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 caused a global pandemic [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 post-acute sequelae of COVID (including breathlessness, cough, fatigue, muscle aches and weakness, sleep difficulties, and cognitive dysfunction), commonly known as long COVID, for weeks, months, or years after the acute stage of illness has passed [4-8]. The risk of long COVID appears to be higher in people who are hospitalized following SARS-CoV-2 infection compared with those who have less severe disease. It also appears to be higher in those who are not vaccinated against COVID-19 compared with those who are vaccinated [4].
Currently, data are insufficient to support recommendations for or against the use of any vitamin, mineral, herb, fatty acid, or other dietary supplement ingredient to prevent or treat COVID-19 [9]. Nevertheless, the sales of dietary supplements marketed to support immune health increased after the emergence of COVID-19 [10,11]. 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 [12].
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 [13-15].
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 [13,14].
The adaptive immune system is pathogen specific and 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) that destroy infected cells (a process known as cell-mediated immunity) [15]. 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 [13,15]. Vaccinations enable the adaptive immune system to protect the body from exposures to the same pathogen in the future [14].
The body’s immune response to pathogens leads to inflammation, causing redness, swelling, heat, pain, and a loss of tissue function [16]. Inflammation helps eliminate the pathogen and initiate the healing process, but it can also cause symptoms and severe pathologies [16,17]. For example, the 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 [17]. Other signs of inflammation that can appear in patients with COVID-19 include elevated levels of C-reactive protein and interleukin-6 [2]. Some patients with COVID-19 experience a cytokine storm, a critical condition caused by the excessive production of inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 [3,18]. This condition increases disease severity and the 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 [9,14,19]. Other dietary supplement ingredients, such as botanicals and probiotics, do not have essential roles in the body but might affect immune function.
Some studies have investigated whether dietary supplement ingredients might enhance immune function in people with COVID-19. However, measuring the impact that vitamins, minerals, and other dietary supplement ingredients have on the immune system is difficult because the immune system is a complex network of organs, tissues, and cells. Immune function can be assessed indirectly by examining a person’s risk of infectious diseases and the severity of their symptoms, but there is no single method for directly measuring immune system function and resistance to disease [20,21]. This can make it difficult to interpret the results of clinical trials that evaluate the use of supplements in people with COVID-19. In addition, many of these trials were exploratory, had small sample sizes, were not randomized or placebo controlled, and used varying supplement doses and formulations [22-24].
Other studies have examined the associations between serum or plasma concentrations of vitamins or minerals and the risk of COVID-19 or disease severity. However, serum or plasma nutrient concentrations might not reflect body stores [25]. Furthermore, the onset of disease can alter nutrient concentrations [26,27]; it cannot be assumed that the nutrient concentrations observed in these studies contributed to the onset of COVID-19 or its severity.
This fact sheet summarizes the state of the science on the safety and efficacy of several dietary supplements. Ingredients are presented in alphabetical order. 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 [28,29].
Andrographis
Andrographis paniculata, also known as Chuān Xīn Lián, is an herb that is native to subtropical and Southeast Asia [30]. 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 [31-34]. 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 [30,32,34-39].
Efficacy
Because studies conducted before the emergence of COVID-19 suggested that andrographis supplementation might reduce the severity of respiratory tract infections [32,33,40,41], some researchers have investigated whether andrographis might have a similar effect on COVID-19.
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 [37,38,42,43]. 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 [44-46]. COVID-19 symptoms, especially cough, improved within a few days after patients started taking the lower dose (60 mg) of andrographis, and all patients recovered after 3 weeks [47]. 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 years with minor symptoms within 72 hours of a COVID-19 diagnosis [44,48]. Andrographis is commonly used in Thailand in patients with mild COVID-19 [49]. A retrospective study of 605 hospitalized patients (mostly unvaccinated) with mild COVID-19 who took andrographis extract (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 due to COVID-19 [49]. In a clinical trial in Thailand, 146 patients with mild to moderate COVID-19 were randomized to receive either andrographis extract (180 mg/day andrographolide) for 5 days or placebo [50]. Both groups also received the antiviral medication favipiravir as part of standard treatment. The study evaluated whether the use of andrographis could prevent progression to severe COVID-19, but there was no significant difference between the groups in the proportion of patients who progressed to severe disease by day 4 (1.37% in the andrographis group vs. 2.74% in the placebo group). However, the researchers reported a significant decrease in levels of the inflammatory cytokine interleukin-1 beta between days 0 and 5 among patients who received andrographis.
A clinical trial in Tbilisi, Georgia, randomized 86 hospitalized patients with mild to moderate COVID-19 (mean age 45–50 years, vaccination status not specified) into two groups [51]. Thirty-four patients took 6 capsules daily of a product called Kan Jang/Nergecov (containing andrographis and Eleutherococcus senticosus for a total daily dose of 90 mg andrographolides), and 52 patients took a placebo for 14 days. 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 reduce the severity of sore throat, muscle pain, and nasal discharge but not the severity of cough or fever. In addition, the use of Kan Jang/Nergecov did not reduce the duration of hospitalization or the time to viral clearance.
Safety
The safety of andrographis has not been well studied, but no safety concerns have been reported when typical doses of the herb (340–1,200 mg/day) have been used for several days or weeks [33,34,52]. Clinical trials have found minor adverse effects, including nausea, vomiting, vertigo, skin rashes, diarrhea, and fatigue [32,34,40]. Allergic reactions might also occur [34,39]. Findings from some animal studies suggest that andrographis might adversely affect fertility, so experts recommend against using this supplement during pregnancy and the preconception period [31,33,34].
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 [52-54]. Because of its potential immune-stimulating effects, andrographis might also reduce the effectiveness of immunosuppressants [35,52]. Whether the potential immunostimulatory effect of andrographis might worsen the cytokine storm associated with COVID-19 is not known [39].
Echinacea
Echinacea, commonly known as purple coneflower, is an herb that grows in North America and Europe [55]. 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 [28].
Echinacea contains volatile terpenes, polysaccharides, polyacetylenes, alkamides, phenolic compounds, caffeic acid esters, and glycoproteins [28,55,56]. However, echinacea’s purported active constituents are not well defined [56], and the chemical composition of various echinacea species differs [28].
Echinacea might have antioxidant and antibacterial activities, stimulate monocytes and natural killer cells, and inhibit viruses from binding to host cells [15,55]. 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 [15,57]. 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 [55,56].
Efficacy
Several studies suggest that echinacea offers limited benefits for preventing the common cold [58,59], so some research has examined whether echinacea might have similar effects on COVID-19.
A preliminary in vitro study found that Echinaforce, an E. purpurea preparation, inactivated SARS-CoV-2 [60]. However, the results from the few clinical trials that have examined whether echinacea reduces the risk of SARS-CoV-2 infection or the severity of disease have been mixed. A clinical trial in Iran enrolled 100 nonhospitalized adults (mean age 45–47 years) who were suspected to have COVID-19 based on chest computed tomography (CT) scans or x-rays and clinical symptoms [61]. This study was conducted before COVID-19 vaccines were available. Patients received either echinacea (species and dose not specified) plus ginger (Zingiber officinale, dose not specified) and hydroxychloroquine for 7 days or hydroxychloroquine alone. 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 the 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 [62]. 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). None of the participants were vaccinated 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 tested positive for SARS-CoV-2 infection 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 a total of 4,000 mg/day Echinaforce for up to 10 days; all participants also received concomitant treatments. Participants who took Echinaforce were less likely to test positive for SARS-CoV-2 infection 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.
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 [63]. However, limited evidence from clinical trials suggests that the use of echinacea decreases—not increases—levels of proinflammatory cytokines [63].
Safety
Echinacea appears to be safe, and only a few adverse effects have been reported. The most common adverse effects are sleeplessness, skin rashes, and gastrointestinal upset (e.g., diarrhea) [56,64,65]. 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 [56].
The safety of using echinacea during pregnancy is not known, so experts recommend against the use of echinacea supplements by pregnant people [66]. Echinacea might interact with several medications. For example, echinacea might increase cytochrome P450 activity, thereby reducing levels of some drugs metabolized by these enzymes [67]. In addition, echinacea might reduce the effectiveness of immunosuppressants due to its potential immunostimulatory activity [68].
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 [69,70]. Elderberry contains many compounds—including anthocyanins, flavonols, and phenolic acids—that might have antioxidant, anti-inflammatory, antiviral, antimicrobial, and immune-stimulating effects [15,70-74]. Studies of the effects of elderberry have primarily used elderberry extracts, not the berries themselves [70].
Efficacy
Sales of elderberry supplements more than doubled shortly after the COVID-19 pandemic began in the United States [75]. Some research has evaluated whether elderberry could benefit people with COVID-19, but no clinical trials have been completed. The interest in elderberry was 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 [70]. Elderberry’s effects on the common cold and influenza have been examined in a few small clinical trials, with promising results [71]. A 2021 systematic review of five clinical trials of elderberry to prevent or treat viral respiratory illnesses found beneficial effects on some outcomes [76]. 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. However, the authors noted that the evidence is uncertain because the studies were small, heterogeneous, and of poor quality.
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 [70,75,77]. The heat from cooking destroys this toxin, so cooked elderberry fruit and properly processed commercial products do not pose this safety concern [15,70,72,75,77]. Elderberry might affect insulin and glucose metabolism, so according to experts, people with diabetes should use it with caution [75]. The safety of elderberry during pregnancy is not known, so experts recommend against the use of elderberry supplements by pregnant people [66,70].
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 [69].
Due to its potential immunostimulatory activity, elderberry might reduce the effectiveness of immunosuppressant medications [78].
Ginseng
Ginseng is the common name of several species of the genus Panax, most commonly P. ginseng (also called Asian ginseng or Korean ginseng) and P. quinquefolius (American ginseng) [79,80]. Asian ginseng grows mainly in China and Korea, whereas American ginseng grows in the United States and Canada [79].
Triterpene glycosides, also known as ginsenosides, are some of the main purported active constituents of ginseng [79,81]. 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 [79,81]. 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 [81].
Animal and laboratory studies suggest that ginseng stimulates B-cell proliferation and increases the production of some interleukins and interferon-gamma [79]; these cytokines affect immune activation and modulation [13]. 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 [79,82].
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 [79].
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 [81,83].
Safety
Ginseng appears to be safe. Most of its adverse effects, including headache, sleep difficulty, and gastrointestinal symptoms, are minor [81-83]. However, doses of more than 2.5 g/day might cause insomnia, tachyarrhythmias, hypertension, and nervousness [79,81].
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 [84-87]. However, one of these case reports involved use of Rumanian ginseng [86], 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 [81,88,89].
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 [89,90].
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 requirements of 97% to 98% of healthy individuals) ranges from 30 to 410 mg for infants and children, depending on age, and from 310 to 420 mg for adults [91].
Magnesium is a cofactor for more than 600 enzymatic reactions, and it plays a role in blood pressure regulation, normal heart rhythm, and innate and adaptive immunity [14,25,92-94]. Magnesium also has antithrombotic and bronchodilation effects and is required for the activation of vitamin D [92,94-98]. Because of these effects, magnesium supplementation may be beneficial for people with some respiratory disorders, such as asthma and pneumonia [99,100].
Healthy people do not routinely develop overt signs of magnesium deficiency, but many people do not consume the recommended amounts of magnesium [25,101]. 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 [92,95,102-105]. Low magnesium intakes or status are also associated with hypertension, impaired pulmonary function, cardiovascular disease, type 2 diabetes, and obesity [25,98,106]. These conditions are associated with poorer COVID-19 outcomes.
Efficacy
Because of magnesium’s effects on immunity, inflammation, and the cardiovascular system, some scientists have investigated whether magnesium supplementation affects the risk of COVID-19 or the severity of its symptoms.
A few studies have found that people who have COVID-19 develop dysmagnesemia (abnormally low or high blood levels of magnesium) [107-109]. For example, in an analysis of serum magnesium levels in 300 patients (mean age 66.7 years) who were admitted to the hospital with COVID-19 in France, 48% had abnormally low magnesium levels (<0.75 mmol/L) and 9.6% had abnormally high magnesium levels (≥0.95 mmol/L) [109]. In addition, an observational study in Iran among 459 patients (mean age 61.8 years) with COVID-19 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 [107]. However, hypomagnesemia is common in critically ill patients, regardless of their COVID-19 status [98]. Furthermore, renal failure, other health conditions, and the use of certain medications, which might apply to many people with COVID-19, can also cause both hypomagnesemia and hypermagnesemia [110]. 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 [25,111]. 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. For example, a retrospective study in Singapore enrolled 43 hospitalized patients age 50 years or older with COVID-19 [97]. Patients 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 were less likely to need oxygen therapy, intensive care support, or both than those who did not receive the supplementation.
Another small study in Serbia in five hospitalized patients (mean age 39.6 years) with COVID-19, difficulty breathing, and oxygen saturation at or below 95% found that taking a supplement that provided 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 [112]. However, in studies that use combination treatments, the potential contribution of one component is impossible to determine.
A clinical trial in Iran randomized 64 hospitalized adults (mean age 48 years) with moderate COVID-19 to receive either 300 mg magnesium daily or placebo from hospital admission to discharge [113]. Fewer people in the magnesium group required oxygen therapy than in the placebo group (9 patients vs. 14 patients). Magnesium supplementation also significantly improved oxygen saturation in arterial blood. However, patients who received magnesium did not have a shorter average hospital stay than those who received placebo (mean of 7.32 days vs. 7.28 days), and the study found no differences between the two groups in respiratory rate or fever.
Safety
Magnesium in foods is considered safe at any intake. 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 [91]. 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 to 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 [114-117].
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 [118,119]. Its levels decrease with age [119]. Most melatonin supplementation studies have evaluated its ability to control sleep and wake cycles, promote sleep, and reduce jet lag [119]. Studies have also examined the use of melatonin supplements for reducing blood pressure [120].
Laboratory and animal studies suggest that melatonin enhances immune response by increasing the proliferation and maturation of natural killer cells, T and B cells, granulocytes, and monocytes [36,121,122]. Melatonin also appears to have anti-inflammatory and antioxidant effects [36,118,119,121-123]. 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 [124].
Efficacy
Some studies have evaluated the use of melatonin in people with COVID-19 because of its reported anti-inflammatory, antioxidant, and immune-enhancing properties.
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 [125]. However, this study did not report the dose or duration of melatonin supplement use. 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 [126]. 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 from baseline values (suggesting higher oxygen levels) 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.
A few clinical trials have evaluated the use of melatonin as an adjuvant therapy in patients with COVID-19, although none of these were placebo-controlled trials [127-131]. One prospective trial in Iraq randomized 158 patients (mean age 56 years) with severe COVID-19 to receive 10 mg/day melatonin plus standard of care for 14 days or standard of care alone [127]. Patients who received melatonin were less likely to develop thrombosis or sepsis by day 17 than patients who received only standard of care, and a smaller percentage of patients died in the melatonin group (1.2%) than in the standard of care group (17.1%). A study in Iran evaluated the effects of administering 9 mg/day melatonin for 14 days on clinical symptoms in patients (mean age 51–53 years) with mild to moderate COVID-19 [129]. Twenty-four patients were randomized to receive melatonin plus standard of care, while the 20 patients in the control group received standard of care alone. After treatment, the percentage of patients with fatigue, cough, and dyspnea was lower in the melatonin group than in the control group, although there was no difference between the groups in the occurrence of other clinical symptoms. The mean time to hospital discharge was also shorter among patients who received melatonin. No patients died in either group, and no adverse events were reported.
Safety
Typical doses of 1 to 10 mg/day melatonin appear to be safe for short-term use [36,132]. Reported side effects, which are usually minor, include dizziness, headache, nausea, upset stomach, rash, and sleepiness [119,132]. However, some reports have linked high blood levels of melatonin with delayed puberty and hypogonadism [119].
Studies have not evaluated melatonin supplementation during pregnancy and breastfeeding, but some research suggests that these supplements might inhibit ovarian function [133]. Therefore, some experts recommend that people who are pregnant or breastfeeding avoid taking melatonin [132].
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 [134-136].
N-acetylcysteine
N-acetylcysteine (NAC) is a derivative of the amino acid cysteine. It is an antioxidant that increases glutathione levels in the body [137,138]. NAC has mucolytic activity, so it helps reduce respiratory mucus levels [137,139]. Laboratory research suggests that NAC might affect immune system function and suppress viral replication [139]. NAC also decreases levels of interleukin-6 and has other anti-inflammatory effects [137,138].
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) for use as a mucolytic agent and for decreasing respiratory secretion viscosity [140]. Oral products that contain NAC are also sold as dietary supplements[141].
Efficacy
Some 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 [142,143]. Because of these findings and its effects in the body, researchers have examined the use of NAC in patients with COVID-19. In a retrospective study in Greece of 82 patients (mean age 61–64 years) who were 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 [144]. 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 two 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 [126]. Another group of 22 patients received pentoxifylline alone. Patients who received NAC and pentoxifylline had a significantly lower lipid peroxidation index 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 Iran randomized 225 people (mean age 47–54 years) with COVID-19 who were not hospitalized into three groups of 75 patients [145]. None of the participants were vaccinated against COVID-19. One group received 600 mg NAC twice daily for 5 days in addition to standard of care, the second group received the mucolytic medication bromhexine and standard of care, and the third group received standard of care only. Fewer patients in the NAC group (11 patients) required hospitalization than in the standard of care group (21 patients). The study also reported shorter average hospital stays for patients in the NAC group, and while there were seven deaths in the standard of care group, no patients in the NAC group died.
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 [146]. 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. Another trial in Iran evaluated the use of intravenous NAC in 92 patients (mean age 56–59 years) with mild to moderate acute respiratory distress syndrome caused by COVID-19 [147]. Patients in this study received an intravenous infusion of 40 mg/kg/day NAC for 3 days or placebo. The use of NAC did not affect the 28-day mortality rate. The study also reported no differences between the groups in other clinical outcomes, such as the proportion of patients who required mechanical ventilation, the mean number of ventilator-free days, or the median length of hospital stay.
Safety
As an FDA-approved drug, the safety profile of NAC has been evaluated [140]. Reported side effects of oral NAC include nausea, vomiting, abdominal pain, diarrhea, indigestion, and epigastric discomfort [143]. 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 [148]. The combination of NAC and nitroglycerine (a medication used to treat angina) can cause hypotension and severe headaches [149,150].
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 in dietary supplements, such as those containing fish oil. 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; the intake that is assumed to ensure nutritional adequacy) for omega-3s that ranges from 0.5 to 1.6 g/day for infants and children, depending on age, and from 1.1 to 1.6 g/day for adults [151]. The FNB has not established intake recommendations for EPA and DHA specifically because they are not essential nutrients; only the omega-3 fatty acid alpha linolenic acid (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 [151]. Omega-3s also form eicosanoids; these signaling molecules affect the body’s cardiovascular, pulmonary, immune, and endocrine systems [151,152]. 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 [153,154].
Higher intakes and blood levels of EPA and DHA are associated with lower levels of inflammatory cytokines [153,155]. 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 [151]. 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 [156].
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 adjusting for potential confounders [157]. Findings were similar for 45,757 individuals in the United States and for 27,373 participants in Sweden [157].
Because of these findings and the potential anti-inflammatory and immune-stimulating effects of omega-3s, several studies have investigated the use of omega-3s in patients with COVID-19. An analysis of red blood cell levels of EPA plus DHA among 100 hospitalized patients (mean age 72.5 years) with COVID-19 did not find a difference in the risk of death among quartiles of EPA plus DHA levels [155]. However, a study that analyzed data from 110,584 individuals (mean age 68 years) in the U.K. Biobank database reported that people with the highest levels of plasma DHA had a 21% lower risk of testing positive for SARS-CoV-2 and a 26% lower risk of being hospitalized for COVID-19 than those with the lowest levels [158]. No associations were found between plasma DHA levels and the risk of death from COVID-19.
In a clinical trial in Iran, 42 of 128 critically ill patients (mean age 64–66 years) with COVID-19 received a 1,000 mg omega-3 supplement containing 400 mg EPA and 200 mg DHA for 14 days [159]. Patients who received 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 and white blood cell count. A study in Norway investigated whether taking a daily supplement of 5 mL of cod liver oil could reduce the incidence of SARS-CoV-2 infection or serious COVID-19 [160]. This dose of cod liver oil contained 1.2 g of long-chain omega-3s, including 400 mg EPA and 500 mg DHA; 10 mcg (400 IU) vitamin D3; 250 mcg vitamin A; and 3 mg vitamin E. The study randomized 34,601 adults (mean age 44.9 years) without COVID-19 to receive either cod liver oil or a corn oil placebo for up to 6 months. Among the full study population, the incidence of SARS-CoV-2 infection was only 1.32%, and cod liver oil supplementation did not appear to provide a benefit; there was no difference between the two groups in the incidence of SARS-CoV-2 infection or the number of cases of serious COVID-19.
Safety
The FNB did not establish a Tolerable Upper Intake Level (UL; the maximum daily intake that is 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 [151].
Doses of 2 to 15 g/day EPA and/or DHA might also increase bleeding time by reducing platelet aggregation [151]. 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 [161]. 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 [162].
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 [163,164]. Because of their antiplatelet effects at high doses, omega-3s might interact with anticoagulants [165]. 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” [166]. Omega-3s might also interact with other medications. For example, omega-3s might reduce blood pressure, so they could increase the risk of hypotension if taken with antihypertensive agents [167,168].
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 when administered in adequate amounts [169]. They include certain bacteria (e.g., Lactobacillus acidophilus, L. rhamnosus [LGG], 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 [170]. 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 [17]. They might reduce inflammation and 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 [17,171-174]. However, the mechanisms of their potential effects on immune function are unclear. In addition, research findings for one probiotic strain cannot be extrapolated to others [17,175].
Efficacy
Several systematic reviews and meta-analyses published before the emergence of COVID-19 evaluated the use of probiotics 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 [174,176-179]. 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 adjusting for potential confounders [157]. Findings were similar for 45,757 individuals in the United States and for 27,373 participants in Sweden [157].
A trial in the United States evaluated whether LGG could reduce the risk of COVID-19 in people who had been exposed to COVID-19 through a household contact within the past 7 days [180]. The study randomized 182 participants to take 20 billion CFU of LGG once daily (children under 5 years took 10 billion CFU) or placebo for 28 days. There was no difference between the groups in the incidence of COVID-19 diagnoses. However, only 26% of participants who received LGG reported illness symptoms by day 28 compared with 43% of participants who received placebo. In addition, the participants in the LGG group who did experience symptoms had a longer time to symptom onset.
Some studies have examined whether probiotics could be useful adjuvant therapies for people with COVID-19. For example, this possibility was examined in a clinical trial in Italy among 70 patients (median age 59 years) who were hospitalized with COVID-19 [181]. 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 mixture (Sivomixx) that contained 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 who took the probiotics than in those who did not. Probiotic administration also reduced the risk of mortality, transfer to ICU, and respiratory failure.
In a clinical trial in Mexico, adults (median age 34–39 years) with COVID-19 were randomized to take one probiotic capsule or placebo per day [182]. The probiotic capsule contained the Lactiplantibacillus plantarum strains KABP022, KABP023, and KABP033 and the Pediococcus acidilactici strain KABP021 for a total daily dose of at least 2 x 109 CFU. Of the 300 patients randomized to receive either probiotics or placebo, 78 (53%) in the probiotics group achieved complete symptomatic remission and viral clearance by day 30 compared with 41 patients (28%) in the placebo group. Patients who received probiotics also had lower nasopharyngeal viral loads on days 15 and 30. Among the 116 patients who had evidence of lung infiltrates at baseline, those in the probiotics group showed a significant reduction in the severity of their lung infiltrates at days 15 and 30.
A systematic review and meta-analysis evaluated the results of eight randomized controlled trials (including all the clinical trials discussed above), which included a total of 1,027 participants [183]. The authors found with moderate certainty of evidence that the use of probiotics in patients with COVID-19 reduces the incidence of certain COVID-19 symptoms, such as diarrhea and cough, compared with placebo. However, the analysis found no reduction of mortality in people who received probiotics based on low certainty of evidence.
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 [173]. Side effects, which are usually minor, include gastrointestinal symptoms, such as gas [17,174]. However, potential safety concerns can include systemic infections, especially in individuals who are immunocompromised [173]. 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 [184,185].
Probiotics are not known to interact with medications. However, antibiotic and antifungal medications might decrease the effectiveness of some probiotics [186,187].
More information on probiotics is available in the ODS health professional fact sheet on probiotics.
Quercetin
Quercetin is a flavonol (a polyphenolic compound) that is present in many fruits, vegetables, spices, and beverages, including citrus fruits, apples, onions, berries, broccoli, cilantro, dill, tea, and red wine [188-192]. Research suggests that quercetin might have antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects [189-195]. It might also inhibit platelet aggregation [189,195]. Quercetin has very low oral bioavailability, ranging from 3% to 17% [190], but combining it with sunflower lecithin increases its bioavailability by as much as 20 times [189,191].
Efficacy
Results have been mixed in the few clinical trials that have examined 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 the symptoms of these infections [196,197]. However, data are very limited on the use of quercetin supplementation in patients with COVID-19.
One open-label clinical trial in Pakistan evaluated the effects of quercetin on viral clearance and symptom resolution in outpatients with mild to moderate COVID-19 [198]. In the trial, 108 patients who were not vaccinated against COVID-19 were randomized to receive quercetin plus standard of care (mean age 41 years) or standard of care alone (mean age 54 years). The quercetin group received 200 mg quercetin with sunflower lecithin three times a day during the first week of the study and 200 mg twice daily during the second week. By the end of the first week, 34 patients (68%) in the quercetin group tested negative for SARS-CoV-2 compared with only 12 patients (24%) in the standard of care only group, and COVID-19 symptoms had resolved in 26 patients (52%) in the quercetin group and in 12 patients (24%) in the standard of care only group. By week 2, nearly all the patients in both groups tested negative for SARS-CoV-2 infection, and most patients no longer had COVID-19 symptoms. A confounding factor in this study was that patients in the standard of care only group were significantly older than those in the quercetin group.
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 [199]. 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 [188,196,200].
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) [200]. In addition, quercetin might reduce blood pressure in people with hypertension [201], so it could potentiate the effects of antihypertensive medications.
Selenium
Selenium is an essential mineral found in many foods, including Brazil nuts, seafood, meat, poultry, eggs, and dairy products. It is also found in 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 [202].
Selenium helps support both the innate and adaptive immune systems and reduces the risk of infections [14,104,203-208]. As an antioxidant, selenium might help reduce the systemic inflammatory response that can lead to acute respiratory distress syndrome and organ failure [204,206,209].
Low selenium status in humans has been associated with lower natural killer cell activity, an increased risk of some bacterial infections, and the increased virulence of certain viruses [9,14,205,208-210]. In addition, some research suggests that taking 100 to 300 mcg/day selenium supplements improves immune function, and one study in the United Kingdom found that doses of 50 or 100 mcg/day enhanced the immune response to a poliovirus vaccine [205,211].
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 [207,212].
Efficacy
Because selenium has been shown to have antiviral, anti-inflammatory, and immune-enhancing effects, researchers have investigated some potential associations between selenium status and COVID-19. However, no clinical trials have evaluated the use of selenium supplements in people with COVID-19.
Some research shows that patients who were hospitalized with COVID-19 had low selenium status at admission, and this low status might adversely affect the body’s immune response [9,213-215]. In addition, selenium deficiency might increase the risk of mortality from COVID-19 [208]. For example, in a small study in Germany, the mean serum selenium level of 33 patients with COVID-19 (5.1 mcg/dL) was significantly lower than the mean value from a healthy cross-sectional study of 1,915 European residents (8.4 mcg/dL) [214]. A value of 8.0 mcg/dL is typically considered adequate [216]. In addition, the 27 patients who survived COVID-19 had a significantly higher mean serum selenium level (5.3 mcg/dL) than the six who did not (4.1 mcg/dL) [214]. 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 the average selenium status was higher than in those living in areas where the average selenium status was lower, based on hair selenium levels in the various regions [212]. However, selenium status can be assessed in multiple ways, and because some selenium is bound to albumin in the blood [217] selenium measurements can be confounded if they are not adjusted for albumin levels in people with severe illness.
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 [202]. These upper limits, however, do not apply to individuals receiving selenium under the care of a physician. Higher intakes can cause a 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, fatigue, irritability, and nervous system abnormalities.
Cisplatin, a chemotherapy agent used to treat some cancers, can reduce selenium levels in hair, plasma, and serum [218,219].
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, kiwifruit, 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 [202].
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 [23,64,220-222]. 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 [221]. It might also inhibit viral replication [223].
Vitamin C deficiency impairs immune function and increases susceptibility to infections [221]. Some research suggests that supplemental vitamin C enhances immune function [9,224], but its effects might vary depending on an individual’s vitamin C status [225].
Vitamin C deficiency is uncommon in the United States, affecting only about 7% of individuals age 6 years and older [226]. People who smoke and those who eat a limited variety of foods (such as some older adults and people with alcohol or drug use disorders) are more likely than others to have insufficient vitamin C intakes [222,224].
Efficacy
Because vitamin C plays a role in the immune system, some scientists have investigated whether it might reduce the risk of COVID-19 or the severity of symptoms. Evidence from studies evaluating vitamin C supplementation for the common cold, pneumonia, and viral infections, including Epstein-Barr and herpes zoster, also spurred interest in vitamin C for COVID-19 [220,223,224,227].
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 [9,228]. 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 [229]. Vitamin C and zinc supplementation did not affect mortality. Another retrospective chart review included 152 patients (median age 68 years) with COVID-19 who were on mechanical ventilation [230]. 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.
A small clinical trial in Mexico examined the effects of administering 1,000 mg vitamin C every 12 hours for 5 days plus the drug pentoxifylline to 22 hospitalized adults (mean age 57.9 years) with pneumonia that resulted from COVID-19 [126]. Patients who received vitamin C and pentoxifylline had significantly lower levels of the inflammatory markers interleukin-6 and procalcitonin at the end of the treatment period 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 (a measure of oxidative stress). 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 [231]. 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 [232]. 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/day administered over 8–10 hours) increased the oxygenation index in 50 patients with moderate to severe COVID-19; all patients eventually recovered [233].
The LOVIT-COVID and REMAP-CAP trials evaluated the use of intravenous vitamin C in hospitalized patients with COVID-19 in Asia, North America, Europe, and Australia [234]. Although these trials were initially separate, the researchers chose to combine the data from the two trials before enrollment began. The trials randomized 1,568 patients who were critically ill in the ICU and 1,022 hospitalized patients who were not critically ill (median age 60–62 years) to two treatment arms: a vitamin C arm or a control arm (in which patients received either placebo or no vitamin C). Patients who received vitamin C were given intravenous vitamin C (50 mg/kg of body weight) every 6 hours for 96 hours. The trials stopped recruitment when it became apparent that vitamin C was likely to be ineffective or could worsen patient outcomes. After reviewing the data from the trials, the authors reported that administering vitamin C to these patients did not increase the number of organ support-free days or improve the odds of survival to hospital discharge.
In a pilot trial in China, 56 patients (mean age 66.7 years) with COVID-19 in the ICU received either intravenous vitamin C (12 g twice daily) or placebo for 7 days or until ICU discharge or death [235]. Vitamin C administration did not affect 28-day mortality rates. An open-label trial in Pakistan randomized 150 hospitalized patients (mean age 52–53 years) with severe COVID-19 to receive intravenous vitamin C (50 mg/kg/day) plus standard of care or standard of care alone [236]. There were no significant differences between the groups in the number of patients who required mechanical ventilation or who died; however, COVID-19 symptoms resolved faster in patients who received vitamin C than in those who received standard of care (mean of 7.1 days vs. 9.6 days), and patients who received vitamin C spent less time in the hospital (mean of 8.1 days vs. 10.7 days). Other small, short-term studies of intravenous vitamin C found this treatment did not provide a clinical benefit to patients with COVID-19 [237,238].
The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel concludes that there are insufficient data to support a recommendation for or against the use of vitamin C to treat COVID-19 in nonhospitalized patients [23]. Because clinical trials have not shown a clinical benefit of vitamin C in hospitalized patients with COVID-19, the COVID-19 Treatment Guidelines Panel recommends against using vitamin C to treat these patients.
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 [202]. 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 [239-241]. In people with hemochromatosis, high doses of vitamin C could exacerbate iron overload and damage body tissues [202,222]. The FNB recommends that these individuals be cautious about consuming vitamin C doses above the RDA [202].
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 [242].
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. Small amounts can also be found 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 (400–600 IU) for children, depending on age, and from 15 to 20 mcg (600–800 IU) for adults [243]. 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 [243]. Researchers have not definitively identified the serum concentrations of 25(OH)D that are associated with vitamin D deficiency and adequacy. The FNB considers people with levels below 30 nmol/L (12 ng/mL) to be at risk of vitamin D deficiency; levels of 50 nmol/L (20 ng/mL) or more are considered adequate for bone health and overall health in most people [243]. However, the 25(OH)D levels used in clinical trials to define deficient and adequate vitamin D status vary.
In addition to its well-known effects on calcium absorption and bone health, vitamin D plays a role in immunity [244]. Vitamin D appears to lower viral replication rates, suppress inflammation, and increase levels of T-regulatory cells and their activity [24,123,245-249]. In addition, immune cells (e.g., B lymphocytes, T lymphocytes) express the vitamin D receptor, and some immune cells (e.g., macrophages, dendritic cells) can convert 25(OH)D into 1,25(OH)2D. This ability suggests that vitamin D might modulate both innate and adaptive immune responses [24,245,247,249].
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 [250,251]. Surveys indicate that most people in the United States consume less than the recommended amounts of vitamin D [252]. 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 [253]. 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 [243].
Efficacy
Because 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) [254], some scientists have evaluated the use of vitamin D for COVID-19.
Some studies link lower vitamin D status with a higher incidence of COVID-19 and more severe disease [215,255-263], but others do not [264-268]. 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 in healthy participants (median of 32.5 nmol/L [13 ng/mL]) [256]. In addition, the prevalence of vitamin D deficiency (defined as serum 25(OH)D <30 nmol/L [12 ng/mL]) was significantly higher in patients with COVID-19 than in healthy participants, and vitamin D deficiency was associated with more severe COVID-19. A systematic review and meta-analysis of 31 observational studies did not find significant associations between serum 25(OH)D levels below 50 nmol/L (20 ng/ml) and the incidence of COVID-19, risk of mortality, ICU admission, or need for ventilation among patients with COVID-19 [269]. However, this analysis found that mean 25(OH)D levels were significantly lower in patients with COVID-19 than in 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 [215,270-274] and that people who regularly took vitamin D supplements (amounts not specified) were less likely to develop COVID-19 than those who did not [275]. For example, 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 [276]. Black individuals with 25(OH)D levels below 100 nmol/L (40 ng/mL) had a higher risk of COVID-19 than those with higher levels, but the results showed no associations between 25(OH)D levels and the risk of COVID-19 among White individuals.
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 [243,277]. 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 the risk of SARS-CoV-2 infection after adjusting for confounders, including ethnicity, body mass index (BMI) category, age at assessment, and sex [268].
A systematic review and meta‐analysis of 17 observational studies examined the association between 25(OH)D levels and the severity of COVID‐19 [278]. The studies included in this analysis were conducted in Europe, the United States, Asia, and the Middle East and had enrolled a total of 2,756 adults with COVID-19. The authors reported that patients with vitamin D deficiency had an increased risk of mortality, a higher rate of hospitalization, and longer hospital stays than patients who were not deficient. In this analysis, the researchers used the 25(OH)D levels defined by the individual studies to assess vitamin D deficiency. 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 [279-281]. However, these reviews found inconsistent associations between vitamin D status and the risk of SARS-CoV-2 infection.
Although many observational studies suggest a link between low vitamin D status and a 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 [27]. 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 observational studies have examined whether vitamin D supplementation might reduce COVID-19 severity [97,157,282-284]. For example, an analysis of data on 77 hospitalized adults (mean age 88 years) with COVID-19 in France (where vitamin D supplementation is routinely recommended for those over 65 years of age) 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 [282]. 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 (20,000–50,000 IU) daily to biweekly for 7 days to 7 weeks had a lower risk of death from the disease [284]. This finding was replicated in another cohort of 542 hospitalized patients, some of whom received similar doses of vitamin D3 supplements [284].
A randomized clinical trial in Mexico found that a moderate dose of vitamin D3 reduced the risk of SARS-CoV-2 infection in frontline health care workers who were caring for patients with COVID-19 [285]. In this trial, which was conducted before COVID-19 vaccines were available, health care workers (median age 37.5 years) from four hospitals in Mexico City received either 100 mcg (4,000 IU) vitamin D3 or placebo daily for 30 days. Of the 192 participants who completed follow-up, those who received vitamin D3 were 77% less likely to acquire SARS-CoV-2 infection than those who received placebo. In addition, this protective effect was independent of baseline vitamin D status.
Several other randomized clinical trials have investigated the use of high doses of vitamin D3 in people with COVID-19. A clinical trial in 240 hospitalized patients (mean age 56.2 years) with moderate to severe COVID-19 compared the effects of a single dose of 5,000 mcg (200,000 IU) vitamin D3 administered about 10 days after symptom onset with placebo [286]. The mean baseline 25(OH)D level among participants was 52.3 nmol/L (20.9 ng/mL). Vitamin D did not significantly reduce the length of hospitalization or the risk of mortality while hospitalized, ICU admission, or the need for mechanical ventilation, even among the 115 patients with vitamin D deficiency at baseline (defined as 25(OH)D <50 nmol/L [20 ng/mL]).
In the open-label COVIT-TRIAL, 254 patients (median age 88 years) with COVID-19 at nine medical centers in France were randomized to receive a single high dose of vitamin D3 (10,000 mcg [400,000 IU]) or a lower dose (1,250 mcg [50,000 IU]) [287]. The study found that the high dose of vitamin D3 reduced overall mortality among patients at day 14, suggesting that this dose had a protective effect. However, by day 28, there was no longer a significant difference in mortality between the high-dose group and the lower-dose group. A clinical trial in Argentina evaluated the effect of a single high dose of vitamin D3 in 218 hospitalized patients (mean age 59.1 years) with COVID-19 [288]. The patients were randomized to receive either 12,500 mcg (500,000 IU) vitamin D3 or placebo. Compared with placebo, the single dose of vitamin D3 did not prevent respiratory worsening or shorten the length of hospital stay. It also did not affect rates of ICU admission or in-hospital mortality.
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 [289]. Patients who received 125 mcg vitamin D had shorter durations 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 who received 25 mcg, but the durations of other symptoms—including fever, fatigue, headache, sore throat, body aches, and chills—did not differ between the groups.
The Vitamin D for COVID-19 (VIVID) trial is examining whether vitamin D3 supplementation helps reduce the severity of COVID-19 and the risk of transmission to household members [290]. The study has enrolled 2,024 adults age 30 years and older; roughly half are people who had received a COVID-19 diagnosis within 7 days of enrollment, and the other half are close household contacts who were not vaccinated. The participants will receive vitamin D3 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).
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 [24].
Safety
Daily intakes of up to 25 to 100 mcg (1,000–4,000 IU) vitamin D in foods and dietary supplements are safe for infants and children, depending on age, and intakes up to 100 mcg (4,000 IU) are safe for adults [243]. 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 [291-293].
Several types of medications might interact with vitamin D. For example, orlistat, statins, and steroids can reduce vitamin D levels [294,295]. In addition, taking vitamin D supplements with thiazide diuretics might lead to hypercalcemia [294].
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 [202].
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 [104,205,244,296,297]. Vitamin E has also been shown to limit inflammation by inhibiting the production of proinflammatory cytokines [298]. Vitamin E deficiency impairs both humoral and cell-mediated immunity and increases susceptibility to infections [205,297,299]. Some studies suggest that taking high doses of vitamin E supplements (60–800 mg/day) for 1 to 8 months enhances lymphocyte proliferation, interleukin-2 production, and natural killer cell activity in adults age 60 or older [300-302].
Frank vitamin E deficiency is rare, except in individuals with intestinal malabsorption disorders [202,244]. 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 [297].
Efficacy
Vitamin E plays a role in immune function. However, studies that have evaluated the efficacy of vitamin E supplementation in people with infectious diseases, such as respiratory tract infections, have reported mixed results [299,303-306]. A very limited amount of research has been conducted on vitamin E and COVID-19.
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 [126]. 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.
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 [202]. These upper limits, however, do not apply to individuals receiving vitamin E under the care of a physician. Because vitamin E has anticoagulant effects, high vitamin E intakes can increase the risk of bleeding and 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 [242,307,308].
More information on vitamin E is available in the ODS health professional fact sheet on vitamin E.
Zinc
Zinc is an essential nutrient that is present in a wide variety of foods. The highest amounts of zinc are found in animal foods, including oysters, crab, lobster, beef, pork, and poultry. Beans, nuts, whole grains, and dairy products also contain some zinc. The RDA for zinc is 2 to 13 mg for infants and children, depending on age, and 8 to 12 mg for adults [309].
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 [14,309-312]. Zinc also has antiviral and anti-inflammatory properties, and it helps maintain the integrity of tissue barriers, such as the respiratory epithelia [9,123,313,314]. In addition, zinc is involved in the sense of taste.
Zinc deficiency adversely affects immune function by impairing the formation, activation, and maturation of lymphocytes. In addition, zinc deficiency alters the ratios of helper and suppressor T cells, decreases production of interleukin-2, and decreases activity of natural killer cells and cytotoxic T cells [14,209,310,312,315]. Furthermore, zinc deficiency is associated with elevated levels of proinflammatory mediators [313]. These effects on immune response probably increase susceptibility to infections [316] and inflammatory diseases, especially those affecting the lungs [313].
Studies have found associations between low zinc status and an increased risk of viral infections [244], and people with zinc deficiency have a higher risk of diarrhea and respiratory diseases [14]. Poor zinc status is also common among individuals with HIV and hepatitis C and is a risk factor for pneumonia in older adults [209,314,317,318].
Although zinc deficiency is not common in the United States, 15% of the U.S. population might obtain marginal amounts of zinc [319]. Older adults are among the groups most likely to have low intakes.
Efficacy
Because of zinc’s role in the immune system and in maintaining epithelial integrity, its antiviral activities, and its anti-inflammatory effects, some studies have investigated whether adequate zinc intakes might reduce the risk of COVID-19 and the severity of some of its symptoms, including diarrhea and the loss of taste and smell. Evidence that zinc lozenges might help shorten the duration of the common cold [320] also spurred interest in using zinc supplementation in patients with COVID-19.
An observational study of 249 patients (median age 65 years) with COVID-19 who were 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 days vs. 8 days), and had higher mortality rates (21% vs. 5%) than those with higher zinc levels [321]. A similar study in India found that 47 hospitalized patients (median age 34 years) with COVID-19 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); however, both of these median values would be considered normal [322]. 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 in a group of randomly chosen healthy individuals who were used as control group (97.6 mcg/dL) [323]. 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 [324].
In a case report from the United States, four patients age 26 to 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/day zinc for 10 to 14 days [325]. The symptoms—including fever, cough, headache, shortness of breath, body aches, and fatigue—in all four patients began to decline within 24 hours of starting the zinc treatment, and all patients 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 compared mortality rates among 242 patients who were 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 [326]. Zinc supplementation did not affect mortality rates.
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 [231]. Zinc, ascorbic acid, and the combination of zinc and ascorbic acid did not shorten the duration of symptoms. In a study in Tunisia, 470 adults (mean age 54.2 years) with COVID-19 were randomized to receive either 25 mg of zinc twice daily for 15 days or placebo [327]. This study enrolled both inpatients and outpatients with COVID-19. Compared with patients in the placebo group, those who received zinc had a 42% lower risk of the combined outcome of death or admission to the ICU within 30 days of randomization. This difference was primarily due to a reduction in ICU admissions, because the death rate was not significantly different between the groups. Inpatients who received zinc had shorter hospital stays than those who received placebo (mean of 7.1 days vs. 10.6 days). Outpatients who received zinc had a shorter duration of COVID-19 symptoms than those who received placebo (mean of 9.6 days vs. 12.8 days), although the two groups had similar hospital admission rates. Some concerns were raised about the data presented in this study [328]. The study authors acknowledged that the original paper included some errors and provided corrections in a subsequent publication [329]. However, the authors stated that these errors did not affect the overall conclusions of the trial.
According to the NIH COVID-19 Treatment Guidelines Panel, data are insufficient to recommend for or against the use of zinc supplements to treat COVID-19 [22]. In addition, the COVID-19 Treatment Guidelines Panel recommends against using doses of zinc supplements above the RDA to prevent COVID-19, except in a clinical trial.
Safety
Intakes up to 4 to 34 mg/day zinc in foods and dietary supplements are safe for infants and children, depending on age, and intakes up to 40 mg/day are safe for adults [309]. 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 [64,309]. Chronic consumption of 150 to 450 mg/day can cause low copper status, reduced immune function, and reduced levels of high-density lipoproteins [330]. In clinical trials among children, using zinc supplementation to treat diarrhea increased the risk of vomiting more than placebo [331,332].
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 [333,334]. In addition, some medications, such as thiazide diuretics and certain antibiotics, can reduce zinc absorption [335,336].
More information on zinc is available in the ODS health professional fact sheet on zinc.