteers (locomotive engineers and assistants aged 24 to 45 years). All persons had normal colour perception and visual acuity. Spectral sensitivity, colour contrast sensitivity and stability of colour perception were determined at baseline of experiment and on days 1, 5, 20 and 40 and then
Arushanyan et al., 2003 studied the effect of Eleutherococcus root on
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
A study was conducted to assess in normal volunteers (n = 12) the influence of a standardised Eleutheroccus extract (standartised to 0.3% eleutheroside B and 0.5% eleutheroside E + ground root) on the activity of cytochrome P450 CYP2D6 and 3A4. Probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity) were administered orally at baseline and again following treatment with standardised Eleutheroccus extract (485 mg twice daily) for 14 days. Urinary concentrations of dextromethorphan and dextorphan were quantified, and dextromethorphan metabolic ratios (DMRs) were determined at baseline and after standardised Eleutheroccus extract treatment. Likewise, plasma samples were collected
relevant metabolites. There were no statistically significant differences between pre- and post- standardised Eleutheroccus extract treatment DMRs indicating a lack of effect on CYP2D6 (P > 0.05). For alprazolam there also were no significant differences in the pharmacokinetic parameters determined by noncompartmental modeling (Cmax, Tmax, area under the curve,
4.2. Clinical Efficacy
4.2.1. Dose response studies
No data available.
4.2.2. Clinical studies (case studies and clinical trials)
Indication – weakness, fatique
Numerous clinical studies have been performed in Soviet Union during the 1960s and 1970s (Afanasiev et al., 1973; Baburin, 1966a, 1966b; Baburin et al., 1970a, 1972; Baburin & Polonsky, 1970b,; Berdyshev, 1970, 1977; Blokhin, 1966; Brandis & Pilovitskava, 1966a, 1966b; Dalinger, 1966a, Egorov & Baburin, 1966; Gagarin, 1977; Oleynichenko, 1966). An
In 35 clinical trials without controls, involving over 2,100 healthy subjects
The effects of a 33% ethanol extract of the roots were assessed in another 35 clinical trials without controls in 2,200 patients at the age between 19 and 72 years
Eleutherococcus root is reported to improve the adaptation of sailors in the tropics and influence positively body functions and the work capacity of sailors on a cruise (Berdyshev, 1970, 1977), to help adaptation to high altitudes (Kalashnikov, 1977) and in the Arctic (Gagarin, 1977; Brekhman, 1977; Kalashnikov, 1977, 1986). During
Brekhman, 1968a carried out experiments on more than 1,500 sportsmen.
No adverse effects were observed except for an occasional feeling of sleepiness after administration of the extract. This condition has been associated with a hypoglycemic condition. During one series of tests in 1961 and 1962, 30 male and female Olympic athletes took the extract in a dose of 2 ml
30 minutes before sleep and 4 ml one hour before training. The control group received a placebo. The group of Olympic athletes was given the extract, included sprinters,
Asano et al., 1986a has investigated the effects of a preparation of Eleutherococcus root on physical performance and resources in maximal and submaximal work. A
3 consecutive days prior to treatment, and two tests were carried out after treatment with either 2 ml extract (containing 0.53 mg syringin (eleutheroside B) and 0.12 mg
The aim of studies by Cicero et al., 2004 was to test the effect of a middle term Eleutherococcus root administration on elderly, health related quality of life (HRQOL). Twenty elderly hypertensive and digitalised volunteers (age ≥ 65 years) were randomised in a
Hartz et al., 2004 conducted a
Kuo et al., 2010: The aim of the study was to examine the effects of Eleutherococcus senticosus (ES) supplementation on endurance capacity, cardiovascular functions and metabolism of recreationally trained males for 8 weeks. Nine recreationally trained males in college consumed 800 mg/day of ES (root or rhizome, extraction solvent not specified, contains 0.11% eleutheroside B and 0.12% eleutheroside E (HPLC)) or starch placebo (P) for 8 weeks according to a
Subjects cycled at 75% V˙ O2 peak until exhaustion. The examined physiological variables included endurance time, maximal heart rate during exhaustion exercise, V˙ O2, rating of perceived exertion and respiratory exchange ratio. The biochemical variables including the plasma free fatty acid (FFA) and glucose were measured at rest, 15 min, 30 min and exhaustion. The major finding of this study was the V˙ O2 peak of the subjects elevated 12% (P < 0.05), endurance time improved 23% (P < 0.05) and the highest heart rate increased 4% (P < 0.05) significantly. The second finding was at
30 min of 75% V˙ O2 peak cycling, the production of plasma FFA was increased and the glucose level was decreased both significantly (P < 0.05) over
Schaffler et al., 2013: Multicenter, phase IV study was designed as a prospective, exploratory, open, controlled, randomised
144 participants suffering from asthenia and reduced working capacity related to chronic stress were randomised to the treatments. Validated scales and tests were used to investigate cognitive performance; feeling stressed; fatigue and exhaustion; alertness, restlessness and mood; quality of life and sleep; physical complaints and activities; and physiological stress parameters including cortisol awakening response (CAR), at baseline, after 2 and 8 weeks of treatment. Results: almost all parameters improved significantly over time without group differences. Significant differences were found in mental fatigue and restlessness, both in favor of COM vs. ES. COM was not superior to SMT in any parameter at week 8. An attenuation of the CAR was seen at week 2 without group differences. All treatments were well tolerated. The authors conclude that effects of adding Eleutherococcus senticosus root extract to stress management training are, if any, negligible.
Several experiments carried out in the Soviet Union during the 1970s appear to demonstrate that Eleutherococcus root extract, given prophylactically, can reduce the overall disease incidence by up to 35% (Galanova, 1977; Schezin et al., 1977; Kalashnikov, 1977).
Shadrin et al., 1986; have reported results of estimation of prophylactic and immunostimulating effects of Eleutherococcus preparations. The prophylactic effect of the Eleutherococcus liquid extract compared with influenza virus infections and other acute respiratory illnesses was examined in a controlled study
The effect of Eleutherococcus on respiratory viral infectious morbidity in children in organised collectives has been studied. The search involved 764 children
ESCOP ,2009; cites a
Eleutherosides B and E; reported as equivalent of 4 grams of dried roots) or placebo daily for 6 months as a prophylactic treatment to recurrent episodes of Herpes simplex type II infections. Based on questionnaires (covering the 6 months before treatment and after 6 months of treatment), 75% of patients in the Eleutherococcus root group reported an improvement in the frequency, severity and duration of outbreaks compared to 34% in the placebo group; the results were significant in favour of the verum group (p = 0.0002 to 0.0007).
Li et al., 2009; in Cochrane systematic review assessed the efficacy and safety of Eleutherococcus in patients with acute ischemic stroke. Authors included 13 randomised controlled trials (962 participants); the period of follow up in all included trials ranged from 10 to 30 days. None of the trials reported the
Data from combinations
Park et al., 2009: A
(p=0.030) in AIF groups than placebo group. No serious adverse effect was observed, and there was no difference in incidence of adverse effect between AIF and placebo groups. AIF was found to be safe, tolerable and effective for symptomatic improvement of pain and physical function.
Aslanyan et al., 2010: The aim of this study was to assess the effect of a single dose of
4.2.3. Clinical studies in special populations (e.g. elderly and children)
Only a few studies have tested the effect of Eleutherococcus root in children.
Effect of Eleutherococcus root on respiratory viral infectious morbidity in children in organised collectives has been studied by Barkan et al., 1980.
Sheparev et al., 1986; investigated the effect of preventive administration of Eleutherococcus root extract on the health of children under school age. The morbidity rate is reported to have decreased by
Vereshchagin, 1978; Vereshchagin et al., 1982; have studied the effect of adaptogens on antibiotic therapy in children aged
No clear information on posologies in children of different age groups can be taken from these studies. The use of Eleutherococcus root is generally not recommended in children below the age of 12 years.
Turkewicz & Daniljuk, 1966a; Turkewicz et al., 1966b; analysed the results with Eleutherococcus root or Eleutherococcus leaves liquid extracts (no futher details reported) in the treatment of patients with psychosis in the elderly and atherosclerotic psychoses. Patients at the age between 65 and 90 years were given
Davydov & Krikorian 2000; reported that Eleutherococcus root improves
Cicero et al., 2004; in his study tested the effect of a middle term Eleutherococcus root administration on elderly hypertensive and digitalised volunteers (age ≥ 65 years) (see section 4.2.2.).
4.3. Overall conclusions on clinical pharmacology and efficacy
Numerous clinical studies on Eleutherococcus preparations have been conducted since 1960s. In most of the studies, results were generally reported to be positive: e.g. blood pressure was normalised, serum prothrombin and cholesterol levels were reduced, and overall wellbeing and physical work performance improved (Farnsworth et al., 1985). However, these trials lacked good methodology (for example, very few patients were involved, lacked proper controls and randomisation, experiments were not
In conclusion, none of the studies would be sufficient to substantiate efficacy of Eleutherococcus preparations in a clearly defined clinical condition, although, in total, the data available are sufficient to justify further research into the concept of adaptogens.
Brekhman, 1968a has coined the term “adaptogen” to designate substances which in a
There are numerous studies intended to support the adaptogenic nature of Eleutherococcus root extracts in both animal models and humans. Although many clinical studies have been published, most of them are not of appropriate quality and does not prove the efficacy of the Eleutherococcus root in a
Despite the great number of studies, Eleutherococcus root preparations do not reach the level of WEU/scientific evidence that would be sufficient to grant a marketing authorisation. However, the studies provide a solid basis for plausibility of the traditional use. Please refer to the HMPC reflection paper on the adaptogenic concept (EMEA/HMPC/102655/2007) for an in depth discussion.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
In general, only minimal adverse events have been reported. Systematic studies that were designed to detect adverse events are absent. Case reports and general evidence point to the following effects: Eleutherococcus root may cause insomnia in some people if taken too close to bedtime. In the study involving atherosclerotic patients, some cases of insomnia, shifts in heart rhythm, tachycardia, extrasystoles were reported (Golikov AP, 1966b).
Another study involving 55 patients with rheumatic heart disease (Mikunis et al., 1966a, 1966b), showed that 2 of the patients out of 55 (at high dose levels of the extract) reported headaches, pericardial pain, palpitations, and elevated blood pressure.
Another study (Koshkareva et al., 1966), involving 11 patients diagnosed as hypochondriacs, reported that the Eleutherococcus root extract was well tolerated at dose levels of
In the study, which comprised 40 patients treated with 500 mg Eleutherococcus extract (extraction solvent not known) for 6 months, no adverse effects were reported (Lee et al., 2008).
No adverse reactions were reported in the
In the study that explored the effects of 120 mg/day Eleutherococcus senticosus root extract (DER 16- 25:1, ethanol 30%v/v) in 144 participants, the treatment was well tolerated (Schaffler et al., 2013).
5.2. Patient exposure
No exact data on patient exposure are available. In clinical investigations of more than 20,000 patients and test persons no signs of acute toxicity have been observed (Fulder, 1980). On the basis of the
5.3. Adverse events and serious adverse events and deaths
Information on adverse events is inconsistent. See section 5.1.
The following adverse reactions have been reported in a few studies (all performed in 1966): insomnia, shifts in heart rhythm, tachycardia, extrasystoles, palpitations, headache, pericardial pain, elevated blood pressure, irritability, melancholy and anxiety. In the study performed by Hartz et al., 2004 nervousness, headache, breast tenderness and uterine bleeding was mentioned, however, the differences between test and placebo group were negligible (see 5.1).
The ‘Botanical Safety handbook’ mentions insomnia as side effect rarely observed in association with clinical studies (Mc Guffin et al., 1997). The ‘Essential guide to herbal safety’ reports that insomnia, palpitations, headache, tachycardia, pericardial pain and hypertension have been reported in a few cases in patients with cardiovascular disorders. Furthermore, side effects are more likely if normal doses are exceeded (Mills et al., 2005).
ESCOP, 2009; states that none of undesirable effects is confirmed. According to Blumenthal et al., 1998, no side effects are known.
In the more recent clinical studies no side effects were reported (Cicero et al., 2004; Lee et al., 2008; Kuo et al., 2010; Schaffler et al., 2013).
Information regarding combinations
There is a report of spontaneous subarachnoidal hemorrhage in a
In the review of spontaneously reported adverse reactions in association with complementary and alternative medicine substances in Sweden amoung 64 493 reports (submitted between 1987 and 2006), 57 reports concerned combination product consisting of Echinacea purpurea + Eleutherococcus senticosus + Adhatoda vasica. Urticaria, angioedema, anaphylactic reaction, exathema, increased hepatic enzymes, fever were among reported adverse reactions (Jacobsson et al., 2009).
Currently the following side effects are mentioned in the monograph and list entry: “Insomnia, irritability, tachycardia and headaches may occur. The frequency is not known”. During the
Serious events and deaths
None known for Eleutherococcus root preparations administrated orally.
5.4. Laboratory findings
No data available.
5.5. Safety in special populations and situations
Use in pregnancy and lactation
Effects on fertility or effects during lactation have not been reported for humans (Sonnenborn et al., 1993).
In a therapy accompanying investigation in 619 pregnant women with a high risk for a prenatal dystrophy no teratogenic or
Bolkhovitinova, 1986 investigated the influence of Eleutherococcus root on pregnancy termination for mother and on the fetus in 1770 pregant women with a high risk of fetal hypotrophy. . The most favourable pregnance outcome was observed in women who received therapy of 3 weeks three times daily by 20 to 30 drops of the fluid extract of Eleutherococcus root in 3 courses
A few sources (Mc Guffin et al., 1997; Gardner et al., 2013; Mills et al., 2005) report a case of neonatal androgenisation which was attributed to maternal use of “pure Siberian ginseng”. Further
No teratogenic or other effects have been observed in available studies on animals. However, adequate clinical data are lacking, therefore safety during pregnancy and lactation has not been fully established. In accordance with general medical practice and in absence of sufficient data, Eleutherococcus root should not be used during pregnancy and lactation.
Several sources (McRae, 1996; Williamson, 2003; Mills et al., 2005; Barnes et al., 2007; Huang et al., 2011a) report the case of raised serum digoxin concentrations in a
The elevated digoxin levels may be due to an interference with the digoxin immunoassay (due to the structural similarity between Eleutherococcus glycosides and digoxin), especially since no toxic effects of elevated digoxin were observed. However, such high interference (almost 3 fold increase) of Eleutherococcus with the digoxin assay methods was not confirmed in the study performed by Dasgupta, 2008b.
It was observed that Eleutherococcus interferes moderately with digoxin measurements. Eleutherococcus showed falsely elevated digoxin values using FPIA, falsively decreased values using the microparticle enzyme immunoassay (MEIA), no interference with the EMIT (enzyme multiplied immunoasssay, turbidimetric, chemiluminesscent assay (CLIA), Tina quant and Syncron LX system (Dasgupta et al., 2003; Dasgupta, 2008b). In the subsequent studies the modest apparent digoxin concentrations and falsively elevated digoxin concentrations using Digoxin III assay were observed (Dasgupta et al., 2008a), whereas no measurable interference was observed using homogeneous sequential chemilumiscent assay (LOCI digoxin) (Dasgupta et al., 2011).
It has been reported that Eleutherooccus preparations do not affect CYP3A4 and CYP2D6 activity (Donovan et al., 2003). According to the study of Takahashi et al., 2010, Eleutherococcus in vitro inhibits drug transport mediated by
In the review of the risk of drug interaction in the cardiovascular pharmacotherapy and herbal medicines, Izzo et al., 2005 reports increased plasma digoxin concentrations (some component might impair digoxin elimination or interfere with the digoxin assay) and refers to the case reported by McRae, 1996.
Heinrich et al., 2008 in his review confirms low risk of Eleutherococcus interactions by assessing clinically relevant interactions with the cytochrome P450 enzyme systems of herbal extracts used for upper respiratory tract infections.
Barnes et al., 2007; concludes that taking into account the constituents and pharmacological actions of Eleutherococcus preparations and their constituents, the potential interaction with other medicines administered concurrently, particularly those with anticoagulant, hypoglycaemic and /or hypo/hypertensive activity should be considered.
From literature, monographs and databases of the Member States, no case reports on overdose of Eleutherococcus root preparations are available.
No reports identified.
Withdrawal and rebound
No reports identified.
Effects on ability to drive or operate machinery
No studies on the effect on the ability to drive and operate machines have been published.
Known hypersensitivity to the active substance or to Araliaceae (WHO, 2002). However, literature that points to the occurrence of a general hypersensitivity to Araliacea has not been found.
Controversial information regarding arterial hypertension as contraindication can be found in literature. Arterial hypertension as contraindication is stated in reviews (Farnsworth et al., 1985; Bleakney, 2008) and monographs (Blumenthal et al., 1998; Duke et al., 2002; McGuffin et al., 1997; Mahady et al., 2001; WHO, 2002; Aicher et al., 2006). Barnes et al., 2007 mentions that Eleutherococcus is unsuitable for individuals with high blood pressure (180 mm/Hg or higher). Mills et al., 2005 states that some medical scientists and expert bodies consider it to be contraindicated in hypertension, but it also been used to treat hypertension. ESCOP, 2009; Mashkowsky, 1997; indicates no known contraindications.
All of these reviews and monographs regarding contraindicated arterial hypertension refer directly or indirectly (Farnsworth et al., 1985) to publications of Dalinger,1966b; Lapchik, 1967. Dalinger, 1966b has published a study conducted in 35 workers (aged
A study of Lapchik, 1967 does not refer to the clinical use of Eleutherococus and should not be taken into account.
In the publication of Golikov AP, 1966b, arterial hypertension with high level of blood pressure (no exact values) is stated as relative contraindication. However, no increase of blood pressure was reported in this study that could serve as a justification of such statement.
No side effects with respect to the elevated blood pressure have been reported in more recent clinical studies or spontaneous reporting schemes.
Taking into account the above mentioned considerations, during the
5.6. Overall conclusions on clinical safety
The oral administration of Eleutherococcus root preparations can be regarded as safe under the conditions of use that are described in the monograph/list entry. Preparations of Eleutherococcus root intended for adults and adolescents over 12 years of age have been on the market in the Member States for more than 30 years without any indication of serious risks. In general, only minimal adverse events have been reported. Reported adverse effects include insomnia, irritability, tachycardia and headache.
There is one case report that describes elevated serum digoxin level when used concomitantly with Eleutherococcus preparation. However, the validity of the report has been questioned, as the identity of the used preparation was not clearly stated. The elevated digoxin levels might be due to an interference with the some digoxin immunoassay methods, however this requires further investigation.
Studies in healthy human volunteers showed no clinical relevant impact on CYP2D6 or CYP3A4 pathways for elimination. Recent in vitro studies have shown that Eleutherococcus inhibits drug transport mediated by
No adequate data are available on use in children below the age of 12 years, therefore Eleutherococcus root cannot be recommended in this age group.
No teratogenic or other effects have been observed in available studies on animals. However, adequate clinical data is lacking, therefore safety during pregnancy and lactation has not been fully established. In accordance with general medical practice and in absence of sufficient data, Eleutherococcus root should not be used during pregnancy and lactation.
6. Overall conclusions
Preparations from Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. root have been traditionally used for many decades as a tonic for the relief of symptoms in case of decreased performance such as fatigue and sensation of weakness, exhaustion, tiredness and loss of concentration, also as a prophylactic and restorative tonic for enhancement of mental and physical position, and as adaptogen to increase body resistance to such stressful exposures. The period of at least 30 years of medicinal use including at least 15 years within the European Union as requested by Directive 2004/24/EC for qualification as a traditional herbal medicinal product is documented for the following preparations:
1.Comminuted herbal substance
2.Powdered herbal substance
3.Liquid extract (1:1), ethanol
6.Dry aqueous extract
7.Tincture (1:5, ethanol 40% v/v)
8.Liquid extract (1:11), sweet wine
9.Liquid extract (1:20), sweet wine
Traditional use for symptoms of asthenia such as fatigue and weakness is considered plausible on the basis of
Despite the high number of studies, Eleutherococcus root preparations do not reach the level of well- established use. The clinical data is still inconclusive and strong evidence for clinical efficacy cannot be deducted.
Oral administration of Eleutherococcus root can be regarded as safe at traditionally described and used doses in adults and adolescents over 12 years of age.
Due to the lack of adequate data, Eleutherococcus root is not recommended in children below 12 years of age, in pregnancy and lactation.
Duration of use: Not to be taken for more than 2 months. If the symptoms persist for more than
2 weeks during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.
Eleutherococcus root aqueous and ethanolic extracts in AMES assay test with Salmonella typhimurium strains TA 100 and TA 98 and in the micronucleus test in mice showed a negative outcome. Although there is one of the strains of Salmonella typhimurium lacking in the published AMES test, negative outcome in
Following preparations are included in the Community list:
1.Comminuted herbal substance
2.Liquid extract (1:1), ethanol
5.Dry aqueous extract
6.Tincture (1:5, ethanol 40% v/v).