Echinacea for Colds

By Dennis Awang, PhD, FCIC, and Adriane Fugh-Berman, MD

Does echinacea work to prevent or treat upper respiratory infections (URIs)? This is not a simple question. Although numerous trials of echinacea-containing products exist, many trials tested echinacea combined with other herbs. This article will review echinacea-only trials, but this limitation narrows the range of products only slightly: Products tested are made from different species and different parts of plants.

The taxonomy of echinacea has recently been revised. Until now, Echinacea purpurea, E. angustifolia, and E. pallida, all of which are used commercially, were considered three different species. E. angustifolia is now considered a variety of E. pallida, respectively designated E. pallida var angustifolia and E. pallida var pallida.1 We are adopting the new taxonomy, but all literature to date refers to the old taxonomy.

Single-herb products tested in clinical trials that are available in the United States include two E. purpurea products: Echinaforce® (Bioforce), a hydroalcoholic extract (65% ethanol, extract ratio 5.9:1) of fresh herb (95%) and root (5%), and Echinaguard® (United States) or Echinacin® (Madaus AG, Germany), the freshly expressed juice from aerial parts of flowering E. purpurea, stabilized with 22% ethanol.2

Prevention of URIs

None of the three placebo-controlled RCTs of echinacea-only products for the prevention of URIs found a benefit. A three-armed trial in 302 subjects (289 were analyzed) compared E. pallida var angustifolia root extract to E. purpurea root extract and placebo (2 x 50 drops daily 5 x/wk ´ 12 weeks); there was no differ- ence among groups in the time to occurrence of the first URI, nor in the proportion of groups that developed URIs.3

Another trial, published in two publications, tested pressed juice of E. purpurea herb (4 mL twice daily for 8 weeks) in 109 subjects and found no benefit on the incidence, duration, or severity of colds or URIs.4,5

The only trial using a rhinovirus challenge found no effect of echinacea (an uncharacterized preparation containing 0.16% cichoric acid, but devoid of echinacoside and alkamides, consistent with an aqueous extract of E. purpurea) on the incidence of experimentally induced infection, or incidence of colds.6

Treatment of URIs

Six randomized, placebo-controlled trials, with a total of 881 subjects, found echinacea beneficial for URI treatment in at least one treated group. Tested extracts included: E. pallida root (two publications of the same trial);7,8 pressed juice;9,10 E. purpurea root;11,12 two doses of Echinaforce;11 and Echinacea Plus® tea, containing E. purpurea herb, E. angustifolia herb, and a dry extract of E. purpurea root in a 6:1 ratio.13

Except for two extracts of E. purpurea root, most formulations were significantly better than placebo in the primary outcome measures. Most trials examined duration of symptoms; the Hoheisel study (sometimes classified as a prevention trial) administered echinacea at first onset of symptoms and found a significant reduction in proportion of subjects who developed a "real cold," as well as shorter duration of symptoms.10

Extracts of E. purpurea root may be inferior to E. pallida var pallida root or E. purpurea herb. The Brinkeborn study, a four-armed study in 559 subjects that compared placebo to two potencies of Echinaforce and E. purpurea root extract, found that Echinaforce, but not the E. purpurea root extract, was superior to placebo.12 The Braunig 1992 trial compared two doses, 450 mg (90 drops) vs. 900 mg (180 drops) daily of E. purpurea root extract to placebo and found a significant (P < 0.0001) benefit only in the latter group;11 however, this trial has been criticized as not truly blinded.14

It is interesting to note that these trials seem to bear out the conclusions of the German Commission E, the organization that until 1995 evaluated herbal products for the German government. Before most of these trials were published, Commission E had issued positive monographs on E. pallida var pallida root and E. purpurea herb, and had concluded that evidence of efficacy for other extracts, notably E. purpurea root and E. pallida var angustifolia, was not sufficient. E. pallida var angustifolia was thought to be active because of promising pharmacological studies, but the Commission E, based on research by Bauer and Wagner,15 concluded that earlier pharmacological studies of E. pallida var angustifolia actually involved E. pallida var pallida.

Active Compounds/Mechanisms

Active constituents of echinacea are believed to be alkylamides (alkamides), caffeic acid derivatives (e.g., cichoric acid, caftaric acid), ketoalkenes/ketoalkynes, glycoproteins, and polysaccharides. Compounds vary in type and ratio among plant parts and species, and the most effective constituents remain to be determined. "Standardized" extracts of echinacea are widely available, but cannot be compared to each other, as preparations are standardized to different compounds. Echinacoside, a caffeic acid derivative, which often has been used to "standardize" commercial echinacea preparations, and occurs in E. pallida var angustifolia and E. pallida var pallida, is virtually absent from E. purpurea, and lacks immunostimulatory effect.16 Cichoric acid, also used to "standardize" extracts, is regarded as a significant active constituent of freshly squeezed juice preparations, but is unsuitable for standardizing extracts of E. pallida var angustifolia, because only traces exist in that species. Cichoric acid is very susceptible to enzymatic degradation and is rapidly degraded unless echinacea expressed juice is treated thermally or with alcohol.

A recent HPLC analysis of alcoholic extracts of the roots of the three Echinacea species reports that cichoric acid and verbascoside, two caffeic acid derivatives, are dominant in E. purpurea; cynarin and dodeca-2E, 4E, 8Z, 10Z/E-tetraenoic acid isobutylamide are the major constituents of E. pallida var angustifolia; and echinacoside and 6-O-caffeoylechinacoside predominate in E. pallida var pallida.17

Although the predominant mechanism of action of echinacea extracts has been thought to be through stimulation of phagocytosis, a recent double-blind, placebo-controlled crossover study in 40 healthy men found no effect of freshly expressed juice of E. purpurea herb, compared to placebo juice (each phase lasted 14 days, with a four-week washout between phases) on phagocytic activity of mononuclear leucocytes and monocytes.18 This study also found no benefit of echinacea on production of tumor necrosis factor (TNF-a) or interleukin-1b by LPS-stimulated blood monocytes. The authors of this study note that the three small studies done previously were all by the same group and found inconclusive results. The Schwartz study noted significantly decreased serum ferritin (P = 0.0005) during the echinacea phase, compared to the placebo phase. Noting that serum ferritin is closely associated with the concentration of acute phase proteins, Schwartz et al suggest that the effect of echinacea on pro-inflammatory reactions should be explored. Although many in vitro assays and in vivo experiments using parenteral administration have shown enhanced phagocytosis, it has been noted that polysaccharides credited with stimulating macrophage cytotoxicity would be unlikely to survive oral administration.19

Quality

A survey of 25 commercial echinacea-containing products evaluating alkamide and cichoric acid content revealed extreme variation among different formulations, among different species, and among plant parts.20 Large differences also were found in comparable drugs from different manufacturers, as well as among different lots of the same preparation.

Adverse Reactions

Four cases of anaphylaxis, 12 cases of acute asthma, and 10 cases of urticaria/angioedema attributed to echinacea were reported to the Australian Adverse Drug Reactions Advisory Committee; three of five cases evaluated by the reviewers had positive skin prick tests.21

Four episodes of erythema nodosum temporally associated with use of an unidentified preparation of purported echinacea occurred over 18 months in a 41-year-old healthy man (who also was taking St. John’s wort and occasional loratidine).22 He remained free of episodes for one year after discontinuing the purported echinacea product.

With oral products, unpleasant taste is the most common side effect, but allergic skin reactions may also occur. Parenteral administration of E. purpurea squeezed sap (Echinacin) may cause shivering, fever, or muscle weakness.23

A 49-year-old woman treated with intramuscular injections of a homeopathic product (containing E. pallida var angustifolia D2 1.1 mL, lachesis D8 [snake venom] 0.3 mL, and "echinacea comp Hevert inject" 0.3 mL), administered with her own blood, developed numbness and weakness in her arm and was diagnosed with acute disseminated encephalomyelitis.24 Given confounding factors, it is difficult to attribute these effects to echinacea.

Theoretical concerns that echinacea may worsen symptoms of autoimmune disease have been raised, but no such cases have been reported.

Pregnancy

A controlled study compared 206 women who reported gestational use of echinacea to the Motherisk program (112 reported first trimester use) with 206 controls; there were no significant differences between groups for major or minor malformations.25

Summary

Echinacea extracts may reduce the duration of symptoms associated with URIs, but atopic individuals may experience adverse reactions, including anaphylaxis. There is no evidence that echinacea is beneficial in preventing URIs, and this use should be discouraged. Preparations made from pressed juice of E. purpurea herb (Echinacin and others) or E. pallida var pallida root appear to be superior to those made from E. purpurea root. The most active constituents have not been identified, so "standardized" products of echinacea are no guarantor of effectiveness. Additionally, products on the market vary widely.

Dr. Awang is President, MediPlant Consulting, White Rock, British Columbia, Canada.

References

1. Binns SE, et al. A taxonomic revision of echinacea (Asteraceae: Heliantheae). Syst Bot, in press.

2. Bauer R. Standardization of Echinacea purpurea expressed juice with reference to cichoric acid and alkamides. J Herbs Species Med Plant 1999;6:51-62.

3. Melchart D, et al. Echinacea root extracts for the prevention of upper respiratory tract infections: A double-blind, placebo-controlled randomized trial. Arch Fam Med 1998;7:541-545.

4. Grimm W, Müller H-H. A randomized controlled trial of the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections. Am J Med 1999;106:138-143.

5. Schoneberger D. Einflu[latin sharp s] der immunstimulierenden Wirkung von Pre[latin sharp s]saft aus Herba Echinaceae purpureae auf Verlauf und Schweregrad von Erkaltungskrankheiten. Forum Immuno-logie 1992;2:18-22.

6. Turner RB, et al. Ineffectiveness of Echinacea for prevention of experimental rhinovirus colds. Antimicrob Agents Chemother 2000;44:1708-1709.

7. Braunig B, Knick E. Therapeutische Erfahrungen mit Echinacea pallida bei grippalen Infekten. Naturheilpraxis mit Naturmedizin 1993;1:72-75.

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12. Brinkeborn RM, et al. Echinaforce and other Echinacea fresh plant preparations in the treatment of the common cold. Phytomedicine 1999;6:1-5.

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14. Melchart D, et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2000;(2):CD000530.

15. Bauer R, Wagner H. Echinacea species as potential immunostimulatory drugs. In: Wagner H, Farnsworth NR, eds. Economic and Medicinal Plant Research. Vol. 5. New York, NY: Academic Press; 1991:253-321.

16. Bauer R. Echinacea: Biological effects and active principles. In: Lawson LD, Bauer R, eds. Phytomedicines of Europe Chemistry and Biological Activity. Washington, DC: American Chemical Society; 1998;140-157.

17. Sloley BD, et al. Comparison of chemical components and antioxidant capacity of different Echinacea species. J Pharm Pharmacol 2001;53:849-857.

18. Schwarz E, et al. Oral administration of freshly expressed juice of Echinacea purpurea herbs fail to stimulate the nonspecific immune response in healthy young men: Results of a double-blind, placebo-controlled crossover study. J Immunother 2002;25: 413-420.

19. Awang D. Standardization of herbal medicines. Altern Ther Women’s Health 1999;1:57-59.

20. Osowski S, et al. Pharmaceutical comparability of different therapeutic Echinacea preparations [in German]. Forsch Komplementarmed Klass Naturheilkd 2000;7:294-300.

21. Mullins RJ, Heddle R. Adverse reactions associated with echinacea: The Australian experience. Ann Allergy Asthma Immunol 2002;88:42-51.

22. Soon SL, Crawford RI. Recurrent erythema nodosum associated with Echinacea herbal therapy. J Am Acad Dermatol 2001;44:298-299.

23. Parnham MJ. Benefit-risk assessment of the squeezed sap of the purple coneflower (Echinacea purpurea) for long-term oral immunostimulation. Phytomedicine 1996;3:95-102.

24. Schwarz S, et al. Acute disseminated encephalo-myelitis after parenteral therapy with herbal extracts: A report of two cases. J Neurol Neurosurg Psychiatry 2000;69:516-518.

25. Gallo M, et al. Pregnancy outcome following gestational exposure to echinacea. Arch Intern Med 2000;160: 3141-3143.