Medical Hypotheses 1999 52 2 171 178 1999 Harcourt Brace Co Ltd Article No mehy 1997 0639 Vitamin C supplementation and common cold symptoms factors affecting the magnitude of the benefit H Hemil Department of Public Health University of Helsinki Helsinki Finland Summary Placebo controlled trials have shown that vitamin C supplementation decreases the duration and severity of 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 that on 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 this work used regular vitamin C supplementation but it is conceivable that therapeutic supplementation starting early at the onset of the cold episode could produce comparable benefits Since few trials have examined the effects of therapeutic supplementation and their results have been variable further therapeutic trials are required to examine the role of vitamin C in the treatment of colds INTRODUCTION METHODS In placebo controlled studies regular vitamin C supplementation 1 g day has consistently decreased morbidity due to the common cold 1 8 While the biochemical basis 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 significance of 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 some part 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 in high vitamin C doses and whether the effect depends on the characteristics of subjects Since the literature on vitamin C common cold studies has previously been thoroughly surveyed 4 10 11 the older 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 the present quantitative analysis 12 31 and the results are shown in Table 1 Regular supplementation refers here to initiating supplementation with healthy people and continuing 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 in the possibility of there being an effect on the incidence of colds and not on the severity of symptoms so that appropriate 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 Hemil PhD Department of Public Health PO Box 41 University of Helsinki Helsinki FIN 00014 Finland Fax 358919127570 171 172 Hemil 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 the doses corresponding to the observed effects d Induced rhinovirus infection e Severity of symptoms on the 4th day of infection f Twins living together g Twins living apart h Constitutional 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 the standard 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 were double blind Some of the placebo groups were given 10 70mg day of vitamin C to ensure that the effects of the larger dose were not due to the alleviation of a true dietary deficiency 25 26 28 30 The Relative Effect on the severity of common cold episodes in the vitamin C groups relative to the placebo groups was calculated for each study as the difference between the outcomes in the vitamin C and placebo group divided by the outcome in the placebo group Table 1 Pooled confidence intervals for the four groups were not calculated since in several studies standard error and standard deviation were not reported The discussion of therapeutic trials is also restricted to studies that employed 1 g day of vitamin 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 the severity 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 the outcome