Vitamin C for COVID-19: real-time analysis of all 47 studies

Vitamin C for COVID-19: real-time meta analysis of 30 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for progression and recovery. 10 studies from 6 different countries show statistically significant improvements in isolation (6 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 11% [0‑21%] improvement. Results are better for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids recovery but is not antiviral. Early treatment is more effective than late treatment. High dose IV treatment is more effective.

• In exclusion sensitivity analysis, statistical significance is lost after excluding only one of 30 studies in pooled analysis.

• The treatment regimen varies widely across studies and may be high-dose IV vitamin C.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 3% of vitamin C studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments are significantly more effective.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix.

	Studies	Early treatment	Late treatment	Prophylaxis	Patients	Authors
All studies	30	43% [-23‑73%]	16% [0‑30%]	-6% [-31‑14%]	32,026	339
With exclusions	18	30% [10‑46%]	23% [11‑33%]	0% [-3‑3%]	2,220	226
Peer-reviewed	26	43% [-23‑73%]	19% [-1‑36%]	-6% [-31‑14%]	31,115	281
RCTs	9	30% [10‑46%]	43% [11‑63%]		817	101
Percentage improvement with vitamin C treatment

Covid Analysis et al., 1/18/2022, preprint, 1 author.

Characteristics of the COVID-19 patients treated at Gulu Regional Referral Hospital, Northern Uganda: A cross-sectional study

Baguma et al., Research Square, doi:10.21203/rs.3.rs-1193578/v1 (Preprint)

Retrospective COVID+ hospitalized patients in Uganda, 385 patients receiving vitamin C treatment, showing higher mortality with treatment, without statistical significance.

risk of death, 48.5% higher, RR 1.48, p = 0.54, treatment 385, control 96, OR converted to RR, multivariable, control prevalance approximated with overall prevalence.

Baguma et al., 12/28/2021, retrospective, Uganda, Africa, preprint, 16 authors, study period March 2020 - October 2021.

Vitamin C inhibits Angiotensin-Converting Enzyme-2 in Isolated Rat Aortic Ring

Amssayef et al., Cardiovascular & Hematological Disorders-Drug Targets, doi:10.2174/1871529X21666211214153308 (Peer Reviewed) (Ex Vivo)

Ex Vivo study showing vitamin C inhibiting vascular ACE2.

Amssayef et al., 12/14/2021, peer-reviewed, 3 authors.

Ex Vivo studies are an important part of preclinical research, however results may be very different in vivo.

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

Ried et al., Cureus, doi:10.7759/cureus.19902 (Peer Reviewed)

RCT 237 patients in Turkey, 162 treated with IV vitamin C in addition to HCQ/AZ/zinc/vitamin D used for all patients, showing significantly faster recovery with the addition of IV vitamin C.

97% of patients were vitamin D deficient, and lower vitamin D levels were associated with ICU admission and longer hospital stay.

Only 1 of 237 hospitalized patients died (average age 63, range 22-99) - a 70-year-old patient with heart and lung disease and severely deficient vitamin D levels (6 nmol/L). IV vitamin C (sodium ascorbate) was given as 50 mg/kg every six hours on day 1, followed by 100 mg/kg every six hours (four times daily, 400 mg/kg/day) for seven days. ACTRN12620000557932.

risk of no recovery, 30.6% lower, RR 0.69, p = 0.008, treatment 69 of 162 (42.6%), control 46 of 75 (61.3%), NNT 5.3, day 15 mid-recovery.

Ried et al., 11/25/2021, Randomized Controlled Trial, Turkey, Europe, peer-reviewed, 3 authors, average treatment delay 4.0 days.

The effect of supplementation with vitamins A, B, C, D, and E on disease severity and inflammatory responses in patients with COVID-19: a randomized clinical trial

Beigmohammadi et al., Trials, doi:10.1186/s13063-021-05795-4 (Peer Reviewed)

Small RCT 60 ICU patients in Iran, 30 treated with vitamins A, B, C, D, and E, showing significant improvement in SOFA score and several inflammatory markers at day 7 with treatment.

5,000 IU vitamin A daily, 600,000 IU vitamin D once, 300 IU of vitamin E twice a day, 500 mg vitamin C four times a day, and one ampule daily of B vitamins [thiamine nitrate 3.1 mg, sodium riboflavin phosphate 4.9 mg (corresponding to vitamin B2 3.6 mg), nicotinamide 40 mg, pyridoxine hydrochloride 4.9 mg (corresponding to vitamin B6 4.0 mg), sodium pantothenate 16.5 mg (corresponding to pantothenic acid 15 mg), sodium ascorbate 113 mg (corresponding to vitamin C 100 mg), biotin 60 μg, folic acid 400 μg, and cyanocobalamin 5 μg]. IRCT20200319046819N [1].

[1] irct.ir/trial/46838

risk of death, 88.9% lower, RR 0.11, p = 0.11, treatment 0 of 30 (0.0%), control 4 of 30 (13.3%), NNT 7.5, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization >7 days, 41.0% lower, RR 0.59, p = 0.25, treatment 4 of 30 (13.3%), control 16 of 30 (53.3%), NNT 2.5, adjusted, OR converted to RR.

relative SOFA score @day 7, 45.5% better, RR 0.55, p < 0.001, treatment 30, control 30.

Excluded in meta analysis: combined treatments may contribute more to the effect seen.

Beigmohammadi et al., 11/14/2021, Single Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 6 authors, this trial uses multiple treatments in the treatment arm (combined with vitamins A, B, D, E) - results of individual treatments may vary.

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

Tehrani et al., Urology Journal, doi:10.22037/uj.v18i.6863 (Peer Reviewed)

RCT 54 late stage patients, 18 treated with IV vitamin C (2g every 6h for 5 days), showing significant relative improvements in oxygen saturation and respiratory rate.

risk of death, 87.1% lower, RR 0.13, p = 0.13, treatment 0 of 18 (0.0%), control 4 of 26 (15.4%), NNT 6.5, relative risk is not 0 because of continuity correction due to zero events.

hospitalization time, 17.6% lower, relative time 0.82, p = 0.23, treatment 18, control 26.

Tehrani et al., 11/8/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 10 authors, average treatment delay 9.0 days.

Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial

Leal et al., SSRN, doi:10.2139/ssrn.3949424 (Preprint)

80 patient RCT with 40 patients treated with a comprehensive regimen of nutritional support, showing significantly lower mortality with treatment. Treatment contained cholecalciferol, vitamin C, zinc, spirulina maxima, folic acid, glutamine, vegetable protein, selenium, resveratrol, omega-3 fatty acids, l-arginine, magnesium, probiotics, and B-complex IV. Adherence was strictly monitored. NCT04507867.

risk of death, 85.7% lower, RR 0.14, p = 0.03, treatment 1 of 40 (2.5%), control 7 of 40 (17.5%), NNT 6.7.

risk of mechanical ventilation, 57.1% lower, RR 0.43, p = 0.31, treatment 3 of 40 (7.5%), control 7 of 40 (17.5%), NNT 10.0.

Excluded in after exclusion results of meta analysis: combined treatments may contribute more to the effect seen.

Leal et al., 10/25/2021, Randomized Controlled Trial, Mexico, North America, preprint, 7 authors, study period 1 September, 2020 - 28 February, 2021, this trial uses multiple treatments in the treatment arm (combined with comprehensive nutritional support) - results of individual treatments may vary.

Nutritional risk factors for SARS-CoV-2 infection: prospective study from the NutriNet-Santé cohort

Deschasaux-Tanguy et al., European Journal of Public Health, doi:10.1093/eurpub/ckab165.243 (Peer Reviewed)

Analysis of 7,766 adults in France, showing higher intakes of vitamin C, folates, vitamin K, dietary fibre, and fruit and vegetables associated with a lower seroprevalence of anti-SARS-CoV-2 antibodies.

Deschasaux-Tanguy et al., 10/20/2021, peer-reviewed, 9 authors.

Effects of high dose vitamin C administration in Covid-19 patients

Simsek et al., Annals of Medical Research, doi:10.5455/annalsmedres.2020.10.1043 (Peer Reviewed)

Retrospective 139 hospitalized patients in Turkey, 58 treated with high dose vitamin C, showing improved kidney functioning with treatment. Mortality was lower with treatment, but not reaching statistical significance with the small sample size.

risk of death, 44.1% lower, RR 0.56, p = 0.18, treatment 6 of 58 (10.3%), control 15 of 81 (18.5%), NNT 12.

risk of ICU admission, 10.2% lower, RR 0.90, p = 0.66, treatment 18 of 58 (31.0%), control 28 of 81 (34.6%), NNT 28.

Simsek et al., 9/27/2021, retrospective, Turkey, Europe, peer-reviewed, 16 authors.

No significant benefit of moderate-dose vitamin C on severe COVID-19 cases

Zheng et al., Open Medicine, doi:10.1515/med-2021-0361 (Peer Reviewed)

Retrospective 397 severe COVID-19 patients in China, showing worse outcomes with vitamin C treatment, without statistical significance. IV vitamin C 2-4g/day. Subject to confounding by indication and immortal time bias. Exclusion criteria were (a) the duration of hospitalization was less than 3 days; (b) vitamin C treatment started before admission; and (c) the length of vitamin C use was less than 3 days. Includes vitamin C use started at any time during hospitalization, for many patients this was >15 days later (Figure A2). Duration of treatment varied widely (Figure A1). Treatment was determined by clinicians according to the condition of each patient.

risk of death, 157.0% higher, RR 2.57, p = 0.33, treatment 12 of 70 (17.1%), control 7 of 327 (2.1%), adjusted, propensity score matching.

risk of death, 169.0% higher, RR 2.69, p = 0.07, treatment 12 of 70 (17.1%), control 7 of 327 (2.1%), adjusted, IPTW.

clinical improvement ≥ 2 points, 35.1% worse, RR 1.35, p = 0.17, treatment 18 of 70 (25.7%), control 16 of 327 (4.9%), adjusted, propensity score matching.

clinical improvement ≥ 2 points, 31.6% worse, RR 1.32, p = 0.11, treatment 18 of 70 (25.7%), control 16 of 327 (4.9%), adjusted, IPTW.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, immortal time bias may significantly affect results, treatment start times unknown, treatment may not have started at baseline.

Zheng et al., 9/22/2021, retrospective, China, Asia, peer-reviewed, 10 authors, study period 13 February, 2020 - 29 February, 2020.

High-dose vitamin C ameliorates cardiac injury in COVID-19 pandemic: a retrospective cohort study

Xia et al., Aging, doi:10.18632/aging.203503 (Peer Reviewed)

Retrospective 113 severe and critical patients in China with cardiac injury, 51 treated with high dose vitamin C, showing treatment associated with improvement of myocardial injury.

Xia et al., 9/7/2021, China, Asia, peer-reviewed, 5 authors.

Characterization of Critically Ill COVID-19 Patients at a Brooklyn Safety-Net Hospital

Capone et al., Cureus, doi:10.7759/cureus.9809 (Peer Reviewed)

Retrospective 102 ICU patients in the USA, 73 receiving vitamin C and zinc, showing a negative correlation of treatment with mortality, but not reaching statistical significance (p = 0.31).

Capone et al., 8/17/2021, USA, North America, peer-reviewed, 11 authors.

Do body mass index (BMI) and history of nutritional supplementation play a role in the severity of COVID-19? A retrospective study

Mohseni et al., Nutrition & Food Science, doi:10.1108/NFS-11-2020-0421 (Peer Reviewed)

Retrospective 603 patients in Iran, 34 taking vitamin C supplements, showing increased risk of COVID-19 cases in unadjusted results. IR.SHOUSHTAR.REC.1399.015.

risk of case, 44.2% higher, RR 1.44, p = 0.002, treatment 34 of 43 (79.1%), control 307 of 560 (54.8%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Mohseni et al., 8/4/2021, retrospective, Iran, Middle East, peer-reviewed, 4 authors.

Efficacy of diammonium glycyrrhizinate combined with vitamin C for treating hospitalized COVID-19 patients: a retrospective, observational stud

Tan et al., QJM, doi:10.1093/qjmed/hcab184 (Peer Reviewed)

PSM retrospective 207 hospitalized patients in China, 46 treated with diammonium glycyrrhizinate and vitamin C, showing lower risk of ARDS with treatment.

risk of death/intubation, 24.5% lower, RR 0.75, p = 0.74, treatment 1 of 46 (2.2%), control 14 of 115 (12.2%), NNT 10.0, OR converted to RR.

risk of ARDS, 73.3% lower, RR 0.27, p = 0.002, treatment 7 of 46 (15.2%), control 41 of 115 (35.7%), NNT 4.9, OR converted to RR.

Tan et al., 7/26/2021, retrospective, China, Asia, peer-reviewed, 7 authors, this trial uses multiple treatments in the treatment arm (combined with diammonium glycyrrhizinate) - results of individual treatments may vary.

Nutritional and lifestyle changes required for minimizing the recovery period in home quarantined COVID-19 patients of Punjab, Pakistan

Rabail et al., Food Science & Nutrition, doi:10.1002/fsn3.2458 (Peer Reviewed)

Survey of 80 recovered COVID-19 patients in Pakistan, showing faster recovery with vitamin C, vitamin D, and zinc supplementation.

Rabail et al., 7/9/2021, peer-reviewed, 11 authors.

20-Week Study of Clinical Outcomes of Over-the-Counter COVID-19 Prophylaxis and Treatment

Margolin et al., Journal of Evidence-Based Integrative Medicine, doi:10.1177/2515690X211026193 (Peer Reviewed)

Retrospective 113 outpatients, 53 (patient choice) treated with zinc, quercetin, vitamin C/D/E, l-lysine, and quina, showing lower cases with treatment. Results are subject to selection bias and limited information on the groups is provided. See [1].

[1] journals.sagepub.com/doi/full/10.1177/2515690X211058417

risk of case, 94.4% lower, RR 0.06, p = 0.003, treatment 0 of 53 (0.0%), control 9 of 60 (15.0%), NNT 6.7, relative risk is not 0 because of continuity correction due to zero events.

risk of COVID-19 or flu-like illness, 81.1% lower, RR 0.19, p = 0.01, treatment 2 of 53 (3.8%), control 12 of 60 (20.0%), NNT 6.2.

Margolin et al., 7/6/2021, retrospective, USA, North America, peer-reviewed, 5 authors, this trial uses multiple treatments in the treatment arm (combined with zinc, quercetin, vitamin D/E, l-lysine, and quina) - results of individual treatments may vary.

The use of vitamin C in the intensive care unit during the COVID-19 pandemic

Özgünay et al., The European Research Journal, doi:10.18621/eurj.938778 (Peer Reviewed)

Retrospective 160 ICU patients, 32 with raised neutrophil/lymphocyte ratio treated with vitamin C, showing no significant differences.

risk of death, 9.3% lower, RR 0.91, p = 0.69, treatment 17 of 32 (53.1%), control 75 of 128 (58.6%), NNT 18.

risk of mechanical ventilation, 1.1% higher, RR 1.01, p = 1.00, treatment 23 of 32 (71.9%), control 91 of 128 (71.1%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Özgünay et al., 7/4/2021, retrospective, Turkey, Europe, peer-reviewed, 7 authors.

Role of high dose oral liposomal vitamin C in reducing mortality in patients with COVID-19

Vishnuram et al., Indian Journal of Basic and Applied Medical Research, doi:10.36848/IJBAMR/2020/29215.55599 (Peer Reviewed)

Retrospective 8,634 hospitalized patients in India, showing lower mortality with high-dose vitamin C in unadjusted results. No group details are provided, the text and table appear to show different results, and some numbers do not match.

risk of death, 54.2% lower, RR 0.46, p = 0.03, treatment 164 of 8,634 (1.9%), control 10 of 241 (4.1%), NNT 44.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, minimal details of groups provided.

Vishnuram et al., 6/30/2021, retrospective, India, South Asia, peer-reviewed, 5 authors.

Use of Intravenous Vitamin C in Critically Ill Patients With COVID-19 Infection

Li et al., Journal of Pharmacy Practice, doi:10.1177/08971900211015052 (Peer Reviewed)

PSM retrospective 8 ICU patients treated with vitamin C and 24 matched controls, showing no significant difference. Authors note that "it is possible for the delayed timing of IV vitamin C to have blunted the beneficial effects as these patients may have already progressed to the late fibroproliferative phase or ARDS". IV vitamin C 1.5 grams every 6 hours.

risk of death, 10.5% higher, RR 1.11, p = 1.00, treatment 7 of 8 (87.5%), control 19 of 24 (79.2%), PSM.

Excluded in after exclusion results of meta analysis: very late stage, ICU patients.

Li et al., 6/8/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 6 authors.

Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID-19

May et al., British Journal of Pharmacology, doi:10.1111/bph.15579 (Review) (Peer Reviewed)

Review of data supporting the use of megadose vitamin C as a treatment for sepsis and COVID-19.

May et al., 6/1/2021, peer-reviewed, 3 authors.

Effect of high-dose intravenous vitamin C on prognosis in patients with SARS-CoV-2 pneumonia

Suna et al., Med. Clin. (Barc.), doi:10.1016/j.medcli.2021.04.010 (Peer Reviewed)

Retrospective 323 hospitalized patients, 153 treated with vitamin C, showing no significant differences. Patients in each group were in different time periods, with the vitamin C group first. Time based confounding is possible due to improvements in SOC.

risk of death, 21.3% lower, RR 0.79, p = 0.52, treatment 17 of 153 (11.1%), control 24 of 170 (14.1%), NNT 33.

risk of ICU admission, 1.9% higher, RR 1.02, p = 1.00, treatment 11 of 153 (7.2%), control 12 of 170 (7.1%).

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Suna et al., 5/11/2021, retrospective, Turkey, Europe, peer-reviewed, 5 authors.

Vitamin C inhibits SARS coronavirus-2 main protease essential for viral replication

Malla et al., bioRxiv, doi:10.1101/2021.05.02.442358 (Preprint)

In Vitro study showing that vitamin C inhibits SARS-CoV-2 3CL^pro. Authors note that the different clinical results may be explained in part by the widely varying dosages used, and they conclude that vitamin C and/or derivatives may become an important treatment for COVID-19 and other viral infections.

Malla et al., 5/3/2021, preprint, 9 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

High Dose Intravenous Vitamin C for Preventing The Disease Aggravation of Moderate COVID-19 Pneumonia. A Retrospective Propensity Matched Before-After Study

Zhao et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.638556 (Peer Reviewed)

PSM retrospective 110 patients, 55 treated with high-dose IV vitamin C, showing lower progression to severe disease with treatment. Patients in each group were in different time periods, time based confounding is likely due to SOC improving over time. ChiCTR2000033050.

risk of progression, 72.0% lower, RR 0.28, p = 0.03, treatment 4 of 55 (7.3%), control 12 of 55 (21.8%), NNT 6.9, adjusted, PSM.

time to viral-, 7.7% higher, relative time 1.08, p = 0.79, treatment 55, control 55, PSM.

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Zhao et al., 4/22/2021, retrospective, propensity score matching, China, Asia, peer-reviewed, 15 authors, average treatment delay 4.0 days.

The effect of vitamin E and vitamin C in patients with COVID-19 pneumonia; a randomized controlled clinical trial

Hakamifard et al., Immunopathologia Persa, doi:10.34172/ipp.2021.xx (Peer Reviewed)

RCT with 38 patients treated with vitamin C and vitamin E, and 34 control patients, showing lower ICU admission with treatment, but not statistically significant.

risk of ICU admission, 46.3% lower, RR 0.54, p = 0.46, treatment 3 of 38 (7.9%), control 5 of 34 (14.7%), NNT 15.

hospitalization time, 1.0% lower, relative time 0.99, p = 0.82, treatment 38, control 34.

Hakamifard et al., 4/14/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, this trial uses multiple treatments in the treatment arm (combined with vitamin E) - results of individual treatments may vary.

COVID-19 severity in relation to sociodemographics and vitamin D use

Abdulateef et al., Open Medicine, doi:10.1515/med-2021-0273 (Peer Reviewed)

Survey of 428 recovered COVID-19 patients in Iraq, showing fewer hospital visits for patients on prophylactic vitamin C or D. Hospitalization was lower for those on vitamin C, D, or zinc, without statistical significance.

risk of hospitalization, 18.7% lower, RR 0.81, p = 0.69, treatment 8 of 132 (6.1%), control 22 of 295 (7.5%), NNT 72, unadjusted.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Abdulateef et al., 4/8/2021, retrospective, Iraq, Middle East, peer-reviewed, 7 authors, study period July 2020 - August 2020.

Clinical characteristics of hospitalised patients with COVID-19 and the impact on mortality: a single-network, retrospective cohort study from Pennsylvania state

Gadhiya et al., BMJ Open, doi:10.1136/bmjopen-2020-042549 (Peer Reviewed)

Retrospective 283 patients in the USA showing higher mortality with all treatments (not statistically significant). Confounding by indication is likely. In the supplementary appendix, authors note that the treatments were usually given for patients that required oxygen therapy. Oxygen therapy and ICU admission (possibly, the paper includes ICU admission for model 2 in some places but not others) were the only variables indicating severity used in adjustments.

risk of death, 0.7% higher, RR 1.01, p = 0.98, treatment 19 of 55 (34.5%), control 36 of 226 (15.9%), adjusted, OR converted to RR, multivariate logistic regression.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Gadhiya et al., 4/8/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

3219 hospitalised patients with COVID-19 in Southeast Michigan: a retrospective case cohort study

Mulhem et al., BMJ Open, doi:10.1136/bmjopen-2020-042042 (Peer Reviewed)

Retrospective database analysis of 3,219 hospitalized patients in the USA. Very different results in the time period analysis (Table S2), and results significantly different to other studies for the same medications (e.g., heparin OR 3.06 [2.44-3.83]) suggest significant confounding by indication and confounding by time.

risk of death, 32.2% higher, RR 1.32, p = 0.01, treatment 157 of 794 (19.8%), control 359 of 2,425 (14.8%), adjusted, OR converted to RR, logistic regression.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Mulhem et al., 4/7/2021, retrospective, database analysis, USA, North America, peer-reviewed, 3 authors.

Ascorbic Acid as an Adjunctive Therapy in Critically Ill Patients with COVID-19: A Multicenter Propensity Score Matched Study

Al Sulaiman et al., Research Square, doi:10.21203/rs.3.rs-354711/v1 (Preprint)

Retrospective 158 critically ill patients receiving vitamin C and propensity matched controls, showing mortality OR 0.77 [0.48-1.23], and statistically significantly lower thrombosis, OR 0.42 [0.18-0.94]. 1000mg of vitamin C was given daily.

risk of death, 14.9% lower, RR 0.85, p = 0.27, treatment 46 of 142 (32.4%), control 59 of 142 (41.5%), NNT 11, OR converted to RR, PSM.

Al Sulaiman et al., 4/2/2021, retrospective, propensity score matching, Saudi Arabia, Middle East, preprint, 12 authors.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK)

Holt et al., Thorax, doi:10.1136/thoraxjnl-2021-217487 (Peer Reviewed)

Prospective survey-based study with 15,227 people in the UK, showing lower risk of COVID-19 cases with vitamin A, vitamin D, zinc, selenium, probiotics, and inhaled corticosteroids; and higher risk with metformin and vitamin C. Statistical significance was not reached for any of these. Except for vitamin D, the results for treatments we follow were only adjusted for age, sex, duration of participation, and test frequency. NCT04330599. COVIDENCE UK.

risk of case, 2.9% higher, RR 1.03, p = 0.86, treatment 49 of 1,580 (3.1%), control 397 of 13,647 (2.9%), adjusted, OR converted to RR, minimally adjusted, group sizes approximated.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Holt et al., 3/30/2021, prospective, United Kingdom, Europe, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021.

Methylene blue for treatment of hospitalized COVID-19 patients: a randomized, controlled, open-label clinical trial, phase 2

Hamidi-Alamdari et al., Clinical and Translational Investigation, doi:10.24875/RIC.21000028 (Peer Reviewed)

RCT 80 hospitalized patients with severe COVID-19, 40 treated with methylene blue + vitamin C + N-acetyl cysteine, showing lower mortality, shorter hospitalization, and significantly improved SpO₂ and respiratory distress with treatment. NCT04370288.

risk of death, 44.4% lower, RR 0.56, p = 0.38, treatment 5 of 40 (12.5%), control 9 of 40 (22.5%), NNT 10.0.

hospitalization time, 37.6% lower, relative time 0.62, p = 0.004, treatment 40, control 40.

Hamidi-Alamdari et al., 3/8/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 23 authors, this trial uses multiple treatments in the treatment arm (combined with methylene blue and N-acetyl cysteine) - results of individual treatments may vary.

Vitamin C may increase the recovery rate of outpatient cases of SARS-CoV-2 infection by 70%: reanalysis of the COVID A to Z Randomized Clinical Trial

Hemilä et al., Research Square, doi:10.21203/rs.3.rs-289381/v1 (Preprint) (meta analysis)

Reanalysis of Thomas et al. showing that vitamin C increased the recovery rate by 70%, p = 0.025.

Hemilä et al., 3/2/2021, preprint, 3 authors.

The efficiency and safety of high-dose vitamin C in patients with COVID-19: a retrospective cohort study

Gao et al., Aging, doi:10.18632/aging.202557 (Peer Reviewed)

Retrospective 76 COVID-19 patients, 46 treated with intravenous high-dose vitamin C, showing lower mortality and improved oxygen requirements with treatment. Dosage was 6g intravenous infusion per 12hr on the first day, and 6g once for the following 4 days.

risk of death, 86.0% lower, RR 0.14, p = 0.04, treatment 1 of 46 (2.2%), control 5 of 30 (16.7%), NNT 6.9, adjusted, KM.

Gao et al., 2/26/2021, retrospective, China, Asia, peer-reviewed, 14 authors.

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

Thomas et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.0369 (Peer Reviewed)

Small 214 low-risk outpatient RCT showing non-statistically significant faster recovery with zinc and with vitamin C. NCT04342728. A secondary analysis concludes that vitamin C increases recovery rate by 71% (p = 0.036) [1]. See also [2].

[1] pubpeer.com/publications/6DFC3BD2E1DAA79A9BBD1DAF5D9BB4#1

[2] patrickholford.com/blog/vitamin-c-speeds-up-covid-recovery

risk of death, 204.2% higher, RR 3.04, p = 0.49, treatment 1 of 48 (2.1%), control 0 of 50 (0.0%), continuity correction due to zero event.

risk of hospitalization, 30.6% lower, RR 0.69, p = 1.00, treatment 2 of 48 (4.2%), control 3 of 50 (6.0%), NNT 55.

recovery time, 17.9% lower, relative time 0.82, p = 0.15, treatment mean 5.5 (±3.7) n=48, control mean 6.7 (±4.4) n=50, mean time to a 50% reduction in symptoms.

Thomas et al., 2/12/2021, Randomized Controlled Trial, USA, North America, peer-reviewed, 11 authors.

Case Cluster of RT-PCR COVID-19 Positive Patients with an Unexpected Benign Clinical Course With Vitamin D, Melatonin, Vitamin C, and Viscum Album

Hancock et al., SSRN, doi:10.2139/ssrn.3779211 (Preprint)

Case series of 24 COVID-19 patients (12 confirmed PCR+) treated with vitamin D, vitamin C, and melatonin, showing positive outcomes with no patient having worse than a mild case, including 7 high risk patients.

Hancock et al., 2/9/2021, preprint, 4 authors.

Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: A cross-sectional comparative study in Jigawa, Northwestern Nigeria

Muhammad et al., SAGE Open Medicine, doi:10.1177/2050312121991246 (Peer Reviewed)

Case control study with 50 symptomatic COVID-19 patients and 21 healthy controls in Nigeria, showing that COVID-19 patients had significantly lower levels of selenium and zinc, and vitamins A, C, and E. Control patients were younger than COVID-19 patients. The p value for zinc in Table 2 appears to be a typo.

Muhammad et al., 2/1/2021, Nigeria, Africa, peer-reviewed, 8 authors.

Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study

Zhao et al., Ann. Palliat. Med., doi:10.21037/apm-20-1387 (Peer Reviewed)

Retrospective case study of 12 severe/critical COVID-19 patients finding that high dose IV vitamin C improved inflammatory response, immune and organ function. There was no control group.

Zhao et al., 2/1/2021, peer-reviewed, 14 authors.

Vitamin C supplementation is necessary for patients with coronavirus disease: An ultra-high-performance liquid chromatography-tandem mass spectrometry finding

Xing et al., Journal of Pharmaceutical and Biomedical Analysis, doi:10.1016/j.jpba.2021.113927 (Peer Reviewed)

Prospective study with 31 COVID-19 patients and 60 controls reporting on a new method to assess plasma vitamin C concentrations. Vitamin C was deficient (11.4µmol/l vs. 52µmol/l for healthy controls), and returned to a normal range (76µmol/l) with intravenous vitamin C. Authors recommend high dose intravenous vitamin C for COVID-19 patients at a dose of 100mg/kg/day.

Xing et al., 1/27/2021, peer-reviewed, 13 authors.

Vitamin C and COVID-19

Hemilä et al., Frontiers in Medicine, doi:10.3389/fmed.2020.559811 (Review) (Peer Reviewed)

Review of the use of vitamin C for infections and the potential benefit for COVID-19.

Hemilä et al., 1/18/2021, peer-reviewed, 2 authors.

Safety and Effectiveness of High-Dose Vitamin C in Patients with COVID-19; A Randomized Controlled open-label Clinical Trial

JamaliMoghadamSiahkali et al., Research Square, doi:10.21203/rs.3.rs-139942/v1 (Preprint)

Small late stage RCT for the addition of vitamin C to HCQ and lopinavir/ritonavir, with 30 treatment and 30 control patients, finding a significant reduction in temperature and a significant improvement in oxygenation after 3 days in the vitamin C group. However, hospitalization time was longer and there was no significant difference in mortality.

risk of death, no change, RR 1.00, p = 1.00, treatment 3 of 30 (10.0%), control 3 of 30 (10.0%).

risk of mechanical ventilation, 25.0% higher, RR 1.25, p = 1.00, treatment 5 of 30 (16.7%), control 4 of 30 (13.3%).

hospitalization time, 30.8% higher, relative time 1.31, p = 0.03, treatment 30, control 30.

JamaliMoghadamSiahkali et al., 1/9/2021, Randomized Controlled Trial, Iran, Middle East, preprint, 17 authors.

Efficacy of High Dose Vitamin C, Melatonin and Zinc in Iranian Patients with Acute Respiratory Syndrome due to Coronavirus Infection: A Pilot Randomized Trial

Darban et al., Journal of Cellular & Molecular Anesthesia, doi:10.22037/jcma.v6i2.32182 (Peer Reviewed)

Small RCT in Iran with 20 ICU patients, 10 treated with high-dose vitamin C, melatonin, and zinc, not showing significant differences. IRCT20151228025732N52.

risk of progression, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 10 (20.0%), control 3 of 10 (30.0%), NNT 10.

ICU time, 6.0% lower, relative time 0.94, p = 0.30, treatment 10, control 10.

Darban et al., 12/15/2020, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, this trial uses multiple treatments in the treatment arm (combined with melatonin and zinc) - results of individual treatments may vary.

Vitamin C—An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19

Holford et al., Nutrients, doi:10.3390/nu12123760 (Review) (Peer Reviewed)

Review of vitamin C use for respiratory infections including COVID-19 and the mechanisms of action. Authors note that evidence to date indicates oral vitamin C (2–8 g/day) may reduce the incidence and duration of respiratory infections, and intravenous vitamin C (6–24 g/day) has been shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical ventilation for severe respiratory infections. Authors conclude that given the favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in respiratory infections, it may be worthwhile testing patients’ vitamin C status and treating them accordingly with intravenous administration within ICUs and oral administration in hospitalised COVID-19 patients.

Holford et al., 12/7/2020, peer-reviewed, 7 authors.

The Role of Vitamin C as Adjuvant Therapy in COVID-19

Kumari et al., Cureus 12(11): e11779, doi:10.7759/cureus.11779 (Peer Reviewed)

RCT 150 hospitalized patients in Pakistan showing 26% faster recovery, p < 0.0001. 36% lower mortality, not statistically significant due to the small number of events. Dosage was 50 mg/kg/day of intravenous vitamin C.

risk of death, 36.4% lower, RR 0.64, p = 0.45, treatment 7 of 75 (9.3%), control 11 of 75 (14.7%), NNT 19.

risk of mechanical ventilation, 20.0% lower, RR 0.80, p = 0.67, treatment 12 of 75 (16.0%), control 15 of 75 (20.0%), NNT 25.

recovery time, 26.0% lower, relative time 0.74, p < 0.001, treatment 75, control 75, days to symptom-free.

hospitalization time, 24.3% lower, relative time 0.76, p < 0.001, treatment 75, control 75, days spent in hospital.

Kumari et al., 11/30/2020, Randomized Controlled Trial, Pakistan, South Asia, peer-reviewed, 10 authors.

Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app

Louca et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000250 (preprint 11/30/20) (Peer Reviewed)

Survey analysis of dietary supplements showing no significant difference in PCR+ cases with vitamin C usage in the UK, however significant reductions were found in the US and Sweden. These results are for PCR+ cases only, they do not reflect potential benefits for reducing the severity of cases. A number of biases could affect the results, for example users of the app may not be representative of the general population, and people experiencing symptoms may be more likely to install and use the app.

risk of case, no change, RR 1.00, p = 1.00, OR converted to RR, United Kingdom, all adjustment model.

Louca et al., 11/30/2020, retrospective, United Kingdom, Europe, peer-reviewed, 26 authors.

Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study

Behera et al., PLoS ONE, doi:10.1371/journal.pone.0247163 (preprint 11/3) (Peer Reviewed)

Retrospective matched case-control prophylaxis study for HCQ, ivermectin, and vitamin C with 372 healthcare workers, showing lower COVID-19 incidence for all treatments, with statistical significance reached for ivermectin.

HCQ OR 0.56, p = 0.29
Ivermectin OR 0.27, p < 0.001
Vitamin C OR 0.82, p = 0.58

risk of case, 18.0% lower, RR 0.82, p = 0.58, treatment 29 of 67 (43.3%) cases, 38 of 148 (25.7%) controls, adjusted, case control OR, model 2 conditional logistic regression.

risk of case, 29.0% lower, RR 0.71, p = 0.24, treatment 29 of 67 (43.3%) cases, 38 of 148 (25.7%) controls, adjusted, case control OR, matched pair analysis.

Behera et al., 11/3/2020, retrospective, India, South Asia, peer-reviewed, 13 authors.

The significance of oral ascorbic acid in patients with COVID-19

Patel et al., Chest Infections, doi:10.1016/j.chest.2020.08.322 (Peer Reviewed)

Retrospective 176 hospitalized patients, 96 treated with oral vitamin C (from 500mg to 1500mg daily), showing lower mortality with treatment.

risk of death, 29.5% lower, RR 0.71, p = 0.18, treatment 22 of 96 (22.9%), control 26 of 80 (32.5%), NNT 10.

risk of death, 15.6% lower, RR 0.84, p = 0.60, treatment 15 of 30 (50.0%), control 16 of 27 (59.3%), NNT 11, ICU patients.

Patel et al., 10/1/2020, retrospective, USA, North America, peer-reviewed, 8 authors.

Effects of high dose vitamin c on patient outcomes in ARDS patients admitted to intensive care with COVID-19; multi-center retrospective study

Yüksel et al., Intensive Care Medicine Experimental, 9:S1, 001458, doi:10.1186/s40635-021-00413-8 (Preprint)

PSM retrospective 86 ICU patients on mechanical ventilation in Turkey, showing lower mortality with high dose vitamin C treatment (≥200mg/kg for 4 days).

risk of death, 18.8% lower, RR 0.81, p = 0.04, treatment 31 of 42 (73.8%), control 40 of 44 (90.9%), NNT 5.8, propensity score matching.

Yüksel et al., 9/20/2020, retrospective, Turkey, Europe, preprint, 13 authors.

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

Arvinte et al., Med. Drug Discov, doi:10.1016/j.medidd.2020.100064 (Peer Reviewed)

Pilot study with 21 ICU patients finding low serum levels of vitamin C and vitamin D in most patients. Older age and low vitamin C level appeared to be co-dependent risk factors for mortality.

Arvinte et al., 9/8/2020, peer-reviewed.

Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome

Chiscano-Camón et al., Critical Care, doi:10.1186/s13054-020-03249-y (Peer Reviewed)

Small study of 18 COVID-19 ARDS patients showing that vitamin C levels were very low - 17 patients had undetectable levels and one had a low level (2.4 mg/L).

Chiscano-Camón et al., 8/26/2020, peer-reviewed, mean age 59.0, 5 authors.

Pilot Trial of High-dose vitamin C in critically ill COVID-19 patients (preprint 8/10/2020)

Zhang et al., Annals of Intensive Care, doi:10.1186/s13613-020-00792-3 (Peer Reviewed)

Small RCT for high dose vitamin C for ICU patients showing reduced (but not statistically significant) mortality. Dosage was 12g of vitamin C/50ml every 12 hours for 7 days at a rate of 12ml/hour.

risk of death, 50.0% lower, RR 0.50, p = 0.20, treatment 6 of 27 (22.2%), control 11 of 29 (37.9%), NNT 6.4, adjusted, ICU mortality.

risk of death, 80.0% lower, RR 0.20, p = 0.04, treatment 5 of 27 (18.5%), control 11 of 29 (37.9%), NNT 5.2, adjusted, ICU mortality for SOFA>=3.

risk of death, 50.0% lower, RR 0.50, p = 0.31, treatment 6 of 27 (22.2%), control 10 of 29 (34.5%), NNT 8.2, adjusted, 28 day mortality.

risk of death, 70.0% lower, RR 0.30, p = 0.07, treatment 5 of 27 (18.5%), control 10 of 29 (34.5%), NNT 6.3, adjusted, 28 day mortality for SOFA>=3.

Zhang et al., 8/10/2020, Randomized Controlled Trial, China, Asia, peer-reviewed, 11 authors.

The use of IV vitamin C for patients with COVID-19: a case series

Hiedra et al., Expert Review of Anti-infective Therapy, doi:10.1080/14787210.2020.1794819 (Peer Reviewed)

Case study of 17 patients receiving IV vitamin C for COVID-19, finding a significant decrease in inflammatory markers, including ferritin and D-dimer, and a trend to decreasing FiO₂ requirements, after vitamin C administration. There was no control group.

Hiedra et al., 8/1/2020, peer-reviewed, 8 authors.

Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19?

Feyaerts et al., Nutrition, doi:10.1016/j.nut.2020.110948 (Review) (Peer Reviewed)

Review concluding that there is clear evidence that vitamin C in high doses can reduce interleukin-6 and endothelin-1 mediators. Authors suggest a relatively low dose as prophylaxis, and in cases of severe COVID-19, an (intravenous) high-dose regimen may be beneficial.

Feyaerts et al., 7/25/2020, peer-reviewed, 2 authors.

Clinical comorbidities, characteristics, and outcomes of mechanically ventilated patients in the State of Michigan with SARS-CoV-2 pneumonia

Krishnan et al., J Clin Anesth., doi:10.1016/j.jclinane.2020.110005 (Peer Reviewed)

Retrospective 152 mechanically ventilated patients in the USA showing unadjusted lower mortality with vitamin C, vitamin D, HCQ, and zinc treatment, statistically significant only for vitamin C.

risk of death, 30.7% lower, RR 0.69, p = 0.04, treatment 40 of 79 (50.6%), control 52 of 73 (71.2%), NNT 4.9, adjusted, OR converted to RR.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Krishnan et al., 7/20/2020, retrospective, USA, North America, peer-reviewed, 13 authors.

Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19)

Biancatelli et al., Frontiers in Immunology, doi:10.3389/fimmu.2020.01451 (Review) (Peer Reviewed)

Review of the evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients.

Biancatelli et al., 6/19/2020, peer-reviewed, 4 authors.

In silico virtual screening-based study of nutraceuticals predicts the therapeutic potentials of folic acid and its derivatives against COVID-19

Kumar et al., VirusDisease, doi:10.1007/s13337-020-00643-6 (preprint 5/27) (Peer Reviewed)

In Silico analysis finding that magnesium ascorbate, a form of Vitamin C, was found to be the top compound among 106 nutraceuticals for binding to M^pro of SARS-CoV-2.

Kumar et al., 5/27/2020, peer-reviewed, 3 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Povidone-Iod..	(meta)
Conv. Plasma	(meta)	Probiotics	(meta)
Curcumin	(meta)	Proxalutamide	(meta)
Ensovibep	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption