Eleutherococcus

Scientific Name(s): Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. Family: Araliaceae

Common Name(s): Siberian ginseng , Devil's shrub , eleuthero , shigoka , touch-me-not , wild pepper , Kan Jang

Uses

Eleutherococcus is similar to common ginseng in its properties and alleged effects; however, documentation is limited. Extracts of the root have been used for a wide variety of therapeutic purposes and are said to have an adaptogenic effect. It exhibits cardiovascular as well as mood- and energy-enhancing effects.

Dosing

Doses of powdered root 1 to 4 g per day have been used in trials. Doses of E. senticosus extracts are recommended at less than 1 g/day. Limited trials have been conducted in elderly patients and in children.

Contraindications

Information is lacking. Patients in a compromised state, who are febrile, or have unstable cardiovascular or diabetic conditions should not use eleutherococcus.

Pregnancy/Lactation

Information regarding safety and efficacy during pregnancy and lactation is lacking; however, because of a potential effect on developing myocytes, consider Siberian ginseng contraindicated during pregnancy.

Interactions

Interactions with digoxin and hexobarbital have been described. Mechanisms for interaction are not established.

Adverse Reactions

Few adverse reactions have been reported.

Toxicology

Use of eleutherococcus extract has been associated with little or no toxicity.

Botany

E. senticosus belongs to the same family (Araliceae) as Panax ginseng and is synonymous with Acanthopanax senticosus (Rupr. ex Maxim.) Harms. The geographical distribution of eleutherococcus coincides with that of P. ginseng in forests of broadleaf trees, including spruce and cedar. It grows at elevations of up to 800 m or more above sea level. The plant is a shrub, commonly growing to a height of 2 to 3 m or, less commonly, 5 to 7 m. It has gray or grayish-brown bark, numerous thin thorns, and long-stalked and palmate leaves. Eleutherococcus has separate male and female plants with globular umbrella-shaped flowers. Male plants produce violet flowers, while female plants have yellowish flowers; the fruit are black, oval berries. Most commonly, the root is used in herbal medicine; however, the leaves and berries also produce pharmacologically active metabolites. Because it grows abundantly in areas such as Russia and China, eleutherococcus has become a popular substitute for Chinese ginseng. 1 , 2

History

Eleutherococcus has been used and studied extensively in Russia. It is used as a health food, tonic, and sedative in China and wider Asia, as well as in traditional Korean folk medicine as a tonic, an adaptogen, and to strengthen “qi” (life force). 3 , 4

As with its relative Chinese ginseng, root extracts of the plant have been promoted as “adaptogens,” which aid the body in responding to external (eg, environmental) and internal (eg, disease) stress. The plant extract has been traditionally used to normalize high or low blood pressure, to stimulate the immune system, and to increase work capacity. Reputed effects include increasing body energy levels, protecting from motion sickness and against toxins, controlling alloxan-induced diabetes, reducing tumors, and controlling atherosclerosis. 2 , 5

Chemistry

The chemical composition of the roots and leaves varies with season. The roots contain the maximum active ingredient in October, with the level dropping sharply in July. Methanolic extracts of eleutherococcus root contain a glycoside fraction that includes various eleutherosides (isofraxidin, sesamin, syringin) as well as glucose, sucrose, betulinic acid, vitamin E, beta-carotene, caffeic acid, and beta-sitosterol. The eleutherosides found in the roots, leaves, and berries are designated as A through M and have varied structures belonging to different groups of chemical compounds. 2 , 6

Several studies have differentiated between the botany, chemistry, and pharmacology of common ginseng ( P. ginseng and P. quinquefolium ) and Siberian ginseng ( E. senticosus ). 7 Only eleutheroside A has a saponin structure similar to that of ginseng ginsenosides/panaxosides. 8 While some eleutherosides share common properties with panaxosides, others exhibit very different effects. Seven glycans (eleutherans A, B, C, D, E, F, and G) have been isolated from aqueous extract of the crude drug shigoka (Siberian ginseng) root. 9 The following new lignans have been isolated from the root of eleutherococcus: 7SR,8RS-dihydrodrodiconiferyl alcohol, dehydrodiconiferyl alcohol, 7,8-trans-dihydrodehydrodiconiferyl alcohol-4-O-beta-D- glucopyranoside, meso-secoisolariciresinol, and (-)-syringoresinol-4-O-beta-D-glucopyranoside. 10 The antiplatelet compound 3,4-dihydroxybenzoic acid has also been isolated from this species. 11 Eleutherosides have been isolated, identified, and measured in the rhizomes, roots, and liquid extracts of eleutherococcus. 12 Other relatively new compounds that have been isolated include phenylpropanes and polysaccharides, ciwujianosides C1 and D1, 13 and at least 10 phenolic compounds such as isofraxidin. 14 Chemical analysis methods for eleutherococcus, such as reversed phase high-performance liquid chromatography, have been published. 15 , 16 , 17

Uses and Pharmacology

Cardiac effects

Although not clearly established, eleutherococcus appears to exert an endothelium dependent, nitric oxide-mediated vascular relaxation. 18

Animal data

At high dosages, Siberian ginseng led to abrupt cessation of myocardial contractions in rats with increased levels of intracellular calcium. At low doses, the extract induced cells to beat with a regular and strong rhythm and had no effect on calcium levels, suggesting a negative effect on developing fetal myocytes. 19

Clinical data

In a study that examined the effects of eleutherococcus in hypotensive children between 7 and 10 years of age, an eleutherococcus extract improved subjective signs, raised systolic and diastolic blood pressures, and increased total peripheral resistance. 20 In another study in 20 hypertensive elderly patients, no effect on blood pressure was found at 300 mg/day of dry extract. Higher dosages were not studied. 21

Other reported cardiovascular actions include effects in myocardial infarction, 22 malignant arrhythmias, 23 and myocarditis. 24

Chronic fatigue/mental stress

In a review of older studies, a trend toward improved performance in mental tasks was observed. 25

Clinical data

A study investigating the effect of eleutherococcus 2 g/day in adults with chronic idiopathic fatigue showed an improvement after 1 month, but this effect was not sustained at 2 months. 26 In a study in elderly patients, self-reported mental health and social functioning was enhanced by administration of dry eleutherococcus extract 300 mg for 4 weeks. With continued use of the extract, these differences were attenuated, 21 possibly consistent with the concept that adaptogens should only be used in a “pulsed” manner.

Physical stress/endurance
Animal data

In animal experiments, various eleutherosides have been evaluated for endurance effect, with certain compounds more effective than others. 27 , 28 , 29

Clinical data

Eleutherococcus has been dubbed the “herb of Russian athletes,” 30 but both supporting evidence and negative trials exist regarding outcome variables, such as oxygen consumption, respiratory exchange, heart rate, and plasma glucose. 30 Dosing in these trials has been up to 4 g/day.

Measurements of testosterone and cortisol have shown a detrimental effect on the recovery process similar to that of overtraining. 30

Other
Diabetes

In an animal study of endurance, oral administration of eleutherococcus extract did not affect plasma lactic acid, glucagon, insulin, or liver glycogen. Decreased plasma glucose levels were found in resting rats. 28 In a small trial in healthy, nondiabetic adults, postprandial glucose levels were raised following eleutherococcus administration, 31 suggesting that caution should be used when administering the product to diabetic patients.

Hepatoprotective

Aqueous extracts of the stem of the eleutherococcus plant reduced serum tumor necrosis factor and aspartate and alanine transaminases, improved histology, and inhibited hepatocyte apoptosis in mice with induced hepatic failure. 4

Immunomodulation

Some studies indicated a modulatory effect on the immune system with enhanced T cell and lymphocyte activity, 32 , 33 while others have shown no effect. 30

Neuroprotective

Aqueous extracts of Siberian ginseng showed a protective effect, possibly due to cyclo-oxygenase-2 inhibition, in transient focal cerebral ischemia induced by artery occlusion in rats. 3

Osteoporosis

A protective effect is suggested based on experiments in induced osteoporotic mice. Decreased urinary excretion of calcium and increased plasma levels of calcium and phosphorous were observed. 34

Eleutherococcus extract binds to progesterone, mineralocorticoid, and glucocorticoid receptors. 35 Siberian ginseng extracts exerted no effect on prolactin in rats despite the high concentrations and long periods of exposure used in experimentation. 36 Additionally, eleutherococcus compounds bind to estrogen receptors, with no apparent effect in cell cultures. 37

Eleutherococcus extract appears to protect cell cultures from the effects of gamma radiation but to a lesser degree than common ginseng. The mechanism seems to involve alteration of cellular metabolism rather than DNA repair. 38 , 39

Dosage

As an adaptogen, eleutherococcus has been given as powdered root in doses of 1 to 4 g/day. 30

Eleutheroside compounds have 36 to 143 times the physiologic activity of the roots from which they are extracted. Extracts of E. senticosus are recommended at less than 1 g/day. 5

Use in elderly patients and children has been studied to a limited extent. 20 , 21 , 26

Pregnancy/Lactation

Information regarding safety and efficacy during pregnancy and lactation is lacking.

Because of a potential effect on developing fetal myocytes, use of Siberian (and other) ginseng is contraindicated during pregnancy. 19

Interactions

Based on experiments with standard comparators (dextromethorphan for CYP2D6 and alprazolam for CYP3A4), it is unlikely that eleutherococcus compounds rely on the CYP-450 pathways for elimination. 40

The interaction of Siberian ginseng with digoxin has been the subject of many papers and case reports. Interference with the digoxin assay, impaired elimination of digoxin, and possible confounding with compounds other than eleutherococcus have all been suggested as reasons for this apparent effect. 20 , 40 , 41 , 42 , 43

Mice exhibited increased sleep latency and duration when exposed to eleutherococcus extract and hexobarbital, which may be due to inhibition of hexobarbital metabolism. 44

In rats, no significant effect on the kinetics of warfarin was observed with concomitant “Kan Jang” (mixed eleutherococcus extract preparation) administration. 45

Adverse Reactions

Adverse reactions, toxicity, contraindications, and warnings similar to those for Panax species (see Ginseng, Panax) apply.

High doses of eleutherococcus are associated with irritability, insomnia, and anxiety. In human trials, few adverse reactions are reported. 21 , 32 Adverse reactions have included skin eruptions, headache, diarrhea, hypertension, and pericardial pain in rheumatic heart patients.

Eleutherococcus was associated with increased aggressive behavior in mice. 29

In a small study, Siberian ginseng demonstrated a hyperglycemic effect in healthy adults so caution should be used when administering to diabetic patients. 31 In other reports, adverse reactions have included slight languor or drowsiness immediately after administration, possibly due to a hypoglycemic effect.

Toxicology

Use of eleutherococcus extract has been associated with little or no toxicity. 2 , 7 , 8 No pathologic, cytotoxic, or histologic changes were noted in mice that ingested infusions of the plant for up to 96 days. 29

Bibliography

1. Eleutherococcus senticosus . USDA, NRCS. 2006. The PLANTS Database ( http://plants.usda.gov , 14 February 2007). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Brekhman I , Fulder S . Man and Biologically Active Substances: The Effect of Drugs, Diet, and Pollution on Health . Oxford: Pergamon Press, 1980.
3. Bu Y , Jin ZH , Park SY , et al. Siberian ginseng reduces infarct volume in transient focal cerebral ischaemia in Sprague-Dawley rats . Phytother Res . 2005;19:167-169.
4. Park EJ , Nan JX , Zhao YZ , et al. Water-soluble polysaccharide from Eleutherococcus senticosus stems attenuates fulminant hepatic failure induced by D-galactosamine and lipopolysaccharide in mice . Basic Clin Pharmacol Toxicol . 2004;94:298-304.
5. Brekhman I , Favorov VV , Abramov AK , et al. Comparative study of Eleutherococcus preparations made from raw material of various origin [in Russian]. Farmatsiia . 1991;40:39-41.
6. Farnsworth N , Kinghorn AD , Soejarto DD , Waller DP . Siberian ginseng ( Eleutherococcus senticosus ): Current status as an adaptogen . Econ Med Plant Res . 1985;1:155-215.
7. Wagner H , Norr H , Winterhoff H . Plant adaptogens . Phytomedicine . 1994;1:63-76.
8. Wagner H , Wurmbock A . Chemistry, pharmacology and TLC of ginseng and Eleutherococcus drugs [in German]. Dtsch Apoth Ztg . 1977;117:743-748.
9. Hikino H , Takahashi M , Otake K , Konno C . Isolation and hypoglycemic activity of eleutherans A, B, C, D, E, F, and G: glycans of Eleutherococcus senticosus roots . J Nat Prod . 1986;49:293-297.
10. Makarieva TN , Dmitrenok AS , Stonik VA , Patel AV , Canfield LM . Lignans from Eleutherococcus senticosus (Siberian ginseng) . Pharm Sci . 1997;3:525-527.
11. Yun-Choi HS , Kim JH , Lee JR . Potential inhibitors of platelet aggregation from plant sources, ΙΙΙ . J Nat Prod . 1987;50:1059-1064.
12. Solovyeva AG , Petukhova TV , Greshnykh RD . Anaylsis and standardization of Eleutherococcus roots and rhizomes and its liquid extract by the amount of biologically active compounds [in Russian]. Farmatsiia . 1989;38:25-27.
13. Umeyama A , Shoji N , Takei M , Endo K , Arihara S . Ciwujianosides Dl and Cl: powerful inhibitors of histamine release induced by anti-immunoglobulin E from rat peritoneal mast cells . J Pharm Sci . 1992;81:661-662.
14. Nishibe S , Kinoshita H , Takeda H , Okano G . Phenolic compounds from stem bark of Acanthopanax senticosus and their pharmacological effect in chronic swimming and stressed rats . Chem Pharm Bull . 1990;38:1763-1765.
15. Chen G , Lu C , Ma S . Determination of syrgingin in slices of radix Acanthopanax senticosi by RP-HPLC [in Chinese]. Zhongguo Zhong Yao Za Zhi . 1999;24:472-473.
16. Yat P , Arnason JT , Awang DV . An improved extraction procedure for the rapid, quantitative high-performance liquid chromatographic estimation of the main eleutherosides (B and E) in Eleutherococcus senticosus (Eleuthero) . Phytochem Anal . 1998;9:291-295.
17. Anetai M , Yamagishi T , Kaneshima H . Determination of some constituents in Acanthopanax senticosus Harms. Ill. Differences among part, diameter, age, and harvest time . Hokkaidoritsu Eisei Kenkyushoho . 1995;45:63-65.
18. Kwan CY , Zhang WB , Sim SM , Deyama T , Nishibe S . Vascular effects of Siberian ginseng ( Eleutherococcus senticosus ): endothelium-dependent NO- and EDHF-mediated relaxation depending on vessel size . Naunyn Schmiedebergs Arch Pharmacol . 2004;369:473-480.
19. Poindexter BJ , Allison AW , Bick RJ , Dasgupta A . Ginseng: Cardiotonic in adult rat cardiomyocytes, cardiotoxic in neonatal rat cardiomyocytes . Life Sci . 2006;79:2337-2344.
20. Kaloeva ZD . Effect of the glycosides of Eleutherococcus senticosus on the hemodynamic indices of children with hypotensive states [in Russian]. Farmakol Toksikol . 1986;49:73.
21. Cicero AF , Derosa G , Brillante R , Bernardi R , Nascetti S , Gaddi A . Effects of Siberian ginseng ( Eleutherococcus senticosus maxim.) on elderly quality of life: a randomized clinical trial . Arch Gerontol Geriatr Suppl . 2004;9:69-73.
22. Afanaseva TN , Lebkova NP . Effect of Eleutherococcus on the subcellular structures of the heart in experimental myocardial infarct [in Russian]. Biull Eksp Bio Med . 1987;103:212-215.
23. Tian BJ , Gao TL , Song ZL . Effects of ciwujia ( Acanthopanax senticosus harms) on reperfusion-induced arrhythmia and action potential alterations in the isolated rat heart [in Chinese]. Zhongguo Zhong Yao Za Zhi . 1989;14:493-495, 508, 512.
24. Shang SY , Ma YS , Wang SS . Effect of eleutherosides on ventricular late potential with coronary heart disease and myocarditis [in Chinese]. Zhong Xi Yi Jie He Za Zhi . 1991;11:280-281, 261.
25. Panossian A , Wagner H . Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration . Phytother Res . 2005;19:819-838.
26. Hartz AJ , Bentler S , Noyes R , et al. Randomized controlled trial of Siberian ginseng for chronic fatigue . Psychol Med . 2004;34:51-61.
27. Kimura Y , Sumiyoshi M . Effects of various Eleutherococcus senticosus cortex on swimming time, natural killer activity and corticosterone level in forced swimming stressed mice . J Ethnopharmacol . 2004;95:447-453.
28. Martinez B , Staba EJ . The physiological effects of Aralia , Panax and Eleutherococcus on exercised rats . Jpn J Pharmacol . 1984;35:79-85.
29. Lewis WH , Zenger VE , Lynch RG . No adaptogen response of mice to ginseng and Eleutherococcus infusions . J Ethnopharmacol . 1983;8:209-214
30. Gaffney BT , Hugel HM , Rich PA . The effects of Eleutherococcus senticosus and Panax ginseng on steroidal hormone indices of stress and lymphocyte subset numbers in endurance athletes . Life Sci . 2001;70:431-442.
31. Sievenpiper JL , Arnason JT , Leiter LA , Vuksan V . Decreasing, null and increasing effects of eight popular types of ginseng on acute postprandial glycemic indices in healthy humans: the role of ginsenosides . J Am Coll Nutr . 2004;23:248-258.
32. Bohn B , Nebe CT , Birr C . Flow-cytometric studies with Eleutherococcus senticosus extract as an immunomodulatory agent . Arzneimittelforschung . 1987;37:1193-1196.
33. Borchers AH . Comparative effects of three species of ginseng on human peripheral blood lymphocyte proliferative responses . Int J Immunother . 1998;14:143-152.
34. Kropotov AV , Kolodnyak OL , Koldaev VM . Effects of Siberian ginseng extract and ipriflavone on the development of glucocorticoid-induced osteoporosis . Bull Exp Biol Med . 2002;133:252-254.
35. Pearce PT , Zois I , Wynne KN , Funder JW . Panax ginseng and Eleutherococcus senticosus extracts—in vitro studies on binding to steroid receptors . Endocrinol Jpn . 1982;29:567-573.
36. Di Carlo G , Pacilio M , Capasso R , Di Carlo R . Effect on prolactin secretion of Echinacea purpurea , hypericum perforatum and Eleutherococcus senticosus . Phytomedicine . 2005;12:644-647.
37. Bennetau-Pelissero C , Latonnelle KG , Lamothe V , Shinkaruk-Poix S , Kaushik SJ . Screening for oestrogenic activity of plant and food extracts using in vitro trout hepatocyte cultures . Phytochem Anal . 2004;15:40-45.
38. Ben-Hur E , Fulder S . Effect of Panax ginseng saponins and Eleutherococcus senticosus on survival of cultured mammalian cells after ionizing radiation . Am J Chin Med . 1981;9:48-56.
39. Minkova M , Pantev T . Effect of Eleutherococcus extract on the radioprotective action of adeturone . Acta Physiol Pharmacol BuIg . 1987;13:66-70.
40. Donovan JL , DeVane CL , Chavin KD , Taylor RM , Mardowitz JS . Siberian ginseng ( Eleutherococcus senticosus ) effects on CYP2D6 and CYP3A4 activity in normal volunteers . Drug Metab Dispos . 2003;31:519-522.
41. Dasgupta A , Reyes MA . Effect of Brazilian, Indian, Siberian, Asian, and North American ginseng on serum digoxin measurement by immunoassays and binding of digoxin-like immunoreactive components of ginseng with Fab fragment of antidigoxin antibody (Digibind) . Am J Clin Pathol . 2005;124:229-236.
42. Dasgupta A , Wu S , Actor J , Olsen M , Wells A , Datta P . Effect of Asian and Siberian ginseng on serum digoxin measurement by five digoxin immunoassays. Significant variation in digoxin-like immunoreactivity among commercial ginsengs . Am J Clin Pathol . 2003;119:298-303.
43. McRae S . Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng . CMAJ . 1996;155:293-295.
44. Medon PJ , Ferguson PW , Watson CF . Effects of Eleutherococcus senticosus extracts on hexobarbital metabolism in vivo and in vitro . J Ethnopharmacol . 1984;10:235-241.
45. Hovhannisyan AS , Abrahamyan H , Gabrielyan ES , Panossian AG . The effect of Kan Jang extract on the pharmacokinetics and pharmacodynamics of warfarin in rats . Phytomedicine . 2006;13:318-323.

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