Faculty peer reviewed
Each year doctors are presented with the dilemma of the common cold. Adults in the U.S. experience an average of 3 colds per year, and children up to 8-10, resulting in over 500 million colds annually.(1) Patients often visit the doctor with cold symptoms requesting antibiotics. Since the etiology of the common cold is viral, antibiotic therapy is ineffective and inappropriate, and only contributes to bacterial antibiotic resistance. More than 200 viruses can cause the common cold, including rhinoviruses, coronaviruses, adenoviruses, respiratory syncytial virus, and parainfluenza viruses.(2) Rhinovirus is the most common culprit.3 Although considered a self-limited benign illness, the common cold is not without complications, including otitis media, sinusitis, and exacerbations of reactive airway diseases.(3) Additionally, the economic impact is far-reaching due to related work absences. Thus, it is clear why patients implore doctors for treatment of this ailment. In more recent years the use of zinc cold remedies has become popular. The question is, are they safe and effective?
The idea of using zinc to control viral disease is not novel. In 1937 zinc sulfate was sprayed intranasally during the poliovirus epidemic in Canada. It was theorized that zinc ions formed a protective coating around olfactory nerves, thereby preventing virus absorption. Unfortunately, this intervention did not alter the attack rate.(4) In more recent years the use of zinc acetate/gluconate lozenges and zinc gluconate nasal spray has become widespread. The basis for therapeutic zinc use is founded on scientific observation over the years. Empirical virology has shown that zinc interferes with rhinoviral coat proteins, thereby preventing viral particle assembly and replication. Mechanistically, it was suggested that zinc ions formed complexes with viral coat proteins.5 Scientific observation has also demonstrated that zinc can alter immune system regulation. By studying the effects of zinc on plasma cytokines, it was determined that patients treated with zinc had reduced levels of intracellular adhesion molecule-1 (ICAM-1). Researchers proposed that zinc ions formed complexes with ICAM-1. This effect is significant because human rhinovirus 14 docks onto somatic cells using ICAM-1; thus, less ICAM-1 results in fewer infected cells.(3) Driessen et al. provided further empirical evidence regarding the immune-regulatory effects of zinc. They demonstrated that in patients with excess zinc, after immune challenge with bacterial endotoxin, there was upregulation of interferon gamma (increased T cell activation) and increased secretion of tumor necrosis factor-alpha and interleukin 1-beta (increased monocyte activation).(6) While much has been revealed regarding the therapeutic actions of zinc, more research is necessary to establish a concrete mechanism for zinc against the common cold.
Regarding the clinical efficacy of zinc, a number of studies have been performed, and the results are inconclusive. One structured review looked at 14 randomized controlled trials (RCTs) evaluating zinc lozenges and nasal sprays/gels. The review created 11 criteria to assess validity of experimental design, and found that only four studies were valid. Of the four studies, three found no therapeutic effect from zinc lozenges or nasal spray, and only one study reported benefit from zinc nasal gel, showing decreased symptom severity and duration with early treatment.(1) In contrast, a second review article looking at 7 double-blind RCTs using zinc gluconate lozenges showed an overall benefit, with decreased cold duration (1-3 days) and symptom severity. This study suggested that 13.3 mg of zinc (the lowest therapeutic dose) should be administered every two hours, with greater efficacy if treated within 24-48 hours of symptom onset. The review also showed astringent taste and nausea as common adverse reactions. Ultimately, it is difficult to judge the overall scientific efficacy of zinc against the common cold due to inconsistent study results. There are many reasons behind this variability, including poor study design (small sample size, artificially-induced vs. natural infection), poor follow-up, sub-therapeutic dosing, and use of additives (mannitol, citric acid, or sorbitol), which have been purported to decrease efficacy by binding to zinc ions.(7)
As for the question of safety, we can again look to 1937 and the use of prophylactic zinc sulfate. Of the 5000 children treated, approximately 10-13% were found to be anosmic months later.(4) This result was further corroborated by an animal study in 1978. Harding et al. showed that mice treated with intranasal zinc sulfate experienced immediate and total anosmia. Up to 80% of the mice were anosmic for 6 weeks, and some still showed changes at 1 year.(4) This result has since been reproduced by McBride et al. in 2003. This study showed that intranasal zinc sulfate produces total disruption of connections from the olfactory epithelium to the olfactory bulb. However, this anosmia was brief, and most mice recovered in 5-30 days.(8)
Of more significance is the safety profile for intranasal zinc gluconate, the key ingredient in nasal sprays/gels, such as Zicam. One study coined the term “zinc-induced anosmia syndrome,” characterized by burning and anosmia. It described a series of patients, all of whom reported sniffing deeply with gel application, followed by anosmia within hours. They reported some degree of recovery over time.(9) Another case series showed that olfaction impairment persisted for up to 2 years, and proposed that the anosmia was potentially permanent. It was hypothesized that zinc cations acted to block the nonspecific cation channel necessary for olfactory receptor cell depolarization, and subsequent transduction of odors to the olfactory bulb. Recent animal studies show that odor detection in mice is affected only at doses ~100 times greater than a single application of Zicam, and even at massive doses the anosmia resolved over time.(10) Despite this, Zicam nasal sprays/gels have been associated with anosmia or hyposmia in over 300 consumers. In June 2009, the FDA discontinued Zicam nasal products, and alerted the public to the possibility of permanent anosmia. This is of particular concern in children, who may not report decreased olfaction and are at increased risk for repeated exposure.(11) The advisory did not concern oral zinc tablets and lozenges.
In conclusion, the evidence for the efficacy of zinc cold remedies remains questionable, and the treatment is not without risk. More valid scientific studies with enhanced methodology are necessary to find conclusive results. The search for effective cold therapies must continue.
Amanda Benkoff is a 4th year student at NYU Medical School.
Peer reviewed by Dr. Robert Holzman, Professor of Medicine, NYU Medical Center
1. Caruso TJ, Prober CG, Gwaltney, JM Jr. Treatment of naturally acquired common colds with zinc: a structured review. Clin Infect Dis. 2007;45(5):569-574.
2. Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med. 1996;125(2):81-88.
3. Prasad AS, Beck FW, Bao B, Snell D, Fitzgerald JT. Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate. J Infect Dis. 2008;197(6):795-802.
4. Jafek BW, Linschoten MR, Murrow BW. Anosmia after intranasal zinc gluconate use. Am J Rhinol. 2004;18(3):137-141.
5. Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J. 2000;79(10):778-780, 782.
6. Driessen C, Hirv K, Kirchner H, Rink L. Zinc regulates cytokine induction by superantigens and lipopolysaccharide. Immunology. 1995;84:272-277.
7. Marshall, S. Zinc gluconate and the common cold, review of randomized controlled trials. Can Fam Physician. 1998;44:1037-1042.
8. McBride K, Slotnick B, Margolis FL. Does intranasal application of zinc sulfate produce anosmia in the mouse? An olfactometric and anatomical study. Chem Senses. 2003;28(8):659-670.
9. Alexander TH, Davidson TM. Intranasal zinc and anosmia: the zinc-induced anosmia syndrome. Laryngoscope. 2006;116(2):217-220.
10. Slotnick B, Sanguino A, Husband S, Marquino G, Silberberg A. Olfaction and olfactory epithelium in mice treated with zinc gluconate. Laryngoscope. 2007;117(4):743-749.
11. U.S. Department of Health and Human Services. FDA: Loss of sense of smell with intranasal cold remedies containing zinc. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm166059.htm. Accessed September 21, 2009.