A Somber Return to China, 1981

The Paulings in Tianjin, June 1981.

In the summer of 1981, Linus Pauling participated in the First International Conference on Human Nutrition, which took place in Japan and China. The conference lasted from May 31 to June 8, and was sponsored by the China Medical Association and the Foundation for Nutritional Advancement, the latter of which Pauling was president. The conference took place in Tokyo, Japan and Tianjin, China, travels to which would comprise the first part of a trip that would also take the Paulings to Germany and to London. Their daughter Linda and her husband Barclay accompanied Linus and Ava Helen to the Orient.

Pauling made the opening remarks at the beginning of the conference in Tokyo on June 1. After the Tokyo sessions were completed three days later, the Paulings flew to Peking, traveled in an official vehicle to Tianjin (a “red flag limousine,” as recorded by Pauling in his journal) and stayed in the State Guest House in the same suite used by Richard Nixon during his iconic 1972 trip to China.  From June 4-8, Pauling participated in the conference, which was jointly planned by the FNA and Professor Chou Pei-yuan, the President of the University of Beijing. This was the second and last time Pauling was to visit China.

A day after arriving in China, the Paulings toured Tianjin Medical College, Tianjin Hospital and Tianjin Children’s Hospital before attending a formal reception given by Li Xiannian, who eventually became the Chinese Head of State in 1983. The conference in China formally opened on June 6, again with Pauling delivering the opening remarks. In them, he discussed the roots of his interest in the field of nutrition, and also reflected upon the early years of his scientific career beginning with his focus on minerals and later interest in the nature of life, which arose in 1929 largely because of the presence of Thomas Hunt Morgan (who had discovered the concept of the gene) at Caltech.

An unidentified individual, Arthur Sackler, the Chinese Minister of Health and Linus Pauling, June 1981.

In his talk, Pauling explained that he had decided to learn more about organic chemistry in order to understand how molecules are built and how they interact with each other, beginning with hemoglobin. During this time, Pauling also studied antibodies, immunology, sickle cell anemias, and other heretic anemias. In 1954 he decided to look at other groups of diseases to see if they could be classed as molecular diseases, and chose to study mental illness over cancer, because he felt that many people were working on cancer already. After researching mental illness for ten years, he became interested in vitamins.

According to Pauling, his interest in vitamins came about when he learned that the Canadian scientists Abram Hoffer and Humphry Osmond were treating schizophrenia patients with large amounts of niacin. Simultaneously, Gerald Milner had been giving large amounts of ascorbic acid to mentally ill patients, with positive results. Pauling later observed that vitamin C had value in the control of cancer, so he became involved with cancer. Near the end of his address, Pauling remarked, “As I look back on my life, I see that I have enjoyed myself very much and a good bit of this enjoyment has come from the continued recognition of something new about the universe.”

Other talks given over the course of the Tianjin conference included “Vitamin C and Cancer,” delivered by Pauling; “Extending Life Span of Patients with Terminal Cancer Using High Doses of Vitamin C,” given by Dr. Akira Murata from the Department of Agriculture at Saga University, Japan; and “A Study on Fortified Foods with Ascorbic Acid Phosphate,” given by Professor Chou Deqin, from the Chinese Institute of Military Hygiene.

The conference closed on Monday, June 8. The next day, the Paulings took part in a sight-seeing tour of the Great Wall and the Ming tombs. Later that week, Pauling gave a talk on chemical bonds in transition metals at Peking University, and continued to give lectures and meet with various scientists throughout the rest of his time in China.

Photo of Ava Helen Pauling taken in China, six months prior to her death.

The trip took a dramatic turn for the worse when, in the afternoon of June 19, Ava Helen had a heart attack and was taken to the hospital. Though she left the hospital the next day, she remained medicated and too sick to travel for a few days after, causing the Paulings to change their plans. She remained weak for the rest of their time in China, though recovered enough to complete their planned itinerary through Germany and London.

When the couple returned to California and Ava Helen underwent exploratory surgery, it was determined that she was facing a recurrence of stomach cancer, from which she had been suffering for the past five years. Her cancer was deemed inoperable and only a few short months later, on December 7, 1981, Ava Helen would pass away, three weeks shy of her 78th birthday.

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.

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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.

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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.

Remembering Abram Hoffer

Abram Hoffer and Linus Pauling, November 1992.

“As a physician, I am ambivalent about my association with the medical fraternity.  I am happy to be in a profession which has discovered so much information in the field of disease and health, but I am unhappy and distressed with such an association which almost invariably rejects at first hand the discoveries and views of scientists which it will eventually embrace with equal fervor.  Is there no end to this irresponsible hostility of physicians towards scientists such as Linus Pauling?  But this is the way it is.”

-Abram Hoffer, May 1986.

The Canadian physician Abram Hoffer, a pioneer of orthomolecular medicine, died in May 2009 at the age of 91.  The Hoffer name is stamped throughout the Ava Helen and Linus Pauling Papers as, in many respects, his career mirrored the final decades of Linus Pauling’s own work.

Hoffer’s career achievements are summed up nicely in this obituary published by the CNW Group:

Abram Hoffer became a pioneer of progress early on his career, challenging the dominant view at the time that schizophrenia was the result of poor mothering, and was instrumental in the authoring of research on the genetics of this common mental illness with the renowned geneticist Ernst Mayer. After co-discovering the first effective lipid-lowering agent, Vitamin B3 (niacin), the native of Saskatchewan became equally as instrumental in the development and execution of the first controlled clinical trials in psychiatry. This resulted in the creation of the then-controversial treatment of acute schizophrenia through principles of respect, shelter, sound nutrition, appropriate medication and the administration of large doses of water-soluble vitamins. In particular, Dr. Hoffer identified through research that large doses of Vitamin B3 (niacin) and Vitamin C could eliminate the symptoms of schizophrenia and reduce relapses. He dedicated his life to curing-not palliating-schizophrenia.

Hoffer’s breakthroughs in the medical understanding of schizophrenia paralleled similar work being conducted by Linus Pauling.  As Pauling noted in 1991

Dr. Hoffer, over 40 years ago, developed the basic principles of megavitamin therapy, a part of orthomolecular medicine.  I devised the word ‘orthomolecular’ to describe substances, such as vitamins, that are present in the human body, and are required for life.  I proposed, in 1968, that significant improvement in health and in the control of disease could be achieved by varying the concentrations of these substances in such a way that they would have their maximum effects.  Many physicians now call themselves orthomolecular physicians.

For the bulk of their association, Hoffer and Pauling, though inhabiting similar orbits, retained their independence from one another as researchers – each supported the other in various ways, but no scientific collaboration actually occurred.

This arrangement would change in the late 1980s as Hoffer became increasingly interested in the potential treatment of cancer using orthomolecular methods.  Based on his study of fifty patients Hoffer concluded that Pauling and Ewan Cameron’s hypothesis “that vitamin C in large doses did improve enormously the outcome of treatment for cancer,” was correct.  As he recalled in 2000

Linus asked me if I intended to publish the data. I replied that I did not. I added that in my opinion there was little point in trying to do so since it would be impossible to gain entry into any medical journal, that they would not accept any paper that dealt favorably with megadose vitamin therapy. The New England Journal of Medicine, which had published the Mayo Clinic attack on Pauling, refused to publish his rebuttal. Linus urged me to do a complete follow up study of every patient I had treated. I was flattered and agreed that I would. He said that he would see that the material would be published. But when I returned home I decided not to do the follow up. It would have meant an enormous amount of work. I thought that Dr. Pauling was being kind to me. Two years later I received a letter from Linus in which he said, bluntly, ‘Abram where is the study?’ I decided that he was serious about it.

Hoffer and Pauling’s shared interest in the vitamin C and cancer issue would result in two published papers as well as a book manuscript intended as a follow-up to Cameron and Pauling’s Cancer and Vitamin C (1979).  Despite Pauling’s enthusiasm for the project (“It is wonderful,” he wrote of Hoffer’s 1988 typescript. “It should have a great effect in convincing cancer patients, people in general, and even physicians that vitamin C has value in the control of cancer.”) the book and its unorthodox approach could not find a publisher, an issue further hampered by Pauling’s own flagging health.

Linus Pauling greatly admired Abram Hoffer’s work, to the point of declaring his support for a 1990 effort to nominate Hoffer for the Nobel Prize in Medicine.  Though both men are now gone, the record of their shared interests and collaboration remains extant in the Pauling archive.

For more information on the Hoffer-Pauling cancer work, see Pauling’s “Hoffer” research notebook listings or the finding aid description for their proposed book How to Control Cancer with Vitamins.  For more on Abram Hoffer, including a short film, see this memorial page.

Orthomolecular Psychiatry

"Mental Deficiency & Brain Chemistry." May 1, 1964.

“Ortho means ‘right’ — the right molecules in the right amounts. Orthomolecular medicine is the use of the right molecules or orthomolecular substances that are normally present in the human body in the amounts that lead to the best of health and the greatest decrease in disease. It is the most effective prevention in the treatment of disease.“

-Linus Pauling. Interview by Deborah Kesten. Healthline. April 1983.

Linus Pauling was well known — though not always celebrated — for his steadfast endorsement of the health benefits of megadoses of vitamin C. He began promoting the use of vitamin C as a preventative measure against colds in the mid-1960s. In the late-1960s, he published some of his early findings, calling his theory of vitamins and health “orthomolecular medicine” stemming from the Greek root ortho meaning “right” or “correct”.

Pauling applied his orthomolecular research to mental health as well, describing numerous psychological problems as the result of an imbalance of molecules.

Listen: Pauling describes the rapid evolution of his research agenda

In 1968, Pauling introduced the concept of orthomolecular psychiatry to the medical community with his publication of “Orthomolecular Psychiatry: Varying the concentrations of substances normally present in the human body may control mental disease” [PDF]. This article first appeared in Science and has since been reprinted in a number of other journals as well as the book Orthomolecular Psychiatry: Treatment of Schizophrenia, for which Pauling was a co-editor.

In his article, Pauling stated his belief that mental disease is caused almost entirely by the combination of abnormal reaction rates and abnormal molecular concentrations of substances essential to the human body.

The majority of chemical reactions that take place in humans employ an enzyme as a catalyst. As such, if a certain enzyme fails to function properly, the rate of the reaction that utilizes the enzyme will be severely reduced. Pauling developed two ways to push reactions in the forward direction, consequently solving the problem of rate reduction. He stated that this molecular propulsion could be accomplished by either introducing large amounts of the enzyme’s substrate or by somehow increasing the amount of the enzyme that is synthesized. He came to these conclusions by manipulating the Michaelis-Menten equation, which gives the rate law for a reaction catalyzed by an enzyme.

In his 1968 article, Pauling likewise described a variety of vitamins and other essential substances as well as the consequences of deficiencies of each. Among the substances discussed are vitamin B12, nicotinic acid, and vitamin C. Pauling believed that simply introducing more of a deficient substance would alleviate the effects of the deficiency.

Pauling’s concept of orthomolecular psychiatry is in application today. For example, Phenylketonuria, or PKU, is caused by poor functioning of the enzyme that processes phenylalanine. According to Pauling, this disease could be treated in two ways. One option is the introduction of mass amounts of the enzyme’s substrate to counterbalance the effects of the dysfunction. The second, and practiced, treatment is to require PKU patients to adhere to a strict low-protein diet, which significantly lowers the amount of phenylalanine they consume. (This approach also happened to have been an important component of the treatment that Pauling himself followed when battling glomerular nephritis in the 1940s)  Nevertheless, both treatment possibilities are examples of orthomolecular therapy.

Anecdote published in Chemtech, September 1994.

Orthomolecular psychiatry was an exciting theory for Pauling. The orthomolecular concept was originally applied only to the brain, but it wasn’t long before Pauling began to extend it to the entire body. Eventually, he would consider problems ranging from diabetes to cavities as treatable using the orthomolecular concept.

For more information on orthomolecular psychiatry and related topics, visit It’s in the Blood! A Documentary History of Linus Pauling, Hemoglobin, and Sickle Cell Anemia. To view more content related to Linus Pauling, visit Linus Pauling Online.