Zinc, Antiviral Effects, and the Common Cold

Zinc is vitally important in human health. Most nutritionally oriented health care professionals would probably recommend zinc in the treatment of the common cold. Some important questions regarding what dose, how often, and what formulation should be addressed to ensure a standard of care and practice is met. A review of the literature gives some insight into what practitioners can effectively, scientifically, and safely recommend to patients.

Zinc is a silvery, white metal that has an atomic number of 30 and an atomic mass of 65. It is a major constituent of the American penn,y and it is also a minor constituent of the alloy brass. The great Swiss physician Paracelsus integrated the necessity of micronutrient chemistry into human health in the 16^th century. He referred to the mineral by the German word “zinke” to reflect its jagged or pointed appearance of its crystals.¹

Zinc is the second most abundant trace mineral in the human body after iron. The adult human body contains between 2000 to 3000 milligrams of elemental zinc. Ninety percent is stored in muscles and bones. Zinc in the serum is primarily protein bound to albumin, globulin, and transferrin. Thirty to 40% of zinc is concentrated within the cell nucleus, 50% in the cytosol, and 10% is in the cell membrane.²

One of the main intracellular proteins to sequester zinc is the cysteine-rich metallothionein. There are four different isoforms of metallothionein. There are at least seven different cysteine binding sites per molecule. Methallothionein releases zinc in response to oxidative stress or viral infection. The increased release of free zinc is mediated by cellular cytokines and other cell signaling chemicals. The free zinc interacts with various aspects of the immune system and the pathogen. Increased zinc decreases NF-KB (nuclear factor kappa beta), which helps to decrease inflammation.^2,3

Zinc is estimated to be involved in 10% of all protein synthesis reactions in the human body. It is believed to be involved in 750 different transcription factors that code for various proteins. It is involved in different aspects of DNA synthesis and RNA transcription and translation. Zinc is also estimated to be involved in 2000 different enzymatic reactions. It is involved in multiple aspects of growth and development. It is also involved in multiple aspects of innate and acquired immune function.³

It estimated that 17% to 20% of the world’s population or 1.6 billion people have some degree of zinc deficiency. Zinc deficiency can impact proper growth and development. Zinc deficiency is also associated with mild to severe immune deficits.³

The RDA for zinc was established in 1974 and set at 15 milligrams per day. The revised RDA for zinc is currently 8 milligrams for adult females and 11 milligrams for adult men. The highest food source of zinc by a large margin is oysters.⁴

Zinc has demonstrated to have multiple effects on both innate and acquired immunity. It affects both production and activity of B and T lymphocytes, NK (natural killer cells), neutrophils, monocytes, macrophages, cytokine production, chemotaxis, phagocytosis, and intracellular destruction of pathogens. Zinc has shown to stabilize membrane structure and help prevent pathogen invasion. Zinc also reduces cellular oxidative stress and functions as an antioxidant. It should be emphasized that the effects of zinc on the immune system are exceedingly complex and still relatively poorly understood.^4,5

Zinc has demonstrated direct antiviral effects. Zinc has demonstrated varying degrees of antiviral activity against herpes, picorna, influenza, corona, metapneumo, flavidae, toga, roto, HIV, and papilloma viruses. Two primary antiviral mechanisms have been demonstrated. The first is protease inhibition. Proteases are a group of enzymes that function to cleave larger nascent viral proteins into smaller active proteins. This step is necessary for viral reproduction. The discovery of modern pharmaceutical antiviral medicine frequently targets viral protease inhibition. Zinc functions as a natural viral protease inhibitor via direction inhibition of the protease active site.

The second mechanism of antiviral activity is through inhibition of polymerase activity. Polymerase is an enzyme that synthesizes copies of viral DNA or RNA. The process of creating new copies is called transcription. The DNA is transcribed to RNA, which is ultimately translated to viral protein. Zinc directly inhibits viral polymerase from creating new copies of either genetic material. As mentioned earlier, another possible third mechanism of antiviral activity is at the cell membrane level, where zinc might help prevent viral uptake.^3,4,5

One meta-analysis compared zinc acetate lozenges to zinc gluconate lozenges in the treatment of the common cold and to examine dose dependent effects. Seven randomized placebo-controlled studies involving 575 participants were included. Three trials with zinc acetate showed a 40% decrease in the duration of cold in treated patients. Four trials with zinc gluconate showed a 28% decrease in the duration of cold in treated patients. Five trials involved an elemental zinc dose between 80 to 92 milligrams per day and showed a 33% decrease in the duration of cold in treated patients. Two trials involved an elemental dose between 192 and 207 milligrams per day and showed a 35% decrease in the duration of cold in treated patients. The difference between the high and lower doses of zinc in alleviating cold duration was not statistically significant. Additionally, lozenge composition and dosage schedule were deemed important.⁶

Another randomized placebo-controlled trial involving 100 Cleveland Clinic employees with colds showed an improvement in the zinc-treated group. Half the sick employees took a zinc lozenge supplying 13.3 milligrams of elemental zinc every two hours as long as they had symptoms. The other half took placebo. Cold symptoms lasted an average of 4.4 days in the zinc-treated group compared to 7.6 days in the placebo group.⁷

Zinc supplementation potentially reduced cold duration by an average of 2.25 days in a review of 10 studies.⁸

A Cochrane review of zinc supplementation for both therapeutic and preventive outcomes was performed in 2011. A meta-analysis of 13 randomized placebo-controlled trials helped to shed light on the benefits of zinc in the common cold. Pooled data revealed that the elemental zinc dosage ranged from 10 to 24 milligrams per lozenge, taken every one to four hours for a duration of three to seven days. In 11 of 13 studies, zinc supplementation was initiated within 24 hours after the onset of symptoms. In two of 13 studies, zinc was initiated within 48 hours after the first onset of symptoms. In six of 13 studies, the average cold was improved by 0.97 days compared to placebo. The severity of symptoms with zinc supplementation was 0.39 when compared to placebo. Side effects of bad taste and nausea were noticed at an odds ratio of 2.64 and 2.15 with zinc supplementation respectively. An additional two studies on the use of zinc to prevent the occurrence and severity of common cold was reviewed. There was some evidence the preventive use of zinc for five months helped to reduce absenteeism and prescriptions in school aged children.^9,10

The ingestion of large doses of zinc for prolonged periods of time suppresses the immune system in much the same way as zinc deficiency. Decreased NK activity, decreased neutrophilic phagocytosis, decreased monocyte function, and increased B cell apoptosis were observed. Additionally, an increase in pro-inflammatory cytokines like IL1, IL6, and interferon were noted with large zinc doses. In one study of 11 healthy adult subjects who took 150 milligrams of elemental zinc twice per day for six weeks showed a decrease in lymphocyte stimulation to phytohemagglutinin and a decrease in chemotaxis and phagocytosis by polymorphonuclear leukocytes. Another study involved fifteen participants (70 years and older), who took 220 milligrams of zinc sulphate twice per day for one month. An increase in T-lymphocyte activity, delayed hypersensitivity reaction, and increased IgG antibody response was noted. Other studies show that the use of elemental zinc in doses that exceeds 40 milligrams per day does not have deleterious effects on the immune system when used for less two weeks. Large doses of zinc cause transient nausea in many people. Elemental doses of zinc between 225 and 450 milligrams can cause vomiting in many individuals.^11,12

There are several important factors to consider beside the elemental zinc dosage when directed at the treatment and prevention of the common cold. First is the solubility of the zinc molecule used. Second is the degree of ionization of the zinc compound. The better the solubility, the higher the degree of ionization of the zinc compound, producing a larger concentration of cationic positive 2 charged elemental free zinc ions. This appears to better produce a local effect at the site of viral infection and inhibit pathogenic inflammation created there. It is plausible that the local effects of zinc are primarily directly antiviral via one of the two and possible three mechanisms mentioned earlier. An upregulation of the immune system and white blood cells can also occur but is realistically a little slower to develop than the immediate antiviral effects. Taken together, direct antiviral activity and the immune enhancement effects both contribute to the use of zinc in the treatment of the common cold. It is further worth mentioning that the types of zinc compounds with the highest degree of solubility and ionization are indeed the type of zinc compounds that reveal the best effects in treatment of the common cold. Zinc acetate, zinc gluconate, and zinc sulphate are among these compounds. Zinc citrate, zinc oxide and other chelated forms of zinc are less soluble.^1,2,3,4,5

Zinc may be effective in the prevention and treatment of the common cold. Highly soluble and ionizable forms of zinc in the forms of lozenges and liquids are probably the best compounds to use. The earlier zinc supplementation is started the better. Within 48 hours, but probably within 24 hours of the first onset of cold symptoms is best. An elemental dose between 5 and 25 milligrams of zinc can be recommended. Repeated dosing every one to four waking hours is best. Taken for a minimum of three days and up to 7 to 14 days or when symptoms disappear is reasonable. Side effects of nausea and upset stomach are common and can occur. Reducing the dose and following the intake of food may help. Larger daily doses beyond 75 to 150 milligrams of elemental zinc are not recommended for most people. Taking high doses beyond two weeks of the first onset of cold symptoms is not recommended. Of course, it is advised to consult a licensed health care professional for specific dosing and treatment instructions. Also, if pregnant, nursing, or under the age of 12, consult a licensed health care practitioner for specific guidelines.

References

1. Krezel M and Maret W. The biological inorganic chemistry of zinc ions. Archives of Biochemistry and Biophysics. 2016 December 1; vol 611:3-19.
2. Plum LM et al. The Essential Toxin: Impact of Zinc on Human Health. Int J Environ Res Public Health. 2010 Apr; 7(4):1342–1365.
3. Read SA et al. The Role of Zinc in Antiviral Immunity. Adv Nutr. 2019 Jul; 10(4):696-710.
4. Prasad AS. Zinc in Human Health: Effect of Zinc on Immune Cells. Mol Med. 2008 May-Jun; 14(5-6): 53-357.
5. Ibs KH and Rink L. Zinc-Altered Immune function. Journal of Nutrition. May 2003; volume 133 issue 5:1452S-1456S.
6. Hemila H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM Open. 2017 May; 8(5): 2054270417694291.
7. Mossad SB et al. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med. 1996 Jul 15; 125(2):81-88.
8. Wang MX et al. Zinc Supplementation Reduces Common Cold Duration among Healthy Adults: A Systematic Review of Randomized Controlled Trials with Micronutrients Supplementation. Am J Trop Med Hyg. 2020 Jul; 103(1):86-99.
9. Rao G and Rowland K. Zinc for the common cold—not if, but when. J Fam Pract. 2011 Nov; 60(11):669-671.
10. Singh M and Das RR. Zinc for the Common Cold. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD001364.
11. Chandra RK. Excessive Intake of Zinc Impairs Immune Responses. JAMA. 1984; 252(11):1443-1446.
12. Duchateau J et al. Beneficial effects of oral zinc supplementation on the immune response of old people. Am J Med. Clinical Trial. 1981 May; 70(5):1001-4.