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Eleuthero

Botanical Name: Eleutherococcus senticosus (Rupr. and Maxim.) Maxim.
Pharmacopoeial Name: Radix Eleutherococci.
Synonym: Acanthopanax senticosus (Rupr. and Maxim.) Maxim.
Common Names: Eleuthero, Siberian ginseng.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Antineoplastic treatments Myelosuppressive chemotherapies Radiation /	Eleuthero promotes myelopoiesis, helps protect white blood cell (WBC) counts during cyclophosphamide or other myelosuppressive chemotherapies. May synergize with radioprotective agents. Laboratory support and limited clinical evidence; controlled studies lacking, but interaction likely.	Pretreat, coadminister, and continue after chemo/radiotherapy until WBC count normalized (use with related adaptogenic herbs).

herb description

Family

Araliaceae.

Habitat and Cultivation

Native to northern and eastern Russia, northern China, Korea, and Japan; commercially grown in Siberia, as well as parts of China.

Parts Used

Root; the leaf is also used in Russia.

Common Forms

Dried: Powdered root.

Tincture: 1:5.

Fluid Extract: 1:1, 33% to 40% ethanol.

Standardized Preparations: Usually based on eleutheroside E >1.0% and/or eleutheroside B.

herb in clinical practice

Overview

Eleuthero is considered one of the defining adaptogen medicinal plants. Adaptogens have no equivalent among conventional pharmaceutical agents. The term was coined by Soviet researcher Lazarev in 1947 and subsequently defined by Brekhman in terms of three salient qualities: nonspecific (in relation to a wide range of stressor stimuli), nontoxic (cause minimal disturbance to normal physiological function), and normalizing (direction of action varies depending on the prior state of response to stressor and always normalizes). ^1,2The properties of adaptogens have been reviewed recently by Panossian ³ and Wagner. ⁴ Panossian and Wagner ⁵ also recently published an important paper distinguishing between the adaptogenic effects of the herb resulting from chronic dosing protocols compared with the stimulating effect of single acute doses.

With more than 1000 studies, eleuthero was initially the most widely studied adaptogenic herb, although Panax ginseng has a more voluminous literature. Eleuthero has established immunomodulating, anabolic, radioprotective, chemoprotective, antiviral, gonadotrophic, antiviral, and insulinotropic/antidiabetic effects; enhances learning, memory, visual and auditory acuity, and exercise endurance and recovery; and has antitoxic and antialcohol effects, as well as a range of antineoplastic actions.

Western reviews of some of the literature are available by Wagner and Norr, ⁴ Farnsworth et al., ⁶ McKenna et al., ⁷ Davidov and Krikorian, ⁸ and Baranov. ⁹ Therapeutic monographs are available from the European Scientific Cooperative on Phytotherapy, ¹⁰ World Health Organization (WHO), ¹¹ German Commission E, ¹² and British Herbal Medical Association. ¹³

Confusion over nomenclature for the herb exists both with the binomial name (it is known as Acanthopanax senticosus in Chinese medicine) and the common name; the previous name “Siberian ginseng” implies similarity with “true” Panax ginseng . The current common name “eleuthero” was recently adopted in commerce to emphasize that although both plants are adaptogenic, eleuthero is pharmacologically distinct from Panax ginseng in terms of both constituents and activity profile. Medical reports often fail to use the correct binomial designation to identify herbal ingredients, and eleuthero has notoriously been confused with the entirely different species Panax ginseng (see Ginseng monograph).

Historical/Ethnomedicine Precedent

Eleuthero root (Ci Wu Jia) has been used in traditional Chinese medicine as a spleen (Pi) and kidney (Shen) qi tonic and is claimed to calm the Spirit/Mind (Shen) . The root bark is considered a separate remedy. Eleuthero was incorporated into Western medicine in Russia in the early 1960s after two decades of Soviet research to locate more economic adaptogenic species than the slow-growing Panax ginseng , and it was introduced to the U.S. market in the 1970s. ⁹ As with many herbs used in Chinese medicine, Ci Wu Jia is used in complex formulae corresponding to specific classical diagnostic patterns and is prescribed in higher typical dose levels than in Western usage. ¹⁴

Known or Potential Therapeutic Uses

Stress reduction and neuroendocrine balancing (e.g., dysglycemia, adrenal deficiency); fatigue, convalescence; enhancement of stamina, exercise, athletic, and work capacity and performance; increasing mental alertness and cognitive performance (e.g., memory, visual acuity); adjunctive to radiation and chemotherapy treatment; various psychological complaints (e.g., insomnia, depression); immunoprotection and immunomodulation; prophylaxis of infection, especially viral infection; antineoplastic.

Key Constituents

Lignans and other phenylpropanoids.

A series of “eleutheroside” compounds have been identified (eleutherosides A-M), but none of these is unique to eleuthero, and not all are the eleutheroside homologous compounds.

Oleanic acid derivatives (eleutherosides I-M), senticosides A-F, and polysaccharides, including glycans (eleutherans A-G); miscellaneous sterols, saponins, vitamins, and carbohydrates.

Therapeutic Dosing Range

Dried Root: 2 to 3 g daily (Western); 9 to 30 g daily (Chinese).

Tincture: 3.0 to 12.0 mL daily (equivalent 1:1).

Standardized Dry Extract: 150 to 300 mg three times daily; 10:1 extracts standardized to eleutherosides B and E.

interactions review

Strategic Considerations

Authoritative monographs on eleuthero do not list any known interactions between eleuthero and pharmaceuticals. ^10-13The WHO monograph does refer to a case report that suggested eleuthero extracts interacted with digoxin. This case is considered likely an issue of adulteration or of interference between certain constituents of the herb and the digoxin assay and is discussed later (see Theoretical, Speculative, and Preliminary Interactions Research).

The general adaptogenic properties of eleuthero (according to the criteria of Lazarev and Breckhman) have been substantiated by a number of indexed Western studies, particularly regarding performance enhancement, although the bulk of the supporting literature, both experimental and clinical, is in Russian-language journals, much of it dating from the 1950s through the 1970s. Authoritative evaluations of the original literature in terms of study design, statistics, methods, and materials are not generally available. In the 1980s, Farnsworth et al. ⁶ and Baranov ⁹ attempted to summarize a number of eleuthero studies from the earlier Russian literature.

From an integrative perspective, the use of eleuthero in oncological settings is of particular interest because of the putative protective effects against chemotherapy- and radiation-induced toxicity suggested by the Russian research. Unfortunately, little corroborative work has been undertaken in the West to support the Soviet-era data. This is discussed later as a generic interaction.

As with other adaptogenic herbs, the nonspecific immunomodulating properties may bring about beneficial interactions with antimicrobial agents, although for eleuthero there are minimal data on this application. ¹⁵ (See also Ginseng [Panax ginseng] monograph.)

Effects on Drug Metabolism and Bioavailability

An in vitro fluorometric probe study failed to detect any effect of eleutherosides E and B on a battery of recombinant human cytochrome P450 (CYP450) isoforms (1A2, 2C9, 2C19, 2D6, and 3A4). ¹⁶ A “before and after” study on 12 healthy human volunteers failed to establish any effect of standardized Eleutherococcus extract (485 mg twice daily) with dextromethorphan and alprazolam probes. The authors concluded that the extract is likely to alter disposition of drugs metabolized by 3A4 and 2D6. ¹⁷ From the limited data currently available, pharmacokinetic interactions caused by eleuthero effects on phase-one drug-metabolizing enzymes seems unlikely, and clinical reports of such interactions have not to date been made.

herb-drug interactions

Antineoplastic Chemotherapy, Including 6-Mercaptopurine, Cyclophosphamide

Cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox), mercaptopurine (6-mercaptopurine, 6-MP, NSC 755; Purinethol).

	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

Eleuthero extracts are used to reduce adverse effects of antineoplastic therapies through a variety of mechanisms, including protection against and reversal of leukopenia, reduction of chemical toxicities, and enhancement of general stress resistance.

Research

In vitro and animal studies confirm that eleuthero extracts can modulate the immune system through a variety of mechanisms. These include increases in phagocytosis, natural killer (NK), and cytotoxic T-cell activity; modulation of T helper cell types 1 and 2 (Th1 and Th2) cytokines; and increased endogenous granulocyte colony-stimulating factor (G-CSF) production. ^18-28 Two human studies are available. A flow-cytometry study was performed by Bohn et al. ²¹ on healthy human volunteers, who consumed 10 mL of eleuthero extract three times daily for 4 weeks. Significant increases in Th1 and NK cell numbers were observed, with increased activity of T cells. Russian researchers Kupin et al. ^29,30 reported stimulation of immunological reactivity in breast cancer patients treated with eleuthero extracts. Although limited, these studies suggest that eleuthero has immunostimulating and immunomodulating activities in humans.

Coadministration of eleuthero with various antineoplastic agents (as well as radiation) has been reported in a number of Russian studies. Farnsworth et al. ⁶ report several animal studies in the Russian literature by Monakhov ^31,32 and other researchers that involved a variety of antitumor agents, including 6-mercaptopurine, cyclophosphamide, and ethydimine. An in vitro study by Hacker and Mendon ³³ found that eleuthero extracts at 75 µg/mL potentiated the effects of antileukemic agents cytarabine and N6-adenosine against murine L1210 leukemia cells. In a controlled study, Brekhman ³⁴ reported a reduction of adverse effects in a controlled study of 80 breast cancer patients undergoing chemotherapy and/or radiation treatment when treated concurrently with eleuthero extracts, compared with controls not treated with eleuthero. Radioprotective effects of the herb have also been documented. ^35,36 A rodent study by Minkova and Pantev ³⁷ found that a radioprotective drug known as “adenturone” was potentiated by prophylactic pretreatment with eleuthero, although the dose of herb used was very high (5 g/kg orally).

Integrative Therapeutics, Clinical Concerns, and Adaptations

The documented evidence supporting benefits of coadministration of eleuthero with chemotherapy and/or radiation in oncology patients is limited, but sufficient data exist to justify the inclusion of eleuthero with other adaptogenic herbs in protective protocols designed to minimize myelosuppressive side effects of cancer treatment. (See also Ginseng monograph.)

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Digoxin and Related Cardiac Glycosides

Digoxin (Digitek, Lanoxin, Lanoxicaps; purgoxin).

Extrapolated, based on similar properties:
Deslanoside (cedilanin-D), digitoxin (Cystodigin), ouabain (g-strophanthin).

An isolated case report describes a 74-year-old man with atrial fibrillation, stable on taking digoxin, who was tested for excessively high serum digoxin levels during routine monitoring, although he was asymptomatic. The digoxin was stopped, but the elevated level persisted. The patient disclosed self-administration of eleuthero. The product was not specified, and no analysis was performed to confirm the identity of the commercial preparation reported as consumed. After cessation of the supplement, digoxin levels normalized, and the patient resumed digoxin therapy. ⁴¹ Because eleuthero contains no cardiac glycosides, two hypotheses have been advanced to explain the apparent interaction. First, variation in eleuthero commercial products is well known. ⁴² Second, commercial samples of eleuthero, especially those sourced from China, have been documented on occasion as being contaminated with the species Periploca sepiumBge., a different Chinese herbal substance whose bark resembles that of eleuthero. Periplocais cardiotoxic in the doses that equate to nontherapeutic levels of eleuthero because of the presence of cardiac glycosides. ⁴³ Given the failure to test the composition of the suspected eleuthero product involved in the case, Awang ⁴⁴ postulated that adulteration with Periplocacould explain the apparent test elevations.

An alternative explanation is that the botanical preparation may have interfered with the digoxin assay, causing falsely elevated readings. A recent investigation by Dasgupta et al. ⁴⁵ supports this possibility, showing in vitro, as well as in vivo with human subjects, that eleuthero extracts can interfere with fluorescence polarization, creating false elevations in digoxin assay readings. The modest “false” elevated digoxin test readings caused by eleuthero may not explain the total apparent increase found in the case reported by McRae, ⁴¹ and combination factors still may have been involved. Finally, it has not been established that eleuthero is without effect on the P-glycoprotein transporter, of which digoxin is a substrate.

In summary, currently available data do not support the existence of any interaction between eleuthero and cardiac glycosides.

Antimicrobial Agents, Including Aminoglycoside Antibiotics

Evidence:
Kanamycin (Kantrex), paromomycin (monomycin; Humatin).

An uncontrolled study by Vereshchagin et al. ¹⁵ suggests that coadministration of eleuthero with antibiotics (monomycin/paromomycin or kanamycin) in the treatment of children with Shigella- or Proteus-related gastrointestinal infections was more effective than treatment with antibiotic alone. As discussed by Brinker, ⁴⁶ this possible interaction is circumstantially supported by some experimental data on the effects of eleuthero on increasing lymphocyte and NK cell activity. ²¹ Full evaluation of the original Russian-language study in unavailable in English, and the absence of corroborative data on antimicrobial-eleuthero combinations indicates that the potential interaction required may best be categorized as “overstated” at this time. It is theoretically arguable that such an interaction may be of widespread clinical applicability with a variety of antimicrobial drug classes, but this hypothesis remains to be tested. (See also interactions between Panax ginsengand beta-lactam antibiotics as discussed in the Ginseng monograph.)

Monoamine Oxidase-B (MAO-B) Inhibitors

Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), procarbazine (Matulane), tranylcypromine (Parnate).

Reports of a ginseng-phenelzine interaction persist in the literature on Panax ginseng. These reports have been shown to be incorrect, arising from a confusion of Panax ginsengwith eleuthero. ⁴⁷ In any event, the reports contained insufficient or inadequate data for evaluation.

Citations

1.Brekhman II, Maianskii GM. Eleutherococcus—a means of increasing the nonspecific resistance of the organism. Izv Akad Nauk SSSR Biol (Russian) 1965;5:762-765.View Abstract
2.Brekhman II, Dardymov IV. New substances of plant origin which increase nonspecific resistance. Annu Rev Pharmacol 1969;9:419-430.View Abstract
3.Panossian A, Wikman G, Wagner H. Plant adaptogens. III. Earlier and more recent aspects and concepts on their mode of action. Phytomedicine 1999;6:287-300.View Abstract
4.Wagner H, Norr H. Plant adaptogens. Phytomedicine 1994;1:63-76.
5.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.View Abstract
6.Farnsworth NR, Kinghorn AD, Soejarto DD, Waller DP. Siberian ginseng (Eleutherococcus senticosus): current status as an adaptogen. In: Wagner H, Hikino HZ, Farnsworth NR, eds. Economic and Medicinal Plant Research. 1 vol. London: Academic Press; 1985:155-215.
7.McKenna D, Jones K, Hughes K, Humphrey S. Eleuthero. Botanical Medicines. 2nd ed. Binghamton, NY: Haworth Press; 2002:255-270.
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11.WHO. Radix Eleutherococci. WHO Monographs on Selected Medicinal Plants. 2 vol. Geneva: World Health Organization; 2002:97-105.
12.Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs^. Austin, TX: American Botanical Council: Integrative Medicine Communications; 1998.
13.BHMA. Eleutherococcus. In: Bradley P, ed. British Herbal Compendium. Bournemouth, UK: British Herbal Medical Association; 1992:89-91.
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16.Henderson GL, Harkey MR, Gershwin ME et al. Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci 1999;65:PL209-PL214.View Abstract
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20.Schmolz MW, Sacher F, Aicher B. The synthesis of Rantes, G-CSF, IL-4, IL-5, IL-6, IL-12 and IL-13 in human whole-blood cultures is modulated by an extract from Eleutherococcus senticosus L. roots. Phytother Res 2001;15:268-270.View Abstract
21.Bohn B, Nebe CT, Birr C. Flow-cytometric studies with Eleutherococcus senticosus extract as an immunomodulatory agent. Arzneimittelforschung 1987;37:1193-1196.View Abstract
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23.Wang JZ, Tsumura H, Ma N et al. Biochemical and morphological alterations of macrophages and spleen cells produced by antitumor polysaccharide from Acanthopanax obovatus roots. Planta Med 1993;59:54-58.View Abstract
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27.Glatthaar-Saalmuller B, Sacher F, Esperester A. Antiviral activity of an extract derived from roots of Eleutherococcus senticosus. Antiviral Res 2001;50:223-228.View Abstract
28.Jeong HJ, Koo HN, Myung NI et al. Inhibitory effects of mast cell-mediated allergic reactions by cell cultured Siberian ginseng. Immunopharmacol Immunotoxicol 2001;23:107-117.View Abstract
29.Kupin V, Polevaya E, Sorokin A. Increased immunologic reactivity of lymphocytes in oncologic patients treated with Eleutherococcus extract. In: Brekhman I, ed. New Data on Eleutherococcus: Proceedings of the Second International Symposium of Eleutherococcus. Moscow: Vladivostok: DVNTS AN SSSR, 1986; 1984.
30.Kupin VI, Polevaia EB. Stimulation of the immunological reactivity of cancer patients by Eleutherococcus extract. Vopr Onkol (Russian) 1986;32:21-26.View Abstract
31.Monakhov BV. Eleutherococcus senticoccus extract and therapeutic activity of cyclophosphamide, ethymidine or benzo-tepa. Vopr Onkol (Russian) 1967;13:94-97.
32.Monakhov BV. Reduction of toxicity of some antiblastoma drugs by Eleutherococcus extract. Vopr Onkol (Russian) 1967;13:71-76.
33.Hacker B, Medon PJ. Cytotoxic effects of Eleutherococcus senticosus aqueous extracts in combination with N6-(δ-2-isopentenyl)-adenosine and 1-β-d-arabinofuranosylcytosine against L1210 leukemia cells. J Pharm Sci 1984;73:270-272.
34.Brekhman II. Report on the use of Eleutherococcus with breast cancer patients. Eleutherococcus: Clinical Data. Institute of Oncology, Georgia: USSR Foreign Trade Publication, Medexport, USSR; 1970.
35.Yonezawa M, Katoh N, Takeda A. Radiation protection by Shigoka extract on split-dose irradiation in mice. J Radiat Res (Tokyo) 1989;30:247-254.View Abstract
36.Miyanomae T, Frindel E. Radioprotection of hemopoiesis conferred by Acanthopanax senticosus Harms (Shigoka) administered before or after irradiation. Exp Hematol 1988;16:801-806.
37.Minkova M, Pantev T. Effect of Eleutherococcus extract on the radioprotective action of adeturone. Acta Physiol Pharmacol Bulg 1987;13:66-70.View Abstract
38.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.View Abstract
39.Medon PJ, Thompson EB, Farnsworth NR. Hypoglycemic effect and toxicity of Eleutherococcus senticosus following acute and chronic administration in mice. Zhongguo Yao Li Xue Bao 1981;2:281-285.View Abstract
40.Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.
41.McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. C MAJ 1996;155:293-295.View Abstract
42.Harkey MR, Henderson GL, Gershwin ME et al. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr 2001;73:1101-1106.View Abstract
43.Chen J, Chen T. Chinese Medical Herbology and Pharmacology. City of Industry, CA: Art of Medicine Press Inc; 2004.
44.Awang DV. Siberian ginseng toxicity may be case of mistaken identity. CMAJ 1996;155:1237.View Abstract
45.Dasgupta A, Wu S, Actor J et al. 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.
46.Brinker F. Herb Contraindications and Drug Interactions. 3rd ed. Sandy, OR: Eclectic Medical Publications; 2001.
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