Linus Pauling, vitamin C, and the common cold

by Harri Hemilä

  1. Pauling's Background
  2. Pauling and vitamin C
  3. Pauling’s meta-analyses on vitamin C and the common cold
  4. Vitamin C and infections other than the common cold
  5. Fig. 2.   Placebo-controlled studies in which 1 g/day or more of vitamin C was administered to the participants regularly over the trial period.
  6. Table 3. Results of three major early vitamin C and common cold trials (based on Hemilä (2006): Table 3 on p 14 which gives more details)
  7. References

This text is based on pages 11-13, 28, 35-36 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

This file:

Version May 29, 2012

Before the 1970s a few physicians had concluded from their own observations that vitamin C administration would be beneficial against the common cold (e.g., Ruskin 1938; Markwell 1947; Bessel-Lorck 1959; Regnier 1968). The authors of the influential Sheffield trial examining the effects of vitamin C deprivation of human subjects concluded that common cold episodes "lasted longer in the deprived group" (Bartley, Krebs & O’Brien 1953 p 43). Some other early controlled trials also indicated that vitamin C intake may affect the common cold, but the results of various trials were not quite consistent and the early positive findings did not affect mainstream medicine.

The notion that vitamin C might be of benefit against colds achieved wide popularity in the 1970s when Linus Pauling wrote a best-selling book entitled Vitamin C and the Common Cold in which he claimed that supplementation would prevent and alleviate common cold episodes (Pauling 1970a, 1971c, 1971d, 1976a; Marinacci 1995 pp 249- 51). In 1971, Pauling’s book received the Phi Beta Kappa award for the best scientific book of the year in the USA. Pauling’s book made million of Americans interested in vitamin C supplements and, in the academic world, it led to the initiation of dozens of new trials intended to find out whether Pauling was right or wrong (Fig. 2). To understand why Pauling’s book could have such an enormous impact on the vitamin C field, his personal background must be briefly reviewed.

Pauling's Background

Pauling is widely considered the greatest chemist of the previous century (e.g. Greenberg 1984; Lipscomb 1994; Pauling 1994; Dunitz 1997; McConnell 1996; Mason 1997; NLM 2007a; OSU 2007a, 2007b, 2007c, 2007d UC 2009;  see a list of biographies on Pauling). "In 1931, at only thirty years old, the Oregon-raised Linus Pauling knew he was the world’s best chemist. Ten years later the rest of the world’s chemists agreed" (Watson 1999, 2001). "Pauling helped to transform chemistry from a largely phenomenological subject to one based firmly on structural and quantum mechanical principles" (Perutz 1994). "The extrapolation from physics to chemistry and the articulation of chemistry as an independent subject was the handiwork of a single individual. Linus Pauling ranks … as one of the great thinkers and visionaries of the millennium… Chemistry grew and prospered simply by proving time and again that Pauling was correct in just about all his conjectures, for he projected with unerring accuracy into future with only 0.01% of today’s structural information" (Desiraju 2000).

Pauling was also one of the founders of molecular biology (Gray 1949; Judson 1979; Pauling 1986b, 1993; Kay 1989; Crick 1992; Perutz 1994; Rich 1995; Mason 1997; Morgan 1998; Edison 2001; Eisenberg 2003; Gruber & Lupas 2003; Simoni et al. 2003; UC 2007 ). Before any protein structures had been solved, Pauling conceived, for example, that "A molecular explanation of biological specificity results from a detailed complementariness in structure of two molecules … The significance of the hydrogen bond for physiology is greater than that of any other structural feature," and "Enzymes are molecules that are complementary to the activated complexes of the reactions that they catalyze." Pauling discovered the basic structural features of proteins, α-helix and β-sheet, and invented the concept of the "molecular evolutionary clock." In one of his major papers, Pauling et al. (1949) showed that hemoglobin from patients suffering from sickle cell anemia had a different electric charge from that from healthy individuals, and this report laid the groundwork for establishing the field of molecular medicine (Azar 1996; Strasser 1999, 2002; Eaton 2003; Gormley 2007). Pauling received the Nobel Prize in Chemistry in 1954 (Pauling 1954; NF 2007e).

At the end of the Second World War, Pauling served on a presidential committee formed to plot the path of science in the post-war period. The resulting Vannevar Bush Report led to the expansion of the National Institutes of Health (NIH), allowing for extramural research funding, and the creation of the National Science Foundation (Paradowski 1996). In 1946 Pauling joined the Emergency Committee of Atomic Scientists, chaired by Albert Einstein, whose most important task was to make people in all countries aware of the transformation of the world brought about by the development of the atomic bomb. During 1958, Pauling sent a copy of the petition opposing nuclear weapons testing, with endorsement by 11,021 scientists from 49 countries including 40 members of the US National Academy of Sciences, 216 members of the Soviet Academy of Sciences and 36 Nobel Laureates, to Dag Hammarskjöld, the Secretary-General of the United Nations. Public opinion worldwide led to test-ban negotiations in late 1958. On the same day (10th Oct 1963) that the limited test ban treaty signed by the USA, UK, and the USSR went into effect, it was announced that Linus Pauling would be awarded the Nobel Peace Prize for 1962 (Pauling 1963; Kreisler 1983; Mason 1997; Jolly 2002; NF 2007f). Because Pauling was the best-known American scientist publicly arguing for disarmament, he began to come under attack from right-wing political groups. Because of the pressures of McCarthyism on government officials, Pauling encountered difficulties in obtaining a passport. For example, he was without a passport when his Nobel Prize in Chemistry was announced in 1954, but the Undersecretary of State overruled the Passport Division, enabling him to travel to Sweden to receive his award (Allison 1960; Paradowski 1996; Mason 1997; Nye 1999).

See a list of biographies on Linus Pauling.

Pauling and vitamin C

With such a particularly strong background in science and high-level competence in politics, it is obvious that Pauling’s 1970 book Vitamin C and the Common Cold reached extensive readerships in both lay and academic circles and had great impact. Because of Pauling’s book, the demand for vitamin C substantially increased. In the USA, the production of vitamin C increased from 8.9 million pounds in 1969 to 11.7 in 1971, corresponding to an increase of 39% in two years and an annual growth rate of 18% (CMR 1972a), in contrast to the annual growth rate of about 6% in the 1960s (CMR 1972c). About 5.6 million pounds of vitamin C were also imported to the US between January and November 1971, up about 160% from the amount imported during the same period in 1970 (CMR 1972b). In the USA, Pauling personified the issue of vitamin C (Apple 1996). The US Food and Drug Administration (FDA) was alarmed by this increasing interest in the consumption of large doses of vitamins, and proposed that over-the-counter sales be restricted to relatively low-potency products, with ‘megadoses’ requiring a physician’s prescription. The health food industry felt threatened and it encouraged customers to protest. Members of the US Congress received more mail on this issue than any other, except for the Vietnam War, and the FDA had to give up their attempt. Why, it was asked, did FDA threaten the sales of vitamins, and do nothing comparable about tobacco and alcohol, whose ill effects in excess were not debatable (Apple 1996).

In addition to his book intended for lay people, Pauling (1971a) carried out a meta-analysis of 4 placebo-controlled trials, which was one of the very first meta-analyses in medicine. The results of 3 of the 4 trials are shown in Table 3. The fourth trial by Wilson et al. (1973a,b,c) was available to Pauling only as an abstract (Wilson & Loh 1969) and the final report was complicated with 48 significance tests, with several outcomes in various subgroups, so that it does not provide unambiguous data (Kinlen & Peto 1973). In his meta-analysis, Pauling concluded that it was highly unlikely that all the reported effects on common cold morbidity from vitamin C supplementation could be explained by chance alone. Pauling (1971a) also pointed out that, out of these 4 trials, the greatest benefit was found by Ritzel (1961; Brubacher 1989), who used the largest dose, 1 g/day. Pauling thus concluded that gram doses of vitamin C daily would prevent colds in the general population.

Pauling analyzed previously published trials but did not carry out any experimental work on the common cold himself. His book and other activities, however, led to the initiation of several new trials. Before the 1970s, there was only one trial which used ≥1 g/day of vitamin C regularly over the trial (Ritzel 1961), but within a decade of Pauling’s book about 20 new trials using such high doses regularly over the trial had appeared (Fig. 2). However, the interest in vitamin C and colds disappeared in the middle of the 1970s. This waning interest was caused by the publication of two negative reviews in wide-circulation journals (Chalmers 1975; Dykes & Meier 1975), and by a particularly influential trial, carried out at the National Institutes of Health (NIH) and published in JAMA, which concluded that the apparent benefits of vitamin C were simply explained by the placebo effect (Karlowski et al. 1975). Thus all these three important negative papers were published the same year. Furthermore, the Karlowski trial (1975) and the Dykes and Meier review (1975) were published in the same issue of JAMA, and Thomas Chalmers was both the principal investigator of the Karlowski, Chalmers, et al. trial (1975; Chalmers 1996) and the author of the other review published in the same year (Chalmers 1975). The importance of these three papers is reflected, for example, by the comment in the TIME magazine: "Three reports now cast a further shadow on Pauling’s theory … that large doses of vitamin C would prevent or cure the common cold" (Anonymous 1975 [see Pauling 1975] ). Only a few trials on vitamin C and the common cold were initiated after the middle of the 1970s, after the publication of these three influential papers (Fig. 2).

Since this large set of new trials was carried out, there has been general consensus that vitamin C has no effects on colds, and the three papers published in 1975 are the most usual references for such negative statements. For example, based on these three papers, vitamin C was stated to be useless for colds in major textbooks on infectious diseases (Gwaltney 1979, 1985, 1990, 1995; Liu 1989; Dick et al. 1992, 1998; Cherry 1987, 1992, 1998), in Cecil Textbook of Medicine (Kapikian 1985; Hendley 1996, 2000), various textbooks on nutrition (Halsted 1993; Thurnham et al. 2000; Hamilton & Whitney 1982, 1994; Whitney & Rolfes 1993; Shils et al. 1994), and the US nutritional recommendations (FNB 1980 p 77, 1989a p 120).

The conclusion that vitamin C is useless for colds has also reached the clinicians. For example, a survey of general practitioners in the Netherlands revealed that 47% of respondents considered that homeopathy is efficacious in the treatment of the common cold, whereas only 20% of the respondents considered that vitamin C was (Knipschild et al. 1990). On a scale from 0 to 10, with the high scores corresponding to stronger belief in efficacy, homeopathy for colds received a mean score of 4.7, whereas vitamin C for colds received a mean of only 2.5.

In the UK, 52% of 86 general practitioner trainees considered that homeopathy was useful, whereas only 7% considered large doses of vitamins useful, although no specific indications for usage were presented for either therapy (Reilly 1983). In the USA, 21% of 348 pediatricians considered that homeopathy may be effective, and 21% considered that highdose antioxidant vitamins may be so, but again no indications for usage were presented (Sikand & Laken 1998). Accordingly, the use of vitamin C to treat the common cold comes unambiguously under the Eisenberg et al. notion (1993; Dalen 1998) that "medical interventions not taught widely at [US] medical schools or generally available at [US] hospitals" are unconventional or alternative medicine (Barrett & Herbert 1994; Turow 1997; Goodwin & Goodwin 1984; Goodwin & Tangum 1998).

Pauling’s meta-analyses on vitamin C and the common cold

In his first meta-analysis in the Proceedings of the National Academy of Sciences, Linus Pauling analyzed the findings of 4 placebo-controlled trials in which at least 0.1 g/day of vitamin C was administered regularly to the study group (1971aTable 3). Linus Pauling (1971a) combined the P-values derived from 4 placebo-controlled trials by the Fisher method, concluding that there was strong evidence that vitamin C decreased the ‘incidence of colds’ (P = 0.0014), and the ‘integrated morbidity’ due to colds (P = 0.000022).

In his second meta-analysis in the American Journal of Clinical Nutrition, Pauling (1971b) focused on ‘days of illness per person’ in the best two trials (Cowan et al. 1942; Ritzel 1961). Combining the P-values by the Fisher method led him to conclude that "The null hypothesis of equal effectiveness of ascorbic acid and placebo is rejected at the level P less than 0.001."

Among the 4 trials included in Pauling’s meta-analysis (1971a), the largest dose was used by Ritzel (1961), and Pauling based his quantitative estimations on this trial. Ritzel found that the common cold symptoms in the vitamin C group were 31% shorter and the number of colds 45% lower in the vitamin C group. Pauling also calculated the combination of duration and incidence, ‘integrated morbidity’ referring to the total sickness days per person during the trial, and this was reduced by 61% in the Ritzel trial. Pauling (1971a) then modeled the dose-dependency of vitamin C effect with exponential formulas for which he took constants from the Ritzel trial.

Pauling assumed that the main problem in his estimation was inaccuracy caused by ‘experimental error,’ although he did note that "The values are, of course, expected to depend somewhat on the nature of the population and environment" (1971a). However, even with these explicit reservations he was far too optimistic. He could not imagine how great the variations in the results would be in the forthcoming trials. Neither did he consider the possibility that the effects observed by Ritzel may have been caused at least in part by low dietary vitamin C intake, in which case a smaller dose might have produced a similar benefit, and in such a case modeling the vitamin C effect as a function of the supplementary dose would be completely erroneous. Pauling attributed the difference between the study groups entirely to the large dose given to the treatment group. Furthermore, Ritzel carried out his trial with schoolchildren in a skiing school in the Swiss Alps, children who are not a good representative selection of the general population even though technically the trial was good as it was randomized, double-blind and placebo-controlled. Thus, when Pauling extrapolated the results of Ritzel to all people (i.e., to children at school and adults), he took a bold step and went wrong (Hemilä 1997b). Pauling (1971a, 1971b) put much weight on the ‘integrated morbidity’ outcome and summarized the findings of trials by this outcome in his later texts as well (1976a, 1976b, 1976c, 1986a). This measure led Pauling to adhere strongly to the idea of regular supplementation. However, this is not a good combined measure, since the effects on incidence and duration/severity have quite different patterns (Hemilä 1994), and it is thus more to the point to analyze these two outcomes separately. Thus, Pauling was qualitatively correct in his conclusion that vitamin C does affect the duration and severity of colds, and probably the incidence of colds in certain specific conditions, but he was greatly over-optimistic.

It is worth noting that the Ritzel trial (1961) falls to the group of 6 trials with participants under heavy acute physical and/or cold stress that consistently found reduction in common cold incidence (Hemilä 1996b; Douglas & Hemilä 2005;  Hemilä, et al. 2007). Thus, it was not a misjudgment by Pauling to put the greatest weight on this trial, but his error was to extrapolate the findings to the general population. The other trial on which Pauling put great weight was the Cowan et al. trial (1942Table 3) which was carried out with schoolchildren during the war years and probably the dietary vitamin C intake was low and in this respect the benefit may be explained by the correction of marginal deficiency as in the UK studies with schoolboys and male students (Hemilä 1997b; Hemilä 2006 pp 46-7).

As regards the errors in Pauling’s quantitative conclusions, it should obviously be taken into account that essentially all of the trials available today were carried out after Pauling worked on the topic and, even more importantly, were carried out precisely because Pauling popularized the topic (Fig. 2). Without bold conjectures, progress in science is slow or non-existent, and in this respect the accuracy of Pauling’s extrapolation from the single placebo-controlled trial using regular 1 g/day supplementation available to him in the early 1970s is of secondary concern. Furthermore, Pauling’s own view of science was that an occasional mistake, even when published, was not as bad as lowering one’s sights to less challenging research (Lipscomb 1994).

For the most up to date summary of the trials of vitamin C and the common cold, see Hemilä, et al. 2007 - the references are available via the net.

See a separate list for Paulings papers related to vitamin C.

Vitamin C and infections other than the common cold

The effect of vitamin C on the common cold was not studied for any particular biological reason, but because of the publicity aroused by Linus Pauling on the topic (Fig. 2). The common cold is a ubiquitous ailment with high incidence and is therefore easy to research. Nevertheless, a large number of animal studies have indicated that vitamin C intake may affect a wide variety of infections caused by viruses, bacteria, and protozoa (see Animal studies).

In the early twentieth century, several authors suggested that low intake of vitamin C may decrease resistance to in fections other than the common cold (Hess 1917, 1920, 1932; Clausen 1934; Robertson 1934; Perla & Marmorston 1937a ). Thomas Barlow, who defined the disease infantile scurvy, pointed out that in infantile scurvy "If the cachexia is very profound the supervention of bronchitis, pleuro-pneumonia, severe diarrhoea, or an intercurrent exanthem may bring about a fatal issue" (1894). Casimir Funk, who coined the term ‘vitamin[e]’ (1912), stated that an epidemic of pneumonia in the Sudan disappeared when an antiscorbutic, vitamin C containing, treatment was given to the numerous cases of scurvy which appeared at about the same time (cited in Robertson 1934).

Hess (1920 p 88) summarized a large series of autopsy findings on scorbutic patients: "Pneumonia, lobular or lobar, is one of the most frequent complications [of scurvy] and causes of death. Active tuberculosis is a not uncommon secondary manifestation" and the histopathological findings: "Secondary pneumonias, usually broncho-pneumonic in type, are of common occurrence, and in many [scurvy] epidemics constitute the prevailing cause of death. Tuberculosis lesions are also frequently present, and are stated to assume fresh activity as a result of the nutritional disorder (p 99). In the chapter on the prognosis of scurvy, Hess commented: "An important factor in the prognosis of scurvy … is the marked susceptibility to infection. Even latent or subacute scurvy causes peculiar susceptibility to diphtheria (especially the nasal type), or coryza, bronchitis, and pneumonia. A perusal of the literature shows that this susceptibility was noted by the older authors in relation to adults" (p 227).

There have been suggestions by German and US physicians that vitamin C might have therapeutic benefits for pneumonia patients (McCormick 1951; Klenner 1971; see also Hemilä & Douglas 1999). Gander and Niederberger (1936) concluded from a series of 15 cases that "The general condition is always favorably influenced [by vitamin C] to a noticeable extent, as is the convalescence, which proceeds better and more quickly than in cases of pneumonia which are not treated with vitamin C". Referring to seven German papers, Glazebrook and Thomson (1942) commented that "there is evidence that [vitamin C] is of value in pneumonia, particularly in hastening convalescence, and the claims made do not appear to have been contradicted." Benefit of intravenous vitamin C was reported in a series of over 40 cases (Klenner 1948, 1951), and in 3 cases of viral pneumonia (Dalton 1962).

Large-dose oral vitamin C was also claimed beneficial for patients with viral pneumonia (Cathcart 1981; Luberoff 1978). In one of his last texts, Albert Szent-Györgyi (1978) mentioned a personal experience: "Last year I collected a rather unfortunate personal experience. I broke down with pneumonia which I could not shake off for months, until I discovered that the quantities of ascorbic acid which I took (one gram daily) had become insufficient at my age (84 years). When I went up from one gram to eight, my troubles were over."

A recent Cochrane review found three prophylactic and two therapeutic trials indicating that vitamin C may affect susceptibility to and severity of pneumonia under some conditions  (Hemilä & Louhiala 2007) - the references are available via the net.

The limited and fragmentary data on the potential therapeutic effects of vitamin C on other infections have been summarized elsewhere (e.g., Stone 1972; Briggs 1984; Levy 2002; Hemilä 1997a, 1998;  Hemilä and Koivula 2008 + refs).

Fig. 2.   Placebo-controlled studies in which 1 g/day or more of vitamin C was administered to the participants regularly over the trial period.

Common cold studies in which 1 g/day or more vitamin C was administered to participants
 Regular supplementation refers here to initiating supplementation with healthy people and continuing over the occurring common cold episodes. The number of studies published over two consecutive years is combined and plotted for the first of the two years. For the list of references to these trials, see Hemilä (1992a, 1994a). This figure is reproduced from Hemilä (1997b).

Table 3. Results of three major early vitamin C and common cold trials (based on Hemilä (2006): Table 3 on p 14 which gives more details)

Trial Vitamin C Placebo Difference P(one-tail)
RITZEL (1961)

Schoolchildren in a skiing camp in Swiss Alps, 1 g/day vit C, 1 week

Participants 139 140

Common cold  episodes 17 31 -45% 0.015
Duration of colds, mean 1.8 2.6 -31% <0.05
Days per group 31 80 -61%
Constitutional symptoms during the common cold (headache, muscle ache, etc.)

Cases 8 21 -62% 0.006
Days per group 9 48 -81%
COWAN et al. (1942)

Schoolchildren in USA, 0.2 g/day vit C,  4 months

Participants 208 155

Cold episodes, mean per person 1.9 (SD 1.0) 2.2 (SD 1.0) -14% 0.003
Days lost from school per person 1.1 (SD 1.1) 1.6 (SD 1.6) -31% 0.0003
FRANZ et al. (1956)

Schoolchildren in USA, 0.2 g/day vit C, 4 months

Participants 44 45

Common cold episodes 14 15

Colds cured or improved in 5 days 13 8 +74% 0.012


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**  See Background  See Book Reviews

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Phi Beta Kappa Award in Science   PBK Society    PBK Wiki summary

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