Cancer and Vitamin C: Crossroads of New Research

[Part 9 of 9]

In 2018, a third edition of Ewan Cameron and Linus Pauling’s book, Cancer and Vitamin C, was published. Released nearly a quarter century after Pauling’s death, this edition marked the first time that someone other than Pauling or Cameron contributed to the volume. The second edition, which was published in 1993, included an updated preface and a few new indices, but the text itself remained entirely Cameron and Pauling’s. The 2018 edition also includes a new preface and a new index, but both were written by Stephen Lawson of the Linus Pauling Institute at Oregon State University. Lawson used the new additions to ably present recent scholarship connecting the efficacy of vitamin C to the treatment of cancer.

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One bit of background that Lawson sought to clarify at the outset was the story of why vitamin C treatments for cancer had not been initially supported by outside research. As noted in our previous posts, Pauling and Cameron believed that external research corroborating their results would provide an effective avenue for convincing skeptics of the curative powers of vitamin C. The Mayo Clinic eventually agreed to conduct a study of this sort, but found that vitamin C did not improve cancer patients’ prognoses, and in some instances their outcomes were actually worse.

Even though Pauling and Cameron did not agree with the Mayo Clinic’s findings, they had a hard time making their case to the public about why the study was in error. But as described by Lawson in the 2018 preface, Pauling and Cameron recognized that the Mayo Clinic’s treatment protocols were different than their own in important ways. Specifically, Cameron and Pauling had always delivered vitamin C intravenously, whereas the Mayo Clinic researchers dosed their patients orally. At the time, Pauling and Cameron could not prove why this should make a difference, but they believed that it was a key reason why the Mayo Clinic did not get positive results. While science could not confidently address this scenario in 1979 – or even in 1993 at the time of the second edition – by 2018 researchers had developed a much clearer idea of the importance of intravenous application.

Beginning in 1999, a team of researchers began actively exploring the absorption of vitamin C and, in particular, whether or not there was a difference between oral and intravenous applications. As they conducted their work, the group discovered a previously unknown vitamin C transport molecule in the stomach, which helped to deliver ascorbic acid into the bloodstream. The team subsequently learned that there was an upper limit to how much vitamin C the transport molecules could carry. This effectively meant that no matter how much vitamin C a person ingested orally – vitamin C that would end up in the stomach – only a finite amount could actually be absorbed and utilized, due to the limited carrying capacity of the transport molecule. The exact amount of vitamin C that a transport molecule can carry is still being researched, with data to this point indicating that quantities may vary based on factors such as age.

In tandem with this discovery, researchers were also interested in understanding what happens when vitamin C enters the bloodstream, be it intravenously or through transport molecules in the stomach. As Lawson notes, studies found that one byproduct of high levels of vitamin C in the bloodstream (regardless of how it got there) is hydrogen peroxide. Hydrogen peroxide has the ability to fight cancer by altering its DNA, robbing its cells of ATP (the “muscle” of the cell), and fatally damaging its energy-producing mitochondria. When deployed at scale, this three-pronged attack might be presumed to fight cancer very effectively.

That said, hydrogen peroxide therapy has not been used with cancer patients, because there is no safe and effective way to deliver the substance into the bloodstream without damaging other healthy cells. While the connection between vitamin C dosing and internal hydrogen peroxide production is not well-understood, these preliminary findings suggest that high blood concentrations of vitamin C could create hydrogen peroxide in sufficient quantity as to be effective at neutralizing cancer cells.

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Several other new areas of research were highlighted in the 2018 edition, including the connection between vitamin C and hypoxia inducing factor (HIF). Some cancer tumors grow so fast that blood vessels cannot be created quickly enough to deliver oxygen to the expanding mass. To compensate for this lack of blood vessels in these hypoxic (or low oxygen) environments, tumor cells induce HIF, which stimulate the growth of blood vessels within the tumor. This inducement of HIF allows fast-growing tumors to continue to propagate and wreak havoc, rather than succumbing to oxygen starvation. For reasons that remain unclear, when vitamin C is introduced into a fast-growing tumor it represses the activation of HIF, compelling the tumor to remain in its hypoxic state and eventually die.

Emerging research on the relationship between vitamin C and dehydroascorbic acid (DHA) is also included in the 2018 edition. DHA is an oxidation product of vitamin C, and when present has been shown to reduce the amount of colorectal cancer in the body.

A collection of sixteen relatively recent clinical trials are likewise surveyed in the book, all of which examined the outcomes of different kinds of cancer patients when given vitamin C in conjunction with other chemotherapeutics. All sixteen found that patients’ outcomes improved once they were given the vitamin C in concurrence with their chemotherapy treatment. Five other studies were conducted on cancer patients given vitamin C but not chemotherapy. Results of these trials were mixed but, as Lawson points out, the non-chemotherapy researchers were primarily interested in determining optimal doses of vitamin C and measuring how quickly patients depleted their vitamin C infusions. Many of the trials also found that patient outcomes improved.

As with the original text of the book, a collection of case studies were also discussed by Lawson. And though they serve mostly as anecdotal evidence, Lawson shows that significant improvements in patients’ health have been documented once they have been administered vitamin C treatment.

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One of the biggest takeaways that a reader might glean from the 2018 edition is that, even though a significant amount of research has been conducted on the vitamin C and cancer connection, medical practitioners have been hesitant to deploy the treatment because the studies have seemed less than rigorous, or because other practitioners have found that it does not work with their patients. Lawson counters these sentiments by noting that most cancer research is novel and that only the most promising ideas go on to clinical trials. Further, because an optimum vitamin C dose has not yet been codified, doctors commonly administer vitamin C on an ad hoc basis. Worse still, doctors also sometimes administer the treatment as a “last ditch” effort after chemotherapy and all other treatments have failed. Pauling and Cameron demonstrated in their first edition that vitamin C needs to be administered continuously and before chemotherapy to be maximally effective. Clearly much remains to be done before the work that Pauling and Cameron started with their first edition can be called complete.

Cancer and Vitamin C: A Major Conference

Pauling in 1989. Photo by Paolo M. Sutter.

[Part 8 of 9]

When the first edition of their book, Cancer and Vitamin C, was published in 1979, popular support for the curative powers of vitamin C did not materialize in quite the way that the authors, Linus Pauling and Ewan Cameron, had hoped. In part due to negative press associated with a critical study conducted by researchers at the Mayo Clinic, mainstream readers found themselves disinclined to buy into the thesis that vitamin C could fight cancer in the ways that Pauling and Cameron had put forth.

But over time, the conventional wisdom began to shift a bit, and in 1989 scientists from around the world convened in Bethesda, Maryland to once again discuss the merits of vitamin C as a cancer fighting agent. Sponsored by the National Institutes of Health (NIH), the conference was attended by respected scientific leaders, many of whom left the three-day event with a sense that the world might finally start to agree with Pauling and Cameron.

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Held in April 1989, “Ascorbic Acid: Biological Functions and Relation to Cancer” marked the first time that two agencies within the NIH – the National Cancer Institute and the National Institute of Diabetes and Digestive Kidney Diseases – had co-sponsored an event. In total, about 130 people attended the meeting, with some 40 talks and papers presented over the three days.

Because of the breadth of its participants, the research presented at the conference covered multiple angles of the vitamin C and cancer connection. One speaker was Dr. Balz Frei from the University of California, Berkeley (and later the director of the Linus Pauling Institute) who discussed how peroxidation and prooxidant reactions can lead to cancer. Frei pointed out that these reactions happen frequently, and that behaviors like smoking can make the reactions even more prolific, which helps to explain how smoking can lead to cancer. Frei also found that these reactions did not occur when cells were exposed to vitamin C, but as soon as the vitamin C was removed, the reactions began again. Similarly, a team from Japan led by Dr. Etsuo Diki found that free radicals, when present in the body, can lead to cancer, and that vitamin C was capable of destroying them more quickly than could any other substance under study.

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Even though much of the research was presented by scholars new to the field, many of the old believers were in attendance as well, including Pauling and several colleagues from his institute. Pauling’s talk focused on a recent study involving mice who were afflicted with cancer via ultraviolet light, and then treated solely with vitamin C. Pauling’s team found that, once treated, cancerous growths did not develop further and incidences of cancer reduced in general. Another similar study conducted by Pauling and his team on mice and spontaneous cancer in the mammary glands found that when the mice were given vitamin C, the time to onset of cancer was notably delayed.

Others presented similar types of work. One paper demonstrated that the effectiveness of chemotherapy improved when vitamin C was added to the drinking water of mice with cancer. And a team from Pennsylvania found that mice that were given vitamins C and B12 exhibited a complete inhibition of cancer growth with no damage to healthy, non-cancerous cells. The team’s results had been so encouraging that they treated a collection of human patients with vitamins C and B12, with positive results.

A different group found that, when vitamin C was given in conjunction with chemotherapy, patients tended to retain a statistically significant amount of healthy tissue as compared to those who were not given vitamin C. Other presentations found that vitamin C in cancer patients is not excreted in urine, despite drops in blood concentration, leading to the conclusion that the vitamin was being “used up” in fighting cancer. Vitamin C also seemed to reduce the toxicity of certain chemotherapeutics, including Adriamycin, a well-known cancer drug.

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The conference ended with a talk from the macro perspective by Dr. Gladys Block, an epidemiologist at the National Cancer Institute. Block determined that, to date, there had been 47 studies conducted which demonstrated that vitamin C provided a measure of protection against cancer, and that 34 of these put forth data that was statistically significant. Block argued that if chance was the only reason why vitamin C had been found useful, then only one or two of the studies would have been statistically significant. But the fact that 34 studies met the threshold of statistics was both decidedly meaningful and encouraging. Block’s remarks closed the event, which concluded with “thunderous applause and a standing ovation.”

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?

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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.

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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.

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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.

The History of the Pauling Blog: Of White Whales and Other Challenges

[Extracts from an interview by Tiah Edmunson-Morton with Chris Petersen, conducted on the occasion of the Pauling Blog’s tenth anniversary. This transcript has been lightly edited for clarity. Part 3 of 4.]

Tiah Edmunson-Morton: How many students have worked on the blog?

Chris Petersen: Well, thirty-three people have written for the blog and I would say that probably more than twenty-five of them have been students. It’s mostly students.

So the people that have written for it have been students and me and a sort of random collection of other people. [Pauling biographer] Tom Hager contributed a couple of things he actually had written for something else, but we re-posted them. We also had a guy named John Leavitt, who was an employee of the Linus Pauling Institute of Science and Medicine when it was in the Bay Area, who has taken an active interest in us for a long time. And he’s been our – I called him our East Coast Bureau Chief for a while because he’s based in Connecticut. He’s sent us quite a bit of stuff and we’ve published him.

Another hat that I wear within the department is Remote Reference Coordinator, and so sometimes somebody will contact us with a fairly in-depth inquiry about Pauling and it’s going to be published in a book or in a paper or whatever. And I’ll invite them to write something for the blog and tell them that it actually has a pretty good audience and it’s going to expose your project to a wider audience than maybe it would otherwise receive. And we’ve gotten guest posts based on that as well.

But those are few and far between, relatively speaking. It’s been mostly students, and a full gamut of students too – undergraduates, master’s-seeking, and Ph.D. students. We’ve had good luck with the [Oregon State University] Honors College; we’ve recruited a lot out of the Honors College here. We’ve had good luck with the History of Science program, we’ve had good luck with the English program. But not necessarily just those three – again, there’s a bit of word of mouth from time to time, and just good luck as well happens from time to time too.

TEM: What is the most memorable thing that a student found or researched or asked you about?

CP: Yeah, that’s an easy answer for me. I don’t know what the year was, it’s been a few years ago, but there’s a controversy – a very weird scientific controversy – on something called quasicrystals. Quasicrystals, I would not pretend to be an expert on them, but I can say that they are exotic and they are related to structural chemstry and there’s a lot of math involved.

And so I knew that Pauling had done a lot of writing and speaking about quasicrystals in the ’80s, and he got into basically a dispute with another guy named Dan Shechtman about – I think Shechtman was pro-quasicrystals and Pauling was anti, I’m honestly not even sure at this point. But there was a dispute and Shechtman was right and, as it turned out, Shechtman won the Nobel Prize in 2011 for this work on quasicrystals. And this stands as a piece of evidence about Pauling’s stubbornness and about his inflexibility at times, which was very much a part of his personality, especially as he got older.

I wanted to do something with this, but I knew that I didn’t have the ability to do it and I didn’t figure many students would either. But we finally had somebody who came across my desk who I thought, “she might be able to pull this off.” And she did.

So she devoted a lot of time to this. She was married and her husband created animated gifs to use as illustrations because she felt like that was necessary to provide context for what she was writing. And she worked from home for a while because I think she was having some health issues, and she finally emailed it to me. And she emailed it as a full package and in the email she quoted Moby Dick. And part of the quote – I don’t know the whole thing – but “from hell’s heart I stabbeth thee” was part of what she said because she had slayed this white whale of this set of posts about quasicrystals.

And it was terrific, it really was. She was an extraordinary talent. And that was, I think, pretty much the end of her time with us; I don’t know what happened to her since, I hope that she’s done well. But she was exceptional and that really stands out in memory as just being a terrific accomplishment; something that I couldn’t have done. I think that most of what we publish is good to pretty good to excellent, and most of it I could do if I had the time and wherewithal. But I don’t know if I could have done that. She did and it was great. So, “from hell’s heart I stabbeth thee.” [laughs]

TEM: I was sort of thinking that the answer to that would not be quasicrystals but that it would be something more controversial. So Pauling also had other controversial aspects of his life and his career and I’m curious about how you’ve dealt with that?

CP: Yeah. I think that the blog is mostly friendly to Pauling and I think that’s valid. We are not an exercise in hagiography though, and we have written things that are not necessarily flattering. I think the quasicrystals instance is one of them, in fact.

The topic du jour these days is whether or not Pauling was a eugenicist, and we’ve written on that. It’s tricky, for sure, but I think we’ve taken a pretty balanced approach to that. And the last bit that we did was actually a summary of a talk that was given here by somebody from our Resident Scholar Program. So that’s been another thing that we’ve done is writing profiles on the different people who have come here as Resident Scholars to do work on Pauling; there have been several of them. And this guy gave a nice talk that, I think, presented the nuance pretty well, and I wrote that post. I was there for his presentation, I re-watched it, I wrote up the notes, and I thought a lot about how to present this. And I think that stands as a nice statement on Pauling’s point of view related to eugenics, which I’m not going to get into here. But that is one instance.

Another instance that I think is valid is his relationship with his children. We’ve done two sets of posts on his two sons that are no longer living – Crellin was the youngest one and was actually the first one to die, and then Peter was the second oldest of the kids who had a tough life on a lot of levels. And we took a deep dive on both of them and engaged with their life stories in a way that, I’m sure, nobody else has.

Pauling, I think, he was of a different generation of parent than I am. He was very focused on his career and he had a wife who saw it as her role – early on, at least – to care for the children and to create a scenario in which he could do his work most effectively.

And he did a lot of very effective work, but I think it also had an impact on his kids on some level. I think that he loved them, I think that he certainly provided for them well after they were out of the home – most of them. But that warmth was not always necessarily there and the time was not there for sure, and that’s a criticism. And I think that comes through in the writing on some level.

So those are a couple bits. Another thing we’ve done is written extensively about lawsuits. And he was involved in a lot of lawsuits. The ones that we’ve engaged with are well in the past and they’re libel lawsuits – mostly papers or magazines calling him a communist, and him being very litigious about it. And, so there was a Supreme Court verdict that came through that basically shot his point of view down and that was the end of him being successful with these lawsuits, but he pursued them doggedly and a sort of persnickety side of his personality arises.

He could be a little cranky at times and he probably had a right to be as far as that was concerned, but in my reading of the documents and just in his interactions with people as a writer of letters, he was always very formal and he sometimes could be pretty terse and not especially warm. So we dug into the lawsuits in significant depth and I think that showed pieces of his personality as far as that’s concerned.

We’ve done a lot of work on vitamin C, especially vitamin C and cancer, and to a lesser degree vitamin C and the common cold, and vitamin C and heart disease. And Pauling was obsessed with vitamin C – I think that’s a fair statement – and was not necessarily willing to hear contradictory points of view very much, or perhaps pursued lines of inquiry that were not super scientific but were favorable to his perspective or were overly favorable.

And so some of that has emerged in the writing. But I also think, there seems to be a trend now – a rising trend – of scientists who are starting to think that he was on to something, and that’s been fun to document as well. So the idea basically is that if you take vitamin C orally you are not able to absorb most of it, you excrete most of it in your urine. So there’s a threshold of absorption. And he knew that, I think, but tried to suggest different ways of taking it, kind of a steady dose over the course of an entire day that would increase the concentration in the blood. But some of the things that he said were going to happen concerning the promise of vitamin C to heal in various ways were lost because you just couldn’t absorb the ascorbic acid into your body.

But in more recent time, scientists seem to be coming to the understanding that if you take it intravenously it’s a different transport mechanism and you’re able to absorb a lot more and, in fact, some of what he thought was going to happen may actually be true. And this is of, like, last Fall – there was a seminar at the Linus Pauling Institute for their Diet and Optimum Health Conference that was devoted entirely to that. So I sent one of our students to cover it and it was great. It’s really fun for me to be able to follow that a little bit and to convey that a little bit, because he took a real beating for his point of view on that. And his tactics were not the best tactics, but it’s pretty interesting to me that, these many years later, he actually may have been right about some of that stuff.

Cameron and Pauling’s Attack on Conventional Views of Cancer

Announcement published in the LPISM Newsletter, Spring 1979.

[An examination of “Ascorbic Acid and Cancer: A Review,” published in 1979. This is part 2 of 2.]

Linus Pauling and Ewan Cameron began their paper “Ascorbic Acid and Cancer: A Review” – published with Brian Leibovitz in Cancer Research in March 1979 – by detailing the history of research on ascorbate and establishing a connection between cancer and scurvy. This line of thinking was predicated on the observation that cancer patients, like scurvy patients, were abnormally deficient in Vitamin C. The authors, in turn, traced this observation back to the importance of Vitamin C in maintaining the balance of the intercellular matrix. They likewise emphasized that cancer is a disease that originates in the body, emanating from the patient’s own cells.

The paper next identified the two main traits of cancer: abnormal cell proliferation and invasiveness. Keeping these characteristics in mind, the authors hypothesized that the release of an enzyme, hyaluronidase, contributed to occurrences of cancer. Hyaluronidase breaks down the gel-like substance that surrounds cells, they argued, and creates a pathway that allows cells of any kind to continue multiplying. In healthy individuals, this process is self-limiting. When the process goes completely unchecked however, cells can become malignant and invade the surrounding tissue. Pauling and Cameron believed this to be the likely mechanism for metastasis, the point in a cancer’s progression at which survival rates plummet.

While they knew that it was highly unlikely that a simple infusion of Vitamin C would cure a cancer patient – as it would do in the case of scurvy – Pauling and Cameron theorized that an infusion of this sort would contribute to the inhibition of hyaluronidase, thus keeping cell proliferation in check. As they repeatedly emphasized in their review, Vitamin C’s main benefit was to increase host resistance to diseases that caused unrestrained cell proliferation. What Vitamin C did not do was guarantee complete remission.

Once they had described ascorbic acid’s defensive role, the authors moved on to its limited ability to take the offensive. One function that increased Vitamin C was believed to carry out was the capacity to “encapsulate” a tumor or disseminated tumors to the point where they were no longer malignant. As Pauling pointed out to his colleagues, when his wife Ava Helen was first diagnosed with stomach cancer and surgeons went in to remove her tumor, they noted that the mass had unusual presentation for its location and appeared to be encapsulated. Ava Helen had been taking large doses of Vitamin C for several years before she was first diagnosed, and her husband attributed the nature of her tumor and the ease of its removal to her intake of Vitamin C.

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Central to the review paper were the clinical results that Ewan Cameron had compiled at the Vale of Levin Hospital in Alexandria, Scotland. Cameron had begun to see positive results early on, but found that his studies were somewhat skewed because so many of his patients were terminal and ended up dying regardless of their treatment. Cameron was worried that his data did not present much of an argument in favor of Vitamin C, a situation that was further muddied by the fact that, “the terminal stages of cancer are a compound of so many human, individual, pathological and even emotional variables, as to be nearly impossible to quantify.”

In an effort to provide what the authors believed to be a more accurate picture of Vitamin C’s treatment benefits, Cameron’s later studies measured survival time in ascorbic acid patients and compared them with non-ascorbic acid patients. This comparison revealed that a patient on supplemental ascorbic acid survived, on average, four times as long as a patient with a similar prognosis who had not received ascorbic acid.

In conducting his trials, Cameron encountered the additional barrier of patients who failed to adhere to the Vitamin C regimen once they were released from the hospital. Cameron called this mode of behavior the “reverse placebo” effect, noting that some patients, when left to their own devices, would discontinue their ascorbic acid intake because it was “just Vitamin C.” Believing that it would be treated with greater respect if it sounded more like a drug, Cameron half-jokingly suggested that pharmacies rename Vitamin C as “Pauleron” to dissuade patients from underestimating its potential.

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In the final section of their review paper, Pauling and Cameron warned of unexpected and unexplained potential consequences associated with ascorbic acid therapy. In particular, some of Cameron’s patients, after showing marked improvement for several weeks or even months, succumbed to what Pauling called a “whirlwind” of cancer. Autopsies later revealed sudden massive tumor growth and dissemination.

Interestingly, most of these “whirlwind” tumors contained a large volume of necrotic cancer cells. Pauling put forth two possible explanations for this, which he included in the review. One explanation was that, though necrotic cancer cells can be less harmful than live cancer cells, the inflammation caused by their presence might cause rapid tumor growth or become toxic to the patient in such a large volume.

A second explanation, which he thought more plausible, was based on the understanding that abruptly discontinuing Vitamin C caused ascorbate levels to plummet. In this circumstance, if ascorbic acid was inhibiting tumor growth as believed, a drastic and sudden decrease in the treatment could lead to rapid, unrestrained tumor growth.

Pauling couldn’t provide solid evidence for either possibility, but he felt that both supported the review’s hypothesis. In the first instance, ascorbic acid could be killing the cancer cells. In the second, the negative consequences of withdrawing ascorbic acid inversely suggested the benefit of continued ascorbic acid use.

Pauling and Cameron concluded their review by listing areas of ascorbate research that were encouraging but had, to date, only received preliminary investigation. Specifically, the paper pointed out that no trials had been conducted to consider the effects of ascorbate in general cancer management.

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The Cameron, Pauling and Leibovitz review provoked mixed reactions. Many readers, particularly aspiring physicians, were intrigued and encouraged by the results. On the other hand, quite a few others remained skeptical and focused on the aspects of treatment that Vitamin C could not promise to provide. Shortly after the review came out, Pauling received a letter from a medical student who reported that the paper had been torn out of archived copies of Cancer Research at both Cornell Medical College and the Sloan-Kettering Cancer Center. Pauling confirmed that this had happened at both locations, but was unable to persuade anyone to rectify the situation.

In the fall of 1979, a handful of months after the review was published, the Mayo Clinic released the results of its own clinical trial, which concluded that Vitamin C did not contribute to longer survival times, nor did it offer any therapeutic benefit for cancer patients. When the results were published in the New England Journal of Medicine, Cameron wrote a letter to the editor providing a rebuttal of sorts.

In Cameron’s letter, he pointed out that the Mayo Clinic hadn’t followed the same procedures as those used at the Vale of Leven. Importantly, in Cameron’s trial, only 5% of patients had received recent chemotherapy treatment. By contrast, in the Mayo Clinic trial, only 5% of patients hadn’t received recent chemotherapy. Cameron also suggested that patients, fearful that they were in the control group and not receiving supplemental ascorbate, were dosing themselves with Vitamin C, as it was easy to obtain outside of the trial setting. If this was indeed the case, the Mayo Clinic data likely supported the Cameron-Pauling hypothesis.

Despite Cameron’s centrality to the debate, the editor of the New England journal refused to print his letter, a decision that only increased the levels of skepticism surrounding Cameron and Pauling’s work.

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In publishing their review and the papers that led up to it, Pauling and Cameron sought to update the popular view of cancer as an invasion of foreign cells that needed to be entirely destroyed to produce clinical success. Once people accepted a new view of cancer, Pauling believed that attitudes toward cancer treatment would also change.

Perhaps most importantly, Pauling and Cameron wanted physicians to stop assuming that troubling side effects were a sign of a treatment’s success and instead to begin concentrating more on the overall health of patients. Though they focused primarily on Vitamin C, the duo hoped that their review would encourage researchers to gather more evidence for an orthomolecular approach to cancer, one that would emphasize vitamins and natural methods as opposed to cytotoxic chemicals.

Although Pauling and Cameron’s perspective was not widely accepted during their lifetimes, researchers today are increasingly focusing on alternatives to chemotherapy and radiation. Immunotherapy, still in its infancy during Pauling’s life, has now become a standard treatment for certain cancers. Additionally, researchers have been able to show that high-dose Vitamin C, administered intravenously at even higher levels than Pauling and Cameron had attempted, does indeed provide therapeutic benefits in some cancers.

Ascorbic Acid and Cancer: A Review

Ewan Cameron, Ava Helen and Linus Pauling. Glasgow, Scotland, October 1976.

[Ed Note: Today’s post is the first installment of a two-part look at Linus Pauling, Ewan Cameron and Brian Leibovitz’ extensive 1979 review of the published literature pertaining to research on ascorbic acid and cancer.]

Students of Linus Pauling’s life will know full-well that Pauling expended significant energy over his latter decades advocating for the use of ascorbic acid, or Vitamin C, in the treatment of cancer. One of his lengthier research endeavors, and certainly among his most controversial, Pauling’s interest in and advocacy of ascorbic acid therapy prompted a wide array of responses from scientists, journalists, and patients, among many others.

Pauling’s views also attracted the disdain of most medical professionals. One notable exception to this theme was Ewan Cameron, a Scottish surgeon who became so invested in the work that he eventually relocated to California to join the staff of the Linus Pauling Institute of Science and Medicine.

Prior to his immigration, Cameron had shared a rich correspondence with Pauling through which the colleagues bounced ideas off one another and even co-wrote papers. Cameron, who was head of his department at the Vale of Leven Hospital in Alexandria, was permitted to run a clinical trial testing the efficacy of ascorbic acid treatments on terminal cancer patients. He then relayed his data to Pauling, who studied the Alexandria results and contributed his thoughts on the chemical mechanisms that might be underlying them.

In 1979, Pauling, Cameron and a third author published a major literature survey titled “Ascorbic Acid and Cancer: A Review.” Appearing in the March 1979 edition of Cancer Research, the paper marked a crescendo of the duo’s eight years of work in the cancer field; work which they attempted to bolster using all of the previous and ongoing studies that they could find.

The survey, which took up ten journal pages and included 358 references, was published with the hope that it might serve to counter some of the skepticism that its authors were encountering, while also inspiring new researchers to turn their own attentions toward the potential benefits of ascorbic acid. As was typical during this period of Pauling’s career, the reception that the paper received was mixed at best.

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One of the 1,000+ references gathered by Brian Leibovitz for use in “Ascorbic Acid and Cancer: A Review.”

Pauling and Cameron first began toying with the idea of a grand literature review in 1976. Having struggled mightily with both the medical community and mainstream publishers for five years, the duo had, by 1976, finally managed to get a few papers into print. Encouraged by these successes, the co-authors agreed that gathering all available research on Vitamin C and cancer, and presenting it in one paper, would make for a very useful contribution to a decidedly nascent field.

There was a secondary ambition in play as well. Though brimming with ideas, the resources available to the two scientists were scarce and, as a result, they had arrived at an impasse of sorts. Lying at the heart of the matter was the fact that basically all of the leading medical journals had refused to publish the clinical work that Cameron and Pauling had conducted, because they hadn’t been able to follow a proper double-blind study protocol. Instead, Cameron had matched his ascorbic acid patients – by age, sex, and cancer type -with previous patients who had been treated at the Vale of Levin hospital but hadn’t received ascorbic acid.

Likewise, Cameron believed so strongly in the benefits of ascorbic acid that he refused to withhold it from incoming cancer patients who might otherwise populate a control group for his study. In his correspondence with Pauling, Cameron confided that to withhold ascorbic acid treatment from sick patients would stand as a violation of the Hippocratic Oath.

(Oddly enough, Dr. Thomas Addis – the doctor whose conservative therapies saved Pauling from an almost certain death sentence when he was diagnosed with glomerulonephritis in the 1940s – argued against the use of ascorbic acid for exactly the same reason. To discontinue traditional methods of cancer treatment he believed to be effective came at the cost of his patients, and Addis refused to do it.)

Memorial Sloan-Kettering Cancer Center in New York had conducted its own trial in 1974, but Cameron and Pauling suspected that there were problems with the scientific design of that study as well. Preventing this from happening again, especially as Pauling and Cameron were gaining increased attention from the medical community, was another motivation for publishing the review. Finally, the research that they had gathered also helped the co-authors in preparing a new book, Cancer and Vitamin C, which came out in 1979, only a few months after the review was published.

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Brian Leibovitz

In putting together their article, Pauling and Cameron enlisted the additional help of Brian Leibovitz, a graduate student at Stanford who had worked at LPISM from 1975 to 1977. Leibovitz’ main task was straightforward: obtain reprints of anything related to ascorbic acid and cancer. Pauling also requested that Leibovitz look into other papers that focused on the environment shared by cells, as he and Cameron both believed that the intercellular environment held important – if, as yet, undiscovered – resources for treating cancer.

Leibovitz expressed great dedication to the multi-year project, continuing to collect references even after finishing up at LPISM and moving to Oregon. In the end, Leibovitz gathered over a thousand sources; for his work, his name appeared on the review as a third co-author.

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Once it had been completed, Pauling encountered trouble finding a home for the review. Originally a friend had offered to have it published in Cancer Research, but upon seeing the manuscript, the editor complained that the paper was much too long. In response, Cameron worked on shortening the text while Pauling looked into other avenues for publication, including The Journal of Preventative Medicine and Cancer Reviews.

While Cancer Reviews was kind enough to respond that they were not interested in publishing anything on ascorbic acid, The Journal of Preventative Medicine did not reply at all. Just as the authors were about to give up, the editor of Cancer Research got back in touch, suggesting a series of changes and promising to publish the survey once it met with the requirements that he had outlined.

Intravenous Vitamin C: The Current Science

Jeanne Drisko with Murray Susser. Both Drisko and Susser are past presidents of the American College for Advancement in Medicine.

[Part 2 of 2]

At her public lecture, “Intravenous Vitamin C: Does it Work?” delivered at the Linus Pauling Institute’s Diet and Optimum Health Conference in September 2017, Dr. Jeanne Drisko of the University of Kansas Medical Center, Kansas City, provided an overview of current research on the potential impact of intravenous vitamin C in treating disease.

She began this portion of her talk by reflecting on the factors that have continued to propel her own scientific interest in the topic, despite the headwinds generated by critics of the work. For one, Drisko has taken heart in the fact that intravenous vitamin C is used in many clinics around the world. Indeed, at a 2006 integrative medicine conference, Drisko and colleague Mark Levine took a survey of participants and found that some 8,000 patients had received intravenous vitamin C from doctors attending the meeting. Because Drisko maintains contacts in both conventional and alternative medical circles, she knows that naturopaths have been using intravenous vitamin C as well.

Drisko then pointed out that one barrier to more widespread acceptance of vitamin C as a cancer treatment is that, conventionally, it does not make sense to administer it in tandem with chemotherapy, since vitamin C is known to be an antioxidant and chemotherapy is a prooxidant. That said, Levine and Drisko’s colleague in Kansas, Qi Chen, have found that when vitamin C is given intravenously, it actually works as a prooxidant because it produces hydrogen peroxide. As such, it actually becomes a very good compliment to chemotherapy. Moreover, studies conducted by Drisko and others have found no evidence of conflict arising as a result of vitamin C dosages given alongside chemotherapy. On the contrary, researchers have reported a synergistic relationship in many cases.

In explaining why this is so, Drisko noted that when vitamin C is injected into a vein, it takes on the form of an ascorbyl radical, which she described as a “very promiscuous and active molecule that likes to interact with transition metals” like copper and iron. These interactions lead to the formation of hydrogen peroxide, which is quickly turned into water and oxygen by the enzymes glutathione peroxidase and catalase, such that levels of hydrogen peroxide in the bloodstream are promptly rendered as unmeasurable.

However, when vitamin C gets into the extracellular fluid it also becomes hydrogen peroxide. The difference in this case is that glutathione peroxidase and catalase do not intervene and the hydrogen peroxide is not broken down into water and oxygen. Instead, the hydrogen peroxide diffuses throughout the extracellular fluid, bathing the cells.

While the presence of hydrogen peroxide in the cells might seem unsafe, Levine’s cell culture tests have found that hydrogen peroxide caused harm only to cancer cells. In reporting his results, Levine explained that the glutathione peroxidase and catalase enzymes are not as efficient in attacking cancer cells because they direct their activity towards reproduction rather than other processes. The fact that glutathione peroxidase and catalase are not active in the extracellular fluid renders vitamin C as a pro-drug and hydrogen peroxide as an actual drug.

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Drisko’s research portfolio on the use of intravenous vitamin C includes the first randomized controlled trial involving ovarian cancer patients, work that was published in 2014. The trial studied two groups of patients: one group received standard care, which included carboplatin and paclitaxel chemotherapy for six cycles. The other group received this same care along with 75 to 100 gram doses of intravenous vitamin C.

The trial made clear that this form and dosage of vitamin C therapy is safe to administer. It also yielded a statistically significant improvement in how certain types of patients felt during their cancer treatment. Drisko called this a “feel good effect” which she believes is neurological. This same impact, however, was not observed in patients suffering from more advanced stage three and stage four cancers. Drisko is currently following up on these results by looking at the role that vitamin C might play in brain chemistry.

While her work has generated positive results, Drisko is also aware that vitamin C should not be used in all cases. Importantly, vitamin C is known to be potentially harmful when given in large doses under certain conditions. One such case is in individuals suffering from a deficiency of Glucose-6-Phosphate Dehydrogenase, or G6PD. On its own, G6PD can cause anemia, but when combined with high levels of vitamin C it leads to hemolysis, or the destruction of red blood cells. As a matter of standard protocol, Drisko checks her own patients for G6PD deficiencies, but she knows of others who have been unaware of this biological conflict and who have had to send patients to the emergency room.

Drisko will likewise opt against administering intravenous vitamin C when a patient reports a history of oxalate kidney stones, which can form as a result of excessive vitamin C intake. For individuals who have gone ten years or more since their last instance of oxalate kidney stones, Drisko administers vitamin C, but she does so cautiously, monitoring kidney functions and liver enzymes throughout the process.

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Another barrier to studying intravenous vitamin C is that it is a difficult substance to measure since it is processed by the body so quickly. To get around this difficulty, Drisko developed a finger stick method that emerged from her interactions with a diabetic ovarian cancer patient. Over the course of these interactions, Drisko found cause to contact a glucometer manufacturer who told her that, because vitamin C and glucose molecules are so similar, the glucometer would indicate levels of both. Making use of this similarity, Drisko started taking finger stick glucose readings both before and right after her patients received their doses, and using this process she is now able to ascertain a rough estimate of how much vitamin C has been absorbed by the body.

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Qi Chen

In attempting to achieve greater certainty about appropriate dosage levels of vitamin C to administer, Qi Chen and Mark Levine have conducted experiments wherein they give intravenous vitamin C to mice and rats with tumors. This work is a follow-up to Levine’s original studies in the 1990s, which showed that vitamin C given orally could not be absorbed above a 10 millimolar concentration. In their more recent invesigations, Levine and Chen have found that blood concentration levels of 20 to 30 millimolar can be achieved as a result of intravenous application. They also found that the tumors in their mice studies would take up the vitamin C and that hydrogen peroxide formed in the tumors and subcutaneous tissue, but not in the blood.

Drisko gives her patients two to three infusions of vitamin C per week in advanced cases. Ideally, the vitamin C would be administered as the fluid loading dose for chemotherapeutic drugs, but it is often difficult to carry out both vitamin C and chemotherapy treatments on the same day because patients are already burdened by a busy treatment schedule and the facilities providing the two types of treatments are often not in the same location. (A new dosing device that attaches to the hip, developed by Channing J. Paller at Johns Hopkins, could help to get around some of these barriers.) Drisko’s treatment schedule uses a “stair-step” methodology wherein doses ranging from 0 to 100 grams are able to achieve 20 millimolar blood concentrations.

The appropriate duration of vitamin C treatment for cancer is still an open question. What is known is that it takes at least a couple of months before effects start to show. This stands in stark contrast to chemotherapy, which makes a much quicker impact.

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Drisko concluded her talk by sharing the hopeful story of a woman who had participated in her ovarian cancer trial. This patient had been part of the group that had received the standard chemotherapy treatment only. She had subsequently relapsed very quickly and was believed to have only months to live. In her conversations with Drisko, the patient expressed a strong desire to live long enough to give her grandson a present at Christmas, and she requested that Drisko give her vitamin C in addition to her chemotherapy, since she was no longer part of the trial.

Initial CT-PET images showed that the woman was suffering from an accumulation of fluid, or ascites, full of cancer cells that were pushing against her organs. At the start of her intravenous vitamin C treatment in 2004, a second CT-PET scan showed both the malignant ascites as well as a residual tumor that could not be removed surgically.

Subsequent scans after Drisko began her treatment showed gradual improvement. In 2007, the pictures included fewer ascites and the tumor was somewhat smaller, trends that continued to be seen in 2012. By 2014, calcification appeared in the tumor and around the fluid, with further calcification showing in 2015. In essence, what the scans were revealing was an eight-year process of “turning her cancer into a scar.” While this is only a single example, it is a powerful one, and may prove to be harbinger of medical breakthroughs to come.

Intravenous Vitamin C: The Historical Progression

Jeanne Drisko

[Part 1 of 2]

Jeanne Drisko, MD, Director of Integrative Medicine at the University of Kansas Medical Center, Kansas City, was a featured speaker during the public session of the Linus Pauling Institute’s Diet and Optimum Health Conference, held September 13-16, 2017.  She delivered a public lecture titled “Intravenous vitamin C and cancer treatment: Does it work?” Dr. Maret Traber, a principal investigator at LPI, introduced Drisko, describing her as a “leading expert on intravenous vitamin C.”

Drisko began her talk by tracing the history of vitamin C research, noting the ways in which previous studies had made her own research possible. The first person Drisko spoke of was Nobel laureate Albert Szent-Gyӧrgyi (1893-1986), who isolated ascorbic acid while working at Cambridge University and the Mayo Foundation between 1927 and 1930. Drisko then pointed out that, in the 1940s, vitamin C was used widely in clinical settings to treat pertussis, or whooping cough, along with other bacterial and viral infections. Importantly, these treatments were not administered orally. At the time, pharmaceutical preparations of vitamin C were not of a quality that could be administered intravenously, so they was injected into the muscles.

The use of vaccines was also on the rise during this period and Drisko pointed out that the development of the polio vaccine was particularly connected to the clinical fate of vitamin C. Albert Sabin (1906-1993), who had developed an oral polio vaccine, also carried out trials on the effects of vitamin C injections on primates. Sabin found no benefit and suggested that focus turn toward vaccines instead. It was at this point, Drisko explained, that the use of vitamin C injections went “underground,” drifting well outside of the medical mainstream.

One individual who remained interested in the promise of vitamin C was Frederick Klenner (1907-1984), who began using intravenous ascorbic acid at his North Carolina clinic in the 1940s. Drisko described Klenner as keeping “vitamin C use alive,” by administering both muscular and intravenous injections, while the broader medical community turned elsewhere. In particular, Klenner used vitamin C to treat children suffering from polio and found that even advanced cases could be approached successfully. During this time, Klenner also trained other practitioners in the methods that he was pioneering at his clinic.

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Ewan Cameron, Ava Helen and Linus Pauling. Glasgow, Scotland, October 1976.

Next, Drisko turned to Linus Pauling. To begin, Drisko noted that since Pauling was already well known, his interest in oral vitamin C was written off by many who were familiar with his prior work. Others, however, did look to Pauling as an authority, and among them was the Scottish surgeon Ewan Cameron (1922-1991), who contacted Pauling after reading some of his papers in the early 1970s. In his initial correspondence, Cameron informed Pauling that he had been giving about ten grams of vitamin C to cancer patients and had observed that they tended to live longer. As a result of their shared interest, Pauling and Cameron decided to collaborate on a series of papers investigating the potential clinical import of large doses of vitamin C.

As they delved deeper into this work, Pauling became convinced of the need to carry out more rigorous trials. Lacking the funds to do so, he instead turned to the National Institutes of Health. Fatefully for Pauling, Charles Moertel (1927-1994), an oncologist at the Mayo Clinic who was eager to debunk the effectiveness of vitamin C, agreed to lead the NIH investigation. Specifically, Moertel carried out a double-blind placebo-controlled trial in which ten grams of vitamin C were administered orally, and he found no benefit. (He was not aware that Cameron had been injecting vitamin C intravenously.) Moertel published his results in the New England Journal of Medicine and the press picked it up. Once the negative conclusion had been widely circulated, subsequent mainstream interest in the medical application of vitamin C suffered a near fatal blow.

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Mark Levine

Research on intravenous vitamin C began to re-emerge during the 1990s, led in part by NIH scientist Mark Levine. Levine’s nutrition experiments were novel, and did not emerge from the types of medical training that he could have been expected to received. For context, Drisko described her own education, wherein courses on nutrition were optional and held on Saturday mornings. She attended them because she was interested, but she also went along with the convention of the time; one emphasizing that nutrition was of lesser importance relative to other aspects of medical practice.

Levine, on the other hand, did not follow this line and decided to study vitamin C in depth. In the trials that he carried out at the National Institutes of Health, Levine tracked patients deprived of vitamin C and showed that they had indeed become vitamin C deficient. He followed this by administering oral doses of vitamin C, which demonstrated repletion. At the end of his trial, Levine also administered one gram of vitamin C intravenously. He was not allowed to administer a higher dose to his subjects, due to fears of toxicity, but it was his guess that ten gram doses would yield peak blood levels of vitamin C.

Ultimately, Levine demonstrated that oral vitamin C was not capable of yielding maximal vitamin C blood levels, because the body does not absorb oral doses well and excretes it very quickly. Intravenous administration, on the other hand, bypassed these metabolic processes, leading to higher blood levels. With Levine’s work in mind, Drisko summarized the difference between Cameron’s research and Moertel’s Mayo Clinic trial: “Cameron gave a drug and the Mayo Clinic gave a vitamin.”

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Hugh Riordan

Drisko’s mentor, Hugh Riordan (1932-2005), was another individual responsible for keeping vitamin C research alive. The founder of what is now known as the Riordan Clinic in Wichita, Kansas, Riordan belonged to a group of orthomolecular physicians who saw vitamins as providing restoration of a healthy baseline in all humans.

After Levine published his paper on vitamin C absorption, Riordan went to visit him in Maryland to convince him to continue following this path of inquiry. The two ultimately collaborated on several case studies and welcomed others into their fold, a progression that helped incubate today’s group of researchers investigating the use of intravenous vitamin C.

As of 2016, the intravenous vitamin C group included Qi Chen, who works on basic research at the University of Kansas with Drisko; John Hoffer at McGill University, who explores the effects of high doses of vitamin C on cancer; Garry Buettner and Joseph Cullen at the University of Iowa, who looks at the redox capacity of vitamin C in patients undergoing radiation therapy; and Ramesh Natarajan at Virginia Commonwealth University, who is researching the use of vitamin C in the treatment of sepsis.

Drisko noted that there are differences in the lines of research followed within the current group. On the one hand, her cancer trials use megadoses of vitamin C at 75 to 100 grams. Natarajan, on the other hand, only uses 4 or 5 grams in the ICU for sepsis.  For Drisko, these differences emphasize that there is still a lot of research to be done to understand exactly what is going on.

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At present, attitudes toward vitamin C within the medical community can be mostly lumped into two categories. One is comprised of “early adopters,” as Drisko defines herself, who continue to carry out research to refine vitamin C treatments. The other consists of those who adhere more closely to the conclusions of the Moertel study, and who thus believe that claims supporting the effectiveness of vitamin C have been disproven. The distance between these two groups was characterized by Drisko as a “gulf of disapproval.”

However, current trends suggest that the gulf is being bridged. While some state medical boards still restrict the therapeutic use of vitamin C, Drisko and others have succeeded in garnering increasing levels of support from both colleagues and institutions. Shifts in funding opportunities are also beginning to emerge: though Drisko was unable to secure federal dollars for her work on ovarian cancer, the Gateway for Cancer Research non-profit stepped in to provide crucial support. With evidence of the efficacy of the treatment building from a growing number of trials, the possibility of obtaining federal grants is becoming more realistic. Likewise, drug companies are now looking at ways to patent vitamin C therapy, and some vitamin C treatment patients have succeeded in receiving reimbursement from their insurance companies.

Next week, we will provide an overview of the science underlying this renewal in optimism about the potential to fight disease with intravenous ascorbic acid.

Vitamin C and Heart Disease: An Open Question

A note on LDL cholesterol and Lipoprotein (a) written by Pauling on his office chalkboard.

[An analysis of Linus Pauling’s research on vitamin C and heart disease, part 4 of 4]

In June 1992, Linus Pauling visited the Texas Heart Institute, after which he accepted an offer to write an editorial for the organization’s journal. He completed his short piece, “Can Vitamins Help Control Heart Disease and Strokes?” in March 1993, a little over a year before he passed away.

The Texas Heart Institute article turned out to be Pauling’s final public statement of consequence on the question of ascorbic acid and cardiovascular health. In his text, he argued once again that, although physicians had long known that arterial lesions cause heart disease, they had not yet accepted the evidence that lesions are brought about by low levels of vitamin C in the blood. This consensus had been maintained despite a widely accepted understanding that vitamin C is necessary to repair bodily tissues via collagen production.

Unfortunately for Pauling, the research required to clearly shift scientific opinion was not forthcoming. Pauling realized that a major study needed to be funded to show a strong relationship between intake of larger doses of nutritional supplements (especially vitamin C) and even greater preventative or therapeutic health benefits for victims of cardiovascular disease. As the idea’s chief proponent, Pauling would have seemed to be a primary figure in attracting grant funds for such a study. However, in part because of the intense controversy over Pauling’s previous work with vitamin C and the common cold, and vitamin C and cancer, Pauling’s reputation had been badly marred within the medical mainstream, and research dollars had become very difficult for Pauling to source.

Partly as a result, his and Matthias Rath’s work stressing the importance of vitamin C as a key factor in combating heart disease was perhaps a case of too little, too late. Though the tandem had succeeded in establishing a general sense of the potential importance of vitamin C in heart disease prevention, the circumstances surrounding their work were not ripe enough for the duo to develop a more complete and lasting understanding of the types and levels of nutrients needed to ensure optimum heart health.

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Linus Pauling giving an interview at Deer Flat Ranch, September 1993.

Other material considerations further compounded the problem. For one, at precisely the same time that the cardiovascular work was gaining traction, the Linus Pauling Institute of Science and Medicine was in the depths of dire financial straits. Furthermore, Linus Pauling was now nearly 93 years old and in declining health. As he battled with the cancer diagnosis that would ultimately claim his life, Pauling realized that could no longer go on assisting Rath. Meanwhile, Rath’s relationship with others in the Institute had fallen into turmoil, and the Linus Pauling Heart Foundation, which Rath directed, was withering on a vine of financial insolvency.

Rath was ultimately asked to leave the Institute amidst a period of legal disarray, partly a result of his having never signed the Institute’s mandatory employee patent agreement. In the wake of his departure from the Institute, and following the death of Linus Pauling in August 1994, the Unified Theory of Human Cardiovascular Disease largely slipped into obscurity, though some echo of it has remained in the public consciousness.

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In the years that followed Pauling’s death, the Institute’s cardiovascular program continued to investigate the role that nutrients like vitamin C, E, and B6 might play in limiting oxidative damage brought about by low density lipoproteins (LDL) in individuals suffering from atherosclerosis. Similar work is on-going today in multiple laboratories.

At present, the scientific understanding of the importance of vitamin C in preventing or treating heart disease remains somewhat mixed. Although vitamin C does not appear to directly lower blood cholesterol levels, evidence exists that it does significantly lower low density lipoprotein and Lp (a) levels, which in turn helps to protect arteries from blockage by these cholesterol-carrying molecules.

Total blood cholesterol may also lessen with increased vitamin C intake due to the fact that vitamin C is an HMG-CoA reductase inhibitor, meaning that if vitamin C levels are high, the body manufactures less cholesterol. Additionally, vitamin C’s benefits to the body as both a primary collagen producer and as an antioxidant contribute to what most studies agree to be a significant, though still not fully understood, protective effect against heart disease when taken in doses of 400 to 2,000 mg daily. As in Pauling’s era, this level of supplementation is far above the current Recommended Daily Allowance for adult men and women, which is 60 mg per day.

Likewise, the interaction between lysine and vitamin C that many of Pauling’s case study patients found to be highly therapeutic – with anecdotal reports of actual reversal of atherosclerosis in certain patients – has not been investigated further. And so it is that, more than twenty years after his death, Linus Pauling’s ideas on the impact that nutritional supplementation might make on heart health remain just as tantalizing and out of reach as they were when Pauling was alive and active.

The Unified Theory of Human Cardiovascular Disease

[An examination of Pauling’s research on vitamin C and heart disease, part 3 of 4.]

In early 1991, Dr. Howard Bachrach of Southold, New York informed Linus Pauling of experimental results indicating that lipoprotein (a) [commonly abbreviated as Lp(a)] binding to arterial walls could be suppressed through the use of supplemental lysine. In the weeks that followed, Bachrach continued to exchange information with Pauling and his colleague at the Linus Pauling Institute of Medicine, Matthias Rath, in hopes of determining if lysine, vitamin C, or some combination of the two might not only prohibit but actually reverse plaque accretion in vitamin C-deficient guinea pigs.

A breakthrough came about on February 28, 1991 – Linus Pauling’s 90^th birthday – when Rath reported to his colleagues his finding that Lp(a), as synthesized in the liver, was in fact regulated in an unknown way by the amount of vitamin C present in the body.

Lp(a) was understood by Rath and Pauling to form from low density lipoprotein (LDL) and Apoliprotein A-1 [abbrevied apo(a)] in the liver in amounts largely determined by the rate of synthesis of apo(a). This rate of synthesis was increased by low vitamin C concentrations in the blood. Rath and Pauling published the finding in Medical Science Research, arguing that plaque formation was not caused by LDL cholesterol, as previously thought, but lipoprotein (a) instead. Crucially, high doses of vitamin C was identified by the authors as being central to reducing these dangerous lipoprotein (a) levels.

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This discovery formed the basis for what Pauling and Rath would eventually call their Unified Theory of Human Cardiovascular Disease. Fundamental to this framework was Pauling and Rath’s belief that cardiovascular disease was a degenerative disease caused by vitamin C deficiency. The theory also put forth that humans’ inability to synthesize their own vitamin C drove the disease, though it was also aggravated by genetic defects and exogenous risk factors, such as free radicals introduced by cigarette smoke or oxidatively modified triglyceride-rich lipoproteins exerting a noxious effect on the vascular wall.

Further, lipoprotein (a) was put forth as an evolutionary surrogate for vitamin C in animals – like primates and guinea pigs – that no longer produced their own ascorbic acid. This collection of species shows much higher levels of Lp(a) in the blood, a characterstic seen by Pauling and Rath as serving as an ad hoc biological mechanism used by the body to repair damaged tissues through deposit on weakening arterial walls. Too much Lp(a), however, leads to plaque formation, causing angina, heart attack, and stroke. A lack of vitamin C thus leads indirectly to the deterioration of arteries.

From there, the researchers argued that this problem could be easily fixed if only the recommended doses of vitamin C were increased to levels many times larger than those prescribed by the federal government. Were the body enabled to make use of supplemental vitamin C to produce collagen – as all animals that synthesize vitamin C internally do – humans would be much more efficient at repairing damaged arterial walls. Indeed, vitamin C could function not only to strengthen arterial walls, but also to reduce the amount of Lp(a) being produced by the body and consequently – as a co-factor in the hydroxylation reaction that converts cholesterol to bile acids – lowering the amount of free cholesterol in the blood as well.

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Published in the Linus Pauling Institute of Science and Medicine Newsletter, March 1992.

To Pauling and Rath, the logic supporting their theory was clear. Critics, however, demanded large clinical studies to support the claims, and this was research that the Institute, which was struggling mightily for funds, did not have the resources to pursue.

It was at this point that other interested researchers took up the torch. One of them, Dr. James Enstrom at UCLA, led a 1992 study of over 11,000 human subjects. Enstrom’s work indicated that those individuals who regularly took supplements of vitamin C at federally recommended levels enjoyed significantly lower rates of heart disease than did those not subscribing to a supplementation routine. This data led Enstrom’s team to wonder – in tandem with Pauling and Rath – whether larger doses would achieve an even greater protective effect.

In 1993, hoping to add additional support to the hypothesis, Pauling published three case studies in the Journal of Orthomolecular Medicine. Each study focused on individuals who had suffered from severe cardiovascular disease and undergone surgical procedures, including heart bypass. The individuals in question had read Pauling’s papers with Rath and had decided to try adding lysine and vitamin C to their diet. In certain cases, members of the study group had already been taking fairly high doses of vitamin C and then added lysine.

The 1993 data clearly were not anything like controlled studies and were reported on anecdotally by Pauling. Further, the amounts of lysine and vitamin C ingested varied significantly between individuals, but was generally in the range of between 3 to 6 grams per day of each supplement. Many within the study group reported rapid relief and positive responses.

Though far from authoritative, the published case studies did help to bolster Pauling and Rath’s position, attracting increased interest in the work. However, the duo also received plenty of letters, some filled with irritation, from people who had incorporated supplementation and saw no positive change. Some correspondents, in fact, were getting worse.