Medical Hypotheses (1999) 52(2), 171-178© 1999 Harcourt Brace & Co. Ltd
Article No. mehy. 1997.0639

Vitamin C supplementation andcommon cold symptoms: factors
affecting the magnitude of thebenefit
H. Hemilä
Department of Public Health, University of Helsinki, Helsinki, Finland

Summary Placebo-controlled trials have shown that vitamin C supplementation decreases the duration and severityof common cold infections. However, the magnitude of the benefit has substantially varied, hampering conclusions
about the clinical significance of the vitamin. In this paper, 23 studies with regular vitamin C supplementation(>1 g/day) were analyzed to find out factors that may explain some part of the variation in the results. It was found thaton average, vitamin C produces greater benefit for children than for adults. The dose may also affect the magnitude of
the benefit, there being on average greater benefit from ≥2 g/day compared to 1 g/day of the vitamin. In five studies
with adults administered 1 g/day of vitamin C, the median decrease in cold duration was only 6%, whereas in two
studies with children administered 2 g/day the median decrease was four times higher, 26%. The trials analyzed in thiswork used regular vitamin C supplementation, but it is conceivable that therapeutic supplementation starting early atthe onset of the cold episode could produce comparable benefits. Since few trials have examined the effects oftherapeutic supplementation and their results have been variable, further therapeutic trials are required to examine therole of vitamin C in the treatment of colds.

INTRODUCTIONMETHODS

In placebo-controlled studies, regular vitamin C supplementation (≥1 g/day) has consistently decreased morbidity
due to the common cold (1-8). While the biochemicalbasis of this effect is not well understood, vitamin C does
have diverse effects on the immune system (3,5,9).
Since the magnitude of the benefit has varied substantially in the controlled trials, the clinical significanceof vitamin C in common cold therapy remains an open
question. The purpose of the present work was to investigate whether factors can be identified to explain somepart of the variation in the results of the controlled
trials. The particular questions addressed in the present
analysis were whether dose-dependency can be seen inhigh vitamin C doses, and whether the effect depends onthe characteristics of subjects.

Since the literature on vitamin C common cold studies
has previously been thoroughly surveyed (4,10,11), theolder literature was not searched anew. The previous
searches were extended by MEDLINE searches to identify
newer vitamin C-common cold trials. All placebocontrolled studies using regular vitamin C supplementation with ≥1 g/day of the vitamin were selected for thepresent quantitative analysis (12-31), and the results areshown in Table 1. Regular supplementation refers here
to initiating supplementation with healthy people andcontinuing over the occurring common cold episodes.
For a concise summary of the original results, see ref. 3.
The Anderson 1974 study (17) with adults is excluded
from Table 1, since there is evidence of biased distribution of subjects in the eight study groups (5,17). The
Carson 1975 study (20) with adults administered 1 g/day
is excluded, since the authors were interested solely inthe possibility of there being an effect on the incidenceof colds, and not on the severity of symptoms, so thatappropriate data are not available. The results of the
Karlowski 1975 study (22,32) were recently reanalyzed

Received 11 July 1997
Accepted 8 September 1997
Correspondence tor. Harri Hemilä, PhD, Department of Public Health,PO Box 41, University of Helsinki, Helsinki, FIN-00014 Finland.
Fax:+358919127570.

171

172 Hemilä

Notes: The mean Relative Effect and the mean dose were calculated using the number of episodes in the vitamin C group as the weight.
The differences in outcomes indicated by parentheses are not included in the calculations.
a
1 g/day of D-isoascorbic acid;b
Single-blind study (all the other studies in the table are double-blind studies);c
At the onset of a cold episode an additional 3 g/day was given for 3-5 days; in the present analysis, 4 and 6 g/day are regarded as thedoses corresponding to the observed effects.
dInduced rhinovirus infection;eSeverity of symptoms on the 4th day of infection;f
Twins living togetherg
Twins living apart;hConstitutional symptoms: headache, chills and fever, general malaise, nausea or vomiting;i
The explicit number of colds was not reported; the number of subjects in the vitamin C group is 37.
Medical Hypotheses (1999) 52(2), 171-178© 1999 Harcourt Brace & Co. Ltd

Vitamin C supplementation and the common cold 173

Notes: c indicates the contrast used in the calculation of the linear trend. Variance (Var) was calculated from thestandard error (SE) and the number of episodes (32). Group 1 was administered vitamin C for 5 days during colds,
whereas group 2 was administered vitamin C each day during the study. Group 3 received vitamin C both ways.

(7), and the linear trend in their results has been analyzed
in this work (Table 2) with the analysis of variance (34).
All the studies with children used schoolchildren as
subjects. The total number of subjects in the studies
in Table 1 was over 6100. All studies except one (14) weredouble-blind. Some of the placebo groups were given
10–70mg/day of vitamin C to ensure that the effectsof the larger dose were not due to the alleviation of atrue dietary deficiency (25,26,28,30). The Relative Effecton the severity of common cold episodes in the vitamin C
groups relative to the placebo groups was calculated foreach study as the difference between the outcomes inthe vitamin C and placebo group divided by the outcomein the placebo group (Table 1). Pooled confidence intervals for the four groups were not calculated since inseveral studies standard error and standard deviation
were not reported. The discussion of therapeutic trials
is also restricted to studies that employed ≥1 g/day ofvitamin C (22,35-40).
THE COMMON COLD STUDIES

To estimate the magnitude of the benefit of vitamin C
supplementation on common cold symptoms, all placebocontrolled trials with regular supplementation (≥1 g/day)were searched. The Relative Effect of vitamin C on theseverity of cold episodes for each outcome was calculated(Table 1). In some studies, 2-3 outcome parameters were
measured to quantify the duration or severity of episodes,
the results on different parameters occasionally differing
considerably. For the present analysis, we selected theoutcome seemingly most important for the patient, suchas days of absence from work or school, or days in bed,
© 1999 Harcourt Brace & Co. Ltd

when several parameters were measured in the study.
Nevertheless, in such cases the effect on the durationof symptoms is still shown in parenthesis in Table 1.
In order to analyze the dose-dependency of vitamin C
intake, the trials were divided into those using 1 g/day
and those using ≥2 g/day. Furthermore, as the weight
and/or age of the subjects can modify the effect of a fixed
dose, the studies with children were concurrently separated from the studies with adults (Table 1). Finally,
because three of the adult trials used military recruits
who are highly atypical representatives of the generaladult population, these three trials were segregated fromthe other adult studies (Table 1).
The mean Relative Effect was calculated for the fourgroups of trials in Table 1, excluding the soldier trials,
using the number of episodes in the vitamin C group as
the weight, thereby giving more precise results greater
weight in calculating the mean (Table 1). The resultant
mean Relative Effect values have been plotted in Figure 1
as a function of vitamin C dose. Assuming that the mean
Relative Effect is a valid estimate for each of the fourgroups, the results suggest that larger doses (≥2 g/day)produce a greater benefit than small doses (1 g/day) for
both adults and children.
The assumption that the dose-dependency is linear
allows crude extrapolation of doses that could possibly
decrease the severity of cold episodes by half (Fig. 1).
For children and adults respectively 3.9 and 10 g/day ofvitamin C would yield Relative Effect = –50%. However,in the case of children there are only two rather small
trials in the high dosage group, and there is a great
variation in the results of the low dosage trials (Table 1).
In the case of adults, two trials with high dosages used
Medical Hypotheses (1999) 52(2), 171-178

174 Hemilä

Fig. 1 The effect of vitamin C dosage on the severity of common cold episodes. The mean
Relative Effect on severity values for schoolchildren (■) and adults (●) was taken from
Table 1. Linear regression analysis was used to extrapolate the dose producing Relative
Effect = -50%. The regression lines were forced through Relative Effect = 0% at 0 g/day ofvitamin C since such a dose must equal placebo.

induced rhinovirus infection (16,31), and one trial founda great divergence in two different outcomes (13). The
evidence for dose-dependency is thus not strong in
Figure 1. Still, as children on average weigh considerably
less than adults, the difference between them is also
consistent with the notion that a higher dose per unitof weight produces a greater benefit at the dosage levels
studied so far.
Several factors have varied between the trials, suchas the characteristics of subjects, the types of infecting
viruses, the geographic location, etc. The dietary vitamin
C intake by the control group may also affect thedifferences between the vitamin and placebo groups, but
the dietary intake has not been estimated at all in mosttrials. The definition of outcome has varied greatly andin several trials there has been a smaller effect on the
duration but a larger effect on the severity of colds(13,19,25-27). Such factors, along with random variation,
can explain a large part of the differences between the
results, hampering the comparison of the studies.
In two trials (18,22) different vitamin C doses were
given to separate groups within the same study. Becauseof the similarity of subjects and the constant outcome
definition across the study groups, these two trials are
more pertinent to the question of dose-dependency thanthe comparison of means of dissimilar studies. Karlowski
et al (22) examined the effect of 3 and 6 g/day of vitamin
Medical Hypotheses (1999) 52(2), 171-178

C on adults, and Coulehan et al (18) examined the effectof 1 and 2 g/day on children (Fig. 2). Extrapolation fromthe results of Coulehan et al suggests that 3.5 g/day
would decrease the duration of cold episodes by half,consistent with the estimate derived from all studies withchildren.
Karlowski et al's results suggest that 18 g/day would
decrease the duration of episodes by half (Fig. 2). Finally,
Karlowski et al reported the standard errors of the mean
duration of episodes for their four study groups (Table 2).
The linear trend in their study groups can consequently
be analyzed by the analysis of variance. The linear trend
explains a significant part of the differences between thegroups, whereas the remaining non-linear differences
are easily explained by random variation (Table 2). The
results of the Karlowski study are the most unambiguous
evidence so far indicating that there is dose dependency
in the >1 g/day region.
Three of the adult trials used military recruits as subjects, and there is extreme variation in their results. Twoof these trials (15,19) found the greatest benefit among
all the 1 g/day and ≥2 g/day studies, whereas the third(27) found the smallest benefit among all the ≥2 g/day
studies (Table 1). The trials reporting the great benefit
were carried out in a special exercise during the wintertime in northern Canada (19) and with the crew on asubmarine (15). The Pitt and Costrini study reporting© 1999Harcourt Brace & Co. Ltd

Vitamin C supplementation and the common cold 175

Fig. 2 The effect of vitamin C dosage on the duration of common cold episodes in the Coulehan
1974 and Kariowski 1975 trials. The Relative Effect on severity values are taken from Table 1 for
the Coulehan 1974 study (■) and the Karlowski study (●). Kariowski et al (22,32) also had atherapeutic group which was administered 3 g/day of vitamin C for 5 days during cold episodes
and for this group Relative Effect = –9.5% (Table 2). In this figure, it is assumed that there is no
meaningful difference between the regular and therapeutic supplementation and therefore the
Kariowski results are plotted on the basis of total vitamin C dosage during the cold episodes (c.f.
Table 2).

the minor benefit was carried out in a training camp in
South Carolina (27). In the latter trial, the subjects wereon average sick 36% (20/56) of the study days (27,41).
The subjects have usually been sick less than 10% of
the study days (3), as in the large-scale trial with adults
by Anderson et al (13), where it was 7% (6/90). Becauseof the exceptional conditions in the Pitt and Costrini
study it is not clear to what extent their results canbe generalized to other circumstances. Thus, the substantially greater benefit found in the other two trials
with military recruits (15,19) might be caused by differences in the experimental conditions. It is possible thatspecific circumstances for example in accommodation(41) and in training conditions are important factors
affecting the role of vitamin C in military recruits.
DISCUSSION

The effect of vitamin C on the common cold has beenstudied quite extensively since the early 1970s when
Linus Pauling, a dual Nobel laureate, wrote a popularbook on the topic suggesting that, in gram doses, thevitamin would substantially decrease morbidity due tothe common cold (1). Although in further trials thebenefit was not as great as Pauling had concluded fromthe early studies, the duration and severity of common© 1999 Harcourt Brace & Co. Ltd

cold has consistently been lower in vitamin C groups
indicating a physiological effect (Table 1).
In his quantitative analysis, Pauling (2) based his estimation of benefit on a single trial carried out by Günther
Ritzel in the early 1960s with schoolboys in a skiing
camp in the Swiss Alps (12,33). However, the conditions ata skiing camp are highly exceptional and later studies
with children have mostly found smaller effects (Table 1).
Moreover, Pauling did not restrict his estimate tochildren, and it appears that the extrapolation of Ritzel's
results to adults was among the reasons for the great
discrepancy between Pauling's quantitative conclusions(2) and the effects seen in later studies carried out largely
with adults (Table 1; see also ref. 8).
The magnitude of the benefit from vitamin C supplementation is an important issue in evaluating the clinicalsignificance of the vitamin in common cold therapy, eventhough it is unrealistic to assume that a single estimateof benefit would be valid for all subjects. A major problem
in the comparison of the studies is the great variation in
the outcomes between trials. For example, in the control
group of Miller's study (25) the mean duration of 'days
in bed' was 1.0, whereas in Ludvigsson's control group(26) the mean duration of 'symptoms present' was 14
days. Since it is obvious that such outcomes and theirarithmetical differences between vitamin C and placebo
Medical Hypotheses (1999) 52(2), 171-178

176 HemiIägroups are not comparable between different studies,
the present analysis was based on the relative effect on
outcomes, which are more comparable between studies.
Although severity and duration may appear to be independent outcome parameters, the duration may largely
be considered as a way of estimating the severity of
episodes. This is most evident in the case of days ofabsence from school or work, or days in bed, whichclearly depend on the severity of symptoms.
The published trials indicate that the effect of a given
vitamin C dose is on average greater for children thanfor adults (Table 1, Fig. 1). This difference may be largely
due to the smaller weight of children, i.e. a greater dose
per unit of weight, but it is possible that there also are
age-dependent physiological differences. Furthermore,
there is evidence of dose-dependency in both children
and adults (Figs 1 & 2, Table 2). Accordingly, even though
the median decrease in duration by 1 g/day can be considered clinically insignificant in adults (–6%; Table 1), thismay be an underestimate of the potential benefits ofhigher doses, particularly when given to children. For
children the median decrease with 2 g/day of vitamin C
was four times higher (–26%). Finally, as the results ofthe trials are mean values for a group of children, it isobvious that vitamin C is much more (and much less)beneficial for some individual children than is suggestedby the result of a single study, or by the median of agroup of studies.
It is noteworthy in Table 1 that only 22% (639/2901)
of all cold episodes were observed in studies withchildren and the 2 g/day studies with children cover only
2% (54/2901) of all episodes. Thus, if a weighted generalmean is calculated for all results in Table 1, there is heavy
domination by the adult studies, which have mostly
found only a slight benefit. Consequently, such a generalestimate would completely hide the possibility of there
being a worthwhile benefit in children.
In two studies with children, the vitamin C level inplasma (18) and urine (25) increased in subjects givena placebo (sic!) suggesting that tablets were exchangedby playful children. In this respect, the study by Carret al (28) is interesting inasmuch as a marked benefit
was observed in twins living apart, but no benefit in twins
living together (Table 1), who apparently exchanged thetablets to a great extent - not so easy for twins living
apart. It is thus possible that some of the published results
underestimate the true physiological effects because oftechnical shortcomings in the studies.
Linear extrapolation suggests that 4 g/day can on
average reduce the severity of cold episodes by half inchildren, and 10-18 g/day may produce a similar effectin adults (Figs 1 & 2). Obviously, these estimates are
imprecise and should be interpreted highly cautiously,
but it seems probable that the doses used in the placeboMedical Hypotheses (1999) 52(2), 171-178

controlled trials (≤2 g/day for children; ≤6 g/day for adults)
have not been large enough to demonstrate the maximum effect of vitamin C supplementation (Figs 1 & 2).
Several physicians have used vitamin C in the treatmentof the common cold (42-50). Bee (47) proposed 10-15g/
day for treating colds, and Cathcart (48,49) suggested thatthe optimum dose may be over 30 g/day. It is noteworthy
that extrapolation with the data from the adult studies
yields estimates crudely of the same magnitude (Figs 1 & 2).
The quantitative analysis in the present work was basedon studies using regular vitamin C supplementation,and it is important to consider whether the resultant
estimates may be extrapolated to therapeutic doses
administered after an episode occurs. This is an importantquestion, since regular supplementation is more costly
and cumbersome. Although vitamin C is safe even when
consumed at high levels of intake for long periods of time(51-54), any potential harm is even less with short-term
supplementation during common cold episodes.
Two research groups compared the effect of therapeutic and regular vitamin C supplementation on colds.
Karlowski et al (22) and Anderson et al (13,35) foundthat the estimates derived from regular supplementation
do not overestimate the benefit of a 5-day therapeutic
regime (7), suggesting that the estimates in Figure 1 may
crudely apply to appropriate therapeutic supplementation. A few other trials have examined the role of therapeutic regimes, some reporting benefit from vitamin C(36-38), while some others found no effect (37-40).
In therapeutic trials, there are additional sources oftechnical variation when compared to regular supplementation studies. In the latter type of study, the vitaminis given over the entire cold episode. In the therapeutic
trials, however, both a delay in the initiation of the treatment, and an inappropriately short treatment period
might decrease the benefit. The former effect was observed in one of the therapeutic trials (36), and the latter
effect may explain the inefficacy of vitamin C in threetherapeutic trials in which supplementation lasted for
only 2-3 days while the mean duration of cold episodes
was 5-8 days (37-39). Finally, it is noteworthy that noneof the published therapeutic trials used children as
subjects, whereas the regular supplementation studies
have on average found a considerably greater benefit forchildren (Table 1, Fig. 1). Vitamin C is a cheap substanceand safe even in large doses (51-54). It would seem
worthwhile to carry out well-planned therapeutic trials
to obtain better quantitative estimates of the optimum
doses and maximum therapeutic effects, and to better
understand the potential differences between various
groups of people. It also seems worthwhile to consider
carefully the most relevant outcomes, as the effect onseverity has often been greater than the effect on
duration of symptoms.
© 1999 Harcourt Brace & Co. Ltd

Vitamin C supplementation and the common cold 177

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