Vitamin C and COVID-19 Research Resource

In March 2020, the World Health Organization (WHO) published a ‘Coordinated Global Research Roadmap for the 2019 Novel Coronavirus’. In this document vitamin C was highlighted as an adjunctive intervention with biological plausibility to improve the outcome of COVID-19 infected patients (pages 36-7).

• Observational studies
• Intervention trials
• Registered clinical trials
• Use in clinical practice
• Case reports
• Mechanisms of action
• Review articles
• In the media

Vitamin C and COVID-19 observational studies

Low vitamin C levels can predispose people to viral infections. In addition, viral infections can further decrease vitamin C levels due to enhanced requirements for the vitamin during infections. Below is a summary of COVID-19 and vitamin C observational studies which indicate that patients with COVID-19 have depleted vitamin C status. Definitions: vitamin C deficiency ≤11 µmol/L (<0.2 mg/dL); hypovitaminosis C ≤23 µmol/L (<0.4 mg/dL).

Observational studies

Study 1	Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome
Date online	26 August 2020
Location	Barcelona Spain
Cohort	18 patients with SARS-CoV-2-associated acute respiratory distress syndrome (ARDS)
Findings	17 patients had <1.5 mg/L (<8.5 µmol/L) vitamin C 1 patient had 2.4 mg/L (14 µmol/L) vitamin C
Reference	Chiscano-Camón et al. Crit Care. 2020 24(1):522. doi:10.1186/s13054-020-03249-y

Study 2	Serum levels of vitamin C and vitamin D in a cohort of critically Ill COVID-19 patients of a North American community hospital intensive care unit in May 2020: A pilot study
Date online	18 September 2020
Location	Thornton, Colorado, USA
Cohort	21 critically ill COVID-19 patients
Findings	Total cohort (n = 21) mean vitamin C status 22 ± 4 µmol/L (45% deficient, 70% hypovitC) Survivors (n = 11) mean vitamin C status 29 ± 7 µmol/L (40% deficient, 50% hypovitC) Non-survivors (n = 10) mean vitamin C status 15 ± 2 µmol/L (50% deficient, 90% hypovitC)
Reference	Arvinte et al. Med Drug Discov. 2020 8:100064. doi:10.1016/j.medidd.2020.100064

Study 3	Vitamin C supplementation is necessary for patients with coronavirus disease: An ultra-high-performance liquid chromatography-tandemmass spectrometry finding
Date online	27 January 2021
Location	Shanghai, China
Cohort	31 COVID-19 patients (+/- IV vitamin C) and 51 healthy controls
Findings	6 COVID-19 patients (no IV vitamin C): mean plasma vitamin C level 2 mg/dl (11 µmol/L) 25 COVID-19 patients given 100 mg/kg/d IV vitamin C: mean plasma vitamin C level 13.5 mg/L (76 µmol/L) 51 healthy controls: mean plasma vitamin C level 9.2 mg/L (52 µmol/L)
Reference	Xing et al. J Pharm Biomed Anal. 2021, 196:113927. doi: 10.1016/j.jpba.2021.113927

Study 4	Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: A cross-sectional comparative study in Jigawa, Northwestern Nigeria
Date online	1 February 2021
Location	Jigawa, Northwestern Nigeria
Cohort	50 COVID-19 symptomatic patients 21 healthy controls
Findings	Patients had 0.33 mg/dL (19 µmol/L) vitamin C Controls had 0.44 mg/dL (25 µmol/L) vitamin C (p <0.001)
Notes	Oxidative stress markers were elevated in the patients relative to controls and correlated with vitamin C in the patients (r = -0.605, p = 0.004)
Reference	Muhammad et al. SAGE Open Medicine. 2021 9:1-8. doi/10.1177/2050312121991246

Study 5	Oxidative Stress Status in COVID-19 Patients Hospitalized in Intensive Care Unit for Severe Pneumonia. A Pilot Study
Date online	7 February 2021
Location	Liège, Belgium
Cohort	9 ICU patients with severe COVID-19 pneumonia
Findings	Patients had 3.9 (3.1–6.1) µg/mL or 22 (18-35) µmol/L vitamin C Reference rage 6.2–15.2 µg/mL or 35-86 µmol/L (p = 0.004)
Notes	These low concentrations were despite the patients receiving 124 (95-172) mg/day of vitamin C in their liquid nutrition
Reference	Pincemail et al. Antioxidants. 2021 10(2):257. doi: 10.3390/antiox10020257

Study 6	Evaluation of nutritional status in pediatric patients diagnosed with Covid-19 infection
Date online	11 May 2021
Location	Ankara, Turkey
Cohort	49 paediatric patients (aged 1 month to 18 years), diagnosed with COVID-19 then hospitalized
Findings	17% of the patients had vitamin C deficiency
Reference	Molla et al. Clin Nutr ESPEN. 2021. doi: 10.1016/j.clnesp.2021.04.022.

Study 7	COVID‑19: Up to 82% critically ill patients had low Vitamin C values
Date online	9 July 2021
Location	Barcelona, Spain
Cohort	67 critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS)
Findings	Mean vitamin C concentration was 8 ± 3 µmol/L (0.14 ± 0.05 mg/dL); range of <6 – 61 µmol/L (<0.10 – 1.08 mg/dL) 55 patients (82%) had values <23 µmol/L (<0.40 mg/dL) 12 patients (18%) had values <6 µmol/L (<0.10 mg/dL)
Reference	Tomasa‑Irriguible and Bielsa‑Berrocal. Nutr Res. 2021 20(1):66. doi: 10.1186/s12937-021-00727-z.

Study 8	COVID‑19: Up to 82% critically ill patients had low Vitamin C values
Date online	15 August 2022
Location	St. Gallen, Switzerland
Cohort	74 COVID-19 patients 8 unidentified volunteers
Findings	COVID-19 patients had significantly lower plasma ascorbate levels (2.8 [0.5, 15] µmol/L) than the controls (47 [44, 52] µmol/L; p < 0.001) Survival analysis showed that plasma AA < 11.4 µM was associated with a lengthy hospitalization and a high risk of death.
Reference	Sinnberg et al. Antioxidants (Basel). 2022;11(8):1580. doi: 10.3390/antiox11081580.

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Vitamin C and COVID-19 intervention trials

Randomised controlled trials (RCTs) of patients with respiratory infections, pneumonia and sepsis have indicated that vitamin C administration may be able to improve some patient outcomes. Critically ill patients with sepsis require intravenous administration of gram doses of vitamin C to normalise their plasma vitamin C levels. Below is a summary of vitamin C and COVID-19 intervention trials which indicate that some symptoms of COVID-19 patients may be improved with vitamin C administration.

• Intravenous vitamin C – randomised controlled trials (5 RCTs)
• Intravenous vitamin C – retrospective cohort studies (8 studies)
• Oral vitamin C – randomised controlled trials (3 RCTs)
• Oral vitamin C – retrospective cohort studies (1 study)
• Vitamin C intake or status and COVID-19 risk (2 studies)

Intravenous vitamin C – randomised controlled trials

RCT 1	Pilot trial of high-dose vitamin C in critically ill COVID-19 patients
Date online	9 August 2020
Location	Hubei, China (multicentre)
Trial type	Randomised placebo-controlled trial
Cohort	54 critically ill COVID-19 patients (27 and 29 per group)
Intervention	24 g/day IV vitamin C (12 g/12 hours) for 7 days (or placebo)
Findings	no difference in ventilation-free days (26.5 vs 10.5 days, p = 0.560) ↑ oxygenation PaO2/FiO2 (229 vs 151 mmHg, p = 0.01) ↓ Interleukin-6 (19.4 vs 158 pg/ml, p = 0.04) ↓ ICU and hospital mortality in patients with SOFA scores ≥3 (HR, 0.32 [95% CI 0.10-1.06]; p = 0.07) No adverse events were reported.
Notes	Trial was stopped early due to lack of patients
Reference	Zhang et al. Ann Intensive Care, 2021, 11, 5

RCT 2	The role of vitamin C as adjuvant therapy in COVID-19
Date online	30 November 2020
Location	Karachi, Pakistan
Trial type	Randomised controlled trial (open label)
Cohort	150 severe COVID-19 patients (75 per group)
Intervention	50 mg/kg bodyweight/day IV vitamin C (or standard therapy alone)
Findings	Became symptom-free earlier (7.1 vs 9.6 days, p <0.0001) Spent fewer days in the hospital (8.1 vs 10.7 days, p <0.0001) No difference regarding need for mechanical ventilation (16% vs 20%, p = 0.4) No difference regarding mortality (9.3% vs 14.6%, p = 0.3)
Reference	Kumari et al. Cureus 2020 12(11): e11779. doi:10.7759/cureus.11779

RCT 3	Safety and effectiveness of high‑dose vitamin C in patients with COVID‑19: a randomized open‑label clinical trial
Date online	11 February 2021
Location	Tehran, Iran
Trial type	Randomised controlled trial (open-label)
Cohort	60 patients with COVID-19 (30 per group)
Intervention	6 g/d IV vitamin C (or standard care) for 5 days
Findings	↓ body temperature on 3rd day of hospitalization (p = 0.001) ↑ peripheral capillary oxygen saturations (SpO2) on 3rd day of hospitalization (p = 0.014) Comparable SpO2 levels (oxygen saturation) at discharge ↑ length of hospitalization (8.5 days vs. 6.5 days, p = 0.028). No difference in length of intensive care unit (ICU) stay or mortality No adverse events were reported
Reference	JamaliMoghadamSiahkali et al. Eur J Med Res. 2021, 26(1):20. doi: 10.1186/s40001-021-00490-1

RCT 4	An investigation into the effects of intravenous vitamin C on pulmonary CT findings and clinical outcomes of patients with COVID 19 pneumonia A Randomized Clinical Trial
Date online	8 November 2021
Location	Tehran, Iran
Trial type	Randomised controlled trial (open-label)
Cohort	50 patients with moderate to severe COVID-19
Intervention	IV vitamin C at 2 g every 6 hours (8 g/day) for 5 days (n = 18) or standard care (n = 26)
Findings	↑ oxygen saturation (p = 0.02) ↓ respiratory rate (p = 0.03) ↓ lung involvement (p = 0.02) No difference in C-reactive protein levels (p = 0.1) No difference in duration of hospitalisation (p = 0.2) No difference in mortality (0 vs 4 deaths, p = 0.2)
Reference	Tehrani et al. Urol J. 2021 doi: 10.22037/uj.v18i.6863

RCT 5	Therapies to prevent progression of COVID-19, including hydroxychloroquine, azithromycin, zinc, and vitamin D3 with or without intravenous vitamin C: An international, multicenter, randomized trial
Date online	25 November 2021
Location	Turkey (7 hospitals)
Trial type	Multicenter, randomised, open-label study
Cohort	237 hospitalised patients with COVID-19
Intervention	IV vitamin C (50 mg/kg every six hours on day 1, followed by 100 mg/kg every six hours (average: 28 g/day) for seven days + hydroxychloroquine, azithromycin, zinc, and vitamin D3 (n = 162) vs hydroxychloroquine, azithromycin, zinc, and vitamin D3 (n = 75)
Findings	IVC therapy contributed to a quicker recovery (57% vs 39% symptom free and discharged by day 15; p = 0.007)
Reference	Ried et al. Cureus. 2021. doi: 10.7759/cureus.19902

RCT 6	Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial
Date online	19 March 2022
Location	Philadelphia, USA
Trial type	Randomised controlled trial
Cohort	66 patients with COVID-19 requiring supplemental oxygen
Intervention	Escalating doses of IV vitamin C plus standard of care (n = 44) vs standard of care alone (n = 22)
Findings	Overall clinical improvement at 72 h was not achieved, however, point estimates for the composite outcome and its individual components of decreased use of supplemental oxygen, decreased use of bronchodilators, and the time to discharge were all favourable for the treatment arm, particularly at earlier time points (see figures).
Reference	Coppock et al. Life (Basel). 2022;12(3):453. doi: 10.3390/life12030453

RCT 7	Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit
Date online	15 June 2022
Location	Canada, France, New Zealand
Trial type	Randomised placebo-controlled trial
Cohort	63 patients with SARS-CoV-2 infection (within a total cohort of 872 patients with sepsis)
Intervention	IV vitamin C (50 mg/kg body weight) every 6 hours for up to 96 hours (n = 37) vs matched placebo (n = 26)
Findings	A non-significant decrease in risk of death or persistent organ dysfunction in the vitamin C group (RR 0.81, 95% CI 0.57–1.16).
Reference	Lamontagne et al. N Engl J Med. 2022;386(25):2387-2398. doi: 10.1056/NEJMoa2200644.

RCT 8	Efficacy of intravenous vitamin C in management of moderate and severe COVID-19: A double blind randomized placebo controlled trial
Date online	30 August 2022
Location	Patna, Bihar, India
Trial type	Double blind randomized placebo-controlled trial
Cohort	60 patients with moderate to severe COVID-19
Intervention	IV vitamin C - 1 gram 8 hourly (3 g/day) (n = 30) or IV placebo (n = 30) for four days
Findings	10 (33%) died in intervention group vs 13 (43%) in placebo group (P > 0.05) (despite 87% in intervention group being more severe vs 67% in placebo group) 11 (37%) required invasive mechanical ventilation in intervention group vs 14 (47%) in placebo group (P > 0.05) 10 (33%) required vasopressor therapy in intervention group vs 8 (27%) in placebo group (P > 0.05)
Reference	Kumar et al. J Family Med Prim Care. 2022;11(8):4758-4765. doi: 10.4103/jfmpc.jfmpc_2437_21.

Intravenous vitamin C - retrospective cohort studies (11 studies)

Study 1	The efficiency and safety of high-dose vitamin C in patients with COVID-19: a retrospective cohort study
Date online	26 February 2021
Location	Xi'an, Shaanxi, China
Trial type	Retrospective cohort
Cohort	76 patients with COVID-19
Intervention	Loading dose of 6 g intravenous infusion per 12 hr on the first day, and 6 g once for the following 4 days (n=46) or standard therapy group (n=30)
Findings	Risk of 28-day mortality was reduced (HR=0.14, 95% CI, 0.03-0.72) Oxygen support status was improved compared with standard therapy (64% vs 36%) No adverse safety events were associated with high-dose vitamin C therapy
Notes	Mortality differences were even more pronounced for (A) those with severe COVID-19 (HR= 9.91, 95% CI, 1.82-54.00) and (B) those aged >60 years (HR=7.98, 95% CI, 1.24-51.22).
Reference	Gao et al. Aging. 2021:13. doi: 10.18632/aging.202557.

Study 2	High Dose Intravenous Vitamin C for Preventing The Disease Aggravation of Moderate COVID-19 Pneumonia. A Retrospective Propensity Matched Before-After Study
Date online	22 April 2021
Location	Shanghai, China
Trial type	Retrospective propensity matched
Cohort	110 patients with moderate COVID-19 pneumonia (55 per group)
Intervention	100 mg/kg/day IV vitamin C for 7 days vs standard care
Findings	↓ number of patients progressing to severe type (4/55 vs 12/55; RR 0.28 [0.08, 0.93], P = 0.03) ↓ duration (P < 0.001) and ↓ incidence (2/21 vs 10/22, P = 0.08) of systemic inflammation (SIRS) ↓ C-reactive protein levels (P = 0.05), ↓ activated partial thromboplastin (blood clotting) time (P = 0.02), ↑ CD4+ (helper) T cells (P = 0.04) No Effect on time to negative nucleic acid load
Reference	Zhao et al. Frontiers Pharmacol, 2021, 12:638556.

Study 3	Effect of high-dose intravenous vitamin C on prognosis in patients with SARS-CoV-2 pneumonia
Date online	11 May 2021
Location	Ankara, Turkey
Trial type	Retrospective
Cohort	232 patients with severe acute respiratory syndrome due to COVID-19 infection
Intervention	2 g/day IV vitamin C initiated within a median duration of 3 days after admission (n=153) vs no vitamin C (n=170)
Findings	Those in the VC group were not significantly different in terms of the length of hospital stay (p=0.05), re-admission rate (p=0.943), admission to intensive care, need for advanced oxygen support (p=0.488), need for advanced medical treatment (p<0.001), and mortality (p=0.52) No adverse effects associated with the use of IV vitamin C treatment were recorded.
Reference	Suna et al. Med Clin (Barc). 2021;S0025-7753(21)00252-9. doi: 10.1016/j.medcli.2021.04.010.

Study 4	Use of Intravenous Vitamin C in Critically Ill Patients With COVID-19 Infection
Date online	8 June 2021
Location	New York, United States of America
Trial type	Retrospective observational cohort study with propensity score matching
Cohort	ICU patients with COVID-19 infection
Intervention	1.5 grams IV vitamin C every 6 hours for up to 4 days (n = 8) vs matched patients (n = 24)
Findings	Patients in the IV vitamin C group had higher rates of hospital mortality [7 (88%) vs. 19 (79%), P = 0.049] and mean SOFA scores post-treatment (12.4 ± 2.8 vs. 8.1 ± 3.5, P < 0.005). There was no difference in the daily vasopressor requirement or in ICU length of stay between the treatment and control groups.
Reference	Li et al. J Pharm Pract. 2021;8971900211015052. doi: 10.1177/08971900211015052.

Study 5	High-dose intravenous vitamin C attenuates hyperinflammation in severe coronavirus disease 2019
Date online	26 June 2021
Location	Wuhan, China
Trial type	Retrospective cohort
Cohort	236 patients with severe COVID-19
Intervention	Intravenous vitamin C (IVC) at 100 mg/kg body weight every 6 hours on the first day, then 100 mg/kg body weight every 12 h for the next 5 days (n=85) or standard therapy group (n=151)
Findings	IVC intervention was associated with reduced levels of inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-α)
Reference	Xia et al. Nutrition 2021, 91-92:111405. doi: 10.1016/j.nut.2021.111405.g.

Study 6	The use of vitamin C in the intensive care unit during the COVID-19 pandemic
Date online	July 2021
Location	Bursa, Turkey
Trial type	Retrospective cohort
Cohort	160 ICU patients with COVID-19
Intervention	IV vitamin C at 3x 2g (n=32) or no vitamin C (n=128)
Findings	No differences observed between groups for inflammatory parameters (e.g. C-reactive protein, procalcitonin, D dimer), length of stay or mortality.
Reference	Özgünay et al. Eur Res J 2021. doi:10.18621/eurj.938778

Study 7	High-dose vitamin C ameliorates cardiac injury in COVID-19 pandemic: a retrospective cohort study
Date online	9 September 2021
Location	Wuhan, China
Trial type	Retrospective cohort
Cohort	113 severe and critical COVID-19 patients with cardiac injury
Intervention	Intravenous vitamin C (IVC) at 100 mg/kg body weight every 6 hours on the first day, then 100 mg/kg body weight every 12 h for the next 5 days (n = 51) or standard therapy group (n = 62)
Findings	More patients in ameliorated cardiac injury group received IVC (53 vs 33%, p = 0.035) IVC was associated with ameliorated cardiac injury independent of other medications (OR 2.42 [1.02, 5.73], p = 0.04) IVC was associated with reduced levels of inflammatory markers (C-reactive protein, interleukin-6, interleukin-8, tumor necrosis factor-α) at day 21 of hospitalisation (p <0.05)
Reference	Xia et al. Aging 2021, 13. doi: 10.18632/aging.203503.

Study 8	Effect of Vitamin C on Clinical Outcomes of Critically Ill Patients With COVID-19: An Observational Study and Subsequent Meta-Analysis
Date online	11 February 2022
Location	Athens, Greece
Trial type	Retrospective cohort
Cohort	113 adult COVID-19 patients with critical COVID-19
Intervention	Intravenous vitamin C (1-3 g/day; n = 10) No vitamin C (n = 103)
Findings	ICU mortality 20% (2/10) in vitamin C group vs 48% (49/103) in control group (P = 0.1) Vasopressor free days 9 vs 0 for vitamin C group vs control group (P = 0.3) Continuous renal replacement therapy free days 26 vs 19 for vitamin C group vs control group (P = 0.6)
Reference	Gavrielatou et al. Front Med (Lausanne). 2022;9:814587. doi: 10.3389/fmed.2022.814587.

Study 9	No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
Date online	22 September 2021
Location	Wuhan, China
Trial type	Retrospective cohort
Cohort	397 adult patients with severe COVID-19
Intervention	Intravenous vitamin C (2-4 g/day; n = 70) No vitamin C (n = 327)
Findings	No difference in mortality between groups No difference in clinical improvement between groups
Reference	Zheng et al. Open Med (Wars) 2021, 16(1):1403-1414. doi: 10.1515/med-2021-0361

Study 10	High-dose intravenous vitamin C decreases rates of mechanical ventilation and cardiac arrest in severe COVID-19
Date online	29 March 2022
Location	Missouri, USA
Trial type	Retrospective cohort
Cohort	100 patients with severe COVID-19
Intervention	Intravenous vitamin C (3 g every 6 h for 7 days; n = 25) Control - no vitamin C (n = 75)
Findings	Average time to death was significantly longer for HDIVC patients (22.9 days versus 13.7 days for control patients; P = 0.0139). Patients who received HDIVC had significantly lower rates of mechanical ventilation (52.93% vs. 73.14%; P = 0.0499) and cardiac arrest (2.46% vs. 9.06%; P = 0.0439).
Reference	Hess et al. Intern Emerg Med. 2022;1-10. doi: 10.1007/s11739-022-02954-6.

Study 11	Effect of high-dose intravenous vitamin C on prognosis in patients with SARS-CoV-2 pneumonia
Date online	22 April 2022
Location	Ankara, Turkey
Trial type	Retrospective cohort
Cohort	323 patients with severe COVID-19
Intervention	Intravenous vitamin C (2 g/day; n = 153) Control - no vitamin C (n = 170)
Findings	Vitamin C group relative to control group: length of hospital stay (p = 0.05), re-admission rate (p = 0.9), admission to intensive care (ns), need for advanced oxygen support (p = 0.5), need for advanced medical treatment (p < 0.001), and mortality (p = 0.5)
Notes	V vitamin C was relatively low dose (2 g/day) and was administered a median of 3 days after admission. Duration of vitamin C administration was not stated.
Reference	Suna et al. Med Clin. 2022;158(8):356-360. doi: 10.1016/j.medcle.2021.04.027 2022;1-10.

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Oral vitamin C - randomised controlled trials (3 RCTs)

RCT 1	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
Date online	12 February 2021
Location	Ohio and Florida, USA
Trial type	Randomised controlled trial (open-label)
Cohort	214 patients with SARS-CoV-2 infection (48 - 58 per group)
Intervention	8 g/d oral vitamin C or 50 mg/d zinc gluconate or both vitamin C and zinc gluconate or standard care for 10 days
Findings	Non-significant decrease in number of days to reach 50% reduction in symptoms of approx. one day for treatment groups compared with standard care: Standard care group 6.7 (± 4.4) days Vitamin C group 5.5 (± 3.7) days Zinc gluconate group 5.9 (± 4.9) days Both vitamin C and zinc gluconate group 5.5 (± 3.4) days
Notes	Trial was stopped early as interventions assumed to be ineffective (although the difference between the vitamin C and standard care groups was greater than originally anticipated by the authors). Independent statistical analysis of the data has indicated that vitamin C increased the rate of recovery by 71% (P = 0.036)
Reference	Thomas et al. JAMA Network Open 2021 4(2):e210369. doi:10.1001/jamanetworkopen.2021.0369

RCT 2	The Effect of Vitamin C on Pathological Parameters and Survival Duration of Critically Ill Coronavirus Disease 2019 Patients: A Randomized Clinical Trial
Date online	15 December 2021
Location	Rasht, Iran
Trial type	Double blind randomised controlled trial
Cohort	120 critically ill patients infected with COVID-19 (31 intervention group, 69 control group)
Intervention	500 mg/day oral vitamin C for 14 days
Findings	Higher mean survival duration compared with control group (8 vs. 4 days, p < 0.01) Linear association between the number of days of vitamin C intake and survival duration Lower serum potassium levels, but no difference in other blood parameters
Reference	Majidi et al. Front Immunol. 2021;12:717816. doi: 10.3389/fimmu.2021.717816.

RCT 3	A Pilot of a Randomized Control Trial of Melatonin and Vitamin C for Mild-to-Moderate COVID-19
Date online	July-August 2022
Location	Lancaster County, Pennsylvania
Trial type	Randomized, double-blind, placebo-controlled trial
Cohort	98 patients with mild-to-moderate symptoms of COVID-19 infection
Intervention	vitamin C 1000 mg/d orally (n = 32) or melatonin 10 mg/d orally (n = 32) or placebo (n = 34), orally for 14 days
Findings	Vitamin C 1000 mg once daily had no effect on symptom progression or quality of life impact.
Reference	Fogleman et al. J Am Board Fam Med. 2022;35(4):695-707. doi: 10.3122/jabfm.2022.04.210529.

Oral vitamin C - retrospective cohort studies (1 study)

Study 1	Ascorbic acid as an adjunctive therapy in critically ill patients with COVID-19: a propensity score matched study
Date online	3 September 2021
Location	Riyadh, Saudi Arabia
Study type	Retrospective propensity score matched
Cohort	296 critically ill patients with COVID-19
Intervention	1000 mg/d oral vitamin C for 11 (7-18) days (n = 148 patients)
Findings	No association of low dose oral vitamin C with in hospital or 30-day mortality, or acute kidney injury, liver injury, respiratory failure/mechanical ventilation Longer ICU and hospital length of stay observed for vitamin C group Decreased incidence of thrombosis in vitamin C group (6 vs 13%; OR 0.42 [0.18 – 0.94) p = 0.03)
Reference	Sulaiman et al. Sci Rep. 2021; 11(1):17648. doi: 10.1038/s41598-021-96703-y.

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Vitamin C intake or status and COVID-19 risk (3 studies)

Study 1	Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study
Date online	16 February 2021
Location	Bhubaneswar, India
Study type	Case control
Cohort	372 health-care workers who tested positive (cases) or negative (controls)
Intervention	67 took prophylactic vitamin C at 500 mg/day (or twice daily) vs 305 who did not
Findings	Vitamin C prophylaxis was not associated with SARS-CoV-2 infection (OR 0.71, 95% CI, 0.40–1.26)
Reference	Behera et al. PLoS ONE 16(2): e0247163.

Study 2	The role of vitamin C in pneumonia and COVID-19 infection in adults with European ancestry: a Mendelian randomisation study
Date online	30 August 2021
Location	Chinese study
Study type	Genome-wide association study (GWAS)
Cohort	52,018 people of European ancestry
Methodology	Used single nucleotide polymorphisms (SNPs) that were associated with circulating levels of vitamin C (note: they did not use measured vitamin C levels)
Findings	Genetically predicted circulating levels of vitamin C was not associated with susceptibility to severe COVID-19, COVID-19 hospitalisation, any COVID-19 infection nor pneumonia.
Comments	There are significant issues with using genetically predicted vitamin C concentrations – see commentary by Hemilä and Chalker, Eur J Clin Nutr. 2022. 1-2. doi: 10.1038/s41430-022-01091-9
Reference	Hui et al. Eur J Clin Nutr 2021 1-4. doi: 10.1038/s41430-021-00993-4

Study 3	Relationship Between Plasma Vitamin C and COVID-19 Susceptibility and Severity: A Two-Sample Mendelian Randomization Study
Date online	9 March 2022
Location	Chinese study
Study type	Genome-wide association study (GWAS)
Cohort	52,018 people of European ancestry
Methodology	Mendelian randomization analysis was conducted to examine the effect of selected single nucleotide polymorphisms and COVID-19 susceptibility, hospitalization, disease severity (note: they did not use measured vitamin C levels)
Findings	Genetic predisposition to the levels of plasma Vitamin C was not associated with COVID-19 susceptibility, hospitalization and severity.
Comments	There are significant issues with using genetically predicted vitamin C concentrations – see commentary by Hemilä and Chalker, Eur J Clin Nutr. 2022. 1-2. doi: 10.1038/s41430-022-01091-9
Reference	Chen et al. Front Med (Lausanne). 2022;9:844228. doi: 10.3389/fmed.2022.844228

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Registered vitamin C and COVID-19 clinical trials

Registered vitamin C and COVID-19 clinical trials can be found at clinicaltrials.gov.

Some of these trials are testing vitamin C as a prophylactic (preventative), while others are testing it as an adjunctive therapy/treatment (i.e. in addition to standard care). Some of these trials are using vitamin C alone (monotherapy), while others are using combination therapies. Some are using oral vitamin C and others intravenous vitamin C administration (summarised in Carr and Rowe, Nutrients, 2020. doi: 10.3390/nu12113286)

Largest vitamin C and COVID-19 trials

• Lessening Organ Dysfunction with VITamin C—COVID-19 (LOVIT-COVID; Canada; n = 800; NCT04401150), also an arm of REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-Acquired Pneumonia; NCT02735707)
• Use of Ascorbic Acid in Patients With COVID-19 (Italy; n = 500; NCT04323514)
• Early Infusion of Vitamin C for Treatment of Novel COVID-19 Acute Lung Injury (EVICT-CORONA-ALI; USA; n = 200; NCT04344184)
• Coronavirus 2019 (COVID-19)- Using Ascorbic Acid and Zinc Supplementation (COVIDAtoZ; USA; n = 520; NCT04342728)

Published study protocols

• Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
• Impact of vitamins A, B, C, D, and E supplementation on improvement and mortality rate in ICU patients with coronavirus-19: a structured summary of a study protocol for a randomized controlled trial
• High-dose vitamin C intravenous infusion in the treatment of patients with COVID-19: A protocol for systematic review and meta-analysis

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Vitamin C and COVID-19 in clinical practice

Many clinicians and clinical teams worldwide are administering vitamin C to their COVID-19 patients. Some protocols use vitamin C monotherapy in addition to standard care, others as part of combination therapies, for both prophylaxis and treatment.

Clinical protocols

• MATH+ Hospital Treatment Protocol for Covid-19. See also review by Marik, Expert Rev Anti Infect Ther, 2020.(doi: 10.1080/14787210.2020.1808462)
• I-MASK+ Prophylaxis & Early Outpatient Treatment Protocol for COVID-19 
• Development and implementation of a COVID-19 near real-time traffic light system in an acute hospital setting (page 4)
• Expert consensus on comprehensive treatment of COVID-19 in Shanghai

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Vitamin C and COVID-19 in case reports

Case reports do not have untreated patients as comparators so cannot provide definitive evidence that vitamin C is exerting any additional benefit over standard therapy alone.

Case reports with positive outcomes

• Vitamin C and COVID-19: An Orthomolecular Perspective on Physiological Mechanisms
• Intravenous Vitamin C and an Orthomolecular Protocol as Therapy for COVID19: A Case Report

• High Dose Intravenous Vitamin C as Adjunctive Therapy for COVID-19 Patients with Cancer: Two Cases
• Unusual early recovery of a critical COVID-19 patient after administration of intravenous vitamin C
• The use of IV vitamin C for patients with COVID-19: a case series doi: 10.1080/14787210.2020.1794819
• Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study 
• Reversal of the pathophysiological responses to gram-negative sepsis by megadose vitamin C

Case reports with negative outcomes

• Novel coronavirus 2019 (COVID-19): A case report and review of treatments 
• Oxalate nephropathy caused by excessive vitamin C administration in 2 patients with COVID-19 
• Kidney transplant dysfunction in a patient with COVID - 19 infection: role of concurrent Sars-Cov 2 nephropathy, chronic rejection and vitamin C-mediated hyperoxalosis: case report

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Evidence for mechanisms of action

Many mechanisms of action have been proposed for vitamin C against SARS-CoV-2 and COVID-19, based on previous research with similar viruses and respiratory infections, e.g. anti-viral, anti-inflammatory, anti-oxidant, and immunomodulatory. Below are in vitro (laboratory-based) and in vivo (clinical) studies that have been carried out with SARS-CoV-2 and COVID-19 patients.

In vitro (laboratory-based) studies

• Vitamin C (in the form of magnesium ascorbate) binds to a key protease in the virus, Mpro (Kumar et al. ResearchSquare preprint, 2020)

In vivo (clinical) studies

Intravenous vitamin C administration to COVID-patients:

• Decreased interleukin-6 (IL-6), an inflammatory biomarker (Zhang et al. Ann Intensive Care, 2021) 
• Associated with decreased C-reactive protein (an inflammatory marker), decreased activated partial thromboplastin (blood clotting) time, and increases CD4+ (helper) T cells (Zhao et al. Frontiers Pharmacol, 2021)
• Associated with decreased inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and tumour necrosis factor-α (TNFα) (Xia et al. Nutrition, 2021 and Xia et al. Aging, 2021)

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Vitamin C and COVID-19 review articles

Many review articles and commentaries have been written about vitamin C and COVID-19. Published articles that have specifically focused on vitamin C are shown below. Meta-analyses, which combine the outcomes from multiple studies, are now also becoming available.

Meta-analyses

• Vitamin C Supplementation for the Treatment of COVID-19: A Systematic Review and Meta-Analysis
• Impact of high-dose vitamin C on the mortality, severity, and duration of hospital stay in COVID-19 patients: A meta-analysis
• Effect of Vitamin C on Clinical Outcomes of Critically Ill Patients With COVID-19: An Observational Study and Subsequent Meta-Analysis
• The effectiveness of high-dose intravenous vitamin C for patients with coronavirus disease 2019: A systematic review and meta-analysis
• Vitamin C and COVID-19 treatment: A systematic review and meta-analysis of randomized controlled trials
• Outcomes in vitamin C studies (online meta-analysis)
• Intravenous vitamin C use and risk of severity and mortality in COVID-19: A systematic review and meta-analysis

Published review articles

• Role of high dose vitamin C in management of hospitalised COVID-19 patients: A minireview
• Intravenous Ascorbic Acid and Lung Function in Severely Ill COVID-19 Patients
• The Variable Nature of Vitamin C-Does It Help When Dealing with Coronavirus?
• Vitamin C and its therapeutic potential in the management of COVID19
• A possible role for ascorbic acid in COVID-19
• Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C
• Role of vitamin C in preventing of COVID-19 infection, progression and severity
• High-Dose Vitamin C Supplementation as a Legitimate Anti-SARS-CoV-2 Prophylaxis in Healthy Subjects-Yes or No?
• COVID-19, oxidative stress, and male reproductive dysfunctions: Vitamin C as a potential remedy?
• The effects of vitamin C on the multiple pathophysiological stages of COVID-19
• The protective role of vitamin C in the management of COVID
• Vitamin C intervention for critical COVID-19: A pragmatic review of the current level of evidence
• Vitamin C—An adjunctive therapy for respiratory infection, sepsis and COVID-19 
• Overview of the possible role of vitamin C in management of COVID-19 
• Repositioning vitamin C as a promising option to alleviate complications associated with COVID-19 
• The emerging role of vitamin C in the prevention and treatment of COVID-19 
• The long history of vitamin C: From prevention of the common cold to potential aid in the treatment of COVID-19
• Efficacy and safety of vitamin C in the management of acute respiratory infection and disease 
• Low level of vitamin C and dysregulation of vitamin C transporter might be involved in the severity of COVID-19 Infection 
• A possible application of high dose vitamin C in the prevention and therapy for coronavirus infections
• Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19?
• Ascorbate as prophylaxis and therapy for COVID-19 - Update from Shanghai and U.S. medical institutions
• Vitamin C for COVID-19: A living systematic review 
• Is vitamin C an effective agent for the prevention of COVID-19 and treatment of severe infection in the ICU? 
• Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?
• Vitamin C in the treatment of COVID-19
• Feasibility of vitamin C in the treatment of post viral fatigue with focus on long COVID, based on a systematic review of IV vitamin C on fatigue
• Therapeutic potential of mega-dose vitamin C to reverse organ dysfunction in sepsis and COVID-19
• The Potential Use of Vitamin C to Prevent Kidney Injury in Patients with COVID-19
• Common anti-oxidant vitamin C as an anti-infective agent with remedial role on SARS-CoV-2 infection. An update

Published commentaries

• Vitamin C for COVID-19 Treatment: Have We Got Enough Evidence?
• Potential benefit of high-dose intravenous vitamin C for coronavirus disease 2019 pneumonia
• Effect of high-dose intravenous vitamin C on prognosis in patients with SARS-CoV-2 pneumonia
• A Debate on Vitamin C: Supplementation on the Hotline for Critically Ill Patients with COVID-19
• Vitamin C and COVID-19: should clinical trials be prioritized for low-income settings and vitamin C deficient populations?
• Vitamin C as a Possible Therapy for COVID-19 
• High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection
• Role of vitamin C in critically ill patients with COVID-19: is it effective? 
• Micronutrient status of COVID-19 patients: a critical consideration 
• A new clinical trial to test high-dose vitamin C in patients with COVID-19 
• Multi-level immune support by vitamins C and D during the SARS-CoV-2 pandemic

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Vitamin C and COVID-19 in the media

There are many articles in the global media regarding vitamin C and COVID-19. Some of the posts directly related to this topic are shown below.

Clinical studies in the media

• Vitamin C could be the secret weapon in the fight against coronavirus 
• Vitamin C trials in China podcast

Clinical practice in the media

• Holistic approaches may have reduced coronavirus deaths at this London hospital 
• New York hospitals treating coronavirus patients with vitamin C 

Case reports in the media

• 'Unusual' IV High-Dose Vitamin C Success Story in COVID-19
• COVID patient with sepsis makes 'remarkable' recovery following megadose of vitamin C 
• Richmond doctor shares story of COVID-19 infection, survival 
• Emergency room doctor, near death with coronavirus, saved with experimental treatment 

Reviews/overviews in the media

• Vitamin C can 'help to prevent severe Covid and speed up recovery'
• Coronavirus update: Vitamin C could save the lives of those severely affected by COVID-19
• Vitamin C can help severe Covid-19 cases, NZ-led review finds 
• Vitamin C and COVID-19: A Review
• Vitamin C and COVID-19: Researchers call for status testing and intravenous / oral supplementation 
• Vitamin C's effectiveness against COVID may hinge on vitamin's natural transporter levels
• This vitamin may help treat COVID, study finds 
• Coronavirus: Vitamin C treatment 'encouraging' says NZ researcher 
• Big vote of confidence for Vitamin C as viral fighter. Now being tested 
• Is it ethical to keep ignoring the potential of vitamin C to fight the virus? 
• Grassroots clinicians pick up on Vitamin C treatment for coronavirus 

Podcasts/videos

• Can vitamin C in critical COVID save lives?
• Affordable Vitamin C for Covid

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Feedback

“A useful repository of studies on vitamin C and COVID‑19 is managed by Professor Anita Carr at the University of Otago who has herself has contributed much to research with Vitamin C and both communicable and non-communicable disease.”
Prof R Mithen, Chief Scientist, NZ High Value Nutrition National Science Challenge.

“I live in Canada and I was exposed to COVID‑19 in late December, and fell seriously ill [positive COVID test]. Everyone has a different experience with the virus but what stuck out to me was my constant craving for orange juice, I drank gallons of it, which I usually don’t drink. The sickness passed and I stopped craving it. I really think there is something to these studies.”
B Okojie, Canada.

“I feedback quite a lot of information to our Access and Choice practitioners who are seeing a lot of people in primary care with health anxiety. I have highlighted your page to help explain why there is evidence of the use of vitamin C in the treatment of COVID but not as a preventative in place of vaccination.”
H Gibbs, Nutrition Development Advisor, WellSouth Primary Health Network, NZ

Contact

Contact Associate Professor Anitra Carr if you wish to provide relevant resources or receive further information.

Email anitra.carr@otago.ac.nz
Tel +64 3 364 0649

How to cite this resource

Carr, A.C. Vitamin C and COVID-19 Research Resource, 
otago.ac.nz/christchurch/research/nutrition-in-medicine/vitamin-c