Barrett B, Brown R, Rakel D, et al. Echinacea for treating the common cold: a randomized trial. Ann Intern Med. 2010;153(12):769-777.

Hundreds of studies have been published on Echinacea spp. including dozens of clinical trials that evaluate the efficacy of different preparations in preventing or treating the common cold. Many of the studies were manufacturer-sponsored and of moderate to poor quality. The 2 main types of echinacea products are primarily rich in hydrophilic compounds derived from the fresh aerial parts of E. purpurea or higher in lipophilic components when processed as hydro-ethanolic extracts of the roots of E. purpurea and/or E. angustifolia. The well-designed studies have yielded both positive and negative outcomes, depending on the products tested. Systematic reviews and meta-analyses have produced varying interpretations. Hence, additional well-designed studies are needed. The purpose of this study was to assess the efficacy of a combination of solid extracts from echinacea roots in treating the common cold in a randomized, double-blind, controlled trial.

Patients (aged ≥ 12 years, n = 719) were recruited from the Dane County, Wisconsin community via advertising and word of mouth from January 2004 to August 2008. They had to have at least 1 symptom of the common cold (nasal discharge, nasal obstruction, sneezing, and sore throat). Patients were excluded if they were receiving antibiotics, antivirals, nasal steroids, decongestants, antihistamines, combination cold formulas, echinacea, zinc, or vitamin C. Also excluded were patients with a history of allergic rhinitis who reported sneezing or itching of the nose or eyes; those with a history of asthma who reported current cough, wheezing, or shortness of breath; and those having autoimmune or immune deficiency disease. Patients were randomized to 1 of 4 parallel groups: (1) control group without placebo tablets, (2) blinded placebo tablets, (3) blinded echinacea, and (4) open-label echinacea.

The echinacea preparation (MediHerb; Warwick, Queensland, Australia) was a tablet that contained dried, concentrated extracts derived from the equivalent of 675 mg of E. purpurea root and 600 mg of E. angustifolia root, each standardized to 2.1 mg of alkamides, important biologically active lipophilic compounds in these echinacea roots. Phytochemical analysis of the product at successive points from 2004 to 2007 showed no trends toward lower amounts of alkamides or phenolics in later years. This preparation is sold to health practitioners only and is not generally available in retail outlets or on the Internet. The patients consumed 2 tablets at enrollment, then 2 tablets 3 more times in the first 24 hours of the study, followed by 1 tablet 4x/day for the next 4 days. Thus, the patients received solid extracts from 10.2 grams of dried echinacea roots of both types during the first 24 hours and extracts from 5.1 grams/day for the following 4 days.

The primary endpoints were mean global cold symptom severity and mean duration of symptoms. Illness symptom severity was assessed twice daily via the Wisconsin Upper Respiratory Symptom Survey short version (WURSS-21). The WURSS-21 is a validated questionnaire with 21 questions that are scored 0-7, where 0 = none and 7 = severe. For this study, the daily high score was 294 (severe symptoms for all parameters). Secondary endpoints were: interleukin-8 (IL-8) and neutrophil counts (markers for immune response, which were obtained from nasal washes at enrollment and 2 days later), self-reported health measures for physical and mental health (Medical Outcomes Study Short Form-8), stress (Cohen Perceived Stress Scale), optimism (revised Life Orientation Test), and social support (Ryff Personal Relationships scale).

Baseline measures were similar among groups. Adherence to treatment was excellent, with 95% of patients taking tablets as directed. Blinding was intact. The mean global severity of symptom score was 236 for the blinded echinacea group, 258 for the open-label echinacea group, 264 for the blinded placebo group, and 286 for the no-tablet group. This is a mean difference of 28 points between the blinded groups (P = 0.089). Illness duration was 6.34 days in the blinded echinacea group, 6.76 days in the open-label echinacea group, 6.87 days in the blinded placebo group, and 7.03 days in the no-tablet group. This is a mean difference of 0.53 days in the blinded groups (P = 0.075). Therefore, no statistically significant difference was detected between the blinded echinacea and the blinded placebo group for either symptom severity or duration of symptoms. A subgroup analysis of 351 patients who were enrolled within 24 hours of their first symptoms revealed that despite both echinacea groups having lower illness duration and global severity scores than the control (placebo tablet and no-tablet) groups, there were no statistically significant differences between the groups.

Secondary outcome measures did not display any statistically significant differences among any groups. Nasal neutrophil counts and IL-8 levels tended to increase faster in the echinacea groups than in the control groups, but the differences were not statistically significant. For these tests, 33 subjects failed to undergo the second required nasal wash 24-72 hours after the first.

The frequency of adverse effects (AEs) was similar among groups. Based on responses to questioning, there were no patterns of AEs that could be attributed to echinacea.

The design of this study was previously described as a means of evaluating the effect of placebo and therapeutic pill-taking versus no treatment or pill-taking in conjunction with enhanced doctor-patient interaction in an open-label format. This was to be the first time this methodology was employed in studying effects on the common cold.¹ However, the authors did not discuss this aspect in detail when interpreting the outcomes for this article.

The authors conclude that, "This dose regimen of the echinacea formulation did not have a large effect on the course of the common cold, compared with either blinded placebo or no pills. However, the trends were in the direction of benefit, amounting to an average half-day reduction in the duration of a weeklong cold, or an approximate 10% reduction in overall severity."

A limitation of the study was that all of the patients were from 1 county and had community-acquired colds. People in other regions may have reacted differently to treatment. Another limitation was that patients with other viral infections (like the flu) were not actively excluded. Possibly the most important limitation was that the authors realized after concluding the study that it may have been underpowered to detect a difference in the primary endpoints.

This trial may be the largest randomized controlled trial on an echinacea preparation published to date. The study was funded by the National Center for Complementary and Alternative Medicine at the National Institutes of Health. The echinacea manufacturer did not provide any funding, which supports the credibility of the results. Since echinacea species and their plant parts contain different chemical profiles, and liquid versus tablet preparations differ in oropharyngeal tissue exposure, various products can have different activities and benefits—as reflected in some clinical trials that show a benefit of liquid preparations of fresh whole plant or aerial portions of E. purpurea in treating the common cold. Hence, this study is not the final word on the efficacy of echinacea.

Several prominent herbal experts have weighed in on the study in press releases dated December 21, 2010² and December 24, 2010.³ Mark Blumenthal, ABC Founder and Executive Director, stated, "Unlike some previous echinacea clinical trials which turned out negative, these authors do not represent themselves as having produced the definitive study on echinacea, and they carefully craft their language to show that the conclusions, although not showing a statistically significant beneficial effect, did show trends toward benefit, which are of therapeutic value to some consumers."

Australian herbalist and study co-author Kerry Bone wrote, "Perhaps a study with higher doses might have delivered a better result. Nonetheless, it should not be a surprise to many herbal clinicians like myself who have been mainly using echinacea root as a preventative in their practices. It might be contrary to popular thinking, but animal experiments have shown that echinacea root takes time to induce its immune effects. This is why any benefit once an infection takes hold is probably marginal, and it is best suited as a preventative. I have been involved in several clinical trials (either as co-author or advisor) that have demonstrated the long-term use of Echinacea root boosts immunity and prevents infections [unpublished findings]."^2,3

Francis Brinker, ND, the author of Herb Contraindications and Drug Interactions (now in its 4^th edition) wrote, "The authors describe 2 main types of echinacea preparations in general: (1) stabilized fresh juice of aerial parts of E. purpurea rich in hydrophilic derivatives such as polysaccharides/glycoproteins, and (2) aqueous-ethanolic extracts or the roots of E. purpurea or E. angustifolia richer in hydrophobic constituents such as alkamides....In the introduction they note 3 positive studies and 5 negative studies. The positive studies and preparations used all include liquid extracts of E. purpurea aerial plant....These studies support the use of the first type of preparation noted by the authors, if liquid extracts of the aerial parts are included along with its liquid expressed juice....In the 5 negative studies noted, none used liquid E. purpurea aerial plant extracts....It should be recognized from an empirical rationale and the evidence that acute infections can best be treated by concentrating the appropriate therapy locally, i.e., with frequent use of liquid E. purpurea aerial/whole plant extracts."³

The Med. Dept. of A. Vogel Bioforce AG provided some interesting observations^3,4: "We notice that WURSS-21 has never demonstrated any kind of effect for echinacea in any study....It cannot be excluded that the study in fact included participants without cold infection....We do not understand why Barrett used a very similar and highly specific extract, which before was never rigorously tested in a clinical setting. Much evidence exists for the efficacy of E. purpurea above-ground parts which supplemented with 5% of E. purpurea roots yield statistically significant effects....The study—although under the surveillance of the government—raises more questions than it answers, and due to many serious flaws provides us with uncertain conclusions about the general efficacy of echinacea."

"Blumenthal also told the Associated Press that the most compelling clinical literature published to date supports the clinical efficacy of 2 different brands of extracts of E. purpurea root and aerial parts. For the first, there have been 3 clinical trials on the Echinaforce^® extract produced by A. Vogel in Switzerland, imported into the US and distributed in health food stores by Bioforce USA.⁵ The second brand, called Echinamide^®, on which 2 published clinical trials⁶ have shown some benefit for cold symptoms, is produced in Canada by Natural Factors and sold in the US in health food stores."³

The editors of the Annals of Internal Medicine (the publisher of the study) sum up the study well, "This study is unlikely to change the debate on the efficacy of echinacea in treating the common cold."

—Heather S. Oliff, PhD

References

¹Henson S. Placebo effects related to pill-taking and doctor-patient relationship. HerbClip. February 26, 2010 (No. 100393-395). Austin, TX: American Botanical Council. Review of Rationale and methods for a trial assessing placebo, echinacea, and doctor-patient interaction in the common cold by Barrett B, Rakel D, Chewning B, et al. Explore. Nov./Dec. 2007;3(6):561-572.

²American Botanical Council clarifies Echinacea trial published in Annals of Internal Medicine. (Member Advisory). Dec. 21, 2010. Available online at: http://cms.herbalgram.org/press/2010/ABCClarifiesEchinaceaTrialinAIM.html.

³American Botanical Council clarifies Echinacea trial published in Annals of Internal Medicine. (Member Advisory). Revised Dec. 24, 2010. Available online at: http://cms.herbalgram.org/press/2010/ABCClarifiesEchinaceaTrialinAIM.html.

⁴A. Vogel Bioforce AG. Statement from Med. Dept. A. Vogel Bioforce AG on the Article by Barrett et al., Annals of Internal Medicine (2010): "Echinacea for Treating the Common Cold." Roggwil, Switzerland. Dec. 23, 2010.

⁵Brinkeborn RM, Shah DV, Degenring FH. Echinaforce^® and other Echinacea fresh plant preparations in the treatment of the common cold. A randomized, placebo controlled, double-blind clinical trial. Phytomedicine. 1999;6(1):1-6.