Pauling’s Study of Schizophrenia: A New Model Vitamin

Irwin Stone. (Image by Oscar Falconi)

[Part 2 of 9]

“I have decided, on the basis of the evidence presented by Irwin Stone, that there is very strong evidence now, that most human beings are suffering from hypoascorbemia, a mild sort of deficiency of ascorbic acid in the blood; perhaps it is wrong for me to call it a mild sort. The point that I call to your attention is that I believe that for all or almost all human beings, the amount of vitamin C that is contained in the food is less that the optimum amount, and that the state of health of almost all human beings is not so good as it would be if they were to ingest a larger amount.”

-Linus Pauling, speech to the American Schizophrenia Association, July 1971.

Linus Pauling’s chance encounter with the work of Abram Hoffer and Humphry Osmond convinced him that metabolic diseases could be treated by megadosing with certain vitamins; a practice that he labeled “orthomolecular medicine.” As Pauling’s interest in the topic grew, he sought out as much of the existing scientific literature as he could find, and quickly began to see a pattern.

As early as the 1940s, there seemed to be evidence of a positive correlation between increased niacin intake and improvement of certain psychoses in patients. The literature also supported Hoffer and Osmond’s finding that vitamin megadosing was not likely to cause significant side effects. On the contrary, many of the era’s commonly prescribed anti-psychotic drugs often caused severe side effects, sometimes even at low doses. The benefit of this new alternative was made clear by Osmond in a 1970 letter to Pauling, in which he noted that

[we are] dealing with a set of highly physiologically active substances [such as niacin] which do not, however, seem to produce the sort of danger which one finds in most physiologically active substances.

Though Pauling was convinced that orthomolecular therapy was effective, his continuing review of the literature cast doubt on whether or not niacin was, in fact, the most effective vitamin to use in treating patients with psychoses, such as schizophrenia. Though niacin was clearly safe, certain investigators had reported marginal success rates with their patients. Enough data of this sort had been reported to lead Pauling away from niacin and in the direction of a new vitamin. It was here that Irwin Stone entered his life.

---

In March 1966, Pauling traveled to New York to accept an award from the Carl Neuberg Society for International Scientific Relations. In his speech, Pauling – then sixty-five years old – expressed hope that he might live for another twenty years, so that he might witness the scientific advances that he believed to be forthcoming. Irwin Stone, a biochemist who worked mostly in the brewing industry, was in the audience that evening, and he felt as though he could virtually guarantee another twenty years or more for Pauling.

In a letter that he wrote after the speech, Stone told Pauling about research that he had been conducting on the health effects of vitamin C, stressing that he had been megadosing with the vitamin for the past few years and was healthier than ever as a result. In relaying this, Stone acknowledged that the story seemed implausible and admitted that he had remained a bit skeptical himself until he was involved in a car accident. Buoyed by his high dose vitamin C regimen, Stone recovered from the incident far faster than he or his doctors believed possible, and from then on he had been convinced. In Stone’s view, vitamin C would easily buy Pauling another twenty years, and maybe up to fifty!

When Stone sent his letter, he could not have known that Pauling was hatching his own interest in orthomolecular medicine; Pauling’s first paper on the subject did not appear until a year later. As such, Pauling knew that Stone’s testimony was not informed or biased by previous knowledge of his work. The letter did, however, add to Pauling’s growing belief in power of high dose supplementation in the treatment of disease. Likewise, Pauling had also been given a new model that he might explore for mental illness in lieu of the niacin trials conducted by Hoffer, Osmond and others. The next step then, was to see how effective megadoses of vitamin C might be for patients suffering from schizophrenia.

Evolution and the Need for Ascorbic Acid

Linus Pauling, 1970

Linus Pauling’s belief in the value of vitamin C emerged from many sources, but key among them was the fact that humans, for most of their history, have been unable to produce their own ascorbic acid. This stands in stark contrast to nearly every other animal, virtually all of whom are able to synthesize their own ascorbic acid internally. Pauling viewed this human characteristic as having emerged from an evolutionary adaptation that, in his view, had sentenced modern humans to lives of sub-optimal health.

In December 1970, Pauling detailed this point of view in an article titled “Evolution and the Need for Ascorbic Acid,” which was published in the Proceedings of the National Academy of Sciences. In it, Pauling began by stating that the minimum daily requirements then espoused for vitamin C – 35 mg for an infant and 60 mg for an adult – were only enough to stave off scurvy and remained grossly insufficient to supporting ideal human functioning. In so doing, Pauling framed the onset of scurvy as not just the first symptom of low ascorbic acid levels, but rather the last symptom before death.

Pauling then pointed out that, along with the guinea pig, the Indian fruit-eating bat, and an early ancestor of the Passeriformes bird, humans are among a tiny minority of the world’s animals who are incapable of synthesizing their own ascorbic acid. The question is, why?

---

Table 1 (excerpted) from Pauling’s 1970s PNAS article.

Pauling took an evolutionary view as he searched for an answer. In his article, he began by defining the eobiontic period – a two to three billion year period after the “hot thin soup” era – as a phase characterized by profound biochemical evolution. It was during this time period, about 25 million years ago, where Pauling believed that humans lost the ability to self-produce ascorbic acid.

To demonstrate how this might have happened, Pauling detailed a similar circumstance with thiamine, which is also an essential nutrient for mammals. At some point during the eobiontic period, certain species also began to lose their ability to synthesize thiamine and many researchers, including Pauling, believed that this was because “the supply of food available to an earlier ancestor provided an adequate supply of these vitamins, enough to make it advantageous to discard the mechanism for synthesizing them.” According to the theory, those species that did not discard this mechanism were disadvantaged because maintaining synthetic production became a burden. “[I]t cluttered up the cells,” Pauling wrote, “added to the body weight, and used energy that could be better used for other purposes.”

Pauling believed that the abundant availability of foods rich in vitamin C also led humans to evolve away from synthesizing ascorbic acid. Pauling listed 110 of these foods in a table within his article. They included sweet red peppers, sweet green peppers, hot red chili peppers, parsley, black currants, and broccoli spears among many others.

---

Irwin Stone. (Image by Oscar Falconi)

Pauling also examined the research of three colleagues to add support for his theory: British researcher G.H. Bourne, American biochemist Irwin Stone, and American physician Edmé Régnier. Pauling looked to these three in particular to try and calibrate the level of ascorbic acid intake that would result in ideal human functioning.

In 1949, G.H. Bourne conducted a study focusing on the diets of gorillas and found that they consumed nearly 4.5 g of ascorbic acid per day through green foods. The variety of foods consumed by gorillas was also deemed by Bourne to be similar to that likely consumed by humans prior to the development of agriculture. By comparing the diets of the two, as well as their proportional body weights, Bourne determined that contemporary humans should strive to consume closer to 1 or 2 grams of ascorbic acid per day, rather than the the 7 to 30 mg recommended at the time.

Later, in the mid-1960s, Irwin Stone performed a set of experiments with a similar aim. After discovering that the daily rate of vitamin C synthesis for rats ranged from 26 mg kg^-1 to 58 mg kg^-1, Stone determined that the best intake of ascorbic acid for optimum human health was between 1.8 g to 4.1 g per day – the levels that individuals of varying sizes would produce if the rat synthesis rate were scaled accordingly.

Only a couple years after Stone released his hypothesis, Edmé Régnier produced his own theory that settled on a regiment of 5 g of ascorbic acid per day. Further, after several trials in which Régnier administered varying amounts of ascorbic acid to study participants, Régnier concluded that 45 out of 50 colds had been prevented by doses of 600 mg of ascorbic acid. Not long after, Pauling would write a book that did much to popularize the use of vitamin C in the treatment and prevention of the common cold.

---

After considering the research of the previous three scientists as well as conducting trials of his own, Pauling theorized that optimal human intake of ascorbic acid likely ranged from 2.3 g to 9.5 g. Pauling’s minimum recommendation was 2.3 g because that was the average amount of ascorbic acid provided by the 110 natural foods listed in his table. Likewise, Pauling deduced that the amount required to achieve optimal health would not exceed 9.5 g, because that was the high-end total available through a smaller selection of foods described in the same table.

Pauling also recognized the importance of biochemical individuality, age, size, and gender, and considered all of these factors in publishing his 2.3 g to 9.5 g range. He likewise took comfort in knowing that his conclusions were similar to those of Stone and Bourne, and this corpus of research convinced Pauling, for the remainder of his life, that vitamin C was an essential key to achieving optimal health.

Pauling 115

This is where we’ll be today.

This coming Sunday will mark the 115th anniversary of Linus Pauling’s birth on February 28, 1901. While we here at Oregon State University are commemorating the birthday anniversary with cake and conversation at the Linus Pauling Science Center, the Pauling Blog observes the occasion in our traditional manner, by looking back at Pauling’s life 100, 75, 50 and 25 years ago.

Lucile, Linus, Belle and Pauline, 1916.

1916

As a junior at Washington High School in Portland, Oregon, Pauling took his first chemistry class in spring 1916.  That fall he began his senior year at Washington and then, in 1917, enrolled at Oregon Agricultural College, at the age of sixteen and lacking a high school diploma. Pauling did not graduate from high school because he neglected to take a required history course, and back then OAC didn’t require high school equivalency for admission.  Linus was always a good student, of course, but during his junior year at Washington he struggled a bit, earning C’s in English and Latin, alongside the expected A’s in solid geometry and chemistry.

Pauling family portrait taken in 1941. Back of photograph is annotated, “1941. Daddy very ill.”

1941

With the onset of war in Europe, Pauling faced a major personal crisis of his own in 1941. While giving a lecture in New York, Pauling made light of his alarmingly swollen face:

I am happy also that this occasion has brought me in touch with many old friends – with Paul Emmett and Joe Mayer and many others. Several of them said to me tonight that I appeared to be getting fat. This is not so. You know, when I was a boy in Oregon I used to go around a great deal in the green, damp Oregon woods, and I always came into contact with poison oak, which caused my face to swell and my eyes to swell shut, and me to apply so much lead acetate solution that it is a wonder that I didn’t die of lead poisoning. Yesterday I must have bumped into something similar, for my face began to swell, and I began to be afraid that I would have to speak here tonight with my eyes swollen shut – which I could have done, with the practice I have had speaking in the dark. Well, while I was wondering what the responsible protein could have been, I decided that it was a visitation – that I was being punished for thinking wicked thoughts. The other day I said “It is too bad that something doesn’t happen to Senator Wheeler – nothing serious, just something that would lay him up with his eyes shut for two or three weeks” and my wife said “No what you want is something that would keep his mouth shut – his eyes are closed already.”

As it turned out, Pauling’s edema was the result of his having fallen ill with glomerulonephritis, a kidney disease that was usually fatal.  Fortunately for Pauling and for the history of science, he sought out an alternative treatment from Dr. Thomas Addis that saved his life.

Even prior to the Japanese attack on Pearl Harbor, the U.S. was shifting gears in response to the outbreak of World War II. This shift made a direct impact on Pauling’s work at Caltech, and he began putting the brakes on his massive program of research on the structure of proteins in favor of new studies funded by government war contracts, including, in 1941, investigations of elastic explosives and rocket propellants.

Linus Pauling, 1966.

1966

Pauling’s life and work took another dramatic shift in 1966 when he made the acquaintance of Irwin Stone, initially through correspondence.  At a talk on “Science and World Problems” delivered in New York, Pauling had made mention of a desire to live another fifteen years, so that he might be able to witness some of the major advances that he foresaw as being on the close horizon.  Stone was in the audience and sent Pauling a hugely influential letter that detailed a “High Level Ascorbic Acid Regimen” that could “help you achieve this goal and possibly tack on a few extra decades.”  Pauling was intrigued and thus began his famous fascination with vitamin C.

Linus Pauling and a guest in his office at the Linus Pauling Institute of Science and Medicine, 1991.

1991

Now 90 years old, Pauling experienced a difficult year in 1991.  As the year began, the United States was preparing to invade the Persian Gulf, an action that Pauling protested vehemently, taking out a paid advertisement in the New York Times imploring the government to “stop the rush to war.”

Closer to home, Pauling’s friend and close colleague Ewan Cameron, with whom he had published some of his most controversial papers on vitamin C, passed away at the age of 68, a victim of cancer.  That fall, Pauling himself was also diagnosed with prostate and rectal cancer, which he began treating using megadoses of vitamin C and an experimental hormone therapy.  He would live for three more years before passing away on August 19, 1994.

Vitamin C and the Common Cold: The Roots of Controversy

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)

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.

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’s Impact on Pauling

Linus Pauling and Irwin Stone, 1977.

[Part 2 of 2]

Four years after Irwin Stone first convinced Linus Pauling to start taking megadoses of vitamin C, Pauling decided to share with the world the successes that he had observed in his own improved mental and physical health.

In 1970 Pauling began to work on a book, Vitamin C and the Common Cold, and he wrote to Stone asking permission to dedicate it to him. He also sent Stone a copy of the manuscript to review. Stone wrote back praising the work.

The book is excellent and should go far to eliminate this thoroughly unnecessary and annoying condition, at least among your readers. The audience will increase over the years, especially if Medicine can eventually see the light.

Stone continued to encounter difficulty getting his own scientific articles about ascorbic acid published and he certainly did not have the funding to run his own clinical trials. Partly as a result, he too was writing a book about vitamin C and all of the many diseases that he thought were related to hypoascorbemia. A  major thrust of the book was its plea for large scale research on the topic. Stone hoped to get popular opinion on board with his ideas in order to place pressure on physicians and nutritionists to do research in this area.

Pauling’s Vitamin C and the Common Cold was a popular success. Many readers around the world were persuaded by his ideas and began to take vitamin C supplements to prevent and treat colds. Some of his acclaim rubbed off on Irwin Stone, who wrote to Pauling telling him that he too was finally receiving recognition from popular media sources, including NBC.

In 1971 Stone retired to San Jose, California and devoted the rest of his life to researching and promoting the need for high consumption of vitamin C by humans. That same year he finished his book, The Healing Factor: Vitamin C Against Disease, and asked that Pauling write a foreword for it. Pauling was glad to do so, calling it “an outstanding contribution to knowledge.”

Stone’s inscription to Pauling in a first edition of The Healing Factor, 1972.

Despite their popular appeal, Pauling and Stone continued to encounter problems convincing medical practitioners and researchers to take their ideas about ascorbic acid seriously. Stone believed that this was so because vitamin C would be a much more inexpensive cure than the current treatments of the time, causing pharmaceutical companies and doctors to lose money.

One medical doctor, Ewan Cameron, did believe in the effectiveness of vitamin C against cancer and was treating his terminal cancer patients with megadoses of it in Glasgow, Scotland. He formed a trans-Atlantic research partnership with Pauling in 1971 and they began to collaborate on papers discussing the use of vitamin C against cancer, eventually publishing ten articles together.

Through his partnership with Pauling, Cameron also began to correspond with Stone about the implementation of vitamin C against cancer and their shared difficulties getting the medical community to accept their hypotheses.

Cameron maintained a unique viewpoint on the treatment of cancer and how ascorbic acid might fit into a clinical regimen. In December 1974, he explained his views to Stone.

It is completely contrary to all contemporary medical thought to even suggest that such a mundane substance as ascorbic acid could have any value in such a complicated disease as cancer. This is because cancer research is concentrating all its energies in searching for more and more sophisticated ways of selectively destroying cancer cells. The research is becoming so complex and so unproductive, that it is natural to assume that ‘the answer’ must be extraordinarily complex and almost beyond human comprehension….We would make much more progress if we accept that cancer cells are normal cells that merely happen to be behaving in an abnormal way. We would then accept that cancer cells have an equal right to live, and concentrate our energies in suppressing the abnormal behavior pattern.

Throughout their correspondence, Cameron described his successes treating cancer with ascorbic acid. But he also noted that a number of patients showed no improvement from it or, at best, their cancer was brought to a standstill. He was disappointed that his primary successes were mostly by way of increasing patients’ survival time, not in curing them. Cameron thought that the greatest success would be in prophylaxis – taking megadoses of ascorbic acid throughout one’s life in order to prevent cancer.

---

In 1978 Stone wrote a letter to the editor of Nutrition Today in response to the publication’s recent issue focusing on ascorbic acid. His letter shows how fervently he believed in hypoascorbemia.

I regard our most serious medical problem to be the dangerous complacency that the orthodox medical establishment exhibits toward Chronic Subclinical Scurvy and its refusal to do anything to correct and alleviate this potentially-fatal human birth defect. Chronic Subclinical Scurvy has killed more human victims, caused more disease and misery among Mankind than any other single factor in the past and is continuing this evil record in the present. I’m worried about the future, because that is where I’m spending the rest of my life.

Meanwhile, Stone and Pauling’s relationship continued to flourish. In 1977 Pauling invited Stone to become a member of the Board of Associates of the Linus Pauling Institute of Science, an offer that was accepted. Pauling also attended Stone’s surprise 70th birthday party that year. In 1981 Stone was unable to make it to Pauling’s 80th birthday, but he did pass along a message.

You will recall the promise I made you in 1966 of 50 more healthy years of life with Megascorbics. You thought I was exaggerating and said you would be satisfied with 15 years. Well the 15th year is now and I am looking forward to attending your 115th birthday party in 2016. Megascorbics makes you practically indestructible.

In response, Pauling wrote, “I am glad to express my thanks to you for having written to me in 1966. Your letter and the reprints of your papers changed my life.” While Pauling did not make it to 2016, he did live until 1994, passing away at 93 years of age.

The last letter that Pauling wrote to Stone concerned a joint award from the Academy of Orthomolecular Psychiatry and the Orthomolecular Medical Society that Stone was to receive. The Linus Pauling Institute of Science and Medicine was also going to surprise him with a second award. Pauling wrote,

For many years you have been an inspiration to me, because of your devotion to vitamin C and your conviction that a high intake of vitamin C has great value in improving the health of human beings. You have rendered a great service to the people of the world through your continued study of vitamin C over a period of fifty years.

Unfortunately, Dr. Irwin Stone died on May 4, 1984, at the age of 77, while in Los Angeles to receive the award. He died by choking on regurgitated food, the result of a constricted esophagus that had plagued him ever since his car accident many years prior.

Irwin Stone received two honorary doctorates, many additional awards, and 26 patents. He also published over 120 scientific papers throughout his life (at least 50 were about vitamin C) and wrote one book, The Healing Factor, published in 1972. He was father to one son, Steven, and was married to his wife Barbara for over 50 years.

In December 1986, two years after his death, Barbara Stone sent Pauling a card congratulating him on the publication of his latest book, How to Live Longer and Feel Better. She wrote “Irwin would have enjoyed reading it and noting the many references to him and other colleagues.” Pauling hadn’t exaggerated in his 1981 letter: Irwin Stone really did change his life and made a profound impact on the scientific legacy that Pauling leaves behind today.

Irwin Stone: An Influential Man

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.

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.

Vitamin C Deficiency in Humans: An Issue of Evolution?

Linus Pauling and Irwin Stone, 1977.

[Part 3 of 4 in a series on Vitamin C and the Common Cold]

In the chapter “Vitamin C and Evolution” from his book Vitamin C and the Common Cold, Pauling wondered about the reasons why the rest of the animal world can synthesize vitamin C, while human beings, along with a very small group of mammals, cannot. His answer was gene mutation, using the instance of thiamine as evidence.

All animals need thiamine as an essential vitamin; in its absence they develop a disease similar to beriberi. Pauling theorized that over 500 million years ago, when the common ancestor to present-day birds and mammals lived, there existed an environment imbued with an abundance of green plants containing thiamine. By way of gene mutation, one of the animals living during that era must have lost the mechanism which allowed it to synthesize thiamine. This was advantageous to the animal – which was probably plant-eating – because it could obtain the thiamine it needed from the plants it ingested while simultaneously conserving the energy that it would have used to manufacture the vitamin.

Pauling pointed out that possessing this extra energy would have caused the animal to flourish and to have more offspring than others of its kind. The advantageous mutation would be passed on to certain of the progeny, who would in turn pass it on to their own offspring, and so on. Eventually the mutation would spread, and a few million years later all mammals and birds would possess the mutation.

Pauling believed that in the same way that all animals lost the biochemical machinery to produce thiamine, so too did human beings, primates, guinea pigs and a particular Indian fruit-eating bat lose the ability to synthesize vitamin C. A mutation that results in the inability to synthesize a substance is simple and occurs often; it only requires a single gene to be damaged or deleted. The reverse process is more complex and takes much longer. The mutation that removed the ability to synthesize vitamin C probably took place about 25 million years ago, in the ancestor of modern primates and humans.

In his book, Pauling next asked the question, why didn’t all mammals and birds lose the ability to synthesize vitamin C the way that they lost the ability to synthesize thiamine? Pauling theorized that the change likely occurred in the guinea pig and the Indian fruit-eating bat independently of the common precursor of the primates, due to an abundance of vitamin C in their diets. The fact that the majority of animals possess the ability to synthesize vitamin C indicates that there is not sufficient vitamin C in their dietary environment for them to obtain the vitamin solely from their nutrition intake.  To Pauling, this also suggested the existence of a deficiency of ascorbic acid in the human diet.

Dr. Irwin Stone, a biochemist in Staten Island, New York, was the person responsible for sparking Linus Pauling’s interest in vitamin C. Dr. Stone, a leader in the ascorbic acid field at the time, sent a letter to Pauling in 1966 informing him of a high-level ascorbic acid regimen that he had been developing over the past three decades, which Pauling and his wife began to follow. Stone believed that humans need between 3 and 5 grams of vitamin C per day, reinforcing this claim by citing the British researcher G. H. Bourne’s evidence that gorillas ingest about 4.5 g of ascorbic acid per day.

Gorillas, like humans, do not synthesize vitamin C, and so need to obtain it from their diet. In 1949 Bourne pointed out that before the development of agriculture, humans lived mainly off of raw, green plants with little meat; a diet similar to that of the modern gorilla. Bourne concluded that

it may be possible, therefore, that when we are arguing whether 7 or 30 mg of vitamin C a day is an adequate intake we may be very wide of the mark. Perhaps we should be arguing whether 1 g or 2 g a day is the correct amount.

Irwin Stone also took into consideration the amount of ascorbic acid that other animals, such as rats, manufacture. The rat synthesizes vitamin C at a rate of between 26 mg and 58 mg per day per kilogram of body weight. If the same rate of manufacture were applied to humans, a person weighing 70 kg (154 lbs) would need to ingest between 1.8 g and 4.1 g of ascorbic acid per day.

From there, Pauling verified the amounts of various vitamins contained in 110 different raw fruits and vegetables corresponding to a diet of 2,500 kilocalories per day, and found that “for most vitamins this amount is about three times the daily allowance recommended by the Food and Nutrition Board.” For ascorbic acid, the difference was much more drastic: the average amount of ascorbic acid in a day’s ration of the 110 raw foods was 2.3 g, which was about 42 times the recommended amount. Pauling argued that

If the need for ascorbic acid were really as small as the daily allowance recommended by the Food and Nutrition Board the mutation would surely have occurred 500 million years ago, and dogs, cows, pigs, horses, and other animals would be obtaining ascorbic acid from their food, instead of manufacturing it in their own liver cells.

Pauling found that the average ascorbic acid content for the fourteen most vitamin C-rich plant foods is 9.4 g per 2,500 kilocalories, leading him to the conclusion that the optimum daily vitamin C intake for an adult human being is between 2.3 g and 9 g – quantities in line with what he saw as existing in the natural diet of the human lineage and numbers far beyond the recommendations issued government nutritional authorities, then or now.

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.

Excerpt from “Cold Preventive”, New York Times, November 19, 1970.

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.

Extract from “The VIP Line,” Miami Herald, June 7, 1971.

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.

Cancer and Vitamin C Redux

Group photo of the Linus Pauling Institute of Science and Medicine staff, 1989. Ewan Cameron stands adjacent to Linus Pauling

The conversation concerning the possible use of vitamin C in the treatment of cancer continues to gather momentum. 

As we’ve noted before on the PaulingBlog, the possibility that ascorbic acid might be a useful tool in the fight against cancer was a topic of intense interest to Linus Pauling and a handful of his colleagues (Ewan Cameron and Irwin Stone, among others) over the last two decades of his life.  Pauling’s devotion to the subject, and often-fiery defenses of his beliefs, attracted no small amount of criticism from the scientific and medical mainstream.  More than anything else, Pauling’s vitamin C and cancer research is the source of the “Pauling as quack” notions still prevalent in certain circles.

With Pauling’s death in 1994, the push for rigorous study of the vitamin C and cancer question steadily dissipated.  In recent time however, thanks in large part to new findings published by the National Institutes of Health, the possibilities suggested by Pauling, Cameron, Stone and others are now re-entering the scientific discourse.  As reported yesterday in Cancer Monthly, a new commentary written by Dr. Balz Frei and Stephen Lawson of the Linus Pauling Institute, and published in the August 12, 2008 issue of the Proceedings of the National Academy of Science, (free extract available here) lends further credence to the preliminary results reported in early August by the NIH.  Quoting from Cancer Monthly

“[Pauling and Cameron’s] research was intriguing enough that the National Cancer Institute (NCI) launched two subsequent studies on the subject at the Mayo Clinic.  However, when those studies failed to show that vitamin C increased survival in terminal cancer patients, interest in the antioxidant as an anticancer therapy began to wane….Where the NCI studies were likely missing the mark was by giving vitamin C orally in relatively small doses, say the commentary authors….’We know that IV vitamin C produces levels in blood that are many times greater than those achieved with oral supplementation, and these very high concentrations may be necessary to kill cancer cells,’ says Lawson.”

In the spirit of lending added historical perspective to this evolving topic, the PaulingBlog is pleased to provide exclusive access to Linus Pauling’s first complete speech typescript on the subject at hand.  Below the fold is the entirety of a fourteen-page talk titled “Ascorbic Acid and Cancer,” delivered by Pauling to the California Orthomolecular Medical Society at a meeting in San Francisco on February 14, 1976. While this typescript does not represent the first presentation that Pauling gave on the topic (the earliest talks date back to at least November 1971), the content published below does represent the oldest complete vitamin C and cancer speech typescript held in the Ava Helen and Linus Pauling Papers.