Common concerns and unfounded bias regarding vitamin C

We frequently see a number of concerns regarding maximum absorption and safety as well as incorrect statements regarding vitamin C and it’s potential use for colds, COVID-19 and other respiratory infections. This document addresses and answers some of these concerns. Authored by Scientific Advisory Board forVitaminC4covid.com

VITAMIN C AND COLDS

There is no benefit of vitamin C for colds at any dose. FALSE

Most often cited is H. Hemila’s Cochrane review . The authors reported: ‘Thirty-one comparisons examined the effect of regular vitamin C on common cold duration (9,745 episodes). In adults the duration of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C shortened colds by 18%. The severity of colds was also reduced by regular vitamin C administration.’ The authors concluded that….‘given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted.’

The abstract of a more recent review of Vitamin C and Infections states “Regularly administered vitamin C has shortened the duration of colds, indicating a biological effect….Two controlled trials found a statistically significant dose–response, for the duration of common cold symptoms, with up to 6–8 g/day of vitamin C. Thus, the negative findings of some therapeutic common cold studies might be explained by the low doses of 3–4 g/day of vitamin C. Three controlled trials found that vitamin C prevented pneumonia. Two controlled trials found a treatment benefit of vitamin C for pneumonia patients.”

MAXIMUM ABSORPTION – ‘EXPENSIVE URINE’

Doses of vitamin C above 1 or 2g are simply cleared from the blood, excreted in the urine, and may even contribute to kidney stone formation. FALSE

Pharmacokinetic studies in healthy volunteers support a 200 mg daily dose to produce a plasma level of circa 70 to 90 μmol/L . Complete plasma saturation occurs between 1 g daily and 3 g every four hours, being the highest tolerated oral dose, giving a predicted peak plasma concentration of circa 220 μmol/L . The same dose given intravenously raises plasma vitamin C levels approximately ten-fold. Higher intakes of vitamin C are likely to be needed during viral infections with 2–3 g/day required to maintain normal plasma levels between 60 and 80 μmol/L , due to the enhanced requirements for the vitamin during infections.

Supplementing up to at least 2.5 g for most people on most days more than doubles blood plasma levels compared to ‘RDA’ levels, even though the excess is finally excreted. If you supplement 2 g a day spread out through the day you can expect your circulating plasma level to be three times higher than someone who just gets the RDA level. This is a big advantage because it is much harder for viruses and certain pathogenic bacteria, to survive at these concentrations.

SAFETY ISSUES

High intake of vitamin C causes kidney stone formation. FALSE

Regarding kidney stone formation, the Kidney Stone Research Laboratory of the University of Cape Town conducted a controlled trial in which ten volunteer subjects were required to ingest 4 g of vitamin C per day for five days. Unlike the earlier studies, they put a preservative in the urine collection bottles to prevent the conversion of ascorbate to oxalic acid. The samples were analysed for numerous physicochemical risk factors of kidney stone formation. These risk factors were not significantly altered and the authors concluded that ingestion of large doses of vitamin C does not increase the risk of forming kidney stones and earlier trials had faulty study designs involving unpreserved urine samples . A prospective cohort study of 85,557 women with no history of kidney stones, with 1078 incidences of kidney stones over 14 years of follow-up, reported that vitamin C intake was not associated with a risk of kidney stone development .

A systematic review of studies giving vitamin C found a correlation between ascorbic acid supplementation and the incidence of kidney stones in men, but not women . A study administering intravenous ascorbic acid in doses ranging from 0.2 to 1.5 g/kg body weight measured urinary oxalic excretion during and over 6 h post infusion. The authors conclude that less than 0.5% of a very large intravenous dose of ascorbic acid was recovered as urinary oxalic acid in people with normal renal function . A cautious position would be to exclude those with a history of kidney stones or kidney dysfunction from high-dose oral or intravenous vitamin C unless medically supervised. Short-term high-dose vitamin C in the region of 2–8 g/day is unlikely to be of significant concern in people with normal kidney function.

Vitamin C is dangerous for those with the genetic disorders of either glucose-6-phosphatedeficiency (G6PD), haemochromatosis or thalassaemia.

The latter relates to those with due to enhanced iron absorption with vitamin C. G6PD deficiency is not considered an exclusion criterion in the use of up to 6 g/day oral or intravenous vitamin C for short-term use in critical infection. The FLCCC report that 3 g every 6 h appears to be safe in patients with G6PD. It may be wise for those with haemochromatosis or thalassaemia to avoid high-dose vitamin C taken with iron-rich foods or supplements and short-term high-dose vitamin C to be medically monitored.

High dose vitamin C gives you diarrhoea and are dangerous.

The US DRI, having thoroughly considered the wide literature on vitamin C and many kinds of speculated harms, stated that the safe range is up to 2 g/day . The European Food Safety Authority stated that the lowest observable adverse effect level is 3–4 g/day (in relation to gastrointestinal effects) . Injectable vitamin C phials state “there are no contraindications to the administration of ascorbic acid. As much as 6 g has been administered parenterally to normal adults without evidence of toxicity ”.

Looser bowel movements and diarrhoea rarely occur below 3 g/day and tolerance is increased considerably when fighting a viral infection . Diarrhoea has not been reported as a complication in hospital-based oral treatment and does not occur with intravenous vitamin C administration. A survey of 9328 patients given an average intravenous dose of 24 g of vitamin C every 4 days, primarily for cancer, infection or fatigue, reported that 101 (1%) had side effects, mostly minor, including lethargy/fatigue, a change in mental status and vein irritation/phlebitis .

There’s no evidence that vitamin C has any effect on COVID-19. FALSE.

Given the potential benefit of vitamin C, in oral and intravenous doses of 2–8 g/day, to reduce duration and severity of the common cold, pneumonia, sepsis and ARDS, this warrants investigation in relation to whether early oral supplementation could be beneficial in preventing conversion from mild infection to more critical COVID-19 infection and, if given intravenously to those with critical COVID-19 symptoms, in reducing mortality and ICU stay, thus speeding up recovery.

Interestingly, many of the risk factors for COVID-19 overlap with those for vitamin C deficiency . Certain sub-groups (male, African American, older, those suffering with co-morbidities of diabetes, hypertension, COPD), all at higher risk of severe COVID-19, have also been shown to have lower serum vitamin C levels . Average plasma vitamin C levels are generally lower in men than women, even with comparative intakes of vitamin C, which has been attributed to their higher body weight . A hypothesis of altered sodium-dependent vitamin C transporter (SVCT1 and 2) expression in these sub-groups has also been proposed . In old versus young rat hepatocytes, the vitamin C level declines by 66%, which is largely attributed to reduced absorption due to a 45% decline in SVCT1 with age . It is noteworthy that inflammatory cytokines, also present in co-morbidities, downregulate SVCT2, resulting in the depletion of intracellular vitamin C .

There are currently 45 trials registered on Clinicaltrials.gov investigating vitamin C with or without other treatments for COVID-19. In the first RCT to test the value of vitamin C in critically ill COVID-19 patients, 54 ventilated patients in Wuhan, China, were treated with a placebo (sterile water) or intravenous vitamin C at a dose of 24 g/day for 7 days . After 7 days of treatment, the ratio of PaO2/FiO2 in the vitamin C group was 229 mmHg versus 151 mmHg in the control group (p = 0.01), and this also improved over time in the vitamin C group, but fell in the control group. On day 7, the IL-6 level was lower in the vitamin C group than in the placebo group: 19 pg/mL versus 158 pg/mL (p = 0.04). The more severely ill patients with SOFA scores ≥ 3 in the vitamin C group exhibited a reduction in 28-day mortality: 18% versus 50% (p = 0.05) in univariate survival analysis . No study-related adverse events were reported. The effects of treatment on the ratio PaO2/FiO2 and on IL-6 are clinically important, but further studies are needed to determine if the trend in lower mortality can be confirmed. The trial was originally designed for 140 subjects and was thus underpowered, with only 54 patients due to a lack of new admissions.

The largest registered trial is the Lessening Organ Dysfunction with Vitamin C-COVID (LOVIT-COVID) trial in Canada, which is recruiting 800 patients who are randomly assigned to vitamin C (intravenous, 50 mg/kg every 6 h) or a placebo for 96 h, i.e., equivalent to 15 g/day for a 75 kg person (NCT04401150). This protocol has also been added as a vitamin C arm in the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP; NCT02735707). The study design provides further rationale for the use of vitamin C in COVID-19 patients . There is also a high-dose (10 g/day) vitamin C intervention study in 500 adults is in progress in Palermo, Italy (NCT04323514).
There is concern, however, that these study designs limit the use of vitamin C to a maximum of four days, which may be inadvisable in acutely ill patients due to the potential return of symptoms if the inflammation is not resolved. This issue was illustrated by the CITRIS-ALI trial, which showed a maximum reduction in mortality compared to placebo on day 4, the final day of vitamin C administration, but a decreased difference between the groups after 28 days .

In the UK, the Chelsea and Westminster hospital ICU, where adult ICU patients were administered 1 g of intravenous vitamin C every 12 h together with anticoagulants , has reported 29% mortality , compared to the average 41% reported by the Intensive Care National Audit and Research Centre (ICNARC) for all UK ICUs . While the authors have stated that the addition of an antioxidant in the form of vitamin C could have contributed to the lower mortality rate, it should be noted that other clinical factors and procedures could also account for the improved mortality and that the Chelsea and Westminster ICU serves a more affluent sector of the population with less deprivation on the basis of the Index of Multiple Deprivation (IMD). Deprivation, while a risk factor for COVID-19 mortality, is also a predictor of low vitamin C status. In the UK, an estimated 25% of men and 16% of women in the low-income/materially deprived population are deficient in vitamin C > 11 µmol/L .

The Frontline COVID-19 Critical Care Expert Group (FLCCC), a group of emergency medicine experts, have reported that, with the combined use of 6 g/day intravenous vitamin C (1.5 g every 6 h), plus steroids and anticoagulants, mortality was 5% in two ICUs in the US (United Memorial Hospital in Houston, Texas, and Norfolk General Hospital in Norfolk, Virginia), the lowest mortality rates in their respective counties .

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