Dietary Supplements in the Time of COVID-19

Fact Sheet for Health Professionals

Data are insufficient to support recommendations for or against the use of any vitamin, mineral, herb or other botanical, fatty acid, or other dietary supplement ingredient to prevent or treat COVID-19.

Introduction

COVID-19, the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in 2019 and has infected more than 650 million people worldwide as of January 1, 2023 [1]. Common initial signs and symptoms include cough, fever, fatigue, headache, muscle aches and pain, and diarrhea [2]. Some individuals with COVID-19 become severely ill, usually starting about 1 week after symptom onset; severe COVID-19 often involves progressive respiratory failure and may also result in life-threatening pneumonia, multiorgan failure, and death [2,3]. In addition, many individuals who have had COVID-19 report symptoms of long COVID (including breathlessness, cough, fatigue, muscle aches and weakness, sleep difficulties, and cognitive dysfunction) for several weeks, months, or longer after the acute stage of illness has passed [4-8]. Risk of long COVID appears to be higher in people who are hospitalized following SARS-CoV-2 infection as well as those who are not vaccinated against COVID-19 [4].

Currently, data are insufficient to support recommendations for or against the use of any vitamin, mineral, herb or other botanical, fatty acid, or other dietary supplement ingredient to prevent or treat COVID-19. And by law, dietary supplements are not allowed to be marketed as a treatment, prevention, or cure for any disease; only drugs can legally make such claims [9]. Nevertheless, sales of dietary supplements marketed for immune health increased after the emergence of COVID-19 because many people hoped that these products might provide some protection from SARS-CoV-2 infection and, for those who develop COVID-19, help reduce disease severity [10-13].

The immune system defends the body from pathogens that cause disease and is comprised of innate responses, which are the first line of defense, and adaptive responses, which become engaged later [14-16].

The innate immune system includes physical barriers, such as the skin and gut epithelium, that help prevent pathogen entry. It also includes leukocytes (white blood cells)—such as neutrophils, macrophages (which release cytokines), and natural killer cells—that attempt to find and eliminate foreign pathogens. However, these components are nonspecific, meaning that unlike the adaptive immune system, they do not recognize and respond to specific pathogens [14,15].

The adaptive immune system consists of B lymphocytes (B cells) that secrete antibodies into the blood and tissues (a process known as humoral immunity) and T lymphocytes (T cells; a process known as cell-mediated immunity), both of which are pathogen specific [16]. The adaptive response takes several days or weeks to develop, but it generates immunological memory; as a result, a subsequent exposure to the same pathogen leads to a vigorous and rapid immune response [14,16]. Vaccinations target the adaptive immune system, protecting the body from exposures to the same pathogen in the future [15].

The body’s immune response to pathogens leads to inflammation, causing redness, swelling, heat, pain, and loss of tissue function [17]. Inflammation helps eliminate the pathogen and initiate the healing process, but it is also a cause of symptoms and severe pathologies [17,18]. For example, activation of CD8 T cells as part of the adaptive immune response can increase inflammation and cause pulmonary damage. This process can lead to acute respiratory distress syndrome, which has occurred in some patients with COVID-19 [18]. Other signs of inflammation, including elevated levels of C-reactive protein and interleukin-6, sometimes develop in patients with severe COVID-19 [2]. Some patients with COVID-19 experience a cytokine storm, a critical condition caused by excessive production of inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 [3,19]. This condition increases disease severity and risk of death, so tempering the body’s inflammatory response is an important component of COVID-19 management.

People require several vitamins and minerals—including vitamin C, vitamin D, and zinc—for proper immune function, and clinical deficiencies of these nutrients can increase susceptibility to infections [15,20]. Other dietary supplement ingredients, such as botanicals and probiotics, do not have essential roles in the body but might affect immune function.

Measuring the impact on the immune system of vitamins, minerals, and other dietary supplement ingredients is difficult because the immune system is a complex network of organs, tissues, and cells. No single, straightforward measure of immune system function and resistance to disease exists. Indirectly, immune function can be assessed by examining a person's risk of infectious diseases and severity of symptoms.

COVID-19 vaccines are safe and highly effective at reducing the risk of disease, including the risk of severe illness [21,22]. Pharmacologic treatments are also available, but no cure for COVID-19 exists. Thus, interest in dietary supplement ingredients that might enhance immune function and reduce inflammation to help prevent COVID-19 or manage its signs and symptoms remains high. Many of these ingredients have not been studied in people with COVID-19, but research suggests that they might improve immune function and help prevent or reduce symptoms of the common cold, influenza, and other respiratory tract infections. Therefore, some scientists believe that they might hold promise for COVID-19, although the strength of the evidence supporting these speculations varies widely. For example, many studies have examined associations between serum or plasma concentrations of vitamins or minerals and risk of COVID-19 infection or disease severity. However, serum or plasma nutrient concentrations might not reflect body stores. Furthermore, the onset of disease can cause low (or sometimes high) nutrient concentrations; it cannot be assumed that the nutrient concentrations observed in these studies contributed to the onset of COVID-19 or its severity. In addition, many clinical trials in patients with COVID-19 had small samples, were not randomized or placebo controlled, and measured multiple outcomes, complicating the interpretation of their results.

This fact sheet summarizes the state of the science on the safety and efficacy of these dietary supplements. Ingredients are presented in alphabetical order. Citations to published research and in-process clinical trials throughout the world from the ClinicalTrials.gov databaseexternal link disclaimer are provided; unless otherwise stated, these trials are being conducted in the United States. In addition, this fact sheet briefly discusses interactions between dietary supplement ingredients and medications. However, especially for botanicals, this information is often based on individual case reports and theoretical interactions derived from animal studies, cellular assays, or other indirect evidence. In most cases, potential interactions have not been adequately evaluated in clinical settings [23,24].

The content of this fact sheet is current as of the publication date, but because this is an evolving area of research, additional evidence might have become available since that time.

Andrographis

Andrographis paniculata, also known as Chuān Xīn Lián, is an herb that is native to subtropical and Southeast Asia [25]. Its leaves and other aerial (above ground) parts are used in traditional Ayurvedic, Chinese, and Thai medicine for relieving symptoms of the common cold, influenza, and other respiratory tract infections [26-29]. The active constituents of andrographis are believed to be andrographolide and its derivatives, which are diterpene lactones that might have antiviral, anti-inflammatory, and immune-stimulating effects [25,27,29-34].

Efficacy

Studies conducted before the emergence of COVID-19 suggest that andrographis supplementation might reduce the severity of respiratory tract infections [27,28,35,36]. Because of these findings, some scientists believe that andrographis could help treat the symptoms of COVID-19, but studies have not thoroughly assessed use of this herb for this purpose [31,33,34,37].

A few in vitro studies suggest that andrographolide isolated from andrographis might bind the main protease of SARS-CoV-2, thereby inhibiting its replication, transcription, and host cell recognition [32,33,37,38]. In a small clinical trial in Thailand, researchers examined the effects of 60 mg or 100 mg andrographis extract (called Fah Talai Jone in Thailand), given three times per day in 12 people with mild to moderate COVID-19 symptoms [39-41]. COVID-19 symptoms, especially cough, improved within a few days after patients started taking the low dose (60 mg) andrographis, and all patients recovered after 3 weeks [42]. No information was provided on the effects of the 100 mg andrographis dose.

On the basis of these findings, a larger placebo-controlled trial was conducted among 60 participants, and Thailand’s health ministry subsequently approved a pilot program to use Fah Talai Jone for individuals age 18 to 60 with minor symptoms within 72 hours of a COVID-19 diagnosis [39,43]. Andrographis is commonly used in Thailand in patients with mild COVID-19 [44], but its effects have been mixed. A retrospective study of 605 hospitalized patients (mostly unvaccinated) in Thailand with mild COVID-19 who took andrographis (total daily dose of 180 mg andrographolide) or received only standard of care for 5 days found that the use of andrographis was not significantly associated with risk of pneumonia [44].

A clinical trial in Tbilisi, Georgia, randomized 86 hospitalized patients with mild to moderate COVID-19 (mean age 45 to 50 years, vaccination status not specified) into two groups where 34 took 6 capsules daily of a product called Kan Jang/Nergecov (containing andrographis and Eluetherococcus senticosus for a total daily dose of 90 mg andrographolides) and 52 took a placebo for 14 days [45]. Of the 71 patients who completed the study, 10% of those who took Kan Jang/Nergecov progressed to severe disease compared with 24% who took placebo. Kan Jang/Nergecov also appeared to relieve the severity of sore throat, muscle pain, and nasal discharge but not severity of cough, duration of hospitalization, time to viral clearance, or fever.

A clinical trialexternal link disclaimer in progress in Thailand is comparing the effects of andrographis (three capsules, three times per day for a total daily dose of 180 mg andrographolide) with an extract of Boesenbergia rotunda (a plant in the ginger family) or standard supportive treatment for 5 days in 3,060 adults with asymptomatic COVID-19 infection.

Safety

The safety of andrographis has not been well studied, but no safety concerns have been reported when typical doses of the herb (340 to 1,200 mg/day) have been used for several days or weeks [28,29,46]. Clinical trials have found minor adverse effects, including nausea, vomiting, vertigo, skin rashes, diarrhea, and fatigue [27,29,35]. Allergic reactions might also occur [29,34]. Findings from some animal studies suggest that andrographis might adversely affect fertility, so experts recommend against its use by pregnant women and by men and women during the preconception period [26,28,29].

According to animal and laboratory studies, andrographis might decrease blood pressure and inhibit platelet aggregation, so it could interact with antihypertensive and anticoagulant medications by enhancing their effects [46-48]. Because of its potential immune-stimulating effects, andrographis might also reduce the effectiveness of immunosuppressants [30,46]. Whether the potential immunostimulatory effect of andrographis might worsen the cytokine storm associated with COVID-19 is not known [34].

Echinacea

Echinacea, commonly known as purple coneflower, is an herb that grows in North America and Europe [49]. Although the genus Echinacea has many species, extracts of E. purpurea, E. angustifolia, and E. pallida are the most frequently used in dietary supplements. The echinacea supplements on the market in the United States often contain extracts from multiple species and plant parts [23].

Echinacea contains volatile terpenes, polysaccharides, polyacetylenes, alkamides, phenolic compounds, caffeic acid esters, and glycoproteins [23,49,50]. However, echinacea’s purported active constituents are not well defined [50], and the chemical composition of various echinacea species differs [23].

Echinacea might have antioxidant and antibacterial activities, stimulate monocytes and natural killer cells, and inhibit viruses from binding to host cells [16,49]. It might also reduce inflammation by inhibiting the inflammatory cytokines interleukin-6, interleukin-8, and tumor necrosis factor and increasing levels of the anti-inflammatory cytokine interleukin-10 [16,51]. Most studies of echinacea have assessed whether it helps prevent and treat the common cold and other upper respiratory illnesses, but it has also been used in traditional medicine to promote wound healing [49,50].

Efficacy

Several studies suggest that echinacea offers limited benefits for preventing the common cold [52,53], so some researchers have suggested that echinacea might have similar effects on COVID-19 [16,34,54,55].

A preliminary in vitro study found that Echinaforce, an E. purpurea preparation, inactivated SARS-CoV-2 [56]. However, results have been mixed from the few clinical trials that have examined whether echinacea reduces the risk of SARS-CoV-2 infection or severity of disease. In a clinical trial in Iran conducted before the availability of COVID-19 vaccines, 100 adults (mean age 45–47 years) with suspected COVID-19 based on chest computed tomography (CT) scan or x-ray and clinical symptoms who were not hospitalized took either echinacea (species and dose not specified) plus ginger (Zingiber officinale, dose not specified) and hydroxychloroquine for 7 days or hydroxychloroquine alone [57]. Coughing, muscle pain, and shortness of breath were alleviated in 91% to 98% of individuals who took the combination of echinacea, ginger, and hydroxychloroquine, whereas only 69% to 79% of individuals who took hydroxychloroquine alone experienced these benefits. However, the combination treatment did not reduce severity of fever or sore throat or the rate of hospitalization for COVID-19.

Another clinical trial in Bulgaria included 120 healthy participants age 18 to 75 years [58]. Half of the participants took 2,400 mg Echinaforce daily over three periods of 2 months, 2 months, and 1 month with washouts of 1 week between each period; the other half served as a control group (there was no placebo). All participants were unvaccinated against COVID-19 at the start of the trial. Several became partially or fully vaccinated during the trial, but there was no significant difference in vaccination rates between groups. Participants were followed to determine if they had a positive test result for COVID-19 or developed another acute respiratory tract infection. During the trial, participants in the echinacea group who had COVID-19 or another respiratory tract infection were treated with 4,000 mg/day Echinaforce for up to 10 days; all participants also received concomitant treatments. Participants who took Echinaforce were less likely to have a positive test result for COVID-19 than those in the control group, but there were no differences between groups in the number of symptomatic episodes of COVID-19. In addition, treatment with Echinaforce reduced SARS-CoV-2 viral load but did not affect the number of days it took to achieve SARS-CoV-2 viral clearance. According to ClinicalTrials.govexternal link disclaimer, a few other clinical trials are assessing the effects of echinacea on COVID-19. For example, one trialexternal link disclaimer in Bulgaria will examine whether Echinaforce supplements at doses of 1,200 to 2,800 mg/day reduce SARS-CoV-2 viral shedding and transmission in about 75 children and adults age 12 to 75 with COVID-19. Another trialexternal link disclaimer in Spain will examine whether echinacea (dose not specified) for 10 days improves symptoms severity in about 230 nonhospitalized adults with mild COVID-19.

Because echinacea might have immunostimulatory effects, some investigators have suggested that it might worsen the cytokine storm that can develop in patients with COVID-19 [54]. However, limited evidence from clinical trials suggests that the use of echinacea decreases—not increases—levels of proinflammatory cytokines [54].

Safety

Echinacea appears to be safe. The most common of echinacea’s few adverse effects are gastrointestinal upset such as diarrhea, sleeplessness, and skin rashes [50,59,60]. Isolated reports of elevated liver enzymes and liver injury have been associated with its use, but these events could have been caused by a contaminant or the product’s preparation. In rare cases, echinacea can cause allergic reactions [50].

The safety of echinacea during pregnancy is not known, so experts recommend against the use of echinacea supplements by pregnant women [61].

Echinacea might interact with several medications. For example, echinacea might increase cytochrome P450 activity, thereby reducing levels of some drugs metabolized by these enzymes [62]. In addition, echinacea might reduce the effectiveness of immunosuppressants due to its potential immunostimulatory activity [63].

Elderberry (European Elder)

Elder berry (usually written elderberry) is the fruit of a small deciduous tree, Sambucus nigra (also known as European elder or black elder), that grows in North America, Europe, and parts of Africa and Asia [64,65]. Elderberry contains many compounds—including anthocyanins, flavonols, and phenolic acids—that might have antioxidant, anti-inflammatory, antiviral, antimicrobial, and immune-stimulating effects [16,65-69]. Studies of the effects of elderberry have primarily used elderberry extracts, not the berries themselves [65].

Efficacy

Sales of elderberry supplements more than doubled shortly after the COVID-19 pandemic began in the United States [70], and some researchers have recommended studying the use of elderberry to treat COVID-19 symptoms [16,67,71,72].

The interest in elderberry is based on preliminary laboratory and animal research suggesting that constituents of elderberry might help prevent upper respiratory tract infections by inhibiting viruses from binding to host cells and by stimulating the immune system [65]. Elderberry’s effects on the common cold and influenza have been examined in a few small clinical trials with promising results [66]. A 2021 systematic review of five clinical trials of elderberry to prevent or treat viral respiratory illnesses found beneficial effects on some outcomes [73]. The authors found that elderberry supplementation for 2 to 16 days might reduce the severity and duration of the common cold and the duration of flu but does not appear to reduce the risk of the common cold [73]. However, the authors noted that the evidence is uncertain because the studies were small, heterogeneous, and of poor quality.

According to ClinicalTrials.govexternal link disclaimer, a few clinical trials are examining whether elderberry helps prevent or treat COVID-19. For example, one trialexternal link disclaimer will examine whether 600 milligrams (mg) elderberry extract (ElderCraft) daily for 13 weeks reduces the incidence, duration, and severity of upper respiratory infections, including COVID-19, in 420 participants age 20 to 65 years. Another trialexternal link disclaimer in the United Kingdom is assessing whether an elderberry supplement (Sambucol; 15 mL four times per day) for 14 days reduces symptom severity and rates of hospital admission in 204 adults with mild or moderate COVID-19.

Safety

Elderberry flowers and ripe fruit appear to be safe for consumption. However, the bark, leaves, seeds, and raw or unripe fruit of S. nigra contain a cyanogenic glycoside that is potentially toxic and can cause nausea, vomiting, diarrhea, dehydration due to diuresis, and cyanide poisoning [65,70,74]. The heat from cooking destroys this toxin, so cooked elderberry fruit and properly processed commercial products do not pose this safety concern [16,65,67,70,74]. Elderberry might affect insulin and glucose metabolism, so according to experts, people with diabetes should use it with caution [70]. The safety of elderberry during pregnancy is not known, so experts recommend against the use of elderberry supplements by pregnant women [61,65].

Recent analyses suggest that some elderberry supplements have been adulterated because they are highly diluted or contain a cheaper ingredient, such as black rice extract, instead of elderberry [64].

Due to its potential immunostimulatory activity, elderberry might reduce the effectiveness of immunosuppressant medications [75].

Ginseng

Ginseng is the common name of several species of the genus Panax, most commonly Panax ginseng (also called Asian ginseng or Korean ginseng) and Panax quinquefolius (American ginseng) [76,77]. Asian ginseng grows mainly in China and Korea, whereas American ginseng grows in the United States and Canada [76].

Triterpene glycosides, also known as ginsenosides, are some of the main purported active constituents of ginseng [76,78]. Although ginseng contains numerous ginsenosides, research has focused on the Rb1 ginsenoside and compound K, a bioactive substance formed when the intestinal microbiota metabolize ginsenosides [76,78]. Both the product’s preparation method and variations in people’s intestinal microbiota can affect the type and quantity of ginseng’s bioactive compounds in the body [78].

Animal and laboratory studies suggest that ginseng stimulates B-lymphocyte proliferation and increases production of some interleukins and interferon-gamma [76]; these cytokines affect immune activation and modulation [14]. Ginseng might also inhibit virus replication and have anti-inflammatory activity. However, whether ginseng has a clinically meaningful effect on immune function in humans is not clear [76,79].

Another botanical, eleuthero (Eleutherococus senticosus), is sometimes confused with true ginseng. Eleuthero used to be called Siberian ginseng, but it comes from the Eleutherococcus genus of plants, not the Panax genus, and it does not contain ginsenosides [76].

Efficacy

Several clinical trials have examined whether ginseng helps prevent upper respiratory tract infections, such as the common cold and flu, but results have been mixed and none of the trials addressed COVID-19 [78,80]. Based on this limited evidence of ginseng's effects on immune function and treatment of upper respiratory tract infections, some researchers recommend studying the use of ginseng as an adjuvant therapy for COVID-19 [81-83].

According to ClinicalTrials.govexternal link disclaimer, a few clinical trials are examining whether ginseng helps reduce the duration and severity of COVID-19 symptoms. For example, one clinical trialexternal link disclaimer in Hong Kong aims to determine whether ginseng and other ingredients, as part of individually tailored traditional Chinese medicine, will help about 150 children and adults with COVID-19 recover more quickly after hospital discharge [84]. Another trialexternal link disclaimer in Vietnam will examine whether a combination product containing ginseng combined with standard of care for 10 days reduces the duration and severity of symptoms in 300 adults with mild to moderate COVID-19.

Safety

Ginseng appears to be safe. Most of its adverse effects, including headache, sleep difficulty, and gastrointestinal symptoms, are minor [78-80]. However, doses of more than 2.5 g/day might cause insomnia, tachyarrhythmias, hypertension, and nervousness [76,78].

A few case reports of vaginal bleeding and mastalgia (breast pain) in the 1970s and 1980s from the use of ginseng preparations raised concerns about the safety of ginseng. As a result, some scientists concluded that ginseng has estrogenic effects [85-88]. However, one of these case reports involved use of Rumanian ginseng [87], and whether this was true ginseng is not clear. In addition, eleuthero was often referred to, incorrectly, as ginseng at that time because it was called Siberian ginseng. So, it is unclear whether these case reports reflected the effects of true ginseng. Nevertheless, some experts caution that ginseng might not be safe for use during pregnancy [78,89,90].

Ginseng might interact with many medications. For example, it might increase the risk of hypoglycemia if taken with antidiabetes medications, increase the risk of adverse effects if taken with stimulants, and reduce the effectiveness of immunosuppressants [90,91].

Magnesium

Magnesium is an essential mineral that is present in many foods, including green leafy vegetables, nuts, seeds, and whole grains. The Recommended Dietary Allowance (RDA, average daily level of intake sufficient to meet the nutrient requirement of 97%–98% healthy individuals) ranges from 30 to 410 mg for infants and children, depending on age, and from 310 to 420 mg for adults [92].

Magnesium is a cofactor for more than 600 enzymatic reactions and plays a role in both innate and adaptive immunity as well as blood pressure regulation and normal heart rhythm [15,93-96]. Magnesium also has antithrombotic and bronchodilation effects and is required for the activation of vitamin D [93,96-100]. Because of these effects in the body, magnesium supplementation may be beneficial for people with some respiratory disorders, such as asthma and pneumonia [101,102].

Healthy people do not routinely develop overt signs of magnesium deficiency, but many people do not consume recommended amounts of magnesium [94,103]. Low magnesium status is associated with decreased immune cell activity, increased oxidative stress, and increased inflammation, including increased levels of some inflammatory cytokines, such as interleukin-6 [93,97,104-107]. Low magnesium intakes or status are also associated with hypertension, impaired pulmonary function, cardiovascular disease, type 2 diabetes, and obesity [94,100,108]. These conditions are associated with poorer COVID-19 outcomes.

Efficacy

Data are insufficient to support a recommendation for or against the use of magnesium supplements to prevent or treat COVID-19. However, many researchers believe that ensuring adequate magnesium status is important in the management of COVID-19 because of magnesium’s effects on immunity, inflammation, and the cardiovascular system [93,96-98,100,101,104,105,109-112].

A few studies have found that people who have COVID-19 develop dysmagnesemia (abnormally low or high blood levels of magnesium) [113-115]. For example, in an analysis of serum magnesium levels of 300 patients (mean age 66.7 years) admitted to the hospital with COVID-19 in France, 48% had abnormally low magnesium levels (less than 0.75 mmol/L) and 9.6% had abnormally high magnesium levels (0.95 mmol/L or higher) [115]. In addition, an observational study in Iran among 459 patients with COVID-19 (mean age 61.8 years) found that those who died from the disease had lower magnesium levels than those who survived, although the mean magnesium levels for both groups were within the normal range [113]. However, hypomagnesemia is common in critically ill patients, regardless of their COVID-19 status [100]. Furthermore, renal failure, other health conditions, and use of certain medications, which might apply to many people with COVID-19, can also cause both hypomagnesemia and hypermagnesemia [116]. Finally, serum magnesium levels might not reflect total body magnesium stores, and hypoalbuminemia might cause spuriously low magnesium levels because about 25% of magnesium is bound to albumin [94,117]. Therefore, the presence of dysmagnesemia among patients with COVID-19 does not necessarily mean that magnesium intakes affect the risk of the disease or its severity. In addition, like other critical illnesses, COVID-19 might cause dysmagnesemia.

A few observational studies have examined the effects of magnesium supplementation in patients with COVID-19. In a retrospective study in Singapore among 43 hospitalized patients age 50 years or older with COVID-19, those who received daily supplementation with 150 mg magnesium, 1,000 international units (IU) (25 mcg) vitamin D3, and 500 mcg vitamin B12 for a median of 5 days, starting within the first day of hospitalization for most patients, were less likely to need oxygen therapy, intensive care support, or both than those who did not receive the supplementation [99].

Another small study in Serbia in five hospitalized patients with COVID-19 (mean age 39.6 years), difficulty breathing, and oxygen saturation at or below 95% found that taking a supplement providing 200 mg magnesium, 1,200 mg potassium, 50 mg zinc, and 1,000 mg citric acid every 4 hours for 48 hours increased oxygen saturation by a mean of 3.6 points [118]. However, with studies that use combination treatments, the potential contribution of one component is impossible to determine.

Clinicaltrials.gov lists a few trialsexternal link disclaimer that are examining the use of combinations of magnesium with other ingredients in patients with COVID-19. For example, one trialexternal link disclaimer in China is investigating whether a nutritional supplement containing 400 mg magnesium, vitamins and other minerals, probiotics, L-arginine, methionine, glutamine, and other ingredients twice daily for 14 days improves outcomes in 145 adults age 60 to 90 years with mild to moderate COVID-19. Another trialexternal link disclaimer in Mexico aims to determine whether 350 mg magnesium and 4,000 IU (100 mcg) vitamin D per day for four months improves signs and symptoms of long COVID in about 200 adults with this condition.

Safety

Magnesium in foods is considered safe at any intake. Supplemental magnesium from dietary supplements or medications that contain magnesium, such as some laxatives, is safe at intakes up to 65 to 350 mg/day for children, depending on age, and up to 350 mg/day for adults [92]. These upper limits, however, do not apply to individuals receiving magnesium treatment under the care of a physician. Intakes that are higher than the upper limits can cause diarrhea, nausea, and abdominal cramping. Magnesium toxicity, which usually develops after serum concentrations exceed 1.74–2.61 mmol/L, can cause hypotension, nausea, vomiting, facial flushing, urine retention, ileus, depression, and lethargy and patients can ultimately develop muscle weakness, difficulty breathing, extreme hypotension, irregular heartbeat, and cardiac arrest or even die.

Magnesium supplementation can interact with several medications. For example, it can decrease the absorption of bisphosphonates and form insoluble complexes with antibiotics. In addition, the use of loop diuretics, thiazide diuretics, or proton pump inhibitors can deplete magnesium levels [119-122].

More information on magnesium is available in the Office of Dietary Supplements (ODS) health professional fact sheet on magnesium.

Melatonin

Melatonin is a hormone produced by the pineal gland in the brain, mainly during the night, that helps regulate circadian rhythms [123,124]. Its levels decrease with aging [124]. Most melatonin supplementation studies have evaluated its ability to control sleep and wake cycles, promote sleep, and reduce jet lag [124]. Studies have also examined the use of melatonin supplements for reducing blood pressure [125].

Laboratory and animal studies suggest that melatonin enhances immune response by increasing the proliferation and maturation of natural killer cells, T and B lymphocytes, granulocytes, and monocytes [31,126,127]. Melatonin also appears to have anti-inflammatory and antioxidant effects [31,123,124,126-128]. However, whether these properties have a clinically significant effect on immunity in humans is not clear. Melatonin supplementation also appears to improve some markers of oxidative stress and cardio-metabolic risk in individuals with type 2 diabetes and coronary heart disease [129].

Efficacy

No evidence shows that melatonin helps prevent or treat COVID-19. However, some researchers recommend studying melatonin’s effects on COVID-19 because of its reported anti-inflammatory, antioxidant, and immune-enhancing properties [31,126-128,130].

One study found that among 26,779 people tested for COVID-19, those who reported using melatonin supplements were less likely to have the disease [131]. A small clinical trial in Mexico examined the effects of 50 mg melatonin every 12 hours for 5 days plus the drug pentoxifylline in 22 hospitalized adults (mean age 57.9 years) with pneumonia that resulted from COVID-19 [132]. Another group of 22 patients received pentoxifylline alone. Patients who received melatonin and pentoxifylline had a significantly lower lipid peroxidation index (a measure of oxidative stress) than at baseline, whereas those who received pentoxifylline alone did not. Both treatments significantly increased nitrite levels (suggesting higher oxygen levels) from baseline values and reduced levels of the inflammatory marker C-reactive protein. Neither treatment affected total antioxidant capacity or levels of the inflammatory markers interleukin-6 and procalcitonin.

Other clinical trial evidence suggests that melatonin might help attenuate cytokine levels in people with diabetes, multiple sclerosis, and other health conditions [127]. Therefore, some researchers believe that melatonin supplements might help modulate the cytokine storm that can develop in COVID-19 [127], but studies have not tested this hypothesis.

According to ClinicalTrials.govexternal link disclaimer, several other trials are underway in people with COVID-19, including a small trialexternal link disclaimer examining the effects of 10 mg melatonin supplementation three times daily for 14 days in about 30 adults age 18 years and older with COVID-19 who are not hospitalized [133]. Another trialexternal link disclaimer is investigating the effects of 10 mg melatonin plus 1,000 mg vitamin C daily on the symptoms and outcomes of about 150 adults age 50 years and older with COVID-19 who have not been hospitalized [134].

Safety

Typical doses of 1–10 mg/day melatonin appear to be safe for short-term use [31,135]. Reported side effects, which are usually minor, include dizziness, headache, nausea, upset stomach, rash, and sleepiness [124,135]. However, some reports have linked high blood levels of melatonin with delayed puberty and hypogonadism [124].

Studies have not evaluated melatonin supplementation during pregnancy and breastfeeding, but some research suggests that these supplements might inhibit ovarian function [136]. Therefore, some experts recommend that women who are pregnant or breastfeeding avoid taking melatonin [135].

Melatonin might interact with several medications. For example, melatonin might have anticoagulant effects, so it might increase the risk of bleeding if used with anticoagulants. It also might reduce the effects of both anticonvulsants and immunosuppressants [137-139].

N-acetylcysteine

N-acetylcysteine (NAC) is a derivative of the amino acid cysteine. It is an antioxidant and increases glutathione levels in the body [140,141]. NAC has mucolytic activity, so it helps reduce respiratory mucus levels [140,142]. Laboratory research suggests that NAC might affect immune system function and suppress viral replication [142]. NAC also decreases levels of interleukin-6 and has other anti-inflammatory effects [140,141].

Much of the research on NAC has used an inhaled, liquid form of this compound. This form—which is classified as a drug, not a dietary supplement—is approved by the U.S. Food and Drug Administration (FDA) as a mucolytic agent and for decreasing respiratory secretion viscosity [143]. Products containing NAC are also sold as dietary supplements [144].

Efficacy

Data are insufficient to support a recommendation for or against the use of NAC supplements to prevent or treat COVID-19. However, studies have evaluated the use of oral NAC to treat bronchopulmonary diseases, such as bronchitis and chronic obstructive pulmonary disease (COPD) with some promising results in reducing numbers of episodes and symptom severity [145,146].

The results from two studies suggest that NAC might benefit patients with COVID-19. In a retrospective study in Greece of 82 patients (mean age 61–64 years) hospitalized with moderate or severe COVID-19 pneumonia, 600 mg NAC twice daily for 14 days in addition to standard of care reduced the risk of progression to severe respiratory failure with the need for mechanical ventilation [147]. NAC also reduced 14- and 28-day mortality rates; at 14 days, 10 of 40 patients in the control group and 0 of 42 in the NAC group had died, and 12 of the patients in the control group and 2 in the NAC group had died at 28 days.

A small clinical trial in Mexico examined the effects of 600 mg NAC every 12 hours for 5 days plus the drug pentoxifylline in 22 hospitalized adults (mean age 57.9 years) with pneumonia that resulted from COVID-19 [132]. Another group of 22 patients received pentoxifylline alone. Patients who received NAC and pentoxifylline had a significantly lower lipid peroxidation index (a measure of oxidative stress) as well as lower levels of the inflammatory markers interleukin-6 and procalcitonin than at baseline, whereas those who received pentoxifylline alone did not. NAC plus pentoxifylline also significantly increased total antioxidant capacity, whereas pentoxifylline alone did not. Both treatments significantly reduced levels of the inflammatory marker C-reactive protein and increased plasma nitrite levels (suggesting higher oxygen levels).

A clinical trial in Brazil examined the effects of intravenous NAC (which is classified as a drug) in 135 hospitalized patients (median age 58–59 years) with confirmed or suspected COVID-19 [148]. Patients received either 21 g NAC, administered intravenously over 20 hours, or placebo, in addition to standard of care. NAC had no effect on the need for or duration of mechanical ventilation or admission to the intensive care unit (ICU), time in the ICU, or mortality.

Because of these findings; NAC’s potential antioxidant, anti-inflammatory, and antiviral effects; and its mucolytic activity, some researchers believe that using NAC as an adjuvant treatment might improve outcomes in patients with COVID-19 [140-142]. Several additional clinical trialsexternal link disclaimer are examining this possibility. For example, one trialexternal link disclaimer will evaluate the effects of 600, 1,200 or 1,800 mg NAC three times daily with or without the drug famotidine for 3 months in 42 adults who have COVID-19 and are not hospitalized [149]. Another trialexternal link disclaimer is examining whether NAC combined with glycine for 2 weeks improves outcomes in about 64 hospitalized adults age 55 to 85 years who have COVID-19 [150].

Safety

As an FDA-approved drug, the safety profile of NAC has been evaluated [143]. Reported side effects of oral NAC include nausea, vomiting, abdominal pain, diarrhea, indigestion, and epigastric discomfort [146]. No safety concerns have been reported for products labeled as dietary supplements that contain NAC.

NAC might have anticoagulant effects and might reduce blood pressure so it could have additive effects if taken with anticoagulants and antihypertensive medications [151]. The combination of NAC and nitroglycerine (a medication used to treat angina) can cause hypotension and severe headaches [152,153].

Omega-3 fatty acids

Omega-3 fatty acids (omega-3s) are polyunsaturated fatty acids that are present in certain foods, such as flaxseed and fatty fish, as well as dietary supplements, such as those containing fish oil. Several different omega-3s exist, including alpha linolenic acid (ALA), but most scientific research focuses on the long-chain omega-3s, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The main food sources of EPA and DHA are fatty fish and fish oil.

The Food and Nutrition Board (FNB) of the National Academies of Sciences, Engineering, and Medicine established an Adequate Intake (AI; intake assumed to ensure nutritional adequacy) for omega-3s that ranges from 0.5 to 1.6 g per day for infants and children, depending on age, and from 1.1 to 1.6 g per day for adults [154]. The FNB has not established intake recommendations for EPA and DHA specifically because they are not essential nutrients; only ALA, which our bodies cannot synthesize, is essential. Our bodies can then convert ALA into EPA and DHA.

Omega-3s play important roles as components of the phospholipids that form the structures of cell membranes [154]. Omega-3s also form eicosanoids; these signaling molecules affect the body’s cardiovascular, pulmonary, immune, and endocrine systems [154,155]. Omega-6 fatty acids, the other major class of polyunsaturated fatty acids, also form eicosanoids, and these eicosanoids are generally more potent mediators of inflammation, vasoconstriction, and platelet aggregation than those made from omega-3s. Thus, higher concentrations of omega-3s than of omega-6s tip the eicosanoid balance toward less inflammatory activity [156,157].

Higher intakes and blood levels of EPA and DHA are associated with lower levels of inflammatory cytokines [156,158]. Omega-3s might also affect immune function by upregulating the activity of macrophages, neutrophils, T cells, B cells, natural killer cells, and other immune cells.

A deficiency of omega-3s can cause rough, scaly skin and dermatitis [154]. However, researchers have not identified cut-off concentrations of DHA or EPA below which functional endpoints, such as for visual or neural function or for immune response, are impaired. Almost everyone in the United States obtains sufficient amounts of omega-3s to avoid a deficiency, but many people might benefit from higher intakes of EPA and DHA, particularly to maintain or improve cardiovascular health [159].

Efficacy

Whether higher intakes or blood levels of omega-3s reduce the risk or severity of COVID-19 is not known. However, self-reported use of omega-3 supplements (dose not reported) more than three times per week for at least 3 months among 372,720 U.K. residents age 16 to 90 years was associated with a 12% lower risk of SARS-CoV-2 infection after adjustment for potential confounders [160]. Findings were similar for 45,757 individuals in the United States and for 27,373 participants in Sweden.

Because of these findings and the potential anti-inflammatory and immune-stimulating effects of omega-3s, several researchers believe that omega-3s might benefit patients with COVID-19 [15,96,106,156,158,161-164]. An analysis of red blood cell levels of EPA plus DHA among 100 hospitalized patients with COVID-19 (mean age 72.5 years) did not find a difference in the risk of death among quartiles of EPA plus DHA levels [158]. In a clinical trial in Iran, 42 of 128 critically ill patients with COVID-19 (mean age 64 to 66 years) received a 1,000 mg omega-3 supplement containing 400 mg EPA and 200 mg DHA for 14 days [165]. Patients receiving the supplement had a significantly higher 1-month survival rate compared with those who were not supplemented. The omega-3 supplement also improved several measures of respiratory and renal function, including arterial pH, blood urea nitrogen, and creatinine levels, but it did not affect other measures including oxygen saturation or white blood cell count.

A few other clinical trialsexternal link disclaimer are examining whether omega-3 supplements help reduce the risk of COVID-19 or help lower levels of inflammation. For example, one trialexternal link disclaimer in about 100 healthy adults age 30 to 66 years in Jordan is investigating whether a wild salmon and fish oil complex providing 300 mg of omega-3s daily for 2 months affects levels of interleukin-1 beta, interleukin-6, and tumor necrosis factor; these cytokines are involved in the cytokine storm [166]. Another trialexternal link disclaimer in Norway is examining whether a daily cod liver oil supplement providing a total of 1,200 mg of long-chain omega-3s (mainly EPA and DHA) for 6 months reduces the risk of developing COVID-19 and reduces the severity of disease in about 80,000 healthy adults age 18 to 75 years [167].

Safety

The FNB did not establish a Tolerable Upper Intake Level (UL; maximum daily intake unlikely to cause adverse health effects) for omega-3s, although it noted that high doses of DHA and/or EPA (900 mg/day EPA plus 600 mg/day DHA or more for several weeks) might reduce immune function by suppressing inflammatory responses [154].

Doses of 2–15 g/day EPA and/or DHA might also increase bleeding time by reducing platelet aggregation [154]. However, according to the European Food Safety Authority (EFSA), long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day appears to be safe for adults [168]. EFSA noted that these doses have not been shown to cause bleeding problems or affect immune function, glucose homeostasis, or lipid peroxidation. Similarly, FDA has concluded that dietary supplements providing no more than 5 g/day EPA and DHA are safe when used as recommended [169].

Commonly reported side effects of omega-3 supplements—including unpleasant taste, bad breath, heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat—are usually mild [170,171]. Because of their antiplatelet effects at high doses, omega-3s might interact with anticoagulants [172]. However, according to the FDA-approved package inserts for omega-3 pharmaceutical preparations, studies with omega-3s have not found that these medications result in “clinically significant bleeding episodes” [173]. Omega-3s might also interact with other medications. For example, omega-3s might increase the risk of hypotension if taken with antihypertensive agents and might increase levels of cyclosporine (an immunosuppressant drug) [174-176].

More information on omega-3s is available in the ODS health professional fact sheet on omega-3s.

Probiotics

Probiotics are live microorganisms that confer a health benefit on the host when administered in adequate amounts [177]. They include certain bacteria (e.g., Lactobacillus acidophilus, Lactobacillus rhamnosus, and Bifidobacterium longum) and yeasts (e.g., Saccharomyces boulardii). Probiotics are naturally present in some fermented foods, added to some food products, and available as dietary supplements.

Probiotics are identified by their strain, which includes the genus, species, subspecies (if applicable), and an alphanumeric strain designation [178]. Their amounts are measured in colony-forming units (CFUs), which indicate the number of viable cells. Common amounts used are 1 x 109 (1 billion CFU; commonly designated as 109 CFU) and 1 x 1010 (10 billion CFU or 1010 CFU).

Probiotics act mainly in the gastrointestinal tract [18]. They might improve immune function in several ways, including enhancing gut barrier function, increasing immunoglobulin production, inhibiting viral replication, and enhancing the phagocytic activity of white blood cells. However, the mechanisms of their potential effects on immune function are unclear [18,179,180]. In addition, research findings for one probiotic strain cannot be extrapolated to others [18,181].

Efficacy

Several systematic reviews and meta-analyses published before the emergence of COVID-19 evaluated probiotic use to prevent or treat respiratory tract infections in children and adults. All of these studies found that probiotics have beneficial effects on some, but not all, outcomes [180,182-185]. Several studies have also suggested that probiotics improve outcomes in patients who have ventilator-associated pneumonia and other infections, although the evidence is of low quality and high heterogeneity [186,187]. In addition, self-reported use of probiotic supplements more than three times per week for at least 3 months among 372,720 U.K. residents age 16 to 90 years was associated with a 14% lower risk of SARS-CoV-2 infection after adjustment for potential confounders [160]. Findings were similar for 45,757 individuals in the United States and for 27,373 participants in Sweden.

Probiotics might also help reduce inflammation. A meta-analysis of 42 randomized clinical trials in 2,258 participants found that probiotic supplementation with lactobacillus, bifidobacteria, saccharomyces, or combinations of strains for 1 to 52 weeks significantly reduced serum levels of some proinflammatory cytokines, including C-reactive protein, tumor necrosis alpha, interleukin-2, and interleukin-6 [188]. However, probiotic administration had no effect on other proinflammatory cytokines, including interleukin-8 and interleukin-17.

Because of these findings, many researchers believe that probiotics could be useful adjuvant therapies to treat COVID-19 [164,189-196]. This possibility was examined in a clinical trial in Italy among 70 patients (median age 59 years) hospitalized with COVID-19 [197]. All patients received hydroxychloroquine, antibiotics, and tocilizumab (a monoclonal antibody), alone or in combination. In addition, 28 of the 70 patients also took a probiotic (Sivomixx) containing a mixture of Streptococcus, Lactobacillus, and Bifidobacterium strains three times daily for a total daily dose of 2,400 billion bacteria for 14 days. Signs and symptoms—including diarrhea, fever, asthenia (weakness), headaches, myalgia (muscle pain), and dyspnea (difficulty breathing)—were significantly lower within 7 days in patients taking the probiotic than in those who did not. Probiotic administration also reduced the risk of mortality, transfer to ICU, and respiratory failure.

Another clinical trial examined the effects of an enzyme and probiotic combination in 200 adults (mean age 41 years) with post-COVID fatigue and muscle weakness who had received a negative COVID-19 test result 3 weeks before, on average [198].The supplements used were capsules containing 500 mg of ImmunoSEB and 5 billion CFU of ProbioSEB CSC3. Participants took two capsules in the morning and two in the evening on an empty stomach, plus two capsules with lunch. The investigators measured fatigue using questions about such issues as tiredness, difficulty starting tasks, lack of energy or muscle strength, difficulty concentrating, and memory. After 14 days of treatment, fatigue resolved in 91% of individuals who took the enzyme and probiotic supplement and only 15% of individuals who took the placebo.

Several additional clinical trialsexternal link disclaimer are underway. For example, one trialexternal link disclaimer in Canada plans to investigate whether probiotic administration for up to 25 days reduces the duration and severity of symptoms of COVID-19 in about 84 adults age 18 years and older with moderate forms of the disease who are not hospitalized [199]. Another trialexternal link disclaimer is examining the effects of Lactobacillus rhamnosus GG supplementation for 28 days on the microbiome of 182 children and adults age 1 year and older with a household exposure to someone diagnosed with COVID-19 but who do not have any COVID-19 symptoms [200].

Safety

Probiotics, such as strains of Lactobacillus, Bifidobacterium, and Propionibacterium, have a long history of use in food and are often present in the normal gastrointestinal microbiota, indicating that probiotic supplements are safe for most people [179]. Side effects, which are usually minor, include gastrointestinal symptoms, such as gas [18,180]. However, potential safety concerns can include systemic infections, especially in individuals who are immunocompromised [179]. For example, in a few cases (mainly in individuals who were severely ill or immunocompromised), the use of probiotics was linked to bacteremia, fungemia (fungi in the blood), or infections that resulted in severe illness [201,202].

Probiotics are not known to interact with medications. However, antibiotic and antifungal medications might decrease the effectiveness of some probiotics [203,204].

More information on probiotics is available in the ODS health professional fact sheet on probiotics.

Quercetin

Quercetin is a flavonol (a polyphenolic compound) present in many fruits, vegetables, spices, and beverages, including citrus fruits, apples, onions, berries, broccoli, cilantro, dill, tea, and red wine [205-209]. Research suggests that quercetin might have antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects [206-212]. It might also inhibit platelet aggregation [206,212]. Quercetin has very low oral bioavailability, ranging from 3% to 17% [207], but combining it with sunflower lecithin increases its bioavailability by as much as 20 times [206,208].

Efficacy

Results have been mixed in a few clinical trials examining the effects of 500 and 1,000 mg/day quercetin (sometimes in combination with vitamin C or niacin) on the risk of upper respiratory tract infections and the severity of symptoms of these infections [213,214]. Because of its molecular structure and pharmacological properties, some researchers believe quercetin might inhibit the SARS-CoV-2 virus so they recommend studying its use to reduce the risk of COVID-19 [206,208,209,211,215] Quercetin might also reduce inflammation and organ damage, such as acute kidney injury, that occurs in some critically ill patients with COVID-19 [207,210,216]. Others recommend studying the combination of quercetin with vitamin C because these substances might have antioxidant synergy [212]. However, at this time, only a couple of preliminary clinical trials have examined the use of quercetin supplementation in patients with COVID-19.

In an open-label clinical trial in Pakistan, 152 adults age 18 to 80 with COVID-19 who had mild to moderate symptoms and were not hospitalized were divided into two groups. The first group received Quevir, a supplement containing 200 mg quercetin with sunflower lecithin (Quercetin Phytosome), twice daily plus standard of care (analgesics, fever-reducing medications, oral steroids, and antibiotics) or standard of care only for 30 days [217]. Individuals receiving quercetin supplements were significantly less likely to require hospitalization than those who did not receive quercetin supplements. Among patients who required hospitalization, stays were shorter if they received the quercetin supplements. Quercetin supplementation also reduced the need for oxygen therapy. A follow-up open-label study by the same researchers compared the effects of supplementation with Quevir (three times daily for a total dose of 600 mg/day quercetin for 7 days, followed by 400 mg/day for 7 more days) with the effects of standard of care in 42 adults with mild to moderate COVID-19 who were not hospitalized [218]. Of 21 individuals who received quercetin and standard of care, 16 had negative SARS-CoV-2 test results after 1 week of treatment, whereas only 2 of 21 patients in the standard-of-care group had negative test results. After 2 weeks of treatment, all patients who received quercetin and standard of care had negative SARS-CoV-2 test results, as did 19 of 21 patients in the standard-of-care group. A confounding factor in this study, however, was that patients in the standard-of-care group were significantly older (mean of 56.2 years) than those in the quercetin group (42.5 years).

Several additional clinical trialsexternal link disclaimer are underway. For example, one trialexternal link disclaimer in Turkey is examining whether 500 mg/day quercetin for 3 months reduces the risk of COVID-19 in healthy adults and whether 1,000 mg/day for 3 months improves outcomes in adults with COVID-19 [219]. Another trialexternal link disclaimer in Pakistan is comparing the effect of 400 mg/day quercetin (Quercetin Phytosome) for 30 days to that of standard of care on COVID-19 disease progression in 152 adults with COVID-19 who are not hospitalized [220].

Safety

According to FDA, up to 500 mg quercetin per serving is generally recognized as safe (GRAS) as an ingredient in foods and beverages, including grain products, pastas, processed fruits, fruit juices and soft candies [221]. Less is known about quercetin supplements, but no serious adverse effects have been reported in clinical trials that used up to 1,000 mg/day for up to 12 weeks [205,213,217,218,222]. Reported side effects from one clinical trial that administered 200 mg quercetin twice daily for 30 days included gastric pain and reflux, constipation, diarrhea, flatulence, and sleep disorders, but the rate of these effects was similar in the treatment and control groups [217].

Quercetin might affect drug-metabolizing enzymes, such as CYP3A4, which could increase the bioavailability of cyclosporine, pravastatin (used to treat high cholesterol), and fexofenadine (an antihistamine) [222]. In addition, quercetin might reduce blood pressure in people with hypertension [223], so it could potentiate the effects of antihypertensive medications.

Selenium

Selenium is an essential mineral contained in many foods, including Brazil nuts, seafood, meat, poultry, eggs, and dairy products as well as bread, cereals, and other grain products. The RDA for selenium ranges from 15 to 70 mcg for infants and children, depending on age, and from 55 to 70 mcg for adults [224].

Selenium helps support both the innate and adaptive immune systems through its role in T-cell maturation and function and in natural killer cell activity. It also reduces the risk of infections [15,106,225-230]. As an antioxidant, selenium might also help reduce the systemic inflammatory response that can lead to acute respiratory distress syndrome and organ failure [226,228,231].

Low selenium status in humans has been associated with lower natural killer cell activity, increased risk of some bacterial infections, and increased virulence of certain viruses [15,227,230-232]. In addition, some research suggests that 100 to 300 mcg/day selenium supplements improve immune function and that doses of 50 or 100 mcg/day enhance the immune response to poliovirus vaccine [227].

Selenium status varies by geographic region because of differences in the amounts of selenium in soil and in local foods consumed [224,233]. Selenium deficiency is very rare in the United States and Canada, but low selenium status is common in some areas of the world, such as parts of Europe and China [229,234].

Efficacy

Data are insufficient to support a recommendation for or against the use of selenium supplements to prevent or treat COVID-19. However, many researchers recommend studying selenium as an adjuvant therapy for COVID-19 because of its antiviral, anti-inflammatory, and immune-enhancing effects [106,225-227,229-231,234-238].

Before the emergence of COVID-19, a Cochrane Review of 16 clinical trials with a total of 2,084 critically ill patients (because of burns, head injury, brain hemorrhage, cerebrovascular accident, or elective major surgery) found that intravenous selenium supplementation (which is classified as a drug) for 5 to 28 days or until discharged (length of treatment not specified) reduced overall mortality rates by 18% but did not affect 28-day or 90-day mortality rates [228]. Intravenous selenium also had no effect on duration of ICU stay or hospital stay or on number of days on a ventilator. However, the authors note that these findings should be viewed with caution because the evidence was of very low quality.

Some research shows that patients hospitalized with COVID-19 have low selenium status at admission, and this low status might adversely affect the body’s immune response [236,237,239]. In addition, selenium deficiency might increase the risk of mortality from COVID-19 [230]. For example, in a small study in Germany, the mean serum selenium level of 33 patients with COVID-19 (50.8 mcg/L) was significantly lower than the mean value from a healthy cross-sectional study of 1,915 European residents (84.4 mcg/L) [237]. A value of 80 mcg/L is typically considered adequate. In addition, the 27 patients who survived COVID-19 had a significantly higher mean serum selenium level (53.3 mcg/L) than the six who did not (40.8 mcg/L) [237]. Similarly, a retrospective analysis in China of data from about 70,000 people with COVID-19 found significantly higher survival rates in those living in areas where average selenium status was higher than in those living in areas where average selenium status was lower, based on hair selenium levels in the various regions [234]. However, selenium status can be assessed in multiple ways and because 37% of selenium is bound to albumin in the blood [240], selenium measurements can be confounded if not adjusted for albumin levels in severe illness.

No clinical trials of selenium supplementation in patients with COVID-19 have been published, but several trialsexternal link disclaimer are underway. For example, one trialexternal link disclaimer in Spain is investigating whether daily micronutrient supplementation with 110 mcg selenium along with 10 other vitamins and minerals for 14 days in 300 adults with COVID-19 reduces the need for hospitalization due to the disease [241]. Another trialexternal link disclaimer is examining the effects of 2,000 mcg selenium (as a selenious acid infusion) on day 1 followed by 1,000 mcg on days 2–14 plus standard-of-care therapy in 100 hospitalized adults with moderate, severe, or critical COVID-19 [242].

Safety

Up to 45 to 400 mcg/day selenium from foods and dietary supplements is safe for infants and children, depending on age, and up to 400 mcg/day is safe for adults [224]. These upper limits, however, do not apply to individuals receiving selenium under the care of a physician. Higher intakes can cause garlic odor in the breath and a metallic taste in the mouth as well as hair and nail loss or brittleness. Other signs and symptoms of excess selenium intakes include nausea, diarrhea, skin rashes, mottled teeth, fatigue, irritability, and nervous system abnormalities.

Cisplatin, a chemotherapy agent used to treat ovarian, bladder, lung, and other cancers can reduce selenium levels in hair, plasma, and serum [243,244]. Some studies have examined whether selenium supplementation helps reduce the side effects of cisplatin and other chemotherapy agents, but the evidence is uncertain [244,245].

More information on selenium is available in the ODS health professional fact sheet on selenium.

Vitamin C

Vitamin C, also called ascorbic acid, is an essential nutrient found in many fruits and vegetables, including citrus fruits, tomatoes, potatoes, red and green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, and cantaloupe. The RDA ranges from 15 to 115 mg for infants and children, depending on age, and from 75 to 120 mg for nonsmoking adults; people who smoke need 35 mg more per day [224].

Vitamin C plays an important role in both innate and adaptive immunity, probably because of its antioxidant effects, antimicrobial and antiviral actions, and effects on immune system modulators [59,246-249]. Vitamin C helps maintain epithelial integrity, enhance the differentiation and proliferation of B cells and T cells, enhance phagocytosis, normalize cytokine production, and decrease histamine levels [247]. It might also inhibit viral replication [250].

Vitamin C deficiency impairs immune function and increases susceptibility to infections [247]. Some research suggests that supplemental vitamin C enhances immune function [251], but its effects might vary depending on an individual’s vitamin C status [252].

Vitamin C deficiency is uncommon in the United States, affecting only about 7% of individuals age 6 years and older [253]. People who smoke and those whose diets include a limited variety of foods (such as some older adults and people with alcohol or drug use disorders) are more likely than others to obtain insufficient amounts of vitamin C [248,251].

Efficacy

Currently, data are insufficient to support a recommendation either for or against the use of vitamin C supplements to prevent or treat COVID-19. However, many researchers recommend studying vitamin C as an adjuvant therapy for COVID-19, including its possible ability to reduce inflammation and vascular injury in these patients [106,128,164,246,249,254-257].

Interest in the use of vitamin C supplements to treat COVID-19 comes from research showing that taking 200 mg/day or more vitamin C supplements on a regular basis helps reduce the duration of the common cold and the severity of its symptoms [246,250]. Vitamin C supplements also appear to reduce the risk of developing a cold in people exposed to extreme physical stress—including marathon runners, skiers, and soldiers in subarctic areas [250]. In addition, vitamin C supplementation might benefit people with pneumonia who have low vitamin C levels [258] as well as people with viral infections, including Epstein-Barr and herpes zoster [251]. Vitamin C’s antioxidant action might also help reduce oxidative stress during infections [246,250]. People with low vitamin C status might benefit more from vitamin C supplementation than those who already obtain sufficient vitamin C [252].

A few observational studies have examined the effects of vitamin C supplementation on mortality rates in patients with COVID-19 and have had mixed findings [257]. For example, a retrospective chart review of 102 patients (median age 63 years) with COVID-19 who were receiving intensive care included 73 patients who received vitamin C plus zinc (doses not specified); the other patients did not receive these supplements [259]. Vitamin C and zinc supplementation did not affect mortality. Another retrospective chart review included 152 patients with COVID-19 (median age 68 years) who were on mechanical ventilation [260]. The 79 patients who received vitamin C supplements (doses not specified) had a significantly lower mortality rate than those who did not receive vitamin C supplements. In addition, self-reported use of vitamin C supplements (doses not reported) more than three times per week for at least 3 months among 372,720 U.K. residents age 16 to 90 years, 45,757 individuals in the United States, and 27,373 individuals in Sweden was not associated with higher or lower risk of SARS-CoV-2 infection [160].

A small clinical trial in Mexico examined the effects of 1,000 mg vitamin C every 12 hours for 5 days plus the drug pentoxifylline in 22 hospitalized adults (mean age 57.9 years) with pneumonia that resulted from COVID-19 [132]. Patients who received vitamin C and pentoxifylline had significantly lower levels of the inflammatory markers interleukin-6 and procalcitonin than at baseline, whereas those who received pentoxifylline alone did not. Vitamin C plus pentoxifylline also significantly increased total antioxidant capacity, but pentoxifylline alone did not. Both treatments significantly increased nitrite levels (suggesting higher oxygen levels) from baseline values and reduced levels of the inflammatory marker C-reactive protein, but neither treatment affected the lipid peroxidation index. The COVID A to Z trial compared the effects of daily supplementation with 8,000 mg ascorbic acid, 50 mg zinc (as zinc gluconate), or both for 10 days with standard of care in 214 adults (mean age 45.2 years) with COVID-19 who were not hospitalized [261]. None of the supplements shortened symptom duration.

Studies have also examined the effects of vitamin C administered intravenously. Intravenous administration of vitamin C can produce plasma concentrations that are much higher than those produced by oral doses [262]. FDA classifies intravenous forms of vitamin C as drugs; only oral forms can be classified as dietary supplements. According to some case reports from China, for example, high-dose intravenous vitamin C (10–20 g per day administered over 8 to 10 hours) increased the oxygenation index in 50 patients with moderate to severe COVID-19; all patients eventually recovered [263]. In a pilot trial in China, 56 patients with COVID-19 (mean age 66.7 years) in ICU received either intravenous vitamin C (12 g twice daily) or placebo for 7 days or until ICU discharge or death [264]. Vitamin C administration did not affect 28-day mortality rates. In another trial of 60 patients with severe COVID-19 infection (mean age 58 to 61 years) and receiving oral lopinavir/ritonavir and hydroxychloroquine, 30 patients were also given intravenous vitamin C (1.5 g four times daily) for 5 days [265]. Vitamin C administration did not affect mortality, length of ICU stay, or oxygen saturation at discharge.

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel notes that in patients who do not have COVID-19, intravenous vitamin C alone or in combination with other nutrients and medications improves some but not all outcomes in critically ill patients with sepsis, acute respiratory distress syndrome, or pneumonia [249]. However, the Panel concludes that data are insufficient to support a recommendation for or against the use of vitamin C to treat COVID-19 [249].

Several other clinical trialsexternal link disclaimer are examining whether vitamin C (administered intravenously or as a dietary supplement) in combination with other dietary supplement ingredients, medications, or both helps prevent or treat COVID-19. For example, one trialexternal link disclaimer in Italy is investigating intravenous administration of 10 g ascorbic acid in addition to conventional therapy in about 500 children and adults who are hospitalized with COVID-19 pneumonia [266]. Another trialexternal link disclaimer is evaluating whether daily supplementation with 1,000 mg ascorbic acid plus 10 mg melatonin for 14 days affects the symptoms and outcomes of COVID-19 in about 150 adults aged 50 years and older who are not hospitalized [134].

Safety

Vitamin C in foods and dietary supplements is safe at intakes up to 400 to 1,800 mg/day for children, depending on age, and up to 2,000 mg/day for adults [224]. These upper limits, however, do not apply to individuals receiving vitamin C treatment under the care of a physician. Higher intakes can cause diarrhea, nausea, and abdominal cramps. High vitamin C doses might also cause falsely high or low readings on some blood glucose meters that are used to monitor glucose levels in people with diabetes [267-269]. In people with hemochromatosis, high doses of vitamin C could exacerbate iron overload and damage body tissues [224,248]. The FNB recommends that these individuals be cautious about consuming vitamin C doses above the RDA [224].

Vitamin C supplementation might interact with some medications. For example, it might reduce the effectiveness of radiation therapy and chemotherapy by protecting tumor cells from the action of these agents [270].

More information on vitamin C is available in the ODS health professional fact sheet on vitamin C.

Vitamin D

Vitamin D, whose forms are vitamin D2 and vitamin D3, is an essential nutrient that is naturally present in only a few foods, such as fatty fish (including salmon and tuna) and fish liver oils, and in small amounts in beef liver, cheese, and egg yolks. Fortified foods, especially fortified milk, provide most of the vitamin D in American diets. The RDA for vitamin D ranges from 10 to 15 mcg (400 IU to 600 IU) for children, depending on age, and from 15 to 20 mcg (600 to 800 IU) for adults [271]. The body can also synthesize vitamin D from sun exposure.

Vitamin D obtained from sun exposure, foods, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. The first hydroxylation, which occurs in the liver, converts vitamin D to 25-hydroxyvitamin D [25(OH)D]. The second hydroxylation occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D]. Serum concentration of 25(OH)D is currently the main indicator of vitamin D status [271]. Although researchers have not definitively identified serum concentrations of 25(OH)D associated with deficiency and adequacy, the FNB advises that levels below 30 nmol/L (12 ng/mL) are associated with vitamin D deficiency, and levels of 50 nmol/L (20 ng/mL) or more are considered adequate for bone and overall health in most people [271]. However, 25(OH)D levels defined as deficient or adequate vary from study to study.

In addition to its well-known effects on calcium absorption and bone health, vitamin D plays a role in immunity [272]. Vitamin D appears to lower viral replication rates, suppress inflammation, and increase levels of T-regulatory cells and their activity [128,255,273-277]. In addition, immune cells (e.g., B lymphocytes and T lymphocytes) express the vitamin D receptor, and some immune cells (e.g., macrophages and dendritic cells) can convert 25(OH)D into the active 1,25(OH)2D. This ability suggests that vitamin D might modulate both innate and adaptive immune responses [255,274,276,277].

Vitamin D deficiency affects the body’s susceptibility to infection and has been associated with influenza, hepatitis C, human immunodeficiency virus (HIV) and other viral diseases [278,279]. Surveys indicate that most people in the United States consume less than recommended amounts of vitamin D [280]. Nevertheless, according to a 2011–2014 analysis of serum 25(OH)D concentrations, most people in the United States age 1 year and older had adequate vitamin D status [281]. Sun exposure, which increases serum 25(OH)D levels, is one of the reasons serum 25(OH)D levels are usually higher than would be predicted on the basis of dietary vitamin D intakes alone [271].

Efficacy

Currently, data are insufficient to support a recommendation for or against the use of vitamin D supplementation to prevent or treat COVID-19. However, some evidence suggests that vitamin D supplementation helps prevent respiratory tract infections, particularly in people with 25(OH)D levels less than 25 nmol/L (10 ng/mL) [282]. Scientists are therefore actively studying whether vitamin D might also be helpful for preventing or treating COVID-19.

Some studies link lower vitamin D status with a higher incidence of COVID-19 and more severe disease [239,283-291] but others do not [292-296]. For example, a comparison of serum 25(OH)D levels in 335 patients with COVID-19 in China with levels in 560 age- and sex-matched healthy participants found significantly lower 25(OH)D concentrations (median of 26.5 nmol/L [10.6 ng/mL]) in patients with COVID-19 than healthy participants (median of 32.5 nmol/L [13 ng/mL]) [284]. In addition, the prevalence of vitamin D deficiency [defined as serum 25(OH)D less than 30 nmol/L (12 ng/mL)] was significantly higher in patients with COVID-19 than healthy participants, and vitamin D deficiency was associated with more severe COVID-19. Another study from Spain also found lower 25(OH)D levels as well as higher rates of vitamin D deficiency in 216 hospitalized patients with COVID-19 than in 197 healthy individuals, although it did not find any relationship between disease severity and vitamin D levels or deficiency status [285]. Similarly, a study of 120 patients (mean age 62.3 years) hospitalized in Algeria with severe COVID-19 found a linear inverse association between vitamin D status and mortality rates; patients with adequate 25(OH)D levels (higher than 78 nmol/L [30 ng/mL]) had a 13.3% mortality rate, whereas those with severe deficiency [25(OH)D lower than 26 nmol/L (10 ng/mL)] had a 46.9% mortality rate [286]. A systematic review and meta-analysis of 31 observational studies (including some of those described above) did not find significant associations between serum 25(OH)D levels below 50 nmol/L (20 ng/ml) and incidence of COVID-19, risk of mortality, ICU admission, or need for ventilation among COVID-19 patients [297]. However, mean 25(OH)D levels were significantly lower in COVID-19 patients than healthy individuals, based on the results from five studies that examined this outcome.

Other studies found that people with vitamin D deficiency were more likely to have COVID-19 and a poorer prognosis than those who were vitamin D sufficient [239,298-302] and that people who regularly took vitamin D supplements (amounts not specified) were less likely to develop COVID-19 than those who did not [303]. A retrospective study of 4,638 individuals (mean age 52.8 years) who were tested for COVID-19 examined associations between vitamin D levels (measured during the previous year but not within 14 days of COVID-19 testing) and COVID-19 test results [304]. Black individuals with 25(OH)D levels below 100 nmol/L (40 ng/mL) had higher risk of COVID-19 than those with higher levels, but the results showed no associations between vitamin D levels and COVID-19 risk among White individuals. Another study in 235 patients (mean age 58.7 years) hospitalized with COVID-19 found that those with vitamin D sufficiency had less severe disease [305]. In this study, people with vitamin D sufficiency [defined as 25(OH)D levels higher than 75 nmol/L (30 ng/mL)] also had lower levels of C-reactive protein and higher lymphocyte percentages than those with vitamin D insufficiency. These changes might have reduced the risk of the cytokine storm [275,305].

Some of these investigators did not consider confounders, such as obesity and race. Many people with obesity, for example, have lower vitamin D status and more severe COVID-19 than individuals with a healthy weight [271,306]. An analysis of 348,598 U.K. Biobank participants (median age 49 years), of whom 449 had COVID-19, did not find a link between 25(OH)D concentrations and risk of SARS-CoV-2 infection after adjusting for confounders including ethnicity, body mass index (BMI) category, age at assessment, and sex [296].

A systematic review and meta-analysis of 39 studies from around the world (primarily in adults) that examined associations between 25(OH)D levels and SARS-CoV-2 infection rates and COVID-19 severity found that participants with vitamin D deficiency [defined as 25(OH)D levels <25 nmol/L to ≤75 nmol/L (<10 ng/mL to ≤30 ng/mL) depending on the study] had a higher risk of SARS-CoV-2 infection and more severe COVID-19 disease than those with adequate vitamin D levels [307]. However, associations between vitamin D deficiency and ICU admission, pulmonary complications, hospitalization, inflammation, and mortality were inconsistent. Other systematic reviews and meta-analyses have found that patients with COVID-19 who have vitamin D deficiency or lower vitamin D status or who do not take vitamin D supplements have more severe disease and higher mortality rates than others [308-310]. However, these reviews found inconsistent associations between vitamin D status and risk of SARS-CoV-2 infection. A study in Ireland that examined 25(OH)D levels in 149 patients (mean age 48 years) at a median of 79 days after the onset of COVID-19 illness found no relationship between 25(OH)D levels and fatigue or exercise tolerance, both of which are common symptoms of long COVID [311].

Although many observational studies suggest a link between low vitamin D status and higher incidence of COVID-19 and more severe disease, vitamin D status measurements after disease onset might not reflect preinfection vitamin D status. In a small study in nine healthy men (median age 22 years), administration of a lipopolysaccharide to induce systemic inflammation significantly reduced 25(OH)D levels within hours [312]. Because COVID-19 induces an inflammatory response, some of the associations between low 25(OH)D concentrations and COVID-19 might be explained by reverse causality [i.e., the disease might have caused the low 25(OH)D concentrations].

Some evidence suggests that vitamin D supplementation might reduce COVID-19 severity. Self-reported use of vitamin D supplements (dose not reported) more than three times per week for at least 3 months among 372,720 U.K. residents age 16 to 90 years was associated with a 9% lower risk of SARS-CoV-2 infection after adjustment for potential confounders [160]. Findings were similar for 45,757 individuals in the United States and 27,373 individuals in Sweden.

An analysis of data on 77 hospitalized adults in France (where vitamin D supplementation is routinely recommended for those over 65 years of age) with COVID-19 (mean age 88 years) found that those who had received bolus oral doses of 1,250 mcg (50,000 IU) vitamin D3 per month or 2,000 mcg (80,000 IU) or 2,500 mcg (100,000 IU) vitamin D3 every 2 or 3 months throughout the preceding year had less severe disease and lower mortality rates than those who did not receive vitamin D supplementation [313]. In addition, a nonrandomized retrospective study in Spain of 537 patients hospitalized with COVID-19 (median age 70 years) found that the 79 patients who received calcifediol (25-OHD3, 532 mcg on the first day and 266 mcg on days 3, 7, 14, 21, and 28) combined with medications had a lower mortality rate during the first 30 days of hospitalization than those who received medications without calcifediol [314].

An observational study in the United Kingdom found that of 444 hospitalized patients (median age 74 years) with COVID-19, those who received various vitamin D3 regimens with doses of 500 to 1,250 mcg (20,000 to 50,000 IU) daily to biweekly for 7 days to 7 weeks had a lower risk of death from the disease [315]. This finding was replicated in another cohort of 542 hospitalized patients, some of whom received similar doses of vitamin D3 supplements [315]. Similarly, an observational study in Singapore found that the 17 of 43 hospitalized patients aged 50 years or older with COVID-19 who received 25 mcg (1,000 IU) vitamin D3, 150 mg magnesium, and 500 mcg vitamin B12 daily for a median of 5 days (initiated within the first day of hospitalization for most patients) were less likely to need oxygen therapy, intensive care support, or both than those who did not receive the supplementation [99].

Because of these findings, many researchers recommend additional research on whether higher vitamin D intakes or vitamin D supplementation can reduce the risk and severity of COVID-19 [96,97,106,128,164,239,255,273,275,276,284,298,299,305,316-322].

In an open letter, more than 200 scientists and doctors recommended that adults increase vitamin D intakes from all sources to achieve serum 25(OH)D levels above 75 nmol/L (30 ng/mL) to prevent COVID-19 or reduce its symptoms [323]. They also recommended that adults whose 25(OH)D levels are not tested achieve a daily vitamin D intake of 50 to 100 mcg daily (2,000–4,000 IU); individuals at increased risk of vitamin D deficiency (e.g., those who have obesity, have dark skin, or live in care facilities) might need even larger amounts. These scientists and doctors also recommended that hospitals measure the serum 25(OH)D levels of all patients hospitalized for COVID-19 and that patients with levels below 75 nmol/L (30 ng/mL) receive vitamin D supplementation.

This open letter is not an official guidance document, however. The NIH COVID-19 Treatment Guidelines Panel states that data are currently insufficient to support a recommendation for or against the use of vitamin D to prevent or treat COVID-19 [277]. Guidelines on vitamin D and COVID-19 from the National Institute for Health and Care Excellence (NICE) in the United Kingdom state that individuals older than 4 years should consider taking 10 mcg (400 IU) of vitamin D daily between October and early March to maintain bone and muscle health [324]. However, the United Kingdom does not fortify milk with vitamin D [325]. In addition, NICE does not recommend that people take vitamin D supplements solely to prevent or treat COVID-19, except as part of a clinical trial [324].

A clinical trial in 240 hospitalized patients (mean age 56.2 years) with moderate to severe COVID-19 compared the effects of a single oral dose of 5,000 mcg (200,000 IU) vitamin D3 administered about 10 days after symptom onset with placebo [326]. The mean baseline 25(OH)D level among participants was 52.3 nmol/L (20.9 ng/mL). Vitamin D treatment did not significantly reduce the length of hospitalization or risk of mortality while hospitalized, ICU admission, or need for mechanical ventilation, even among the 115 patients with vitamin D deficiency at baseline [defined as 25(OH)D below 50 nmol/L (20 ng/mL)]. Another clinical trial in Saudi Arabia compared the effects of 125 mcg (5,000 IU) vitamin D3 daily for 14 days with the effects of 25 mcg (1,000 IU) vitamin D3 in 69 adults (mean age 49.8 years) who were hospitalized with mild to moderate COVID-19 [327]. Patients receiving 125 mcg vitamin D had shorter duration of coughing (mean of 6.2 days vs. 9.1 days) and loss of taste (mean of 11.4 days vs. 16.9 days) than those receiving 25 mcg, but the duration of other symptoms—including fever, fatigue, headache, sore throat, body aches, and chills—did not differ between groups.

Many additional clinical trialsexternal link disclaimer are examining whether vitamin D supplementation, alone or in combination with other treatments, helps prevent COVID-19 or reduce its severity. For example, the CORONAVIT trialexternal link disclaimer is comparing the impact of 20 mcg (800 IU) or 80 mcg (3,200 IU) daily vitamin D3 supplementation with U.K. standard of care (10 mcg vitamin D3 [400 IU]) for 6 months on risk and severity of COVID-19 in 6,200 healthy U.K. residents age 16 years and older [328]. Another trialexternal link disclaimer is examining whether vitamin D3 supplementation for 28 days (240 mcg [9,600 IU] on days 1 and 2, followed by 80 mcg [3,200 IU] on days 3 through 28) in about 2,700 adults age 30 years and older who were recently diagnosed with COVID-19 helps reduce the severity of disease and risk of transmission to household members [329].

Safety

Daily intakes of up to 25–100 mcg (1,000 IU–4,000 IU) vitamin D in foods and dietary supplements are safe for infants and children, depending on age, and up to 100 mcg (4,000 IU) are safe for adults [271]. These upper limits, however, do not apply to individuals receiving vitamin D treatment under the care of a physician. Higher intakes (usually from supplements) can lead to nausea, vomiting, muscle weakness, confusion, pain, loss of appetite, dehydration, excessive urination and thirst, and kidney stones. In extreme cases, vitamin D toxicity causes renal failure, calcification of soft tissues throughout the body (including in coronary vessels and heart valves), cardiac arrhythmias, and even death [330-332].

Several types of medications might interact with vitamin D. For example, orlistat, statins, and steroids can reduce vitamin D levels [333,334]. In addition, taking vitamin D supplements with thiazide diuretics might lead to hypercalcemia [333].

More information on vitamin D is available in the ODS health professional fact sheet on vitamin D.

Vitamin E

Vitamin E, also called alpha-tocopherol, is an essential nutrient that is present in several foods, including nuts, seeds, vegetable oils, and green leafy vegetables. The RDA for vitamin E is 4 to 15 mg for infants and children, depending on age, and 15 to 19 mg for adults [224].

Vitamin E is an antioxidant that plays an important role in immune function by helping to maintain cell membrane integrity and by enhancing antibody production, lymphocyte proliferation, and natural killer cell activity [106,227,272,335,336]. Vitamin E has also been shown to limit inflammation by inhibiting the production of proinflammatory cytokines [337]. Vitamin E deficiency impairs both humoral and cell-mediated immunity and increases susceptibility to infections [227,336,338]. Some studies suggest that high-dose vitamin E supplements (60 to 800 mg/day) for 1 to 8 months enhance lymphocyte proliferation, interleukin-2 production, and natural killer cell activity in adults age 60 or older [339-341].

Frank vitamin E deficiency is rare, except in individuals with intestinal malabsorption disorders [224,272]. For this reason, research on the ability of vitamin E to improve immune function tends to use supplemental vitamin E rather than simply ensuring that study participants achieve adequate vitamin E status [336].

Efficacy

The effects of vitamin E supplementation on infectious diseases, such as respiratory tract infections, in studies are mixed [338,342]. In one clinical trial, 90 mg (200 IU) vitamin E supplements (as DL-alpha-tocopherol) daily for 1 year reduced the risk of upper respiratory tract infections, particularly the common cold, by 16% in 617 adults age 65 or older but not lower respiratory tract infections [343]. Supplementation with 50 mg/day vitamin E (as DL-alpha tocopheryl acetate) for 5–8 years also reduced the risk of pneumonia by 69% in 2,216 men age 50–69 years who smoked 5–19 cigarettes per day and exercised, but it did not affect the risk of pneumonia in another 5,253 men who smoked more than 19 cigarettes per day or did not exercise [344]. In another clinical trial in 652 adults age 60 years or older, 200 mg vitamin E supplements (as alpha-tocopheryl acetate) for about 14 months did not affect the incidence of acute respiratory tract infections and actually increased illness severity [345]. For example, rates of fever were 37% in individuals receiving vitamin E and 25% in those receiving placebo; illness duration was also significantly longer, at 19 days, for those receiving vitamin E than for the others, whose average illness duration was 14 days.

Data are insufficient to support a recommendation for or against the use of vitamin E supplements to prevent or treat COVID-19. However, because of its effects on immune function, many researchers recommend studying vitamin E to see if it reduces the risk of COVID-19 or reduces symptoms of the disease [106,227,235,238,272,336-338,346].

A small clinical trial in Mexico examined the effects of 800 mg vitamin E (as alpha-tocopheryl acetate) every 12 hours for 5 days plus the drug pentoxifylline in 22 hospitalized adults (mean age 57.9 years) with pneumonia that resulted from COVID-19 [132]. Another group of 22 patients received pentoxifylline alone. Patients who received vitamin E and pentoxifylline had significantly lower levels of the inflammatory markers interleukin-6 and procalcitonin than at baseline, whereas those who received pentoxifylline alone did not. Vitamin E plus pentoxifylline also significantly decreased the lipid peroxidation index (a measure of oxidative stress), but pentoxifylline alone did not. Both treatments significantly increased nitrite levels (suggesting higher oxygen levels) and reduced levels of the inflammatory marker C-reactive protein, but neither treatment affected total antioxidant capacity.

Clinicaltrials.govexternal link disclaimer does not list any other trials investigating vitamin E alone in patients with COVID-19, but studies are using vitamin E in combination with other ingredients. For example, a clinical trialexternal link disclaimer in Spain is investigating whether a micronutrient supplement containing 45 mg vitamin E (as alpha-tocopherol) and 10 other vitamins and minerals for 14 days reduces the need for hospitalization in 300 outpatient adults with COVID-19 [241]. Another trialexternal link disclaimer in Saudi Arabia is examining whether taking a dietary supplement containing 90 mg vitamin E (form not specified) plus 1,500 mcg vitamin A (as beta-carotene), 250 mg vitamin C, 15 mcg selenium, and 7.5 mg zinc for 14 days affects the progression of disease and the risk of cytokine storm in 40 adults with COVID-19 [347].

Safety

All intake levels of vitamin E in foods are considered safe. Up to 200 mg to 800 mg/day supplemental vitamin E is safe for children, depending on age, and up to 1,000 mg/day is safe for adults [224]. These upper limits, however, do not apply to individuals receiving vitamin E under the care of a physician. Higher vitamin E intakes can increase the risk of bleeding because of the vitamin’s anticoagulant effect and can cause hemorrhagic stroke.

Vitamin E supplementation might interact with certain medications, including anticoagulant and antiplatelet medications. It might also reduce the effectiveness of radiation therapy and chemotherapy by protecting tumor cells from the action of these agents [270,348,349].

More information on vitamin E is available in the ODS health professional fact sheet on vitamin E.

Zinc

A wide variety of foods contain zinc, an essential nutrient. These foods include oysters, crab, lobster, beef, pork, poultry, beans, nuts, whole grains, and dairy products. The RDA for zinc is 2–13 mg for infants and children, depending on age, and 8–12 mg for adults [350].

Zinc is involved in numerous aspects of cellular metabolism. Zinc is necessary for the catalytic activity of approximately 100 enzymes, and it plays a role in many body processes, including both the innate and adaptive immune systems [15,350-353]. Zinc also has antiviral and anti-inflammatory properties, and it helps maintain the integrity of tissue barriers, such as the respiratory epithelia [128,354,355]. In addition, zinc is required for sense of taste and smell.

Zinc deficiency adversely affects immune function by impairing the formation, activation, and maturation of lymphocytes. In addition, zinc deficiency decreases ratios of helper and suppressor T cells, production of interleukin-2, and activity of natural killer cells and cytotoxic T cells [15,231,351,353,356]. Furthermore, zinc deficiency is associated with elevated levels of proinflammatory mediators [354]. These effects on immune response probably increase susceptibility to infections [357] and inflammatory diseases, especially those affecting the lungs [354].

Studies have found associations between low zinc status and increased risk of viral infections [272], and people with zinc deficiency have a higher risk of diarrhea and respiratory diseases [15]. Poor zinc status is also common among individuals with HIV and hepatitis C and is a risk factor for pneumonia in older adults [231,355,358,359].

Although zinc deficiency is not common in the United States, 15% of the U.S. population might obtain marginal amounts of zinc [360]. Older adults are among the groups most likely to have low intakes.

Efficacy

Currently, data are insufficient to support recommendations for or against the use of zinc to prevent or treat COVID-19. However, because of zinc’s role in the immune system and in maintaining epithelial integrity, its antiviral activities, and its anti-inflammatory effects, some researchers believe that adequate zinc intakes might reduce the risk of COVID-19 and its severity [96,106,128,140,164,231,255,354,361-363]. Evidence that zinc lozenges might help shorten the duration of the common cold [364] has also spurred interest in zinc supplementation to help treat COVID-19. In addition, some researchers believe that zinc supplements might help reduce the severity of some of the symptoms of COVID-19, including diarrhea and a loss of taste and smell [365-367].

An observational study of 249 patients (median age 65 years) with COVID-19 admitted to a hospital in Spain found that patients with serum zinc levels lower than 50 mcg/dL had more severe disease at admission, took longer to recover (median of 25 vs. 8 days), and had higher mortality rates (21% vs. 5%) than those with higher zinc levels [368]. A similar study in India found that 47 hospitalized patients with COVID-19 (median age 34 years) had lower median serum zinc levels at admission (74.5 mcg/dL) than 45 randomly selected healthy individuals who were not hospitalized and were used as a control group (median age 32 years; 105.8 mcg/dL), although both of these median values would be considered normal [369]. In addition, patients with COVID-19 who had zinc levels below 80 mcg/dL had higher rates of complications than those with higher levels. Mean serum zinc concentrations were also lower (71.7 mcg/dL) in 35 hospitalized patients (median age 77 years) with COVID-19 in Germany, especially in the six patients who did not survive the disease, than a group of randomly chosen healthy individuals who were used as control group (97.6 mcg/dL) [370]. However, hypozincemia is part of the acute-phase response during infection, and zinc concentrations can also decline substantially as a result of acute physiological stress [371].

In another study, self-reported use of zinc supplements (dose not reported) more than three times per week for at least 3 months among 372,720 U.K. residents age 16 to 90 years as well as 45,757 individuals in the United States and 27,373 individuals in Sweden was not associated with higher or lower risk of SARS-CoV-2 infection [160].

In a case report from the United States, four patients age 26–63 years with COVID-19 were treated with high-dose zinc citrate, zinc gluconate, or zinc acetate lozenges every 2 to 4 hours for a total dose of 115 to 184 mg of zinc per day for 10 to 14 days [372]. The symptoms—including fever, cough, headache, shortness of breath, body aches, and fatigue—of all four patients began to decline within 24 hours of starting the zinc treatment, and all ultimately recovered. However, case studies such as these that do not have a placebo control arm cannot show whether the treatment was responsible for the outcomes.

A retrospective study included 932 patients (average age of 62–63 years) hospitalized with COVID-19 between March and April 2020 [373]. All patients were treated with hydroxychloroquine and azithromycin, and 411 also received 50 mg zinc (as zinc sulfate) twice daily for 5 days; the other 521 patients did not receive the zinc supplements. Zinc supplementation did not affect the length of time the patients remained in the hospital, on a ventilator, or in the ICU. However, among patients who did not require intensive care, those receiving zinc had a lower rate of mortality or transfer to a hospice and a higher likelihood of being discharged to their homes. Another retrospective study compared mortality rates among 242 patients hospitalized with COVID-19; 196 patients (median age 65 years) received supplementation with 100 mg/day zinc (as zinc sulfate), and 46 patients (median age 71 years) received no supplements [374]. Zinc supplementation did not affect mortality rates.

In a clinical trial in Egypt, 191 patients (mean age 43 years) with COVID-19 received either 50 mg zinc (as zinc sulfate) twice daily plus hydroxychloroquine or hydroxychloroquine only for 5 days [375]. The numbers of patients who recovered within 28 days, needed mechanical ventilation, or died was not significantly different between groups.

The COVID A to Z trial compared the effects of daily supplementation with 50 mg zinc (as zinc gluconate), 8,000 mg ascorbic acid, or both for 10 days with standard of care in 214 adults (mean age 45.2 years) who had COVID-19 and were not hospitalized [261]. Zinc, ascorbic acid, and the combination did not shorten the duration of symptoms.

According to NIH treatment guidelines, data are insufficient to recommend for or against the use of zinc supplements to treat COVID-19 [376]. In addition, the guidelines recommend against doses of zinc supplements above the RDA to prevent COVID-19, except in a clinical trial.

Several other clinical trialsexternal link disclaimer of zinc supplementation, mostly in combination with other dietary supplement ingredients and/or medications, to help prevent or treat COVID-19 are underway. For example, one trialexternal link disclaimer is examining the effects of 50 mg/day zinc (as zinc sulfate) in adults age 60 years or older or age 30 to 59 years with an underlying health condition with COVID-19 who are not hospitalized but have a high risk of complications due to their age or underlying health conditions [377]. Another trialexternal link disclaimer is investigating whether supplementation with zinc, vitamin C, vitamin D (doses not specified), and hydroxychloroquine for 24 weeks helps prevent COVID-19 in about 600 medical workers aged 18 years and older [378].

Safety

Intakes up to 4–34 mg/day zinc in foods and dietary supplements for infants and children, depending on age, and up to 40 mg/day for adults are safe [350]. These upper limits, however, do not apply to individuals receiving zinc treatment under the care of a physician. Higher intakes can cause nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches [59,350]. Chronic consumption of 150–450 mg/day can cause low copper status, reduced immune function, and reduced levels of high-density lipoproteins [379]. In clinical trials among children, zinc supplementation to treat diarrhea increased the risk of vomiting more than placebo [380,381].

Zinc supplementation might interact with several types of medications. For example, zinc can reduce the absorption of some types of antibiotics as well as penicillamine, a drug used to treat rheumatoid arthritis [382,383]. In addition, some medications, such as thiazide diuretics and certain antibiotics, can reduce zinc absorption [384,385].

More information on zinc is available in the ODS health professional fact sheet on zinc.

References

  1. Johns Hopkins University & Medicine. Coronavirus Resource Center.external link disclaimer 2021.
  2. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med 2020;383:2451-60. [PubMed abstract]
  3. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020;383:2255-73. [PubMed abstract]
  4. Brightling CE, Evans RA. Long COVID: which symptoms can be attributed to SARS-CoV-2 infection? Lancet 2022;400:411-3. [PubMed abstract]
  5. Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, et al. Characterizing Long COVID in an International Cohort: 7 Months of symptoms and their impact. medRxiv 2021:2020.12.24.20248802.
  6. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet2021;397:220-32. [PubMed abstract]
  7. Greenhalgh T, Knight M, A'Court C, Buxton M, Husain L. Management of post-acute covid-19 in primary care. BMJ 2020;370:m3026. [PubMed abstract]
  8. Rubin R. As their numbers grow, COVID-19 "long haulers" stump experts. JAMA 2020. [PubMed abstract]
  9. U.S. Food and Drug Administration. Questions and Answers on Dietary Supplements.external link disclaimer 2019
  10. Günalan E, Cebioğlu İ K, Çonak Ö. The popularity of the biologically-based therapies during coronavirus pandemic among the Google users in the USA, UK, Germany, Italy and France. Complement Ther Med 2021;58:102682. [PubMed abstract]
  11. Hamulka J, Jeruszka-Bielak M, Górnicka M, Drywień ME, Zielinska-Pukos MA. Dietary supplements during COVID-19 outbreak. Results of Google Trends analysis supported by PLifeCOVID-19 online studies. Nutrients 2020;13. [PubMed abstract]
  12. New Hope Network. Dietary supplements 2020: A global perspective.external link disclaimer 2020.
  13. New Hope Network. Market overview 2020: Supplement sales shift with changing trends and refocused needs.external link disclaimer 2020.
  14. Parkin J, Cohen B. An overview of the immune system. Lancet 2001;357:1777-89. [PubMed abstract]
  15. Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients 2020;12. [PubMed abstract]
  16. Brendler T, Al-Harrasi A, Bauer R, Gafner S, Hardy ML, Heinrich M, et al. Botanical drugs and supplements affecting the immune response in the time of COVID-19: Implications for research and clinical practice. Phytother Res: PTR 2020. [PubMed abstract]
  17. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2018;9:7204-18. [PubMed abstract]
  18. Lehtoranta L, Latvala S, Lehtinen MJ. Role of probiotics in stimulating the immune system in viral respiratory tract infections: a narrative review. Nutrients 2020;12. [PubMed abstract]
  19. Gao YM, Xu G, Wang B, Liu BC. Cytokine storm syndrome in coronavirus disease 2019: A narrative review. J Intern Med 2020. [PubMed abstract]
  20. Venturi S, Venturi M. Iodine, thymus, and immunity. Nutrition 2009;25:977-9. [PubMed abstract]
  21. Tenforde MW, Olson SM, Self WH, Talbot HK, Lindsell CJ, Steingrub JS, et al. Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged ≥65 Years — United States, January–March 2021. MMWR Morb Mortal Wkly Rep 2021;70:674-9. [PubMed abstract]
  22. Centers for Disease Control and Prevention. COVID-19 Vaccines Workexternal link disclaimer. 2021.
  23. Gurley BJ, Fifer EK, Gardner Z. Pharmacokinetic herb-drug interactions (part 2): drug interactions involving popular botanical dietary supplements and their clinical relevance. Planta Med 2012;78:1490-514. [PubMed abstract]
  24. Weber WJ, Hopp DC. National Center for Complementary and Integrative Health perspectives on clinical research involving natural products. Drug Metab Dispos 2020;48:963-5. [PubMed abstract]
  25. Cáceres DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK. Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind-placebo study. PhytomedicinePhytomedicine 1999;6:217-23. [PubMed abstract]
  26. Akbar S. Andrographis paniculata: a review of pharmacological activities and clinical effects. Altern Med Rev 2011;16:66-77. [PubMed abstract]
  27. Hu XY, Wu RH, Logue M, Blondel C, Lai LYW, Stuart B, et al. Andrographis paniculata (Chuān Xīn Lián) for symptomatic relief of acute respiratory tract infections in adults and children: A systematic review and meta-analysis. PLoS One 2017;12:e0181780. [PubMed abstract]
  28. Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med 2004;70:293-8. [PubMed abstract]
  29. Kligler B, Ulbricht C, Basch E, Kirkwood CD, Abrams TR, Miranda M, et al. Andrographis paniculata for the treatment of upper respiratory infection: a systematic review by the natural standard research collaboration. Explore (New York, NY) 2006;2:25-9. [PubMed abstract]
  30. Puri A, Saxena R, Saxena RP, Saxena KC, Srivastava V, Tandon JS. Immunostimulant agents from Andrographis paniculata. J Nat Prod 1993;56:995-9. [PubMed abstract]
  31. Banerjee A, Czinn SJ, Reiter RJ, Blanchard TG. Crosstalk between endoplasmic reticulum stress and anti-viral activities: A novel therapeutic target for COVID-19. Life Sci 2020;255:117842. [PubMed abstract]
  32. Enmozhi SK, Raja K, Sebastine I, Joseph J. Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach. J Biomol Struct Dyn 2020:1-7. [PubMed abstract]
  33. Murugan NA, Pandian CJ, Jeyakanthan J. Computational investigation on Andrographis paniculata phytochemicals to evaluate their potency against SARS-CoV-2 in comparison to known antiviral compounds in drug trials. J Biomol Struct Dyn 2020:1-12. [PubMed abstract]
  34. Silveira D, Prieto-Garcia JM, Boylan F, Estrada O, Fonseca-Bazzo YM, JAMAl CM, et al. COVID-19: Is there evidence for the use of herbal medicines as adjuvant symptomatic therapy? Front Pharmacol 2020;11:581840. [PubMed abstract]
  35. Wagner L, Cramer H, Klose P, Lauche R, Gass F, Dobos G, et al. Herbal medicine for cough: a systematic review and meta-analysis. Forsch Komplementmed 2015;22:359-68. [PubMed abstract]
  36. Poolsup N, Suthisisang C, Prathanturarug S, Asawamekin A, Chanchareon U. Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials. J Clin Pharm Ther 2004;29:37-45. [PubMed abstract]
  37. Shi TH, Huang YL, Chen CC, Pi WC, Hsu YL, Lo LC, et al. Andrographolide and its fluorescent derivative inhibit the main proteases of 2019-nCoV and SARS-CoV through covalent linkage. Biochem Biophys Res Commun 2020. [PubMed abstract]
  38. Kesheh MM, Shavandi S, Haeri Moghaddam N, Ramezani M, Ramezani F. Effect of herbal compounds on coronavirus; a systematic review and meta-analysis. Virol J 2022;19:87. [PubMed abstract]
  39. American Botanical Council. Thailand approves Asian herb andrographis to treat COVID-19. HerbalEGram 2021;18:3.
  40. The Nation Thailand. Two hospitals ready to trial traditional Thai medicine in treating COVID-19.external link disclaimer 2020.
  41. The Nation Thailand. Trials underway to test efficacy of Andrographis Paniculata extract for COVID-19.external link disclaimer 2020.
  42. The Nation Thailand. Study shows Fah Talai Jone may kill Covid-19, but can offer no protectionexternal link disclaimer. 2020.
  43. Bloomberg. Thailand clears use of herbal medicine for Covid-19 treatmentexternal link disclaimer. 2020.
  44. Tanwettiyanont J, Piriyachananusorn N, Sangsoi L, Boonsong B, Sunpapoa C, et al. Use of Andrographis paniculata (Burm.f.) Wall. ex Nees and risk of pneumonia in hospitalised patients with mild coronavirus disease 2019: A retrospective cohort study. Front Med (Lausanne) 2022;9:947373. [PubMed abstract]
  45. Ratiani L, Pachkoria E, Mamageishvili N, Shengelia R, Hovhannisyan A, Panossian A. Efficacy of Kan Jang(®) in Patients with Mild COVID-19: Interim Analysis of a Randomized, Quadruple-Blind, Placebo-Controlled Trial. Pharmaceuticals (Basel, Switzerland) 2022;15. [PubMed abstract]
  46. Natural Medicines Comprehensive Database. Andrographisexternal link disclaimer. 2021.
  47. Amroyan E, Gabrielian E, Panossian A, Wikman G, Wagner H. Inhibitory effect of andrographolide from Andrographis paniculata on PAF-induced platelet aggregation. Phytomedicine 1999;6:27-31. [PubMed abstract]
  48. Zhang CY, Tan BK. Mechanisms of cardiovascular activity of Andrographis paniculata in the anaesthetized rat. J Ethnopharmacol 1997;56:97-101. [PubMed abstract]
  49. Sharifi-Rad M, Mnayer D, Morais-Braga MFB, Carneiro JNP, Bezerra CF, Coutinho HDM, et al. Echinacea plants as antioxidant and antibacterial agents: From traditional medicine to biotechnological applications. Phytother Res: PTR 2018;32:1653-63. [PubMed abstract]
  50. LiverTox. Echinacea. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. [PubMed abstract]
  51. Aucoin M, Cardozo V, McLaren MD, Garber A, Remy D, et al. A systematic review on the effects of Echinacea supplementation on cytokine levels: Is there a role in COVID-19? Metabol Open 2021;11:100115. [PubMed abstract]
  52. David S, Cunningham R. Echinacea for the prevention and treatment of upper respiratory tract infections: A systematic review and meta-analysis. Complement Ther Med 2019;44:18-26. [PubMed abstract]
  53. Karsch-Völk M, Barrett B, Kiefer D, Bauer R, Ardjomand-Woelkart K, Linde K. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2014;2:Cd000530. [PubMed abstract]
  54. Aucoin M, Cooley K, Saunders PR, Carè J, Anheyer D, Medina DN, et al. The effect of Echinacea spp. on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review. Adv Integr Med 2020. [PubMed abstract]
  55. Boozari M, Hosseinzadeh H. Natural products for COVID-19 prevention and treatment regarding to previous coronavirus infections and novel studies. Phytother Res: PTR 2020. [PubMed abstract]
  56. Signer J, Jonsdottir HR, Albrich WC, Strasser M, Züst R, Ryter S, et al. In vitro virucidal activity of Echinaforce®, an Echinacea purpurea preparation, against coronaviruses, including common cold coronavirus 229E and SARS-CoV-2. Virol J 2020;17:136. [PubMed abstract]
  57. Mesri M, Esmaeili Saber SS, Godazi M, Roustaei Shirdel A, Montazer R, Koohestani HR, et al. The effects of combination of Zingiber officinale and Echinacea on alleviation of clinical symptoms and hospitalization rate of suspected COVID-19 outpatients: a randomized controlled trial. J Complement Integr Med 2021. [PubMed abstract]
  58. Kolev E, Mircheva L, Edwards MR, Johnston SL, Kalinov K, Stange R, et al. Echinacea Purpurea For the Long-Term Prevention of Viral Respiratory Tract Infections During Covid-19 Pandemic: A Randomized, Open, Controlled, Exploratory Clinical Study. Front Pharmacol 2022;13:856410. [PubMed abstract]
  59. Crawford C, Brown LL, Costello RB, Deuster PA. Select Dietary Supplement Ingredients for Preserving and Protecting the Immune System in Healthy Individuals: A Systematic Review. Nutrients 2022;14:4604. [PubMed abstract]
  60. Jawad M, Schoop R, Suter A, Klein P, Eccles R. Safety and efficacy profile of Echinacea purpurea to prevent common cold episodes: a randomized, double-blind, placebo-controlled trial. Evid Based Complement Alternat Med 2012:841315. [PubMed abstract]
  61. Holst L, Havnen GC, Nordeng H. Echinacea and elderberry-should they be used against upper respiratory tract infections during pregnancy? Front Pharmacol 2014;5:31. [PubMed abstract]
  62. Penzak SR, Robertson SM, Hunt JD, Chairez C, Malati CY, Alfaro RM, et al. Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects. Pharmacotherapy 2010;30:797-805. NEW PMID 20653355 [PubMed abstract]
  63. Natural Medicines Comprehensive Database. Echinaceaexternal link disclaimer. 2021.
  64. Gafner S, Borchardt T, Bush M, Sudberg S, Feuillere NG, Tenon MYR, et al. Tales from the elder: adulteration issues of elder berry. HerbalEGram 2021.
  65. Porter RS, Bode RF. A review of the antiviral properties of black elder (Sambucus nigra L.) products. Phytother Res: PTR 2017;31:533-54. [PubMed abstract]
  66. Hawkins J, Baker C, Cherry L, Dunne E. Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complement Ther Med 2019;42:361-5. [PubMed abstract]
  67. Harnett J, Oakes K, Carè J, Leach M, Brown D, Cramer H, et al. The effects of Sambucus nigra berry on acute respiratory viral infections: a rapid review of clinical studies. Adv Integr Med 2020. [PubMed abstract]
  68. Vlachojannis JE, Cameron M, Chrubasik S. A systematic review on the sambuci fructus effect and efficacy profiles. Phytother Res: PTR 2010;24:1-8. [PubMed abstract]
  69. Kinoshita E, Hayashi K, Katayama H, Hayashi T, Obata A. Anti-influenza virus effects of elderberry juice and its fractions. Biosci Biotechnol Biochem 2012; 76:1633-8. [PubMed abstract]
  70. Adams KK, Baker WL, Sobieraj DM. Myth busters: dietary supplements and COVID-19. Ann Pharmacother 2020;54:820-6. [PubMed abstract]
  71. Kronbichler A, Effenberger M, Eisenhut M, Lee KH, Shin JI. Seven recommendations to rescue the patients and reduce the mortality from COVID-19 infection: An immunological point of view. Autoimmun Rev 2020;19:102570. [PubMed abstract]
  72. Sargin SA. Potential anti-influenza effective plants used in Turkish folk medicine: A review. J Diet Suppl 2020;265:113319. [PubMed abstract]
  73. Wieland LS, Piechotta V, Feinberg T, Ludeman E, Hutton B, Kanji S, et al. Elderberry for prevention and treatment of viral respiratory illnesses: a systematic review. BMC Complement Med Ther 2021;21:112. [PubMed abstract]
  74. Ulbricht C, Basch E, Cheung L, Goldberg H, Hammerness P, Isaac R, et al. An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration. J Diet Suppl 2014;11:80-120. [PubMed abstract]
  75. Barak V, Halperin T, Kalickman I. The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines. Eur Cytokine Netw 2001;12:290-6. [PubMed abstract]
  76. Mancuso C, Santangelo R. Panax ginseng and Panax quinquefolius: From pharmacology to toxicology. Food Chem Toxicol 2017;107:362-72. [PubMed abstract]
  77. U.S. Department of Agriculture, Natural Resources Conservation Service. PLANTS Databaseexternal link disclaimer. 2020.
  78. Antonelli M, Donelli D, Firenzuoli F. Ginseng integrative supplementation for seasonal acute upper respiratory infections: A systematic review and meta-analysis. Complement Ther Med 2020;52:102457. [PubMed abstract]
  79. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf 2002;25:323-44. [PubMed abstract]
  80. Seida JK, Durec T, Kuhle S. North American (Panax quinquefolius) and Asian Ginseng (Panax ginseng) preparations for prevention of the common cold in healthy adults: a systematic review. Evid Based Complement Alternat Med;2011:282151. [PubMed abstract]
  81. Shi H, Xia Y, Gu R, Yu S. Ginseng adjuvant therapy on COVID-19: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021;100:e27586. [PubMed abstract]
  82. Jalali A, Dabaghian F, Akbrialiabad H, Foroughinia F, Zarshenas MM. A pharmacology-based comprehensive review on medicinal plants and phytoactive constituents possibly effective in the management of COVID-19. Phytother Res: PTR 2020. [PubMed abstract]
  83. Luo CH, Ma LL, Liu HM, Liao W, Xu RC, Ci ZM, et al. Research progress on main symptoms of novel coronavirus pneumonia improved by traditional Chinese medicine. Front Pharmacol 2020;11:556885. [PubMed abstract]
  84. ClinicalTrials.gov. Special Chinese medicine out-patient programme for discharged COVID-19 patientsexternal link disclaimer. 2020.
  85. Greenspan EM. Ginseng and vaginal bleeding. JAMA 1983;249:2018. [PubMed abstract]
  86. Hopkins MP, Androff L, Benninghoff AS. Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol 1988;159:1121-2. [PubMed abstract]
  87. Punnonen R, Lukola A. Oestrogen-like effect of ginseng. Br Med J 1980;281:1110. [PubMed abstract]
  88. Palmer BV, Montgomery AC, Monteiro JC. Gin Seng and mastalgia. Br Med J 1978;1:1284. [PubMed abstract]
  89. Seely D, Dugoua JJ, Perri D, Mills E, Koren G. Safety and efficacy of panax ginseng during pregnancy and lactation. Can J Clin Pharmacol 2008;15:e87-94. [PubMed abstract]
  90. Natural Medicines Comprehensive Database. Panax Ginsengexternal link disclaimer. 2020.
  91. Sotaniemi EA, Haapakoski E, Rautio A. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes care 1995;18:1373-5 [PubMed abstract]
  92. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997.
  93. Dominguez LJ, Veronese N, Guerrero-Romero F, Barbagallo M. Magnesium in infectious diseases in older people. Nutrients 2021;13:180. [PubMed abstract]
  94. Costello RB, Rosanoff A. Magnesium In: Marriott BP, Birt DF, Stallings VA, Yates AA, eds. Present Knowledge in Nutrition Cambridge, MA: Elsevier; 2020:349-74.
  95. Rude RK. Magnesium In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease Baltimore, Maryland: Lippincott Williams & Wilkins; 2012.
  96. Story MJ. Essential sufficiency of zinc, ω-3 polyunsaturated fatty acids, vitamin D and magnesium for prevention and treatment of COVID-19, diabetes, cardiovascular diseases, lung diseases and cancer. Biochimie 2021;187:94-109. [PubMed abstract]
  97. DiNicolantonio JJ, O'Keefe JH. Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in covid-19 patients. Mo Med 2021;118:68-73. [PubMed abstract]
  98. Cooper ID, Crofts CAP, DiNicolantonio JJ, Malhotra A, Elliott B, Kyriakidou Y, et al. Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management. Open Heart 2020;7:e001356. [PubMed abstract]
  99. Tan CW, Ho LP, Kalimuddin S, Cherng BPZ, Teh YE, Thien SY, et al. Cohort study to evaluate the effect of vitamin D, magnesium, and vitamin B(12) in combination on progression to severe outcomes in older patients with coronavirus (COVID-19). Nutrition 2020;79-80:111017. [PubMed abstract]
  100. Micke O, Vormann J, Kisters K. Magnesium and COVID-19 - Some Further Comments - A Commentary on Wallace TC. Combating COVID-19 and Building Immune Resilience: A Potential Role for Magnesium Nutrition? J Am Coll Nutr. 2020;1-9. doi:10.1080/07315724.2020.1785971. Cited in: PMID: 32649272. Journal of the American College of Nutrition 2020:1-3. [PubMed abstract]
  101. Tang CF, Ding H, Jiao RQ, Wu XX, Kong LD. Possibility of magnesium supplementation for supportive treatment in patients with COVID-19. Eur J Pharmacol 2020;886:173546. [PubMed abstract]
  102. Shechter M, Merz CN, Paul-Labrador M, Meisel SR, Rude RK, Molloy MD, et al. Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease. Am J Cardiol 1999;84:152-6. [PubMed abstract]
  103. U.S. Department of Agriculture, Agricultural Research Service. Usual Nutrient Intake from Food and Beverages, by Gender and Age, What We Eat in America, NHANES 2013-2016external link disclaimer. 2019.
  104. Pooransari P, Pourdowlat G. Magnesium Sulfate: A Potential Adjuvant Treatment on COVID-19. Frontiers in Emergency Medicine 2021;5:e1.
  105. Iotti S, Wolf F, Mazur A, Maier JA. The COVID-19 pandemic: is there a role for magnesium? Hypotheses and perspectives. Magnes Res 2020;33:21-7. [PubMed abstract]
  106. Shakoor H, Feehan J, Al Dhaheri AS, Ali HI, Platat C, Ismail LC, et al. Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19? Maturitas 2021;143:1-9. [PubMed abstract]
  107. Maier JA, Castiglioni S, Locatelli L, Zocchi M, Mazur A. Magnesium and inflammation: Advances and perspectives. Semin Cell Dev Biol 2021;115:37-44. [PubMed abstract]
  108. Hosseini B, Saedisomeolia A, Allman-Farinelli M. Association between antioxidant intake/status and obesity: a systematic review of observational studies. Biol Trace Elem Res 2017;175:287-97. [PubMed abstract]
  109. van Kempen T, Deixler E. SARS-CoV-2: influence of phosphate and magnesium, moderated by vitamin D, on energy (ATP) metabolism and on severity of COVID-19. Am J Physiol Endocrinol Metab 2021;320:E2-E6. [PubMed abstract]
  110. Damayanthi H, Prabani KIP. Nutritional determinants and COVID-19 outcomes of older patients with COVID-19: A systematic review. Arch Gerontol Geriatr 2021;95:104411. [PubMed abstract]
  111. Wallace TC. Combating COVID-19 and building immune resilience: a potential role for magnesium nutrition? J Am Coll Nutr 2020;39:685-93. [PubMed abstract]
  112. Zeng HL, Yang Q, Yuan P, Wang X, Cheng L. Associations of essential and toxic metals/metalloids in whole blood with both disease severity and mortality in patients with COVID-19. FASEB J 2021;35:e21392. [PubMed abstract]
  113. Alamdari NM, Afaghi S, Rahimi FS, Tarki FE, Tavana S, Zali A, et al. Mortality risk factors among hospitalized COVID-19 patients in a major referral center in Iran. Tohoku J Exp Med 2020;252:73-84. [PubMed abstract]
  114. Sarvazad H, Cahngaripour SH, Eskandari Roozbahani N, Izadi B. Evaluation of electrolyte status of sodium, potassium and magnesium, and fasting blood sugar at the initial admission of individuals with COVID-19 without underlying disease in Golestan Hospital, Kermanshah. New Microbes New infect 2020;38:100807. [PubMed abstract]
  115. Quilliot D, Bonsack O, Jaussaud R, Mazur A. Dysmagnesemia in Covid-19 cohort patients: prevalence and associated factors. Magnes Res 2020;33:114-22. [PubMed abstract]
  116. Swaminathan R. Magnesium metabolism and its disorders. Clin Biochem Rev 2003;24:47-66. [PubMed abstract]
  117. Kroll MH, Elin RJ. Relationships between magnesium and protein concentrations in serum. Clin Chem 1985;31:244-6. [PubMed abstract]
  118. Ostojic SM, Milovancev A, Drid P, Nikolaidis A. Oxygen saturation improved with nitrate-based nutritional formula in patients with COVID-19. J Int Med Res 2021;49:3000605211012380. [PubMed abstract]
  119. Dunn CJ, Goa KL. Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease. Drugs 2001;61:685-712. [PubMed abstract]
  120. Arayne MS, Sultana N, Hussain F. Interactions between ciprofloxacin and antacids--dissolution and adsorption studies. Drug Metab Drug Interact 2005;21:117-29. [PubMed abstract]
  121. Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part II: electrolyte and acid-base disorders complicating diuretic therapy. Expert Opin Drug Saf 2010;9:259-73. [PubMed abstract]
  122. U.S. Food and Drug Administration. FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs)external link disclaimer. 2011.
  123. Claustrat B, Leston J. Melatonin: Physiological effects in humans. Neurochirurgie 2015;61:77-84. [PubMed abstract]
  124. Habtemariam S, Daglia M, Sureda A, Selamoglu Z, Gulhan MF, Nabavi SM. Melatonin and respiratory diseases: a review. Curr Top Med Chem 2017;17:467-88. [PubMed abstract]
  125. Hadi A, Ghaedi E, Moradi S, Pourmasoumi M, Ghavami A, Kafeshani M. Effects of melatonin supplementation on blood pressure: a systematic review and meta-analysis of randomized controlled trials. Horm Metab Res 2019;51:157-64. [PubMed abstract]
  126. Bahrampour Juybari K, Pourhanifeh MH, Hosseinzadeh A, Hemati K, Mehrzadi S. Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus Res 2020;287:198108. [PubMed abstract]
  127. Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci 2020;250:117583. [PubMed abstract]
  128. Corrao S, Bocchio RM, Lo Monaco M, Natoli G, Cavezzi A, Troiani E, et al. Does evidence exist to blunt inflammatory response by nutraceutical supplementation during COVID-19 pandemic? An overview of systematic reviews of vitamin D, vitamin C, melatonin, and zinc. Nutrients 2021;13. [PubMed abstract]
  129. Raygan F, Ostadmohammadi V, Bahmani F, Reiter RJ, Asemi Z. Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial. Clin Nutr 2019;38:191-6. [PubMed abstract]
  130. Kleszczyński K, Slominski AT, Steinbrink K, Reiter RJ. Clinical trials for use of melatonin to fight against COVID-19 are urgently needed. Nutrients 2020;12. [PubMed abstract]
  131. Zhou Y, Hou Y, Shen J, Mehra R, Kallianpur A, Culver DA, et al. A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19. PLoS Biol 2020;18:e3000970. [PubMed abstract]
  132. Chavarría AP, Vázquez RRV, Cherit JGD, Bello HH, Suastegui HC, Moreno-Castañeda L, et al. Antioxidants and pentoxifylline as coadjuvant measures to standard therapy to improve prognosis of patients with pneumonia by COVID-19. Comput Struct Biotechnol J 2021;19:1379-90. [PubMed abstract]
  133. ClinicalTrials.gov. Safety and efficacy of melatonin in outpatients infected with COVID-19 (COVID-19)external link disclaimer. 2020.
  134. ClinicalTrials.gov. The effect of melatonin and vitamin C on COVID-19external link disclaimer. 2020.
  135. Andersen LP, Gögenur I, Rosenberg J, Reiter RJ. The safety of melatonin in humans. Clin Drug Investig 2016;36:169-75. [PubMed abstract]
  136. Voordouw BC, Euser R, Verdonk RE, Alberda BT, de Jong FH, Drogendijk AC, et al. Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab 1992;74:108-17. [PubMed abstract]
  137. Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998;351:1254. [PubMed abstract]
  138. Wirtz PH, Spillmann M, Bärtschi C, Ehlert U, von Känel R. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res 2008;44:127-33. [PubMed abstract]
  139. Natural Medicines Comprehensive Database. Melatoninexternal link disclaimer. 2021.
  140. Bauer SR, Kapoor A, Rath M, Thomas SA. What is the role of supplementation with ascorbic acid, zinc, vitamin D, or N-acetylcysteine for prevention or treatment of COVID-19? Cleve Clin J Med 2020. [PubMed abstract]
  141. De Flora S, Balansky R, La Maestra S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB J 2020;34:13185-93. [PubMed abstract]
  142. Shi Z, Puyo CA. N-Acetylcysteine to combat COVID-19: An evidence review. Ther Clin Risk Manag 2020;16:1047-55. [PubMed abstract]
  143. U.S. Food and Drug Administration. National Drug Code Directoryexternal link disclaimer. 2021.
  144. National Institutes of Health. Dietary Supplement Label Database. 2022.
  145. Wei J, Pang CS, Han J, Yan H. Effect of orally administered n-acetylcysteine on chronic bronchitis: A meta-analysis. Adv Ther 2019;36:3356-67. [PubMed abstract]
  146. Fowdar K, Chen H, He Z, Zhang J, Zhong X, Zhang J, et al. The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: A meta-analysis and systematic review. Heart Lung 2017;46:120-8. [PubMed abstract]
  147. Assimakopoulos SF, Aretha D, Komninos D, Dimitropoulou D, Lagadinou M, Leonidou L, et al. N-acetyl-cysteine reduces the risk for mechanical ventilation and mortality in patients with COVID-19 pneumonia: a two-center retrospective cohort study. Infect Dis 2021;53:847-54. [PubMed abstract]
  148. de Alencar JCG, Moreira CL, Müller AD, Chaves CE, Fukuhara MA, da Silva EA, et al. Double-blind, randomized, placebo-controlled trial with N-acetylcysteine for treatment of severe acute respiratory syndrome caused by coronavirus disease 2019 (COVID-19). Clin Infect Dis 2021;72:e736-e41. [PubMed abstract]
  149. ClinicalTrials.gov. Trial of Famotidine & N-Acetyl Cysteine for Outpatients With COVID-19external link disclaimer. 2021.
  150. ClinicalTrials.gov. Glutathione, oxidative stress and mitochondrial function in COVID-19external link disclaimer. 2021.
  151. Natural Medicines Comprehensive Database. N-Acetyl Cysteine (NAC)external link disclaimer. 2021.
  152. Horowitz JD, Henry CA, Syrjanen ML, Louis WJ, Fish RD, Antman EM, et al. Nitroglycerine/N-acetylcysteine in the management of unstable angina pectoris. Eur Heart J 1988;9 Suppl A:95-100. [PubMed abstract]
  153. Ardissino D, Merlini PA, Savonitto S, Demicheli G, Zanini P, Bertocchi F, et al. Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris. J Am Coll Cardiol 1997;29:941-7. [PubMed abstract]
  154. Institute of Medicine. Food and Nutrition Board. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (macronutrients). Washington, DC National Academy Press; 2005.
  155. Jones PJH, Rideout T. Lipids, sterols, and their metabolies. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TF, eds. Modern Nutrition in Health and Disease. Baltimore, MD: Lippincott Williams & Wilkins; 2014.
  156. Hathaway D, Pandav K, Patel M, Riva-Moscoso A, Singh BM, Patel A, et al. Omega 3 fatty acids and COVID-19: A comprehensive review. Infect Chemother 2020;52:478-95. [PubMed abstract]
  157. James M, Proudman S, Cleland L. Fish oil and rheumatoid arthritis: past, present and future. Proc Nutr Soc 2010;69:316-23. [PubMed abstract]
  158. Asher A, Tintle NL, Myers M, Lockshon L, Bacareza H, Harris WS. Blood omega-3 fatty acids and death from COVID-19: A pilot study. Prostaglandins Leukot Essent Fatty Acids 2021;166:102250. [PubMed abstract]
  159. Harris W. Omega-6 and omega-3 fatty acids: partners in prevention. Curr Opin Clin Nutr Metab Care 2010;13:125-9. [PubMed abstract]
  160. Louca P, Murray B, Klaser K, Graham MS, Mazidi M, Leeming ER, et al. Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app. BMJ Nutr Prev Health 2021.
  161. Chang JP, Pariante CM, Su KP. Omega-3 fatty acids in the psychological and physiological resilience against COVID-19. Prostaglandins Leukot Essent Fatty Acids 2020;161:102177. [PubMed abstract]
  162. Weill P, Plissonneau C, Legrand P, Rioux V, Thibault R. May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients? Biochimie 2020;179:275-80 [PubMed abstract]
  163. Thibault R, Seguin P, Tamion F, Pichard C, Singer P. Nutrition of the COVID-19 patient in the intensive care unit (ICU): a practical guidance. Crit Care 2020;24:447. [PubMed abstract]
  164. Lordan R, Rando HM, Consortium CR, Greene CS. Dietary supplements and nutraceuticals under investigation for COVID-19 prevention and treatment. ArXiv 2021. [PubMed abstract]
  165. Doaei S, Gholami S, Rastgoo S, Gholamalizadeh M, Bourbour F, et al. The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial. J Transl Med 2021;19:128. [PubMed abstract]
  166. ClinicalTrials.gov. The effect of omega-3 on selected cytokines involved in cytokine stormexternal link disclaimer. 2021.
  167. ClinicalTrials.gov. Cod liver oil for Covid-19 prevention studyexternal link disclaimer. 2021.
  168. European Food Safety Authority. Scientific opinion on the tolerable upper intake level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA Journal 2012;10:2815.
  169. U.S. Food and Drug Administration. Qualified Health Claims: Letters of Enforcement Discretionexternal link disclaimer. 2019.
  170. Mazereeuw G, Lanctôt KL, Chau SA, Swardfager W, Herrmann N. Effects of ω-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol Aging 2012;33:1482.e17-29 [PubMed abstract]
  171. Cabré E, Mañosa M, Gassull MA. Omega-3 fatty acids and inflammatory bowel diseases - a systematic review. The British journal of nutrition 2012;107 Suppl 2:S240-52. [PubMed abstract]
  172. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother 2004;38:50-2. [PubMed abstract]
  173. GlaxoSmithKline. LOVAZA® (omega-3 acid ethyl esters) capsules, prescribing informationexternal link disclaimer. 2008.
  174. Appel LJ, Miller ER, 3rd, Seidler AJ, Whelton PK. Does supplementation of diet with 'fish oil' reduce blood pressure? A meta-analysis of controlled clinical trials. Arch Intern Med1993;153:1429-38. [PubMed abstract]
  175. Busnach G, Stragliotto E, Minetti E, Perego A, Brando B, Broggi ML, et al. Effect of n-3 polyunsaturated fatty acids on cyclosporine pharmacokinetics in kidney graft recipients: a randomized placebo-controlled study. J Nephrol 1998;11:87-93. [PubMed abstract]
  176. Natural Medicines Comprehensive Database. Fish Oilexternal link disclaimer. 2021.
  177. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature reviews Gastroenterology & hepatology 2014;11:506-14. [PubMed abstract]
  178. World Gastroenterology Organisation. Probiotics and prebiotics. 2017.
  179. Lehtoranta L, Pitkäranta A, Korpela R. Probiotics in respiratory virus infections. Eur J Clin Microbiol Infect Dis 2014;33:1289-302. [PubMed abstract]
  180. Hao Q, Dong BR, Wu T. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev 2015:Cd006895. [PubMed abstract]
  181. Frei R, Akdis M, O'Mahony L. Prebiotics, probiotics, synbiotics, and the immune system: experimental data and clinical evidence. Curr Opin Gastroenterol 2015;31:153-8. [PubMed abstract]
  182. King S, Glanville J, Sanders ME, Fitzgerald A, Varley D. Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: a systematic review and meta-analysis. Br J Nutr 2014;112:41-54. [PubMed abstract]
  183. Liu S, Hu P, Du X, Zhou T, Pei X. Lactobacillus rhamnosus GG supplementation for preventing respiratory infections in children: a meta-analysis of randomized, placebo-controlled trials. Indian pediatrics 2013;50:377-81. [PubMed abstract]
  184. Laursen RP, Hojsak I. Probiotics for respiratory tract infections in children attending day care centers-a systematic review. Eur J Pediatr 2018;177:979-94. [PubMed abstract]
  185. Wang Y, Li X, Ge T, Xiao Y, Liao Y, Cui Y, et al. Probiotics for prevention and treatment of respiratory tract infections in children: A systematic review and meta-analysis of randomized controlled trials. Medicine 2016;95:e4509. [PubMed abstract]
  186. Rozga M, Cheng FW, Handu D. Effects of probiotics in conditions or infections similar to COVID-19 on health outcomes: An evidence analysis center scoping review. J Acad Nutr Diet 2021;121:1841-54. [PubMed abstract]
  187. Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial. Am J Respir Crit Care Med 2010;182:1058-64. [PubMed abstract]
  188. Milajerdi A, Mousavi SM, Sadeghi A, Salari-Moghaddam A, Parohan M, Larijani B, et al. The effect of probiotics on inflammatory biomarkers: a meta-analysis of randomized clinical trials. Eur J Nutr 2020;59:633-49. [PubMed abstract]
  189. Olaimat AN, Aolymat I, Al-Holy M, Ayyash M, Abu Ghoush M, Al-Nabulsi AA, et al. The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19. NPJ Sci Food 2020;4:17. [PubMed abstract]
  190. Bottari B, Castellone V, Neviani E. Probiotics and Covid-19. Int J Food Sci Nutr 2020:1-7. [PubMed abstract]
  191. Ceccarelli G, Scagnolari C, Pugliese F, Mastroianni CM, d'Ettorre G. Probiotics and COVID-19. Lancet Gastroenterol Hepatol 2020;5:721-2. [PubMed abstract]
  192. Giannoni E, Baud D, Agri VD, Gibson GR, Reid G. Probiotics and COVID-19. Lancet Gastroenterol Hepatol 2020;5:720-1. [PubMed abstract]
  193. Akour A. Probiotics and COVID-19: is there any link? Lett Appl Microbioly 2020;71:229-34. [PubMed abstract]
  194. Di Renzo L, Merra G, Esposito E, De Lorenzo A. Are probiotics effective adjuvant therapeutic choice in patients with COVID-19? Eur Rev Med Pharmacol Sci 2020;24:4062-3. [PubMed abstract]
  195. Mullish BH, Marchesi JR, McDonald JAK, Pass DA, Masetti G, Michael DR, et al. Probiotics reduce self-reported symptoms of upper respiratory tract infection in overweight and obese adults: should we be considering probiotics during viral pandemics? Gut Microbes 2021;13:1-9. [PubMed abstract]
  196. Vignesh R, Swathirajan CR, Tun ZH, Rameshkumar MR, Solomon SS, Balakrishnan P. Could Perturbation of Gut Microbiota Possibly Exacerbate the Severity of COVID-19 via Cytokine Storm? Front Immunol 2020;11:607734. [PubMed abstract]
  197. d'Ettorre G, Ceccarelli G, Marazzato M, Campagna G, Pinacchio C, Alessandri F, et al. Challenges in the management of SARS-CoV2 infection: The role of oral bacteriotherapy as complementary therapeutic strategy to avoid the progression of COVID-19. Front Med (Lausanne) 2020;7:389. [PubMed abstract]
  198. Rathi A, Jadhav SB, Shah N. A Randomized Controlled Trial of the Efficacy of Systemic Enzymes and Probiotics in the Resolution of Post-COVID Fatigue. Medicines 2021;8:47.
  199. ClinicalTrials.gov. Efficacy of probiotics in reducing duration and symptoms of COVID-19 (PROVID-19)external link disclaimer. 2021.
  200. ClinicalTrials.gov. Effect of Lactobacillus on the microbiome of household contacts exposed to COVID-19external link disclaimer. 2020.
  201. Didari T, Solki S, Mozaffari S, Nikfar S, Abdollahi M. A systematic review of the safety of probiotics. Expert opinion on Drug Saf 2014;13:227-39. [PubMed abstract]
  202. Borriello SP, Hammes WP, Holzapfel W, Marteau P, Schrezenmeir J, Vaara M, et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis 2003;36:775-80. [PubMed abstract]
  203. Lewis SJ, Freedman AR. Review article: the use of biotherapeutic agents in the prevention and treatment of gastrointestinal disease. Aliment Pharmacol Ther 1998;12:807-22. [PubMed abstract]
  204. Natural Medicines Comprehensive Database. Lactobacillusexternal link disclaimer. 2021.
  205. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 2007;45:2179-205. [PubMed abstract]
  206. Derosa G, Maffioli P, D'Angelo A, Di Pierro F. A role for quercetin in coronavirus disease 2019 (COVID-19). Phytother Res 2021;35:1230-6. [PubMed abstract]
  207. Diniz LRL, Souza MTS, Duarte ABS, Sousa DP. Mechanistic aspects and therapeutic potential of quercetin against COVID-19-associated acute kidney injury. Molecules 2020;25: 5772. [PubMed abstract]
  208. F DIP, Khan A, Bertuccioli A, Maffioli P, Derosa G, Khan S, et al. Quercetin Phytosome® as a potential candidate for managing COVID-19. Minerva Gastroenterol (Torino) 2021;67:190-5. [PubMed abstract]
  209. Saakre M, Mathew D, Ravisankar V. Perspectives on plant flavonoid quercetin-based drugs for novel SARS-CoV-2. Beni-Suef Univ J Basic Appl Scie 2021;10:21. [PubMed abstract]
  210. Saeedi-Boroujeni A, Mahmoudian-Sani MR. Anti-inflammatory potential of Quercetin in COVID-19 treatment. J Inflamm (Lond) 2021;18:3. [PubMed abstract]
  211. Bastaminejad S, Bakhtiyari S. Quercetin and its relative therapeutic potential against COVID-19: A retrospective review and prospective overview. Curr Mol Med 2020. [PubMed abstract]
  212. Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and vitamin C: an experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front immunol 2020;11:1451. [PubMed abstract]
  213. Heinz SA, Henson DA, Austin MD, Jin F, Nieman DC. Quercetin supplementation and upper respiratory tract infection: A randomized community clinical trial. Pharmacol Res 2010;62:237-42. [PubMed abstract]
  214. Aucoin M, Cooley K, Saunders PR, Cardozo V, Remy D, Cramer H, et al. The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review. Adv Integr Med 2020;7:247-51. [PubMed abstract]
  215. Pan B, Fang S, Zhang J, Pan Y, Liu H, Wang Y, et al. Chinese herbal compounds against SARS-CoV-2: Puerarin and quercetin impair the binding of viral S-protein to ACE2 receptor. Comput Struct Biotechnol J 2020;18:3518-27. [PubMed abstract]
  216. Gu YY, Zhang M, Cen H, Wu YF, Lu Z, Lu F, et al. Quercetin as a potential treatment for COVID-19-induced acute kidney injury: Based on network pharmacology and molecular docking study. PloS One 2021;16:e0245209. [PubMed abstract]
  217. Di Pierro F, Derosa G, Maffioli P, Bertuccioli A, Togni S, Riva A, et al. Possible Therapeutic Effects of Adjuvant Quercetin Supplementation Against Early-Stage COVID-19 Infection: A Prospective, Randomized, Controlled, and Open-Label Study. International journal of general medicine 2021;14:2359-66. [PubMed abstract]
  218. Di Pierro F, Iqtadar S, Khan A, Ullah Mumtaz S, Masud Chaudhry M, Bertuccioli A, et al. Potential Clinical Benefits of Quercetin in the Early Stage of COVID-19: Results of a Second, Pilot, Randomized, Controlled and Open-Label Clinical Trial. International journal of general medicine 2021;14:2807-16. [PubMed abstract]
  219. ClinicalTrials.gov. Effect of Quercetin on Prophylaxis and Treatment of COVID-19external link disclaimer. 2021.
  220. ClinicalTrials.gov. Trial to Study the Adjuvant Benefits of Quercetin Phytosome in Patients With COVID-19 2021external link disclaimer.
  221. U.S. Food and Drug Administration. GRN No. 341, Quercetinexternal link disclaimer. 2010.
  222. Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schäfer B, Hirsch-Ernst KI, et al. Safety Aspects of the Use of Quercetin as a Dietary Supplement. Mol Nutr Food Res 2018;62. [PubMed abstract]
  223. Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetin reduces blood pressure in hypertensive subjects. TJ Nutr 2007;137:2405-11. [PubMed abstract]
  224. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids Washington, DC: National Academy Press; 2000.
  225. Akhtar S, Das JK, Ismail T, Wahid M, Saeed W, Bhutta ZA. Nutritional perspectives for the prevention and mitigation of COVID-19. Nutr Rev 2021;79:289-300. [PubMed abstract]
  226. Zhang J, Saad R, Taylor EW, Rayman MP. Selenium and selenoproteins in viral infection with potential relevance to COVID-19. Redox Biol 2020;37:101715. [PubMed abstract]
  227. Calder PC. Nutrition, immunity and COVID-19. BMJ Nutr Prev Health 2020;3:74-92. [PubMed abstract]
  228. Allingstrup M, Afshari A. Selenium supplementation for critically ill adults. Cochrane Database Syst Rev 2015;2015:Cd003703. [PubMed abstract]
  229. Bermano G, Méplan C, Mercer DK, Hesketh JE. Selenium and viral infection: are there lessons for COVID-19? The Br J Nutr 2021;125:618-27. [PubMed abstract]
  230. Bae M, Kim H. Mini-Review on the Roles of Vitamin C, Vitamin D, and Selenium in the Immune System against COVID-19. Molecules 2020;25: 5346. [PubMed abstract]
  231. Alexander J, Tinkov A, Strand TA, Alehagen U, Skalny A, Aaseth J. Early nutritional interventions with zinc, selenium and vitamin D for raising anti-viral resistance against progressive COVID-19. Nutrients 2020;12. [PubMed abstract]
  232. Guillin OM, Vindry C, Ohlmann T, Chavatte L. Selenium, Selenoproteins and Viral Infection. Nutrients 2019;11. [PubMed abstract]
  233. Kafai MR, Ganji V. Sex, age, geographical location, smoking, and alcohol consumption influence serum selenium concentrations in the USA: third National Health and Nutrition Examination Survey, 1988-1994. J Trace Elem Med Biol 2003;17:13-8. [PubMed abstract]
  234. Zhang J, Taylor EW, Bennett K, Saad R, Rayman MP. Association between regional selenium status and reported outcome of COVID-19 cases in China. Am J clin Nutr 2020;111:1297-9. [PubMed abstract]
  235. BourBour F, Mirzaei Dahka S, Gholamalizadeh M, Akbari ME, Shadnoush M, Haghighi M, et al. Nutrients in prevention, treatment, and management of viral infections; special focus on Coronavirus. Arch Physiol Biochem 2020:1-10. [PubMed abstract]
  236. Notz Q, Herrmann J, Schlesinger T, Helmer P, Sudowe S, Sun Q, et al. Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS. Nutrients 2021;13. [PubMed abstract]
  237. Moghaddam A, Heller RA, Sun Q, Seelig J, Cherkezov A, Seibert L, et al. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients 2020;12. [PubMed abstract]
  238. Di Renzo L, Gualtieri P, Pivari F, Soldati L, Attinà A, Leggeri C, et al. COVID-19: Is there a role for immunonutrition in obese patient? J Transl Med 2020;18:415. [PubMed abstract]
  239. Im JH, Je YS, Baek J, Chung MH, Kwon HY Lee JS. Nutritional status of patients with COVID-19. Int J Infect Dis 2020;100:390-3. [PubMed abstract]
  240. Hong LK, Diamond AM. Selenium In: Marriott BP, Birt DF, Stallings VA, Yates AA, eds. Present Knowledge in Nutrition Cambridge, MA: Elsevier; 2020:443-56.
  241. ClinicalTrials.gov. Efficacy of a Dietary Supplementation in Reducing Hospital Admissions for COVID-19. Randomized Clinical Trial (CoVIT)external link disclaimer. 2021.
  242. ClinicalTrials.gov. Selenium as a Potential Treatment for Moderately-ill, Severely-ill, and Critically-ill COVID-19 Patients. (SeCOVID)external link disclaimer. 2021.
  243. Vernie LN, de Goeij JJ, Zegers C, de Vries M, Baldew GS, McVie JG. Cisplatin-induced changes of selenium levels and glutathione peroxidase activities in blood of testis tumor patients. Cancer Lett 1988;40:83-91. [PubMed abstract]
  244. Sieja K, Talerczyk M. Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy. Gynecol Oncol 2004;93:320-7. [PubMed abstract]
  245. Dennert G, Horneber M. Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients. Cochrane Database Syst Rev 2006;2006:Cd005037. [PubMed abstract]
  246. Holford P, Carr AC, Jovic TH, Ali SR, Whitaker IS, Marik PE, et al. Vitamin C-an adjunctive therapy for respiratory infection, sepsis and COVID-19. Nutrients 2020;12. [PubMed abstract]
  247. Carr AC, Maggini S. Vitamin C and immune function. Nutrients 2017;9. [PubMed abstract]
  248. Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin CareNutr Clin Care 2002;5:66-74. [PubMed abstract]
  249. National Institutes of Health. COVID-19 Treatment Guidelines, Vitamin C. 2021.
  250. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2013:Cd000980. [PubMed abstract]
  251. Johnston CS. Vitamin C. In: Marriott BP, Birt DF, Stallings VA, Yates AA, eds. Present Knowledge in Nutrition 11th ed. Cambridge, MA: Elsevier; 2020:155-69.
  252. Hemilä H. Vitamin C and Infections. Nutrients 2017;9. [PubMed abstract]
  253. Schleicher RL, Carroll MD, Ford ES, Lacher DA. Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES). Am J Clin Nutr 2009;90:1252-63. [PubMed abstract]
  254. Patterson T, Isales CM, Fulzele S. Low level of Vitamin C and dysregulation of Vitamin C transporter might be involved in the severity of COVID-19 Infection. Aging Dis 2021;12:14-26. [PubMed abstract]
  255. Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: The inflammation link and the role of nutrition in potential mitigation. Nutrients 2020;12. [PubMed abstract]
  256. Carr AC, Rowe S. The emerging role of vitamin C in the prevention and treatment of COVID-19. Nutrients 2020;12. [PubMed abstract]
  257. Milani GP, Macchi M, Guz-Mark A. Vitamin C in the treatment of COVID-19. Nutrients 2021;13:1172. [PubMed abstract]
  258. Hemilä H, Louhiala P. Vitamin C for preventing and treating pneumonia. Cochrane Database Syst Rev 2013:Cd005532. [PubMed abstract]
  259. Capone S, Abramyan S, Ross B, Rosenberg J, Zeibeq J, Vasudevan V, et al. Characterization of critically ill COVID-19 patients at a brooklyn safety-net hospital. Cureus 2020;12:e9809. [PubMed abstract]
  260. Krishnan S, Patel K, Desai R, Sule A, Paik P, Miller A, et al. Clinical comorbidities, characteristics, and outcomes of mechanically ventilated patients in the State of Michigan with SARS-CoV-2 pneumonia. J Clin Anesth2020;67:110005. [PubMed abstract]
  261. Thomas S, Patel D, Bittel B, Wolski K, Wang Q, Kumar A, et al. Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: The COVID A to Z randomized clinical trial. JAMA Netw Open 2021;4:e210369. [PubMed abstract]
  262. Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ 2006;174:937-42. [PubMed abstract]
  263. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Med Drug Discov 2020;5:100028. [PubMed abstract]
  264. Zhang J, Rao X, Li Y, Zhu Y, Liu F, Guo G, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Annals of intensive care 2021;11:5. [PubMed abstract]
  265. JamaliMoghadamSiahkali S, Zarezade B, Koolaji S, SeyedAlinaghi S, Zendehdel A, et al. Safety and effectiveness of high-dose vitamin C in patients with COVID-19: a randomized open-label clinical trial. Eur J Med Res 2021;26:20. [PubMed abstract]
  266. ClinicalTrials.gov. Use of ascorbic acid in patients with COVID 19external link disclaimer. 2021.
  267. Cho J, Ahn S, Yim J, Cheon Y, Jeong SH, Lee SG, et al. Influence of vitamin C and maltose on the accuracy of three models of glucose meters. Ann Lab Med 2016;36:271-4. [PubMed abstract]
  268. Lv H, Zhang GJ, Kang XX, Yuan H, Lv YW, Wang WW, et al. Factors interfering with the accuracy of five blood glucose meters used in Chinese hospitals. J Clin Lab Anal 2013;27:354-66. [PubMed abstract]
  269. Tang Z, Du X, Louie RF, Kost GJ. Effects of drugs on glucose measurements with handheld glucose meters and a portable glucose analyzer. Am J Clin Pathol 2000;113:75-86. [PubMed abstract]
  270. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst 2008;100:773-83. [PubMed abstract]
  271. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press; 2010.
  272. Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, La Frano MR, et al. Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: Considerations during the COVID-19 crisis. Nutrients 2020;12. [PubMed abstract]
  273. Fakhoury HMA, Kvietys PR, Shakir I, Shams H, Grant WB, Alkattan K. Lung-Centric Inflammation of COVID-19: Potential Modulation by Vitamin D. Nutrients 2021;13. [PubMed abstract]
  274. Gruber-Bzura BM. Vitamin D and influenza-prevention or therapy? Int J Mol Sci2018;19. [PubMed abstract]
  275. Arboleda JF, Urcuqui-Inchima S. Vitamin D supplementation: A potential approach for coronavirus/COVID-19 Therapeutics? Front Immunol 2020;11:1523. [PubMed abstract]
  276. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020;12. [PubMed abstract]
  277. National Institutes of Health. COVID-19 Treatment Guidelines, Vitamin D. 2021.
  278. Rubin R. Sorting out whether vitamin d deficiency raises COVID-19 risk. JAMA 2021. [PubMed abstract]
  279. Barazzoni R, Bischoff SC, Breda J, Wickramasinghe K, Krznaric Z, Nitzan D, et al. ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2 infection. Clin Nutr 2020;39:1631-8. [PubMed abstract]
  280. U.S. Department of Agriculture ARS. Percent reporting and mean amounts of selected vitamins and minerals food and beverages and dietary supplements by gender and age, in the United States, 2015-2016external link disclaimer. What We Eat in America, NHANES 2015-2016, 2019.
  281. Herrick KA, Storandt RJ, Afful J, Pfeiffer CM, Schleicher RL, Gahche JJ, et al. Vitamin D status in the United States, 2011-2014. Am J Clin Nutr 2019;110:150-7. [PubMed abstract]
  282. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583. [PubMed abstract]
  283. Herrera-Quintana L, Gamarra-Morales Y, Vázquez-Lorente H, Molina-López J, Castaño-Pérez J, Machado-Casas JF, et al. Bad Prognosis in Critical Ill Patients with COVID-19 during Short-Term ICU Stay regarding Vitamin D Levels. Nutrients 2021;13. [PubMed abstract]
  284. Luo X, Liao Q, Shen Y, Li H, Cheng L. Vitamin D deficiency is associated with COVID-19 incidence and disease severity in Chinese people [corrected]. J Nutr 2021;151:98-103. [PubMed abstract]
  285. Hernández JL, Nan D, Fernandez-Ayala M, García-Unzueta M, Hernández-Hernández MA, López-Hoyos M, et al. Vitamin D status in hospitalized patients with SARS-CoV-2 infection. J Clin Endocrinol Metab 2021;106:e1343-e53. [PubMed abstract]
  286. Bennouar S, Cherif AB, Kessira A, Bennouar DE, Abdi S. Vitamin D deficiency and low serum calcium as predictors of poor prognosis in patients with severe COVID-19. J Am Coll Nutr 2021;40:104-10. [PubMed abstract]
  287. Sulli A, Gotelli E, Casabella A, Paolino S, Pizzorni C, Alessandri E, et al. Vitamin D and lung outcomes in elderly COVID-19 patients. Nutrients 2021;13. [PubMed abstract]
  288. AlSafar H, Grant WB, Hijazi R, Uddin M, Alkaabi N, Tay G, et al. COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents. Nutrients 2021;13:1714. [PubMed abstract]
  289. Bychinin MV, Klypa TV, Mandel IA, Andreichenko SA, Baklaushev VP, et al. Low Circulating Vitamin D in Intensive Care Unit-Admitted COVID-19 Patients as a Predictor of Negative Outcomes. J Nutr 2021. Online ahead of print. [PubMed abstract]
  290. Karahan S, Katkat F. Impact of Serum 25(OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey. J Nutr Health Aging 2021;25:189-96. [PubMed abstract]
  291. D'Avolio A, Avataneo V, Manca A, Cusato J, De Nicolò A, Lucchini R, et al. 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients 2020;12. [PubMed abstract]
  292. Zelzer S, Prüller F, Curcic P, Sloup Z, Holter M, Herrmann M, et al. Vitamin D Metabolites and Clinical Outcome in Hospitalized COVID-19 Patients. Nutrients 2021;13: 2129. [PubMed abstract]
  293. Butler-Laporte G, Nakanishi T, Mooser V, Morrison DR, Abdullah T, et al. Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study. PLoS Med 2021;18:e1003605. [PubMed abstract]
  294. Li Y, Tong CH, Bare LA Devlin JJ. Assessment of the association of vitamin D level with SARS-CoV-2 seropositivity among working-age adults. JAMA Netw Open 2021;4:e2111634. [PubMed abstract]
  295. Reis BZ, Fernandes AL, Sales LP, Santos MD, Dos Santos CC, et al. Influence of vitamin D status on hospital length of stay and prognosis in hospitalized patients with moderate to severe COVID-19: a multicenter prospective cohort study. Am J Clin Nutr 2021. Online ahead of print. [PubMed abstract]
  296. Hastie CE, Mackay DF, Ho F, Celis-Morales CA, Katikireddi SV, Niedzwiedz CL, et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr 2020;14:561-5. [PubMed abstract]
  297. Bassatne A, Basbous M, Chakhtoura M, El Zein O, Rahme M El-Hajj Fuleihan G. The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis. Metabolism 2021;119:154753. [PubMed abstract]
  298. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA Netw Open2020;3:e2019722. [PubMed abstract]
  299. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One 2020;15:e0239252. [PubMed abstract]
  300. Baktash V, Hosack T, Patel N, Shah S, Kandiah P, et al. Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgrad Med J 2020. Online ahead of print. [PubMed abstract]
  301. Carpagnano GE, Di Lecce V, Quaranta VN, Zito A, Buonamico E, et al. (2021). Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest 2021;44:765-71. [PubMed abstract]
  302. Merzon E, Tworowski D, Gorohovski A, Vinker S, Golan Cohen A, Green I, et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. FEBS J 2020;287:3693-702. [PubMed abstract]
  303. Ma H, Zhou T, Heianza Y, Qi L. Habitual use of vitamin D supplements and risk of coronavirus disease 2019 (COVID-19) infection: a prospective study in UK Biobank. American J Clin Nutr 2021. [PubMed abstract]
  304. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora VM, Solway J. Association of vitamin D levels, race/ethnicity, and clinical characteristics with COVID-19 test results. JAMA Netw Open 2021;4:e214117. [PubMed abstract]
  305. Maghbooli Z, Sahraian MA, Ebrahimi M, Pazoki M, Kafan S, Tabriz HM, et al. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS One 2020;15:e0239799. [PubMed abstract]
  306. Kompaniyets L, Goodman AB, Belay B, Freedman DS, Sucosky MS, Lange SJ, et al. Body mass index and risk for COVID-19-related hospitalization, intensive care unit admission, invasive mechanical ventilation, and death - United States, March-December 2020. MMWR Morb Mortal Wkly Rep 2021;70:355-61. [PubMed abstract]
  307. Kazemi A, Mohammadi V, K. AS, Golzarand M, Clark CCT, Babajafari S. Association of vitamin D status with SARS-CoV-2 infection or COVID-19 severity: A systematic review and meta-analysis. Adv Nutr 2021:23. [PubMed abstract]
  308. Drame M, Cofais C, Hentzien M, Proye E, Coulibaly PS, Demoustier-Tampere D, et al. Relation between Vitamin D and COVID-19 in Aged People: A Systematic Review. Nutrients 2021;13. [PubMed abstract]
  309. Yisak H, Ewunetei A, Kefale B, Mamuye M, Teshome F, Ambaw B, et al. Effects of Vitamin D on COVID-19 Infection and Prognosis: A Systematic Review. Risk Manag Healthc Policy 2021;14:31-8. [PubMed abstract]
  310. Pereira M, Dantas Damascena A, Galvão Azevedo LM, de Almeida Oliveira T, da Mota Santana J. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Crit Rev Food Sci NutrCrit Rev Food Sci Nutr 2020:1-9. [PubMed abstract]
  311. Townsend L, Dyer AH, McCluskey P, O’Brien K, Dowds J, Laird E, et al. Investigating the Relationship between Vitamin D and Persistent Symptoms Following SARS-CoV-2 Infection. Nutrients 2021;13:2430. [PubMed abstract]
  312. Smolders J, van den Ouweland J, Geven C, Pickkers P, Kox M. Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence. Metabolism: clinical and experimental 2021;115:154434. [PubMed abstract]
  313. Annweiler G, Corvaisier M, Gautier J, Dubée V, Legrand E, Sacco G, et al. Vitamin D supplementation associated to better survival in hospitalized frail elderly COVID-19 patients: The GERIA-COVID Quasi-Experimental Study. Nutrients 2020;12. [PubMed abstract]
  314. Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, Martin-Escalante MD, Cortes-Rodriguez B, et al. Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study. Nutrients 2021;13:1760. [PubMed abstract]
  315. Ling SF, Broad E, Murphy R, Pappachan JM, Pardesi-Newton S, Kong MF, et al. High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study. Nutrients 2020;12. [PubMed abstract]
  316. Malaguarnera L. Vitamin D3 as potential treatment adjuncts for COVID-19. Nutrients 2020;12. [PubMed abstract]
  317. Lanham-New SA, Webb AR, Cashman KD, Buttriss JL, Fallowfield JL, Masud T, et al. Vitamin D and SARS-CoV-2 virus/COVID-19 disease. BMJ Nutr Prev Health 2020;3:106-10. [PubMed abstract]
  318. Zwart SR, Smith SM. Vitamin D and COVID-19: Lessons from spaceflight analogs. J Nutr 2020;150:2624-7. [PubMed abstract]
  319. DeLuccia R, Clegg D, Sukumar D. The implications of vitamin D deficiency on COVID-19 for at-risk populations. Nutr Rev 2020. [PubMed abstract]
  320. Brenner H, Holleczek B, Schöttker B. Vitamin D insufficiency and deficiency and mortality from respiratory diseases in a cohort of older adults: potential for limiting the death toll during and beyond the COVID-19 pandemic? Nutrients 2020;12. [PubMed abstract]
  321. Weiss ST. Vitamin D and COVID-19: Can it be protective? Am J Clin Nutr 2021. [PubMed abstract]
  322. Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity. Journal of infection and public health 2020;13:1373-80. [PubMed abstract]
  323. vitamindforall.org. Over 200 scientists, doctors, & leading authorities call for increased vitamin d use to combat COVID-19external link disclaimer. 2020.
  324. National Institute for Health and Care Excellence. COVID-19 rapid guideline: vitamin D, NICE guideline [NG187]external link disclaimer. 2020.
  325. Buttriss JL, Lanham-New SA. Is a vitamin D fortification strategy needed? Nutr Bull 2020;45:115-22 [PubMed abstract]
  326. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CSC, et al. Effect of a single high dose of vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19, a randomized clinical trial. JAMA 2021:8. [PubMed abstract]
  327. Sabico S, Enani MA, Sheshah E, Aljohani NJ, Aldisi DA, Alotaibi NH, et al. Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial. Nutrients 2021;13. [PubMed abstract]
  328. ClinicalTrials.gov. Trial of vitamin D to reduce risk and severity of COVID-19 and other acute respiratory infections (CORONAVIT)external link disclaimer. 2020.
  329. ClinicalTrials.gov. Vitamin D and COVID-19 Trial (VIVID)external link disclaimer. 2021.
  330. Galior K, Grebe S, Singh R. Development of vitamin D toxicity from overcorrection of vitamin D deficiency: A review of case reports. Nutrients 2018;10. [PubMed abstract]
  331. Auguste BL, Avila-Casado C, Bargman JM. Use of vitamin D drops leading to kidney failure in a 54-year-old man. CMAJ 2019;191:E390-e4. [PubMed abstract]
  332. Vogiatzi MG, Jacobson-Dickman E, DeBoer MD. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab 2014;99:1132-41. [PubMed abstract]
  333. Robien K, Oppeneer SJ, Kelly JA, Hamilton-Reeves JM. Drug-vitamin D interactions: a systematic review of the literature. Nutr Clin Pract 2013;28:194-208. [PubMed abstract]
  334. Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. A randomized, double-blind, placebo-controlled trial. Ann Int Med 1996;125:961-8. [PubMed abstract]
  335. Lee GY, Han SN. The Role of Vitamin E in Immunity. Nutrients 2018;10: 1614. NEW 30388871 333. James PT, Ali Z, Armitage AE, Bonell A, Cerami C, Drakesmith H, et al. The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review. J Nutr 2021;151:1854-78. [PubMed abstract]
  336. James PT, Ali Z, Armitage AE, Bonell A, Cerami C, Drakesmith H, et al. The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review. J Nutr 2021;151:1854-78. [PubMed abstract]
  337. Fiorino S, Gallo C, Zippi M, Sabbatani S, Manfredi R, Moretti R, et al. Cytokine storm in aged people with CoV-2: possible role of vitamins as therapy or preventive strategy. Aging Clin Exp Res 2020;32:2115-31. [PubMed abstract]
  338. Jayawardena R, Sooriyaarachchi P, Chourdakis M, Jeewandara C, Ranasinghe P. Enhancing immunity in viral infections, with special emphasis on COVID-19: A review. Diabetes Metab Syndr 2020;14:367-82. [PubMed abstract]
  339. Meydani SN, Barklund MP, Liu S, Meydani M, Miller RA, Cannon JG, et al. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr 1990;52:557-63. [PubMed abstract]
  340. Meydani SN, Meydani M, Blumberg JB, Leka LS, Siber G, Loszewski R, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA 1997;277:1380-6. [PubMed abstract]
  341. De la Fuente M, Hernanz A, Guayerbas N, Victor VM, Arnalich F. Vitamin E ingestion improves several immune functions in elderly men and women. Free Radic Res 2008;42:272-80. [PubMed abstract]
  342. Rozga M, Cheng FW, Moloney L, Handu D. Effects of Micronutrients or Conditional Amino Acids on COVID-19-Related Outcomes: An Evidence Analysis Center Scoping Review. J Acad Nutr Diet 2021;121:1354-63. [PubMed abstract]
  343. Meydani SN, Leka LS, Fine BC, Dallal GE, Keusch GT, Singh MF, et al. Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. JAMA 2004;292:828-36. [PubMed abstract]
  344. Hemilä H. Vitamin E administration may decrease the incidence of pneumonia in elderly males. Clin Interv Aging 2016;11:1379-85. [PubMed abstract]
  345. Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial. JAMA 2002;288:715-21. [PubMed abstract]
  346. Jovic TH, Ali SR, Ibrahim N, Jessop ZM, Tarassoli SP, Dobbs TD, et al. Could Vitamins Help in the Fight Against COVID-19? Nutrients 2020;12. [PubMed abstract]
  347. ClinicalTrials.gov. Anti-inflammatory/Antioxidant Oral Nutrition Supplementation in COVID-19 (ONSCOVID19)external link disclaimer. 2021.
  348. Doyle C, Kushi LH, Byers T, Courneya KS, Demark-Wahnefried W, Grant B, et al. Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices. CA Cancer J Clin 2006;56:323-53. [PubMed abstract]
  349. Natural Medicines Comprehensive Database. Vitamin Eexternal link disclaimer. 2021.
  350. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Washington, DC: National Academy Press; 2001.
  351. Prasad AS. Zinc: an overview. Nutrition 1995;11:93-9. [PubMed abstract]
  352. Lazzerini M. Oral zinc provision in acute diarrhea. Curr Opin Clin Nutr Metab Care 2016;19:239-43. [PubMed abstract]
  353. Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients 2017;9. [PubMed abstract]
  354. Wessels I, Rolles B, Rink L. The potential impact of zinc supplementation on COVID-19 pathogenesis. Front Immunol 2020;11:1712. [PubMed abstract]
  355. Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The role of zinc in antiviral immunity. Adv Nutr 2019;10:696-710. [PubMed abstract]
  356. Prasad AS. Lessons learned from experimental human model of zinc deficiency. J Immunol Res 2020;2020:9207279. [PubMed abstract]
  357. Wintergerst ES, Maggini S, Hornig DH. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 2007;51:301-23. [PubMed abstract]
  358. Meydani SN, Barnett JB, Dallal GE, Fine BC, Jacques PF, Leka LS, et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr 2007;86:1167-73. [PubMed abstract]
  359. Barnett JB, Hamer DH, Meydani SN. Low zinc status: a new risk factor for pneumonia in the elderly? Nutr Rev 2010;68:30-7. [PubMed abstract]
  360. Reider CA, Chung RY, Devarshi PP, Grant RW, Hazels Mitmesser S. Inadequacy of immune health nutrients: Intakes in US adults, the 2005-2016 NHANES. Nutrients 2020;12. [PubMed abstract]
  361. de Almeida Brasiel PG. The key role of zinc in elderly immunity: A possible approach in the COVID-19 crisis. Clin Nutr ESPEN 2020;38:65-6. [PubMed abstract]
  362. Rahman MT, Idid SZ. Can Zn be a critical element in COVID-19 treatment? Biol Trace Elem Res 2020:1-9. [PubMed abstract]
  363. Skalny AV, Rink L, Ajsuvakova OP, Aschner M, Gritsenko VA, Alekseenko SI, et al. Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review). Int J Mol Med 2020;46:17-26. [PubMed abstract]
  364. Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM Open 2017;8:2054270417694291. [PubMed abstract]
  365. Santos HO. Therapeutic supplementation with zinc in the management of COVID-19-related diarrhea and ageusia/dysgeusia: mechanisms and clues for a personalized dosage regimen. Nutrition Rev 2021. [PubMed abstract]
  366. Abdelmaksoud AA, Ghweil AA, Hassan MH, Rashad A, Khodeary A, Aref ZF, et al. Olfactory Disturbances as Presenting Manifestation Among Egyptian Patients with COVID-19: Possible Role of Zinc. Biol Trace Elem Res 2021:1-8. [PubMed abstract]
  367. Propper RE. Smell/Taste alteration in COVID-19 may reflect zinc deficiency. J Clin Biochem Nutr 2021;68:3. [PubMed abstract]
  368. Vogel-González M, Talló-Parra M, Herrera-Fernández V, Pérez-Vilaró G, Chillón M, Nogués X, et al. Low zinc levels at admission associates with poor clinical outcomes in SARS-CoV-2 infection. Nutrients 2021;13. [PubMed abstract]
  369. Jothimani D, Kailasam E, Danielraj S, Nallathambi B, Ramachandran H, Sekar P, et al. COVID-19: Poor outcomes in patients with zinc deficiency. Int J Infect Dis 2020;100:343-9. [PubMed abstract]
  370. Heller RA, Sun Q, Hackler J, Seelig J, Seibert L, Cherkezov A, et al. Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker. Redox Biol 2021;38:101764. [PubMed abstract]
  371. Ryu M, Aydemir TB. Zinc. In: Marriott BP, Birt DF, Stallings VA, Yates AA, eds. Present Knowledge in Nutrition Cambridge, MA: Elsevier; 2020:393-408.
  372. Finzi E. Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients. International journal of infectious diseases : Int J Infect Dis 2020;99:307-9. [PubMed abstract]
  373. Carlucci PM, Ahuja T, Petrilli C, Rajagopalan H, Jones S, Rahimian J. Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients. J Med Microbiol 2020;69:1228-34. [PubMed abstract]
  374. Yao JS, Paguio JA, Dee EC, Tan HC, Moulick A, Milazzo C, et al. The minimal effect of zinc on the survival of hospitalized patients with COVID-19: An observational study. Chest 2021;159:108-11. [PubMed abstract]
  375. Abd-Elsalam S, Soliman S, Esmail ES, Khalaf M, Mostafa EF, Medhat MA, et al. Do zinc supplements enhance the clinical efficacy of hydroxychloroquine?: A randomized, multicenter trial. Biol Trace Elem Res 2020:1-5. [PubMed abstract]
  376. National Institutes of Health. COVID-19 Treatment Guidelines, Zinc Supplementation and COVID-19. 2021.
  377. ClinicalTrials.gov. Placebo controlled trial to evaluate zinc for the treatment of COVID-19 in the outpatient settingexternal link disclaimer. 2021.
  378. ClinicalTrials.gov. A study of hydroxychloroquine, vitamin C, vitamin D, and zinc for the prevention of COVID-19 infection (HELPCOVID-19)external link disclaimer. 2021.
  379. Hooper PL, Visconti L, Garry PJ, Johnson GE. Zinc lowers high-density lipoprotein-cholesterol levels. JAMA 1980;244:1960-1. [PubMed abstract]
  380. Florez ID, Veroniki AA, Al Khalifah R, Yepes-Nuñez JJ, Sierra JM, Vernooij RWM, et al. Comparative effectiveness and safety of interventions for acute diarrhea and gastroenteritis in children: A systematic review and network meta-analysis. PLoS One 2018;13:e0207701. [PubMed abstract]
  381. Lazzerini M, Wanzira H. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev 2016;12:Cd005436. [PubMed abstract]
  382. Penttilä O, Hurme H, Neuvonen PJ. Effect of zinc sulphate on the absorption of tetracycline and doxycycline in man. Eur J Clin Pharmacol 1975;9:131-4. [PubMed abstract]
  383. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson's disease with zinc: XI. Interaction with other anticopper agents. J Am coll Nutr 1993;12:26-30. [PubMed abstract]
  384. Wester PO. Urinary zinc excretion during treatment with different diuretics. Acta Med Scand 1980;208:209-12. [PubMed abstract]
  385. Lomaestro BM, Bailie GR. Absorption interactions with fluoroquinolones. 1995 update. Drug Saf 1995;12:314-33. [PubMed abstract]

Disclaimer

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 product or service, or recommendation from an organization or professional society, does not represent an endorsement by ODS of that product, service, or expert advice.

Updated: January 18, 2023 History of changes to this fact sheet