Echinacea

June 2008

Echinacea angustifolia DC, Echinacea purpurea (L.) Moench, and Echinacea pallida (Nutt.) Britton. Family: Asteraceae (sunflowers)

American coneflower , black Sampson , black Susan , comb flower , echinaceawurzel , hedgehog , igelkopfwurzel , Indian head , Kansas snakeroot , narrow-leaved purple coneflower , purple coneflower , purpursonnenhutkraut , racine d'echininacea , rock-up-hat , roter sonnenhut , scurvy root , snakeroot , sonnenhutwurzel

Uses

The variation in available commercial products and lack of consistency in clinical trials make specific recommendations difficult. There is limited evidence that echinacea is effective in shortening the duration of symptoms of upper respiratory tract infections, but it has not shown effectiveness as a preventative. Echinacea is hypothesized to be an immunomodulator. There is also interest in its potential use in cancer therapy, but clinical trials are lacking.

Dosing

Many commercial preparations are available containing components derived from different plant parts as well as from different species and varieties. Recommended doses (all administered 3 times daily) include the following: 300 mg dry powdered extract (standardized to 3.5% echinacoside), 0.25 to 1.25 mL liquid extract (1:1 in 45% alcohol), 1 to 2 mL tincture (1:5 in 45% alcohol), 2 to 3 mL expressed juice of E. purpurea , and 0.5 to 1 g dried root or tea. Avoid using echinacea for more than 8 weeks at a time because of the potential for immune suppression. Intravenous (IV) use is not recommended.

Contraindications

Known hypersensitivity to plants of the Asteraceae/Compositae family; any condition in which immune stimulation or suppression would be considered disadvantageous.

Pregnancy/Lactation

Limited clinical evidence, expert opinion, and long-term traditional use suggest oral echinacea to be safe for use during pregnancy at normal dosages. Direct evidence for safety during lactation is lacking. Use caution during administration.

Interactions

None well documented.

Adverse Reactions

Adverse reactions are rare. In clinical trials, adverse reactions caused by echinacea were generally not statistically significant compared with placebo. The most commonly reported reactions were allergy, GI upset, and rash. Individuals with allergy to ragweed or related allergens should use echinacea with caution. A case report of leukopenia, possibly caused by long-term use of echinacea, has been published. Potential immune suppression with long-term use has been suggested.

Toxicology

Little is known definitively about the toxicity of echinacea. Animal studies generally indicate low toxicity.

There are at least 9 species of echinacea. ¹ Those most commonly used medicinally are E. purpurea , E. pallida , and E. angustifolia . ^2, , ³

Echinacea is native to the United States, specifically Kansas, Nebraska, and Missouri. Because of confusion regarding the identification of echinacea species, much of the early research conducted on this plant, particularly European E. angustifolia , was probably conducted on E. pallida . ⁴

E. angustifolia and E. purpurea are perennial herbs with narrow leaves and stout stems that grow from 90 cm to 1.2 m in height that blossoms as a single lavender or purple flower head. When chewed, the plant imparts a pungent taste and causes tingling of the lips and tongue. ¹

Echinacea is a popular herbal remedy in the United States. The plant was used in traditional medicine by American Indians and quickly adopted by settlers. During the 1800s, claims for the curative properties of the plant ranged from blood purification to treatment of dizziness and rattlesnake bites. ^5, , ⁶ During the early part of the 20th century, extracts of the plant were used as anti-infectives; however, the use of these products fell out of favor after the discovery of modern antibiotics. The plant and its extracts continue to be used topically for wound healing and internally to stimulate the immune system.

There is general agreement that no single chemical constituent is responsible for echinacea's biological activity. ^3, , ^7, Most studies indicate that the lipophilic fraction of the root and leaves contains the most potent immunostimulating components. ^7, Many alkamides, predominantly isobutylamides, have been described. ⁸ Caffeic acid glycosides and esters (eg, echinacoside, cynarin, cichoric acid) are found in the root and aerial parts of the plants, but echinoside is not found in E. purpurea . ³ Polysaccharides have been identified in E. purpurea aerial parts and E. pallida root. ³

The alkamides found in echinacea are available following oral administration, whereas the caffeic acid derivatives are not. ^3, The pungent component of the plant is echinacein, an isobutylamide. ^9, Depending on the species, the essential oil obtained from the root may be high in unsaturated alkyl ketones or isobutylamides. ⁴

Cancer

Animal data In mice, the mean survival age was prolonged and thymic lymphoma enlargement suppressed with 8 weeks of echinacea therapy, while other experiments have demonstrated elevated natural killer cell levels and prolonged survival times in leukemic mice. ^10, , ¹¹ Root extract from 3 echinacea species ( E. purpurea , E. angustifolia , and E. pallida ) showed concentration- and time-dependent induction of apoptosis in human pancreatic and colon cancer cell lines. ¹²

Dietary supplementation with E. purpurea in rats undergoing experimental irradiation resulted in the mobilization and enhancement of vitamin E-mediated oxidation/reduction pathways, suggesting that echinacea may have potential as a radioprotector. ^13, An in vitro study demonstrated that typical constituents of echinacea species applied topically were effective in the prevention and/or treatment of skin damage caused by ultraviolet/ultraviolet B radiation. ¹⁴

Clinical data In a trial investigating the effects of an IV-administered polysaccharide fraction of echinacea among patients with advanced gastric cancer, increases in the median number of leukocytes was demonstrated; however, the differences were not considered clinically relevant. ¹⁵ Another study involving 23 patients with tumors showed no effect on cytokine or leukocytes after using a preparation of E. angustifolia . ¹⁶

Immunomodulation Many studies investigating immunomodulatory properties have been conducted with different Echinacea species, extracts, and plant parts. However, there is little agreement on which chemical constituents are responsible for activity on the immune system. ^3, , ^17, Enhanced macrophage function, stimulation of cytokine production (including certain interleukins and tumor necrosis factor alpha), enhanced natural-killer function, and increased mean circulating total white blood cell counts have all been demonstrated in vitro. ^3, , ^18, , ^19, , ²⁰

In healthy adults, stimulation of the immune system via the CD69 marker was demonstrated within 24 hours of echinacea ingestion. ^21, Another study in humans found changes in CD8, T-lymphocytes, and natural killer cells but not in other lymphocyte subpopulations. ^22, A further study found that echinacea extract stimulated cell-mediated immunity in humans following a single dose, but repeated daily doses suppressed the immune response. ^23, Another study in healthy adults found that echinacea attenuated the suppression of exercise-induced mucosal immune response. ²⁴

Upper respiratory tract infection The widespread traditional use of echinacea for the common cold and the availability of clinical trial data make animal data mostly irrelevant.

Treatment A few quality meta-analyses have been conducted on clinical trials investigating the effect of echinacea on the management of the common cold. All have emphasized the difficulty of defining inclusion criteria because individual trial data vary in preparation and dosage used, as well as in outcomes measured. ^25, , ²⁶

In comparing echinacea with placebo, a Cochrane review found an effect in 9 trials, a trend in 1 trial, and no difference in effect in 6 trials. Most of the included trials studied E. purpurea . ^26, Other reviews found a trend toward beneficial effects, but variations in trial data make definitive statements about effect difficult. ^25, , ^27, , ^28, , ²⁹

Prevention The analyses of trial data for the prevention of colds are less compelling in their conclusions than those of treatment. However, the variable of the delay between the appearance of cold symptoms and the time the preparation is taken may add to the difficulty in making comparisons. ^30, The Cochrane meta-analysis includes data from 3 trials and found no difference between echinacea and placebo. ^26, In 2 additional reviews, trial data excluded from the Cochrane meta-analysis showed a trend toward benefit in the prevention of colds. ^29, , ^30, All reviewers concluded that further, more rigorous trials are required. ^26, , ^29, , ³⁰

Other uses

Antiviral Echinacea's in vitro activity against herpes simplex virus has been described for the E. purpurea extracts. A clinical trial investigating the effect of echinacea on the severity and recurrence of genital herpes found no difference over placebo. Antifungal and antibacterial properties also have been described, but clinical trials are lacking. ³

Anti-inflammatory When injected IV in mice or rats, echinacea extract almost completely inhibited carrageenan-induced mice or rat paw edema. Similarly, when the extract was applied topically, it almost completely inhibited the inflammation induced by croton oil applied to the mice or rat ears. ³¹ Activity of echinacea was slightly less than that of topical indomethacin.

Several caffeoyl conjugates isolated from E. angustifolia , including chicoric acid, cynarine, chlorogenic acid, and caftaric acid, demonstrate antihyaluronidase activity. ³²

Alkamides from E. angustifolia exhibited cyclooxygenase-2–dependent prostaglandin E2 inhibition in an experiment on human neuroglioma cells. ³³

One of the major limitations reported in the meta-analyses of available trial data is the lack of standardization of echinacea preparations. Many products lacked active echinacea chemical compounds ^3, , ^25, , ^26, or were contaminated with other chemical entities. ^3, , ²⁵ Recommended doses (all administered 3 times daily) include dry powdered extract 300 mg (standardized to echinacoside 3.5%), liquid extract 0.25 to 1.25 mL (1:1 in alcohol 45%), tincture 1 to 2 mL (1:5 in alcohol 45%), expressed juice of E. purpurea 2 to 3 mL, and dried root or tea 0.5 to 1 g.

IV use of echinacea is not recommended. ^13, Avoid echinacea use for more than 8 weeks at a time because of the potential for immune suppression. ^26, , ^34, , ³⁵

A prospective cohort study (N = 206) found no increased risk for fetal malformations with the use of echinacea during the first trimester. ^36, , ^37, Limitations of the study included small sample size, allowing detection of common malformations only, and the lack of standardization of preparations. ³ The German Commission E compendium considers oral echinacea safe for use during pregnancy in normal recommended dosages. ^6, , ³⁴ Published evidence for use of echinacea during lactation is lacking; however, the German Commission E compendium regards the use of oral echinacea safe during lactation. ^6, , ³⁴

None well documented. Because of the proposed immunomodulatory mechanism of action for echinacea, use caution in coadministration of immunosuppressant drugs. ^3, Limited and conflicting data regarding effects on the cytochrome P-450 enzyme system have been reported. ^3, , ²⁹

Adverse reactions for echinacea are not commonly reported despite widespread usage. ^25, , ^29, In clinical trials, no statistical difference was reported for adverse reactions caused by echinacea compared with placebo. ^3, The most commonly reported reactions are allergy, GI upset, and rash. ^3, , ^29, Individuals with allergy to ragweed, chrysanthemum, marigold, daisies, or related allergens should use echinacea with caution. ^25, , ^26, , ²⁸

A case report of leukopenia, possibly caused by long-term use of echinacea, has been published. ³⁵ In a trial conducted among patients with advanced gastric cancer, an association with the use of IV E. purpurea extract could not be ruled out in the deaths of 2 patients. ¹⁵

Little is known about the toxicity of echinacea despite its widespread use. It has been documented in traditional American medicine for more than a century and generally has not been associated with acute or chronic toxicity. ^3, Purified echinacea polysaccharide is relatively nontoxic. Acute toxicity studies found that doses of arabinogalactan as high as 4 g/kg injected intraperitoneally or IV were essentially devoid of toxic effects. ¹⁹ High-dose oral and IV administration (ie, several times the normal human therapeutic dose) of the expressed juice of E. purpurea to rodents for 4 weeks demonstrated no acute, subacute, genotoxic, carcinogenic, mutagenic, or other toxic reactions. ³⁸

1. Echinacea angustifolia DC. USDA, NRCS. 2007. The PLANTS Database ( http://plants.usda.gov , assessed January 2008). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.

2. Chavez M , et al. Echinacea . Hosp Pharm . 1998;33:180-188.

3. Barnes J , Anderson LA , Gibbons S , Phillipson JD . Echinacea species ( Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) (Moench): a review of their chemistry, pharmacology and clinical properties . J Pharm Pharmacol . 2005;57(8):929-954. PubMed

4. Bauer R , Khan IA , Wagner H . TLC and HPLC analysis of Echinacea pallida and E. angustifolia roots . Planta Med . 1988;54(5):426-430. PubMed

5. Tyler V . The New Honest Herbal . Philadelphia, PA: GF Stickley Co; 1987.

6. Perri D , Dugoua JJ , Mills E , Koren G . Safety and efficacy of echinacea ( Echinacea angustafolia , E. purpurea and E. pallida ) during pregnancy and lactation . Can J Clin Pharmacol . 2006;13(3):e262-267. PubMed

7. Müller-Jakic B , Breu W , Pröbstle A , Redl K , Greger H , Bauer R . In vitro inhibition of cyclooxygenase and 5-lipoxygenase by alkamides from echinacea and achillea species . Planta Med . 1994;60(1):37-40. PubMed

8. Bauer R , Remiger P , Wagner H . New alkamides from Echinacea angustifolia and E. purpurea Roots . Planta Med . 1988;54(6):563-564. PubMed

9. Jacobson M . The structure of echinacein, the insecticidal component of American coneflower roots . J Org Chem . 1967;32(5):1646-1647. PubMed

10. Currier NL , Miller SC . Echinacea purpurea and melatonin augment natural-killer cells in leukemic mice and prolong life span . J Altern Complement Med . 2001:7(3):241-251. PubMed

11. Miller SC . Echinacea: a miracle herb against aging and cancer? Evidence in vivo in mice . Evid Based Complement Alternat Med . 2005;2(3):309-314. PubMed

12. Chicca A , Adinolfi B , Martinotti E , et al. Cytotoxic effects of Echinacea root hexanic extracts on human cancer cell lines . J Ethnopharmacol . 2007;110(1):148-153. PubMed

13. Paranich AV , Pocherniaeva VF , Dubinskaia GM , et al. Effect of supposed radioprotectors on oxidation-reduction of vitamin E in the tissues of irradiated rats [in Russian] . Radiats Biol Radioecol . 1993;33(5):653-657. PubMed

14. Facino R , Carini M , Aldini G , Saibene L , Pietta P , Mauri P . Echinacoside and caffeoyl conjugates protect collagen from free radical-induced degradation: a potential use of echinacea extracts in the prevention of skin photodamage . Planta Med . 1995;61:510-514. PubMed

15. Melchart D , Clemm C , Weber B , et al. Polysaccharides isolated from Echinacea purpurea herba cell cultures to counteract undesired effects of chemotherapy—a pilot study . Phytother Res . 2002;16(2):138-142. PubMed

16. Elsässer-Beile U , Willenbacher W , Bartsch HH , Gallati H , Schulte Mönting J , von Kleist S . Cytokine production in leukocyte cultures during therapy with echinacea extract . J Clin Lab Anal . 1996;10(6):441-445. PubMed

17. Bauer VR , Jurcic K , Puhlmann J , Wagner H . Immunologic in vivo and in vitro studies on echinacea extracts [in German] . Arzneimittelforschung . 1988;38(2):276-281. PubMed

18. Agnew LL , Guffogg SP , Matthias A , Lehmann RP , Bone KM , Watson K . Echinacea intake induces an immune response through altered expression of leucocyte hsp70, increased white cell counts and improved erythrocyte antioxidant defences . J Clin Pharm Ther . 2005;30(4):363-369. PubMed

19. Luettig B , Steinmüller C , Gifford GE , Wagner H , Lohmann-Matthes ML . Macrophage activation by the polysaccharide arabinogalactan isolated from plant cell cultures of Echinacea purpurea . J Nat Cancer Inst . 1989;81(9):669-675. PubMed

20. Steinmüller C , Roesler J , Gröttrup E , Franke G , Wagner H , Lohmann-Matthes ML . Polysaccharides isolated from plant cell cultures of Echinacea purpurea enhance the resistance of immunosuppressed mice against systemic infections with Candida albicans and Listeria monocytogenes . Int J Immunopharmacol . 1993;15(5):605-614. PubMed

21. Brush J , Mendenhall E , Guggenheim A , et al. The effect of Echinacea purpurea , Astragalus membranaceus and Glycyrrhiza glabra on CD69 expression and immune cell activation in humans . Phytother Res . 2006;20(8):687-695. PubMed

22. Schwarz E , Parlesak A , Henneicke-von Zepelin HH , Bode JC , Bode C . Effect of oral administration of freshly pressed juice of Echinacea purpurea on the number of various subpopulations of B- and T-lymphocytes in healthy volunteers: results of a double-blind, placebo-controlled cross-over study . Phytomedicine . 2005;12(9):625-631. PubMed

23. Coeugniet E , Elek E . Immunomodulation with Viscum album and Echinacea purpurea extracts . Onkologie . 1987;10(suppl 3):27-33. PubMed

24. Hall H , Fahlman MM , Engels HJ . Echinacea purpurea and mucosal immunity . Int J Sports Med . 2007;28(9):792-797. PubMed

25. Islam J , Carter R . Use of Echinacea in upper respiratory tract infection . South Med J . 2005;98(3):311-318. PubMed

26. Linde K , Barrett B , Wölkart K , Bauer R , Melchart D . Echinacea for preventing and treating the common cold . Cochrane Database Syst Rev . 2006 Jan 25;(1):CD000530.

27. Caruso TJ , Gwaltney JM Jr . Treatment of the common cold with echinacea: a structured review . Clin Infect Dis . 2005;40(6):807-810. PubMed

28. Koenig K , Roehr CC . Does treatment with Echinacea purpurea effectively shorten the course of upper respiratory tract infections in children ? Arch Dis Child . 2006:91(6):535-537. PubMed

29. Shah SA , Sander S , White CM , Rinaldi M , Coleman CI . Evaluation of echinacea for the prevention and treatment of the common cold: a meta-analysis . Lancet Infect Dis . 2007;7(7):473-480. PubMed

30. Schoop R , Klein P , Suter A , Johnston SL . Echinacea in the prevention of induced rhinovirus colds: a meta-analysis . Clin Ther . 2006:28(2):174-183. PubMed

31. Tubaro A , Tragni E , Del Negro P , Galli CL , Della Loggia R . Anti-inflammatory activity of a polysaccharidic fraction of Echinacea angustifolia . J Pharm Pharmacol . 1987;39(7):567-569. PubMed

32. Facino RM , Carini M , Aldini G . Direct characterization of caffeoyl esters with antihyaluronidase activity in crude extracts from Echinacea angustifolia roots by fast atom bombardment tandem mass spectrometry . Farmaco . 1993;48(10):1447-1461. PubMed

33. Hinz B , Woelkart K , Bauer R . Alkamides from Echinacea inhibit cyclooxygenase-2 activity in human neuroglioma cells . Biochem Biophys Res Commun . 2007;360(2):441-446. PubMed

34. Blumenthal M , sr ed. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines . S. Klein. Boston, MA: American Botanical Council; 1998.

35. Kemp DE , Franco KN . Possible leukopenia associated with long-term use of echinacea . J Am Board Fam Pract . 2002:15(5):417-419. PubMed

36. Gallo M , Sarkar M , Au W , et al. Pregnancy outcome following gestational exposure to echinacea: a prospective controlled study . Arch Intern Med . 2000;160(20):3141-3143. PubMed

37. Rotblatt M , Ziment I . Evidence-Based Herbal Medicine . Philadelphia, PA: Hanley & Belfus; 2002.

38. Mengs U , Clare CB , Poiley JA . Toxicity of Echinacea purpurea . Acute, subacute, and genotoxicity studies . Arzneimittelforschung . 1991;41(10):1076-1081. PubMed