FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, May 18, 2022

Why Does Science Still Ignore Vitamin C?
From colds to Covid, ascorbate has long been marginalized

by Pim Christiaans

OMNS (May 18, 2022) For more than 20 years, Dr. Harri Hemilä, biochemist, physician and epidemiologist, has been analyzing research conducted with vitamin C. In 2017, ORTHO magazine had an interview with him. [1] At that time, the interest in vitamin C was mainly about the common cold. Now it also concerns another virus infection, Covid-19. Has anything changed since then? The near-total lack of interest within medical science for vitamin C still exists. And apparently, medical professors don't give a damn about the vitamin, as if it were a career killer.

Since 2002, Hemilä has considered it his professional duty to analyze studies conducted on vitamin C and to publish the analyses. What is the common thread after more than a hundred scientific publications, of which twelve were published in the years 2020 and 2021, and three in 2022? Well, one of these three reveals that common thread. In a review article of 27 pages in the open access magazine Life, [2] Hemilä unfolds his experiences and explains them in a long telephone conversation with ORTHO. The title of the article speaks volumes: "Bias against Vitamin C in Mainstream Medicine: Examples from Trials of Vitamin C for Infections." Remarkable. It turns out that prejudices ("bias") are a major common thread in the medical scientific world.

Thousand versus half a million

In the article, Hemilä shows, among other things, that the authors of the COVID-A to Z Study wrongly conclude that vitamin C is ineffective against Covid-19, because the data they rely on incorrectly show otherwise. [3] This will be discussed in more detail below.

Hemilä is pleased that Life has published his extensive article on the prejudice against vitamin C for everyone to read. [2] However, he is under no illusions about its impact: "According to the counter on Life's website, more than a thousand people have read my article. The COVID-A to Z Study on JAMA's website also has a counter. And it was at half a million the last time I looked."

In the Life article, Hemilä refers to articles by scientists who note that since the beginning of the last century, doctors and medical scientists have been writing about and discussing nutritional supplements with disdain. According to these researchers, over-the-counter vitamin pills undermined the authority of doctors, because they allowed the patient to self-treat. Moreover, it was not possible to patent nutrients, so there was little to gain for the pharmaceutical industry. And in the second half of the twentieth century, the discovery of patentable antibiotics overshadowed the promising effects of vitamin C against infectious diseases.

It was not until the end of the 1960s that there was renewed interest in the vitamin when Linus Pauling got involved. This led to a series of relatively large studies that, according to Hemilä, supported the effectiveness of vitamin C. Nevertheless, scientific interest in the vitamin fell again in the late 1970s. Hemilä points to the so-called "Karlowski Study" as the main cause, along with two other articles from 1975.

Start of the problem

In 1975, five years after the publication of Linus Pauling's book Vitamin C and the Common Cold, the scientific journal JAMA published the results of the Karlowski Study, a double-blind randomized placebo-controlled trial of vitamin C. [4] Although colds in the group of subjects who took 6 grams of vitamin C were 17% shorter, the authors attribute this outcome entirely to a placebo effect. Hemilä did not agree with this, and in 1996 subjected the data to a thorough re-analysis. [5] Astonished, he concluded that the data in fact do show a real, physiological effect of vitamin C and that the placebo explanation is incorrect. He caught the authors making all kinds of mistakes. For example, 42% of the recorded colds were apparently omitted from the subgroup analysis without further explanation - an unforgiveable sin within the statistics. The data indicate a dose-response effect: the tested dose of 6 grams per day is twice as effective as the tested dose of 3 grams per day. Hemilä calculates that if you draw the line, a study with 12 grams of vitamin C would have been the obvious choice. Such a study, however, never materialized, partly due to the discouraging placebo explanation of the Karlowski Study.

He compares the Karlowski-Study to a zombie: "Although liquidated long ago, it refuses to disappear into the grave and continues to leave a trail of destruction through scientific literature." Hemilä's skilful disassembly of the Karlowski Study has never been disproved, but nevertheless has had little impact. According to him, this study has remained by far the most influential study on vitamin C and the common cold. The vitamin C skeptics couldn't have it any better. There is a good chance that if a skeptical scientist mentions evidence on vitamin C, he will refer to this study.

Recent studies ignore evidence

Even now, according to Hemilä, studies are published with negative conclusions in their summaries, while the data on which they are based imply a very different conclusion. A good example of this is the 'CITRIS-ALI study' that was published in JAMA in 2019. [6]

In that study, participants were 167 patients in the ICU with sepsis and acute respiratory distress syndrome (ARDS). They received intravenous vitamin C (50 mg/kg body weight every 6 hours) or a placebo for four days. The researchers conclude: "A 96-hour infusion of vitamin C showed no significant improvement in organ dysfunction scores, nor did it alter markers of inflammation and vascular damage, compared to placebo." but did not mention a major result: a strong decrease in mortality. Hemilä checked this and explained that during the first four days (when the vitamin C was administered) the mortality in the vitamin C group decreased by 81%. "The main clinically relevant result of the CITRIS-ALI trial was mortality and the measurement of a dozen biomarkers should not distract from that," said Hemilä.

A second study

As a second example, Hemilä provided the previously mentioned COVID-A to Z-Study, which was published in JAMA Network Open in 2021. [3] The aim of that study was to evaluate the effect of 8 grams per day of vitamin C in 520 ambulatory Covid-19 patients. However, the study was terminated prematurely due to the slow influx of patients. This slowness led, as the researchers had mentioned, to a state of "futility." [3] Therefore, in this aborted study, the number of patients remained at 214.

But Hemilä explained that this premature stopping was unjustified, because the effects of vitamin C were actually greater than the researchers had anticipated. [2] The researchers had expected a 1.0 day reduction in the duration of Covid-19, but they found a reduction of 1.2 days. Hemilä calculated that the recovery percentage in the vitamin C group was 70% greater than in the control group. None of this was reflected in the abstract of the article. The researchers, in turn, concluded that vitamin C did not significantly reduce the duration of symptoms.

How can this difference between the facts found and the conclusions of the research be explained? Hemilä does not need to look far: one of the authors of the COVID-A to Z-Study declared in the "Conflict of Interest" statement that she has carried out paid consultancy work for Gilead Sciences." [3] This pharmaceutical company is the producer of Remdesivir, the first virus-inhibiting drug that was approved by the FDA for the treatment of Covid-19. Hemilä writes in his Life article: "What motivation does such a researcher have to find out whether a very cheap nutrient is actually effective against Covid-19 when an expensive drug available is available from a company for which she is a consultant?"

Timing purely coincidental

In February 2020, a team led by Harri Hemilä published a meta-analysis in the Journal of Intensive Care on the effect of vitamin C on the duration of artificial respiration given to ICU patients. [7] The timing was purely coincidental, but could not be better: the SARS-CoV-2 virus had only just started to spread from Wuhan and would cause death and destruction in the rest of the world in the months that followed. Hospitals' intensive care units everywhere were overloaded by Covid-19 victims, some of whom had to be on artificial ventilation for an unusually long time. The article's analysis seemed to imply a benefit from treatment with vitamin C. Hemilä and colleagues had collected data from eight studies involving a total of 685 patients who had ended up in ICU for a variety of reasons. Their calculations indicated that vitamin C had shortened the duration of artificial respiration by an average of 14%. In the most critically ill patients who had been on the ventilator the longest, vitamin C had actually reduced the duration by 25%.

More about vitamin C and Covid-19

The big question now is whether lives would have been saved if the vitamin had been given as standard to all Covid-19 patients in the ICU from the start of the pandemic as a precaution? Very likely, but we'll never know. In any case, Hemilä's hopeful article received little attention. The field has not rushed to start the bigger and better research studies called for in the last paragraphs.

In a telephone interview, Hemilä reacted resignedly to this finding: "It is a very big step to add vitamin C to the treatment protocol for Covid patients in ICUs. Based on our publication, it is too early for that. The studies we had to rely on were small and therefore of poor quality. However, there is very strong evidence for a biological effect of vitamin C, which justifies better and larger studies. In the meantime, you could assuredly give it to patients -- because vitamin C is cheap, and safe even in doses of tens of grams administered orally or intravenously. This is again confirmed by a 2010 review of vitamin C researchers, including the first and last authors of researchers from the most respected institute in the US, the National Institutes of Health (NIH). [8]

Two quotes from Harri Hemilä:

Hemilä is not an uncritical apologist for Linus Pauling's views:

"Pauling had a point, but he was too optimistic about vitamin C," he says. "Unlike Pauling, I don't think that an ordinary, healthy person would benefit from taking more than 500 mg of vitamin C per day. For the elderly, he recommended something like 10 grams of vitamin C per day, and I see no justification for that. But if people are sick, the dose can be increased considerably. That should be better investigated."

About twenty years ago, he considered setting up a clinical trial with vitamin C himself, but he quickly abandoned that plan:

"You need a lot of doctors for such a project and the doctors I approached were not interested. People who matter in science just don't care. I then decided that it makes more sense to continue to focus on analyzing existing data"

Reviews and meta-analysis

In his most recent meta-analysis, Hemilä showed that vitamin C increases left ventricular ejection fraction in cardiac patients. [9] He is also the lead author of a number of authoritative meta-analyses on vitamin C for the Cochrane Database of Systematic Reviews: within the medical science field the conclusions of 'Cochrane reviews' are often taken as the most reliable evidence.

He became best known for his Cochrane review on vitamin C and the common cold. [10] The conclusion is that vitamin C can reduce the severity and duration of a cold, albeit to a modest degree: with a daily intake of at least 1 gram of vitamin C per day an infection with a respiratory virus lasts on average 8% shorter in adults and 18% shorter in children. In 2017 he told ORTHO that you can see these results as a "proof of concept" of the effectiveness of vitamin C against respiratory infections. [1] The small but significant effect proves that vitamin C has an influence on viral infections, and there are indications that the effect is greater at higher doses. Hemilä also published meta-analyses on the effects of vitamin C on pneumonia ("therapeutic supplementation with vitamin C is reasonable") [11] and vitamin C on the length of stay in IC patients: [12] this appears to be on average 8% shorter under the influence of moderate doses of vitamin C.

Against viral and bacterial infections

Hemilä has gradually become very well established in reference to his knowledge about vitamin C, especially with regard to infectious diseases. We should take the opinion of such a person seriously during a disruptive pandemic caused by a virus. For example, the article "Vitamin C and COVID-19," published in the journal Frontiers in Medicine in early 2021. [13] In that article, he reviewed the evidence from about a hundred animal studies that have shown that vitamin C can alleviate a wide range of viral and bacterial infections. In mice with sepsis and acute respiratory distress syndrome (ARDS), high-dose vitamin C administration decreased pro-inflammatory genes, improved epithelial barrier function and improved alveolar fluid clearance. According to Hemilä, vitamin C has a number of biological properties that are important in light of Covid-19 and a weakened immune system: the vitamin stimulates the proliferation and function of T lymphocytes and Natural Killer lymphocytes and increases the production of interferon, which are important functions of the immune system.

Low blood levels

An important indication of the usefulness of vitamin C in the treatment of Covid-19 is the fact that patients in critical condition who end up in intensive care often have greatly reduced blood levels of vitamin C. [13] And a vitamin C deficiency is often associated with pneumonia: "While 0.1 grams of vitamin C per day can maintain a normal plasma level in a healthy person, much higher doses (1-4 grams per day) are needed for critically ill patients to raise plasma vitamin C levels to the normal range. Therefore, high vitamin C doses may be needed to compensate for the increased metabolism to reach normal plasma levels."

Sepsis and ARDS patients

Hemilä acknowledges in the article that there are currently no large double-blind random-controlled trials that provide direct evidence for an effect of vitamin C against Covid-19. [13] Weighing his words on a gold platter, however, he states that pending more and larger studies, high-dose vitamin C administration is already known to be helpful for Covid patients. After all, the vitamin is cheap and safe. He makes a suggestion based on his own review from 2017: "In patients suffering from a viral respiratory infection, 6 to 8 grams of oral vitamin C was significantly more effective than 3 to 4 grams per day. In recent studies of sepsis and ARDS patients, the dose of intravenous vitamin C was 7 to 14 grams over 3 to 4 days." [14]

Currently Hemilä finds that his call to utilize vitamin C has been little heeded. The fact that doctors have not started to give vitamin C to Covid-19 victims en masse can be explained by the appalling lack of good and large-scale studies. But why have they not been implemented? When asked about the state of affairs regarding the science of vitamin C and Covid-19 during the interview, he answered: "I can't say exactly because there is so much published that I can't keep up with it. Most of it is of low quality."

The Chinese Vitamin C Trial (2020)

As early as mid-2020, Hemilä was asked as a reviewer to comment on the protocol of a Chinese double-blind randomized placebo-controlled study. [15] The intention of the study was that 308 Covid-19 patients in the ICU would receive 24 grams daily of vitamin C or a placebo by infusion for a week. However, the execution of the experiment largely failed because of the draconian lockdown measures of the Chinese government, and too few patients ended up in the ICU. It eventually became a 'pilot study' with 56 patients: the duration of artificial respiration did not decrease in the vitamin C group. [16] According to Hemilä, however, the number of test subjects was too low to draw clear conclusions. After the interview, he sent in an e-mail: "You asked about the state of affairs about vitamin C and Covid. See what you find when you type [vitamin C] and [Covid-19] on pubmed." The scientific search engine turns out to cough up sixteen reviews and four clinical studies. Hemilä, disappointed wrote: "That says enough. And most of it is junk."

How it started

How can the half-baked treatment of vitamin C be explained? Harri Hemilä explains it based on his own experiences over the years. His fascination for the vitamin started in the 1970s when he saw Linus Pauling on television. The two-time Nobel laureate has just published his book Vitamin C and the Common cold. In it, he argued, based on the studies available at the time, that the common cold can be treated with high doses of C. A few weeks later, a Swedish professor appeared on Finnish television. "A very arrogant man," Hemilä recalls. "He had a bottle of vitamin C tablets with him and said, "This is junk without any effect." But he had no factual arguments or study results to support his negative statements."

Hemilä was studying biochemistry at the time and he asked himself who is right: Pauling or the skeptical professor? "I started collecting all the articles about vitamin C and infections. I didn't understand how it was possible that the important reviews judged the vitamin so negatively, while you could conclude from the results of studies that C is actually effective."

(Pim Christiaans is journalist, magazine maker and author of health books in the Dutch language. He writes about scientific developments in the field of healthy aging at his website www.lifeunlimited.nl . Christiaans has no financial ties with or interests in companies that manufacture or sell nutritional supplements.)

Translated from Dutch and reprinted in English with permission of the author and Orthomoleculair Magazine, April 2022. Those seeking permission to reprint or translate may contact the magazine's publisher Gert Schuitemaker (ortho@ortho.nl)

References

1. Christiaans P (2017) Vitamine C tegen verkoudheid. Orthomoleculair Magazine. 5:184-189. https://docplayer.nl/154405845-Vitamine-c-tegen-verkoudheid-opnieuw-op-een-rij-gezet-door-finse-wetenschapper.html

2. Hemilä H, Chalker E (2022) Bias against Vitamin C in Mainstream Medicine: Examples from Trials of Vitamin C for Infections. Life 12:62. https://pubmed.ncbi.nlm.nih.gov/35054455.

3. Thomas S, Patel D, Bittel B, et al. (2021) Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: The COVID A to Z randomized clinical trial. JAMA Netw Open. 4:e210369. https://pubmed.ncbi.nlm.nih.gov/33576820

4. Karlowski TR, Chalmers TC, Frenkel LD, et al. (1975) Ascorbic acid for the common cold: A prophylactic and therapeutic trial. JAMA 231:1038-1042. https://pubmed.ncbi.nlm.nih.gov/163386

5. Hemilä H (1996) Vitamin C, the placebo effect, and the common cold: A case study of how preconceptions influence the analysis of results. J Clin Epidemiol. 49:1079-1084. https://pubmed.ncbi.nlm.nih.gov/8826986

6. Fowler AA, Truwit JD, Hite RD et al. (2019) Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA 322:1261-1270. https://pubmed.ncbi.nlm.nih.gov/31573637

7. Hemilä H, Chalker E (2020) Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis. J Intensive Care 8:15. https://pubmed.ncbi.nlm.nih.gov/32047636

8. Padayatty SJ, Sun AY, Chen Q, et al. (2010) Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects. PLoS ONE 5(7):e11414. https://pubmed.ncbi.nlm.nih.gov/20628650

9. Hemilä H, Chalker E, de Man AME (2022) Vitamin C May Improve Left Ventricular Ejection Fraction: A Meta-Analysis. Front Cardiovasc Med. 9:789729. https://pubmed.ncbi.nlm.nih.gov/35282368

10. Hemilä H, Chalker E (2013) Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013(1):CD000980. https://pubmed.ncbi.nlm.nih.gov/23440782

11. Hemilä H, Louhiala P. Vitamin C for preventing and treating pneumonia. Cochrane Database Syst Rev 2013; 8:CD005532. https://pubmed.ncbi.nlm.nih.gov/23925826

12. Hemilä H, Chalker E (2019) Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients 2019; 11:708. https://pubmed.ncbi.nlm.nih.gov/30934660

13. Hemilä H, de Man AME (2021) Vitamin C and COVID-19. Front Med. 7:559811. https://pubmed.ncbi.nlm.nih.gov/33537320

14. Hemilä H (2017) Vitamin C and infections. Nutrients 9:339. https://pubmed.ncbi.nlm.nih.gov/28353648

15. Liu F, Zhu Y, Zhang J, et al. (2020) Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial. BMJ Open 10:e039519. https://pubmed.ncbi.nlm.nih.gov/32641343

16. Zhang J, Rao X, Li Y, et al. (2021) Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann. Intensive Care 11:5. https://pubmed.ncbi.nlm.nih.gov/33420963

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