Doi:10.1016/s1543-1150(03)00012-7

Seminars in Integrative Medicine, Vol 1, No 2 (June), 2003: pp 106-111 domized, placebo-controlled trials found no benefit of echinacea-only benefit for several extracts echina- cea in treating URIs— E. pallida no effect). Echinacea extracts con- tain alkylamides, caffeic acid de- rivatives, ketoalkenes/ketoalkynes associated with allergic skin reac- Echinaceaextractsarewidelysoldfortreatingand preventing infections. Echinacea, also called pur-ple coneflower, is a member of the daisy Composi-tae/Asteraceae) family. The three Echinacea spe-cies used commercially are E. purpurea, E. angustifolia, and E. pallida. Preparations include root extracts,pressed juice of E. purpurea herb (ie, aerial parts), and mixturesof both herb and root. Many single-herb and mixed-herb productsare available. Single-herb products tested in the clinical trialsavailable in the United States include two fresh-pressed E. purpu-rea products: Echinaforce® (Bioforce), a hydroalcoholic extract(65% ethanol; extract ratio 9:1) of fresh herb (95%) and root (5%),and Echinaguard® or Echinacin (Madaus), an extract of E. pur-purea herb in a 20% ethanol base. This review discusses allrandomized, controlled trials of echinacea-only products for treat-ing colds or URIs (Table 1). Sources include MEDLINE, IBIDS, andthe author’s own files.
From Department of Health Care Sci- ences, George Washington UniversitySchool of Medicine, Washington, DC. Address for correspondence and re- CLINICAL TRIALS
prints: Adriane Fugh-Berman, MD, 131218th St. NW, #500, Washington, DC 20036. Three randomized, placebo-controlled trials of echinacea-only products for the prevention of URIs were identified. None of 2003 Elsevier Inc. All rights reserved. these trials found a benefit. A three-armed trial of 302 subjects in which 289 were analyzed compared E. angustifolia root extract to E. purpurea root extract and placebo (50 drops twice daily, five E C H I N A C E A F O R P R E V E N T I O N A N D T R E A T M E N T O F U R I Randomized Controlled Trials of Echinacea for the Prevention or Treatment of Upper Respiratory Infections
E. angustifolia) containing0.16% cichoric acid) vs.
placebo, 14 days prior and5 days after rhinoviruschallenge doses daily until symptomsresolved or until Day 10 proportion of patients with“complete” cold;significantly more thoughttheir cold was “shorterthan usual” (two-sided pϭ 0.007) t ϭ 9.499, p Ͻ 0.001);days to symptom change(3.854, SD 0.9735 vs.
2.297, SD 1.204, t ϭ6.865, p Ͻ 0.001).
E. pallida root 900 mg/day vs.
(Cont’d)
reduction in E. purpurearoot group) by patientassessment in ITTanalysis, only theEchinaforce concentratesignificantly reducedcomplaint index (p ϭ 0.01) 0.044; time to improvementshorter among those withcolds (by about 2 days, pϽ 0.001 group and the placebogroup, low dose was notbetter than placebo,symptom scores alsoapparently better in thehigh-dose group p valuenot apparent fromtranslation) times per week for 12 weeks). No difference was at least one treated group. Seven trials, with a total noted among the groups in the time to occurrence of more than a thousand subjects, tested various of the first URI, nor in the proportion of groups echinacea extracts: E. pallida root,5,6 E. purpurea that developed URIs.1 Another trial tested pressed pressed juice (Echinagard® and Echinacin®,7,8 E. juice of E. purpurea herb extract (4 mL twice purpurea root,9,10 two doses of Echinaforce® daily for 8 weeks) in 109 subjects and found no (containing E. purpurea root 5%, herb 95%)10 and benefit on the incidence, duration, or severity of Echinacea Plus® tea (containing E. purpurea colds or URIs.2,3 The only trial of experimentally herb, E. angustifolia herb, and E. purpurea root induced colds found no effect of an echinacea dry extract) and a mixture of E. angustifolia root, extract containing 0.16% cichoric acid on the in- E. purpurea root, and E. purpurea herb.11,12 Most cidence of experimentally induced infection or formulations (all except for two extracts of E.
purpurea root and the mixture of E. angustifolia In contrast, all but one randomized, placebo- root9,10 with E. purpurea root and herb12) were controlled trials of echinacea-only products iden- significantly better than placebo in the primary tified for the treatment of URIs found a benefit in outcome measures. Most trials examined duration E C H I N A C E A F O R P R E V E N T I O N A N D T R E A T M E N T O F U R I of symptoms. The Hoheisel study, sometimes clas- garded as the most active constituent of fresh- sified as a prevention trial, told participants to squeezed juice preparations, but remains unsuit- take echinacea at the first onset of symptoms and able for standardizing extracts since only traces found a significant reduction in the proportion of exist in the roots of E. angustifolia. subjects who developed a “real cold,” as well as a The predominant mechanism of action of echi- shorter duration of symptoms among those who nacea extracts appears to be through stimulation of phagocytosis. A double-blind study in 24 The Barrett 2002 study is the only treatment healthy men found that an ethanolic E. purpurea trial that found no effect at all. This trial, however, root extract increased phagocytosis significantly is highly problematic because of the choice to use more than the placebo.15 Stimulation of phagocy- alfalfa as a “placebo.” Alfalfa contains L-canava- tosis was demonstrated in most in vitro assays.
nine, a non-protein amino acid known to affect Echinacea extracts may also enhance natural the immune system. In humans, alfalfa has been killer cell activity. In in vitro assays utilizing pe- linked to flares of quiescent systemic lupus ery- ripheral blood mononuclear cells from three thematosus (SLE) and reversible SLE-like syn- groups of subjects (healthy, with AIDS, or with drome in those without a history of SLE.13 An chronic fatigue syndrome), E. purpurea whole- agent that may affect the immune system is obvi- plant extract increased antibody-dependent cellu- ously not an inappropriate placebo for a study of lar cytotoxicity against human herpes virus-6 in- fected H9 cells and enhanced natural killer cellfunction in all groups.16 Although parenteral ad- ministration of several polysaccharides has stim- ORMULATIONS, ACTIVE CONSTITUENTS, AND
ulated macrophage cytotoxicity, these polysac- MECHANISMS OF ACTION
charides would be unlikely to survive oraladministration.14 Extracts of E. purpurea root may be inferior to E. pallida root or E. purpurea herb. The Brinkeborn study, a four-armed study of 559 sub- ADVERSE REACTIONS/INTERACTIONS
jects that compared placebo to Echinaforce® (twopotencies) and E. purpurea root extract, found With oral products, an unpleasant taste is the that the E. purpurea root extract was not superior most common side effect. Allergic skin re- to placebo. The Braunig 1992 trial compared two actions may also occur. Adverse events attributed doses of E. purpurea root extract (90 drops daily to echinacea include 4 cases of anaphylaxis, 12 vs. 180 drops daily) to placebo and found a benefit cases of acute asthma, and 10 cases of urticaria/ only in the high-dose group; this trial has been angioedema reported to the Australian Adverse Drug Reactions Advisory Committee. Three of five Although alkylamides are believed to be the cases evaluated by the reviewers had positive skin most active constituents of echinacea, caffeic acid prick tests.17 Parenteral administration of E. pur- derivatives (ie, cichoric acid, echinacoside), ke- purea juice may cause shivering, fever, and mus- toalkenes/ketoalkynes glycoproteins, and polysac- cle weakness.18 A case report documents four charides may also be active. Compounds vary in episodes of erythema nodosum, over 18-month type and ratio among plant parts and species, so period, that were temporally associated with use the most effective constituent(s) remain to be of echinacea (an unidentified preparation) in a determined.14 Although “standardized” extracts 41-year-old, healthy man, who was also taking St.
of echinacea are available, preparations are stan- John’s wort and occasional loratidine.19 He re- dardized to different compounds, some of which mained free of episodes for 1 year after discon- are of questionable significance. Echinacoside, a tinuing echinacea. Theoretical concerns that caffeic acid derivative, is most often used to “stan- echinacea may worsen symptoms of autoimmune disease have been raised, but no such cases have While echinacoside may be suitable for standard- izing extracts made from the roots of E. angusti- A controlled study compared 206 women who folia and E. pallida, the roots of E. purpurea lack reported gestational use of echinacea to the Moth- echinacoside. Cichoric acid, another caffeic acid erisk program (112 reported first trimester use) derivative used to “standardize” extracts, is re- with 206 controls. No significant differences ex- isted between groups for major or minor malfor- ucts should be viewed as distinct phytopharma- In summary, evidence supports the efficacy of DISCUSSION
echinacea extracts for reducing the duration ofsymptoms associated with URIs, but atopic pa- Little research has been done on therapies for tients may experience adverse reactions, includ- the prevention and treatment of colds. A MED- ing anaphylaxis. The evidence from these trials LINE search on cold and the randomized, con- does not suggest that echinacea is beneficial in trolled trials that have been conducted between preventing URIs. Preparations made from pressed 1995 and 2001 revealed 40 trials, 29 of which juice of E. purpurea herb (eg, Echinacin® and were for therapies to prevent or treat colds. More others) or E. pallida root appear superior to those trials (four) have been completed on echinacea made from E. purpurea root. Notably, these trials preparations than on any other therapy, except bear out the conclusions of the German Commis- zinc (also four). To date, most reviews of echina- sion E, which is the body that evaluated herbal cea have included combinations of echinacea with products for the German government before dis- other herbs (most commonly Baptisia tinctoriaand Thuja occidentalis); sometimes homeopathic banding in 1995. Before most of these trials were components are also included.21,22,23 One paper published, Commission E had issued positive reviewed echinacea-only products but only in- monographs on E. pallida root and E. purpurea cluded trials conducted between 1994 and 1999.24 herb and concluded that evidence of efficacy for Mixing studies of combination-herb products with other extracts was insufficient. The most active single-herb products clouds the picture. Even constituents have not been identified, so stan- when echinacea is assessed alone, preparations dardized products of echinacea are no guarantor made from different species and plant parts pre- of effectiveness. The use of echinacea to prevent dictably have different effects. These diverse prod- REFERENCES
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