Notwithstanding these many uses, the vast majority of scientific evidence clusters around immunostimulation,^5,7-13 and around prevention and treatment of URI.^14-17 While existing randomized blinded trials are of only moderate quality,^18-27 results in general have been positive. Systematic reviews have been cautiously optimistic.^28-32 Evidence regarding echinacea's ability to prevent URI is far from conclusive, but evidence from two moderate-quality randomized trials suggests a relative risk reduction of 10—15 percent.^24,27 For the average adult with three or four colds per year, this would imply the avoidance of one cold in about 2¹/2 years of echinacea ingestion. Costs and risks of chronic dosing have not been well characterized.

Randomized trial evidence for the ability of echinacea used to treat upper respiratory infection is somewhat more positive. Reductions in severity^18-21 and duration^22,26 have been reported in double-blind placebo-controlled randomized trials. Estimates of the degree of symptom severity reduction center on the 25—35 percent range. The two trials claiming reductions in duration have significant methodological limitations, reducing confidence in the reported 2 to 4 day (20—40 percent) duration reduction benefits.^22,26 The better trials^19,21 do not report duration reductions. A trial we conducted among students at the University of Wisconsin — Madison found no benefit at all from an unrefined mixture of E. purpurea and E. angustifolia.³³ Thus, while the sum total of randomized trial evidence suggests modest efficacy of echinacea as an early cold treatment, confidence is tempered by the limited amount and quality of existing evidence.

Safety

Following available scientific evidence, echinacea appears to be a relatively safe herbal medicine. No significant dose-dependent adverse effects have been noted, no overdoses have been reported, and no contraindications or drug interactions have been proven. At least 30 randomized trials have been completed.^{2,23,26-30,32,34} None have reported more adverse effects in the treatment versus the control groups. Although there have been reports of allergic reactions to echinacea,³⁵ including two cases of anaphylaxis reportedly due to echinacea,^36,37 no deaths have been reported.

Perhaps the most convincing rationale for the reasonable safety of echinacea comes from epidemiological evidence. The ratio of reported serious adverse effects (less than 100) to the estimated number of courses of treatment (more than 10 million) yields a risk estimate of less than 1 in 100,000. In the United States, Canada, Europe and Australia, echinacea is one of the most widely used herbal medicines. In the United States, it is estimated that between 15 percent and 40 percent of American adults take one or more herbal medicines in a given year.^38-40 Echinacea accounts for as much as 10 percent of the U.S. herbal market, at least in some market channels (i.e., natural foods).⁴¹ These numbers suggest that 1—4 percent of the general population uses echinacea in a given year. Assuming a U.S. population of approximately 200 million adults and self-treating adolescents, one can estimate that between 2 to 8 million Americans use an echinacea product at least once in a given year. With no deaths and few significant adverse effects reported, the overall risk ratio (number of adverse events / number exposed) appears quite favorable, especially when compared with the thousands of deaths attributed to widely used over-the-counter medicines, such as non-steroidal anti-inflammatory drugs (aspirin, ibuprofen, naproxen) and decongestants (e.g., phenylpropanolamine, now removed from the market).^42-45

Contraindications

The German Commission E approved oral preparations of E. purpurea, with a suggested course of no more than 6 weeks.^46,47 Chronic progressive immuno-mediated diseases such as tuberculosis, rheumatoid arthritis, collagen vascular disease, and multiple sclerosis have been listed as contraindications.²⁸ These warnings are theoretical, based on the harm that could result if the immune-mediated inflammatory components of these diseases were exacerbated by echinacea's immunostimulating properties. Although reasonable as precautions, there is no convincing empirical evidence to support or refute these contraindications.

Data on adverse effects

Parnham has reviewed "the benefit and risks" of E. purpurea.^48,49 He reports that in Germany, from 1989 to 1995, a total of 13 adverse events "possibly associated with the use of Echinacin^®" (pressed juice from fresh E. purpurea herb preserved with 22 percent alcohol; Madaus AG, Cologne, Germany) were reported to the German federal health authority. Of these, four were judged to be caused by echinacea exposure. All were allergic reactions, with skin rash the predominant finding. During the same time period, several million people in Germany treated themselves with or received a physician's prescription for an echinacea product. These results would suggest a very low risk of allergic reaction, similar to that for such common substances as wheat, milk, or peanuts. Parnham also reports an unblinded study of 1,231 children (aged 2 to 20 years) who were treated with Echinacin^® lozenges. This study found a 5 percent overall rate of self-reported adverse effects. Of the 62 reported problems, unpleasant taste was the most frequent, with 21 reports (1.7 percent). Nausea, vomiting, sore throat, abdominal pain, diarrhea, and difficulty swallowing were reported by 6 or less (< 0.5 percent) persons each. A number of smaller open trials and case series have provided some evidence of safety of injected echinacea. For example, R?seler and Moell have each reported treatment series (226 and 120 patients respectively) of patients with post-partum infection who were injected intravenously with 0.1 mL to 1.2 mL of E. purpurea herb juice (Echinacin^®), without noting any observed ill effects.⁴⁹

In 1998, Mullins reported a case in which a woman with atopy (predisposition toward allergy) ingested a liquid formulation combining E. purpurea and E. angustifolia root extracts immediately before experiencing "burning of the mouth and throat ... tightness in the chest, generalized urticaria, and diarrhoea."³⁶ The incident precipitated a two-hour visit to the emergency department, during which "her symptoms resolved completely." Subsequently, Mullins has reported the results of a systematic search revealing 51 possible cases of echinacea-related allergy in Australia, 26 of which were "suggestive of possible immunoglobulin E-mediated hypersensitivity."³⁷ The same report detailed five cases in depth as a case series.³⁷ While echinacea prevalence-of-use data are not available for Australia, use of herbal medicines appears to be similar to that in the United States and Europe.^50,51 This would imply hundreds of thousands of courses of echinacea each year, which would in turn suggest that Mullin's data imply relative safety rather than risk. One other case report has been published. In 2001 Soon and Crawford reported a single case of erythema nodosum (an acute inflammatory/immunological skin reaction) which they thought was "temporally and perhaps causally associated with the use of echinacea."⁵² Although case reports and case series may generate hypotheses suggesting association, they cannot prove causality; hence it is difficult to draw meaningful conclusions from these reports. Clearly, nearly any substance may trigger an allergic reaction in a sensitive individual. Allergies to penicillin, sulfa drugs, pollens, cats, horses, and shellfish are common, often serious, sometimes fatal. Risks of allergy to echinacea appear to be relatively small in comparison. Perhaps the best estimate of allergic risk from echinacea comes from a study of 1,032 people patch-tested for skin sensitivity to echinacea, in which two positive inflammatory reactions were found.⁵³

Reproductive risks

As is true with nearly all medicines, safety of echinacea in pregnancy has not been reliably determined. Only one study has been reported. Gallo and coworkers studied a cohort of 206 women who used echinacea during pregnancy. Cases were risk-matched with 206 controls and assessed for adverse effects in offspring.^54,55 Similar numbers of stillbirths, chromosome abnormalities, and malformations were found in the two groups. Echinacea species, plant part, dose, and duration of use are not reported. The authors conclude that "gestational use of echinacea during organogenesis is not associated with an increased risk for major malformations." While this study suggests a low likelihood of major frequent adverse outcomes, it does not establish safety. While no evidence of increased risk was observed, the study lacked the statistical power to detect potentially important echinacea-associated risks. For example, a hypothetical echinacea-caused serious event (death, malformation) occurring in 1 in 100 infants could easily have been missed in this relatively low-powered case control study.

Toxicology

Using standard toxicological assessment methods, animal experiments have so far failed to demonstrate echinacea-related toxicity. According to Mengs, oral doses up to 15 g/kg and intravenous doses up to 5 g/kg failed to demonstrate major pathology.^56,57 This group concluded that a lethal dose could not be found; hence LD50 (dose at which half of experimental animals are killed) was incalculable.⁵⁶ Lenk et al. have reported that injection of varying doses of concentrated echinacea polysaccharide fractions in 18 mice did allow calculation of LD50 at 2,500 mg/kg.⁵⁸ Due to the nature of animal studies, small sample sizes, unblinded methods, types of echinacea product (concentrated extract), and modes of administration (injection), these results are not generalizable to human use. Nevertheless, these results suggest that there is a wide therapeutic window of safety between the typical doses consumed orally (200 to 2,000 mg in 50—80 kg adults = from 2.5 to 40 mg/kg) and the estimated intravenous lethal dose of 2,500 mg/kg. Although not conclusive, these results are certainly reassuring, especially when compared with much less favorable therapeutic windows for common over-the-counter medications such as analgesics and decongestants.

Laboratory analysis of blood, urine, and organ specimens from animals treated with echinacea products provides some additional evidence of safety. Experiments using rats and mice fed up to 8 g/kg/day over several weeks failed to demonstrate measurable adverse effects. Body weight, organ weight, histopathological analyses of tissue, and blood studies such as complete blood count, liver enzymes, creatinine, urea, cholesterol, triglycerides, and blood glucose have been reported as unaffected by oral dosing of echinacea.^56,57 Genetic studies looking for chromosome aberration and sister chromatid exchange in bacteria and cultured animal cells have similarly been reported as negative for mutagenicity.⁵⁶ A polysaccharide fraction isolated from E. purpurea was reported as negative for mutagenicity in a genotoxicity human lymphocyte assay.⁵⁹ Maximum feasible oral and intravenous doses of ethanol stabilized fresh pressed juice of E. purpurea have similarly been reported as negative for measurable damage in mice or rats.⁵⁷ Injection of E. purpurea extract into chick embryos failed to cause any detectable changes in development.⁶⁰ So far, screens for toxicity have been overwhelmingly negative.

Summary

While by no means conclusive, the evidence published to date suggests the limited effectiveness of echinacea as early treatment for the common cold. Even more limited evidence may favor preventive efficacy, but the effect size is too small to support chronic use. Large, confirmatory randomized trials are sorely needed. Evidence for use in other conditions, while sufficient to spur further research, is insufficient to draw clinically meaningful conclusions.

Safety data are generally positive, but limited. The lack of adverse effects reported from several reasonable quality clinical and toxicological investigations is reassuring, but not conclusive. The fact that no major or dose-dependent toxicities have been reported suggests that echinacea is relatively safe. Nevertheless, it does not prove safety, as rare but important adverse effects have not been ruled out.

It should be remembered that any substance with pharmacological properties will almost certainly have accompanying toxicities. For instance, echinacea's demonstrated immunostimulating properties of macrophage activation and enhanced cytokine production are likely to be associated with immune-related adverse consequences, whether or not these have been demonstrated by current research. For instance, autoimmune diseases such as rheumatoid arthritis, lupus erythematosis, or multiple sclerosis could be triggered or accelerated. Similarly, common problems such as asthma, allergic rhinitis, or skin allergies could be activated or worsened. Or perhaps the immune system's natural-and-healthy manner of resisting infectious disease could be interfered with, leading to increased incidence or severity of bacterial or viral illness. Is there evidence to back up these speculations? No. Have these possibilities been ruled out? Not hardly. So, what is the bottom line? People with allergic, autoimmune or inflammatory disease (and their healthcare advisors) should think very carefully about the possible benefits and risks before dosing with this herbal medicine. For children and pregnant women, where there are no studies reporting benefit, caution is recommended. But for the average healthy adult in the beginning of a common cold, echinacea seems like a reasonable choice, certainly as good as antihistamines, decongestants, zinc, or vitamin C, all of which have a modicum of evidence to support their use, and certainly better than antibiotics, which clearly do not work. Of course, this advice may change as more evidence becomes available.

Bruce Barrett, M.D., Ph.D., is Assistant Professor in the Department of Family Medicine at the University of Wisconsin — Madison Medical School. He is supported in part by a career development grant from the National Center for Complementary and Alternative Medicine at the National Institutes of Health. Dr. Barrett's background includes a doctorate in Anthropology (ethnomedicine and health care systems in Nicaragua) and a Johns Hopkins fellowship in international health (based in Guatemala). He is a member of the American Botanical Council Advisory Board. He has published several articles regarding the ethnobotany and contemporary use of herbal medicines.

References

1. Baetgen D. Behandlung der akuten bronchitis im kindesalter. Praxisstudie mit einem immunstimulans aus Echinacea purpurea [Treatment of acute bronchitis in children. A study of an immunostimulatory agent from Echinacea purpurea in a primary care setting. Translator unknown.]. Therapiewoche Padiatrie 1988;1:65-70.

2. Vonau B, Chard S, Mandalia S, Wilkinson D, Barton SE. Does the extract of the plant Echinacea purpurea influence the clinical course of recurrent genital herpes? Int J STD AIDS 2001;12:154-8.

3. Lersch C, Zeuner M, Bauer A, Siemens M, Hart R, Drescher M et al. Nonspecific immunomodulation with low doses of cyclophosphamide (LDCY), thymostimulin, and Echinacea purpurea extracts (Echinacin) in patients with far advanced colorectal cancers. Cancer Invest 1992;10:343-8.

4. Berman S, Justis JC, Tilles JG, Ma CB. Dramatic increase in immune mediated HIV killing activity induced by Echinacea angustifolia [abstract no. 32309]. International Conference on AIDS 1998;12:582.

5. See DM, Broumand N, Sahl L, Tilles JG. In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or AIDS patients. Immunopharmacology 1997;35:229-35.

6. Yarnell E. Botanical medicines for dermatologic conditions. Alternative & Complementary Therapies 1999; April:106-9.

7. Bauer R. Chemistry, analysis and immunological investigations of Echinacea phytopharmaceuticals. In: Wagner H, editor. Immunomodulatory Agents from Plants. Basel, Boston, Berlin: Birkhauser Verlag; 1999. p. 41-88.

8. Burger RA, Torres AR, Warren RP, Caldwell VD, Hughes BG. Echinacea-induced cytokine production by human macrophages. Int J Immunopharmacol 1997;19:371-9.

9. Eichler F, KrŸger GRF. Effects of non-specific immunostimulants (Echinacin, isoprinosine, and thymus factors) on the infection and antigen expression in herpesvirus-6 exposed human lymphoid cells. In Vivo 1994;8:565-76.

10. Elsasser-Beile U, Willenbacher W, Bartsch HH, Gallati H, Schulte Monting J. Cytokine production in leukocyte cultures during therapy with Echinacea extract. J Clin Lab Anal 1996;10:441-5.

11. Melchart D, Linde K, Worku F, Sarkady L, Holzmann M, Jurcic K et al. Results of five randomized studies on the immunomodulatory activity of preparations of Echinacea. J Altern Complement Med 1995;1:145-60.

12. Stotzem CD, Hungerland U, Mengs U. Influence of Echinacea purpurea on the phagocytosis of human granolocytes. Medical Science Research 1992;20:719-20.

13. Willigmann I, Egert D, Bodinet C, Beuscher N. Chemical and immunological properties of the immunomodulatory active compounds from the roots of different Echinacea species. Planta Med 1993;59:671-3.

14. Abdullah T. A strategic call to utilize Echinacea-garlic in flu-cold season. JAMA 2000;92:48-51.

15. Bone K. Echinacea: What makes it work? Alternative Medicine Review 1997;2:87-9.

16. Gunning K. Echinacea in the treatment and prevention of upper respiratory tract infections. WJM 1999;171:198-200.

17. Hobbs C. Echinacea: A literature review. HerbalGram (Special Supplement) 1994;30:33-47.

18. Br?unig B, Dorn M, Limburg E, Knick E. Echinaceae purpureae radix: zur st?rkung der k?rpereigenen abwehr bei grippalen infekten [Strengthening of the endogenous resistence to influenzal infections. Translation by Ralph McElroy Co., Austin, TX]. Zeitschrift fur Phytotherapie 1992;13:7-13.

19. Brinkeborn RM, Shah DV, Degenring FH. Echinaforce^® and other Echinacea fresh plant preparations in the treatment of the common cold. Phytomedicine 1999;6:1-6.

20. Dorn M, Knick E, Lewith G. Placebo-controlled double-blind study of Echinacea pallida radix in upper respiratory tract infection. Complement Ther Med 1997;5:40-2.

21. Henneicke-von Zepelin HH, Hentschel C, Schnitker J, Kohnen R, K?hler G, WŸstenberg P. Efficacy and safety of a fixed combination phytomedicine in the treatment of the common cold (Acute viral respiratory tract infection): Results of a randomized, double blind, placebo controlled, multicentre study. Curr Med Res Opin 1999;15:214-27.

22. Hoheisel O, Sandberg M, Bertram S, Bulitta M, Sch?fer M. Echinagard treatment shortens the course of the common cold: A double-blind, placebo-controlled clinical trial. European Journal of Clinical Research 1997;9:261-8.

23. Lindenmuth GF, Lindenmuth EB. The efficacy of Echinacea compound herbal tea preparation on the severity and duration of upper respiratory and flu symptoms: A randomized, double-blind placebo-controlled study. J Altern Complement Med 2000;6:327-34.

24. Melchart D, Walther E, Linde K, Brandmaier R, Lersch C. Echinacea root extracts for the prevention of upper respiratory tract infections: A double-blind, placebo-controlled randomized trial. Arch Fam Med 1998;7:541-5.

25. Scaglione F, Lund B. Efficacy in the treatment of the common cold of a preparation containing an Echinacea extract. Int J Immunopharmacol 1995;11:163-6.

26. Schulten B, Bulitta M, Ballering-BrŸhl B, K?ster U, Sch?fer M. Efficacy of Echinacea purpurea in patients with a common cold: A placebo-controlled, randomised, double-blind clinical trial. Arzneimittelforschung 2001;51:563-8.

27. Turner RB, Riker DK, Gangemi JD. Ineffectiveness of Echinacea for prevention of experimental rhinovirus colds. Antimicrob Agents Chemother 2000;44:1708-9.

28. Blumenthal M, Hall T, Goldberg A, Kunz T, Dinda K, Brinckmann J et al., editors. Echinacea: Echinacea purpurea (L.) Moench, E. pallida (Nutt.) Nutt, E. angustifolia D.C. [Family Asteraceae]. In: The ABC Clinical Guide to Herbs. Austin TX: American Botanical Council, [in press].

29. Barrett B, Vohmann M, Calabrese C. Echinacea for upper respiratory infection: Evidence-based clinical review. J Fam Pract 1999;48:628-35.

30. Barrett B. Echinacea for upper respiratory infection: An assessment of randomized trials. Health Notes: Review of Complementary and Integrative Medicine 2000;7:211-8.

31. Giles JT, Palat CT, Chien SH, Chang ZG, Kennedy DT. Evaluation of Echinacea for treatment of the common cold. Pharmacotherapy 2000;20:690-7.

32. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating the common cold. 1-23. 2000. Update Software. Cochrane Library, Issue 4.

33. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, D'Alessio D. Treatment of the common cold with unrefined echinacea: A randomized, double-blind, placebo-controlled trial. Ann Int Med 2002 December 17:137(12):939-46.

34. Melchart D, Linde K, Worku F, Bauer R, Wagner H. Immunomodulation with Echinacea: a systematic review of controlled trials. Phytomedicine 1994;1:245-54.

35. Bielory L. Adverse reactions to complementary and alternative medicine: ragweed's cousin, the coneflower (echinacea), is "a problem more than a sneeze." Ann Allergy Asthma Immunol 2002;88:7-9.

36. Mullins RJ. Echinacea-associated anaphylaxis. Med J Aust 1998;168:170-1.

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

38. Astin JA. Why patients use alternative medicine: Results of a national study. JAMA 1998;279:1548-53.

39. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M et al. Trends in alternative medicine use in the United States, 1990-1997. JAMA 1998;280:1569-75.

40. Landmark Healthcare. The Landmark report on public perceptions of alternative care. 1998 nationwide study of alternative care. 1998. Sacramento CA, Landmark Healthcare, Inc. Random telephone survey of 1500 households.

41. Brevoort P. The Booming U.S. Botanical Market: A New Overview. HerbalGram 1998;44:33-46.

42. Bates DW, Cullen DJ, Laird N, Petersen LA, Small SD, Servi D et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA 1995;274:29-34.

43. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions. JAMA 1999;281:824-9.

44. Cetaruk EW, Aaron CK. Hazards of nonprescription medications. Emerg Med Clin North Am 1994;12:483-510.

45. Griffin MR, Scheiman JM. Prospects for changing the burden of nonsteroidal anti-inflammatory drug toxicity. American Journal of Medicine 2001;110:33S-7S.

46. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, Rister, RS, editors. Klein S, Rister RS, translators. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council, Boston, MA: Integrative Medicine Communications; 1998.

47. Blumenthal M, Goldberg A, Brinckmann J. Herbal Medicine: Expanded Commission E Monographs. Austin, TX: American Botanical Council; 2000.

48. 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.

49. Parnham MJ. Benefit and risks of the squeezed sap of the purple coneflower (Echinacea purpurea) for long-term oral immunostimulant therapy. In Wagner H, editor. Immunomodulatory Agents from Plants, pp 119-36. Basel, Boston, Berlin: Birkhauser Verlag; 1999.

50. Drew AK, Myers SP. Safety issues in herbal medicine: Implications for the health professions. Med J Aust 1997;166:538-41.

51. MacLennan AH, Wilson DH, Taylor AW. Prevalence and cost of alternative medicine in Australia. The Lancet 1996;347:569-73.

52. Soon SL, Crawford RI. Recurrent erythema nodosum associated with Echinacea herbal therapy. J Am Acad Dermatol 2001;44:298-9.

53. De Smet PAGM, Keller K, Hansel R, Chandler RF. Adverse Effects of Herbal Drugs, Volume 3. Berlin, Heidelberg & New York: Springer-Verlag; 1997.

54. Gallo M, Sarkar M, Au W, Pietrzak K, Comas B, Smith M et al. Pregnancy outcome following gestational exposure to Echinacea. Arch Intern Med 2000;160:3141-3.

55. Gallo M, Koren G. Can herbal products be used safely during pregnancy? Focus on echinacea. Can Fam Physician 2001;47:1727-8.

56. Mengs U, Clare CB, Poiley JA. Toxicity of Echinacea purpurea. Arzneimittelforschung 1991;41:1076-81.

57. Mengs U, Leuschner J, Marshall RR. Toxicity studies with Echinacin [abstract]. Third International Conference on Phytomedicine, Munich, Germany, 2000 October 11-13. Phytomedicine 2000;Supplement II;7:32.

58. Lenk W. Akute toxizitat von verschiedenen polysacchariden Echinacea purpurea an der maus. [Acute toxicity of various polysaccharides from Echinacea purpurea in the mouse. Translated by Foit BV, Santa Cruz, CA]. Zeitschrift fur Phytotherapie 1989;10:49-51.

59. Schimmer O, Erlangen, Abel G, Nurnberg, Behninger C. Investigation of the genotoxic potency of a neutral polysaccharide from Echinacea tissue cultures in human lymphocyte cultures. Zeitschrift fur Phytotherapie 1989;10:39-42.

60. Nuckols JT, Chopin SF. Echinacea purpurea injection did not effect early development in chick embryos. Poster Session 2000;48:113A.