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Amid reports that some hospitals are using mega doses of vitamin C, up to 6000 mg per day, to treat covid-19 victims, some people are turning to this popular supplement as a possible prophylactic against the insidiously infectious disease, so much so that companies all over the world are reporting inventory shortages. It should be noted here that doctors are delivering the vitamin C intravenously, in conjunction with other drugs, including hydroxychloroquine. As Dr. Andrew Weber, critical care specialist affiliated to Northwell Health, told the New York Post, “‘The patients who did get vitamin C did significantly better than those who did not get vitamin C.’” Dr. Weber went on to say, “’It helps a tremendous amount, but it is not highlighted because it’s not a sexy drug.’” Sexy or not, do the successful outcomes touted by Dr. Weber, mean that taking mega doses of vitamin C, orally, is a good idea, even if you have not been diagnosed with covid-19?
Busy Little C
First detected/anticipated in 1564 by the Dutch physician, Balduinus Ronnseus, who noticed that
sailors who ate a large number of oranges, were cured of scurvy, vitamin C was first isolated by, among others, the Hungarian, biochemist Albert Szent-GyÖrgyi, in the late 1920s. It was Szent-GyÖrgyi, who in a nod to its inscrutable nature, first dubbed the white crystals of acid sugar “ignose” and then “godnose,” before settling on the term ascorbic acid, in reference to its antiscorbutic properties (1). These same properties, at least in part, are responsible for the lingering ambiguity about the role that vitamin C plays in our bodies.
Most of us are familiar with vitamin C’s role as an antioxidant, a substance that is capable of inhibiting oxidation. But the nutrient acts in myriad other important, mission-critical ways in our bodies, especially as a cofactor, a molecule required for the proper function of an enzyme:
Vitamin C is needed for the biosynthesis of carnitine, without which we can't burn fat.
Without vitamin C, the production of collagen, necessary for strong teeth, hair, bones and supple skin, grinds to a screeching halt.
Vitamin C converts inorganic iron (F3+) to the water-soluble F2+ variety, needed to create haemoglobulin, the protein in red blood cells that carries to oxygen throughout our bodies.
Deprived of vitamin C, our bodies cannot produce substance P, a sensory neurotransmitter that regulates our sense of pain, touch and temperature.
This is, by no means, an exhaustive list, but perhaps it is sufficient to demonstrate that vitamin C is a busy little bee when it comes to making sure enzymes, and as such, our bodies, function as designed. After all, as is evidenced by its role in the formation of haemoglobulin, without vitamin C we can’t breathe, and neither can neutrophils.
Neutrophils Are Not Neutral
Our immune system is our first line of detection and defense against pathogens. Vitamin C
contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Along with its aforementioned role in the formation of collagen fibers, vitamin C also promotes the free radical scavenging activity of our skin, part of our innate immune system (2). This property of vitamin C also provides a possible explanation for why Dr. Weber’s covid-19 patients who received vitamin C got significantly better than those who did not.
Out For A Kill
Chief among the first responders dispatched to the site of infection are neutrophils. In fact neutrophils are on constant patrol, as they enter and leave the circulatory system at the rate of approximately 100 billion per day, in search of malevolent microbes (3). However, don’t be fooled by their name. Neutrophils are anything but neutral. When they arrived at an infectious site, they are literally out for a kill -to kill and to be killed. They also arrive loaded with vitamin C, at concentration levels 50 to 100 times that found in plasma (4). Bingeing on such copious amounts vitamin C suggest a vital, albeit not completely understood, role in the way neutrophils function (2).
Neutrophils Eat. Can They Smell Too?
Neutrophils are phagocytic cells. That just means that when they find their pathogenic prey, they eat them. But how do they find them in the first instance.
As it turns out neutrophils are guided, if not lured to the infection site by so-called chemoattractant, with names like C5a, C5a or fmlP (N-formylmethionyl-leucyl-phenylalanine). These chemofactors or odors can derive either from the pathogen or the inflamed tissue of the host. Regardless of origin, once the neutrophils pick up the scent, of these chemical stimuli, their response is to literally swarm to the infection site (2).
Neutrophils originate in the bone marrow (3). It takes approximately 1 week for them to mature (5). Their migration or deployment to infection sites, known as chemotaxis, may require up to 6 hours, while the formation of 200 fully mature viral bodies, capable of infecting other cells, can take as little as 25 minutes, after the initial infection. Individuals who are vitamin C deficient (6), and patients with severe infection exhibit compromised neutrophil chemotactic ability (2). In other words, the arrival of the pathogen-killing phagocytes is delayed. Does this neutrophil paralysis account for the different outcomes observed in the covid-19 patients who only received hydroxychloroquine and those who received both hydroxychloroquine and vitamin C?
The mechanism(s) by which vitamin C exerts its influence on neutrophil chemotaxis are not at all understood. It is the subject of both ongoing research and debate. Conversely there seems to be a general consensus around its role in pathogen killing.
Waiting to Inhale
As stated previously, upon arrival at the infection site, neutrophils engulf or phagocytize their virulent victims. However, just quarantining its quarry is not sufficient to kill it. This objective is accomplished, in part, with a burst of a noxious cocktail of reactive oxygen species (ROS), aka free radicals, including superoxide anion, hydrogen peroxide, hypochlorous acid and the notorious hydroxyl radical (3). Vitamin C protects neutrophils from this chemical cesspool of their own making (1). That protection does not come without risk.
Heretofore, I have maintained that neutrophils absorb, accumulate vitamin C and/or ascorbic acid. That is only partially true. To be precise, neutrophils can only take up dehydroascorbate, the twice-oxidized, highly reactive, free-radicalized form of vitamin C. Once inside the neutrophil’s vacuole, in order to enhance chemotaxis or to protect the neutrophil from itself, dehydroascorbate must be converted/reduced to ascorbic acid. Glutaredoxin is the enzyme tasked with achieving this feat. It does so by taking two electrons from another small peptide enzyme called glutathione, the only endogenous antioxidant capable of giving up two electrons without becoming a free radical itself. Here’s the thing though! In this instance, the very same enzyme responsible for regenerating active glutathione is also needed to convert oxygen into water. So the neutrophil delays taking a breath, waits to inhale, hoping to survive long enough to kill the (microbe) (1). What is true for neutrophils is also true for us humans.
The Poison is in the Dose?
There was a time when we humans or synthetized vitamin C. We lost that ability with the mutation of the gene responsible for L-gulono-γ-lactone oxidase, the enzyme needed for the final step in vitamin C biosynthesis (6). As a consequence we must rely on our diet and/or supplements to provide us with the recommended dietary allowance (RDA) for vitamin C -90 mg/day for men and 75 mg/day for women. And while that may not seem like a lot, if we only consider the nutrient’s role in the processes described above, never mind the multitude of functions that were excluded, it is actually up to 100-fold times than that of many other vitamins (2). That fact notwithstanding, is there an argument to be made for asymptomatic people supplementing with megadoses of vitamin C? The answer to this question, like so many others around vitamin C, depends on who you ask!
Not Your Average Ascorbic Acid Advocates
No one has done more to advance the idea of megadoses of vitamin C as a cure-all than Linus Pauling. A two-time Nobel laureate and, at age 30, the youngest person elected the National Academy of Science (7), Pauling is remembered as much for his controversial assertions about vitamin C, as he is for his research on the nature of chemical bonds, for which he was awarded his first Nobel Prize. In 1970 Pauling published the wildly popular book Vitamin C and the Common Cold, in which he claimed vitamin C could prevent and/or cure the common cold. But Pauling didn’t stop there. Over the following two decades he, along with the Scottish oncologist, Ewan Cameron, another avid ascorbic acid advocate, continued to tout the efficacy of mega-doses of ascorbic acid as a cure for a variety of disease both physical and mental, life expectancy by decades (1).
As might be expected, the claims were met with incredulity from the mainstream medical/scientific community. Nevertheless, perhaps out of deference to Pauling, and in the guise of the Mayo Clinic and the National Institute of Health, conducted three small clinical studies and review 25 case studies, which were chosen by Cameron.
In the end though, neither the clinical trials nor the case study reviews provided any evidence in support of their claims. For their part, Pauling and Cameron complained, to no avail, that the clinical trials had been designed to fail. They had been too short and, perhaps more importantly, the vitamin C had been administered orally as opposed to intravenously. Feeling abandoned by the establishment, an embittered, yet undaunted, Pauling died in 1994, at the age of 93 (1), leaving the controversy, at which he was at the center, largely unsettled. And so it remained for over 30 years, until three case studies revealed that the priesthood of oncology may have been premature in their haste to label Pauling a quack.
Mega-Doses by the Numbers
The case studies involved three individual, identified only as patient 1, a 51-year old female, patient 2, a 49-year old male and patient 3, a 66-year old female, who had cancer of the kidney, bladder and lymphoma respectively.
Patient 1 and 2 refused chemotherapy and radiation, opting instead for mega-doses of vitamin C, up to 65 g twice per week. Patient 3 underwent a 5-week course of radiation, however, she refused the chemotherapy recommended by her oncologist. And instead, like patients 1 and 2, she chose mega-doses of vitamin C, delivered intravenously. All three patients also took other supplements, including selenium, N-acetylcysteine, α-lipoic acid and glutathione. All three patients saw their condition improve. Of the three, 7 years after initial diagnosis, 4 years after stopping vitamin C therapy and with her renal cancer in complete remission, only patient 1, a long-time cigarette smoker died –from small-cell lung cancer. Diagnosed in 1996 and 1995 respectively, patients 2 and 3 were in good health and remained so for at least 10 years after diagnosis (8).
These patient outcomes may mirror what the Dr. Weber observed in the covid-19 cases mentioned at the outset, but they are not a green light for healthy, asymptomatic individuals should suddenly start supplementing with gram doses of vitamin C.
What the cancer patients and covid-19 patients have in common is that the vitamin C was administered intravenously. They also had severely compromised immune systems. Inflammation is correlated in both disease. It seems Pauling and Cameron were right.
When taken orally, 18 g of Vitamin C per day produces peak plasma concentrations of just 39 mg/L. Quantities in excess of 200 mg, taken orally result in elevated excretion in the urine (9). As well vitamin C concentration in neutrophil is also saturated at 200 mg – 400 mg, when administered orally. Conversely, the same dose, delivered intravenously, can increase plasma concentrations as much as 975 mg/L. Vitamin C is toxic to some cancers at concentrations above 176 mg/L, while toxicity in human, even at the high concentration levels cited here, is low, except under certain conditions, i.e. glucose-6-phosphate dehydrogenase deficiency (8). Mega-doses of vitamin C, taken orally may also have laxative effect and cause diarrhea.
As reported by Lane, Pauling’s pronouncements about vitamin C were based, at least in part, on the fact that a gorilla’s diet included 5000 mg per day, of vitamin C. Even our Paleolithic progenitors, according to Lane, are thought to have consumed 400 milligrams of vitamin C daily (1). And since neither our simian siblings nor our Stone Age ancestors had the luxury -or need for that matter- of ordering their favorite supplement online, we can assume that “consumed” means “eat,” in the purest sense of the word. Nor does it mean that just because we live in a same-day-delivery world, we should gorge ourselves of ascorbic acid capsules, chewables, liquids or powder.
Moreover, because it is hard to imagine a gorilla this side of King Kong, eating over 71 oranges a day, it is reasonable to conclude that in the wild, the essentially herbivorous anthropoid gets his recommended dietary average of vitamin C from a variety of plants, including bamboo fruit, bamboo shoots, wild celery shoots, tree bark, and tree pulp, with an occasional side of termites.
We should do likewise. And no, I am not suggesting we should all be gnawing on that oak tree out in the front yard. We should however get our vitamin C and other vital micronutrients by eating, at least, 5 serving of, ideally fresh or minimally cooked, fruits and vegetables every day. Doing so, as numerous studies have indicated, can mean a significant reduction in likelihood of dying from cancer or cardiovascular disease. Inadequate consumption of fruits and vegetables has even been linked to depression in older adults (10). So if sheltering in place has you feeling a little dragged, you might want to forego the next drag on that cancer stick and, instead, grab a handful of carrot sticks!
The Disclaimer
Finally, the information presented here is not to be interpreted as medical advice or as an endorsement of hydroxychloroquine or any other drug. I am not a doctor and I have not played one since I was a child. It is that child’s curiosity that informs my desire to have a complete understanding of myself, the planet and a deep appreciation for the other sentient beings with whom I share it.
Works Cited
1. Lane, Nick. Oxygen: The Molecure that Made the World. Oxford : Oxford University Press, 2002.
2. Carr, Anitra C and Maggina, Silvia. Vitamin C and Immune Function. Basel : MDPI, 2017.
3. Teng, Tie-Shan, et al. Neutrophils and Immunity: From Bactericidal Action to Being Conquered. New York : Hindawi, 2017.
4. Human Genetic Variation Influences Vitamin C Homeostasis by Altering Vitamin C Transport and Antioxidant Enzyme Function. Michels, Alexander J, Hagen, Tory M and Frei, Baltz. 45-70, s.l. : Annual Review of Nutrition, 2013, Vol. 33.
5. Rogers, Kara. Neutrophil: Leukocyte. Encyclopedia Britannica. [Online] June 29, 2009. https://www.britannica.com/science/neutrophil.
6. Bozonet, Stephanie M, et al. Enhanced Human Neutrophil Vitamin C Status, Chemotaxis and Oxidant Generation Following Dietary Supplementation with Vitamin C-Rich SunGold Kiwifruit. Basel : MDPI, 2015.
7. Offit, Paul. The Vitamin Myth: Why We Think We Need Supplements. [Online] July 19, 2013. [Cited: April 10, 2020.] https://www.theatlantic.com/health/archive/2013/07/the-vitamin-myth-why-we-think-we-need-supplements/277947/.
8. Intravenously administered vitamin C as cancer therapy:. Padayatty, Sebastian J, et al. 7, Ottawa : The Canadian Medical Association Journal, 2006, Vol. 174.
9. High-dose Vitamin C (Ascorbic Acid) Therapy in the Treatment of Patients with Advanced Cancer. Ohno, Satoshi, et al. Kapandriti : International Institute of Anticancer Research, 2009, Vol. 29.
10. Fruit, Vegetable and Antioxidant Intakes are Lower in Older Adults with Depression. Payne, Martha E, et al. 12, s.l. : Elsiever, 2013, Vol. 112. 10.1016/j.jand.2012.08.026..
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