Vitamin C and the Common Cold: Pauling vs. the Physicians

LPSafe_4.053_1980

Diary entry by Linus Pauling, 1980. The text reads: “L[inus] P[auling] / Found enzymes enthralling / He was filled with glee / By Vitamin C”

[Part 2 of 4]

As a double Nobel laureate, Linus Pauling’s recommendation that everyone ingest 1 to 4 grams of vitamin C daily developed into a media frenzy. And with time, the debate took on a distinctly political flavor, with the battle over vitamin C argued on talk shows and in press releases, rather than vindicated in the lab.

Pauling’s accusations that the medical establishment was ignoring the potentially profound benefits of vitamin C in part because of a mutually beneficial relationship with Big Pharma did not, as one might expect, go over well with many medical professionals. Indeed, his work with vitamin C was written off by many as a passing craze, and Pauling was increasingly referred to as a “kook” and a medical “quack.”


Sci 11.022, 22.1

Notes by Linus Pauling regarding vitamin C and the common cold, 1974.

As Pauling and the physicians went back and forth, the two sides sometimes found themselves citing the same data and producing opposite conclusions. Often Pauling argued that the studies under consideration – discarded by dissenting physicians for apparently showing negligible effects – actually suggested a real value to the use of vitamin C that would be amplified if only larger doses were used.

One study in particular, authored in 1942 by A.J. Glazebrook and Scott Thomson, found vitamin C to only slightly decrease the occurrence of colds and their symptoms in a sample of college students. For proponents, the work was heralded nonetheless as significant evidence in vitamin C’s favor. The problem, Pauling believed, was that physicians expected vitamin C to act like a drug, with a concomitant “tendency…to use relatively small amounts and look for big effects.” But vitamin C wasn’t a drug, it was a nutrient, and Pauling thought its effects would not be easily observed in a typical physician’s research paradigm.

In an effort to put the issue to rest, a University of Maryland study in which eleven prisoners were given 3 grams of vitamin C a day for two weeks found that, when inoculated with cold viruses, each subject became ill. While many considered this proof that Pauling was wrong, he dismissed this study as well. For one, it lacked a placebo control group and did not take the severity of symptoms into account. Pauling likewise suspected that the prisoners were infected with a cold virus potent enough to have overwhelmed any protective effect from vitamin C.

On and on the debate raged and, by the time of Pauling’s death in 1994, little consensus had been reached: Pauling stood firm in his beliefs and the physicians hadn’t from their position.


dr_harri_hemila

Harri Hemilä

Today, while Pauling’s faith in and advocacy of vitamin C has endured in the public consciousness, it has not translated into concrete medical practice. Presently, the United States Food and Nutrition Board has set the Recommended Daily Allowance for Vitamin C at 120 mg at the highest (for pregnant women), nearly three times greater than the RDA in the 1970s, but still about 100 times lower than the levels that Pauling believed to be optimal.

So what does the research really show? Is there, in fact, zero evidence that Vitamin C prevents or cures colds, as the Food and Drug Administration once claimed?

Perhaps the best summation of the current state of affairs has been compiled by Dr. Harri Hemilä, a researcher in public health at the University of Helsinki. Hemilä, whose 2005 comprehensive study on the subject is cited by the National Institutes of Health, makes a number of intriguing points.

For one, Hemilä points out that, while the broad body of research seems to indicate that vitamin C supplementation does not decrease cold incidence in most individuals, it does significantly decrease incidence in marathon runners, skiers, and soldiers – all groups subject to consistent exposure to cold weather or physical stress – by as much as 50%. Daily supplements also appear to decrease the symptoms and duration of colds by a modest degree – observations of 14% in children and 8% in adults.

It is important to note that studies of this sort have used what Pauling would have considered to be minimum dosages for optimal health – 1 to 2 grams daily. To date, few investigations have looked into doses higher than 2 grams, presumably because it is known that, for oral doses of more than 1 gram, absorption rates fall below fifty percent. The operating idea then, is that for supplementation above 2 grams, most of the extra vitamin C is unused and excreted in one’s urine.

Yet there does exist some evidence of a more significant impact at higher dosage levels. Hemilä’s survey of the research concludes that, in some studies, doses larger than 2 grams do appear to provide some measure of therapy, if taken at the onset of cold symptoms.

Digging more deeply into the data, however, one finds conflicting results. In one study, taking 8 grams once at the onset of symptoms appeared to decrease symptoms and duration of colds. In another, 10 gram doses were given for three days during a cold, without impact.

Obviously, when trying to measure the impact of any therapy on the progression of an illness – particularly one as protean as the common cold – numerous co-factors can enter the equation. It would seem then that a thoughtful modern study of vitamin C – one that carefully considers the methodology of those conducted in the past – is still needed before we can be certain of its potential impact on the common cold.


pauling-pill

Had Pauling invested in proving his point in the lab after the publication of Vitamin C and Common Cold, perhaps we would have a better understanding of the immune function of this nutrient today. But Pauling felt vitamin C’s protective effects against the cold were not seriously debatable and that, for him, it was time to move on. The physicians, he believed, were set in their ways – a description he often used during the long argument over vitamin C – and it was pointless for him to spend too much of his time and energy trying to disprove them.

Indeed, in Pauling’s mind, there were more important issues to take into the lab than the common cold. Because Pauling wasn’t just busy arguing that vitamin C could cure the common cold. He believed that it might cure cancer, too.

 

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Vitamin C and the Common Cold: The Roots of Controversy

Detail from "The Perils of Pauling", National Observer, November 27, 1971.

Detail from “The Perils of Pauling”, National Observer, November 27, 1971.

[Part 1 of 4]

Growing up in the United States, many children today are told to drink plenty of orange juice to get their vitamin C, in part to avoid getting a cold. And indeed, vitamin C is now widely accepted as an important nutrient. Its antioxidant properties are valuable to cellular health and can protect against heart disease as well as the genetic damage that can lead to cancer and other dysfunctions. It aids the body’s production of collagen and other connective tissues, and is important for optimal healing from injury. It is also implicated in optimal neurotransmission (brain function), and stimulates the production of white blood cells important for immune health. This basic component of healthy living has been repeated so many times on television shows like “Sesame Street,” or in the classroom, or at home around the dinner table, that American children grow up recognizing vitamin C’s  importance as an obvious fact of life.

Perhaps surprisingly then, there is still little consensus in the medical community as to the ability of Vitamin C to significantly reduce the incidence, duration, or severity of the common cold. For Linus Pauling in 1971, it seemed so clear that Vitamin C was critical to human health that he felt compelled to publish his best-selling book, Vitamin C and the Common Cold, feeling that to withhold such simple and valuable information for the public’s general well-being would be negligent. His work sparked a vitamin C craze in America: after the book’s publication, consumption of vitamin C increased so much that bulk prices nearly tripled. The public certainly believed Pauling. Professional physicians, on the other hand, were highly critical.


While the full benefits of vitamin C are better known now than was the case in Pauling’s day, even in the 1970s no one argued against the vitamin’s fundamental importance. The real argument that emerged was about how much Vitamin C was enough, and why.

Oranges and other fruits and vegetables were known to prevent scurvy from at least 1753, when British naval physician James Lind reported on its effectiveness in treating this disease of nutritional deficiency. Vitamin C was first isolated in the early 1930s by Albert Szent-Györgyi, William Waugh, and Charles Glen King, and produced in the lab shortly after by Norman Haworth and Edmund Hirst. Unlike most mammals, human beings do not naturally synthesize vitamin C within our own bodies. Along with Guinea pigs, other primates, and fruit bats, we need to acquire the entirety of our vitamin C through our diet. The Federal Recommended Daily Allowance (RDA) was duly set at 60 mg each day – enough to keep one from falling prey to scurvy – by the time that Pauling arrived on the scene.


Irwin Stone. (Image by Oscar Falconi)

Irwin Stone. (Image by Oscar Falconi)

To Irwin Stone, “giving someone enough vitamin C to prevent scurvy was like feeding them just enough to keep them from starving.” Stone, a biochemist, published on Vitamin C as a food preservative beginning in 1935. In the course of this research, he discerned that a 150 lb human would need to ingest 4 to 10 grams of Vitamin C a day in order to match what a healthy rat produces on its own.

Stone met Pauling in 1966, not long after Pauling had delivered an acceptance speech for the Carl Neuberg Medal, awarded for Pauling’s assessment of sickle cell anemia as a molecular disease. In the speech, Pauling expressed his hope that he might live to see the medical advances that the next 15 years might bring. Afterward, Stone recommended that with vitamin C, Pauling (who was sixty-five years old at the time) might see the advances of the next fifty.  His interest piqued, Pauling began taking 1 gram of Vitamin C per day, and by the late 1970s, this increased to 10 or more grams daily. Around the same time, the RDA was lowered to only 45 mg. In other words, Pauling was now taking over one hundred and sixty times the daily dose of Vitamin C recommended by the government.


The concern in the medical community was, and continues to be, the potential for “overnutrition”; i.e., negative physical effects associated with consuming too much of a particular vitamin or mineral. As Pauling’s ideas gained increasing cultural currency, physicians began to warn that vitamin C consumed in such large doses might cause the development of kidney stones. Pauling countered that this was only likely in a small segment of the population – those with pre-existing hyperoxaluria – and that it could be entirely avoided by ingesting sodium ascorbate pills rather than ascorbic acid or natural sources. Pauling pointed out that, in fact, there were no health problems associated with high dose vitamin C intake other than potential stomach irritation and loose bowels – symptoms now known to occur with a daily intake of approximately two grams. For Pauling, the decision to take large doses in spite of these drawbacks seemed obvious.

But for many clinicians it was not. Leading nutritionist Dr. Victor Herbert attacked Pauling’s claims as unsupported, as did FDA head Charles Edwards, who denounced Pauling as spurring a national frenzy over vitamin C with no scientific basis. This backlash begged the question, if the benefits of Vitamin C were really medically obvious, then why would physicians mislead the public?

Medical Tribune, June 6, 1973.

Medical Tribune, June 6, 1973.

Pauling’s answer, as delivered through the media, provoked even greater controversy. Physicians were misleading the public, he said, because the reality of a cheap, safe alternative to expensive pharmaceuticals would prove economically disastrous for the medical industry. In other words, the physicians, in partnership with drug companies, had an economic interest against vitamin C. “Every day,” Pauling explained, “even every hour, radio and television commercials extol various cold remedies… I am convinced by the evidence now available that ascorbic acid is to be preferred to the analgesics, antihistamines, and other dangerous drugs that are recommended for the treatment of the common cold by purveyors of cold medicines.”

Pauling’s assertion was based in part on the opinion of Albert Szent-Györgyi, who had first isolated Vitamin C, and who told Pauling in a personal letter that,

…right from the beginning I felt that the medical profession misled the public. If you don’t take ascorbic acid with your food you get scurvy, so the medical profession said that if you don’t get scurvy you are all right. I think this is a very grave error. Scurvy is not the first sign of the deficiency, but a premortal syndrome, and for full health you need much more, very much more. I am taking, myself, about 1 gram a day.

Pauling was also drawing on the opinion of others in the medical field, such as Dr. Douglas Gildersleeve, who stated in a 1967 Fact magazine article that,

having worked as a researcher in the field, it is my contention that an effective treatment for the common cold, a cure, is available, that is being ignored because of the monetary losses that would be inflicted on pharmaceutical manufacturers, professional journals, and doctors themselves.

Pauling, in other words, wasn’t alone in staking out this controversial ground.

Irwin Stone: An Influential Man

Irwin Stone. (Image by Oscar Falconi)

Irwin Stone. (Image by Oscar Falconi)

[Part 1 of 2]

Dr. Irwin Stone was a biochemist and chemical engineer who maintained a particular interest in and enthusiasm for vitamin C. Stone was the person who first raised Linus Pauling’s interest in vitamin C, leading to Pauling’s extensive program of research on vitamin C and its uses for the prevention and treatment of disease. Pauling’s contributions to the field are one of the big reasons why many people believe in taking vitamin C for the prevention and treatment of colds today.  But for Pauling, it all started with Irwin Stone.


Stone was born in 1907 and grew up in New York City. He attended the College of the City of New York and then worked at the Pease Laboratories, a well-known biological and chemical consulting lab, from 1924 to 1934. Stone started out as a bacteriologist, but was promoted to Assistant to the Chief Chemist and then to Chief Chemist.

In 1934 the Wallerstein Company, a large manufacturer of industrial enzymes, recruited Stone to set up and direct an enzyme and fermentation research laboratory. Ascorbic acid, or vitamin C, had just been identified and synthesized by a Hungarian research team led by Albert Szent-Györgyi, who later won the 1937 Nobel Prize in Medicine for his work. Stone pioneered processes for implementing the antioxidant properties of ascorbic acid in industrial settings. One specific application that Stone developed was the use of ascorbic acid as a preservative for food – an innovation that landed him three patents.

Stone’s interest in vitamin C lasted throughout his life. He began to study scurvy intensely and by the late 1950s he had formulated a hypothesis that scurvy was not merely a dietary issue, but a flaw in human genetics. (He called it “a universal, potentially-fatal human birth defect for the liver enzyme GLO.”) Stone considered the amount of vitamin C that nutritionists recommended in a healthy diet – the Recommended Daily Allowance (RDA) – to be far from sufficient. In 1968 that recommendation was 55 mg for women and 60 mg for men. The current standard is slightly increased at 75 mg for women and 90 mg for men, with higher recommendations for pregnant and lactating women. But none of these figures are anywhere near Stone’s recommendations.

Stone believed that humans suffer from “hypoascorbemia,” a severe deficiency of vitamin C, caused by our inability to synthesize the substance the way that virtually all other mammals do. Most other mammals synthesize vitamin C in large quantities relative to body weight; proportionately, humans theoretically should be taking between 10-20 grams daily. Stone suggested that about 25 million years ago the primate ancestors of human beings lived in an environment in which they were able to consume relatively massive amounts of ascorbic acid, compared with what we get from our diets today. These material circumstances created an environment in which a genetic mutation occurred that allowed these human ancestors to stop synthesizing the substance. In present day, Stone noted, these amounts of ascorbic acid are not readily available in our diets, so humans may only be getting 1-2% of what they need.

This hypothesis initially led Stone to propose a vitamin C intake of 3 grams for optimal health, 50 times the RDA, and as he further researched ascorbic acid, he recommended increasingly higher doses. He was convinced that taking less than the amount that he recommended would cause “chronic subclinical scurvy,” a state of lowered immunity that increased susceptibility to a variety of illnesses. He felt that large doses of ascorbic acid should be used to prevent and treat infectious and cardiovascular diseases, collagen breakdown, cancer, SIDS, birth defects, AIDS, and health problems normally associated with aging.

Practicing what he preached, Stone and his wife began taking megadoses of vitamin C and they found that it greatly improved their overall health. When the couple both incurred injuries from a serious car accident, they treated themselves in part with large doses of vitamin C and reported a swift recovery. Stone attributed their rapid healing to the large doses of vitamin C.


Letter from Irwin Stone to Linus Pauling, April 4, 1966.  This is the communication that spurred Pauling's interest in vitamin C.

Letter from Irwin Stone to Linus Pauling, April 4, 1966. This is the communication that spurred Pauling’s interest in vitamin C.

In March 1966, Linus Pauling gave a speech on the occasion of his receiving the Carl Neuberg Medal for his work in integrating new medical and biological knowledge. In the speech, Pauling – who was 65 years old at the time – mentioned that he hoped to live for another fifteen years so that he might see several advances of science in medicine that he anticipated to be emerging during that time period.

Irwin Stone was in the audience at this lecture and, on April 4, 1966, he wrote Pauling a fateful letter in which he noted

You expressed the desire, during the talk, that you would like to survive for the next 15 or so years….I am taking the liberty of sending you my High Level Ascorbic Acid Regimen, because I would like to see you remain in good health for the next 50 years.

Pauling was initially skeptical of Stone’s advice, but he had recently learned about other uses of megavitamin therapy and their successes, so he decided to give the regimen a try. It was at that point that Linus and Ava Helen Pauling began taking 3 grams of vitamin C a day.

In July Pauling wrote back to Stone: “I have enjoyed reading your paper and manuscript about hypoascorbemia. I have decided to try your high level ascorbic acid regimen, and to see if it helps me to keep from catching colds.”

Pauling, as it turned out, was impressed by the results. For most of his adult life, he had suffered from severe colds several times a year and had taken a daily dose of penicillin off and on from 1948 to the early 1960s. Pauling thought that the penicillin doses were his primary defense against colds but, in all likelihood, he was probably just killing off his good bacteria and making himself more susceptible to colds through his overuse of antibiotics. Once the Paulings started taking vitamin C, they reporting a noticeable uptick in their physical and emotional energy, and seemed to suffer from fewer colds.

Two years after their initial communications, Stone noticed that Pauling had cited him in a recently published journal article. Stone described his difficulties in getting his research published and the backlash that he was experiencing from physicians. He also asked about Pauling’s health.

The last time I wrote you in 1966, you mentioned that you were going to try my high level ascorbic acid regimen to see if it would help prevent your catching colds. How did it work? At the time you also had a broken leg. I know from personal experience [a reference to his car accident] that it is excellent in bone healing.

Pauling replied

I can report that both my wife and I have been less troubled by colds during the last two years, during which we have been taking 3 to 5 grams of ascorbic a day, than we had been before beginning your regimen.

He also asked about Stone’s research on ascorbic acid and leukemia.

During the late 1960s, Pauling did not make a point of promoting vitamin C megadoses, though he did support the use of megavitamin therapy for the treatment of schizophrenia. But by 1969, he was finally fully convinced of Irwin Stone’s arguments as well as his own personal successes with vitamin C, and he began to promote vitamin C publicly.

Five Controlled Trials

[Part 1 of 4 in a series on Vitamin C and the Common Cold]

Linus Pauling became interested in ascorbic acid thanks to Dr. Irwin Stone, a biochemist from New York. After meeting Pauling in 1966 and hearing Pauling speak of his desire to live for an additional fifteen or twenty years, Dr. Stone sent him his own high-dose ascorbic acid regimen, which Pauling and his wife Ava Helen soon began to follow. After adhering to this program for several years, the Paulings observed a shared feeling of increased well-being and a striking decrease in the number of colds that they were contracting.

Linus Pauling was convinced that vitamin C was powerful enough to cure the common cold, but he was also aware that many authorities did not share his opinion.  He addressed this conflict in Chapter Five of his book Vitamin C and the Common Cold (1970) noting his desire to

resolve the apparent contradiction between the opinions expressed by authorities in nutrition and my own experience, which supported the widely held belief that ascorbic acid has value in decreasing the incidence of infection and ameliorating the severity of the common cold.

Pauling argued that ascorbic acid provides a minimal amount of protection against colds when taken in small amounts, but that the effect is proportionately greater when it is taken in much larger doses. According to Pauling, protection against colds becomes “nearly complete” when, shortly after the onset of a cold, one ingests four to ten grams of ascorbic acid per day. In support of his argument, Pauling cited five controlled trials conducted with various groups of people around the world.  These trials, he felt, supported his idea that health can be improved by adding more vitamin C to one’s diet.

Cowan, Diehl and Baker, 1942

The first study Pauling listed was an analysis of about 400 students at the University of Minnesota, conducted by Cowan, Diehl, and Baker during the winter of 1939-1940, and published in 1942 in the Journal of the American Medical Association. In this study, for twenty-eight weeks about half of the Minnesota students received 100 milligram tablets of vitamin C twice per day, while the other half received a placebo. The investigators concluded that the young adults who were already on a healthy diet were not greatly influenced by the 200 mg of vitamin C per day.  However, the study also yielded other important results.

First, the group receiving ascorbic acid throughout the twenty-eight week period experienced an average of 1.9 colds per person, with a 0.07 cold margin of error. Meanwhile, those in the placebo group reported an average of 2.2 colds per person, with a 0.08 margin of error. The investigators concluded that

the actual difference between the two groups during the year of the study amounts to 1/3 of a cold per person…[o]ne may therefore consider this as probably a significant difference, and vitamin C supplements to the diet may therefore be judged to give a slight advantage in reducing the number of colds experienced.

Pauling pointed out that this amounted to a 15% decrease in the quantity of colds per person. And although the investigators seemed to judge this a bordering-on-negligible amount, Pauling thought differently, wondering in his text if increasing the dosage to 400 mg of ascorbic acid per day would have decreased the colds twofold.

Another point in the Minnesota data that Pauling found compelling was the fact that of the 233 students participating in the ascorbic acid group, only 25 dropped out over the course of the study.  On the other hand, 39 students dropped out of the control group, which had started with 194 participants. Pauling drew the conclusion that a greater percentage of the students receiving ascorbic acid felt that they were benefiting from the study. Pauling likewise noted that the group which received vitamin C only missed an average of 1.1 days of school over the twenty-eight week study, while those who received the placebo lost an average of 1.6 school days.

Glazebrook and Thomson, 1942

In 1942 Glazebrook and Thomson published a similar study in the Journal of Hygiene, though this one focused on an institution of about 1,500 students in Scotland, where the students ranged in age from 15 to 20 years old. Glazebrook and Thomson’s group consumed a total dietary intake of only about 5 to 15 mg of ascorbic acid per student per day. This number was so low mainly because the school’s food was kept hot for two hours or more before serving, a practice which caused the served vegetables to lose much of their vitamin content.

In the Scottish survey, 335 students were given extra ascorbic acid – 200 mg per day for six months – while the remaining 1,100 served as a control. The ascorbic acid group recorded a 30.1 percent incidence of colds and tonsillitis, while the control group reported a 34.5 percent incidence. From these results, Pauling extrapolated that among the students who were given ascorbic acid, there were 13 percent fewer colds – a number close to the 15 percent decrease found in the Minnesota study.

The Scottish students who displayed more severe symptoms of colds or tonsillitis were admitted to Sick Quarters – 23.0 percent of the ascorbic acid group compared to 30.5 percent of the control group. This meant that 25 percent fewer students in the ascorbic acid group were admitted to Sick Quarters than were those in the control group.

Likewise, those receiving vitamin C also managed to stay out of the hospital: the average number of days spent in hospital due to infection for the control group was 5, versus 2.5 for the ascorbic acid group.  Drilling even deeper, there were 17 cases of pneumonia and 16 cases of acute rheumatism reported among the controls, while neither illness showed up in the ascorbic acid group.  Pauling used this data to emphasize the power of ascorbic acid in countering serious infections as well as the common cold.

Linus Pauling at an international vitamin symposium, Sao Paulo, Brazil, 1980.

Franz, Sands and Heyl, 1956

From there, Pauling briefly recounted an observation of 89 volunteer medical students and student nurses whose health was tracked for three months. The paper that resulted was published in a 1956 issue of the Journal of the American Medical Association by Franz, Sands, and Heyl. The study was constructed such that 44 of the students received 195 mg of ascorbic acid per day, while the remaining 45 received none.  In this instance, students in both groups experienced about the same number of colds, but the colds were judged to be less severe for the ascorbic acid group. It was concluded that this decreased severity and rapid improvement was “statistically significant at the 0.05 level.”

Wilson and Low, 1970

While each of the above studies and their results were relevant to Pauling’s case, Wilson and Low’s 1970 Acta Allergologica paper was of greater importance because it was a double-blind investigation. In this instance, neither the subjects – 103 students at a girls’ school in Ireland – nor the investigators evaluating the effects of the preparation knew which subjects had been given the placebo and which ones had been given vitamin C; that is, not until the study had reached its conclusion. As with the previous trials, the amount of 200 mg per day was used, but in the Wilson-Low group, 57 students received ascorbic acid while 46 received a placebo tablet over a period of three winter months.

Wilson and Low’s data indicated that ascorbic acid “reduced the incidence, duration, and severity of the symptoms of both toxic colds (sore throat, headache, fever, malaise) and catarrhal colds (cold in the head, cough, nasal obstruction, nasal discharge).” Symptoms of catarrhal colds lasted 8 days for the ascorbic acid group as opposed to 14 in the placebo group.

Pauling also noted that laboratory work indicated that the girls receiving ascorbic acid showed a higher concentration of ascorbic acid in the white blood cells than did the control group: the girls who had been receiving 200 mg of ascorbic acid once a day for 6 months had, on average, 60 micrograms of ascorbic acid present per hundred million cells, while those in the control group averaged 43 micrograms per hundred million cells. Pauling believed that “[t]his increase may be in part responsible for the increased resistance to infection.”

Ritzel, 1961

While these four studies seemed to show that about 200 mg of vitamin C daily can lessen the duration and symptoms of the common cold, Pauling needed to reinforce his hypothesis that “a somewhat larger intake of ascorbic acid provides somewhat greater protection.” To do so, Pauling turned to another double-blind study carried out in 1961 by the Swiss investigator Gunther Ritzel and published in Helvetica Medica Acta.

Unlike the rest of the literature cited by Pauling, Ritzel used 1000 mg of ascorbic acid, and noted a much greater effect than did the previous 200 mg studies. In his test of 279 skiers, Ritzel provided half of the subjects with 1000 mg of ascorbic acid per day, while the other half received a placebo. Among the vitamin C group, the data indicated a reduction of 61 percent in the number of days of illness from upper respiratory infections, and a 65 percent decrease in individual symptoms. Pauling was quick to note the substantial improvement in Ritzel’s group as compared to the 15 percent decrease brought about in the earlier studies by the daily ingestion of 200 mg of vitamin C. The data all seemed to provide solid evidence for Pauling’s basic rule of thumb:  when it comes to the common cold, the more vitamin C the better.

Vitamin C, the Common Cold and Controversy

By Tom Hager

[Part 3 of 3. For the full text of this article, originally presented as a lecture sponsored by Oregon Health Sciences University, please see this page, available at http://thomashager.net]

Portuguese edition of Vitamin C and the Common Cold, a book that was translated into nine different languages.

Pauling’s reading of the literature convinced him that the more vitamin C you took, approaching megadose levels, the lower your chances of getting sick, and the less sick you got.  It was at this point that Pauling made what I consider to be a fundamental mistake. He decided to publish his ideas without peer review, in the form of a popular book.

He did not feel he could wait. He had, he thought, good evidence that a cheap, apparently safe, easily available nutrient could prevent at least an appreciable fraction of a population from suffering through an affliction that made millions of people miserable. And there might be even greater results. Pauling had read of small villages, snowbound in the winter, where no one got colds because there was no reservoir of respiratory viruses to pass around. When visitors arrived in the spring, they would bring colds with them, and everyone would suffer. What if, through the use of vitamin C, a great many more people strengthened their resistance to colds? The two hundred or so cold viruses rampant in the world would have many fewer places to replicate themselves. The spread of colds would lessen; the population of cold viruses would decrease. “If the incidence of colds could be reduced enough throughout the world,” Pauling thought, “the common cold would dis­appear, as smallpox has in the British Isles. I foresee the achievement of this goal, perhaps within a decade or two, for some parts of the world.” Vitamin C, properly and widely used, might mean the end of the common cold.

Packaging for commercial cold remedies pasted by Pauling into his research notebook, July 1970.

This, of course, would not only greatly lessen the amount of suffer­ing in the world; it would increase the fame of Linus Pauling. He was nearing seventy years of age. It had been nearly twenty years since he had captured international attention for his scientific work with proteins, and won the Nobel Prize for chemistry. His efforts had gone to politics in the years since, and none of his recent scientific work had had much impact. Science was moving on without him. He was becoming a historical figure.

Pauling did not feel like one. He was not ready for emeritus status, trotted out at honorary occasions, shunted aside while the young men made the discoveries. He was still strong, still smart, still a fighter. Or­thomolecular medicine was the newest of his grand plans, and no one had shown that his ideas about creating an optimal molecular environ­ment for the body and mind were wrong. The evidence he had uncov­ered about ascorbic acid and colds, evidence that showed human health could be improved by increasing the amount of vitamin C in the body, was the strongest indication yet that he was right. Bringing it to the public’s attention would not only be good for the public; it would be a striking example of the correctness of his general theory.

Pauling’s book Vitamin C and the Common Cold, written in his usual clear, well-organized, straightforward style, presented the results of his literature search. He discussed the findings of five controlled trials that supported his idea, several anecdotal instances of physicians who had treated colds with vitamin C, and evidence that ascorbic acid was safe in large doses. Pauling felt confident that a several-gram daily dose would do no more harm than to cause loose stools, that vitamin C was safe, especially compared with potentially toxic, commonly avail­able over-the-counter medications such as aspirin. The rest of the book was a summary of his orthomolecular thinking and Irwin Stone’s ideas about evolution. A good deal of space was devoted to the topic of bio­chemical individuality, which resulted in a wide personal variation in the need for vitamin C and other nutrients.

On November 18, 1970, prepublication galleys were released to the press, and an unprecedented public roller-coaster ride began. The next day, the New York Times quoted Pauling as saying that humans needed between 1 and 4 grams of vitamin C per day to achieve optimal health and prevent colds. Pauling also took the occasion to slam the medical establishment – from drug companies to medical journals and physicians – for attempting to quash the evidence in favor of ascorbic acid. Why would they do that? the reporter asked. Look at the cold-remedy industry, Pauling said: It was worth $50 million per year, and that bought a lot of advertising space in medical magazines.

This quickly alienated both physicians and the editors of medical journals, neither of whom liked the implication that profits were more important than health. The medical establishment felt it necessary to respond, and respond quickly, once they saw how Pauling’s idea took off.

The book sold wildly, and so did vitamin C.  Pauling’s timing, at least on the public side, was superb. The 1960s had seen a resurgence of interest in “natural” health based on a holistic attitude that said body, mind, and soul were one. Many streams fed into this alternative health movement: a back-to-the-land, organic-foods orientation; a fas­cination with yoga, acupuncture, meditation, and other Eastern health practices; the rediscovery of the lost Western arts of naturopathy and homeopathy. Pauling’s message about vitamin C resonated with mil­lions of people who were reacting against corporate, reductionistic, paternalistic medicine, with its reliance on drug therapy, with people taking a renewed responsibility for their own health and trying to do it naturally. It was delivered just as natural food stores were popping up on corners in every town in America, each one stocked with a section for herbal remedies, a rack for magazines on alternative health regi­mens, and plenty of shelf space for vitamins.

The publication of Pauling’s book triggered a nationwide run on vitamin C. Sales skyrocketed, doubling, tripling, quadrupling, within a week of its appearance. Druggists interviewed in newspapers across the nation told of people coming in to buy all the vitamin C they had. Wholesale stocks were depleted. “The demand for ascorbic acid has now reached the point where it is taxing production capacity,” said a drug company spokesman less than a month after Pauling’s book ap­peared, adding, “It wouldn’t pay to increase production capacity since we’re sure it’s just a passing fad.”

The reaction was swift. The physician-head of the Food and Drug Administration (FDA), Charles C. Edwards, announced to the press that the national run on vitamin C was “ridiculous” and that “there is no scientific evidence and never have been any meaningful studies in­dicating that vitamin C is capable of preventing or curing colds.” The FDA, Pauling found, had proposed in 1966 that no vitamin C tablets over 100 mg be available without a prescription, and he responded to Edwards with sarcasm. If the FDA had its way and he wanted to take 10 grams of vitamin C to fight off a cold without going to a physician for a prescription, Pauling said, he would have to take 100 tablets. “I think I would have as much trouble swallowing all these tablets as I would swallowing some of the statements made by the Food and Drug Ad­ministration in proposing these regulations,” he said.

The medical press was equally critical of Pauling. The American Journal of Public Health said that Pauling’s book was “little more than theoretical speculation.” The Journal of the American Medical Association said of Pauling’s book, “Here are found, not the guarded statements of a philosopher or scientist seeking truths, but the clear, incisive sentences of an advertiser with something to sell. . . . The many admirers of Linus Pauling will wish he had not written this book.” The Medical Letter launched the harshest attack yet, saying Pauling’s conclusions “are derived from uncontrolled or inadequately controlled clinical studies, and from personal experience” and pointing out that there was no good evidence that vitamin C was safe when taken over a long period of time in large doses.

The controversy over Pauling’s book arose from a simple fact: He had not made his case. The book was a combination of his interesting but unproven speculations about orthomolecular medicine and the human evolutionary need for ascorbic acid, coupled with a select handful of studies that indicated that vitamin C could prevent or ame­liorate colds in a fraction of a population. That might make an inter­esting conference paper, but it was little reason to advocate a wholesale change in the dietary habits of a nation. His critics pointed out that he had no clear theory of how vitamin C exerted it powers and that there was no good study – no study at all – establishing that the long-term ingestion of megadoses of vitamin C was safe. The current dogma in the medical profession was that vitamins were needed only in the small amounts provided by a well-balanced diet. Taking grams of vitamin C every day might cause everything from gastric upset to kid­ney stones, and who knew what else?

The way he had gone about publicizing his ideas, sidestepping the normal channels of scientific peer review to publish a popular book, also fueled criticism. He was behaving like a health faddist, not a scien­tist. In the eyes of most physicians – generally conservative about new therapies, disdainful of the holistic health movement, trained to be­lieve that vitamin C was needed only to prevent scurvy – Pauling looked like a nutritional quack, a vitamin pusher who was essentially prescribing without a license.

Typically, Pauling fought back. To pursue his ideas, in 1973 he cofounded (with Arthur Robinson, a young colleague who later moved to Oregon and this year ran for Congress) the Institute of Orthomolecular Medicine in Palo Alto, California.

He went on to publish more books, adding the flu as another disease vitamin C could fight, then Vitamin C and Cancer, and finally compiled all his ideas into How to Live Longer and Feel Better.

Anecdote published in Chemtech, September 1994.

Criticism from the medical community has never let up. A general belief still exists in most – although not all – of the medical community that Pauling went off his rocker.

However, despite what many physicians believe, the jury is still out. A significant amount of active biomedical research research continues to examine the effects of micronutrients on a variety of conditions. For instance the Linus Pauling Institute at Oregon State University (successor to Pauling’s Orthomolecular Institute) maintains a highly successful research program in 12 laboratories funded with millions of dollars of competitive grant funding. The Institute’s head, Balz Frei, believes that Pauling’s basic approach remains sound – but that his arguments with physicians might have caused as much damage to the study of nutritional science as they did good. In my own view, by putting personal controversy ahead of reasoned consensus both Pauling and his critics polarized the public into groups that still have trouble communicating with each other.

Pauling’s work helped give birth to today’s booming market in nutritional supplements. Vitamin C remains the world’s largest-selling supplement. A large number of advocates strongly believe that ingesting vitamins in amounts far above the RDA can help optimize human health, especially by preventing chronic disease. There is a growing understanding that the key in these studies – as Pauling pointed out long ago – is not to look for vitamins to act like pharmaceuticals, exerting significant effects at low doses, but more like nutrients, with less dramatic effects that accumulate at much higher doses.

Linus Pauling himself lived an active life well into his nineties, performing useful research until the end. He was taking many grams of Vitamin C every day.

Will the controversy he started ever end? Was he a genius, or a crank?

The Birth of Orthomolecular Medicine

By Tom Hager

[Part 2 of 3.  For the full text of this article, originally presented as a lecture sponsored by Oregon Health Sciences University, please see this page, available at http://thomashager.net]

Linus Pauling and Irwin Stone, 1977.

The concept of orthomolecular medicine was Pauling’s grand theory of human health.

His approach was chemical, and viewed the body as a vast laboratory buzzing with chemical reactions: enzyme-substrate reactions, energy-producing reactions, antibody-antigen reactions, the chemical interactions that resulted in genetic duplication, and electrochemical reactions in the brain and nerves. Health, in this view, resulted when the lab was well-run and reactions were moving ahead properly; disease resulted if the proper reactions were hindered or stopped. Optimal health could be achieved by perfecting reaction conditions and making sure that the body maintained the proper balance of chemicals (nutrients, catalysts, and products).

After thinking about this balance for years, he coined a term to describe it: orthomolecular, meaning “the right molecules in the right amounts.”

He first used the term in print in 1967 in relation to psychiatric therapy. He had by then become convinced that conditions such as schizophrenia could be treated with nutrients such as niacin (an approach developed by Abram Hoffer and Humphrey Osmond). However, his theory of orthomolecular psychiatry was either ignored or criticized by the medical community.

Then came Vitamin C.


 

In March 1966, in a speech Pauling gave after receiving the Carl Neuberg Medal – awarded for his work in integrating new medical and biological knowledge – he men­tioned to the audience that he wanted to live another fifteen or twenty years in order to see the wonderful new medical advances that would surely come. A few days later, he received a letter from Irwin Stone, a gregarious Staten Island biochemist he had met briefly at the Neuberg dinner.

Stone told him how much he appreciated his talk and then wrote that asking for twenty more years of life was asking for too little. Why not live another fifty years? It was possible, if Pauling listened to his ad­vice.

Letter from Irwin Stone to Linus Pauling, April 4, 1966. This is the communication that spurred Pauling's interest in vitamin C.

He then told him about vitamin C.

Irwin Stone had been interested in vitamin C since 1935, when he began publishing papers and taking out patents on the use of ascorbic acid, or ascorbate (both synonyms for vitamin C), as a food preserva­tive. Over the years his interest grew as he read a series of scattered re­ports from around the world indicating that ascorbate in large doses might have some effect on treating a variety of viral diseases as well as heart disease and cancer. Convinced of its health-giving power, Stone and his wife started taking up to 3 grams of the vitamin per day- many times the daily dose recommended by the government.

Stone felt better as a result, but it took a car crash to make him a true believer. In 1960 Stone and his wife, driving in South Dakota, both nearly died when they were hit head-on by a drunk driver. They not only survived the crash, however, Stone told Pauling, but healed with miraculous rapidity. This he attributed to the massive doses of vitamin C they took while in recovery.

He emerged from the hospital ready to convince others about the value of ascorbate. He began to read widely, noting that among mam­mals, only man, closely related primates, and guinea pigs were unable to synthesize their own vitamin C internally because they lacked an en­zyme critical in producing the vitamin. As a result, humans had to ob­tain it through their diet. If there was none available, the result was scurvy, the dreaded ailment that had killed thousands of sailors before a British physician discovered it could be prevented by providing lime juice or fresh oranges. The U.S. government had duly set the mini­mum daily requirement for vitamin C at a level just sufficient to pre­vent scurvy.

But Stone believed that it was not enough. Scurvy was not a simple nutritional deficiency, it was a genetic disease, the lethal end point of an inborn error of metabolism, the loss of an enzyme that robbed hu­mans of the ability to produce a needed substance. And it appeared from animal studies that simply preventing scurvy might not be enough to ensure optimal health. Only one good biochemical assess­ment of ascorbic acid production in another mammal had been done, on rats, and it indicated that on a weight-adjusted basis, a 150-pound adult human would need between 1.4 and 4 grams of vitamin C per day to match what rats produced to keep themselves healthy. Stone was convinced that taking less than this amount could cause what he called “chronic subclinical scurvy,” a weakened state in which people were more susceptible to a variety of diseases. In a paper he had writ­ten- and which had already been rejected by six medical journals – he concluded,

This genetic-disease concept provides the necessary rationale for the use of large doses of ascorbic acid in diseases other than scurvy and opens wide areas of clinical research, previously inadequately explored, for the therapeutic use of high levels of ascorbic acid in infectious diseases, collagen diseases, cardiovascular conditions, cancer and the aging process.

In other words, to Stone, giving someone enough vitamin C to pre­vent scurvy was like feeding them just enough to keep them from starv­ing. Full, robust health demanded more. He advised that Pauling start with about one and a half grams per day. It was especially good, Stone said, for preventing viral diseases like colds.

“I didn’t believe it,” Pauling later said jokingly of Stone’s letter. After all, Stone was no physician, nor was he a nutritionist exactly or a professional medical researcher.

Pauling's response to Stone's letter of April 4, 1966. Written in July 1966.

But Pauling was interested enough to try taking more vitamin C himself. He discovered that it helped him fight off the colds that had frequently afflicted him. He felt better. He took a little more. Then more.

But he told few people about it. He remained generally silent about ascorbic acid and its benefits through the late 1960s, limiting his few comments to ideas about how it might be used, along with other nutrients, in the treatment of schizo­phrenics. In late 1969, however, convinced by the theoretical argu­ments of Irwin Stone and impressed by his own success in preventing colds, Pauling began expanding his comments to include the subject of ascorbate and general health, noting in a speech he gave to physi­cians at the Mt. Sinai Medical School his success with the use of vita­min C as a cold preventive. His comments were reported in the newspapers.


Cartoon of Linus Pauling in the laboratory, by Sidney Harris. 1985.

That is how it began. Then, two things happened. First, he received a “very strongly worded” letter from Dr. Victor Herbert, a leading clinical nutritionist and a man who helped set the U.S. recommended daily allowances (RDAs) for vita­mins, who assailed Pauling for giving aid and comfort to the quacks who were bleeding the American public with unsupported claims about the benefits of vitamins. Where, Herbert asked, were the care­fully controlled clinical studies to prove that ascorbic acid had a real effect on colds?

Pauling was taken aback. He had not, in fact, carefully reviewed the literature on vitamin C, limiting his reading to a few of the cita­tions in Irwin Stone’s original papers. But now, “sufficiently irritated by this fellow Herbert,” he began a typically comprehensive tour of the scientific journals.

Second, a writer for Mademoiselle magazine contacted Pauling to get his comments on vitamin C for an article on its health benefits. Pauling offered the reporter the general observation that “optimal amounts of vitamin C will increase health and intelligence” and re­ferred readers to his paper on orthomolecular psychiatry. When the article appeared in November 1969, he found his statement rebutted by Frederick Stare, a professor of nutrition at Harvard, who said Paul­ing “is not an authority on nutrition” and that there was no evidence that increased C helped prevent the common cold; in fact, just the op­posite was true. A large-scale study done with five thousand students in Minnesota twenty years earlier, Stare said, had proven definitively that vitamin C had no effect on colds.

Stung, Pauling quickly tracked down the study and decided that Stare had gotten his facts wrong. The 1942 University of Minnesota study involved 363 student subjects who had been given either a placebo or some extra ascorbic acid over a period of twenty-eight weeks. It was true that the authors had concluded in their summary that there was no “important effect” of vitamin C on infec­tions of the upper respiratory tract. But when Pauling took a closer look at their data, he decided they were wrong. Despite what Pauling considered the very low dose of vitamin C given the students – an aver­age of 180 mg per day compared to the 3,000 mg Pauling was now tak­ing – the researchers had in fact seen an effect:  Subjects receiving the extra vitamin had 15 percent fewer colds, and the colds they got were 30 percent less severe than those receiving the placebo. Vitamin C was not a preventive or cure, but the results were, Pauling estimated, statis­tically significant.

It was confusing, especially when Pauling saw the same thing hap­pening in other reports he found on vitamin C and colds: Partial ef­fects were discounted. The physicians who ran the studies seemed to be looking for total cures, not an indication of an effect. The doses they used were low (150-250 mg was common in these early studies –  several times the current RDA but many times lower than what Pauling and Stone considered a protective dose), and the effects they looked for were too strong.

The problem, Pauling decided, was that the researchers were look­ing for vitamin C to act like a drug. In traditional drug testing, small differences in dosage could have tremendous effects, and overdoses were deadly. The tendency was to use relatively small amounts and look for big effects.

Pauling research notebook entry on Gunther Ritzel's 1961 study. Notes dated February 22, 1971.

But to Pauling, vitamin C was a nutrient, not a drug. When the medical researchers saw a small effect, he thought the logical next step should have been to follow up with larger doses. His literature search uncovered at least one study that showed what might happen if they did. In 1961 a Swiss researcher named Gunther Ritzel had given half of a group of 279 skiers 1,000 mg per day of vitamin C – more than five times the Minnesota dose – and the other half a placebo. Ritzel found that those skiers receiving ascorbic acid had 61 percent fewer days of illness from upper respiratory tract infections and a 65 percent decrease in the severity of their symptoms compared to the placebo group.

This, Pauling thought, was very strong evidence in favor of his ideas. Plot the dose of vitamin C along the bottom of a graph and the effects on colds up the side and you could draw a straight line from the Minnesota results (a small effect with small dose) to the Swiss findings (a larger effect with larger dose). He found a few other papers in which the results fit the pattern. True, some of the research he looked at showed no effect at all – most of these studies, Pauling estimated, were flawed because they used too low doses, too short duration, shoddy oversight, or improper blinding – but the important thing was that a small group of careful clinical studies existed that supported Pauling and Stone’s general theory of vitamin C and health: The more C you took, approaching megadose levels, the lower your chances of getting sick, and the less sick you got.