Vitamin C for the management of COVID-19: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background:

Vitamin C is a vital nutrient that functions as an antioxidant and is important as a co-factor and regulator of several immune system pathways. The role of vitamin C in the treatment of COVID-19 is largely debatable. We conducted this meta-analysis to evaluate the efficacy and safety of vitamin C in the treatment of COVID-19.

Methods:

We searched several electronic databases from inception to March 2023 to retrieve randomized controlled trials on the use of vitamin C for COVID-19. RevMan 5.4 was used to calculate risk ratios (RRs) and mean differences (MDs) along with confidence intervals (95% CI) using a random-effects model.

Results:

We included nine randomized controlled trials in our meta-analysis. Vitamin C did not reduce the all-cause mortality in patients with COVID-19 compared to the standard treatment (RR 0.92, 95% CI: 0.83–1.02; I² = 1%). Vitamin C was found to be associated with a similar incidence of ventilation in COVID-19 patients when compared to standard treatment (RR 0.98, 95% CI: 0.87–1.11, I² = 0%). There were no significant differences between both groups regarding the incidence of hospitalization (RR 1.00, 95% CI: 0.98–1.02; I² = 0%), incidence of recovery (RR 1.57, 95% CI: 0.45–5.50; I² = 52%), hospital mortality (RR 0.68, 95% CI: 0.44–1.06; I² = 0%) and length of hospital stay (MD −0.63, 95% CI: −3.04 to 1.78; I² = 81%).

Conclusion:

Vitamin C administration did not reduce all-cause mortality in COVID-19 patients. Additional studies are required to evaluate the role of vitamin C in the prevention and treatment of COVID-19 especially in ICU patients.

Introduction

COVID-19, a global health crisis caused by the SARS-CoV-2 virus, has presented unprecedented challenges in the development of effective therapeutics due to its rapid mutation rate and varied clinical presentations[1]. COVID-19 primarily affects the respiratory system but can also impact multiple organs due to its inflammatory and thrombotic effects. The disease’s severity can vary significantly, influenced by factors such as age, comorbidities, and immune system status^[2,3^]. Amidst these challenges, vitamin C has emerged as a potential therapeutic agent due to its potent antioxidant properties and crucial role in immune function[4]. The management of COVID-19 remains uncertain, with evolving strategies including antivirals, steroids, supportive care, and vaccination strategies^[5–7^]. High-dose intravenous vitamin C has been explored for its potential benefits in critically ill patients, suggesting a possible role in reducing inflammation and viral replication[8].

The efficacy of vitamin C in treating COVID-19 has been studied in various studies, with mixed results. Some studies suggest that vitamin C, especially when administered intravenously at high doses, may reduce the severity of COVID-19 symptoms, decrease the duration of hospital stay, and potentially improve outcomes in patients with severe disease[9]. However, the evidence is not uniformly conclusive, and further research is needed to fully understand the role of vitamin C in COVID-19 treatment. The combination of vitamin C with other treatments, such as quercetin or diammonium glycyrrhizinate, has also been investigated, showing some promise in improving patient outcomes^[10,11^].

Dosage is a critical factor in the potential therapeutic use of vitamin C for COVID-19. Studies have examined a wide range of dosages, from moderate oral doses to high doses administered intravenously. The optimal dosage likely depends on the severity of the disease and the specific objectives of treatment (e.g., prophylaxis vs treatment of severe cases). High-dose intravenous vitamin C has been the focus of several studies, given its potential to achieve plasma concentrations that are not attainable with oral administration[9].

The role of vitamin C in COVID-19 has been studied before in previous meta-analyses^[12,13^]. Three new randomized controlled trials (RCTs) have been published since then, and they have not been pooled in a meta-analysis before. Through this review, we intend to clarify the therapeutic potential of vitamin C, offering insights into its utility as part of the management strategy for COVID-19 by including all RCTs published on this topic.

Methods

This meta-analysis was registered with PROSPERO (CRD42023401004), conducted according to the guidelines laid down by the Cochrane Handbook for Systematic Reviews of Interventions[14], and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines[15] and AMSTAR (Assessing the methodological quality of systematic reviews) guidelines. The TITAN 2025 guidelines[16] were followed, and no artificial intelligence tools were used in the conception, conduct, or reporting of this meta-analysis.

Data sources and searches

We searched the following databases and trial registers from inception till May 2023: the Cochrane Central Register of Controlled Trials (CENTRAL, via The Cochrane Library), MEDLINE (PubMed), Embase, and ClinicalTrials.gov using a search strategy consisting of a combination of relevant keywords and Medical Subject Headings (MeSH). Additionally, we conducted a grey literature search and backward citation tracking using reference lists of relevant articles. The main keywords used for the search included “Vitamin C,” “COVID-19,” and “Ascorbic Acid.”

Eligibility criteria

We included all studies that fulfilled the following criteria: (1) study design: RCTs only; (2) population: adult patients (≥18 years) with confirmed COVID-19 (via lab testing) irrespective of the disease severity; (3) intervention: IV or oral vitamin C/ ascorbic acid, as an adjunct to standard care (e.g., oxygen support, steroids); (4) comparator: placebo or standard care (5) outcomes: reporting at least one outcome. We excluded studies that included any intervention other than or in addition to vitamin C. Other study designs, like observational studies and reviews, were also excluded. Because an optimal dose and duration of vitamin C therapy in COVID-19 have not been established, trials with varying dosing regimens and treatment durations were included. Studies evaluating vitamin C in combination with other agents (e.g., zinc or quercetin) were excluded to isolate the independent effect of vitamin C and to minimize confounding from co-interventions that could influence clinical outcomes.

HIGHLIGHTS

• Vitamin C administration did not reduce all-cause mortality in COVID-19 patients.

• Vitamin C has a good safety profile; thus, it should be explored further in future randomized controlled trials to better ascertain its role in the management of COVID-19 patients.

Study selection and data extraction

We imported all the studies retrieved from our literature search in different databases into Rayyan and removed any duplicates. Two authors independently completed the title and abstract screening, followed by full-text screening. Any disagreements between the two reviewers were settled through discussion, and one author acted as an arbiter. Data regarding study characteristics (including authors and study location), patient population (including age and gender), vitamin C/ascorbic acid (including type, dosage, duration, and timing of drug administration), and primary and secondary outcomes were extracted into a pre-piloted Excel sheet.

Outcomes

Our primary outcome was all-cause mortality. Our secondary outcomes included incidence of ventilation, ICU admission, incidence of hospitalization, incidence of recovery, length of stay in the hospital, and hospital mortality.

Risk of bias assessment

To assess the risk of bias of included RCTs, two authors independently applied the revised Cochrane “Risk of Bias” tool (RoB 2.0). RoB 2.0 assesses the risk of bias in five domains: randomization process, blinding and deviations from protocol, missing outcome data, measurement of outcome, and selective outcome reporting. The studies were assigned a rating of low risk of bias, some concerns, and a high risk of bias.

Data synthesis

The meta-analysis was carried out using Review Manager (RevMan, Version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) under a random-effects model utilizing risk ratio (RR) and mean difference (MD) with corresponding 95% confidence intervals (CIs) as the effect measures. For detection and quantification of heterogeneity, we calculated the Chi² test and I² statistic. We interpreted I² values according to Cochrane Handbook for Systematic Reviews of Interventions, section 10.10. Regarding the interpretation of I² values, 0%–40% might not be important, 30%–60% may represent moderate heterogeneity, 50%–90% may signify substantial heterogeneity, and 75%–100% accounts for considerable heterogeneity. P < 0.10 was considered statistically significant for the Chi² test[14].

Subgroup analysis

For primary outcome, we conducted a subgroup analysis based on the severity of COVID in patients (critically ill vs non-critically ill).

Results

We included nine RCTs reporting data from 3345 patients in our meta-analysis^[17–25^]. The detailed study selection process is illustrated in Fig. 1. All the RCTs were conducted in a single country except one. Vitamin C was administered intravenously in all RCTs except one trial[21]. The treatment duration was variable and ranged from 4 days to 14 days. The detailed study characteristics of each trial are presented in Table 1.

Figure 1.

PRISMA 2020 flow chart. Flow chart of included and excluded trials. PRISMA, Preferred reporting items for systematic reviews and meta-analyses.

Table 1.

Characteristics of included studies.

Study ID	Location	No. of patients (vitamin C vs control)	Age (years)	Male (%)	Regimen of vitamin C	Treatment duration	Route of intervention	Severity of COVID-19	Relevant comorbidities	Follow-up duration
Zhang et al (2021)	China	27 vs 29	66.3 (±11.2) vs 67.0 (±14.3)	15(55.6%) vs 22(75.9%)	High-dose (24 g per day for 7 days) IV vitamin C	7 days	Intravenous	Severe SARS-CoV-2-related pneumonia or had a high risk of multiple organs injury	Hypertension (44%), followed by Diabetes (30%) and coronary heart disease (22%)	28 days
Majidi et al (2021)	Iran	31 vs 69	59.4 (± 15.07) vs 63.82 (± 14.58)	19 (61%) vs 41 (58%)	1 capsule of 500 mg of vitamin C	14 days (once daily)	Enteral nutrition	(ICU) for at least 48 h + need for enteral nutrition	-	-
Kumar et al (2022)	India	30 vs 30	57 (12.8) vs 63.3 (16.3)	26 (86.7%) vs 21 (70%)	1 gram Intravenous	4 days (8 hourly)	Intravenous	Clinical signs of pneumonia (fever/ cough) plus, any of the following: respiratory rate > 30; severe respiratory distress; pO2 ≤ 90% on room air. Chest X-ray involving >50% of lung fields	Hypertension, heart disease, stroke, asthma, hypothyroidism	-
Kumari et al (2020)	Pakistan	75 vs 75	52(11) vs 53(12)	99 (56.9%) (in both groups)	-	-	Intravenous	-	-	-
Coppock et al (2020)	USA	44 vs 22	60 (17) vs 61 (11)	22 (50%) vs 11 (50%)	Routine clinical care plus six escalating doses of ascorbic acid. Zero-day AA 0.3 g/kg IV First day 0.6 g/kg IV thereafter 0.9 g/kg IV	5 days	IV infusions	SARS-Cov-2 confirmed via nasal swabs and supplemental O2 requirement	Diabetes, cardiovascular disease, COPD, organ transplant recipient	-
Tehrani et al (2022)	Iran	18 vs 26	58 ± 19 vs 61 ± 17	8 (44.44%) vs 18 (69.23%)	-	5 days	Intravenous	Hospitalized patients with: respiratory rate >30/min or oxygen saturation <93% and pulmonary infiltration> 50%)	Diabetes, hypertension, ischemic heart disease, chronic lung disease, and patients on immunosuppressive drugs.	No follow-up
Rana et al (2023)	Lahore, Pakistan	139 vs 139	58.7 ± 11.9 vs 57.6 ± 12.7	73 (48.9%) vs 76 (51.1%)	10 g of vitamin C diluted in 100 ml of distilled water for 2 hours, and this dose was repeated after 8 hours. The total dose of vitamin C given in 24 hours was 30 grams.	4 days	IV infusions	Having pneumonia, confirmed by chest imaging and admission to the ICU, Patients require assisted ventilation with oxygen saturation levels ≤ 93 at rest or O2 partial pressure/fraction of inspired oxygen (PaO2/FiO2) ≤ 300 mmHg. Patients with shock syndrome and multi-organ failure signs and symptoms need intensive care unit (ICU) monitoring and treatment	Hypertension, diabetes, asthma, COPD, IHD, renal dysfunction	28 days
Adhikari et al (2023)	Multicentric	1493 vs 1098	60.92 (15.56) vs 61.52 (15.93)	922 (61.7%) vs 700 (63.8%)	-	96 Hours (4 days)—6-hourly Regimen	Intravenous	The severity of COVID-19 patients in this trial was classified as either (1) critically ill (defined by admission to ICU and receipt of HFNC, NIV, IMV, or vasopressors) (2) not critically ill.	-	The follow-up duration for the primary outcome (organ support-free days) was up to 21 days or until hospital discharge, whichever occurred first. For the secondary outcome of death or persistent organ dysfunction at trial day 28, follow-up was up to 28 days. Survivors or their relatives were contacted by telephone at 6 months for additional outcomes
JamaliMoghadamSiahkali et al (2021)	Iran	30 vs 30	57.53 (18.27) vs 61 (15.90)	15 (50%) vs 15 (50%)	1.5 g vitamin C IV every 6 h for 5 days	5 Days	Intravenous	Patients with confirmed COVID-19 disease based on clinical findings (mainly fever, dyspnea, dry cough), imaging findings of COVID-19 on spiral chest computer tomography (CT) or high-resolution CT (HRCT) images validated by a trained radiologist, clinical manifestations of acute respiratory distress syndrome or myocarditis, and oxygen saturation lower than 93% from admission or after 48 h from the first COVID-19 treatment	Hypertension, Diabetes Mellitus, Ischemic Heart Disease, COPD. Thyroid disease

Risk of bias in included studies

The quality assessment of the included studies is presented in Supplemental Digital Content Figure 1, available at: http://links.lww.com/MS9/B100. Of the nine studies, three studies were judged to be at low risk of bias, two were judged to have some concerns for bias, and four studies were found to be at high risk of bias because of a lack of randomization and deviations from the intended interventions (Fig. 2).

Figure 2.

Risk of bias of individual studies using the revised cochrane “Risk of bias” tool for randomized trials (RoB 2.0).

Primary outcomes

All-cause mortality

The pooled analysis showed that vitamin C administration was associated with no significant difference in all-cause mortality in COVID-19 patients when compared to the standard treatment (RR 0.92, 95% CI: 0.83–1.02; I² = 1%) (Fig. 3). A subgroup analysis was performed by dividing the patients into critically ill and non-critically ill. Vitamin C administration was associated with no significant difference in all-cause mortality in critically ill (RR 0.90, 95% CI: 0.80–1.02; I² = 10%) and non-critically ill patients (RR 1.03, 95% CI: 0.77–1.02; I² = 0%) with low heterogeneity in both groups. A leave-one-out analysis excluding Majidi et al (2021) was performed, which did not impact the results significantly.

Figure 3.

Comparison of all-cause mortality between patients receiving vitamin C or control. IV, inverse variance.

Secondary outcomes

Incidence of hospitalization

There were no significant differences between both groups regarding the incidence of hospitalization (RR 1.00, 95% CI: 0.98–1.02). The heterogeneity was found to be low (I² = 0%) among studies (Fig. 4).

Figure 4.

Comparison of incidence of hospitalization between patients receiving vitamin C or control. IV, inverse variance.

Incidence of recovery

The incidence of recovery was found to be similar in both groups (RR 1.57, 95% CI: 0.45–5.50) with moderate heterogeneity (I² = 52%) among studies (Fig. 5).

Figure 5.

Comparison of incidence of recovery between patients receiving vitamin C or control. IV, inverse variance.

Hospital mortality

We found no statistically significant difference between the two groups regarding hospital mortality (RR 0.68, 95% CI: 0.44–1.06; I² = 0%) (Supplemental Digital Content Figure 1, available at: http://links.lww.com/MS9/B100).

Incidence of ventilation

Vitamin C was found to have no significant association regarding the incidence of ventilation in COVID-19 patients when compared to standard treatment (RR 0.98, 95% CI: 0.87–1.11, I² = 0%). The heterogeneity among studies was found to be low (Supplemental Digital Content Figure 2, available at: http://links.lww.com/MS9/B100).

Length of stay in the hospital

The pooled analysis showed that the vitamin C group and the standard treatment group had similar lengths of stay in the hospital (MD −0.63, 95% CI: −3.04 to 1.78). The heterogeneity among studies was found to be high (I² = 81%) (Supplemental Digital Content Figure 3, available at: http://links.lww.com/MS9/B100).

Discussion

Our meta-analysis explores the efficacy of vitamin C supplementation as an adjunctive therapy for COVID-19 patients, drawing insights from nine RCTs. Most of these RCTs were conducted in Asia, one in the USA, and one multicentric. The severity of COVID-19 was high in most trials and defined using different criteria like (end-organ damage, ICU admission, increasing oxygen requirements, pneumonia). LOVIT-COVID 2023 and REMAP-CAP 2023 stratified the COVID patients by severity (critically ill vs non-critically ill). We excluded all the trials that involved combination therapies to study the efficacy and safety of only vitamin C on COVID-19. However, many of the trials involved the use of supplemental oxygen. The therapeutic context of vitamin C may influence its efficacy in the management of COVID-19.

According to our pooled analysis, vitamin C administration was not associated with any statistically significant reduction in all-cause mortality when compared to the standard treatment. We did not find any statistically significant differences in the length of stay in hospital, incidence of ventilation, hospital mortality, the incidence of recovery, and the incidence of hospitalization.

When comparing our findings with previously published literature, notable methodological differences help explain discrepant results. A previous meta-analysis conducted by Olczak-Pruc et al[13] included both randomized and non-randomized trials in their analysis. The inclusion of both randomized and nonrandomized studies in a meta-analysis increases bias due to confounding. According to their pooled analysis of only RCTs, vitamin C reduced all-cause mortality in COVID-19 patients. Our study included only RCTs to limit selection bias and confounding. Furthermore, Olczak-Pruc et al pooled studies where vitamin C was administered in combination with other agents, such as zinc or quercetin, making it difficult to isolate the effect of vitamin C. In contrast, our meta-analysis strictly included RCTs evaluating vitamin C monotherapy, providing a clearer understanding of its independent impact. Finally, our analysis also includes two new RCTs. Unlike Olczak-Pruc et al, our analysis shows that vitamin C doesn’t reduce all-cause mortality in COVID-19 patients. According to their analysis, the vitamin C group did not significantly decrease any other adverse events as compared to the standard treatment group. This result is in alignment with our analysis. Our findings are further supported by two previous meta-analyses^[26,27^] that included only RCTs and likewise found no significant reduction. Another study by Bhowmik et al[28] included both prospective and retrospective trials in their study and reported decreased all-cause mortality in the vitamin C group as compared to the control group.

Our analysis includes nine studies; eight of these studies involved giving vitamin C via an IV route and one of them involved an oral route. The treatment duration also ranged from a minimum of 4 days to a maximum of 21 days. The doses also ranged from 1 g all the way to 24 g. Exclusion of the trial involving the oral vitamin C didn’t impact our results. It is also worth noticing that only one trial was multicentric, with a large sample size; all the other trials had a small sample size. Out of the others, one was conducted in America, and the other seven RCTs were conducted in Asia. Due to the small sample size, these trials were significantly underpowered, hence impacting our result. Furthermore, because most of these trials were conducted in Asia, of the limitations of our study is the generalizability of findings.

Our study had several limitations. First, there was considerable variability in trial protocols across RCTs regarding the administration route, timing, and dosage of vitamin C, as well as inconsistencies in reporting the use of oxygen therapy. Variations in admission criteria and evolving standards of care for COVID-19 management contributed to heterogeneity among studies, further complicated by geographical variability. While these factors reflect real-world clinical diversity, they underscore the need for individual patient data (IPD) meta-analyses to adjust for confounding. We addressed these limitations by performing a subgroup analysis of the patients on the basis of the severity of COVID-19. Patients requiring ICU-level care were analyzed in a different subgroup. The only trial with a longer duration of treatment and an oral route of administration was Majidi et al[21]. A leave-one-out sensitivity analysis was performed to assess its impact on the primary outcome.

While statistical heterogeneity was mild, underlying clinical heterogeneity remained a concern.

The severity of COVID-19 was high in most of the trials; however, defined in different ways, ranging from increasing oxygen requirement to multiple end-organ damage. This affects the generalizability of our results. Another limitation was the inclusion of a very small number of RCTs (nine) in our analysis.

Future research should address these limitations by incorporating more comprehensive and standardized RCT protocols, increasing sample sizes, and accounting for clinical and geographical diversity. Different doses, routes of administration, and the timing of treatment initiation should also be explored. Vitamin C has a good safety profile; thus, it should be explored further in future RCTs to better ascertain its role in the management of COVID-19 patients.

Conclusion

Vitamin C administration did not reduce all-cause mortality in COVID-19 patients. Additional studies are required to evaluate the role of vitamin C in the prevention and treatment of COVID-19, especially in ICU patients.

Ethical approval

No ethical approval was required for this study.

Consent

No consent was required for this study.

Sources of funding

No financial support was received for this study.

Author contributions

All authors contributed to the drafting and revision of the manuscript. All authors approved the final version of the manuscript. The individual contributions are as follows:

H.A.: Conception, Drafting, Analysis. I.M.: Acquisition, Analysis, Drafting. A.B.I.M.: Acquisition, Analysis, Drafting. J.S.: Analysis, Interpretation, Drafting. S.V.: Analysis, Interpretation, Drafting. N.T.: Analysis, Interpretation, Drafting. F.K.: Analysis, Interpretation, Drafting. A.M.W.M.: Acquisition, Analysis, Drafting. Feriha Fatima Khidri: Acquisition, Analysis, Drafting. A.S.: Acquisition, Analysis, Drafting. Muhammad Ayyan: Conception, Acquisition, Analysis, Drafting, Reviewing. M.E.: Analysis, Reviewing. H.A.C.: Analysis, Reviewing. A.M.A.A.: Analysis, Reviewing. S.S.: Analysis, Reviewing. N.I.S.: Analysis, Reviewing.

Conflicts of interest disclosure

There was no conflict of interest of all authors of this manuscript.

Research registration unique identifying number (UIN)

Registered in PROSPERO (CRD42023401004). The status has also been changed to completed in PROSPERO.

Guarantor

Asma’a Munasar Ali Alsubari is the guarantor of this article.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Declarations of interest

The authors declare that they have no conflicts of interest and no financial interests related to the material of this manuscript.