Annals of Internal Medicine 2002 (Dec 17); 137 (12): 939–946 ~ FULL TEXT
Bruce P. Barrett, MD, PhD; Roger L. Brown, PhD; Kristin Locken, BA;
Rob Maberry, BA; James A. Bobula, PhD; and Donn D’Alessio, MD
Department of Family Medicine,
University of Wisconsin-Madison,
777 South Mills,
Madison, WI 53715, USA
Why was this study done?
The common cold is a viral illness that is spread by contagion. While it is rarely fatal, it does account for a large amount of discomfort, suffering, and loss of productivity. This study was designed to help define the role of a herbal remedy containing Echinacea in the treatment of the common cold.
What This Study Found
Supplementing with Echinacea (six dosages on day one, followed by three dosages every day after) in 148 students with recent-onset colds was not effective at reducing duration or severity of illness.
BACKGROUND: Echinacea preparations are widely used to treat the common cold.
OBJECTIVE: To assess the efficacy of dried, encapsulated, whole-plant echinacea as early treatment for the common cold.
DESIGN: Randomized, double-blind, placebo-controlled community-based trial.
SETTING: University of Wisconsin-Madison, Madison, Wisconsin.
PARTICIPANTS: 148 registered students with common colds of recent onset.
INTERVENTION: An encapsulated mixture of unrefined Echinacea purpurea herb (25%) and root (25%) and E. angustifolia root (50%) taken in 1-g doses six times on the first day of illness and three times on each subsequent day of illness for a maximum of 10 days.
MEASUREMENTS: Severity and duration of self-reported symptoms of upper respiratory tract infection.
RESULTS: No statistically significant differences were detected between the echinacea and placebo groups for any of the measured outcomes. Trajectories of severity over time were nearly identical in the two groups. Mean cold duration was 6.01 days in both groups as a whole, 5.75 days in the placebo group, and 6.27 days in the echinacea group (between-group difference, -0.52 day [95% CI, -1.09 to 0.22 days]). After controlling for severity and duration of symptoms before study entry, sex, date of enrollment, and use of nonprotocol medications, researchers found no statistically significant treatment effect (adjusted hazard ratio, 1.24 [CI, 0.86 to 1.78]). Multivariable regression models assessing severity scores over time failed to detect statistically significant differences between the echinacea and placebo groups.
CONCLUSION: Compared with placebo, unrefined echinacea provided no detectable benefit or harm in these college students who had the common cold.
From the FULL TEXT Article:
The common cold is one of the world’s most prevalent
illnesses. Upper respiratory tract infection, characterized
by rhinosinusitis, pharyngitis, or tracheobronchitis, is
caused by a wide array of agents. While rhinovirus is most
common, coronavirus, respiratory syncytial virus, adenovirus,
parainfluenza, and influenza virus all play important
roles [1–4]. Effects on health, well-being, and productivity
are significant. Although patients with such complications
as asthmatic bronchospasm, bacterial sinusitis, otitis media,
streptococcal pharyngitis, or pneumonia might benefit
from medical intervention, few if any treatments have
proven effective for community-acquired colds [5–10].
Preparations made from plants of the genus Echinacea
are widely used for the prevention and treatment of colds
[11–13]. Various whole-plant preparations and extracts
made from the flowers, leaves, stems, and roots of E. purpurea,
E. angustifolia, and E. pallida are sold worldwide.
Hundreds of scientific studies, mostly German, have detailed
echinacea’s botanical, chemical, and pharmacologic
characteristics and its clinical effects [14–19].
There is no clear consensus about whether echinacea
can benefit human health. Randomized, controlled trials
have focused on the prevention or treatment of colds. Five
such trials of prevention (four of which have been published)
reported that echinacea had little effect in reducing
the incidence of natural colds [20–23]; Calabrese C. Personal
communication). The findings of the highest-quality
study  are consistent with a 10% to 15% reduction in
relative risk. Results of an induced-cold trial have been
reported as negative but are consistent with a benefit of
10% to 15% . The 11 published treatment trials are
somewhat more positive [25–35], and systematic reviews
have been cautiously optimistic [13, 14, 18, 36, 37]. Reported
benefits have ranged from a 40% to 50% reduction
in severity  and duration  of symptoms in studies
with major methodologic limitations to more modest reductions
of 10% to 30% in the most recent studies [25,
27, 28]. All studies to date have had important limitations,
including lack of objective validated outcome measures,
lack of description and verification of random allocation
and concealment procedures, limitations related to sample
size and power, and limited generalizability.
In spring 1999, we conducted a randomized, doubleblind,
placebo-controlled community-based trial evaluating
the efficacy of an encapsulated whole-plant echinacea
preparation used as early treatment for the common cold.
Participants with early cold symptoms were randomly assigned
(with allocation concealed) to echinacea treatment
or placebo and were followed with self-reported duration
and severity measures for the duration of illness, up to 10
days. All participants provided informed consent before the
study, and the University of Wisconsin Medical School
human subjects committee approved the protocol.
Shaklee Tecnica (Pleasanton, California) provided the
echinacea and placebo preparations. Each active capsule
contained a dried mixture of E. angustifolia root (50%
[123 mg]), E. purpurea root (25% [62 mg]), and E. purpurea herb (25% [62 mg]). Echinacea capsules also contained
thyme (49 mg) and peppermint (31 mg) to disguise
taste and flavor, as well as citric acid (3 mg) as a preservative.
The placebo capsules contained 333 mg of alfalfa.
Each participant was given a bottle containing 132 capsules
and was instructed to take four capsules per treatment
dose six times during the first 24 hours of the study, and
three times each day thereafter until symptoms resolved,
for a maximum of 10 days. Each four-capsule dose totaled
1 g. Thus, the dose schedule was 6 g of echinacea on the
first day and 3 g on each subsequent day.
Participants were recruited from 4 February 1999 until
20 May 1999 from the University of Wisconsin—Madison
student population. Advertisements throughout the
student community (posters, newspaper advertisements,
and e-mail messages) asked respondents to call a cellular
telephone held by a research assistant at the first sign of
cold or flu-like symptoms. Callers were screened by telephone
and were invited to meet with a research assistant if
eligible, usually within a few hours of the initial call. At the
enrollment interview, the research assistant described the
study protocol, obtained informed consent, gathered baseline
data, and provided instruction on the paper questionnaire
and the Web-based survey instrument.
To be included in the study, participants were required
to be at least 18 years of age, to answer “Yes” to the
question “Do you believe that you are coming down with
a cold?”, to report at least 2 of 15 listed cold symptoms (at
least 1 of which had to be specific to the respiratory tract),
and to be apparently able and willing to adhere to the
study protocol. Participants were excluded if they reported
having any listed symptom for more than 36 hours; were
pregnant; were currently using antibiotics, antihistamines,
or decongestants; had specified chronic diseases (autoimmune
disease, chronic bronchitis, HIV infection, lupus,
rheumatoid arthritis); or had a history of asthma or allergic
rhinitis and corresponding symptoms (itchy eyes, sneezing,
wheezing) at the time of enrollment.
Randomization was designed so that each participant
would have a 50% chance of assignment to placebo or
echinacea. The Investigational Drug Service of the University
of Wisconsin Hospitals randomized and sequentially
labeled 200 bottles containing echinacea or placebo, using
a random-number generator (Microsoft Excel, Microsoft
Corp., Redmond, Washington) and a balanced blocks-offour
design. Each sequentially enrolled participant received
the next sequentially numbered bottle of capsules. The placebo
and echinacea capsules were indistinguishable to
study personnel and to the participants. Allocation to echinacea
or to placebo was concealed from participants and
from the investigational team until all data had been collected,
entered, and cleaned.
Primary outcomes were defined prospectively as severity
and duration of self-reported symptoms. Duration was
defined as the number of days from study enrollment to
the last day before the participant answered “No” to the
question, “Do you think that you are still sick today?”
Symptom severity was measured daily on nine-point Likert
scales. The 15 symptoms assessed were dry cough, productive
cough, cough interfering with sleep, sore throat,
scratchy throat, hoarseness, runny nose, plugged or stuffy
nose, sneezing, headache, fever, sweats, muscle aches, feeling
“run down,” and loss of appetite. Each reported symptom
was rated on a nine-point Likert severity scale with the
following label: 1 (very mild), 3 (mild), 5 (moderate), 7
(severe), and 9 (extreme). Global severity of illness (“How
sick do you feel today?”) was assessed by using a similar
For each day of the trial, participants were asked to fill
out both a paper and an electronic version of the questionnaire.
The electronic version was adapted to a Web page
format (www.fammed.wisc.edu/samplecold). Blinded data
were downloaded and inspected periodically throughout
the trial. The parallel data collection system enabled us to
verify the time and date of response, protecting against
errors from retrospective assessments. It also protected
against data entry error and missing data and allowed comparison
of data reported in electronic and paper formats.
Participants were in contact with the enrolling research
assistant by telephone and e-mail throughout the
study. They returned for an exit interview upon study
completion. Adherence was assessed by pill counts (from
bottles returned at the end of the study) and by the daily
questionnaire (which asked the participants whether they
had taken their pills and how many pills they had taken).
Adverse effects were monitored each day and at the exit
Our study was designed to have 150 participants, providing
at least 80% power to detect a benefit of 2 days’
duration or an average reduction of two points in severity.
These prospective power calculations [38, 39] assumed variance similar to that observed in cold studies [9, 10] and
benefits similar to those reported in previous echinacea trials
[27–31]. The minimal clinically important benefit for
the common cold has not been determined [40, 41]. However,
research on other illnesses suggests that an average
two-point reduction in severity on a nine-point scale or a
2-day reduction in duration would be clinically significant
A symptom-dimension measurement model was constructed
by using structural equation modeling techniques
[47, 48, 51]. From the pool of 15 symptoms, 14 items fit
neatly into four symptom dimensions. Loss of appetite was
an infrequent symptom that contributed insignificantly
and was therefore dropped. The four dimensions and their
associated reliability coefficients, calculated by using the
method of Dillon and Goldstein , were cough (0.794),
throat (0.668), nasal (0.663), and fever and aches (0.753).
Reliability coefficients estimate the proportion of variability
that is attributable to participants’ symptoms rather
than to measurement error [45, 49, 50].
were investigated as possible confounders:
1) duration of
symptoms before study entry,
2) severity of illness at enrollment,
3) date of enrollment (seasonal or etiologic agent
4) use of nonprotocol medications, and
We considered all available data in our analysis. Methods
included simple inspection, frequency analysis, analysis
of variance, and multivariable analysis. Confidence intervals
were constructed for all outcomes. A simple sum of the
15 symptom scores was selected as an overall severity
marker for use in regression models. Changes over time in
the summed severity score were explored by using the general
linear mixed model for repeated measures . Individual
symptom scores and dimensional severities were
similarly explored by using mixed modeling approaches . Bootstrap resampling was used to calculate means
and confidence intervals for duration . A Cox multivariable
proportional hazards regression model  for cold
duration was used to control for potential confounding.
The lack of time trends in the Schoenfeld residuals supports
the proportional hazards assumption . The five
potential confounders previously noted were included in
all multivariable models. Statistical analyses were done by
using SAS software (SAS Institute, Inc., Cary, North Carolina).
Role of the Funding Sources
The U.S. Department of Health and Human Services
and the National Institutes of Health provided funding to
Dr. Barrett during the study. Shaklee Tecnica provided
monetary support for project costs and provided the study
materials, but had no role in the design, conduct, or reporting
of the data or in the decision to submit the manuscript
Of 148 enrolled participants, 142 (69 in the echinacea
group and 73 in the placebo group) completed our protocol
successfully (Figure 1). Characteristics of the study
sample are shown in the Table. We did not record the
number of eligible persons who called the research center
but were unwilling to participate in the study; however, it
was clear that most eligible callers were enrolled. The mean
time from onset of the first recognized symptom to study
enrollment was 27 hours.
A total of 853 person-days of illness were reported. Six
participants withdrew, 2 in the placebo group (1 because of
feeling too sick and 1 for undisclosed reasons) and 4 in the
echinacea group (2 because of being too sick to follow the
protocol, 1 because the capsules tasted bad and were diffi-
cult to swallow, and 1 for undisclosed reasons). In the
echinacea group, 27 participants reported taking nonprotocol
medications compared with 25 participants in the
placebo group. Of the 142 participants who completed the
study, 10 (5 in each group) reported having had at least
one symptom for more than 36 hours at enrollment. For
these 10 persons, the duration from first symptom to enrollment
was 36 to 40 hours (n 2), 45 to 48 hours (n
6), 72 hours (n 1), or 168 hours (n 1). Because these
protocol violations were discovered after the trial ended, we chose to include data from these 10 persons in our results.
For the six persons lost to follow-up, no postenrollment
data were available.
After unblinding in July 1999, samples of the echinacea
formulation were sent to three independent laboratories
for analytic testing. Dr. Rudolph Bauer (Institut fuer
Pharmazeutische Biologie, Heinrich-Heine-Universitaet
Duesseldorf, Duesseldorf, Germany) analyzed our formulation
and found that it contained 0.26% echinoside;
0.77% cichoric acid; and 0.82% alkamides, including
0.42% dodecatetraenoic acid isobutylamide by weight [15, 56, 57]. Industrial Labs (Denver, Colorado) analyzed our
product using a standardized method developed by their
methods validation program and reported that it contained
0.20% echinoside, 0.84% cichoric acid, 0.03% chlorogenic
acid, and 0.33% cafeolytartaric acid. Dr. Joseph Rininger
at Paracelsian, Inc. (Langmuir Laboratories, Ithaca,
New York), used cell culture and simulated digestion
methods with bioequivalent doses of our study product to
demonstrate macrophage activation and elevated levels of
tumor necrosis factor. The equivalent of our first-day dose
increased the mean level (SD) of tumor necrosis factor
from 189 23 ng/L to 3679 154 ng/L, while the
equivalent of our subsequent daily dose increased the mean
level to 2347 66 ng/L. Together, these three analyses
demonstrate that our product contained substantial quantities
of phytochemicals as active constituents [14, 15].
Pill counts and daily computerized monitoring demonstrated
protocol adherence. An overall adherence rate of
92% was calculated by dividing the number of pills missing
from the bottles by the number that should have been
missing based on the protocol. On the Web-based questionnaires,
nearly all of the participants reported taking
their pills nearly every day during their participation in the
Before the study, we conducted several informal tests
of blinding. Study personnel, friends, and colleagues could
not distinguish between placebo and echinacea capsules. At
the exit interview, we asked participants, “Do you think
you were taking echinacea or placebo?” Blinding was successful:
Thirty-one of 63 persons taking echinacea and 33
of 72 persons taking placebo guessed correctly (P 0.2).
Seven participants declined to guess.
Of the 853 person-days of illness, 546 (64%) were
captured by both paper and electronic data systems. Two
hundred eighty-seven person-days (34%) were captured by
paper surveys alone, while 18 (2%) were accounted for
solely by the computerized system. Only 2 person-days
(0.2%) were not accounted for by either system. Therefore,
for 142 participants documenting 853 days of illness, our
data capture rate was 99.8%. In constructing the final data
set, we used the computerized data whenever available because
they were verified by time and date. We used data
originally recorded on paper as needed.
Comparing data from the computerized and paper
symptom surveys provided some evidence of instrument
reliability. Responses to the question about global severity
of illness were identical on 512 of the 546 days for which
both instruments provided data (94% concordant, 6% discrepant).
Of 34 discrepancies, 29 were off by one point on
the nine-point Likert scale and 5 were off by two points.
Comparing computer and paper responses to the 15
specific-symptom questions also yielded high levels of concordance.
Of 8,190 answers, 7,777 (95%) were concordant
and 413 (5%) were classified as data discrepancies. Of
these, 293 were off by one point on the nine-point scale,
68 were off by two points, 27 were off by three points, 17
were off by four points, 7 were off by five points, and 1 was
off by six points.
We did not detect a difference in cold duration between
the echinacea and placebo groups. Among the 142
participants completing our protocol, durations ranged
from 2 to 10 days, with a median of 6 days and a mean
(SD) of 6.01 2.34 days (Figure 2). The mean duration
was 5.75 days in the placebo group and 6.27 days in
the echinacea group (difference, 0.52 day [95% CI,
1.09 to 0.22 days]). Therefore, 0.22 day is the largest
potential echinacea-related benefit in duration that would
be statistically compatible with our results. After adjustment
for the five potential confounders, Cox multivariable
regression found no statistically significant treatment effects
on duration (adjusted hazard ratio, 1.24 [CI, 0.86 to
1.78]), with the trend toward longer duration in the echinacea
We did not detect any significant differences in symptom
severity between the echinacea and placebo groups.
Figures 3 and 4 depict daily mean severities and 95% CIs
for the symptoms assessed. The group sizes decrease over
time, following recovery from illness. A general linear mixed model of the unweighted summed severity score
(controlling for the five potential confounders) did not reveal
any statistically significant differences between the
echinacea and placebo groups. Duration of symptoms before
study entry, date of enrollment, and sex were not
statistically significant. Although use of nonprotocol medications
and severity of illness at enrollment had independent
effects on subsequent severity, neither potential confounder
could account for the lack of observed treatment
Models of individual symptoms and of symptom dimensions
(again controlling for the five confounders) similarly
failed to demonstrate treatment effects. Although uncontrolled
linear models of the cough dimension indicated
slightly more rapid recoveries in the placebo group, these
differences were not apparent in more complex models that
better represented dimension severity over time. More severe
illness in the placebo group on the first day of the trial,
before treatment was initiated, appeared to explain the
trends favoring placebo in the linear models. There were
no statistically significant differences between echinacea
and placebo in scaled responses to the global severity question,
“How sick do you feel today?” Mean scores of responses
to this question are shown in Figure 3.
In our analysis, we included all available data from the
142 persons who completed the study protocol. We collected
no useful data for the six participants who were
enrolled but were lost to follow-up. Regression results described
earlier and mean values portrayed in Figures 2, 3,
and 4 do not include data for these six participants and
therefore do not represent an intention-to-treat analysis.
However, to assess whether data from the six persons who
withdrew could have affected our results, we performed an
analysis that imputed symptom-recovery trajectories for
each missing participant based on the average of 1000 randomly
selected trajectories. This analysis yielded results
very similar to those described earlier (data not shown).
Specific adverse effects were reported on the daily
questionnaires 22 times by 15 participants who completed
the study (9 times by 7 participants in the placebo group
and 13 times by 8 participants in the echinacea group). In
the echinacea group, sleeplessness, heartburn, nausea,
stomachache, and upset stomach were each reported by
one participant and bad taste was noted by three participants.
In the placebo group, stomachache was noted by
three participants and nausea, belching, thirst, and abdominal
pain with diarrhea were each noted by one participant.
Reported adverse effects were therefore not statistically different
between the echinacea and placebo groups.
We consider the results of this trial to be negative. We
did not detect the effect size for which the trial was powered
(2 days’ duration and two points in average severity
on a nine-point scale) or any potentially significant trends.
All differences noted between the echinacea and placebo
groups could be explained by natural variability in the underlying symptoms measured. Our results do not support a
benefit of echinacea in the treatment of common cold
symptoms. However, we do not believe that our trial
should be the last word on echinacea. Our results contradict
the current published evidence, and our trial had limitations.
Previous trials have reported statistically signifi-
cant symptomatic benefit with echinacea taken early in the course of an acute upper respiratory tract infection [27–29, 31–35]. These trials, especially those by Brinkeborn 
and Henneicke-von Zepelin  and colleagues, are similar
to our trial in quality but report positive results. In
addition, published systematic reviews have concluded that
there may be benefit to early echinacea treatment [13, 18, 36, 37]. There are several possible reasons for this discrepancy. The positive results of previous trials could be due to bias or chance, and the widespread belief in echinacea’s
benefit could be entirely false.
However, our trial had several limitations that should
temper confidence in its negative results. First, the specific
echinacea preparation used in our trial, a dried, encapsulated
mixture of unrefined E. angustifolia root and wholeplant
E. purpurea, has not been tested previously and may
be ineffective because of bioavailability or phytochemical
constituents. Previous trials with positive results have used
extracts rather than whole-plant products [25, 27–35], and
some have combined echinacea with other plant species
[27, 32–35]. Because phytochemical constituents vary
among botanical species, growing conditions, plant part,
and extraction method, it is possible that one preparation
would provide benefit while another would not.
Second, the type of people included in our study,
healthy undergraduate college students, may not gain
much benefit from echinacea. Previous trials have tended
to include older adults and have sometimes sought to include
those with histories of frequent colds. There is a
prevailing notion that echinacea provides greatest benefit
to persons who are immunocompromised, a state often
evidenced by frequent colds or other viral illnesses. We
made no effort to seek out such persons.
Third, although our modest-size trial would have detected
a large benefit, an effect size of 5% or 10% could
easily have been missed among the natural variability of
symptoms found in persons with community-acquired
colds. From a health measurement perspective, it should be
emphasized that our study was limited because we used
self-reported symptoms as primary outcomes [44, 45, 58, 59]. Subjective self-assessments can introduce several potential
To date, there are no validated instruments for assessing
the common cold [10, 40, 41]. We have begun refining
and validating our instrument , but although its face
validity is strong, construct validity has not been demonstrated. It should also be noted that we monitored participants for a maximum of 10 days and therefore do not
know the frequency of longer illnesses. Finally, five people
in each of our study groups received echinacea after having
symptoms for 36 hours, which may have masked a benefit
of echinacea given earlier in cold presentation. Future research
is necessary to provide more definitive evidence about
whether echinacea is an effective treatment for the common
The authors acknowledge the Native American peoples
who first brought echinacea to the attention of the world community. They thank the study participants and the research assistants who worked with them: Beth Amspaugh, Kira Conroy Williams, and Peter Jung; and Marijka Hambrecht, who very effectively managed the Webbased data collection tool. They thank Carlo Calabrese, John Frey, Jim Gern, Jack Gwaltney, Mike Fleming, Pat McBride, Mary Beth Plane, and Bill Scheckler for helpful comments. In addition, they thank Pam Manning, Chris Jensen, and Eric Zaltas at Shaklee Tecnica for their excellent work.
By the U.S. Department of Health and Human Services
(Institutional National Research Service Award T-32 HP 10010-09 from the Health Resources and Services Administration [Dr. Barrett]), National Center for Complementary and Alternative Medicine at the National Institutes of Health (K23 AT00051-01 [Dr. Barrett]), and Shaklee Tecnica.
Potential Financial Conflicts of Interest:
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