IV Vitamin C - The Hype and The Facts
Intravenous Vitamin C Dosing - The Hype and the Facts of Clinical Treatment
Vitamin C (VC), also known as ascorbic acid, is one of the most important vitamins in the human body. It is critical in the formation of fifteen different enzymes in mammals, and is so important, that it is synthesized independent from diet by most animals and all plants, with the exception of humans. Humans must acquire VC from their diet because we lack the enzyme L-gulonolactone oxidase, which is the final step in the pathway to generating functional VC. Without a sufficient dietary source of VC, humans will develop the fatal disease scurvy, made famous through the Era of Exploration (1500s, think Christopher Columbus sailing to the new world) with transoceanic travel resulting in the deaths of sailors after 2-3 months at sea from a variety of different ailments.
This article will review the history and dietary requirements of VC, as well as how science and peer reviewed articles have shown its benefits through direct human study. This article was heavily influenced by two very well written review articles about VC, which can be found here and here.
Vitamin C Physiology
There are several factors which determine the efficacy of Vitamin C in the body and the tissue concentrations, such as absorption in the GI tract, uptake from the bloodstream by tissues, utilization for enzymatic reactions, and excretion by the kidneys. Any of these may be altered in the body resulting in disease states, and can be altered by age, body composition, genetics, and physical activity level. Out of these factors, the most important is dietary consumption of proper amounts of vitamin C. In a study in the United States in 2003 (Schleicher et al. 2009), 8% of males and 6% of females had VC levels which were lower than the threshold at which scurvy (described later) would occur! These levels are even worse in smokers, where 18% and 15% (males, females) had levels below the threshold for causing scurvy, compared to 5% and 4% in non-smokers.
Vitamin C may be difficult to obtain solely through normal dietary intake as it may be sequestered within partially digested foods, degraded, or otherwise inhibited by the other chemicals or compounds in the food.
Ascorbic acid is the most powerful water soluble antioxidant (Padayatty et al., 2003) in the body, and it is frequently depleted during acute illness (such as heart attacks, inflammation, infections) leading to low levels in the blood. It is possible that these low levels contribute to the worsening of the disease process itself, and may potentially be causal in the initial development of the disease.
Chemistry and Metabolism of Vitamin C
It has been suggested that oxidative stress, chronic inflammation, and cancer are closely linked (Reuter et al., 2010). Oxidative stress can activate a variety of transcription factors, leading to the expression of hundreds of different genes, including those of pro-inflammatory cytokines. VC works as a reducing agent (an electron donor) which accounts for its varied physiologic effects. It also may act on oxidants to neutralize them in the body (an anti-oxidant), in addition to Glutathione. In fact, VC is the most potent water soluble antioxidant in the body! As mentioned previously, the most characterized actions are those electron donor for the development of 15 mammalian enzymes. Some of these enzymes include:
Dopamine beta-hydroxylase (which is found in neurosecretory vesicles and adrenal chromaffin granules, which is needed to synthesize norepinephrine in the adrenal glands);
Peptidylglycine alpha-amidating monooxygenase, which is required to make many hormones from the gastrointestinal system and the hypothalamus;
Trimethyllysine hydroxylase + Gamma-butyrobetaine hydroxylase which are required for the synthesis of amino acids lysine and methionine as well as carnitine.
At higher doses, VC can reduce metals in the body (copper, iron) which generate hydrogen peroxide. This generation of hydrogen peroxide (which is an oxidizing agent), is what generates differential destruction of tumor cells and sparing of normal tissue cells, and helps the body fight bacterial infections (both described later!).
Collagen Formation and Scurvy
Symptoms of scurvy (resulting from the nutritional deficiency of Vitamin C) can include poor wound healing, skin breakdown and loss of tone, bleeding gums/gingiva, loosening or loss of teeth. Collagen is an important component of connective tissue which provides structural integrity and strength, and VC is important in the formation of many of the intermediates in the procollagen-to-collagen pathway. Multiple studies in the 1970s looked to characterize the onset of symptoms of scurvy after discontinuation of VC, and found that it took approximately 40 days for sores in the mouth to occur (swelling or bleeding of the gums, bleeding under the tongue). This occurred later and with more minor symptoms than those in historical records, perhaps because the sailors in the Age of Exploration had much greater nutritional deficiencies and lived under more adverse conditions. In fact, those sailors who had more strenuous work suffered worse symptoms and more infections, likely highlighting the modern need for increased supplementation in athletes or for proper performance recovery.
Dietary Absorption of Vitamin C
VC is absorbed from the small intestine in humans, with peak levels of concentrations in the body occurring 120-180 minutes (2-3 hours) after ingestion. After the vitamin is absorbed from the small intestine into the blood stream, it is a water soluble vitamin which is moved from the blood to the tissues. The major tissues it is distributed to are the liver, brain, and muscle.
VC deficiency leads to symptoms in the mouth (bleeding gums, poor dentition), which can be aided by supplementation. However, oral supplementation using chewable tablets (chewable VC 500mg tablets) can reduce the pH of the saliva leading to increased acidity and breakdown of dental enamel over time, leading to tooth decay or loss as well.
Recommended Dietary Intake of Vitamin C
The recommended dietary allowance (RDA) of VC in the United States and Canada has changed over time. Previously, the RDA was 90mg/day for men and 75mg/day for women. These are based on studies and minimum intake amounts to prevent scurvy. This is a minimal amount, considering there are ~250mg in 5 servings of fruits and vegetables a day, and ~500mg in a typical chewable tablet. However, optimal dietary intake should not be based on merely preventing a rare illness, but on promoting optimum health, fitness recovery, and overall well-being. Low levels of VC in the tissues may not lead to scurvy, but they have been linked to severe fatigue, without any other manifestations of VC deficiency. Recent studies and recommendations have increased the recommended daily intake of VC to 200mg/day, however the exact amount which should be taken for optimum health is not known (Levine et al 1996).
Experimental Findings of Vitamin C Supplementation in Humans
High Dose IV Vitamin C
IV administered VC produces pharmacologic concentrations not possible with oral intake. Vitamin C, given intravenously in doses of up to 100 g have been used for several decades in treating infections, cancer and other conditions (Padayatty et al., 2010). In their review of 9,328 patients treated with high dose IV VC, 101 had minor side effects including lethargy/fatigue (59 patients, or 0.6%), mental status change (21 patients, or 0.2%), and vein irritation (6 patients, or 0.06%), clearly demonstrating its safety profile. One patient developed kidney stones after high dose IV VC, but he had pre-existing kidney disease. It is for this reason that IV VC is contraindicated with pre-existing kidney disease. IV VC can also lead to damage to red blood cells in patients who have a history of glucose-6-phosphate dehydrogenase deficiency, which is a rare disease which also precludes high dose IV VC. Rigorous trials to test scientific benefit have not yet been undertaken, but the safety profile has been clearly demonstrated.
Through IV dosing, blood concentrations can be up to 100 times higher than with oral dosing. Common IV infusions occur in dosages of 1-200 grams in an infusion, occurring 2-3 times per week. Even at relatively low IV VC dosing (2.5g to 10g per infusion), patients have shown decreased symptoms of fatigue, improved emotional and cognitive health, and improved physical endurance. This suggests that the anti-oxidant and anti-inflammatory functions as well as being a cofactor for different enzyme formation from VC can lead to quality of life improvements. Only at higher levels does VC act as a pro- oxidant. These pro-oxidant effects can have anti-infection properties as well as anti-tumor properties (Chen et al., 2005, Chen et al., 2007, Chen et al., 2008).
Common Cold and Viral Illness:
Meta-analysis (grouped study of high quality studies) have attempted to answer the question of whether VC has efficacy in the prophylaxis or treatment of the common cold (acute viral upper respiratory tract infection). These studies included dosing patients with >200mg per day of VC. They found that it did not decrease the total number of common cold cases, but had an effect in reducing the duration (8% in adults, 13% in children) of the illness, as well as the severity of the illness (reduced the symptoms, i.e. less runny nose, less coughing). In those who were heavily involved in physical endurance (Marathon runners), VC supplementation decreased the incidence of the common cold by over 50%!
Ascorbic Acid in Diabetes
Hyperglycemia (high amounts of glucose [aka sugar] in the blood) result in low red blood cell VC concentrations. Those with diabetes have large amounts of uncorrected glucose in their body which causes their red blood cells to become stiff and rigid. Preliminary studies are looking at how supplementation can improve the health of red blood cells in diabetic patients, which would help drive oxygen to tissues, resulting in less fatigue and improve exercise tolerance.
Infections
In humans, neutrophils are a type of white blood cell which are activated during acute infections to produce oxidants and hydrogen peroxide which can kill bacteria. When neutrophils are exposed to bacteria, the neutrophils become activated and rapidly uptake VC from the surrounding media until all of the surrounding vitamin is depleted, increasing the concentrations inside the neutrophil 10 times the original value. Why does this happen? One possibility is that the VC acts as an internal anti-oxidant to protect the neutrophil from the oxidants it makes to kill the bacteria, or that VC catalyzes the reaction to generate oxidants to assist their killing of bacteria. This phenomena has caused physicians to launch studies to determine the benefit of VC supplementation in both preventing bacterial infections and improving outcomes (decreasing morbidity/mortality) in hospitalized patients suffering from bad bacterial infections (sepsis).
Vitamin C and its Anti-Cancer Activity
Blood levels of VC in patients with various cancers have been frequently found to be anywhere from reduced (hypovitaminosis C) to outright deficient (Shenoy et al., 2017). Chemotherapy medications may decrease blood concentrations of VC as well. Only high dose IV VC produces blood and tissue concentrations which are high enough to have anti-tumor activity (Padayatty et al., 2004, Levine et al., 2011, Yun et al., 2015). At these higher concentrations hydrogen peroxide is produced which results in peroxide damage to cancer cells but not normal cells, resulting in slowing of the tumor cell growth or outright destruction of the tumor cell.
It is possible that IV VC can interfere with the mechanism of action of different chemotherapeutic medications, so IV VC should not be given at the same time as these chemotherapeutic regimens. However, the half-life of VC is very short because it is quickly excreted by the kidneys, so can be safely administered the day before chemotherapy. VC can also reduce the toxic effects of some chemotherapeutic medications (Fujita et al., 1982; Park et al., 2012). VC can decrease white blood cell loss, red blood cell loss, reduce weight loss, decreased liver and heart toxicity.
A single infusion of IV VC is not as effective as multiple infusions and a higher frequency of infusions may be more helpful (Takemura et al., 2010; Campbell et al., 2016).
A study was done by Parrow et al., 2013 to look at the effect of IV VC for anti-tumor effects. In Phase I studies it was shown to be safe. In retrospective studies, survival was doubled in patients with metastatic pancreatic cancer. Larger studies should be conducted to more rigorously test this benefit, and are pending in the cancer community.
In patients with various cancers, administration of 25–50 g IV VC decreased a number of different inflammatory mediators and pro-inflammatory mediators (Mikirova et al., 2012, 2016). Because oxidants can enhance inflammation, it is not clear these effects of VC are due to its oxidant scavenging function or its gene regulatory cofactor functions (Song et al., 2017). It is noteworthy that patients with higher levels of inflammation also appear to have a higher requirement for VC (Mikirova et al., 2013).
Conclusions from Review of Vitamin C
1. Vitamin C is an extremely important vitamin in the human body, which must be acquired from the diet.
2. There are many people in the United States who are deficient in Vitamin C despite normal diets.
3. Low levels of Vitamin C can lead to poor skin integrity, poor wound healing, gum or teeth damage, poor exercise tolerance, and fatigue.
4. Vitamin C is important in the creation of many enzymes, in anti-oxidant and anti-inflammatory effects at lower blood concentrations, and pro-oxidant effects resulting in anti-infection and anti-cancer properties at much higher blood concentrations.
5. Supplementation during cold and flu season can decrease the duration and severity of the common cold (viral illness). This effect is much more pronounced in highly physically active people (Marathoners).
6. To avoid dangerously low amounts of Vitamin C in the blood, the recommended dietary intake is currently 200mg/day, which can be acquired from 5 daily servings of fruits and vegetables, oral supplementation through capsules or chewable tablets, or intravenous supplementation.
7. IV supplementation can create blood concentrations of Vitamin C not possible with oral supplementation.
8. IV supplementation of 2.5 to 10 grams in a session resulted in decreased symptoms of fatigue, improved emotional and cognitive health, and improved physical endurance. It can also reduce the severity of side effects of many chemotherapeutic agents (without reducing their effectiveness against cancer cells).
9. IV supplementation of 25 to 50 grams in a session can result in decreased inflammation markers in the blood, and early studies show it can slow the rate of cancer growth or lead to destruction of cancer cells.
10. IV supplementation has been shown in many studies to be extremely safe and well tolerated without frequent adverse effects.