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December 21, 2010. Today the Annals of Internal Medicine published a clinical trial on a proprietaryechinacea formulation and its potential effects on people with common coldsymptoms. The trial results do not show a statistically significant benefit forthe echinacea product, even though there was a “trend” toward a benefit inreduction of symptoms and duration of symptoms.1

ABC Founder and Executive Director Mark Blumenthal was interviewedabout this trial last week by both the Associated Press and Bloomberg BusinessNews.

Associated Press coverage

Predictably, the AP article was widely distributed and has been postedon the websites of many leading newspapers and news outlets, including TheNew York Times, The Washington Post, TheLos Angeles Times, USAToday, The Seattle Times, TheWall Street Journal, National Public Radio, mainstream televisionnews sites (ABC, MSNBC, Fox News), and many others.2

The AP article says, “Barrett and other experts said the findingswould probably be viewed as positive by echinacea supporters but as the ‘nailin the coffin’ by critics

.

"‘It's not a compelling result in either direction,’ saidMark Blumenthal, executive director of the American Botanical Council, whichfollows research on herbal products. He said Barrett is on the group's advisoryboard.

“Blumenthal said the study was well designed, used a good qualityproduct at a reasonable dosage and tested echinacea in a real-world setting,rather than giving colds to research volunteers.”2

Bloomberg News coverage

BloombergNews reporter Nicole Ostrow quotedBlumenthal’s comments about the diversity of echinacea products and problemsinterpreting the clinical research:

“‘Echinacea products are not all alike,’ said Mark Blumenthal, founder and executive director of theAmerican Botanical Council, a nonprofit organization based in Austin, Texas, ina telephone interview on Dec. 15. The challenge is determining which ones havethe most benefit or any benefit.’

“The studies showing the most efficacy for echinacea in fightingcolds looked at formulations made from the root and leaves of Echinaceapurpurea, one of three different species, he said. The tablets usedin the new study contained roots of the purpurea species and another, accordingto the report.”3

Perspectives on the New Echinacea Trial

Blumenthal’s quotes in the AP and Bloomberg articles were based onthe following points he made about this trial during the interviews:

This is a large trial, possibly the largest randomized, controlledtrial on echinacea published to date, including 719 subjects. These subjectswere taken from the general population in 2 Wisconsin communities and the trialis based on the susceptibility to infection by a cold virus. This is incontrast to some echinacea trials in which a rhinovirus is actually inhaled ina controlled situation.

The trial tested short-term use of the echinacea preparation,mostly within 24 hours of the appearance of initial symptoms. Primary endpointsmeasured in the trial were cold symptom severity and duration of symptoms,while the secondary endpoints were levels of interleukin-8 and neutrophil,markers for immune response, which did not increase overall in theechinacea-treated subjects to statistical significance.

The trial used a good quality echinacea preparation, made byMediHerb (Australia) and distributed in the United States by Standard Process(Palmyra, WI). This echinacea preparation is sold to health practitioners onlyand is not generally available in retail outlets or on the Internet.

The MediHerb echinacea preparation is in tablet form and containsdried, concentrated extracts of two types of echinacea, the equivalent of 675mg of E. purpurearoot and 600 mg of E. angustifolia root, each standardized to 2.1 mg ofalkamides, one of the key biologically active chemical compounds found inechinacea roots. In this trial, based on the dosage regimen, the MediHerbechinacea tablet contained a daily dose equivalent of 10.2 grams of (bothtypes) dried echinacea root during the first 24 hours after the subject noticedthe first symptoms of cold, and 5.1 grams per day of dried echinacea rootconsumed during the next 4 days.

The trial contained 4 arms:

• 1 arm hadno placebo pill as a control;
• 1 arm hada placebo pill;
• 1 armused the specific echinacea product in a double-blinded manner;
• 1 armreceived the echinacea tablet in an open label manner, unblended.

This trial was designed and conducted by people who are experts inechinacea research and have published extensively on echinacea clinical trials,particularly the lead researcher, Bruce Barrett, MD, PhD, a professor of familymedicine at the University of Wisconsin in Madison. Mr. Kerry Bone, founder ofMediHerb and an internationally respected author of herb books for healthprofessionals, was also a co-author of the trial.

There was a slight trend toward benefit in symptom reduction inboth echinacea groups, with a reduction in duration by about 12 hours, which,although not statistically significant, the authors note may be consideredclinically significant by some patients.

The authors provided an interesting, cautiously worded, andreasonable conclusion:

This dose regimen of the echinacea formulation did not have alarge effect on the course of the common cold, compared with either blindedplacebo 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.1

Illness duration and severity were not statistically significantwith echinacea compared with placebo. These results do not support the abilityof this dose of the echinacea formulation to substantively change the course ofthe common cold.1

Unlike some previous echinacea clinical trials which turned outnegative,4 these authors do not represent themselves as having produced thedefinitive study on echinacea, and they carefully craft their language to showthat the conclusions, although not showing a statistically significantbeneficial effect, did show trends toward benefit, which are of therapeuticvalue to some consumers.

There are many clinical trials on numerous types of echinaceapreparations in the clinical literature and recent systematic reviews of someof these trials have concluded that there is benefit or trend towards benefitfor the echinacea preparations used in the selected trials.5,6 Blumenthal alsonoted that conducting a meta-analysis of clinical trials on echinaceapreparations is difficult, if not impossible, since so many different types ofechinacea preparations are on the market and have been used in the manyclinical trials. The heterogeneity of these preparations is based on the factthat there are three species of echinacea found in commerce: i.e., Echinaceaangustifolia, E. pallida andE. purpurea, withthe latter being the most popular.

In addition, the echinacea preparations found in the US marketgenerally contain either dried herb material or alcoholic extracts from eitherthe root or the above-ground part of the plant (aerial part), or even fresh-pressedjuice from the fresh aerial parts. And, to further complicate matters forresearchers who are attempting conducted systematic review or meta-analysis ofclinical trials on these preparations, there are mixtures of these echinaceamaterials from two or three species. Since echinacea species and their plantparts contain different chemical profiles, these various products can havedifferent activities and benefits—as reflected in some of the clinical trials.

Blumenthal also told the AP that the most compelling clinicalliterature published to date supports the clinical efficacy of two differentbrands of extracts of Echinacea purpurea root and aerial parts. For the first, therehave been 3 clinical trials on the Echinaforce® extract produced by A. Vogel inSwitzerland, imported into the US and distributed in health food stores byBioforce USA.6 The second brand, called Echinamide®, on which 2 publishedclinical trials7 have shown some benefit for cold symptoms is produced inCanada by Natural Factors and sold in the US in health food stores.

Additional coverage of this trial not based on the AP story wasdone by CNN (online), NBC Nightly News, and other outlets, although the APstory is dominant.

Additional perspectives

Australian herbalist and co-author Kerry Bone, one of the trialsco-authors wrote in an email to Standard Process, the importer of the MediHerbproduct used in the trial:

This is a well designed and conducted study delivering a robustresult. It demonstrated that initiating treatment with a traditional Echinacearoot product has only limited value in altering the course of the common coldonce it has taken hold. Perhaps a study with higher doses might have delivereda better result. Nonetheless, it should not be a surprise to many herbal clinicianslike myself who have been mainly using Echinacea root as a preventative intheir practices. It might be contrary to popular thinking, but animalexperiments have shown that Echinacea root takes time to induce its immuneeffects. This is why any benefit once an infection takes hold is probablymarginal and it is best suited as a preventative. I have been involved inseveral clinical trials (either as co-author or advisor) that have demonstratedthe long-term use of Echinacea root boosts immunity and prevents infections.One such positive trial of Echinacea root in reducing infections in long-haulairline travellers is currently in press (K. Bone, e-mail, December 21, 2010).

Francis Brinker, ND, a respected herbal expert and author of Herb Contraindications and Drug Interactions4th Edition (2011), and a member of the ABC Advisory Board*, wrote:

Once again, a good opportunity was lost. If the open label portionof the study had been done with an equivalent liquid echinacea extract, or evensolid extract in lozenge form, I expect the beneficial results would havereached statistical significance.

For years I have noticed that clinical studies done on echinaceathat include extracts of fresh Echinaceapurpurea whole plant oraerial plant, especially in liquid form, are consistently positive compared tothose using dried echinacea species extracts (or powdered herbs), especially insolid forms (tablets or capsules) to treat viral URTIs [upper respiratory tractinfections]. It makes eminently good sense to treat locally when possible, andcontact of echinacea extracts with the oropharangeal lymphatic tissue isextremely important in acute URTI conditions. Use of solid extracts requiressystemic distribution that is useful as an adjunct, but not as the sole therapeuticintervention when echinacea is concerned. Use of whole powdered echinacea partsand species should be reserved for such or as a preventive measure. Iunderstand the preference when doing research to use a solid form, sinceit makes a placebo-control much easier to make and administer, but it deprivesthe study of utilizing a factor of known empirical efficacy (local tissueexposure) (F. Brinker, e-mail, December 21, 2010).

In a follow-up email on December 23, Dr. Brinker added thesecomments about the trial:

Havingnow read the article in toto, I would like to share some further thoughts andaddress points made by the authors.

Ido applaud the care and consideration with which the study by Barret et al.2010 was developed and executed. I personally know one of the cliniciansinvolved, Dr. Dave Rakel, a former residential fellow in the University ofArizona's Program in Integrative Medicine. Dave is an excellent example of whatis right in medicine's pursuit of viable alternative practices to integrate asadjuncts with conventional practice. All medical research is good to the degreethat it can teach us something about how patients can be treated effectively ornot. The important thing is to accurately interpret and apply the results.

Unfortunately,this study failed in helping to demonstrate the efficacy of a particularechinacea preparation for treating acute colds (though this does not imply thatthe product may not be useful for other purposes), but it did provide furtherevidence on the type of product that is not optimally effective in thiscondition. This also serves an important purpose.

Indeconstructing the article I would like to begin by excerpting the lastsentence: "Individual choices about whether to use echinacea to treat thecommon cold should be guided by personal health values and preferences, as wellas by the limited evidence available.” What is the nature of the limitedevidence? On the first page of the article the authors describe 2 main types ofechinacea preparations in general:

(1)stabilized fresh juice of aerial parts of E.purpurea rich in hydrophilic derivatives such aspolysaccharides/glycoproteins, and

(2)aqueous-ethanolic extracts or the roots of E.purpurea or E. angustifoliaricher in hydrophobic constituents such as alkamides.

However,they did not distinguish liquid versus solid versions of each of these, e.g.,whether the aerial juice is stabilized by 22% ethanol or by drying. Thisdistinction is demonstrably important as shown by the studies they cited ofpositive and negative studies, and by their choice of the dried root extractfor this study.

Inthe introduction they note 3 positive studies and 5 negative studies. Thepositive studies and preparations used all include liquid extracts of E. purpurea aerial plant as follows:Cohen et al 2004 used liquid extracts of E.purpurea aerial plant and E.angustifolia root along with vitamin C and propolis; Goel et al 2004 used aliquid extract of E. purpurea wholefresh plant; Sperber et al 2004 used liquid E.purpurea aerial plant juice. These studies support the use of the first typeof preparation noted by the authors, if liquid extracts of the aerial parts areincluded along with its liquid expressed juice. (Another positive study theydid not mention, Lindemuth & Lindemuth 2000, used tea made from E. purpurea herb and dry root extractplus E. angustifolia herb. Use of E. angustifolia preparations as adjunctsseems entirely appropriate.)

Inthe 5 negative studies noted, none used liquid E. purpurea aerial plant extracts, but the preparations used arethe following: Barrett et al 2002 dried powders of E. angustifolia root and E.purpurea root and herb in capsules; Taylor et al 2003 dried E. purpurea juice in a syrup vehicle;Turner et al 2000 solid extract of uncharacterized echinacea (identified by theauthors in a follow-up letter as being labeled as containing "E. purpurea and E. angustifolia"); Turner et al 2005 liquid extracts of E. angustifolia root; Yale & Liu2004 freeze-dried juice of E. purpureaaerial plant in capsules.

Nowfuture authors will add another "negative" study of echinaceapreparations to their lists: dried extracts of E. purpurea and E. angustifoliaroots. The authors of this article defend their choice of preparations by stating:"When we designed this study in 2002, we decided to use a root-based, alkamide-rich preparation. Researchpublished since that time (32-38) has tended to support our decision."

However,the studies to which they refer are in vitro research, except for 2 humanpharmacokinetic studies that demonstrate absorption of alkamides from theMediHerb product. They do not point to any human clinical studies indicative ofthe efficacy of such preparations, though they did cite several negativestudies that used echinacea root preparations. (A positive study using a solid extract that should benoted is Brinkeborn et al. 1999 using Echinaforce, a fresh E. purpurea whole plant extract, while a solid extract of E. purpurea root in this same study wasnot effective.)

Aninteresting corollary to this is that all of the published studies to dateusing echinacea for the prevention of URTIs have utilized liquid extracts. Itshould be recognized from an empirical rationale and the evidence that acuteinfections can best be treated by concentrating the appropriate therapylocally, i.e., with frequent use of liquid E.purpurea aerial/whole plant extracts (as a gargle to maximize exposure tooropharyngeal tissue and then swallowed), while prevention may be accomplishedwith less frequent dosing of powdered echinacea roots, herb, or solid extractsused for enhancing systemic resistance over a prolonged period. If dosage(species, part, form, size, and frequency) is not optimized, then neither arethe results.

Combiningboth approaches by the internal use of good quality echinacea powdered root,herb, and/or solid extracts as an adjunct to the local and internal use of aliquid fresh E. purpurea plantpreparation for treating acute URTIs therefore seems entirely appropriate andadvisable.

In addition to Dr. Brinker’s comments, A. Vogel Bioforce AG, themanufacturers of the Bioforce echinacea product noted above, released astatement on December 23 in which it offered an analysis of the new trial byBarrett et al.:

Statement from Med. Dept.A.Vogel Bioforce AG on the Article by Barrett et al., Annals of InternalMedicine (2010): “Echinacea for Treating the Common Cold

Barrett and colleagues have published a clinicalstudy, which questions the efficacy of echinacea in the treatment of the commoncold. The study was published in a scientific journal of high impact and can befound at Barrett B, et al. Echinacea for treating the common cold. Annals ofInternal Medicine. 2010;153:769-777.

Study Methods

719 subjects (age > 12 years) with very mild signs and the personal impression of an upcomingcommon cold were assigned to four groups of interventions, unless theircomplaints existed for longer than 36 hours:

Subjects received 8 tablets on the first day and onsubsequent 4 days 4 tablets per day each containing the equivalent of:

• 675 mg of Echinacea purpurea root (alcoholic extractof dried roots);
• 600 mg of Echinacea angustifolia root (alcoholicextract of dried roots**);
• or the same number of Placebo tablets;
• or no treatment.

The primary endpoint was defined as the “areaunder the curve” (AUC) for global severity with duration and severity.Severity was assessed by WURSS-21 questionnaire and the duration by theparticipants impression of having a cold.

The results showed only a statisticallyinsignificant trend in:

• reduction of the cold duration byhalf a day and a;
• reduction of severity ofapproximately 10%***.

The study was designed assuming a relative benefitof 20%, deduced from clinical trials with other echinacea preparations.

Comments to thestudy

From a technical point of view the study by Barrettis of high quality (placebo-control, randomization, blinding).

However, from the medicinal and therapeutical pointof view there are too many severe shortcomings, which completely dismantle therelevance and validity of this study.

Method ofAssessment

For the assessment of the primary endpoint theauthors used a WURSS-21 questionnaire to measure the severity of the commoncold. This questionnaire queries cold-unrelated symptoms like the ability tothink clearly or walk/climb stairs aside of the classical cold-relatedsymptoms. The WURSS-21 is a highly uncommon and rather unspecific tool (global)to assess the course of cold infections accurately. It has been established bythe author himself and so far could not demonstrate significant efficacy forany well-established cold remedy at all. Or in other words: “You cannotmeasure the acceleration of a Porsche via using a thermometer on the wheel”.

PatientSelection

Only volunteers with a minimal Jackson score of 2 were included in the study. The Jackson score is the mostly used score toassess cold symptoms during a common cold and focuses only on common coldsymptoms. To our knowledge there is no data available to substantiate thiscriteria for inclusion. A Jackson score of 2 represents a day with moderateheadache or a day with mild malaise and chilliness. Jackson who actually triedto differentiate virally induced colds from any other unspecific complaints(transitionally causing isolate complaints of the whole picture the coldsyndrome) defined a score of more than 14 over 5 days as the minimalrequirement for a cold infection.

Therefore it cannot be excluded that the study infact included participants without cold infection and the study sample must beconsidered unsuitable. As demonstrated by Schoop et al. (2006) Echinacea helpsin common cold infections, when applying the Jackson’s criteria appropriately.

StatisticalConcerns

Although it has been claimed that this studyrepresents a very large study population, we notice that 4 groups and differentinterventions were studies. Thereby the actual particular groups were muchsmaller (N=164 – 171). Moreover, the sample size calculation was again based onthe assumption of a 20% effect while using the WURSS-21. Again we notice thatWURSS-21 has never demonstrated any kind of effect for echinacea in any studyand therefore the statistical fundament of the whole trial is null.

Interestingly the authors themselves challenged thepower of the study, admitting that their calculation basis was performed before2004 would be outdated today. A minimal number of 200 subjects would have beenrequired to see significance.

InvestigationalProducts

Barrett used the dried roots of two echinaceaspecies, Echinacea purpurea and angustifolia. A very recentwell-designed clinical trial investigated various extracts of Echinaceaangustifolia dried roots in a fairly large population (N=437) and couldonly demonstrate an insignificant trend in prevention and treatment ofclinically induced common colds. We do not understand why Barrett used a verysimilar and highly specific extract, which before was never rigorously testedin a clinical setting. Much evidence exists for the efficacy of Echinacea purpurea above-ground partswhich, supplemented with 5% of Echinaceapurpurea roots yield statistically significant effects (Goel V et al, 2005;Goel et al, 2004; Brinkeborn et al, 1999).

Study Conduct

Enrollment started in January 2004 and ended inAugust 2008 and 3321 subject were screened to find 719 suitable subjects. Withthe very broad inclusion criteria (age, definition of a cold) it is more thanastonishing why only every fifth subject fulfilled the requirements ofinclusion. Also we wondered how the last patient was enrolled in August – inthe mid of summer – and whether the stability of the Echinacea product wasmonitored over the 4-years study period.

Conclusion

The study – although underthe surveillance of the government – raises more questions than it answers anddue to many serious flaws provides us with uncertain conclusions about thegeneral efficacy of echinacea. However, a statement about the generalization ofthe new study results were given by the founder and executive director of theAmerican Botanical Counsil (ABC) Mark Blumenthal:

“the most compellingclinical literature published to date supports the clinical efficacy of twodifferent brands of extracts of Echinacea purpurea root. For the first, therehave been 3 clinical trials on the Echinaforce® extract produced by A. Vogel inSwitzerland, imported into the US and distributed in health food stores byBioforce USA. The second brand, called Echinamide®, on which 2 publishedclinical trials have shown some benefit for cold symptoms is produced in Canadaby Natural Factors and sold in the US in health food stores.”

The clinical study byBarrett deserves attention because it primarily highlights the importance to:

• Investigateechinacea products of documented clinical efficacy;
• Useappropriate measures to detect clinical effects;
• Correctlydefine cases of common colds;
• Plan thesize of the trial not on the grounds of misconceptions.

More information on echinacea from the extensive ABC online archives are available at an echinacea webpage on the ABC website.

The trial was funded by the National Center for Complementary and Alternative Medicine (NCCAM).

*Disclosure statement: Dr. Brinker is also a consultant to Eclectic Institute, a manufacturer of echinacea-based dietary supplements.

**The echinacea product was manufactured by MediHerb Company (Warwick, Queensland, Australia).

***A theoretical interpretation of confidence intervals allowed for estimation of maximal benefit of 20%.

References

1. Barrett B, Brown R, Rakel D, Mundt M, Bone K, Barlow S, Ewers T. Echinacea for Treating the Common Cold: A Randomized Trial. Ann Intern Med. 2010;153:769-777.

2. Nano S. Got a cold? Study says Echinacea won’t help much. Associated Press, Dec. 20, 2010. http://hosted.ap.org/dynamic/stories/U/US_MED_COLD_REMEDIES_ECHINACEA?SITE=NYONI&SECTION=HOME&TEMPLATE=DEFAULT. Accessed Dec. 20, 2010.

3. Ostrow N. Echinacea Shows Little Benefit as Remedy for Treating Colds, Study Finds. http://www.bloomberg.com/news/2010-12-20/echinacea-shows-little-benefit-as-remedy-for-treating-colds-study-finds.html. Accessed Dec. 21, 2010.

4. Turner RB, Bauer R, Woelkart K, Hulsey TC, Gangemi DJ. An evaluation of Echinacea angustifolia preparations in experimental rhinovirus infections. N Engl J Med. 2005;353:341-348.

5. 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. July 2007;7(7):473-480.

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

7. Goel V, Lovlin R, Barton R, Lyon MR, Bauer R, Lee TD, et al. Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2004;29:75-83.

8. A. Vogel Bioforce AG. Statement from Med. Dept. A.Vogel Bioforce AG on the Article by Barrettet al., Annals of Internal Medicine (2010): “Echinacea for Treating theCommon Cold”. Roggiwil, Switzerland. Dec. 23, 2010.