the vitamin c research paper

REVIEW article

The long history of vitamin c: from prevention of the common cold to potential aid in the treatment of covid-19.

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Commentary: The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19

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• 1 Department of Movement Sciences and Wellbeing, University of Naples Parthenope, Naples, Italy
• 2 Centro di Ricerca Interdipartimentale nelle Attività Motorie e Sportive (CRIAMS)—Sport Medicine Centre, University of Pavia, Voghera, Italy
• 3 Department of Pharmacy, University of Salerno, Fisciano, Italy
• 4 Department of Biology, College of Science, University of Bahrain, Sakhir, Bahrain
• 5 IRCCS Mondino Foundation, Pavia, Italy
• 6 Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
• 7 Clinical Nutrition and Dietetics Service, Unit of Internal Medicine and Endocrinology, ICS Maugeri IRCCS, University of Pavia, Pavia, Italy

From Pauling’s theories to the present, considerable understanding has been acquired of both the physiological role of vitamin C and of the impact of vitamin C supplementation on the health. Although it is well known that a balanced diet which satisfies the daily intake of vitamin C positively affects the immune system and reduces susceptibility to infections, available data do not support the theory that oral vitamin C supplements boost immunity. No current clinical recommendations support the possibility of significantly decreasing the risk of respiratory infections by using high-dose supplements of vitamin C in a well-nourished general population. Only in restricted subgroups (e.g., athletes or the military) and in subjects with a low plasma vitamin C concentration a supplementation may be justified. Furthermore, in categories at high risk of infection (i.e., the obese, diabetics, the elderly, etc.), a vitamin C supplementation can modulate inflammation, with potential positive effects on immune response to infections. The impact of an extra oral intake of vitamin C on the duration of a cold and the prevention or treatment of pneumonia is still questioned, while, based on critical illness studies, vitamin C infusion has recently been hypothesized as a treatment for COVID-19 hospitalized patients. In this review, we focused on the effects of vitamin C on immune function, summarizing the most relevant studies from the prevention and treatment of common respiratory diseases to the use of vitamin C in critical illness conditions, with the aim of clarifying its potential application during an acute SARS-CoV2 infection.

Introduction

Vitamin C (ascorbic acid) plays an important role in the normal functioning of the immune system ( 1 – 4 ) and its use in preventing and/or treating infections has strongly attracted the interest of physicians and investigators for almost a century. A plethora of papers have been published on this topic, but, although it is well known that a deficiency of vitamin C due to a low nutritional intake leads to a greater susceptibility to infections ( 5 ), the possibility of reducing the incidence of viral diseases in a well-nourished population through the use of dietary supplements based on vitamin C is not adequately supported in literature. At present, very little evidence supports the benefit of high doses of vitamin C supplementation on immune function in healthy individuals ( 4 , 6 ) and several authors have underlined that this practice is ineffective in preventing the common cold and viral infections in most subjects ( 7 – 12 ). Despite this, the popular belief that an extra intake of vitamin C can boost the immune system is still widespread and every year the market claims that the use of supplements is a winter remedy to prevent infectious disease.

While scientists’ current position is not to recommend the use of vitamin C supplementation to prevent viral invasions in healthy subjects, more promising—though questioned—data seem instead to emerge from the intravenous administration (IA) of this vitamin in acute respiratory conditions or critical illnesses. Furthermore a potential pharmacological role during early phases of the new coronavirus (SARS-CoV2) infection and its related disease (COVID-19) was recently put forward ( 13 – 18 ). The rapid worldwide spread of SARS-CoV2 and the consequent pandemic emergency recognized by World Health Organization urgently requires a global effort to identify anything that can treat symptoms and reduce deaths. At the beginning of June, more than 6,600,000 cases of infection and 391,000 deaths related to COVID-19 had been reported globally and the number of cases is constantly increasing worldwide ( 19 ). Currently, no specific antiviral therapy has been approved for the cure of COVID-19 ( 20 ), and this has led researchers to speculate on a possible adjuvant treatment based on indirect evidence from severely ill patients and patients with sepsis conditions ( 21 ). Sepsis is a life-threatening organ dysfunction caused by an impaired host response to infection, characterized by a dramatic failure of the circulatory, metabolic, and immune systems, and recognized as the primary cause of death from infection: patients who develop septic shock can have hospital mortality rates of up to 50% ( 22 ). On these clinical conditions literature shows that high doses of vitamin C by intravenous infusion may reduce the inflammatory cytokine-related production and potentially improve important outcomes such as the duration of mechanical ventilation time and mortality rates ( 13 – 18 ). This is of particular importance since acute respiratory distress syndrome (ARDS) is one of the most frequent severe conditions registered in COVID-19 patients ( 23 ). ARDS is a serious and, in some cases fatal, syndrome characterized by a strong inflammatory response with massive alveolar damage and multiple organ failure, requiring intensive care unit (ICU) treatment ( 24 ). Authors reported a percentage of ARDS cases of around 15% among hospitalized patients with SARS-CoV2 infection ( 25 ).

Data on the use of intravenous-administered vitamin C in COVID-19 patients are still unavailable, but clinical trials to explore the efficacy of this treatment are currently in progress in several countries ( 26 ) and important results will be available soon.

Based on the above, the aim of this review is firstly to summarize the immunological role of vitamin C with a description of its potential effects as a dietary supplement, on the mechanisms involved during respiratory viral infections, and in relation to the inflammatory response considering different subject categories and clinical conditions; secondly, the manuscript describes the updated literature on the IA of vitamin C in the treatment of severe sepsis and ARDS conditions, with the aim of establishing whether the current clinical background on this topic offers strong enough perspectives to propose vitamin C for a pharmacological application to reduce the dramatic cytokine production and regulate other recognized COVID-19-related immune responses.

Physiology of Vitamin C

Bioavailability.

Vitamin C is an essential nutrient that must be taken through the diet as humans are unable to synthesize it ( 27 ). Thus, our body has developed an effective adaptation system which maintains the organic reserves of vitamin C and prevents its deficiency due to a low dietary intake. These adaptations include a higher absorption and recycling capacity of vitamin C compared to other animal species (e.g., goat and reptiles), which can normally produce it ( 28 , 29 ). Animal studies have shown that vitamin C is preferentially stored in the brain, adrenal gland, liver and lungs ( 30 – 33 ) but its levels in these organs are rapidly depleted after about one week of dietary insufficiency ( 31 ). In humans, skeletal muscle represents the major pool of vitamin C ( 34 ). Muscle fibers also lose vitamin C content very rapidly under inadequate dietary intake. However, a consumption of half a kiwifruit per day seems to be enough to saturate the muscle tissue’s vitamin C concentrations in non-smoking men ( 35 ). Vitamin C homeostasis is finely regulated by at least four mechanisms: intestinal absorption, transport to tissue, renal reuptake, and urine excretion, mainly regulated by a family of proteins named Sodium-Dependent Vitamin C Transporters (SVCT) ( 36 ). Considering the individual variability in healthy subjects, studies suggest that a daily intake of vitamin C from 100 to 400 mg ensures 100% of the bioavailability and blood saturation with a steady state of plasma concentration that reaches a maximum level of approximately 70–80 µmol/L ( 37 , 38 ). Generally, if the intake of vitamin C exceeds 500 mg/day, a further increase in plasma concentration is inhibited and the bioavailability can decrease close to 30% when more than 1,000 mg of vitamin C is administered in a single bout ( 39 ). This occurs because when 500–1,000 mg of vitamin C is administered orally, the intestinal transporter (SVCT1) rapidly achieves its maximal saturation, while the urine excretion of the vitamin is progressively increased ( 38 , 39 ). The measure of plasma vitamin C concentration may be considered, even though the circulant values cannot be used as a reliable marker of the body stores (about 5 g) ( 40 ). A plasma concentration value of vitamin C lower than 23 μmol/L reflects a depletion of the vitamin C pool (state of hypovitaminosis), while clinical symptoms of scurvy occur when plasma values are lower than 11 μmol/L ( 41 ).

Recommended Dietary Allowances

To maintain adequate body stores, recommended dietary allowance (RDA) for vitamin C has been proposed over the years. The RDAs vary among countries: e.g., current recommendations in the United States and Canada is 90 mg/day for adult men and 75 mg/day for adult women ( 42 ), while in Italy the suggested intakes are 105 mg/day and 85 mg/day for adult men and women, respectively ( 43 ). This variation in RDAs can be explained by the different criteria used by various authorities to define the estimated average requirement (EAR) for vitamin C, including prevention of scurvy, immune cell support, maintenance of an adequate plasma vitamin C level, and optimizing health ( 44 ). Furthermore, RDAs vary among subjects as several factors can modify vitamin C requirements, including gender, age, smoking, pregnancy, and lactation ( 44 ).

Several authors and guidelines indicated that males need more vitamin C than females ( 45 – 51 ) probably due to the higher body weight and fat-free mass of men compared to women ( 52 ).

In children and adolescents the RDAs for vitamin C are generally derived from adult needs and adjusted in relation to their lower body mass ( 46 , 47 , 53 ) as reported by Carr and Lykkesfeldt ( 44 ). In Italy, for example, SINU recommends an intake of 45 mg for children from 4 to 6 years of age ( 45 ). Epidemiological studies indicate that a lower vitamin C status can be found in the elderly, suggesting that they require a higher intake compared to adults ( 54 – 56 ). However, currently only France has developed specific guidelines for subjects from 75 years of age, indicating a daily intake of 120 mg ( 57 ).

Vitamin C requirements are higher in women during pregnancy ( 44 ): the hemodilution due to the increase of blood volume and the active absorption of vitamin C by the fetus during its development lead to a reduction of the vitamin status ( 58 ). Even lactation increases the vitamin C requirement of women, to satisfy the vitamin needs of the infant normal growth. Most countries recommend an extra daily intake of 10–20 mg for pregnant women and an extra daily intake of 20–60 mg/day for women during lactation ( 44 ).

Smokers usually have lower plasma values than non-smokers, probably due to increased oxidative stress and higher turnover of vitamin C. In addition to this, a reduced vitamin C status in smokers is also due to the dietary intake of vitamin C, which is usually lower compared to non-smokers ( 59 ). Therefore, in order to compensate these conditions, authorities have recommended an additional intake of 20 to 80 mg/day of vitamin C for these subjects, setting the RDAs for smokers at 120–155 mg/day ( 44 ).

Some other factors have been recognized as reducing vitamin C status ( 60 ), even though they were not considered in general guidelines and the daily additional values of vitamin C potentially required are not currently available. These factors include: 1) passive exposure to tobacco smoking and environmental pollutants, which can enhance oxidative stress; 2) geographic influence, socioeconomic and cultural status, which may have an impact on production, selection and consumption of foods typically rich in vitamin C; 3) food preparation and cooking methods, which can reduce the content of vitamin C in foods since this vitamin is water-soluble and heat-labile.

The potential variability of the metabolism of vitamin C among various ethnic groups is practically unknown and this topic should certainly be further explored. Only one study reported that lower vitamin C concentrations were significantly associated with a higher leukocyte count in African Americans but not in Caucasians, suggesting hypothetical metabolic or pharmacokinetic differences among races ( 61 ).

Vitamin C and Immune System Regulation

Besides an extensive range of biochemical pathways in which vitamin C is involved, it also participates in the response of the innate and adaptive immune system ( 1 ). The intracellular content of vitamin C in immune cells depends on the plasma availability. In healthy adults the content of vitamin C in leukocytes can be saturated with an intake of at least 100 mg of vitamin C per day, through foods, obtaining a concentration of about 3.5, 3, and 1.5 mmol/L, respectively, in lymphocytes, monocytes and neutrophils ( 39 , 62 – 65 ). Leukocytes’ absorption of vitamin C from the blood is very efficient, through SVCT proteins ( 66 ), resulting in an intracellular content which is 50 to 100 times greater than the plasma concentration ( 67 , 68 ). As an effective antioxidant, vitamin C contributes to protecting neutrophils from oxidative stress during the early stages of an immune response, when neutrophils activate phagocytosis and produce reactive oxygen species (ROS) to destroy antigens ( 69 , 70 ). Once the phagocytic capacity is exhausted and neutrophils start to die, vitamin C seems to regulate the process in favor of apoptosis, through the activation of a caspase-dependent cascade, inhibiting the transition to necrosis, and resulting in a more efficient resolution of inflammation ( 71 ).

Vitamin C is also involved in the migration of phagocytes (neutrophils and macrophages) toward the infection sites in response to chemoattractants ( 72 , 73 ). This is particularly important since an impaired neutrophilic chemotaxis has been observed in patients with severe infection ( 74 – 76 ). Furthermore in subjects with low blood concentrations of vitamin C (<50 µmol/L), a daily intake of 250 mg of vitamin C can result in a 20% increase of neutrophils’ migration capacity ( 6 ). Conversely, in individuals with a physiological blood concentration of vitamin C, neutrophils’ mobility cannot be enhanced, as demonstrated by Bozonet et al. ( 4 ), in which neutrophils isolated from healthy volunteers and incubated with a vitamin C solution (200 µmol/L) to artificially increase their content of ascorbate did not show a major chemotactic ability.

Similarly to neutrophils, vitamin C protects lymphocytes from oxidative damage ( 77 ) and has a pivotal role in the development and function of these cells, even though the exact mechanisms have not yet been clarified ( 3 ). In T lymphocytes, vitamin C stimulates differentiation and proliferation from precursors to mature T cells, in a dose-dependent way ( 78 ). Studies on the influence of vitamin C on subtypes of T cells are mainly related to the Th1/Th2 balance. Reports underline that vitamin C can induce a shift of immune responses from Th2 to Th1 ( 3 ), while only one study suggests that vitamin C can induce the Th17 polarization of naïve CD4+ cells in murine model, affecting epigenetic mechanism ( 79 ). At present, no studies exploring the effects of vitamin C on cytotoxic T cells are available ( 3 ). In B lymphocytes, vitamin C seems to affect the production of antibodies, despite conflicting evidence ( 80 – 87 ). Physiological levels of Vitamin C are also necessary for normal natural killer (NK) cell development and function ( 3 ). In vitamin C-deficient mice, NK cytotoxic activity (NKCA) was lower than that in mice with normal levels of vitamin C ( 88 ), while supraphysiological levels of ascorbate do not further increase NKCA ( 89 ).

Vitamin C also regulates inflammatory response. In animal studies, vitamin C deficiency has been linked with higher circulating histamine levels, which can be rebalanced once vitamin C blood level has been normalized ( 90 – 92 ). Furthermore, vitamin C can reduce the production of pro-inflammatory leukocyte-derived cytokines (e.g., TNFα and IL-6), through the modulation of nuclear transcription factor kappa B (NFkB) ( 2 , 93 , 94 ) in at least two ways: 1) through its reduced form (ascorbate), by scavenging cellular ROS and inhibiting ROS-related signaling for the transcription of NFkB ( 95 – 98 ); 2) through its oxidized form (dehydroascorbate), produced as a consequence of quenching ROS, by directly inhibiting the activity of several kinases involved in the TNFα-mediated activation of NFkB (p38 mitogen-activated protein kinase, IkB kinase α and β) ( 99 – 101 ).

However, the effect of vitamin C on the balance of cytokine responses (pro- and anti-inflammatory) is very complex and seems to be dependent on cell type and/or inflammatory condition ( 1 ). Moreover, authors ( 102 , 103 ) have recently suggested that vitamin C may interact with molecular pathways related to inflammatory stress and immune dysfunction during sepsis, involving particular mediators: Epidermal Growth Factor Receptor (EGFR), Mitogen-Activated Protein Kinase-1 (MAPK1), Proto-Oncogene c (JUN), C–C chemokine Receptor type 5 (CCR5), Mitogen Activated Protein Kinase 3 (MAPK3), Angiotensin II Receptor type 2 (AGTR2), and Signal Transducer and Activator of Transcription-3 (STAT3).

The effects of vitamin C on immune function may also be expressed through epigenetic regulations, although this topic is still poorly understood ( 104 , 105 ). The epigenetic remodeling associated with immune cell activation and differentiation includes DNA and histone modification ( 106 ). Vitamin C plays an important role by increasing the activity of epigenetic enzymes, including ten-eleven translocation (TET) proteins and Jumonij-C domain-containing histone demethylases (JHDMs) ( 107 ). In fact, since TET and JHDMs belong to the Fe 2+ /α-ketoglutarate-dependent dioxygenases superfamily ( 105 ), vitamin C, as ascorbate, being able to donate electrons, acts as a cofactor for these enzymes, reducing Fe 3+ to its catalytically active form (Fe 2+ ) ( 63 ). TET proteins are involved in the demethylation of cytosine residues in DNA, while JHDMs regulate the methylation of lysine and arginine residues in histones, resulting in modifications of gene transcription ( 63 , 108 , 109 ) that are involved in the response of both the innate and the adaptive immune system ( 106 , 110 ). The utility of these recently-discovered gene-regulatory functions of vitamin C for the assessment of dietary recommendations has not yet been elucidated and further research is needed to indicate the minimum dose at which vitamin C may have an effective impact on functional or clinical outcomes through epigenetic changes ( 44 ).

Oral Supplementation of Vitamin C for the Prevention and Treatment of the Common Cold and Upper Respiratory Tract Infections

The common cold is one of the most widespread viral upper respiratory tract infections (URTI), characterized by coughing, tiredness, fever, sore throat, and muscle pain, which persist for a period ranging from a few days to not more than 3 weeks ( 111 , 112 ). The term “common cold” refers to an unspecific syndrome caused by several viruses, although the rhinovirus is the most frequent pathogen involved, being found in 30% to 50% of sufferers ( 113 ). Despite symptomatology usually being very mild, the common cold is a major cause of absenteeism from work and school ( 114 ). The popular myth that a very high intake of vitamin C may lead to a lower susceptibility to respiratory tract infections originates from Linus Pauling’s theories published in the seventies. According to Pauling, a daily vitamin C intake of 1,000 mg can reduce the incidence of colds by about 45% and the optimal daily intake of vitamin C to live healthily and prevent disease should be at least 2.3 g ( 115 , 116 ). The response of the US market to this pioneering point of view was immediate and the sales of vitamin C dietary supplements almost doubled over a couple of years ( 117 ). However, other clinical studies with similar aims failed to demonstrate its efficacy ( 118 – 121 ) and, in general, contemporary authors completely refuted Pauling’s ideas, mainly based on non-randomized controlled trials or incorrect application of animal background to humans ( 122 , 123 ). Although a high daily dose of vitamin C does not seem to prevent viral infections in the general population, some categories of subjects with potentially higher risk of viral infection may require particular consideration. These subjects include individuals undergoing a daily heavy physical workload such as soldiers and athletes, who may develop an immune stress condition.

General Population

If we exclude some results that reported only small or inconsistent effects attributable to vitamin C ( 124 ), after decades of investigations, the scientific community established that a high intake of vitamin C is useless in preventing the common cold ( 7 – 11 ), and therefore, a regular daily supplementation is not justified in the general population ( 12 ). Recent meta-analysis has reached similar conclusions regarding the incidence of infection, underlining, however, the possibility of reducing the duration of a cold. Gómez et al. ( 125 ), demonstrated that 8,472 subjects from eight randomized clinical trials (RCTs), showed very strong evidence that vitamin C intake above 80 mg/day does not prevent the common cold in healthy adults and children. Vorilhon et al. ( 126 ), analyzed eight RCTs and confirmed that vitamin C supplementation (dosage from 0.5 g to 2 g/day) is not effective, compared to placebo, in reducing the incidence of upper respiratory tract infections (URTI) in 3,135 children (from 3 months to 18 years of age), although the administration can reduce the duration of URTI by 14%, as previously highlighted by Rondanelli et al. ( 127 ). Positive results on the duration of colds was also suggested by the meta-analysis of Ran et al. ( 128 ) in which the combination of a small, long-term daily dose of vitamin C (no more than 1 g/day) to sustain immunity and a larger dose of vitamin C during the onset of the common cold (usually 3–4 g/day) was associated with the ability to relieve chest pain, fever, and chills, reducing the staying indoors duration, as well as the mean duration of disease.

People Under Heavy Physical Stress

Some authors have reported a high incidence of respiratory infections in military training centers, probably also due to an overcrowding of individuals often coming from different geographical areas ( 129 – 131 ). More data are available on athletes, for whom daily high-intensity training and competitions have been associated with transient immune perturbations, inflammation conditions, and increased susceptibility to infections ( 132 – 134 ). Furthermore, compared to the general population, athletes have a higher exposure to pathogens, due to frequent travel and sports events ( 135 , 136 ), which may potentially increase the risk of developing viral infections.

Data in literature referring to the effect of vitamin C supplementation on the prevention of the common cold in these subjects are interesting, despite being limited at present. As was well described by Hemilä and Chalker, ( 12 ) vitamin C supplementation may decrease the incidence of colds by about 50% in people under extreme physical stress. More recently, Kim et al. ( 137 ) carried out a large randomized, double-blind, placebo-controlled trial in 1,444 Korean soldiers, 695 of whom received vitamin C (6 g/day) for 30 days. They showed that the vitamin C group had a 0.80-fold lower risk of getting the common cold compared to the placebo group (n = 749).

The theoretical basis for the use of vitamin C in physically stressed subjects resides in the significant increase of ROS production due to intense exercise ( 138 ), with remarkable tissue damage/inflammatory response that may have harmful consequences on preventing URTI ( 139 ), possibly requiring a higher antioxidant intake compared to the general population ( 140 ). Despite this, it has recently been established that the administration of a high dose of antioxidants can negatively interfere with exercise-induced redox signaling and muscle adaptations ( 141 – 147 ) and the use of high doses of vitamin C to abolish ROS, especially over a long period, should be avoided ( 148 , 149 ).

Even though the effects of isolated vitamin C on oxidative stress, inflammatory markers, muscle damage and immune response following exercise remain to be clarified in depth ( 146 ), a recent scientific society position stand ( 150 ), a recent review ( 140 ), and a meta-analysis ( 146 ) agree on recommending vitamin C supplementation (0.25–1.0 g/day) as an option to prevent URTI symptoms in athletes under heavy exertion and/or during periods of increased risk of infection (e.g., travel abroad) ( 140 ); athletes with low initial blood concentrations of vitamin C are the major candidates for supplementation ( 146 , 149 , 151 , 152 ).

Oral Supplementation of Vitamin C for the Prevention and Treatment of Pneumonia

Pneumonia is a lower respiratory tract infection characterized by a cough, difficulty in breathing, chest pain, fever, and lung inflammation ( 153 ). Pneumonia is the first cause of death by infection in the United States and the fifth most common cause of death overall ( 154 , 155 ). Streptococcus pneumoniae and Haemophilus influenzae are recognized as the most common agents responsible for pneumonia ( 156 ) but other pathogens are also able to induce pneumonia, including viruses and fungi ( 153 , 154 ).

Results obtained in rats and mice suggested that orally supplemented vitamin C may be useful in reducing susceptibility to viral pneumonia and potentially in reducing the development of ARDS ( 157 , 158 ), which is recognized as the most severe form of acute respiratory infection ( 159 ). However, human findings on vitamin C supplementation and pneumonia remain scarce, with few dated observations mainly based on particular subjects and conditions (e.g., military people, developing countries) and not generalizable ( 5 , 160 ). On this topic, the most recent meta-analysis including 2,774 participants from seven clinical studies, underlined that current evidence is insufficient to sustain the efficacy of vitamin C supplementation in preventing or treating pneumonia, due to the small number of trials and very low quality of the existing results ( 161 ). However, the meta-analysis of Padhani et al. ( 161 ) considered studies from different populations, including three studies on children, without subgroup analysis. Since the pharmacokinetics of vitamin C varies between subgroups and is not yet known in children, an analysis of data should have been done independently and, therefore, conclusions of this study may be questionable.

Oral Supplementation of Vitamin C for the Prevention of COVID-19

COVID-19 is a new, worldwide recognized form of viral pneumonia, caused by SARS-CoV2 infection ( 162 , 163 ). The symptomatology often begins within 2 weeks from contagion and mainly includes fever, fatigue, cough, and shortness of breath ( 164 ). Current knowledge suggests that while the majority of infected subjects (80%–90%) exhibit mild symptoms or can be asymptomatic, about 5% may develop pneumonia, ARDS and multi-organ dysfunction leading to death ( 165 ).

It is unquestionable that an optimal nutritional status effectively reduces inflammation and oxidative stress, improving the immune system regulation ( 166 ). However, no data are currently available on the regular use of high doses of oral vitamin C to reduce the risk of infection by SARS-CoV2 in a healthy general population ( 167 – 169 ) and further studies are needed to explore the role of vitamin C in prevention of COVID-19 ( 169 ). For heavily stressed subjects (athletes in particular), specific data are not currently reported regarding the incidence, prevalence, or natural history of disease related to COVID-19 ( 134 ), despite these subjects’ potentially high risk of exposure to this virus ( 136 , 170 ). Furthermore, scientific opinions have not been expressed regarding the use of oral vitamin C to prevent SARS-CoV2 infection in extreme exercisers. However, a vitamin C supplementation may be effective for improving the health status of patients considered at high risk of viral infections ( 171 ).

Oral Supplementation of Vitamin C for Patients With Metabolic Disorders, Cardiovascular Disease, and Frail Elderly Subjects: Potential Relationship With COVID-19

There are notably some factors that increase the risk of developing SARS-CoV2 infection and affect the severity of COVID-19 ( 172 ). People with pre-existing non-communicable diseases (NCDs) appear to be more susceptible to developing COVID-19 ( 173 , 174 ). NCDs include obesity, diabetes mellitus, chronic lung diseases, cardiovascular diseases (CVD) and various other conditions which are characterized by systemic inflammation which impairs immune response and may exacerbate the cytokine storm related to COVID-19 ( 173 , 174 ).

Obese Subjects

Some studies have shown that obesity is associated to a more severe form of COVID-19 ( 175 , 176 ), even in younger patients (age < 50) ( 177 ), and a BMI > 40 kg/m 2 was identified as a one of the strongest risks of hospitalization due to SARS-CoV2 infection ( 178 ). These findings are worrying considering that obesity is a global phenomenon and in countries such as the U.S about 36% of population is obese ( 179 ). This association could be linked to inflammatory mechanisms, since authors suggest that, compared to individuals with a normal weight, obese subjects have a higher plasma concentration of C-reactive Protein (CRP), an inflammatory biomarker used to predict cardiovascular disease ( 180 ). Based on this, a vitamin C supplementation in these subjects may be useful in reducing inflammation, considering data that showed how a treatment of oral vitamin C (1,000 mg/day) for two months can significantly reduce plasma CRP in healthy, overweight, non-smokers with baseline CRP ≥ 1.0 mg/L ( 181 ). This finding is very interesting, taking into account that participants had an adequate dietary intake of vitamin C, with a baseline mean plasma level of 57.8 μmol/L, and it suggests that the RDAs for vitamin C in obese individuals may be underestimated, as was recently underlined by Rychter et al. ( 182 , 183 ). Research is needed to understand whether by reducing the CRP with vitamin C it could be possible to influence the incidence and/or the progression of inflammation-mediated diseases associated with obesity, including infections and potentially COVID-19 ( 171 ).

Diabetic Subjects

A recent meta-analysis including 33 studies (16,003 patients) confirmed that diabetics have a two-fold higher increase in mortality, as well as severity of COVID-19, compared to non-diabetic COVID-19 patients ( 184 ). Type 2 diabetes mellitus (T2DM) is the most common form of diabetes ( 185 ), characterized by chronic hyperglycemia, inflammation and oxidative stress ( 186 ). The inflammatory condition observable in diabetes may possibly be a mechanism that increases the susceptibility to COVID-19. Low plasma concentrations of vitamin C in people with T2DM was observed ( 187 , 188 ), despite adequate vitamin C intake ( 189 , 190 ). Two mechanisms could particularly explain lower vitamin C levels in these patients: 1) increased urinary excretion, especially in those with microalbuminuria ( 191 ); 2) higher depletion of vitamin C caused by an increase of oxidative stress ( 190 , 192 ). An interesting study on the use of oral vitamin C in diabetic subjects was reported by Mason et al. ( 193 ). It showed an approximately two-fold enhanced SVCT2 expression in skeletal muscle after vitamin C supplementation (1,000 mg for 4 months) in people with T2DM, with an increase of muscle concentration of vitamin C and a decrease of muscle oxidative stress. However, given the small number of subjects investigated in this study (seven participants, six males and one female), larger studies are needed to confirm similar results. Findings from an RCT showed that vitamin C supplementation (1,000 mg/day for 8 weeks) significantly reduced CRP, IL-6, fasting blood glucose (FBG), and triglycerides (TG) in 64 obese, hypertensive and/or diabetic patients, with high levels of CRP ≥ 6 mg/L ( 194 ). In addition, meta-analytic data indicated that vitamin C supplementation for more than 30 days with a dosage ranging from 200 to 1,000 mg significantly reduces FBG in patients with T2DM ( 195 ). Based on the above, vitamin C supplementation may represent a promising option to modulate inflammation and blood glucose in patients with hyperglycemia and elevated CRP, it could potentially be able to improve the health of these individuals and reduce the susceptibility to infections. Investigations are strongly encouraged to establish a possible correlation between an extra intake of vitamin C and a possible decrease of incidence, severity and mortality for COVID-19.

Subjects With CVDs

CVDs (as well as hypertension) are the most common comorbidities among COVID-19 patients ( 174 , 196 , 197 ). Individuals with a CVD are five-fold more at risk of developing the critical stage of the disease, as indicated in a meta-analysis involving over 3,000 patients with COVID-19 ( 198 ). In this case, the main reason for a higher risk of SARS-Cov2 infection is related to the high angiotensin-converting enzyme 2 (ACE2) expression observed in these patients ( 199 – 201 ), since this enzyme is used by the virus to invade cells, promoting viral colonization ( 202 ). It is known that low plasma concentrations of vitamin C are predictive of heightened CVD risk ( 203 – 205 ), but the current literature provides little support for a widespread use of vitamin C supplements to reduce CVD risk or mortality ( 206 ), and available data are also controversial. Many cohort studies and RCTs have shown no relationship between vitamin C intake and CVD risk. However, in most RCTs the participants were not prescreened for a depleted status and this seriously limits the possibility of concluding on the results, as the potential impact of the vitamin C supplementation on the outcomes considered may vary from highly significant to negligible in relation to their vitamin C status at study start ( 207 ).

A few other studies have suggested moderate benefits, and some references have registered a slight increase in risk ( 206 ). A significant barrier to the comprehension of the relationship between vitamin C and CVDs is the lack of mechanistic studies in humans ( 206 ). At present, there are no recommendations for an additional daily dose of vitamin C in CVDs to potentially prevent diseases, including pulmonary infections and COVID-19.

Frail Elderly Subjects

It is particularly important to consider elderly communities when trying to prevent COVID-19. The elderly are more vulnerable compared to the general population due to an increased risk of malnourishment and infections and a high prevalence of NCDs ( 208 ). Age itself is a risk factor for developing COVID-19 ( 209 ), due to a functional decline of the immune system ( 210 , 211 ). Furthermore, malnourishment in these subjects is very frequent for several reasons (e.g., poor socioeconomic conditions, mental status, social status) ( 212 ) and nutritional deficiencies (including vitamin C) have been reported ( 213 ). Malnourishment can worsen an impaired immune system in the elderly, making them more susceptible to infections ( 214 ). In elderly hospitalized subjects (mean age 81 years) suffering from acute bronchitis or pneumonia, a mean plasma vitamin C level at baseline of 23 µmol/L was reported and a concentration of 11 µmol/L was found in one third of the patients ( 215 ). This is particularly important since a low vitamin C concentration (<17 µmol/L) in older people (aged 75–82 years) is considered a strong predictor of all-cause mortality ( 216 ). Notably, in Hunt’s study ( 215 ) administration of vitamin C (0.2 g/day) reduced the respiratory symptom score in the more severe patients. However, at present, it is not known whether a regular supplementation with vitamin C can protect these subjects from chronic inflammation NCDs-related and/or can prevent the onset of viral infections including COVID-19.

Oral Supplementation and Side Effects

Vitamin C has an excellent safety profile, primarily due to its high water solubility and rapid clearance of excess levels by the kidneys ( 44 , 217 ). Although it is not possible to establish a UL for vitamin C, values of 1,000–2,000 mg/day have been suggested as prudent limits by some countries, based on a potential risk of osmotic diarrhea and related gastrointestinal distress in some individuals at higher doses ( 44 , 53 ).

Since vitamin C is partially converted to oxalate and excreted in the urine, high doses of vitamin C could be associated with calcium oxalate stone formation ( 218 , 219 ). Ferraro et al. ( 220 ) studied 156,735 women and 40,536 men, who reported episodes of kidney stones during an average follow-up of 11.3–11.7 years. The authors significantly correlated the total vitamin C intake with a higher risk of incident kidney stones in men, but not in women. However, it is important to outline that this study had limitations to be considered. The presence of confounding factors (e.g., comorbidities, dehydration, dietary intakes of oxalate-forming foods) were not taken into account during the follow-up, and the authors assessed vitamin C intake only through a questionnaire (without measuring blood levels) and with very long time intervals (every 4 years).

Intravenous Administration of Vitamin C: A Potential Role in the Treatment of COVID-19?

While an extra dietary intake of vitamin C to counter pneumonia does not seem promising, several interesting data have emerged from the use of vitamin C through IA, providing an encouraging, but questioned, hypothesis on its potential pharmacological use for the treatment of pneumonia caused by SARS-CoV2 infection. In fact, as opposed to oral supplementation, in which the maximum peak plasma concentration that was achieved with a high-dose (3 g every 4 h) was 220 μmol/L ( 221 ), the IA of vitamin C, bypassing the limitations induced by intestinal transporters (SVCT1), may lead to a higher plasma level (e.g., up to 3,000 μmol/L at day 4 with 200 mg/kg/day, administered in 50 mg/kg/dose every 6 h).

Although the potential antisepsis therapeutic mechanism exerted by vitamin C has not yet been understood ( 103 ), besides the effects described in the previous paragraphs, the use of vitamin C in an infectious emergency may be justified for some reasons: 1) significant clinical evidence from pneumonia, critical illnesses and other acute infections suggests that plasma levels of vitamin C can rapidly drop off (e.g., <30 μmol/L) during the inflammatory response ( 2 , 93 , 94 , 222 – 228 ) probably due to an increased consumption of vitamin C by leukocytes. Considering that intracellular ascorbate concentrations in mononuclear cells and in granulocytes are respectively 80 and 25 times greater than in plasma, an increased replacement and turnover of these cells during these medical conditions can contribute to a decrease of vitamin C in the blood ( 229 ); 2) a negative regulation of SVCT2 transporters induced by inflammatory cytokines, in particular IL-1β and TNFα ( 230 ); 3) the antioxidant defense system of the pulmonary epithelium involves enzymes and vitamin C ( 231 ) and according to Banerjee and Kaul, a sustained high dose of vitamin C available in respiratory secretion could exhibit an effective anti-viral activity ( 232 ). This last point, however, is still a hypothesis at present, since the level of vitamin C in the bronchoalveolar fluid is normally too low to achieve anti-viral activity and furthermore very little is known about the potential increase of vitamin C concentration in bronchial tissue and fluid secretion following a high-dose IA ( 36 ).

Therefore, considering the aspects mentioned above, the infusion of vitamin C has recently been suggested to treat COVID-19 in ICU hospitalized patients ( 13 – 18 ). Below, we summarize the most substantial evidence obtained in critical illness studies based on IA of vitamin C regarding the most relevant outcomes (inflammation, ventilation time, and mortality) which may relate to SARS-CoV2-induced ARDS.

Effects of IA of Vitamin C on Inflammation Markers

In COVID-19 patients the inflammatory response is very dramatic and has been defined as a “cytokine storm”, associated with increased plasma concentration of IL-1β, IL-2, IL-6, IL-10, IFNγ, and TNF-α ( 233 , 234 ), able to induce an acute lung injury (ALI) which results in ARDS and requires urgent ICU interventions ( 162 ). Physiopathology of ARDS involves alteration of pulmonary permeability, rapid lung leukocyte infiltration with a large increase of tissue oxidative stress, leading to respiratory failure and death, which in most cases is due to massive alveolar damage ( 24 , 235 ). A promising background on the use of vitamin C in an experimental model of ALI was found ( 236 – 241 ), with positive evidence on rebalancing cytokine production and specific physiopathological mechanisms involving neutrophils (i.e., neutrophil extracellular traps) ( 4 ) which may contribute to organ damage and mortality in COVID-19 ( 233 ) ( Figure 1 ). Two studies by Fowler et al. are currently available on IA of vitamin C in ICU hospitalized patients and inflammatory response, with mixed results ( 227 , 242 ). In the first preliminary study ( 227 ), vitamin C showed a significant reduction in proinflammatory biomarkers (CRP and procalcitonin) over the first 96 h, without adverse effects registered during the infusion, but the number of ARDS-affected patients treated with vitamin C was too small (50 mg/kg/24 h, n = 8; 200 mg/kg/24 h, n = 8) to allow safe conclusions. In the second larger study ( 242 ), 167 patients with sepsis and ARDS were randomized to receive vitamin C (50 mg/kg every 6 h for 96 h) or placebo; no changes in CRP and thrombomodulin were detected, although the study was criticized for the choice of the inflammatory markers assessed ( 243 ).

Figure 1 Schematic mechanism in which an IA of vitamin C could modulate specific functions of neutrophils (ROS and TNFα, IL-1β mediated), inhibiting pathways involved in the Neutrophil Extracellular Trap formation (NETosis) and reducing the uncontrollable inflammatory cytokine production in the alveolar space. Potential effects on reducing cytokine production have also been speculated in lymphocytes and macrophages. ROS, reactive oxygen species; NFkB, nuclear transcription factor kappa B; ┴, inhibition stimulus; dashed arrow, reduced effect or production.

Effects of IA of Vitamin C on Intensive Care Ventilation Time

The above-mentioned study ( 242 ) also reported a lower duration time of mechanical ventilation support in the supplemented group, with a higher number of ventilator-free days in the vitamin C group than in the placebo group (mean values: 10.6 vs. 13.1 days, respectively). Ventilator-free days were defined as the number of extubated days, considering the time between ICU hospitalization and day 28. Another previous randomized controlled trial (RCT), including burn patients with severe respiratory dysfunction receiving a very high dose of vitamin C (66 mg/kg/h for 24 h), showed a significant decrease of the time of ventilation (mean values: 12.1 vs. 21.3 days, respectively) in those who received vitamin C infusion compared to the control group ( 85 ). The pulmonary benefit reported by these authors is probably due to the antioxidant, anti-inflammatory and microvascular action of the vitamin C ( 244 ).

Different positions on the topic derive from systematic evaluation of the literature, suffering because of the gross limitations of the available primary data. For example, the meta-analysis of Langlois et al. ( 245 ), failed to find any improvement on ventilation time. This work, however, included studies with vitamin C administrated through different routes (enteral or parenteral), most of which (9 out of a total of 11 studies) used antioxidant mixtures instead of vitamin C alone; Zhang and Jativa ( 244 ) analyzed the efficacy of IA of vitamin C on vasopressor sparing effects and the lower need for mechanical ventilation in critical illness, underlining several weaknesses of the available studies considered (four RCTs and one retrospective review), such as the paucity of the sample size, the heterogeneity of subjects enrolled, hospitalization setting, dosages and follow-up; recently, the meta-analysis from Hemilä and Chalker ( 246 ), including eight trials and 685 patients, with promising results on ventilation time, pointed out that the great variation in the reported effects of vitamin C may be linked to the non-homogeneous severity of the illness which mostly impacts the ventilation time required. From this point of view, vitamin C shortened ventilation time on average by 25% when the analysis was restricted to patients requiring mechanical support for more than 10 h.

Effects of IA of Vitamin C on Mortality

Of the critical outcomes considered the potential effect of vitamin C on mortality rates appears to be the most controversial one, with RCTs studies that underline promising results which are not supported by recent meta-analysis. A significant reduction of 28-day mortality during ICU hospitalization was observed in a small group of patients with sepsis treated with IA of vitamin C (25 mg/kg every 6 h, for 72 h) compared to the control group (14.28% Vs. 64.28%, respectively) ( 247 ). More recently, findings from the CITRIS-ALI study ( 242 ) showed a reduced mortality at day 28 in the vitamin C group (29.8%) compared to the placebo group (46.3%). Conversely, according to the meta-analysis of Zhang and Jativa, although vitamin C IA seems to be linked to positive vasopressor effects, temporally reducing the need for mechanical ventilation, no positive effect in favor of overall mortality emerged ( 244 ), leading the authors to conclude that it does seem improbable that vitamin C, considered as a single agent, could be so dramatically decisive on the physiopathology of a critical illness as to influence the incidence of mortality ( 244 ). Similar conclusions were drawn by Wei et al. ( 248 ), who, by including recently published retrospective studies in their meta-analysis, suggest the lack of benefit on 28-day mortality, both in ICU and in-hospital patients with sepsis.

It is important to consider that the effect of vitamin C infusion seems to exert different results on mortality in relation to the type of critical patients involved, especially when administration is in association with other drugs. From this point of view, two retrospective studies showed that vitamin C (1.5 g every 6 h), in combination with hydrocortisone (50 mg every 6 h), and thiamine (200 mg every 12 h) may dramatically reduce mortality by 56% in ICU patients with severe pneumonia ( 249 ) and by 79% in severe sepsis ( 250 ), compared with patients who did not receive vitamin C and thiamine. Unlike these data, a recently published RCT (VITAMINS) showed no benefit from the combination of IA of vitamin C, hydrocortisone and thiamine in comparison to hydrocortisone alone among patients with septic shock ( 251 ). However, as underlined by Carr ( 252 ), since the VITAMINS trial did not include a monotherapy vitamin C subgroup, this trial does not provide any information as to whether IA of vitamin C offers some benefit to septic patients in the absence of corticosteroid administration, and further trials are needed in this direction.

Another critical issue that should be highlighted is the timing of treatment administration. On this topic, important results come from a retrospective cohort study of 208 patients in septic shock ( 253 ), which suggested that the ICU mortality ratio [based on the APACHE (Acute Physiology and Chronic Health Evaluation)–predicted ICU mortality] of patients who received vitamin C with thiamine and hydrocortisone, increased linearly with the delay in treatment from initial sepsis presentation. Indeed, the APACHE-adjusted ICU mortality was significantly reduced only in patients who received vitamin C, thiamine, and steroids within 6 h from sepsis presentation ( 253 ).

Apart from some specific individuals and conditions ( Table 1 ), the evidence described is insufficient to support the efficacy of a regular supplementation with vitamin C for the prevention or treatment of the common cold or pneumonia in the general population. Interesting data on the possible use of vitamin C to prevent infections regard special conditions (e.g., soldiers and athletes) and subjects with metabolic disorders, CVDs or frailty, in which the potential control of inflammation by a vitamin C supplementation could represent an effective aid in reducing the risk of infection, even for COVID-19. However, this last statement needs to be properly supported by future RCTs. Even though the IA of vitamin C could be an adjuvant therapy to quickly restore plasma levels of vitamin C during severe sepsis and ARDS in ICU hospitalized patients ( 254 ), its effects on inflammation response, ventilation time and mortality rates still remain uncertain and results from further RCTs, especially in COVID-19 patients, are urgently needed.

Table 1 Summary of research findings on the use of vitamin C in humans.

Although a significant increase in vitamin C sales was registered immediately after the global pandemic state of emergency was declared, at present, there is no evidence that vitamin C supplementation can protect people from the SARS-CoV2 infection ( 255 ). At the current state of knowledge, health care professionals have the responsibility to guarantee that patients have correct information regarding the lack of data supporting the efficacy of this supplement for the prevention and/or treatment of COVID-19 ( 167 , 168 ).

Author Contributions

All authors contributed to the article and approved the submitted version. GC and MN conceived the original idea of the manuscript and contributed equally to this work as main authors. GD’A revised the manuscript before submission.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The authors thank Simona Aldrovandi for generating table illustrations and Emily Riley for the English revision of the manuscript.

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Keywords: vitamin C supplementation, viral infections, COVID-19, pneumonia, immune function, athletes, non-communicable diseases, frail elderly subjects

Citation: Cerullo G, Negro M, Parimbelli M, Pecoraro M, Perna S, Liguori G, Rondanelli M, Cena H and D’Antona G (2020) The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19. Front. Immunol. 11:574029. doi: 10.3389/fimmu.2020.574029

Received: 18 June 2020; Accepted: 21 September 2020; Published: 28 October 2020.

Reviewed by:

Copyright © 2020 Cerullo, Negro, Parimbelli, Pecoraro, Perna, Liguori, Rondanelli, Cena and D’Antona. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Massimo Negro, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

A Systematic Review on the Role of Vitamin C in Tissue Healing

Affiliations.

• 1 Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, Lands of the Dharug Nation, The University of Sydney, Sydney, NSW 2145, Australia.
• 2 Department of Diabetes and Endocrinology, Blacktown-Mt Druitt Hospital, Sydney, NSW 2148, Australia.
• 3 Westmead Hospital, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2145, Australia.
• 4 University Centre for Rural Health, Faculty of Medicine and Health, University of Sydney, Lismore, NSW 2480, Australia.
• 5 School of Health Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia.
• PMID: 36009324
• PMCID: PMC9405326
• DOI: 10.3390/antiox11081605

Vitamin C is an essential nutrient for humans and animals which are unable to synthesise it themselves. Vitamin C is important for tissue regeneration due to the role it plays in collagen formation, and its antioxidant properties. We reviewed the literature to evaluate potential associations between vitamin C supplementation and healing of an acute or chronic condition. Embase, Medline, PubMed, and the Cochrane Library were searched for studies published prior to April 2022. Studies were eligible if they reported at least one association between vitamin C supplementation and healing outcomes. Eighteen studies met the inclusion criteria and were included in this review. Overall, vitamin C supplementation improved healing outcomes in certain pathologies, predominantly pressure ulcers. However, many of the studies had small sample sizes, combined nutritional treatments, and did not test baseline vitamin C. Future studies should be of larger scale, exclusively using vitamin C to determine its role in tissue healing in other wounds. We recommend consideration of vitamin C supplementation for people with pressure ulcers.

Keywords: ascorbic acid; healing; supplementation; tissue healing; vitamin C; wound healing.

Publication types

Grants and funding.

• N/A/Westmead Hospital

Is a glass of OJ or vitamin C tablets your go-to when the sniffles come? Loading up on this vitamin was a practice spurred by Linus Pauling in the 1970s, a double Nobel laureate and self-proclaimed champion of vitamin C who promoted daily megadoses (the amount in 12 to 24 oranges) as a way to prevent colds and some chronic diseases.

Vitamin C, or ascorbic acid, is a water-soluble vitamin. This means that it dissolves in water and is delivered to the body’s tissues but is not well stored, so it must be taken daily through food or supplements. Even before its discovery in 1932, nutrition experts recognized that something in citrus fruits could prevent scurvy, a disease that killed as many as two million sailors between 1500 and 1800. [1]

Vitamin C plays a role in controlling infections and healing wounds, and is a powerful antioxidant that can neutralize harmful free radicals. It is needed to make collagen , a fibrous protein in connective tissue that is weaved throughout various systems in the body: nervous, immune, bone, cartilage, blood, and others. The vitamin helps make several hormones and chemical messengers used in the brain and nerves. [2]

While megadosing on this vitamin is not uncommon, how much is an optimum amount needed to keep you healthy, and could taking too much be counterproductive?  

Recommended Amounts

• RDA:  The Recommended Dietary Allowance for adults 19 years and older is 90 mg daily for men and 75 mg for women. For pregnancy and lactation, the amount increases to 85 mg and 120 mg daily, respectively. Smoking can deplete vitamin C levels in the body, so an additional 35 mg beyond the RDA is suggested for smokers.
• UL:   The Tolerable Upper Intake Level is the maximum daily intake unlikely to cause harmful effects on health. The UL for vitamin C is 2000 mg daily; taking beyond this amount may promote gastrointestinal distress and diarrhea. Only in specific scenarios, such as under medical supervision or in controlled clinical trials, amounts higher than the UL are sometimes used. [2]

Vitamin C absorption and megadosing

Absorption does not differ if obtaining the vitamin from food or supplements. Vitamin C is sometimes given as an injection into a vein (intravenous) so higher amounts can directly enter the bloodstream. This is usually only seen in medically monitored settings, such as to improve the quality of life in those with advanced stage cancers or in controlled clinical studies. Though clinical trials have not shown high-dose intravenous vitamin C to produce negative side effects, it should be administered only with close monitoring and avoided in those with kidney disease and hereditary conditions like hemochromatosis and glucose 6-phosphate dehydrogenase deficiency.

Vitamin C is involved with numerous metabolic reactions in the body, and obtaining the RDA or slightly higher may be protective against certain disease states. However, a health benefit of taking larger amounts has not been found in people who are generally healthy and well-nourished. Cell studies have shown that at very high concentrations, vitamin C can switch roles and act as a tissue-damaging pro-oxidant instead of an antioxidant. [2,3]   Its effects in humans at very high doses well beyond the RDA are unclear, and can lead to increased risk of kidney stones and digestive upset.

Vitamin C and Health

There is interest in the antioxidant role of vitamin C, as research has found the vitamin to neutralize free radical molecules, which in excess can damage cells. Vitamin C is also involved in the body’s immune system by stimulating the activity of white blood cells. Does this translate to protection from certain diseases?

Although some epidemiological studies that follow large groups of people over time have found a protective effect of higher intakes of vitamin C (from food or supplements) from cardiovascular disease and certain cancers, other studies have not. Randomized controlled trials have not found a benefit of vitamin C supplements on the prevalence of cardiovascular disease or cancer. The inconsistency of the data overall prevents the establishment of a specific vitamin C recommendation above the RDA for these conditions. [2]

Vitamin C has also been theorized to protect from eye diseases like cataracts and macular degeneration. Human studies using vitamin C supplements have not shown a consistent benefit, though there appears to be a strong association between a high daily intake of fruit and vegetables and decreased risk of cataracts. [4]

Despite being a popular fix, vitamin C’s cold-fighting potential hasn’t panned out. Reviews of several studies show that megadoses (greater than 500 mg daily) of supplemental vitamin C have no significant effect on the common cold, but may provide a moderate benefit in decreasing the duration and severity of colds in some groups of people. [2] Small trials suggest that the amount of vitamin C in a typical multivitamin taken at the start of a cold might ease symptoms, but for the average person, there is no evidence that megadoses make a difference, or that they prevent colds. [5]

The Physicians’ Health Study II, a randomized, double-blind, placebo-controlled trial of more than 14,000 male physicians, found a modestly reduced risk of new gout cases in men who took vitamin C supplements of 500 mg daily for up to 10 years. [6] Other short-term trials have found that vitamin C may lower blood levels of uric acid, a substance that can lead to gout if there is too much in the body.

Food Sources

Fruits and vegetables are the best sources of this vitamin.

• Citrus (oranges, kiwi, lemon, grapefruit)
• Bell peppers
• Strawberries
• Cruciferous vegetables (broccoli, Brussels sprouts , cabbage, cauliflower)
• White potatoes

Signs of Deficiency

Vitamin C deficiency is rare in developed countries but may occur with a limited diet that provides less than 10 mg daily for one month or longer. In developed countries, situations at greatest risk for deficiency include eating a diet restricted in fruits and vegetables, smoking or long-term exposure to secondhand smoke, and drug and alcohol abuse. The following are the most common signs of a deficiency.

• Skin spots caused by bleeding and bruising from broken blood vessels
• Swelling or bleeding of gums, and eventual loss of teeth
• Delayed healing of skin wounds
• Fatigue, malaise
• Iron-deficiency anemia due to decreased absorption of non-heme iron  

Did You Know?

• Vitamin C improves the absorption of non-heme iron , the type of iron found in plant foods such as leafy greens. Drinking a small glass of 100% fruit juice or including a vitamin-C-rich food with meals can help boost iron absorption.
• Vitamin C can be destroyed by heat and light. High-heat cooking temperatures or prolonged cook times can break down the vitamin. Because it is water-soluble, the vitamin can also seep into cooking liquid and be lost if the liquids are not eaten. Quick heating methods or using as little water as possible when cooking, such as stir-frying or blanching, can preserve the vitamin. Foods at peak ripeness eaten raw contain the most vitamin C.
• Vitamin C serums and skin creams are popular because normal skin typically contains high concentrations of vitamin C, which stimulates collagen production and protects against damage from UV sunlight. However, research suggests that topical vitamin C may have limited benefits, as very little can penetrate the skin’s surface and will not produce additional benefit if a person obtains adequate vitamin C through food or supplements. [7]

Vitamins and Minerals

• Carpenter KJ. The history of scurvy and vitamin C. Cambridge: Cambridge University Press, 1986.
• Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids . Washington (DC): National Academies Press (US); 2000.
• Poljšak B, Ionescu JG. Pro-oxidant vs. antioxidant effects of vitamin C. Handbook of Vitamin C Research: Daily Requirements, Dietary Sources and Adverse Effects (pp.153-183). January 2009. Nova Science Publishers, Inc.
• Huang G, Wu L, Qiu L, Lai J, Huang Z, Liao L. Association between vegetables consumption and the risk of age-related cataract: a meta-analysis. Int J Clin Exp Med . 2015 Oct 15;8(10):18455-61.
• Douglas RM, Hemila H, Chalker E, Treacy B. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev . 2007:CD000980.
• Juraschek SP, Gaziano JM, Glynn RJ, Gomelskaya N, Bubes VY, Buring JE, Shmerling RH, Sesso HD. Effects of vitamin C supplementation on gout risk: results from the Physicians’ Health Study II trial. The American Journal of Clinical Nutrition . 2022 Sep;116(3):812-9.
• Pullar JM, Carr AC, Vissers MC. The roles of vitamin C in skin health. Nutrients . 2017 Aug 12;9(8):866.

Last reviewed March 2023

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Dietary Supplements for Immune Function and Infectious Diseases

This is a general overview. For more in-depth information, see our health professional fact sheet .

How does your immune system work?

Your immune system is made up of cells , tissues , and organs that help fight viruses , bacteria , and other germs that cause infections and other diseases. For example, your skin helps prevent germs from getting inside your body. Cells that line your digestive tract also help protect against harmful germs that cause diseases. White blood cells try to destroy substances they recognize as foreign to your body. Some white blood cells also recognize germs they have been exposed to before and develop antibodies to defend against them in the future.

What do we know about specific dietary supplement ingredients and immune function?

Your immune system needs certain vitamins and minerals to work properly. These include vitamin C , vitamin D , and zinc . Herbal supplements , probiotics, and other dietary supplement ingredients might also affect your immune system.

Eating a variety of nutritious foods can give you enough vitamins, minerals, and other nutrients for a healthy immune system. However, you might wonder whether taking certain dietary supplements can improve your body’s immune system and its ability to fight infections.

This fact sheet describes what we know about the effectiveness and safety of common vitamins, minerals, and other dietary supplement ingredients that might affect immune function .

Dietary supplement ingredients are presented in each section in alphabetical order.

The health professional version of this fact sheet includes more details and references to the scientific literature .

Vitamins and Minerals

Getting enough vitamins and minerals through the foods and beverages you consume is important for a healthy immune system. It’s especially important to get enough of vitamins A, B6, B12, C, D, E, and K as well as folate , copper , iodine , iron , magnesium , selenium , and zinc.

If your diet doesn’t include adequate amounts of certain vitamins and minerals, your immune system will not be able to function as well as it could, you might be more likely to get infections, and you might not recover as well. If your health care provider determines that you are not getting enough of a specific nutrient, vitamin and mineral supplements can help increase intakes to recommended amounts. In most cases, however, if you don’t have a deficiency , increasing your intake of vitamins and minerals through dietary supplements doesn’t help prevent infections or help you recover from them any faster.

Vitamin A is an essential nutrient found in many foods. It exists in two different forms:

• Preformed vitamin A is found in fish, organ meats (such as liver ), dairy products, and eggs.
• Provitamin A carotenoids are turned into vitamin A by your body. They are found in fruits, vegetables, and other plant-based products. The most common provitamin A carotenoid in foods and dietary supplements is beta-carotene .

Vitamin A is important for healthy immune function as well as vision, reproduction, growth, and development.

Vitamin A deficiency is rare in the United States, but it is common in many low- and middle-income countries.

The recommended daily amount (known as Recommended Dietary Allowance or RDA) ranges from 300 to 1,200 microgram (mcg) retinol activity equivalents (RAE) for infants , children, and teens, depending on age, and from 700 to 1,300 mcg RAE for adults.

Does it work?

Diarrhea in children.

Children with a vitamin A deficiency are more likely to get diarrhea caused by germs. These children also have a higher chance of dying of diarrhea, especially in sub-Saharan Africa and south Asia.

Research suggests that vitamin A supplements lower the risk and severity of diarrhea in children in low- and middle-income countries. However, vitamin A supplementation might not help very young infants in these countries.

HIV infection

HIV infection can decrease your appetite and weaken your body’s ability to use nutrients from food. HIV can also increase the risk of related health problems, such as diarrhea and respiratory diseases.

It’s not clear if vitamin A supplements lower the risk of spreading HIV or keep the disease from getting worse. Some studies in young children with HIV have found that vitamin A supplements help lower the risk of death. However, it’s not clear whether vitamin A supplements affect the risk of diarrhea or respiratory infections in young children with HIV. Other studies in adults with HIV have found that vitamin A supplements do not improve immune function.

Research in pregnant people with HIV has found that vitamin A supplements do not help reduce the chance of passing HIV from mother to infant. However, one study found that pregnant people with HIV who took vitamin A were more likely to carry their babies to full-term.

Measles in children

In low- and middle-income countries where vitamin A deficiency is common, children with measles are more likely to have severe symptoms and may die from the disease. In these children, vitamin A supplements might help prevent measles, but it’s unclear whether they lower the risk of dying from measles.

Pneumonia and other respiratory infections in children

Is it safe.

Preformed vitamin A is safe at daily intakes up to 600 to 2,800 mcg for infants, children, and teens, depending on age, and up to 3,000 mcg for adults. There are no upper limits for beta-carotene and other forms of provitamin A.

Getting too much preformed vitamin A can cause severe headache, blurred vision, nausea , dizziness, muscle aches, and problems with coordination. In severe cases, getting too much preformed vitamin A can even lead to coma and death.

If you are pregnant, taking too much preformed vitamin A can cause birth defects, including abnormal eyes, skull, lungs , and heart. If you are or might be pregnant or breastfeeding, you should not take high-dose supplements of preformed vitamin A.

High intakes of beta-carotene (provitamin A) do not cause the same problems as preformed vitamin A. Consuming high amounts of beta-carotene can turn the skin yellow-orange, but this condition is harmless and goes away when you eat less of it. However, several studies have shown that smokers, former smokers, and people exposed to asbestos who take high-dose beta-carotene supplements have a higher risk of lung cancer and death.

Vitamin A supplements might interact with some medications such as orlistat (used for weight loss), acitretin (used to treat psoriasis ), and bexarotene (used to treat the skin effects of T-cell lymphoma ).

More information about vitamin A is available in the ODS consumer fact sheet on vitamin A .

Vitamin C is an essential nutrient found in citrus fruits and many other fruits and vegetables. Vitamin C is an antioxidant and is important for healthy immune function. The body also needs vitamin C to make collagen .

The RDA ranges from 15 to 115 milligrams (mg) for infants, children, and teens, depending on age, and from 75 to 120 mg for nonsmoking adults. People who smoke need 35 mg more than the RDA per day.

Common cold

Taking vitamin C regularly might help decrease cold symptoms and reduce the number of days a cold lasts. It might also help reduce the risk of getting a cold in people who undergo extreme physical stress, such as marathon runners and soldiers stationed in very cold locations. However, taking vitamin C after coming down with a cold may not be helpful.

Research suggests that vitamin C supplements might be more effective in people who do not get enough vitamin C from foods and beverages.

Sepsis (using intravenous vitamin C, not vitamin C supplements)

Sepsis is a life-threatening complication of an infection that can damage the body’s organs and tissues. It’s not clear whether high-dose intravenous (IV) vitamin C helps treat sepsis, and in some cases it might be harmful. In some studies, IV vitamin C reduced the risk of death, but in other studies it did not affect the risk of death or the amount of organ damage. Other research suggests that IV vitamin C might increase the risk of death or organ damage.

Vitamin C is safe at daily intakes up to 400 to 1,800 mg for children and teens, depending on age, and up to 2,000 mg for adults. Taking higher amounts of vitamin C can cause diarrhea, nausea, and stomach cramps, and it might also cause false readings on blood sugar monitors, which are used by people with diabetes . In people with hemochromatosis (an iron overload disorder ), high amounts of vitamin C might cause iron build-up in the body, which can damage body tissues.

Vitamin C supplements might decrease the effectiveness of radiation therapy and chemotherapy .

More information about vitamin C is available in the ODS consumer fact sheet on vitamin C .

For information about vitamin C and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Vitamin D is an essential nutrient that is naturally present in fatty fish and fish liver oils and in small amounts in beef liver, egg yolks, and cheese. It’s also added to some foods, such as fortified milk. Your body can also make vitamin D when your skin is exposed to the sun. Vitamin D is important for healthy bones and immune function.

The RDA ranges from 10 to 15 mcg (400 International Units [ IU ] to 600 IU) for infants, children, and teens, depending on age, and from 15 to 20 mcg (600 to 800 IU) for adults.

Flu, pneumonia, and other respiratory infections

People with low vitamin D levels might be more likely to get respiratory infections and might have a higher chance of dying from these infections. Some studies suggest that taking vitamin D supplements regularly might slightly reduce the risk of getting a respiratory infection, especially in people with low vitamin D levels. However, other studies have not found that taking vitamin D supplements reduces the risk of respiratory infections. In addition, vitamin D supplements do not appear to help treat respiratory infections.

People with HIV have a higher risk of vitamin D deficiency partly because many HIV medications cause the body to break down vitamin D faster than normal. Having a vitamin D deficiency might also worsen HIV infection. However, studies haven’t shown that vitamin D supplements improve the health of people with HIV.

Vitamin D is safe at daily intakes up to 25 to 100 mcg (1,000 to 4,000 IU) for infants, children, and teens, depending on age, and up to 100 mcg (4,000 IU) for adults. Taking higher amounts can cause nausea, vomiting, muscle weakness, confusion, pain, loss of appetite, dehydration, excessive urination and thirst, and kidney stones . Extremely high doses can cause kidney failure , damaged blood vessels and heart valves, heart rhythm problems, and death.

Vitamin D supplements might interact with some medications such as orlistat (used for weight loss), statins (used to lower cholesterol levels), thiazide diuretics (used for high blood pressure ), and steroids.

More information about vitamin D is available in the ODS consumer fact sheet on vitamin D .

For information about vitamin D and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Vitamin E (also called alpha-tocopherol ) is an essential nutrient found in nuts, seeds, vegetable oils, and green leafy vegetables. It acts as an antioxidant and helps your immune system function properly. Vitamin E deficiency is rare.

The RDA is 4 to 15 mg for infants, children, and teens, depending on age, and 15 to 19 mg for adults.

Pneumonia and other respiratory infections

It’s not clear whether vitamin E supplements reduce the risk or severity of respiratory infections. Some studies have found that vitamin E supplements might help but others have not, and the effects might depend on whether someone has low vitamin E levels. One study in people who had normal vitamin E levels found that those who took high-dose vitamin E supplements had worse respiratory symptoms and were sick longer.

Vitamin E from food is safe at any level. In supplements, vitamin E is safe at daily intakes up to 200 to 800 mg for children and teens, depending on age, and up to 1,000 mg for adults. Taking higher amounts can increase the risk of bleeding and stroke .

Vitamin E supplements might interact with blood thinners and might reduce the effectiveness of radiation therapy and chemotherapy.

More information about vitamin E is available in the ODS consumer fact sheet on vitamin E .

For information about vitamin E and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Selenium is an essential mineral found in many foods, including Brazil nuts, seafood, meat, poultry , eggs, dairy products, bread, cereals, and other grain products. It acts as an antioxidant and is important for reproduction, thyroid gland function, and DNA production.

The RDA ranges from 15 to 70 micrograms (mcg) for infants, children, and teens, depending on age, and from 55 to 70 mcg for adults.

People with HIV have higher risk of selenium deficiency than other people, and this might worsen their infection and increase the risk of death. However, it’s not clear whether taking selenium supplements improves the health of people with HIV. Some studies have found that selenium supplements might improve immune function slightly in people with HIV, but other studies have not.

Selenium is safe at daily intakes up to 45 to 400 mcg for infants, children, and teens, depending on age, and up to 400 mcg for adults. Taking higher amounts can cause a garlic odor in the breath, a metallic taste in the mouth, hair and nail loss or brittleness, skin rash, nausea, diarrhea, fatigue , irritability, and nervous system problems.

Selenium might interact with cisplatin (a drug used in chemotherapy).

More information about selenium is available in the ODS consumer fact sheet on selenium .

For information about selenium and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Zinc is an essential nutrient found in seafood, meat, beans, nuts, whole grains , and dairy products. It’s important for a healthy immune system, making proteins and DNA, healing wounds, and for proper sense of taste.

The RDA ranges from 2 to 13 mg for infants, children, and teens, depending on age, and from 8 to 12 mg for adults.

Some studies suggest that zinc lozenges and zinc syrup speed recovery from the common cold if you start taking them at the start of a cold. However, these products don’t seem to affect the severity of cold symptoms. More research is needed to determine the best dose and form of zinc for the common cold as well as how often and how long it should be taken.

Pneumonia in children

Some studies in lower income countries show that zinc supplements lower the risk of pneumonia in young children. However, zinc doesn’t seem to speed recovery or reduce the number of deaths from pneumonia.

Studies show that zinc supplements help shorten the duration of diarrhea in children in low-income countries, where zinc deficiency is common. The World Health Organization and UNICEF recommend that children with diarrhea take zinc for 10 to 14 days (20 mg/day, or 10 mg/day for infants under 6 months). However, it’s not clear if zinc supplements help children with diarrhea who already get enough zinc, such as most children in the United States.

Many people with HIV have low zinc levels. This occurs because they have trouble absorbing zinc from food and they often have diarrhea, which increases zinc loss. Some studies have found that supplemental zinc decreases diarrhea and complications of HIV, but other studies have not. Zinc supplements do not appear to reduce the risk of death in people with HIV.

Zinc is safe at daily intakes up to 4 to 34 mg for infants, children, and teens, depending on age, and up to 40 mg for adults. Taking higher amounts can cause nausea, vomiting, loss of appetite, stomach cramps, diarrhea, and headaches. High intakes of zinc over a long time can cause low blood levels of copper and impair immune function.

Zinc supplements might interact with antibiotics , penicillamine (used to treat rheumatoid arthritis ), and thiazide diuretics (used to treat high blood pressure).

More information about zinc is available in the ODS consumer fact sheet on zinc .

For information about zinc and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Andrographis

Andrographis is an herb native to Southeast Asia. It might help your body fight viruses, reduce inflammation , and strengthen your immune system.

Common cold and other respiratory infections

Some studies have found that taking andrographis after getting a cold or other respiratory infection might lessen the severity of symptoms and shorten the length of time symptoms last. However, additional studies are needed to confirm these findings.

No safety concerns have been reported when andrographis is used as directed. Side effects of andrographis can include nausea, vomiting, dizziness, skin rashes, diarrhea, and fatigue.

Andrographis might decrease blood pressure and thin the blood, so it could interact with blood pressure and blood thinning medications.

Andrographis might also decrease the effectiveness of medications that suppress the immune system. Andrographis might affect fertility, so some scientists recommend avoiding it if you are pregnant or planning to have a baby.

For information about andrographis and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Echinacea is an herb that grows in North America and Europe. It might help stop the growth or spread of some types of viruses and other germs. It might also help strengthen your immune system and reduce inflammation.

Common cold and flu

Studies have found that echinacea might slightly reduce the risk of catching a cold, but it doesn’t reduce the severity of symptoms or shorten the length of time symptoms last.

It’s unclear whether echinacea is helpful for the flu.

Echinacea appears to be safe. Side effects can include stomach upset, diarrhea, trouble sleeping, and skin rashes. In rare cases, echinacea might cause allergic reactions.

Echinacea might reduce the effectiveness of some medications, including medications that suppress the immune system. Scientists don’t know if echinacea is safe to take during pregnancy.

For information about echinacea and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Elderberry (European Elder)

Elderberry (or elder berry) is the fruit of a tree that grows in North America, Europe, and parts of Africa and Asia. Elderberry might help your body fight viruses and other germs, reduce inflammation, and strengthen your immune system.

Elderberry doesn’t appear to reduce the risk of coming down with the common cold. However, some studies have found that elderberry might help relieve symptoms of colds and flu and help people recover quicker.

Elderberry flowers and ripe fruit appear to be safe to eat. However, the bark, leaves, seeds, and raw or unripe elderberry fruit can be poisonous and can cause nausea, vomiting, diarrhea, and dehydration. Cooked elderberry fruit and properly manufactured supplements do not have this safety concern.

Elderberry might affect insulin and blood sugar levels. It might also reduce the effectiveness of medications that suppress the immune system. Scientists don’t know if elderberry is safe to take during pregnancy.

For information about elderberry and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Garlic is a vegetable that has been used in cooking throughout history . It is also available as a dietary supplement.

Garlic might help your body fight viruses and other germs.

Only a few studies have looked at whether garlic supplements help prevent the common cold or flu, and it’s not clear if garlic is helpful.

Garlic is considered safe. Side effects can include bad breath, body odor, and skin rash.

Garlic might interact with blood thinners and blood pressure medications.

Ginseng ( Panax ginseng or Panax quinquefolius ) is a plant used in traditional Chinese medicine. It might help your body fight viruses, reduce inflammation, and strengthen your immune system.

Another botanical , eleuthero ( Eleutherococus senticosus ), has sometimes been called Siberian ginseng, but it is not related to true ginseng.

Common cold, flu, and other respiratory infections

Ginseng might reduce the risk of coming down with the common cold, flu, or other respiratory infections. However, it’s unclear whether ginseng helps relieve symptoms or affects the length of time symptoms last.

Ginseng appears to be safe. Side effects can include headache, trouble sleeping, and digestive upset. However, high doses (more than 2.5 grams [g]/day) of ginseng might cause insomnia , rapid heartbeat, high blood pressure, and nervousness.

Ginseng might interact with diabetes medications, stimulants , and medications that suppress the immune system.

For information about ginseng and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Tea and tea catechins

Tea ( Camellia sinensis ) is a popular beverage that may have health benefits. Tea extracts are also available as dietary supplements.

Green, black, and oolong tea leaves are processed in different ways. Green tea is made from dried and steamed tea leaves, and black and oolong teas are made from fermented tea leaves.

Tea, especially green tea, has high amounts of substances called catechins. Catechins might help fight viruses and other germs.

Flu and other respiratory infections

Based on only a few studies, it’s unclear whether tea or tea catechins are helpful for the flu or other respiratory infections. Some studies have found that tea and tea catechins might reduce the risk of coming down with upper respiratory infections. They might also reduce the length and severity of some symptoms but not other symptoms.

Tea is safe to drink. Side effects of green tea extract can include nausea, constipation , stomach discomfort, and increased blood pressure. Some green tea extracts might damage your liver, especially if you take them on an empty stomach.

Tea also contains caffeine, which can disturb your sleep and cause nervousness, jitteriness, and shakiness. Safe doses of caffeine for healthy adults are up to 400 to 500 mg/day and up to 200 mg/day for people who are pregnant.

Tea might interact with atorvastatin (a cholesterol-lowering drug) and stimulants, such as bitter orange or ephedrine.

Other Ingredients

Glutamine is an amino acid found in many foods including beef, fish, poultry, dried beans, eggs, rice, grains, and dairy products. Your body makes enough glutamine to meet your needs, except under rare conditions (for example, if you are critically ill in an intensive care unit [ICU] or have had major surgery).

Glutamine helps your immune system work properly.

Critical illness (giving glutamine as an IV or tube feeding)

It’s unclear whether glutamine helps people who are critically ill. Some studies in hospitalized patients who were critically ill or had undergone major surgery found that glutamine given as an IV or tube feeding reduced the risk of getting an infection, but it did not reduce the risk of death.

Glutamine is considered safe. Side effects can include nausea, bloating, burping, pain, gas, and vomiting. These side effects are more likely to occur with higher doses of glutamine.

No interactions between glutamine and medications have been reported.

N-acetylcysteine and glutathione

N-acetylcysteine (NAC) is similar to cysteine, an amino acid. It acts as an antioxidant and helps reduce mucus in the respiratory tract .

NAC raises levels in your body of a substance called glutathione, which also acts as an antioxidant. NAC and glutathione might also help your body fight viruses and other germs, reduce inflammation, and strengthen your immune system.

People with HIV may have low levels of glutathione, which might increase the risk of certain diseases including tuberculosis . However, there is very little research on NAC supplements in people with HIV. Therefore, scientists don’t know whether it’s helpful.

NAC appears to be safe. Side effects can include nausea, vomiting, stomach pain, diarrhea, indigestion, and heartburn.

NAC might interact with blood thinners and blood pressure medications. Taking NAC with nitroglycerine (used to treat chest pain) might cause low blood pressure and severe headaches.

For information about NAC and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Omega-3 fatty acids

Omega-3s are types of fats, including alpha linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is found mainly in plant oils, such as flaxseed, soybean , and canola oils. EPA and DHA are found mainly in fatty fish and fish oils.

Omega-3s are important for healthy cell membranes and proper function of the heart, lungs, brain, immune system, and endocrine system .

The recommended amount of omega-3s for infants is 0.5 g per day, and 0.7 to 1.6 g per day of ALA for children, teens, and adults, depending on age. EPA and DHA do not have individual recommendations.

Omega-3s might help your body fight viruses and other germs, reduce inflammation, and strengthen your immune system.

Acute respiratory distress syndrome (giving omega-3s as an IV or tube feeding)

Acute respiratory distress syndrome (ARDS) is a serious lung condition that can lead to death. In people who do recover, ARDS often causes long-term physical and mental health problems.

Researchers have studied whether giving omega-3s as an IV or tube feeding is helpful for people with ARDS, but results from these studies are not clear. Some studies have found that omega-3s given in this manner might help the lungs work better, but they don’t appear to lower the risk of dying from ARDS. In addition, it’s not clear whether omega-3s given in this manner affect the length of time people are hospitalized with ARDS and need a ventilator to help them breathe.

Respiratory infections in infants and young children

The immune system continues to develop in babies after birth, and their immune cells contain the omega-3s EPA and DHA. However, it’s not clear whether adding omega-3s to infant formula improves immune function or reduces the risk of getting respiratory infections.

A study in school-age children found that children who consumed milk with added EPA and DHA had fewer upper respiratory infections than those who did not consume omega-3s. In another study, however, using an infant formula containing DHA and another fatty acid had no effect on the risk of respiratory infections in infants.

Omega-3s are considered safe. Side effects can include a bad taste in the mouth, bad breath, heartburn, nausea, digestive discomfort, diarrhea, headache, and smelly sweat. Omega-3s might interact with blood thinners, blood pressure medications, and medications that suppress the immune system.

More information about omega-3s is available in the ODS consumer fact sheet on omega-3 fatty acids .

For information about omega-3s and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Probiotics are live microorganisms (bacteria and yeasts) that provide health benefits. They are naturally present in certain fermented foods, added to some food products, and available as dietary supplements. Probiotics act mostly in the stomach and intestines . They might improve immune function and help fight viruses.

Acute diarrhea in infants and children

Acute infectious diarrhea in infants and children causes loose or liquid stools and three or more bowel movements within 24 hours. This condition is often caused by a viral infection and can last for up to a week. Some infants and children also develop fever and vomiting. Some studies have shown that probiotics shorten acute diarrhea by about 1 day, but other studies do not.

Some studies have reported that two strains of probiotics— Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii —were most likely to benefit children with acute infectious diarrhea, but other studies have not.

Probiotics might reduce the risk of some respiratory infections and shorten the length of illness. Some studies in infants, children, and adults have found that probiotics reduce the risk of getting a cold and help relieve some symptoms, such as fever and cough. Other studies in children reported fewer sick days from school and quicker recovery. However, formulations of probiotics vary, and the effects of one product may not be the same as another.

Ventilator-associated pneumonia

It’s not clear whether probiotics help people who are critically ill. Some studies have found that probiotics lower the risk of developing pneumonia in people who are critically ill and need a ventilator to help them breathe, but other studies have not.

Probiotics are considered safe for most people. Side effects can include gas and other digestive symptoms. In people who are very ill or have immune system problems, probiotics might cause severe illness. Probiotics might also cause infections or even life-threatening illness in preterm infants. Although probiotics don’t appear to interact with medications, taking antibiotics or antifungal medications might decrease the effectiveness of some probiotics.

More information about probiotics is available in the ODS consumer fact sheet on probiotics .

For information about probiotics and COVID-19, see the ODS consumer fact sheet, Dietary Supplements in the Time of COVID-19 .

Do dietary supplements interact with medications or other supplements?

Yes, some supplements can interact or interfere with medicines you take.

Tell your doctor, pharmacist , and other health care providers about any dietary supplements and prescription or over-the-counter medicines you take. They can tell you if the dietary supplements might interact with your medicines or if the medicines might interfere with how your body absorbs , uses, or breaks down nutrients.

Where can I find out more about dietary supplements and immune function?

• Office of Dietary Supplements (ODS) Health Professional Fact Sheet on Dietary Supplements for Immune Function and Infectious Diseases

• Herbs at a Glance , National Center for Complementary and Integrative Health
• ODS Frequently Asked Questions: Which brand(s) of dietary supplements should I purchase?

This fact sheet by the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) provides information that should not take the place of medical advice. We encourage you to talk to your health care providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific brand name is not an endorsement of the product.

Updated: November 14, 2023

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Computer Science > Machine Learning

Title: kan: kolmogorov-arnold networks.

Abstract: Inspired by the Kolmogorov-Arnold representation theorem, we propose Kolmogorov-Arnold Networks (KANs) as promising alternatives to Multi-Layer Perceptrons (MLPs). While MLPs have fixed activation functions on nodes ("neurons"), KANs have learnable activation functions on edges ("weights"). KANs have no linear weights at all -- every weight parameter is replaced by a univariate function parametrized as a spline. We show that this seemingly simple change makes KANs outperform MLPs in terms of accuracy and interpretability. For accuracy, much smaller KANs can achieve comparable or better accuracy than much larger MLPs in data fitting and PDE solving. Theoretically and empirically, KANs possess faster neural scaling laws than MLPs. For interpretability, KANs can be intuitively visualized and can easily interact with human users. Through two examples in mathematics and physics, KANs are shown to be useful collaborators helping scientists (re)discover mathematical and physical laws. In summary, KANs are promising alternatives for MLPs, opening opportunities for further improving today's deep learning models which rely heavily on MLPs.

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