ArticlePDF AvailableLiterature Review

Abstract

Authors' conclusions The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted. AVAILABLE AT: http://www.mv.helsinki.fi/home/hemila/CC/CC.htm
Vitamin C for preventing and treating the common cold
(Review)
Hemilä H, Chalker E
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 1
http://www.thecochranelibrary.com
Vitamin C for preventing and treating the common cold (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
16DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
80DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Incidence of colds while taking 0.2 g/day vitamin C regularly, Outcome 1 Proportion of
participants developing 1 cold episodes during the trial. . . . . . . . . . . . . . . . . . . 82
Analysis 2.1. Comparison 2 Duration of the colds occurring when on regular 0.2 g/day vitamin C, Outcome 1 Duration
of common cold symptoms (placebo group duration 100%). . . . . . . . . . . . . . . . . . 84
Analysis 3.1. Comparison 3 Severity of the colds occurring when on regular 0.2 g/day vitamin C, Outcome 1 Indicators
of common cold severity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Analysis 4.1. Comparison 4 Duration of the colds after therapeutic 0.2 g/day vitamin C, Outcome 1 Duration of
common cold symptoms (placebo group duration 100%). . . . . . . . . . . . . . . . . . . 87
Analysis 5.1. Comparison 5 Severity of the colds after therapeutic 0.2 g/day vitamin C, Outcome 1 Indicators of common
cold severity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
88ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
100WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
100HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
101CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
101DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
101SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
102NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
102INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iVitamin C for preventing and treating the common cold (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Vitamin C for preventing and treating the common cold
Harri Hemilä1, Elizabeth Chalker2
1Department of Public Health, POB 41, University of Helsinki, Helsinki, Finland. 2Curtin, Australia
Contact address: Harri Hemilä, Department of Public Health, POB 41, University of Helsinki, Mannerheimintie 172, Helsinki, FIN-
00014, Finland. harri.hemila@helsinki.fi.
Editorial group: Cochrane Acute Respiratory Infections Group.
Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 1, 2013.
Review content assessed as up-to-date: 29 November 2012.
Citation: Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews
2013, Issue 1. Art. No.: CD000980. DOI: 10.1002/14651858.CD000980.pub4.
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Vitamin C (ascorbic acid) for preventing and treating the common cold has been a subject of controversy for 70 years.
Objectives
To find out whether vitamin C reduces the incidence, the duration or severity of the common cold when used either as a continuous
regular supplementation every day or as a therapy at the onset of cold symptoms.
Search methods
We searched CENTRAL 2012, Issue 11, MEDLINE (1966 to November week 3, 2012), EMBASE (1990 to November 2012),
CINAHL (January 2010 to November 2012), LILACS (January 2010 to November 2012) and Web of Science (January 2010 to
November 2012). We also searched the U.S. National Institutes of Health trials register and WHO ICTRP on 29 November 2012.
Selection criteria
We excluded trials which used less than 0.2 g per day of vitamin C and trials without a placebo comparison. We restricted our review
to placebo-controlled trials.
Data collection and analysis
Two review authors independently extracted data. We assessed ’incidence’ of colds during regular supplementation as the proportion
of participants experiencing one or more colds during the study period. ’Duration’ was the mean number of days of illness of cold
episodes.
Main results
Twenty-nine trial comparisons involving 11,306 participants contributed to the meta-analysis on the risk ratio (RR) of developing a
cold whilst taking vitamin C regularly over the study period. In the general community trials involving 10,708 participants, the pooled
RR was 0.97 (95% confidence interval (CI) 0.94 to 1.00). Five trials involving a total of 598 marathon runners, skiers and soldiers on
subarctic exercises yielded a pooled RR of 0.48 (95% CI 0.35 to 0.64).
Thirty-one comparisons examined the effect of regular vitamin C on common cold duration (9745 episodes). In adults the duration
of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C shortened colds
by 18%. The severity of colds was also reduced by regular vitamin C administration.
1Vitamin C for preventing and treating the common cold (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Seven comparisons examined the effect of therapeutic vitamin C (3249 episodes). No consistent effect of vitamin C was seen on the
duration or severity of colds in the therapeutic trials.
The majority of included trials were randomised, double-blind trials. The exclusion of trials that were either not randomised or not
double-blind had no effect on the conclusions.
Authors’ conclusions
The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C
supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular
supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials
that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular
supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis
whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted.
P L A I N L A N G U A G E S U M M A R Y
Vitamin C for preventing and treating the common cold
The common cold is a major cause of visits to a doctor in high-income countries and of absenteeism from work and school. There
are over 200 viruses which can cause the common cold symptoms including runny nose, congestion, sneezing, sore throat, cough, and
sometimes headache, fever and red eyes. Symptoms vary from person to person and cold to cold. Since the common cold is usually
caused by one of the respiratory viruses, antibiotics are useless and therefore other potential treatment options are of substantial public
health interest.
Vitamin C has been proposed for treating respiratory infections since it was isolated in the 1930s. It became particularly popular in the
1970s when Nobel laureate Linus Pauling concluded from earlier placebo-controlled trials that vitamin C would prevent and alleviate
the common cold. Over two dozen new trials were undertaken thereafter. Vitamin C has been widely sold and used as a preventive and
therapeutic agent.
This review is restricted to placebo-controlled trials testing 0.2 g/day or more of vitamin C. Regular ingestion of vitamin C had no
effect on common cold incidence in the ordinary population, based on 29 trial comparisons involving 11,306 participants. However,
regular supplementation had a modest but consistent effect in reducing the duration of common cold symptoms, which is based on 31
study comparisons with 9745 common cold episodes. In five trials with 598 participants exposed to short periods of extreme physical
stress (including marathon runners and skiers) vitamin C halved the common cold risk. The published trials have not reported adverse
effects of vitamin C.
Trials of high doses of vitamin C administered therapeutically, starting after the onset of symptoms, showed no consistent effect on the
duration or severity of common cold symptoms. However, only a few therapeutic trials have been carried out and none have examined
children, although the effect of prophylactic vitamin C has been greater in children. One large trial with adults reported benefit from an
8 g therapeutic dose at the onset of symptoms, and two therapeutic trials using five-day supplementation reported benefit. More trials
are necessary to settle the possible role of therapeutic vitamin C, meaning administration immediately after the onset of symptoms.
B A C K G R O U N D
Description of the condition
The term ‘the common cold’ does not denote any precisely de-
fined disease, but this illness is familiar to most people. Typically
symptoms of the common cold consist of some combination of
nasal discharge and obstruction, sore throat, cough, lethargy and
malaise, with or without fever. The common cold is the leading
cause of acute morbidity and of visits to a physician in high-in-
come countries, and a major cause of absenteeism from work and
2Vitamin C for preventing and treating the common cold (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
school.
The common cold is usually caused by respiratory viruses (rhino,
corona, adeno, parainfluenza, influenza, respiratory syncytial),
which overall have some 200 serotypes (Eccles 2005;Eccles 2009;
Gwaltney 2005;Heikkinen 2003). Thus, the term ‘the common
cold’ does not refer to a single entity but to a group of diseases
caused by numerous unrelated aetiological agents. The most fre-
quent agent causing the common cold is rhinovirus,which is found
in 30% to 50% of sufferers. In a third of participants with cold
symptoms, the aetiology remains undefined even when extensive
virological tests are used. It is not clear to what extent this latter
group is explained by the low sensitivity of the tests, unidentified
viruses, or similar symptoms arising from non-viral aetiology, such
as allergic or mechanical irritation of the airways. Different res-
piratory viruses have different symptom profiles, but the patterns
are not consistent enough to validate aetiological conclusions from
the patients’ symptoms.
Although the great majority of common cold episodes are caused
by the respiratory virus group, the symptom-based definition of
the ‘common cold’ also coverssome diseases caused by other viruses
(varicella, measles, rubella, cytomegalo, Epstein-Barr) and some
bacterial infections. For example, since streptococcal pharyngitis
cannot be differentiated from viral pharyngitison clinical grounds,
it can also be included within the broad definition of the common
cold. Symptoms of illnesses caused by Mycoplasma pneumoniae
(M. pneumoniae) and Chlamydia pneumoniae (C. pneumoniae) may
also be similar to the symptoms caused by the respiratory viruses.
The manifestations of the common cold are so typical that usually
the clinical diagnosis of the common cold can be made reliably
by adult patients themselves. Allergic and vasomotor rhinitis can
sometimes mimic the common cold, but these conditions can
usually be easily differentiated (Heikkinen 2003).
In common cold trials an operational definition of the common
cold is used for logistic reasons; for example, based on the duration
and the set of symptoms to yield an explicitly defined outcome.
However, such limits are biologically arbitrary. There is no exact
minimum duration or combination of symptoms which is mean-
ingful when drawing a conclusion as to whether the symptoms
should be explained by a viral infection, or by allergic or mechan-
ical irritation of nasal airways or throat.
The use of antibiotics for a typical acute common cold episode
is useless since the vast majority of colds are caused by viruses.
Nevertheless, according to some surveys about 50% of common
cold patients in the USA received antibiotics (Gonzales 1997;
Mainous 1996). In this respect, the alternative treatment options
for the common cold are of substantial public health interest.
Description of the intervention
Numerous animal studies with different species have shown that
vitamin C affects resistance to diverse infections by viruses and
bacteria (Hemilä 2006a;Hemilä 1997c). Therefore this vitamin
might play a similar role in infections in human beings. Since the
early 1940s, a number of controlled trials have been carried out to
examine the possible effects of vitamin C on the common cold.
In 1970, the publication of Linus Pauling’s book Vitamin C and
the Common Cold generated huge public interest which persists
today (Pauling 1970a). Pauling had won Nobel Prizes in Chem-
istry (1954) and Peace (1962), and his book had a great influ-
ence. Pauling 1971a also carried out a meta-analysis in which he
combined the P values derived from four placebo-controlled trials
by Fisher’s method and found that there was strong evidence that
vitamin C decreased the ’incidence of colds’ (P = 0.003). In a sec-
ond meta-analysis, Pauling 1971b focused on ’days of illness per
person’ in the best two trials (Cowan 1942;Ritzel 1961) and by
combining the P values by Fisher’s method led him to conclude
that “the null hypothesis of equal effectiveness of ascorbic acid
and placebo [on total morbidity] is rejected at the level P less than
0.001.”
Ritzel 1961 had reported a brief randomised trial of children at
a ski school in the Swiss Alps in which he administered 1 g of
vitamin C daily and found significantly reduced incidence and
duration of colds in children who were administered vitamin C.
Pauling 1971a put much weight on the Ritzel trial. On the basis of
Ritzel’s trial, Pauling proposed that mega-dose supplementation
might profoundly influence both the incidence and severity of the
common cold over all the population. Pauling also presented data
suggesting that human diets might not provide sufficient intake
of vitamin C for best health (Pauling 1970b;Pauling 1976a).
Pauling’s advocacy of vitamin C led to numerous careful trials in
different countries in the following decade, the largest of which
were performed on healthy adult volunteers in Canada (Anderson
1972;Anderson 1974a;Anderson 1975a). The evidence emerging
from all the published trials was confusing (Anderson 1977), but
generally failed to support Pauling’s hope that vitamin C would
be a panacea.
In a meta-analysis, Chalmers 1975 calculated an unweighted av-
erage of the treatment effect in seven placebo-controlled trials and
found that colds in vitamin C groups were 0.11 ± 0.24 (standard
error (SE)) days shorter which is not a statistically or clinically
significant difference. In a qualitative review on vitamin C and
the common cold published in the same year, Dykes 1975 also
concluded that vitamin C had no effect on colds.
However, it has subsequently been pointed out that the influ-
ential reviews by Chalmers 1975 and Dykes 1975 contain seri-
ous errors (Hemilä 1995;Hemilä 1996c;Hemilä 2006a). Hemilä
1995 showed that after extraction of correct data from the trial
reports, correction of errors in calculations, and restriction to trials
in which at least 1 g/day of vitamin C had been used, as Paul-
ing had proposed, Chalmers 1975 would have calculated an eight
times higher estimate of the vitamin C effect: 0.93 ± 0.22 (SE) days
reduction in the duration of colds. Furthermore, both Chalmers
1975 and Dykes 1975 placed considerable weight on the double-
blind, placebo-controlled trial carried out by Karlowski 1975a at
3Vitamin C for preventing and treating the common cold (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the National Institutes of Health (NIH), which concluded that a
statistically significant benefit of vitamin C supplementation was
simply explained by the placebo effect. However, it has been shown
that the placebo effect explanation in the Karlowski 1975a paper
was not consistent with their own data (Chalmers 1996;Hemilä
1996a;Hemilä 1996d;Hemilä 2006a;Hemilä 2006c).
Hemilä 1997b claimed that the highly cited reviews of Chalmers
1975 and Dykes 1975 and the trial by Karlowski 1975a quelled
interest in real, but modest effects of vitamin C on the common
cold after the mid-1970s. Hemilä 1997a pooled the results of the
six largest trials using 1 g/day of vitamin C found no effect on
the common cold incidence (pooled risk ratio (RR) 0.99; 95%
confidence interval (CI) 0.93 to 1.04), which refuted Pauling’s
proposal as to the prophylactic effect of gram-dose vitamin C for
the general population. However, four trials with UK males found
a moderate reduction in common cold incidence with vitamin C
(pooled RR 0.70; 95% CI 0.60 to 0.81), which was explained by
the particularly low dietary vitamin C intake in the UK rather than
high doses of supplements. Also, three trials with participants un-
der heavy acute physical stress found a reduction in the incidence
of colds with vitamin C (pooled RR 0.50; 95% CI 0.35 to 0.69)
(Hemilä 1996b). Thus, it is possible that vitamin C has an effect
on common cold incidence in restricted subpopulations.
Although regular vitamin C supplementation at doses of 1 g/day
has consistently decreased the duration or alleviated the symptoms
of the common cold, there was substantial heterogeneity in the
results (Hemilä 1994). A further meta-analysis found a trend for
trials with children to show greater benefit than trials with adults,
and another trend for trials with 2 g/day to show greater benefit
than trials with 1 g/day, suggesting dose-dependency (Hemilä
1999a).
How the intervention might work
Dozens of studies have found that vitamin C may affect, for ex-
ample, phagocytosis and chemotaxis of leucocytes, replication of
viruses, and production of interferon (Hemilä 2006a;Hemilä
1997c;Thomas 1978;Webb 2007). Vitamin C is an efficient
water-soluble antioxidant and the effects on the immune system
can be explained by the protection against oxidative stress gener-
ated during infections (Akaike 2001;Castro 2006;Hemilä 1992).
Phagocytes have a specific transport system by which the oxidised
form of vitamin C (dehydroascorbic acid) is imported into the
cells, where the reduced form of vitamin C is regenerated (Nualart
2003;Wang 1997). If the major role of vitamin C in the immune
system is that of a physiological antioxidant protecting various
host cells against oxidative stress during an infection, it could have
important effects in certain conditions even though the mech-
anisms are apparently non-specific. Furthermore, heavy physical
stress generates oxidative stress (Ji 1999) and the antioxidant role
of vitamin C can thus also explain its effects on respiratory symp-
toms in physically stressed people. Dozens of animal studies found
that vitamin C reduces the incidence and severity of bacterial and
viral infections indicating that the vitamin has physiological effects
on infections, and not just on laboratory measures of the immune
system (Hemilä 2006a).
For brief notes on the history of this Cochrane Review, see
Appendix 1. Links to the publications cited in this section,
for which full-text versions are available, can be found at
www.mv.helsinki.fi/home/hemila/CC/.
Why it is important to do this review
The common cold causes enormous morbidity worldwide and the
search for simple and effective preventive or therapeutic agents
has been elusive. Even if vitamin C might have modest effects
in restricted population groups, that could be important from a
public health point of view.
O B J E C T I V E S
To find out whether vitamin C reduces the incidence, the duration
or severity of the common cold when used either as a continuous
regular supplementation every day or as a therapy at the onset of
cold symptoms.
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included placebo-controlled trials. We did not restrict to ran-
domised controlled trials.
Types of participants
Trials of children and adults of either gender and any age were
considered eligible.
Types of interventions
The intervention considered was orally administered vitamin C
of at least 0.2 g daily for a single day or for a period. The limit of
0.2 g/day was selected as a choice of convenience. If a trial with
a lower dose finds a negative result, the negative findings can be
attributed to the low dose. Thus, trials with large doses are more
critical for testing Pauling’s proposal that gram doses of vitamin
C would reduce morbidity due to common cold infections. On
4Vitamin C for preventing and treating the common cold (Review)
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the other hand, under certain conditions vitamin C doses lower
than 0.2 g/day might have effects (see Discussion: Possible role of
marginal vitamin C deficiency). Thus, our selection criterion for
dose does not mean that all excluded trials are irrelevant to the
question of the effects of vitamin C. All trials that used a vitamin
C dose lower than 0.2 g/day are listed and briefly described in the
Characteristics of excluded studies table.
In a few instances the placebo included a low dose of vitamin C;
Carr 1981a used 70 mg/day and a few others used 50 mg/day or
less. This was done to ensure that participants were not ’vitamin
C deficient’, recognising that dietary intake of vitamin C is highly
variable. Thus, the goal of these investigators was to test the effects
of large doses for properly nourished participants.
We may include studies in which vitamin C has a co-intervention
if the control group has only the co-intervention so that the only
difference is vitamin C administration.
Types of outcome measures
Primary outcomes
1. ’Incidence’ of colds during regular supplementation was
assessed as the proportion of participants experiencing one or
more colds during the study period.
2. ’Duration’ was the mean number of days of illness of cold
episodes.
Secondary outcomes
1. ’Severity’ of these episodes was assessed in two ways: a) days
confined indoors, or off work or off school per episode and b)
symptom severity scores.
2. ’Evidence of possible medication side effects’ was available
from seven large regular supplementation studies, with the
number of participants reporting possible medication side effects
in the intervention and control groups.
Search methods for identification of studies
Electronic searches
For this 2012 update we searched the Cochrane Central Reg-
ister of Controlled Trials (CENTRAL) 2012, Issue 11, part of
The Cochrane Library, thecochranelibrary (accessed 29 May 2012),
which contains the Acute Respiratory Infections Group’s Spe-
cialised Register, MEDLINE (January 2010 to November week 3,
2012), Embase.com (January 2010to November 2012), CINAHL
(January 2010 to November 2012), LILACS (January 2010 to
November 2012) and Web of Science (January 2010 to November
2012). See Appendix 1 for details of previous searches.
We used the following search strategy to search CENTRAL and
MEDLINE. The search strategy was adapted to search EMBASE
(Appendix 2), CINAHL (Appendix 3), LILACS (Appendix 4) and
Web of Science (Appendix 5).
MEDLINE (OVID)
1 Common Cold/
2 common cold*.tw.
3 Rhinovirus/
4 rhinovir*.tw.
5 coryza.tw.
6 “acute rhinitis”.tw.
7 ((viral or virus*) adj2 rhinit*).tw.
8 or/1-7
9 exp Ascorbic Acid/
10 ascorb*.tw,nm.
11 (vitamin* adj5 c).tw.
12 or/9-11
13 8 and 12
There were no language or publication type restrictions in the
literature searches.
Searching other resources
The review authors screened the reference lists incorporated in two
systematic reviews of the literature published by Briggs 1984 and
Kleijnen 1989 (for the search strategy of the latter, see Kleijnen
1992) and the references in all identified studies. Furthermore, one
of the review authors (HH) has a research involvement spanning
three decades in this topic and has assembled a personal reference
list of papers published in the grey literature or listed in indexing
services that preceded electronic searching.
We also searched the U.S. National Institutes of Health trials reg-
ister www.clinicaltrials.gov and the WHO ICTRP www.who.int/
ictrp on 29 May 2012 (see Appendix 6 for search details).
Data collection and analysis
Selection of studies
For the 2004 version of this review, HH and Bob Douglas (BD)
searched the literature and independently assessed the titles and ab-
stracts to identify potentially relevant articles (Appendix 1). They
obtained and scrutinised full versions of all potentially eligible ar-
ticles. When they disagreed on the relevance of an article, they
discussed it until they reached a consensus. For the 2007 and 2009
updates, the first review author (HH) searched the literature and
assessed the titles and abstracts to identify potentially relevant arti-
cles. For the 2012 update, two review authors (HH, EC) searched
5Vitamin C for preventing and treating the common cold (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the literature and assessed titles and abstracts to identify poten-
tially relevant articles.
Data extraction and management
For the 2004 version of this review, two review authors (HH,
BD) independently extracted pertinent data from the articles se-
lected and entered data into the Review Manager program (see
Appendix 1) (Douglas 2004;RevMan 2011). They sought con-
sensus when they differed in the interpretation of study findings.
Only one new trial satisfying the selection criteria (Constantini
2011a;Constantini 2011b) has been published since the preced-
ing version of this review (Hemilä 2010) and it was included in
this 2012 update.
Assessment of risk of bias in included studies
Most of the included trials were double-blind. Double-blind
means that the participant and others directly involved in treat-
ment do not know to which treatment group the participant has
been allocated, i.e. there must be allocation concealment. Double-
blind also means that there must be blinding of participants and
personnel. Finally, since the outcomes were recorded by person-
nel or the participant, double-blinding also implies that there is
blinding of outcome assessment.
Studies are classified as randomised on the basis of the study re-
ports, but only a few studies described the actual method of ran-
domisation.
Chalmers 1975 proposed that the benefits of vitamin C supple-
mentation on the common cold might be caused by “the result of
the power of suggestion.” His proposal was based on the Karlowski
1975a trial, in which placebo consisted of lactose which is sweet
and differs by taste from ascorbic acid which was used in the vi-
tamin C capsules. Therefore, we collected data on the reported
indistinguishability of vitamin C and placebo preparations.
When the methodological description was unambiguous, one re-
view author (HH) entered the methodological description to the
’Risk of bias’ tables in Characteristics of included studies. When
the description of methods was ambiguous, HH discussed the is-
sue with the co-author (EC) to reach a consensus. The overall risk
of bias is summarised in Figure 1.
6Vitamin C for preventing and treating the common cold (Review)
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Figure 1. Methodological quality summary: review authors’ judgements about each methodological quality
item for each included study.
7Vitamin C for preventing and treating the common cold (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Measures of treatment effect
For the community trials, we selected two primary outcomes
and one secondary outcome to compare vitamin C with placebo
groups, resulting in five tables.
Analysis 1.1: the measure of the treatment effect is the risk ratio
(RR) of ’incidence’ of colds in vitamin C and placebo groups.
Incidence is defined as the proportion of participants with at least
one cold during the study.
Analysis 2.1 and Analysis 4.1: the measure of treatment effect is
the mean difference (MD) in common cold ’duration’. Since dura-
tion of cold episodes varied appreciably across trials, we standard-
ised the mean values and standard deviations (SD) in each group
against the mean of the respective placebo group. In this way, the
placebo group of each trial gets a value of 100%, and therefore the
difference between the vitamin C and placebo group is the effect
of vitamin C in percentages.
Analysis 3.1 and Analysis 5.1: there are two measures of effect on
’severity’: a) the difference in the mean number of days that the
patient was absent from work or school or confined to bed; and b)
the difference in the mean symptom severity score derived from
patient kept records.
In analysing dichotomous data with only a few cases in the trial
groups, the mid-P value is the most appropriate method to cal-
culate the P values for the differences in the treatment groups
(Hemilä 2006a) and was used when comparing groups with small
numbers of cases. Two-tailed P values are used in this review.
Unit of analysis issues
In four of the trials (Anderson 1974a;Anderson 1975a;Audera
2001a;Karlowski 1975a) more than one vitamin C group was
compared with a single placebo group. Where multiple active arms
were analysed in the same meta-analysis, the vitamin C arms were
combined as one entry which appears in the figures, identified as
the lowest lettered trial that the entry contained.
Miller 1977a and Carr 1981a studied twins and the comparison
is paired. The SD values used in this meta-analysis are calculated
from the SE and P values, respectively, of reported paired tests, so
the two trials get proper weight in pooling.
Dealing with missing data
Some trials presented the mean duration or severity of colds, but
not the respective SD. In some trials the P value for the difference
of interest was reported and the SD was calculated from it. In
the Anderson 1972,Anderson 1974a and Anderson 1975a trials,
Fieller’s theorem was used to estimate the SD for individual com-
mon cold episodes from the SD values presented in papers that
were based on a per person experience. In the other trials with
missing SD, we estimated SD as identical with the mean of the
treatment group. This is based on our analysis that for trials report-
ing the SD, the ratio of SD to mean is on average 0.7 so that our
ratio of 1.0 used in the SD imputation is somewhat conservative.
The consequence of this is that we are putting slightly reduced
weight in our estimates of effect on these trials with missing SD
values, compared to the average.
Assessment of heterogeneity
We assessed heterogeneity using the Chi2test and the I2statistic
(Higgins 2003;Higgins 2011). The Chi2test is known to be poor
at detecting true heterogeneity among studies. While a statistically
significant result indicates heterogeneity, a non-significant result
is not evidence of no heterogeneity. The I2statistic examines the
percentage of total variation across studies that is due to hetero-
geneity rather than chance. A value of about 50% for I2indicates
a moderate level of heterogeneity.
Data synthesis
We used the Review Manager (RevMan 2011) software to pool the
results of the three outcomes of the included trials. A pooled fixed-
effect RR of the probability of experiencing at least one cold while
taking vitamin C was computed for ‘incidence’. We computed a
pooled fixed-effect MD in common cold ‘duration’ to derive an
estimate of the percentage of days of illness by which vitamin C
reduced the average common cold.
We considered separately two different approaches to the assess-
ment of severity in the meta-analysis by treating the two measures
of severity as separate subgroups. We computed a standardised
mean difference (SMD) for the two subgroups and for all the tri-
als for which severity data were available. The SMD calculation
method leads to quantitative results but the estimates do not have
any relevant clinical interpretation. Rather the primary statistical
result of the SMD method is the P value for the combined set.
Subgroup analysis and investigation of heterogeneity
We considered three factors as possible explanations for hetero-
geneity observed across the results of these trials. These were vita-
min C dosage, age of the participants (children and adults), and
the presence or absence of heavy, short-term physical stress.
Sensitivity analysis
8Vitamin C for preventing and treating the common cold (Review)
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We undertook sensitivity analyses in Analysis 1.1 and Analysis 2.1
to test the robustness of our conclusions regarding the method-
ological quality of the trials, in which we excluded all studies which
were not randomised and double-blind.
In seven trials in Analysis 2.1 (’Duration of colds in regular sup-
plementation trials’) we imputed the SD values assuming that SD
is equal to the mean of the group (Briggs 1984;Coulehan 1974a;
Coulehan 1974b;Coulehan 1976;Peters1996a;Peters1996b;Pitt
1979). When we excluded these seven trials in a sensitivity anal-
ysis of Analysis 2.1, the pooled results indicated a slightly greater
effect of vitamin C: for adults 8.6% (4% to 13%); for children
14.6% (7% to 22%). Thus, inclusion of the trials with imputed
SD values does not lead to an increase in the estimate of benefit,
but leads to a slight reduction in the calculated benefit.
We also tested whether the exclusion of the Anderson 1974a trial
might affect the estimates of Analysis 1.1 and Analysis 2.1. That
trial had two placebo groups and we selected for our comparisons
the placebo group #4 which was close to the vitamin C groups on
the basis of baseline data (see Hemilä 2006a and Results section
4). Exclusion of the Anderson 1974a trial had minimal effects on
the pooled estimates (not shown).
R E S U L T S
Description of studies
See: Characteristics of included studies;Characteristics of excluded
studies.
Results of the search
The 2012 MEDLINE (Ovid) search identified 17 results, EM-
BASE 58, CENTRAL 6, CINAHL 20, LILACS 0, Web of Sci-
ence 13, Clinicaltrials.gov 3 and WHO Trials Register (ICTRP)
1 search results. With duplicates removed there were 90 search re-
sults. One new trial satisfying our inclusion criteria was identified
in the 2012 search (Constantini 2011a) and two new trials were
added to the excluded trials list (Maggini 2012;Schmidt 2011).
Included studies
Sixty-three separate comparisons of vitamin C against placebo,
reported in 44 publications, met our selection criteria. Eleven of
these publications presented the results of two to six different study
comparisons. Included in the selected papers are the four trials
identified originally by Pauling 1971a to justify his proposals for
mega-dose regular supplementation and therapy (Cowan 1942;
Franz 1956;Ritzel 1961;Wilson 1969). We have used the Wilson
1973a final report of his boarding school trials rather than the
preliminary communication which Pauling 1971a had available
to him.
In Anderson 1974a,Anderson 1975a,Audera 2001a and
Karlowski 1975a more than one active arm is compared with a
single placebo arm. This explains why the total number of partic-
ipants is less in the placebo groups than in the vitamin C groups.
The 63 included trials which have contributed data to this review
fall into four groups.
1. Forty-three community regular supplementation trial arms
which evaluated the effects of regular daily supplementation with
vitamin C (i.e. vitamin C each day over the study irrespective of
the presence of colds) on reducing the incidence or duration or
severity of naturally occurring colds.
2. Ten community therapeutic trial arms that evaluated the
therapeutic effects of high-dosage vitamin C after natural
common cold symptoms had commenced.
3. Seven community trials did not report data suitable for our
meta-analysis and these trials are presented qualitatively.
4. Three laboratory trials (Dick 1990;Schwartz 1973;Walker
1967) in which volunteers were intentionally exposed to known
viruses after vitamin C or placebo administration. As they are
qualitatively different from the community-based trials on
natural common cold infections, they are not included in the
meta-analyses but are presented qualitatively.
Brief details of the circumstances, dosage and quality assessment
of the trials are available in the Characteristics of included studies
table. Links to the trial reports and translations can be found at
www.mv.helsinki.fi/home/hemila/CC/.
Excluded studies
We excluded 25 studies. The major reasons for exclusion were the
lack of placebo control (12 trials) and vitamin C dose < 0.2 g/day
(seven trials). For details, please see the Characteristics of excluded
studies table.
Risk of bias in included studies
Allocation
Most of the identified trials were randomised controlled trials
(RCTs) (Figure 1). Most of the studies also had allocation con-
cealment (Figure 1).
Blinding
Most of the identified trials blinded participants and personnel
and the outcome was assessed by either of the two so that the
outcome assessment was also blinded (Figure 1).
9Vitamin C for preventing and treating the common cold (Review)
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Incomplete outcome data
In many trials there were no drop-outs, and in those trials in which
there were, the number of drop-outs was not substantially different
between the study groups.
Selective reporting
When there are one or a few trials with a positive finding on a
poorly justified outcome, the possibility of publication bias is an
important concern. In our review we have two large groups of tri-
als with the same well-justified primary outcomes: incidence and
duration of colds (Analysis 1.1 and Analysis 2.1). We do not see
any basis to speculate that the consistency in these two outcomes
could be explained by selective reporting. There is no unambigu-
ous definition for severity which we classify as a secondary out-
come, and there might be more problems with selective reporting
on that outcome (Analysis 3.1). However, severity has a lower pri-
ority in our review and the findings are consistent with the effect
on duration (Analysis 2.1).
Other potential sources of bias
The great majority of the trials reported that vitamin C tablets
(usually ascorbic acid) and placebo tablets (usually citric acid) were
indistinguishable (Figure 1 and Characteristics of included studies
table). Thus there is no basis to assume that difference in taste or
appearance between the tablets could have generated substantial
bias in the trials.
Effects of interventions
1. Community regular supplementation trials:
incidence of colds
Analysis 1.1 (Figure 2) presents the meta-analysis of the risk ratio
of at least one cold developing for a participant while on regular
vitamin C supplementation. Regular supplementation means that
vitamin C was administered each day over the study period. The
entry in the meta-analysis for Anderson 1974a represents four
separate trial arms (Anderson 1974a;Anderson 1974b;Anderson
1974c;Anderson 1974d) in which different vitamin C dosages
ranging from 0.25 to 2 g/day were compared with one placebo
group. Thus the 29 entries in Figure 2 represent 32 vitamin C
arms in trials.
10Vitamin C for preventing and treating the common cold (Review)
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Figure 2. Forest plot of comparison: 1 Incidence of colds while taking 0.2 g/day vitamin C regularly,
outcome: 1.1 Proportion of participants developing 1 cold episodes during the trial
11Vitamin C for preventing and treating the common cold (Review)
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The 29 entries represent 11,306 participants, of whom 6105 used
vitamin C for periods ranging from two weeks to five years. The
pooled risk ratio (RR) for all trials was 0.95 (95% confidence in-
terval (CI) 0.92 to 0.98). Although the overall difference between
vitamin C and placebo participants is statistically highly signifi-
cant (P = 0.001), indicating a biological effect of vitamin C, the
narrow CI precludes any clinically relevant effect over wide pop-
ulation groups.
Heterogeneity of results
Among all the studies included in Analysis 1.1 there is substantial
heterogeneity, as indicated by the Chi2test (P = 0.02) and the
rather high I2statistic (38%). Heterogeneity refutes the notion
that vitamin C is universally equivalent to placebo.
Five of the 29 comparisons recorded statistically significant (P <
0.05) protection favouring the vitamin C group: Peters 1996a (RR
0.39), Peters 1993a (RR 0.50), Ritzel 1961 (RR 0.55), Charleston
1972 (RR 0.77) and Anderson 1972 (RR 0.91). Four other trials
recorded a non-significant RR < 0.80 (Moolla 1996a;Moolla
1996b;Peters 1996b;Sabiston 1974). None of the 29 comparisons
significantly favoured the placebo.
Of the eight relatively small trials with RR < 0.8, three were with
marathon runners (Moolla 1996a;Peters 1993a;Peters 1996a),
two with sedentary controls for marathon runners (Moolla 1996b;
Peters 1996b), one with students in a skiing school in the Swiss
Alps (Ritzel 1961), one with Canadian army troops on subarctic
operations (Sabiston 1974), and one with staff and students at
Glasgow University, UK (Charleston 1972).
The bottom of Analysis 1.1 shows a subgroup of five studies which
involved marathon runners, skiers and Canadian soldiers in a sub-
arctic exercise. Division of the 29 trials to the two subgroups re-
sulted in two distinct groups of trials which were significantly dif-
ferent from each other in their pooled estimates of effect. Fur-
thermore, the two subgroups were homogeneous within the two
pools, as indicated by the high P values in the Chi2test, and the
zero values for the I2statistic.
Subgroups: general community trials and heavy acute
physical stress trials
Based on 24 entries with 10,708 participants from the general
community who had no heavy short-term physical stress, the nar-
row CI, which is located close to the zero effect, refutes the pos-
sibility that regular vitamin C supplementation could reduce the
average incidence of colds in the general community: RR 0.97
(95% CI 0.94 to 1.00) (Analysis 1.1;Figure 2).
When the general community meta-analysis was restricted to 17
entries with vitamin C dose 1 g/day, the prophylactic benefit of
vitamin C supplementation was also refuted (RR 0.98; 95% CI
0.95 to 1.01; based on 6661 participants).
In the Karlowski 1975a trial, the dose of vitaminC was the highest,
3 g/day. This study is not included in Analysis 1.1 because the
number of participants who caught a cold during the trial was not
reported; instead the total number of cold episodes per group was
reported. Nevertheless, 3 g/day vitamin C had no effect on the
number of common cold episodes, with RR 0.93 (95% CI 0.73
to 1.20) (Hemilä 1997a).
In five trials with participants undergoing heavy acute physical
activity in the subgroup at the bottom of Analysis 1.1, vitamin
C halved the incidence of colds: RR 0.48 (95% CI 0.35 to 0.64)
(Figure 2, Analysis 1.1.2). All of these five studies were randomised
and double-blind. In three of these studies, the vitamin C dose
was less than 1 g/day so that the benefit in this subgroup cannot
explained by particularly high vitamin C doses, but by the extraor-
dinary conditions of the participants.
Two trials had participants exposed to long-term physical stress.
Pitt 1979 examined 674 US marine recruits for two months and
Constantini 2011a studied 39 competitive young swimmers for
three months. Neither of these trials found effect of vitamin C on
common cold incidence.
To test the effect of study quality onth e findings in Analysis 1.1, we
undertook a sensitivity analysis in which we removed five trials that
were either not randomised or not double-blind from the general
community meta-analyses and this had no effect on the estimate
(RR 0.98; 95% CI 0.94 to 1.01). All trials with participants under
heavy acute physical stress were randomised and double-blind.
Thus, the effect of study quality as assessed by randomisation and
double-blinding did not change the estimatesof the two subgroups
of Figure 2.
2. Community regular supplementation trials:
duration of colds
Analysis 2.1 (Figure 3) presents the effect of vitamin C on the du-
ration of colds which occurred while participants were taking vi-
tamin C regularly, each day over the study. These trials are divided
into two subgroups: adults and children. The division into child
and adult trials was carried out for two reasons: a) children have a
substantially higher incidence of colds reflecting differences in the
immune system maturity, and b) children are on average smaller
so that a fixed dose corresponds to a greater dose per weight.
12Vitamin C for preventing and treating the common cold (Review)
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Figure 3. Forest plot of comparison: 2 Duration of the colds occurring when on regular 0.2 g/day vitamin
C, outcome: 2.1 Duration of common cold symptoms (placebo group duration 100%)
13Vitamin C for preventing and treating the common cold (Review)
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For adults there were 17 entries representing 21 trial arms (four
separate trial arms in Anderson 1974a and two in Karlowski
1975a) and 7215 episodes of illness, and for children there were
14 trial comparisons including 2530 episodes of illness.
A consistent benefit was seen in the duration of colds. For chil-
dren, the pooled effect was a 14.2% (7.3% to 21%) reduction
in common cold duration, and for adults the pooled effect was a
7.7% (3.7% to 12%) reduction in cold duration. The Chi2test for
trial heterogeneity was not significant in either of the subgroups.
In five of the 31 comparisons (Carr 1981b;Constantini 2011a;
Charleston 1972;Ludvigsson 1977a;Ritzel 1961) the effect of
vitamin C was statistically significant within the trial. In the
Constantini 2011a trial, common cold duration was significantly
shorter in male swimmers, but not in female swimmers, there be-
ing a statistically significant interaction between vitamin C effect
and sex.
Five comparisons (Carr 1981a;Constantini 2011b;Peters 1993a;
Peters 1996b;Wilson 1973b) recorded a point estimate favouring
the placebo. Wilson 1973b used only 0.2 g/day vitamin C, which is
the smallest dose in the analysis. Carr 1981a examined twins living
together, whereas the Carr 1981b trial examined twins living apart;
it is possible that the substantially divergent result in these twin
groups is related to the living conditions - those living together
might have exchanged or confused their tablets. The Peters 1996b
trial was very small and the CI is very wide.
The great majority of the trials in Analysis 2.1 used 1 g/day of vi-
tamin C and therefore a systematic examination of possible dose-
dependency across the trials was not feasible. In the child sub-
group, we used sensitivity analysis to test the possibility that low-
dose vitamin C trials might dilute the pooled estimate. When we
removed the trials using < 1 g/day of vitamin C (Miller 1977b;
Miller 1977c;Wilson 1973a;Wilson 1973b), the pooled estimate
of benefit was increased to a 18.1% (9% to 27%) reduction in the
duration of colds in children suggesting that the 14.2% estimate
for all studies of children may be biased downwards because low-
dose trials are included. In the adult subgroup, the estimate of ef-
fect was essentially unchanged, 8.0% (3.8% to 12%), when the < 1
g/day vitamin C trials were removed (Peters 1993a;Peters 1993b;
Peters 1996a;Peters 1996b); these are small trials with doses of
0.5 to 0.6 g/day.
In sensitivity analyses, we removed the studies which were not ran-
domised and double-blind. Exclusion of two trials from the adult
subgroup had no material effect on the estimated benefit of 7%
(3% to 11%), and exclusion of two trials from the child subgroup
similarly had no substantial effect on the estimated benefit of 14%
(7% to 21%). Thus, excluding four trials with lower quality had
no effect on the conclusions of Figure 3.
In summary, this meta-analysis of the duration of colds occurring
while participants were on regular vitamin C supplementation
demonstrated a statistically highly significant, but modest, benefit
to the vitamin C supplemented participants which was greater in
children than in adults.
3. Community regular supplementation trials:
severity of colds
Analysis 3.1 presents the effect of vitamin C on the severity of
common cold episodes occurring during regular vitamin C sup-
plementation. Two measures of the severity of the common cold
were available.
Subgroup 1 in Analysis 3.1 consists of seven entries of 10 vitamin
C study arms in which severity was measured by ’days confined
to home’ or ’days off work or school’. This included 5066 com-
mon cold episodes in adults and children. The large-scale trials
by Anderson 1972 and Ludvigsson 1977b reported statistically
significant reductions in ’days confined to house per episode’ with
vitamin C supplementation. Subgroup 1 found a quantitatively
modest, but statistically highly significant reduction in common
cold severity. This subgroup exhibited significant heterogeneity
between the studies as measured by the Chi2test and I2statistic.
Subgroup 2 in Analysis 3.1 presents the results of symptom sever-
ity scores in nine trials with 2143 episodes. The large-scale trial
by Pitt 1979 found a statistically significant, but small, 5% reduc-
tion in the severity score. There is a statistically highly significant
reduction in common cold severity also in subgroup 2. There is
no heterogeneity in this subgroup.
The measures of ’severity’ that have been used in the included
trials are variable. We calculated the standardised mean difference
(SMD) which normalises the difference between the vitamin C
and placebo groups to the units of standard deviations. Therefore
the pooled results of Analysis 3.1 are not practically useful, rather
the significance level is of main importance in this analysis; P =
0.0004 for the studies that assessed days confined to home or off
work or school, and P = 0.002 for studies which used severity
scores, and P < 0.00001 when the two subgroups were combined.
Although the benefit with respect to days confined to home or
off work or off school is statistically significant, it is modest in
absolute terms.
4. Community therapeutic studies: duration of colds
when treatment commenced after common cold
symptoms began
Analysis 4.1 presents the findings of therapeutic trials, which
means that vitamin C administration was started after the cold
symptoms occurred. This meta-analysis contains seven entries that
incorporate data from 10 different trial arms involving 3249 cold
episodes where participants initiated supplementation at the onset
of cold symptoms. Audera 2001a,Anderson 1974e and Anderson
1975a contain two vitamin C arms.
14Vitamin C for preventing and treating the common cold (Review)
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The pooled result for these therapeutic trials did not exhibit a dif-
ference of vitamin C from placebo in the variety of therapeutic
protocols that were used. The large trial by Anderson 1974e found
a statistically significant but modest benefit but this was counter-
balanced by the negative results in the other trials.
The Anderson 1974e entry combines two arms with different
dosages. Anderson 1974e administered 4 g/day and Anderson
1974f administered 8 g/day on the first day of illness only. The
mean duration of illness episodes for those in the 4 g/day arm
was 3.17 days, while that for 8 g/day arm was 2.86 days com-
pared with the duration in the placebo group #4 of 3.52 days.
However, this trial was bedeviled by the fact that the investigators
originally intended to compare results with two separate placebo
groups. One of the two placebo groups (#6) had statistically sig-
nificant baseline differences when compared with the six vitamin
C groups. The comparisons presented here are with the placebo
group #4 that was close to the vitamin C groups with respect to th e
baseline data (see Hemilä 2006a). If comparisons had been made
with the placebo group #6 or a combination of the two placebo
groups as the investigators had originally intended, the benefits
would have been minimised as the mean episode duration for the
placebo group #4 was 3.52 days, and for placebo group #6 was
2.83 days. Neverthel ess, notwithstanding the placebo group pr ob-
lem, the proportion of ’short colds’, that lasted for only a single
day was significantly larger in the 8 g/day group (46%; 222 out
of 483) compared with the 4 g/day group (39%; 164 out of 417)
(P = 0.046), consistent with a greater benefit with the higher dose
compared with the lower dose.
Tyrrell 1977,Elwood 1977 and Audera 2001a failed to show an
effect on duration. Tyrrell evaluated males and females separately
using a dosage of 4 g/day for the first 2.5 days of illness (total 10
g), Elwood evaluated males and females separately using a dosage
of 3 g/day for the first 3.3 days of illness (total 10 g), and Audera
evaluated 1 and 3 g/day over the first 3 days (total 3 g and 9 g).
In summary, the therapeutic trials do not provide consistent evi-
dence that the duration of colds could be reduced with the proto-
cols that have been tested in the vitamin C trials. The benefit from
the use of an 8 g single dose immediately after the onset of cold
symptoms is interesting but indicates the need for further research
rather than implying practical conclusions.
5. Community therapeutic studies: severity of cold
episodes when treatment commenced after common
cold symptoms began
Analysis 5.1 has four entries which represent seven trial arms
that included 2708 separate common cold episodes for which
cold severity was assessed. Audera 2001a,Anderson 1974e and
Anderson 1975a contain two vitamin C arms.
As with the regular supplementation studies, weseparated the mea-
sures of severity into two subgroups: a) days confined to home, off
work or school, and b) symptom severity scores, and we analysed
these subgroups separately and together.
In subgroup 1, the only comparison which found a significant
benefit to those taking vitamin C was that for Anderson 1975a.
In that study, participants took 1.5 g/day for the first day of the
common cold and 1 g/day for the following four days (total 5.5 g).
Anderson 1974e and Tyrrell 1977 found no meaningful difference
between vitamin C and placebo. The pooled effect for subgroup
1 shows a marginally significant benefit of vitamin C.
The only trial in subgroup 2, Audera 2001a, found no difference
between vitamin C and placebo.
6. Community trials with no data suitable for our
meta-analyses
Table 1 shows the findings in seven trials which did not report
suitable data for our meta-analysis. Two of them were regular sup-
plementation trials and five were therapeutic trials. All these are
placebo-controlled trials which used 0.2 g/day of vitamin C.
The main findings of these trials are described in Table 1.
In two therapeutic trials the authors claimed to be able to identify
the vitamin C and placebo participants from the clinical progress
of the patients (Asfora 1977;Regnier 1968). One therapeutic trial
found a marginally significant effect on the duration of “nose
colds” (Brown 1945), and two therapeutic trials reported no dif-
ference between vitamin C and placebo (Abbott 1968;Tebrock
1956).
In a regular supplementation trial, Elliot 1973 found a significant
effect of vitamin C on the morbidity for sore throats and produc-
tive coughs, but the study was carried out in a Polaris submarine
so that the conditions were special. Scheunert 1949 reported less
respiratory morbidity in persons administered higher doses of vi-
tamin C compared with lower doses, but the study is poorly re-
ported and methodologically unsatisfactory.
7. Laboratory trials with artificially infected
volunteers
Table 2 presents three laboratory trials which were volunteer trans-
mission studies.
Walker 1967 and Schwartz 1973 instilled virus into the noses of
volunteers who had been pre-treated with vitamin C or placebo.
Dick 1990 used a more natural mechanism for the transmission of
a rhinovirus: their experimental volunteers were housed for a week
and worked closely with other volunteers who had been previously
infected by nasal instillation of rhinovirus.
Dick 1990 found that fewer vitamin C treated volunteers became
infected and the cumulative symptom severity score and mucus
weights were significantly less (P = 0.03), but virus shedding was
similar in both groups. Schwartz 1973 found reduced common
cold severity in the vitamin C group (P < 0.02 at day 4), but no
effect on symptom duration, whereas Walker 1967 did not observe
any benefit to those who took vitamin C.
15Vitamin C for preventing and treating the common cold (Review)
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8. Adverse effects from high-dose vitamin C intake
Seven large trials recorded data on symptoms which participants
attributed to the medication they were using.
Over the trials, data were recorded for a total of 2490 recipients
who had used 1 g/day of vitamin C compared with 2066 who
took a placebo. Altogether 5.8% of the vitamin C recipients re-
ported adverse symptoms which they attributed to the medication
compared with 6.0% of those who were taking placebo (data not
shown). No serious symptoms were reported.
D I S C U S S I O N
Despite the variation in methodology and the substantial hetero-
geneity in results from this large number of trial results carried
out over a 70-year period, certain rather strong conclusions can be
drawn.
Common cold incidence
Trials within the general community
An earlier meta-analysis pooled the results of the six largest trials in
which 1 g/day of vitamin C had been administered regularly over
the study period and found no effect of vitamin C on the incidence
of colds with a narrow confidence interval (CI) (risk ratio (RR)
0.99; 95% CI 0.93 to 1.04) (Hemilä 1997a). This earlier meta-
analysis pooled the number of common cold episodes occurring
during the trial, whereas this Cochrane meta-analysis used the
number of participants catching at least one cold as the measure
of common cold incidence. Nevertheless, this second outcome
definition led to the same conclusion for the general community
trials.
When the subgroup of marathon runners, skiers and soldiers on
subarctic operations was excluded in this review (see below), there
was strong evidence that vitamin C supplementation has no effect
on the number of people who catch the common cold (RR 0.97;
95% CI 0.94 to 1.00). This estimate was based on trials in which
the vitamin C dose was 0.2 g/day. However, the negative finding
is not explained by the inclusion of a few trials in which vitamin C
dose was low. When restricting to trials in which the vitamin C dose
was 1 g/day, the estimate was essentially the same. Finally, the
general community trial with the largest dose, 3 g/day of vitamin
C, found no difference in the common cold incidence between the
vitamin C and placebo groups (Hemilä 1997a;Karlowski 1975a).
Trials with people under heavy acute physical stress
A previous meta-analysis identified three trials with participants
under severe acute physical stress, and the pooling of results found
that vitamin C supplementation halved the incidence of colds in
this group (Hemilä 1996b). Two later trials with marathon run-
ners (Moolla 1996a;Peters 1996a) are included in our Cochrane
Review and they have not changed the pooled estimate of effect:
RR 0.48; 95% CI 0.35 to 0.64. All five trials in this group involved
a brief exposure to high physical stress with or without cold stress.
The doses of vitamin C were not particularly high, being between
0.25 and 1.0 g/day. Thus, the benefit in this subgroup cannot be
explained by high vitamin C doses. Similar and higher doses in
the general community have not affected the incidence of colds
(see above).
Furthermore, in the general community the acute respiratory
symptoms usually have a viral cause, but itis not obvious that sim-
ilar symptoms occurring after heavy exercise are caused by a viral
infection because they can also result from exercise-induced bron-
choconstriction (EIB) symptoms caused by an injury to the air-
ways because of exceptional ventilatory exertion (Anderson 2008).
In three trials, vitamin C supplementation reduced the decrease in
pulmonary function associated with EIB (Hemilä 2009c). Thus
the common cold studies of physically stressed people might have
been measuring, at least in part, the effects of vitamin C on EIB
instead of viral infections. Nevertheless, although the aetiology of
symptoms is not clear in the physically stressed subgroup, the ben-
eficial effect of vitamin C on acute respiratory symptoms in this
subgroup is firm.
Two trials with two to three months physical stress on the partic-
ipants found no effect of vitamin C on common cold incidence
(Constantini 2011a;Pitt 1979). It is thus possible that vitamin C
has effects on short-term exposure to physical stress, but not on
long-term physical stress.
Possible role of marginal vitamin C deficiency
Hemilä 1997a has suggested that some of the early benefits of
vitamin C supplementation might be a explained by low dietary
vitamin C intakes in the UK when the studies were carried out
(Baird 1979;Bartley 1953;Glazebrook 1942). These trials were
ruled ineligible for this review because the doses were lower than
0.2 g/day. Low dietary vitamin C intake might also explain the
significant reduction in cold incidence in the Charleston 1972 UK
trial which is included in Analysis 1.1.
Four UK trials also found a reduction in the incidence of recurrent
colds during the study period in males (pooled RR 0.54; 95% CI
0.40 to 0.74) but not in females (Hemilä 1997a). Nevertheless,
a recent UK trial found a reduction in recurrent colds in a nine-
week trial in both sexes (RR 0.13; 95% CI 0.03 to 0.53) (Van
Straten 2002) (see Hemilä 2006a). The most impressive trial in
this UK group is the Baird 1979 study, which was a randomised,
double-blind, placebo-controlled trial, but was excluded from our
Cochrane Review because the vitamin C dose was only 0.08 g/day.
Thus, methodological weaknesses cannot explain the reduction
in common cold incidence in males and the highly significant
modification of vitamin C effect by sex (Hemilä 1997a;Hemilä
16Vitamin C for preventing and treating the common cold (Review)
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2008). Significant sex differences in the effect of vitamin C were
also found in a recent trial with competitive swimmers so that
vitamin C was effective for males but not for females (Constantini
2011a).
The large trial by Anderson 1972 found a statistically significant
but small reduction in common cold incidence (RR 0.91; 95%
CI 0.85 to 0.98). This trial was conducted during the winter in
Toronto, Canada, and participants were selected on the basis of
having had problems with colds during previous winters. A cold
Canadian winter might be a partial explanation for the benefit
if cold along with physical stress makes a prophylactic benefit
for vitamin C more likely. Furthermore, as regards the possible
interaction between vitamin C supplementation and the level of
dietary vitamin C intake, the Anderson 1972 trial is important
as it found that vitamin C supplementation reduced the ’total
days indoors’ by 48% among participants in the vitamin C group
who consumed < 3 oz of fruit juice (common dietary source of
vitamin C), whereas the reduction was only 22% among those
who consumed more juice. A similar modifying effect with fruit
juice was found in the therapeutic trial by Anderson 1975a (see
Hemilä 2006a).
Common cold duration and severity: regular
supplementation trials
Both in adults and in children, regular vitamin C supplementa-
tion resulted in a statistically highly significant reduction in the
duration of common cold episodes that occurred during the pro-
phylactic supplementation period. For adults the estimate of vi-
tamin C effect was 8% and for children it was 14%. However,
when restricting to children trials with 1 g/day of vitamin C,
the pooled estimate was an 18% decrease in the duration of colds.
Although the above findings point to a definite physiological effect
from regular vitamin C supplementation on common cold dura-
tion, the practical significance of these findings is not convincing.
It does not seem reasonable to ingest vitamin C regularly through-
out the year if the anticipated benefit is to slightly shorten the
duration of colds which occur for adults a few times per year and
for children half a dozen times per year. The above estimates are
not trivial, but instead of regular supplementation, it would seem
much more fruitful to consider the possible benefits of therapeutic
supplementation and carry out trials to test whether an equivalent
benefit might be achieved in children through appropriate thera-
peutic supplementation.
In light of the consistent effect of vitamin C on the duration of
colds, an obvious question is whether there might be dose depen-
dency, as suggested by a previous meta-analysis (Hemilä 1999a).
Across the available trials, there is more evidence for the difference
between children and adults than on the variation of vitamin C
effect by the dose used. Few trials have used more than 1 g/day of
vitamin C in the child and adult groups separately. Nevertheless,
Karlowski 1975a and Coulehan 1974a used two different doses
within the same trials, that is, with the same outcome definitions.
Coulehan found that for school children, 2 g/day caused about
twice the benefit of 1 g/day. Karlowski found that for adults, 6
g/day was associated with a double benefit compared with 3 g/
day and variance analysis showed that the linear trend over the 0
g/day, 3 g/day and 6 g/day doses was significant (Hemilä 1996a;
Hemilä 1999a). Although these findings do not establish dose de-
pendency, they support the examination of doses higher than 1 g/
day and comparing different doses.
Regular vitamin C administration also led to decrease in cold sever-
ity when measured as days indoors or daysoff work or school, and
when measured on severity score scales (Analysis 3.1).
As regards the severity of colds, the Pitt 1979 paper is of further
interest. This was a randomised, placebo-controlled, double-blind
trial with 674 marine recruits during an eight-week period using
2 g/day of vitamin C. There was no difference in common cold
incidence and only a 2% reduction in the duration of colds and a
5% reduction in cold severity (P = 0.023) for those in the vitamin
C group. However, eight recruits developed pneumonia as a sequel
to their colds and only one of these was in the vitamin C group
(P = 0.044, Hemilä 2004;Hemilä 2007). Thus, in addition to
the common cold, vitamin C might also affect other respiratory
infections either independently of colds, or as complications of
colds (Hemilä 1999b). A further important finding in the Pitt
1979 trial was that, although the vitamin C tablets were shown to
be indistinguishable from the placebo tablets, 6% (40 out of 674;
P = 0.013) of participants correctly inferred vitamin C or placebo
tablets on the basis of subjective observations, indicating that this
proportion of participants could identify vitamin C purely on the
basis of its physiological effects (Hemilä 2006a).
Common cold duration and severity:
therapeutic trials
Since the regular supplementation trials have unambiguously
shown that vitamin C affects the duration and severity of colds
without changing their incidence in the general population, it
would seem rational to administer vitamin C therapeutically, start-
ing immediately after the first symptoms. However, the therapeu-
tic trials have mostly been negative (Analysis 4.1;Analysis 5.1).
The pooled estimates for the duration and severity of colds do not
show any difference between vitamin C and placebo.
Technically the therapeutic trials are in several ways much more
complicated than regular supplementation trials. If the timing of
supplementation initiation, the duration of supplementation, or
the dosage, influence the size of the benefit, false negative findings
might result from inappropriate study protocols.
Cowan 1950 used a therapeutic dose of about 3 g/day in the
first two days of illness with no effect on common cold duration.
Elwood 1977,Tyrrell 1977 and Audera 2001a used a three-day
supplementation, and none of them found benefit of vitamin C
on common cold duration. However, in their therapeutic trial,
17Vitamin C for preventing and treating the common cold (Review)
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Tyrrell 1977 found a 40% reduction (P = 0.04) in the incidence of
recurrent colds in men during the trial suggesting a beneficial effect
in the way of protecting against new colds (Hemilä 1997a). A five-
day therapeutic trial by Anderson 1975a found a 25% reduction
in ’days spent indoors per subject’ because of illness (P = 0.05)
in the vitamin C group (1 to 1.5 g/day). Also, using a five-day
therapeutic supplementation of 3 g/day in a 2 x 2 factorial design
trial, Karlowski 1975c found that colds were 0.73 days shorter (P
= 0.10; Hemilä 1996a). The benefits in the five-day studies by
Anderson and Karlowski suggest that two to three days might be
too short a time for vitamin C to produce unambiguous benefits.
However, Abbott 1968 used up to two week supplementation, yet
found no therapeutic benefit of 3 g/day vitamin C. Nevertheless,
it seems clear that future therapeutic trials should not use short
supplementation, i.e. less than five days.
It is also possible that the rapidity of initiation of vitamin C sup-
plementation may have an impact on the effect. Asfora 1977 gave
the same participants either vitamin C (6 g/day for five days) or
other medications (aspirin, etc.) during different common cold
episodes, but not in a double-blinded design. When treatment
started within 24 hours of the onset of symptoms, the mean dura-
tion of vitamin C treated colds was 3.6 days, whereas the duration
was 6.9 days with the other medications (Hemilä 2006a). How-
ever, if vitamin C was initiated later than 24 hours following the
onset of symptoms, there was no meaningful difference between
the groups. Regnier 1968 concluded from his therapeutic study
that “the sooner the better” and “vitamin C administration is not
effective when started on thethird or fourth day or later in the viral
infection.” Anderson 1974f found a benefit from an 8 g vitamin
C dose compared with a 4 g dose when administered only on the
first day of illness, which is also consistent with the possibility that
rapid initiation with high doses might be essential.
In several therapeutic trials, tablets were given to participants to
be taken at home so they could start taking them as soon as they
experienced the first symptoms of what they anticipated would
be a cold (Anderson 1975a;Audera 2001a;Cowan 1950;Elwood
1977;Tyrrell 1977). In the Karlowski 1975c trial “if a cold devel-
oped, the volunteers were instructed to return to havetheir symp-
toms and clinical observations recorded and to receive supplemen-
tal study drug to be taken” and thus there was an unknown delay
between the onset of symptoms and the initiation of treatment.
Tebrock 1956 carried out their trial “on participants reporting
to several outpatient industrial clinics under the supervision of
the physicians conducting the study” indicating a delay between
symptom onset and treatment. In the briefly described Abbott
1968 trial, it seems that the tablets were administered by the doc-
tors taking part in the trial and the average time between symptom
onset and treatment initiation remains unknown. Consequently,
even though the time between symptom onset and treatment ini-
tiation may influence the benefit of vitamin C, the data on this
factor are limited.
The larger effect observed using 8 g compared with 4 g as a single
dose in the Anderson 1974f trial and the dose dependency in
the Karlowski 1975a trial (Hemilä 1996a;Hemilä 1999a;Hemilä
2006a) suggest that future therapeutic trials with adults should
use doses of at least 8 g/day. Similarly, the greater reported benefit
of 2 g/day than 1 g/day in the prophylactic Coulehan 1974a trial
suggests that therapeutic trials with children should use doses of
at least 2 g/day.
None of the therapeutic trials examined the effect of vitamin C on
children, although children have a substantially higher incidence
of the common cold. Furthermore, the effect of regular vitamin C
on the duration of colds has been substantially greater in children,
up to 18% reduction in duration by 1 g or 2 g/day, compared with
adults (8%), which also motivates therapeutic trials in particular
with children. Finally, although a tablet is a practical and the most
common form of administering vitamin C, it is worth noting that
administering vitamin C powder directly into the nose has also
been proposed (Gotzsche 1989).
Nevertheless, while the pooled results of our therapeutic trials do
not justify routine vitamin C supplementation for the average per-
son as a therapy for the common cold, the regular supplementa-
tion trials have shown unambiguously that vitamin C has a physi-
ological effect on the duration and severity of colds. Furthermore,
the results of controlled trials and the pooled results of trials apply
to the average of the groups. We expect different sizes of vitamin
C effects in different people, some having greater and some hav-
ing smaller benefits than the average. Thus, given that vitamin
C is safe and inexpensive, it does not seem unreasonable to test
the effect of vitamin C on an individual basis as a therapy for the
common cold soon after the onset of symptoms.
Trials with no data suitable for our meta-
analyses
Seven studies did not report data suitable for our meta-analyses
(Table 1). The findings in these trials were inconsistent. Although
these trials should not be ignored, they do not add substantially
to the findings of our meta-analyses discussed above.
Laboratory studies
Three experimental studies have examined the effect of vitamin
C on experimentally induced common cold infections (Table 2).
These trials which differed in their method of exposing volunteers
to the infecting virus, are instructive. The study by Dick 1990,
which has only been reported in conference proceedings, paid care-
ful attention to the severity of the colds experienced by those who
acquired them from fellow volunteers, who had been inoculated
with a known rhinovirus. They also found that in these more nat-
ural circumstances of acquiring the virus, fewer, but not signifi-
cantly fewer, volunteers on vitamin C developed cold symptoms
but demonstrated similar viral shedding to the placebo group. The
18Vitamin C for preventing and treating the common cold (Review)
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fragmentary descriptions of the Dick studies indicate a biologi-
cal effect of vitamin C on experimentally caused colds. Schwartz
1973 found a reduction in common cold severity in the vitamin
C group, also indicating a biological effect.
Findings in the excluded studies
Exclusion of a trial does not mean that the trial is necessarily un-
informative. For example, we used a limit of 0.2 g/day for vita-
min C as a pragmatic choice. If a trial with a lower dose finds a
negative result, the negative findings can be attributed to the low
dose. However, if a low dose does cause an effect, the effect may be
explained, for example, by a particularly low dietary intake level
(see above). Similarly, if a trial that has no placebo finds no differ-
ence between the intervention and control groups, it is not reason-
able to explain the lack of difference by the placebo effect. Finally,
since we were interested specifically in vitamin C, we excluded
multiple antioxidant trials from our meta-analyses. However, if a
multi-antioxidant formula has no effect on the common cold, it
seems justified to conclude that there is a lack of effect by each
constituent of the supplement (i.e. the finding is negative also for
vitamin C if it is one of the components). In contrast, if a multi-
antioxidant does have a beneficial effect, we cannot draw specific
conclusions since the effect can be caused by any single antioxi-
dant or the combination of several of them together. Therefore,
the excluded trials can yield meaningful information. We do not
summarise the findings of the excluded studies, but encourage the
reader to look at those trials themselves.
Heterogeneity in the effects of vitamin C
A major finding of Analysis 1.1 was statistically significant hetero-
geneity in the effect of vitamin C supplementation on common
cold incidence, indicating that vitamin C may influence common
cold in some particular conditions.
Furthermore, Anderson 1972 found about an 8% increase in the
proportion of participants who were ’not ill during the trial’, ’not
confined to the house’ and ’not off work’ in the vitamin C group.
Accordingly, about one participant in 12 benefited from vitamin
C supplementation in this particular setting (number needed to
treat to benefit (NNTB) 12; Hemilä 2006a). Participants in this
Canadian trial were asked not to enrol in the trial unless they nor-
mally experienced at least one cold in the wintertime and in this
respect the participants do not represent the average population.
Coulehan 1974a studied Navajo school children and found a 16%
higher proportion of children in the vitamin C group who were
’never ill on active surveillance’ by a medically trained clerk or
school nurse (NNTB 6; Hemilä 2006a). Thus, these two trials
indicate that some individual participants of the two studied pop-
ulations may have benefited, even though there is strong evidence
that regular vitamin C does not affect the average incidence of
colds in the general community (Figure 2).
In close parallel with vitamin C, lipid-soluble vitamin E is in-
teresting as these two antioxidants interact. Vitamin C reduces
the oxidised form of vitamin E under in vitro conditions (Hemilä
2006a) and modifies the vitamin E effect on mortality of older
males (Hemilä 2009b). Therefore heterogeneity in the vitamin E
effect on common cold incidence (Hemilä 2006b) and on pneu-
monia incidence (Hemilä 2011) is relevant when considering the
plausible heterogeneity of vitamin C effects on respiratory infec-
tions.
If the effects of vitamin C vary substantially between different
subpopulations, the heterogeneity of the effect means a need for a
careful consideration of goals when planning new trials. Assuming
heterogeneity,further trials should try to identify and characterise
the population groups or living conditions in which vitamin C
might be beneficial, rather than re-examining the effects on ordi-
nary Western people for whom the numerous trials already pub-
lished have not found any substantial overall benefits from daily
supplementation. Also, the notion that various factors may mod-
ify the effects of antioxidants is fundamentally important in re-
stricting broad generalisations from individual trials, irrespective
of whether the finding is positive or negative, and whether or not
the trial is large and carefully conducted.
Potential for bias in the common cold trials
Even though shortcomings in the design and conduct of trials can
lead to erroneous conclusions, a recent meta-analysis of 276 ran-
domised controlled trials found that double-blinding and alloca-
tion concealment, two quality measures that are frequently used
in meta-analyses, were not associated with treatment effects (Balk
2002). Furthermore, there is evidence that the importance of the
placebo effect has been substantially exaggerated (Hrobjartsson
2010).
Nevertheless, we consider that given the expected small effects of
vitamin C and the greatly subjective outcome definitions, only
placebo-controlled trials can yield information of adequate rigour
to meet the objectives of our review. Although we required only
placebo control as an inclusion criterion, essentially all of the trials
we identified were double-blind and randomised (Figure 1). Sen-
sitivity analyses showed that our conclusions were not affected by
the few trials that were methodologically less satisfactory.
Chalmers 1975 proposed that the effect of vitamin C on the com-
mon cold might be explained by “the result of the power of sug-
gestion.” As a support to this proposal he referred to the Karlowski
1975a trial in which the placebo was made of lactose which is
sweet and thus it could be distinguished by taste from ascorbic acid
which was used in vitamin C capsules. However, it was shown that
Karlowski’s findings cannot be logically explained by the break-
ing of the blind code (Hemilä 1996a;Hemilä 2006a). Further-
more, in the great majority of other trials, placebo has contained
19Vitamin C for preventing and treating the common cold (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
citric acid which cannot be distinguished from ascorbic acid by
taste and in most trials the indistinguishability of the vitamin C
and placebo preparations was explicitly stated (Figure 1). Thus,
Chalmers’ proposal is refuted by the indistinguishability of vita-
min C and placebo preparations in numerous double-blinded tri-
als.
Some aspects of this Cochrane Review were commented on re-
cently by two groups of commentators, to which Hemilä replied
(Shamseer 2008).
Safety of vitamin C
None of the vitamin C common cold trials that reported on adverse
effects found evidence that vitamin C might be harmful in doses
that were tested.
In general, vitamin C is considered safe in doses up to several
grams per day. Although there has been speculation about the
potential harm of large doses, it has been shown to be unfounded
(Dykes 1975;Hemilä 2006a). For example, while 0.01 g/day of
vitamin C protects against scurvy, in a recent pharmacokinetic
study participants were administered up to 100 g of vitamin C
intravenously within a few hours without any reported adverse
effects, indicating the safety of such a very large dose in healthy
people (Padayatty 2004).
Bee 1980 proposed 10 to 15 g/day for treating colds and Cathcart
1981 reported that he had orally administered over 30 g/day vita-
min C to common cold patients. Such reports indicate the safety
of such high doses, even though uncontrolled observations do not
provide valid evidence of benefit. There are few reports of severe
harm caused by high-dose vitamin C administration, but they can
usually be attributed to some other coinciding medical condition.
For example, the death of a 68-year old African American man
was not attributed to intravenous injection of 80 g of vitamin C
on two consecutive days per se but to his coincident glucose-6-
phosphate dehydrogenase deficiency (Campbell 1975).
Linus Pauling’s contribution
Among the four trials included in the Pauling 1971a meta-anal-
ysis, the largest dose, 1 g/day, was used by Ritzel 1961. Pauling
based his optimistic quantitative expectations on this rather small
and short trial, which was randomised, double-blind and placebo-
controlled. Ritzel found significant reduction in the incidence (-
45%) and duration (- 31%) of colds, and Pauling calculated a
combination of the duration and incidence, which he labelled ’in-
tegrated morbidity’, referring to the total sickness days per person
during the trial.
The ’integrated morbidity’ was reduced by 61% in the Ritzel trial,
and Pauling 1971a used this finding to extrapolate the effect of
vitamin C to a broader community. The present analysis suggests
that ’integrated morbidity’ is not a good outcome measure, since
the effects on incidence and duration/severity seem to have quite
different patterns, though in the case of the Ritzel study, they
moved together.
Ritzel carried out his trial with school children in a skiing school in
the Swiss Alps, and such children are not a representative selection
of the general population. In our analysis, Ritzel’s trial is included
in the group of five trials with participants exposed to short phys-
ical stress (Figure 2) which highlights the special character of this
trial. Thus, it was not a misjudgement by Pauling 1971a to put
the greatest weight on this trial, but his error was to extrapolate
the findings to the general population (Hemilä 1997b;Hemilä
2006a).
Pauling pointed out various errors in the influential review by
Dykes 1975, but did not contribute thereafter to the vitamin C
and common cold field (Pauling 1976b;Pauling 1976c).
Pauling’s vigorous advocacy was undoubtedly the stimulus for the
wave of methodologically good trials, which now enable us to
understand better the rather confusing role that vitamin C plays
in the defence against the common cold. Significant uncertainties
still persist, which further research should clarify.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
The lack of effect of regularly administered vitamin C on the inci-
dence of the common cold in the general population throws doubt
on the usefulness of this practice. In special circumstances, where
people are engaged in extreme physical exertion or exposed to sig-
nificant cold stress, or both, vitamin C supplementation seems to
have a beneficial prophylactic effect, but caution should be exer-
cised in generalising this finding.
The regular supplementation trials found that 0.2 g/day vitamin
C reduced common cold duration by 8% in adults and by 14%
in children, and 1 to 2 g/day vitamin C reduced common cold
duration by 18% in children. The practical relevance of these
findings is not clear. In our opinion, this level of benefit does
not justify long-term supplementation in its own right. So far,
therapeutic supplementation has not been shown to be effective.
Nevertheless, given the consistent effect of vitamin C on common
cold duration and severity in the regular supplementation studies,
and the low cost and safety, it may be worthwhile for common
cold patients to test on an individual basis whether therapeutic
vitamin C is beneficial for them.
Implications for research
It does not seem worthwhile to carry out further regular supple-
mentation trials in the general population. However, the findings
in marathon runners, skiers, swimmers and soldiers operating in
subarctic conditions warrant further research.
20Vitamin C for preventing and treating the common cold (Review)
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