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Dietary Supplements in the Time of COVID-19

Fact Sheet for Health Professionals
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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 over 170 million people worldwide as of June 1, 2021 [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, thousands of individuals—possibly 10% to 75%—who have had COVID-19 report symptoms of "long COVID" (including fatigue, muscle weakness, sleep difficulties, and cognitive dysfunction) for several months after the acute stage of illness has passed [4-7].

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 [8]. 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 [9-11].

The immune system defends the body against pathogens that cause disease and is comprised of innate responses, which are the first line of defense, and adaptive responses, which become engaged later [12-14].

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 identify 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 [12,13].

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 [14]. 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 [12,14]. Vaccinations target the adaptive immune system, protecting the body from an exposure to the same pathogen in the future [13].

The body’s immune response to pathogens leads to inflammation, causing redness, swelling, heat, pain, and loss of tissue function [15]. Inflammation helps eliminate the pathogen and initiate the healing process, but it is also a cause of symptoms and severe pathologies [15,16]. 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 [165]. 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 [3,17]. 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 [13,18]. Other dietary supplement ingredients, such as botanicals and probiotics, do not have essential roles in the body, but they might affect immune function. However, 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.

Although COVID-19 vaccines are now available and pharmacologic treatments are being developed, 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.

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.

The content of this fact sheet is current as of the publication date, but because this is a rapidly 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 [19]. Its leaves and aerial parts are used in traditional Ayurvedic, Chinese, and Thai medicine for relieving symptoms of the common cold, influenza, and other respiratory tract infections [20-23]. The purported 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 [19,21,21-28].

Efficacy: Studies conducted before the emergence of COVID-19 suggest that andrographis supplementation might reduce the severity of respiratory tract infections [21,22,29,30]. 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 [25,27,28,31].

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 [26,27,31]. 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 3 times per day in 12 people with mild to moderate COVID-19 symptoms [32-34]. 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 [35]. 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 aged 18 to 60 with minor symptoms within 72 hours of a COVID-19 diagnosis [32,36]. One clinical trialexternal link disclaimer in Tibilisi, Georgia is examining whether a product called Kan-Jang® that contains andrographis and Eleutherococcus senticosus (2 capsules, 3 times per day for a total daily dose of 90 to 120 mg of andrographolides) for 2 weeks reduces the severity of inflammatory symptoms (including headache, loss of smell, nasal congestion, cough, muscle pain, and fever) in about 140 adults hospitalized with mild COVID-19 [37]. ClinicalTrials.govexternal link disclaimer does not list any other studies on the use of andrographis for managing COVID-19 symptoms.

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 short periods [22,23,38]. Clinical trials have found minor adverse effects, including nausea, vomiting, vertigo, skin rashes, diarrhea, and fatigue [21,23,29]. Allergic reactions might also occur [22,27]. 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 [20,22,24].

Whether the potential immunostimulatory effect of andrographis might worsen the cytokine storm associated with COVID-19 is not known [28].

Echinacea

Echinacea, commonly known as purple coneflower, is an herb that grows in North America and Europe [39]. 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 [40].

Echinacea contains volatile terpenes, polysaccharides, polyacetylenes, alkamides, phenolic compounds, caffeic acid esters, and glycoproteins [39-41]. However, echinacea’s purported active constituents are not well defined [41], and the chemical composition of various echinacea species differs [40].

Echinacea might have antioxidant and antibacterial activities, stimulate monocytes and natural killer cells, and inhibit viruses from binding to host cells [14,39]. It might also reduce inflammation by inhibiting inflammatory cytokines [14]. 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 [39,41].

Efficacy: Several studies suggest that echinacea offers limited benefits for preventing the common cold [42,43], so some researchers have suggested that echinacea might have similar effects on COVID-19 [14,28,44,45]. However, no studies have evaluated the use of echinacea to prevent or treat COVID-19 in humans.

A preliminary in vitro study found that Echinaforce, a product containing E. purpurea, inactivated SARS-CoV-2 [46]. According to ClinicalTrials.govexternal link disclaimer, no clinical trials are currently planned or underway to assess the effects of echinacea on COVID-19, although studies are assessing echinacea’s effects on the immune system and on the common cold and other upper respiratory tract infections.

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 [44]. However, limited evidence from clinical trials suggests that the use of echinacea decreases—not increases—levels of proinflammatory cytokines [44].

Safety: Echinacea appears to be safe and has few reported adverse effects, the most common of which are gastrointestinal upset and skin rashes [41,47]. 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 [41].

The safety of echinacea during pregnancy is not known, so experts recommend against the use of echinacea supplements by pregnant women [48].

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 [49,50]. Elderberry contains many compounds—including anthocyanins, flavonols, and phenolic acids—that might have antioxidant, anti-inflammatory, antiviral, antimicrobial, and immune-stimulating effects [14,50-54]. Studies of the effects of elderberry have primarily used elderberry extracts, not the berries themselves [50].

Efficacy: Sales of elderberry supplements more than doubled shortly after the COVID-19 pandemic began in the United States [55], and some researchers have recommended studying the use of elderberry to treat COVID-19 symptoms [14,52,56,57].

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 [50]. Elderberry’s effects on the common cold and influenza have been examined in a few small clinical trials with promising results [51], but no clinical trials have evaluated the use of elderberry to prevent or treat COVID-19. ClinicalTrials.gov lists one trialexternal link disclaimer that will examine the ability of a combination of 600 milligrams (mg) elderberry extract with hydroxychloroquine, azithromycin, zinc, vitamin C, vitamin D, N-acetylcysteine, and quercetin to prevent or treat COVID-19 in about 5,000 children and adults [58]. However, this trial has not yet begun to recruit participants, so whether it will move forward is not clear. At this time, no other trials involving elderberry for COVID-19 are planned or in progress, according to ClinicalTrials.govexternal link disclaimer.

Safety: Elderberry flowers and ripe fruit appear to be safe for consumption, but 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 [50,55,59]. The heat from cooking destroys this toxin, so cooked elderberry fruit and properly processed commercial products do not pose this safety concern [14,50,52,55,59]. Elderberry might affect insulin and glucose metabolism, so according to experts, people with diabetes should use it with caution [555]. The safety of elderberry during pregnancy is not known, so experts recommend against the use of elderberry supplements by pregnant women [48,50].

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 [49]. This adulteration might be due to the surge in popularity of these products, which could have created a supply shortage.

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) [60,61]. Asian ginseng grows mainly in China and Korea, whereas American ginseng grows in the United States and Canada [60].

Triterpene glycosides, also known as ginsenosides, are some of the main purported active constituents in ginseng [60,62]. 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 [60,62]. Both the product preparation method and variations of intestinal microbiota among individuals can affect the type and quantity of ginseng’s bioactive compounds in the body [62].

Animal and laboratory studies suggest that ginseng stimulates B-lymphocyte proliferation and increases production of some interleukins and interferon-gamma [60]; these cytokines affect immune activation and modulation [12]. 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 [60,63].

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 [60].

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 [62,64]. 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 to prevent or treat COVID-19 [65,66]. 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 [67]. According to ClinicalTrials.govexternal link disclaimer, no other clinical trials using ginseng alone or in combination with other ingredients to prevent or treat COVID-19 are planned or underway.

Safety: Ginseng appears to be safe. Most of its adverse effects, including headache, sleep difficulty, and gastrointestinal symptoms, are minor [62-64]. However, doses of more than 2.5 g/day might cause insomnia, tachyarrhythmias, hypertension, and nervousness [60,62].

A few case reports of vaginal bleeding and mastalgia (breast pain) in the 1970s and 1980s raised concerns about the safety of ginseng; some scientists concluded that ginseng has estrogenic effects [68-71]. However, one of these case reports involved use of "Rumanian ginseng" [70], 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." Nevertheless, some experts caution that ginseng might not be safe for use during pregnancy [62,72,71].

Melatonin

Melatonin is a hormone produced by the pineal gland in the brain, mainly during the night, that helps regulate circadian rhythms [74,75]. Its levels decrease with aging [75]. Most melatonin supplementation studies have evaluated its ability to control sleep and wake cycles, promote sleep, and reduce jet lag [75].

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 [25,76,77]. Melatonin also appears to have anti-inflammatory and antioxidant effects [25,74-78]. However, whether these properties have a clinically significant effect on immunity in humans is not clear.

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 [25,76-79].

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 [80]. In addition, some clinical trial evidence suggests that melatonin might help attenuate cytokine levels in people with diabetes, multiple sclerosis, and other health conditions [77]. Therefore, some researchers believe that melatonin supplements might help modulate the cytokine storm that can develop in COVID-19 [77], but studies have not tested this hypothesis.

According to ClinicalTrials.govexternal link disclaimer, several 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 aged 18 years and older with COVID-19 who are not hospitalized [81]. 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 aged 50 years and older with COVID-19 who have not been hospitalized [82].

Safety: Typical doses of 1–10 mg/day melatonin appear to be safe for short-term use [25,83]. Reported side effects, which are usually minor, include dizziness, headache, nausea, upset stomach, rash, and sleepiness [75,83]. However, some reports have linked high blood levels of melatonin with delayed puberty and hypogonadism [75].

Studies have not evaluated melatonin supplementation during pregnancy and breastfeeding, but some research suggests that these supplements might inhibit ovarian function [84]. Therefore, some experts recommend that women who are pregnant or breastfeeding avoid taking melatonin [83].

N-acetylcysteine

N-acetylcysteine (NAC) is a derivative of the amino acid cysteine. It is an antioxidant and increases glutathione levels in the body [85,86]. NAC has mucolytic activity, so it helps reduce respiratory mucus levels [85,87]. Laboratory research suggests that NAC might boost immune system function and suppress viral replication [87]. NAC also decreases levels of interleukin-6 and has other anti-inflammatory effects [85,86].

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 [88]. Products containing NAC are also sold as dietary supplements [89].

Efficacy: No evidence shows that NAC helps 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 [90,91].

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 [85-87]. Several clinical trialsexternal link disclaimer are examining this possibility. For example, one small trialexternal link disclaimer in Mexico will evaluate the effects of 600 mg NAC every 12 hours, combined with the drug pentoxifylline, for 5 days in about 11 children and adults with COVID-19 and severe pneumonia [92]. Another trialexternal link disclaimer is examining whether NAC combined with glycine for 2 weeks improves outcomes in about 64 hospitalized adults aged 55 to 85 years who have COVID-19 [93].

Safety: As an FDA-approved drug, the safety profile of NAC has been evaluated [88]. Reported side effects of oral NAC include nausea, vomiting, abdominal pain, diarrhea, indigestion, and epigastric discomfort [91]. No safety concerns have been reported for products labeled as dietary supplements that contain NAC.

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 [94]. 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 [94]. Omega-3s also form eicosanoids; these signaling molecules affect the body’s cardiovascular, pulmonary, immune, and endocrine systems [94,95]. 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 [96,97].

Higher intakes and blood levels of EPA and DHA are associated with lower levels of inflammatory cytokines [95,97]. 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 [13,95,99].

A deficiency of omega-3s can cause rough, scaly skin and dermatitis [94]. 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 [100].

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 aged 16 to 90 years was associated with a 12% lower risk of SARS-CoV-2 infection after adjustment for potential confounders [101]. 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 [13,96,98,102-106]. 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 [98]. 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 [107]. 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 aged 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 [108]. Another clinical 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 aged 18 to 75 years [109].

Safety: The FDA recommends not exceeding 3 g/day EPA and DHA combined, including up to 2 g/day from dietary supplements [110]. Some doses used in clinical trials exceed these amounts. 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 [94].

Doses of 2–15 g/day EPA and/or DHA might also increase bleeding time by reducing platelet aggregation [94]. 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 [111]. EFSA noted that these doses have not been shown to cause bleeding problems or affect immune function, glucose homeostasis, or lipid peroxidation.

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 [112,113].

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 [114]. 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 [115]. 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 [16]. 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 [16,116,117]. In addition, research findings for one probiotic strain cannot be extrapolated to others [16,118].

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 [117,119-122]. 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 [123,124]. 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 aged 16 to 90 years was associated with a 14% lower risk of SARS-CoV-2 infection after adjustment for potential confounders [101]. Findings were similar for 45,757 individuals in the United States and for 27,373 participants in Sweden.

Because of these findings, many researchers believe that probiotics could be useful adjuvant therapies to treat COVID-19 [106,125-131]. This possibility was examined in a clinical trial in Italy among 70 patients (median age 59 years) hospitalized with COVID-19 [132]. 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 the intensive care unit (ICU), and respiratory failure.

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 aged 18 years and older with moderate forms of the disease who are not hospitalized [133]. Another trialexternal link disclaimer is examining the effects of Lactobacillus rhamnosus GG supplementation for 28 days on the microbiome of about 1,000 children and adults aged 1 year and older with a household exposure to someone diagnosed with COVID-19 but who do not have any COVID-19 symptoms [134].

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 [116]. Side effects, which are usually minor, include gastrointestinal symptoms, such as gas [16,115]. However, potential safety concerns can include systemic infections, especially in individuals who are immunocompromised [116]. 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 [135,136].

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

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, kiwifruit, broccoli, strawberries, brussels sprouts, and cantaloupe. The Recommended Dietary Allowance (RDA; average daily level of intake sufficient to meet the nutrient requirement of 97–98% healthy individuals) 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 [137].

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 [138-141]. 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 [139]. It might also inhibit viral replication [142].

Vitamin C deficiency impairs immune function and increases susceptibility to infections [139]. Some research suggests that supplemental vitamin C enhances immune function [143], but its effects might vary depending on an individual’s vitamin C status [144].

Vitamin C deficiency is uncommon in the United States, affecting only about 7% of individuals aged 6 years and older [145]. 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 [140,143].

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 [78,105,106,138,139,144-147].

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 [138,142]. 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 [142]. In addition, vitamin C supplementation might benefit people with pneumonia who have low vitamin C levels [150], as well as people with viral infections, including Epstein-Barr and herpes zoster [143]. Vitamin C’s antioxidant action might also help reduce oxidative stress during infections [138,142]. People with low vitamin C status might benefit more from vitamin C supplementation than those who already obtain sufficient vitamin C [144].

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 [149]. 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 [151]. 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 [152]. 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 (dose not reported) more than three times per week for at least 3 months among 372,720 U.K. residents aged 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 [101].

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 [153]. 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 [154]. The 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 [155]. 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 [156]. 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 [157]. 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 [141]. However, the Panel concludes that data are insufficient to support a recommendation for or against the use of vitamin C to treat COVID-19 [141].

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 [158]. 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 [82].

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 [137]. These values, 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 [159-161]. In people with hemochromatosis, high doses of vitamin C could exacerbate iron overload and damage body tissues [137,140]. The FNB recommends that these individuals be cautious about consuming vitamin C doses above the RDA [137].

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), fish liver oils, 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 international units [IU] to 600 IU) for children (depending on age) and from 15 to 20 mcg (600 to 800 IU) for adults [162]. 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 [162]. 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 [162]. 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 [163]. Vitamin D appears to lower viral replication rates, suppress inflammation, and increase levels of T-regulatory cells and their activity [78,147,164-167]. 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 [147,164,165,167].

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 [168,169]. Surveys indicate that most people in the United States consume less than recommended amounts of vitamin D [170]. Nevertheless, according to a 2011–2014 analysis of serum 25(OH)D concentrations, most people in the United States aged 1 year and older had adequate vitamin D status [171]. 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 [162].

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) [172]. 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 [173-181] but others do not [182-185]. 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]) [173]. 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 [174]. 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 [175]. 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, or risk of mortality, ICU admission, or need for ventilation among COVID-19 patients [186]. However, mean 25(OH)D levels were significantly lower in COVID-19 patients than healthy individuals, based on the results from 5 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 [177,187-191] and that people who regularly took vitamin D supplements (amounts not specified) were less likely to develop COVID-19 than those who did not [192]. 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 [193]. 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 [194]. 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 [166,194].

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 [162,195]. 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, BMI category, age at assessment, and sex [185].

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 [196]. 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 [197-199]. However, these reviews found inconsistent associations between vitamin D status and risk of SARS-CoV-2 infection.

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 pre-infection 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 [200]. 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 aged 16 to 90 years was associated with a 9% lower risk of SARS-CoV-2 infection after adjustment for potential confounders [101]. 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 [201]. In addition, a non-randomized 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 [202].

Because of these findings, many researchers recommend additional research on whether higher vitamin D intakes can reduce the risk and severity of COVID-19 [78,105,106,147,166,167,173,177,187,188,194,203-209].

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 [210]. 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 [165]. 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 [211]. However, the United Kingdom does not fortify milk with vitamin D [212]. 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 [211].

A study of 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 [213]. 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)].

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 aged 16 years and older [214]. 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 aged 30 years and older who were recently diagnosed with COVID-19 helps reduce the severity of disease and risk of transmission to household members [215].

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 children (depending on their age) and up to 100 mcg (4,000 IU) are safe for adults [162]. These values, 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 [216-218].

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

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 [219].

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 [13,219-222]. Zinc also has antiviral and anti-inflammatory properties, and it helps maintain the integrity of tissue barriers, such as the respiratory epithelia [78,2223,224].

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 [13,220,222,225,226]. Furthermore, zinc deficiency is associated with elevated levels of proinflammatory mediators [223]. These effects on immune response probably increase susceptibility to infections [227] and inflammatory diseases, especially those affecting the lungs [223].

Studies have found associations between low zinc status and increased risk of viral infections [163], and people with zinc deficiency have a higher risk of diarrhea and respiratory diseases [13]. Poor zinc status is also common among individuals with HIV and hepatitis C and is a risk factor for pneumonia in older adults [224,226,228,229].

Although zinc deficiency is not common in the United States, 15% of the U.S. population might obtain marginal amounts of zinc [230]. 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 [78,85,105,106,147,223,226,231-233]. Evidence that zinc lozenges might help shorten the duration of the common cold [234] has also spurred interest in zinc supplementation to help treat COVID-19.

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 [235]. However, 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 aged 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 [101].

In a case report from the United States, four patients aged 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 [236]. 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 [237]. All patients were treated with hydroxychloroquine and azithromycin, and 411 also received 220 mg zinc sulfate supplementation that provided 50 mg elemental zinc 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 [238]. 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 [239]. 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 [153]. 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 [240]. 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 220 mg/day zinc sulfate (50 mg elemental zinc) in adults aged 60 years or older or aged 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 [241]. Another trialexternal link disclaimer is investigating whether supplementation with zinc, vitamin C, vitamin D, and hydroxychloroquine for 24 weeks helps prevent COVID-19 in about 600 medical workers aged 18 years and older [242].

Safety: Intakes up to 4–34 mg/day zinc in foods and dietary supplements for children (depending on age) and up to 40 mg/day for adults are safe [219]. These values, 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 [219]. Chronic consumption of 150–450 mg/day can cause low copper status, reduced immune function, and reduced levels of high-density lipoproteins [243]. In clinical trials among children, zinc supplementation to treat diarrhea increased the risk of vomiting more than placebo [244,245].

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

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Disclaimer

This fact sheet by the Office of Dietary Supplements (ODS) provides information that should not take the place of medical advice. We encourage you to talk to your healthcare 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: June 18, 2021 History of changes to this fact sheet