The most influential trial on vitamin C and the common cold: Karlowski et al. (1975)

by Harri Hemilä

  1. The most influential trial on vitamin Cand the common cold: Karlowski et al. (1975)
  2. Problems with Karlowski’s ‘placebo explanation’
  3. An alternative explanation of the bias in ‘knowing’:  Inference from subjective observations
  4. Inference of treatment by subjective observation in the Pitt and Costrini trial (1979)
  5. The conclusions of the Karlowski et al. trial (1975)
  6. Table 8:   Results and subgroup analyses of the Karlowski et al.trial (1975)
  7. Table 10:   Citations to the major vitamin C common cold trials
This text is based on pages 21-27 and 59-60 of Hemilä (2006).
This document has up to date links to documents that are available via the net.
Harri Hemilä
Department of Public Health
University of Helsinki,  Helsinki, Finland
harri.hemila@helsinki.fi
Home:  http://www.mv.helsinki.fi/home/hemila

This file:  http://www.mv.helsinki.fi/home/hemila/karlowski/

Version May 29, 2012


The most influential trial on vitamin Cand the common cold: Karlowski et al. (1975)


In the middle of the 1970s, Karlowski, Chalmers, et al. (1975) published a vitamin C common cold trial which received widespread attention for several reasons. First, the trial was carried out at the NIH. Since the participants in the trial were NIH employees, the social background of this particular trial was highly significant. Secondly, the principal investigator of the trial was Thomas Chalmers, who was an eminent clinical trialist (see Hemilä 2006 p 36). Third, the trial was published in JAMA, a respected journal with a particularly wide circulation. Finally, the same issue of JAMA contained a review of vitamin C and the common cold, which concluded that it has no effects on colds (Dykes & Meier 1975; see Hemilä 2006 pp 42-5; see Criticism).

Technically, the Karlowski trial is not among the best. Karlowski’s placebo capsules contained lactose which is sweet, whereas ascorbic acid was used in the vitamin C capsules, so that some of the participants may have identified their treatment by taste. In fact, the authors concluded from their trial that the results were explained by the placebo effect: "The effects demonstrated might be explained equally well by a break in the double blind" (Karlowski et al. 1975).

 The Karlowski trial lasted for 9 months and included 4 treatment arms. Each participant received 2 kinds of capsule: prophylactic (each day) and therapeutic (5 days during a cold). Ascorbic acid (3 g/day) was used in the active capsules and lactose in the placebo capsules, a different combination being administered to each of the 4 study arms. The mean duration of cold episodes in each study arm is shown in Table 8. After the Karlowski trial was con cluded, the participants were asked in a questionnaire which capsules they thought they had been administered. In the case of prophylactic capsules there was strong bias in favor of correct answers (P < 10-6). In contrast, there was no evidence of bias in the case of therapeutic capsules (P[2-t] = 0.3). After finding that several participants had correctly identified their treatment, Karlowski et al. carried out a subgroup analysis in which they divided participants into those who remained blinded and to those who were unblinded after the trial was concluded. In this subgroup analysis, Karlowski was able to show that all the benefit of vitamin C was seen in the ‘unblinded’ group, whereas there was no effect from vitamin C on the participants who remained ‘blinded’ (Table 8). The authors thus concluded that vitamin C supplementation has no physiological effect, and the apparent benefit was simply caused by ‘the placebo effect.’ Thus, the Karlowski trial seemed to provide direct evidence of the placebo-effect in action. In 1996 Thomas Chalmers stated that he was "more proud of [the Karlowski trial] than almost any other that I have published."

Several consecutive editions of two major textbooks on infectious diseases referred to the Karlowski trial in no uncertain terms: "Many participants correctly surmised from the taste of the contents of the capsules used whether they were receiving vitamin C or a placebo" (Gwaltney 1979, 1985, 1990, 1995), and "It is most probable that the reported benefits are a result of statistical artifacts and placebo effect due to poor study design rather than specific pharmacologic drug effects" (Cherry 1987, 1992, 1998).

The Karlowski trial was also alluded to in two recent editions of the Cecil Textbook of Medicine: "Because the subjective symptoms of a cold disappear in 7 days without intervention, a variety of actually ineffective treatments have been reported to be effective due to inadequate blinding of placebo recipients. One example of this phenomenon was a study of large dose of vitamin C to prevent colds, in which many placebo recipients dropped out of the study because they could tell by tasting the medication that they were not receiving the vitamin C" (Hendley 1996, 2000, 2004). Although the Karlowski trial had stronger evidence of divergence in dropping out than the 5 largest vitamin C common cold trials, the difference between the vitamin C and placebo groups was nevertheless not statistically significant in the Karlowski trial (Hemilä 2006 Table 9, p 23), and in this respect the comment is misleading.

A US Food and Nutrition Board monograph referred to the Karlowski trial when stating that vitamin C has no worthwhile effects on colds (FNB 1989b). Another recent monograph by the Food and Nutrition Board also briefly discusses the role of vitamin C on the common cold, stating that in the Karlowski trial "the break in the double-blind study may have been due to the curiosity of the scientist participants" (FNB 2002 p 37).

Karlowski’s trial has been cited in major reviews of common cold therapy (Coulehan 1979; Sperber & Hayden 1988; Spiers 2002), in BMJ (Editorial 1976), and in a recent review on echinacea and the common cold when proposing that the effects of echinacea in placebo-controlled trials are caused by the placebo effect (Caruso & Gwaltney 2005 [see Hemilä 2005a] ). Although Hemilä (2005a) pointed out that the analysis of the Karlowski trial had been erroneous, Caruso et al. (2007) cited it in also in a later review in which they suggested that the effect of zinc lozenges on the common cold would be explained by the placebo effect. A recent review on complementary and alternative medicines and their immunologic effects in a major immunological journal also referred the Karlowski trial (Mainardi et al. 2009 [see Hemilä 2009]).

Because the notion of ‘breaking blindness’ is technically a highly relevant issue in the field of controlled clinical trials, the Karlowski trial has been cited by several clinical trialists. In a paper discussing frauds and errors in medical research, clinical trialist DeMets (1997) wrote of the Karlowski trial: "Since patients in the study were employees of the NIH, they had either direct or indirect access to laboratories, and were easily able to break the double blind … Patients were asked if they had, in fact, used their own resources in the laboratories to break the blind." This is, however, erroneous, since Karlowski et al. (1975) did not report evidence that their participants actually examined the contents of their capsules. The participants were simply asked to "guess which substance they had been taking." The same comments on the Karlowski trial were reiterated in a more recent paper by DeMets (1999).

A popular textbook Fundamentals of Clinical Trials used the Karlowski trial as an example of unsatisfactory blinding causing false conclusions (Friedman et al. 1998 p 83): "A trial of the possible benefits of ascorbic acid in the common cold started out as a double-blind study. However, it soon became apparent that many of the participants, most of whom were medical staff, discovered whether they were on ascorbic acid or placebo. Since evaluation of severity and duration of colds depended on the participants’ reporting of their symptoms, this unblinding was important. Among those participants who claimed not to know the identity of the treatment, ascorbic acid showed no benefit over placebo. In contrast, among participants who knew or suspected what they were on, ascorbic acid did better than placebo. Therefore preconceived notions about the benefit of a treatment, coupled with a subjective response variable, may have yielded biased reporting. Only the alertness of the investigators prevented them from arriving at probably false conclusions."

The Karlowski trial was also cited in a recent paper in JAMA discussing the blinding of trials (Devereaux et al. 2001), and in recent papers by specialists in controlled trials commenting on the question of breaking of blindness in blinded trials (Bang et al. 2004 [see Hemilä 2005b]; Chow & Shao 2004 [see Hemilä 2006a]; Forder et al. 2005 [see Hemilä 2005d]; Rees et al. 2005; Walter et al. 2005; Gluud 2006 [see Hemilä 2007]; Marmor et al. 2008 [see Hemilä 2008a]; Furberg 2008 [see Hemilä 2008b])

The Karlowski trial was cited as an example of placebo effect in action by the CONSORT group, an international group of clinical trialists, statisticians, epidemiologists, and biomedical editors, who suggested improvements in reporting clinical trials (Begg et al. 1996). The 2010 version of CONSORT recommendation also cited the Karlowski trial (Moher et al. 2010 [see Hemila 2010])

Consecutive editions of the Cochrane Reviewers’ Handbook also cite the Karlowski trial, stating that "There is evidence that participants who are aware of their assignment status report more symptoms, leading to biased results" (Mulrow & Oxman 1994 s 6.4; Clarke & Oxman 2002 ss 6.4 and 6.6; Alderson et al. 2004 ss 6.4 and 6.6; Higgins & Green 2006 ss 6.4 and 6.6). The Karlowski trial was also referred to in a popular textbook of epidemiology as an example of important controlled trials (Rothman 1986 p 54; Rothman & Greenland 1996 p 70).  A popular textbook of Clinical Epidemiology has used the Karlowski trial as an example of placebo effect in several editions (Weiss 1986, 2006).


The ‘placebo-explanation’ of the Karlowski-results was forcefully emphasized in a concurrent and influential review by Thomas Chalmers, the principal investigator of the Karlowski trial (Chalmers 1975, 1996; see Hemilä 2006 pp 36-8; see Chalmers review).

Furthermore, the Karlowski trial was also cited in a text discussing vitamin C and the common cold by Stephen Barrett (1995, 2005; see Hemilä 1995 and  2006 p 64), a prominent and influential crusader against health quackery.

There are several vitamin C common cold trials that are considerably larger, and that do not suffer from the shortcoming that vitamin C could be distinguished from the placebo by taste, 5 larger trials confirming that their vitamin C and placebo tablets were indistinguishable (Table 10). However, these larger and better trials are much less frequently cited than the Karlowski trial. For example, none of them are cited in the major textbooks of infectious diseases (Gwaltney 1979, 1985, 1990, 1995, 2000, 2005; Cherry 1987, 1992, 1998), even though these 5 trials together recorded 27 times as many common cold episodes as the Karlowski trial (Table 10).

Table 10 shows that, excluding the citations in Hemilä’s papers, the Karlowski trial (1975) has been cited 13 times per 100 recorded common cold episodes (33/249), whereas the 5 largest trials together have been cited 0.2 times per 100 recorded cold episodes (14/7,167). Thus, per recorded episode, the Karlowski trial has had 65 times as great an impact as the 5 largest trials combined, even though the latter trials used valid placebos, unlike Karlowski. In this respect, the great impact of the Karlowski trial seems to be a good example of the Mathew effect in science (Merton 1968), in that famous scientists in famous institutions are cited because of their social context, irrespective of the quality of their work. Citation bias has also been documented in several other topics (Gøtzsche 1987; Ravnskov 1992; Kjaergard & Gluud 2002).     


Problems with Karlowski’s ‘placebo explanation’


The authors of the Karlowski trial concluded that the observed benefit in vitamin C groups was explained by the placebo effect (Table 8). Since the ‘placebo explanation’ is such a spectacular conclusion to a double-blind placebocontrolled trial, and since this is by far the most influential vitamin C common cold trial (Table 10), it was considered worthwhile to determine whether Karlowski’s ‘placebo explanation’ is actually consistent with the reported differences between the study groups.

Karlowski et al. (1975) asked participants after the trial to guess the type of capsule they were given, and Karlowski used a ‘correct answer’ as a surrogate for actually ‘knowing,’ without considering that many answers were correct purely by guesswork (Hemilä 2006 Table 11, p 26,). There was strong statistical evidence that participants gave a correct answer to the question on the prophylactic capsules more often than expected, but there was no evidence that participants identified the therapeutic capsules more often than by guessing (Hemilä 2006 Table 11, p 26). However, prophylactic capsules had considerably less effect (-0.48 days; see Hemilä 1996) on the duration of colds than the therapeutic capsules (-0.73 days; P = 0.05; see Hemilä 1996). The greater benefit from the therapeutic capsules is inconsistent with the ‘placebo explanation,’ because there is no statistical evidence that therapeutic capsules were identified by the participants, and at most only 11 (8%) participants identified the therapeutic capsules (Hemilä 2006 Table 11, p 26).

Furthermore, Karlowski et al. did not describe how they divided participants into the two subgroups of ‘blinded’ and ‘unblinded.’ The sum of these two subgroups does not match with data for all participants, although the authors presented the subgroups as if they were complementary. Table 8 shows that the total number of common cold episodes in the placebo group (#0) was 65. The ‘blinded’ placebo subgroup contained 30 episodes, and the ‘unblinded’ placebo subgroup contained 16 episodes, with a total of 46. Thus, there were 19 common cold episodes (= 65 - 46) in the placebo group affecting participants who were neither ‘blinded’ nor ‘unblinded.’ In total, there were 105 common cold episodes (42% of all) missing from Karlowski’s subgroup analysis (Table 8). The maximum effect of vitamin C on common cold duration can be calculated for the ‘missing group’ (-1.4 days/episode; difference between 6 g/day and 0 g/day groups; see Hemilä 1996); thus it is even greater than the effect in the entire study population (-1.2 days/episode [=7.1 – 5.9];  Table 8). Karlowski et al. did not mention the exclusion of the 105 episodes from their subgroup analysis, nor did they offer their rationalization for the greater than average benefit in those participants who were neither ‘blinded’ nor ‘unblinded.’

A number of further problems with the ‘placebo explanation’ are discussed in Hemilä 1996. Consequently, the ‘placebo effect’ explanation is inconsistent with the data reported by Karlowski et al. (1975).

An alternative explanation of the bias in ‘knowing’:  Inference from subjective observations


There has been a persistent popular belief, long predating Pauling’s book (1970a; see Background), that vitamin C is beneficial against the common cold. Consequently, it is possible that several participants inferred the vitamin C treatment from the subjective feeling that their cold symptoms were milder than they expected. Similarly, the impression that the symptoms were prolonged may have led a participant to infer that the placebo was being given, not vitamin C.

Vitamin C has substantially reduced the duration or severity of colds in several placebo-controlled trials (up to 20-50%; Hemilä 1994), so that it would be no surprise if vitamin C could be correctly distinguished from placebo by some people on the basis of subjective observation. Moreover, one double-blind placebo-controlled trial was initiated to examine the therapeutic effects of 6 g/day of vitamin C on common cold symptoms, but the trial was discontinued because the participants receiving the vitamin could be identified by their clinical progress (Asfora 1977). With such positive reports it is quite possible that correct identification of capsules in the Karlowski trial was partly caused by the physiological effects of vitamin C.

In fact, the ‘knowledge inferred from subjective observation’ explanation is directly supported by the data from a parallel publication of the Karlowski trial (Lewis et al. 1975). Among participants who had not tasted their prophylactic placebo capsules, those who had colds during the trial tended to suspect that they were being given placebo (15 of 18), whereas those who did not have colds tended to suspect they were being given vitamin C (6 of 8) (mid-P[2-t] = 0.004). A similar inference can apparently be drawn from the duration or severity of colds, but this was not considered by the authors. The alternative explanation is briefly mentioned but not properly analyzed in the JAMA paper (Karlowski et al. 1975) or in the parallel study report (Lewis et al. 1975), and the ‘placebo explanation’ is strongly favored in both papers. However, the alternative explanation is not mentioned at all in Chalmers’ review (1975).

The re-analysis of the Karlowski trial by Hemilä (1996) was criticized by Thomas Chalmers (1996), but the criticism seems not to be valid (Hemilä 1996c), except for Chalmers’ statement that they used capsules in their trial, and not tablets as erroneously stated in Hemilä (1996). Unfortunately Chalmers died while Hemilä (1996) and the accompanying commentaries were being published (Feinstein 1996).

Inference of treatment by subjective observation in the Pitt and Costrini trial (1979)


The possibility that certain of Karlowski’s participants may have correctly inferred their treatment from subjective observation is supported by the findings of Pitt and Costrini (1979) in a randomized double-blind placebo-controlled trial with Marine recruits in the USA. In this trial, "The placebo tablets were formulated from citric acid and were indistinguishable in appearance and taste from the vitamin C tablets." After the trial, participants were asked which pill they thought they were taking, and the percentage of participants giving various answers was reported; the number of participants corresponding to the percentage is calculated in Table 11 in Hemilä (2006, p 26). There is a statistically significant difference in the number of participants who gave the correct answer (n = 178) compared with those giving an incorrect answer (n = 138). Correct identification may be caused by the positive or negative effects of vitamin C, but the authors found no difference in adverse events between the study groups. Instead they reported a statistically significant, but clinically minor effect on common cold severity (P = 0.012), and an 85% lower incidence of pneumonia in the vitamin C group (see Hemilä 1997c). Pitt and Costrini’s data suggests that some 6% of all participants (40/674) inferred their treatment by subjective observation (Table 11 in Hemilä 2006, p 26).

The conclusions of the Karlowski et al. trial (1975)


The Karlowski et al. (1975) trial is by far the most influential of the trials on vitamin C and the common cold (Table 10). Karlowski et al. concluded that the apparent benefit of vitamin C in their double-blind placebo-controlled trial was explained, paradoxically, by the placebo effect. It was shown that the ‘placebo effect’ explanation is inconsistent with Karlowski’s own data (Hemilä 1996). The rejection of Karlowski’s ‘placebo explanation’ is important since it validates the use of Karlowski’s results in the quantitative estimation of the effects of vitamin C. Karlowski’s results are important in three particular respects.

First, the comparison of the therapeutic and prophylactic methods of supplementation in the same trial provides an estimate of their relative effects. From Karlowski’s results it appears that with a fixed dose, proper therapeutic supplementation can yield approximately as great a benefit as prophylactic supplementation. Most of the published trials have used regular supplementation, and Karlowski’s results suggest that the effects of appropriate therapeutic supplementation might be similar.

Second, Karlowski’s results suggest that there is linear dose-dependency, even with high intakes of up to 6 g/day (Table 8; Hemilä 1996, 1999a), and it seems possible that still higher doses might produce even greater effects. The largest dose (6 g/day) decreased the duration of colds by 17% and crude linear extrapolation suggests that 18 g/day might shorten common cold duration by half. Even though such a crude extrapolation must be regarded cautiously, it is noteworthy that this dose estimate is of the same magnitude as the dosage proposed by a few physicians who used vitamin C in the treatment of the common cold: Bee (1980) proposed 10-15 g/day for treating colds, and Cathcart (1981; Luberoff 1978) suggested that the optimum dose might be over 30 g/day. Thus, it appears possible that the vitamin C doses used in the common cold trials (highest doses 6 g/day for adults and 2 g/day for children) have not been large enough to reveal the maximum effects of supplementation.

Third, the observed effect is quite small in Karlowski’s study when considering the fairly large doses used (up to 6 g/day) compared with the effect in several other trials with smaller doses (Hemilä 1992a, 1999a). One possible explanation of the relatively small benefit is the character of the participants used in the Karlowski trial. Anderson et al. (1972, 1975) found that vitamin C supplementation was much more beneficial for subjects with a low daily intake of fruit juice, which is a major source of vitamin C (Hemilä 2006 Table 13, p 35). Participants in the Karlowski trial were NIH employees and it seems probable that such medically-aware people have on average a much healthier diet than the general population and eat more fruit and fruit juices. Thus, Karlowski’s study with employees of the NIH may underestimate the potential benefits of similar vitamin C doses for subjects with a diet which is more typical of the general population or for subjects with a poor diet.

Karlowski et al. (1975) considered that the effect, even if real, has no clinical importance, and concluded that "It does not seem worthwhile to take two capsules or tablets three times a day for the rest of one’s life to achieve such a small and equivocal benefit." In this conclusion, they missed several important findings in their own trial, which are discussed above. First, they could have noted that three times a day during a cold episode is much more feasible and much less expensive than ‘three times a day for the rest of one’s life,’ and their own results indicated that the effect of therapeutic supplementation may be even greater than that of regular supplementation. Second, as there was a linear dose-dependency in their own results, they could have noted that therapeutic doses larger than 6 g/day might have decreased the duration of episodes by over 17%. Third, since they cited the Anderson et al. paper (1972), reporting that vitamin C supplementation is much more beneficial for subjects with low fruit juice intake, they could have noted that their own subjects were probably not the kind of people that would derive the greatest benefit from vitamin C supplementation. It would seem more relevant to ask what the subgroups that would benefit most from vitamin C supplementation are, rather than to ask whether a fixed numerical value found with NIH employees is great enough to validate regular vitamin C supplementation for the general population.

Published trials suggest that it would be worthwhile to carry out further trials to assess the effects of large therapeutic vitamin C doses on the symptoms of the common cold. Furthermore, the regular supplementation trials have on average found a considerably greater benefit for children than for adults, whereas none of the published therapeutic trials used children as subjects (Hemilä 1999a; Hemilä, et al. 2007). Thus, 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. Furthermore, although a tablet is 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 suggested (Gotzsche 1989).



Table 8: Results and subgroup analyses of the Karlowski et al. trial (1975)

Study group Prophylactic
vit C dose		 Therapeutic
vit C dose		 All subjects All subjects "Blinded"
subjects		 "Blinded"
subjects		 "Unblinded"
subjects		 "Unblinded"
subjects

(g/day) (g/day) Duration of
colds (days)		 No.
of colds		 Duration of
colds (days)		 No. of
colds		 Duration of
colds (days)		 No. of
colds









#0 0 0 7.1 65 6.3 30 8.6 16
#1 0 3 6.5 56 6.7 18 4.7 15
#2 3 0 6.7 52 6.4 14 7.0 8
#3 3 3 5.9 76 6.5 30 4.8 13











Table 10: Citations to the major vitamin C common cold trials 1)

Trial 2) Total no. cold
episodes in the trial		 Total citations
from 1991 to 2002 		 Excluding citations
by Hemilä		 Constituent of the placebo
Karlowski 1975 249 43 33 Lactose





Anderson 1972 1,170 12 4 Citric acid 3)
Anderson 1974 4) 2,182 9 4 Lactose and citric acid 3)
Pitt 1979 1,219 12 3 Citric acid 3)
Ludvigsson 1977b 1,279 11 2 not stated 3)
Elwood 1976 1,317 9 1 not stated 3)





Total episodes
excluding Karlowski		 7,167 Total citations
excluding Karlowski		 14

1) ISI Web of Science search.
2) These trials are the 6 largest administering ≥1 g/day vitamin C regularly during the trial (see Douglas, Hemilä et al. 2007). All were randomized, double-blind, and placebo-controlled.
3) The authors state that placebo and vitamin C tablets looked and tasted the same.
4) Anderson 1974: The number of episodes is based on the total of arms #1, #2, and #3, which were administered ≥1 g/day vitamin C regularly during the trial, and arms #4 and #6, which were administered placebo (see Table 16 of Hemilä 2006).

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Hemilä H (2005b) Assessment of blinding may be inappropriate after the trial [letter]. Contemp Clin Trials 26:513-4    Manu with links to Refs * comments on: Bang et al. (2005)

Hemilä H (2005d) Allocation concealment and blinding: when ignorance is bliss [letter]. Med J Aust 183:165-6 * comments on: Forder et al. (2005)

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Copyright: © 2006-2011 Harri Hemilä. This text is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  

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The most influential trial on vitamin C and the common cold: Karlowski et al. (1975) by Harri Hemilä is licensed under a Creative Commons Attribution 1.0 Finland License.
Based on a work at www.mv.helsinki.fi/home/hemila/karlowski.



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