Preventing Anosmia from Intranasal Zinc Administration

Anosmia Defined

What is anosmia? By definition in the UNESCO/IUBS/EUBIOS Bioethics Dictionary, QUOTE: "ANOSMIA: (Greek a + osme 'without smell'). 'Odor blindness' - the total loss or impairment of the sense of smell. Anosmia may be temporary resulting, for example, from an obstructive respiratory infection or a blow on the head which may damage the olfactory receptors, or be permanent as a result of an irreversible damage to any part of the olfactory apparatus. Sometimes anosmia (the so called specific anosmias) does not involve a total loss or reduction of the sense of smell but is instead specific to particular substances; for example, 3% of the population has trouble smelling the odor of sweat, 12% have diminished sensitivity to musky odors. It is important to note that anosmia may be induced by injuring the olfactory receptors consequent to inhaling caustic substances such as lead, zinc sulfate, or concentrated matter such as cocaine." UNQUOTE.

Here is eMedicine's discussion of taste and smell abnormalities. Search for the word "zinc". Here is the American Academy of Family Physicians page, showing some interesting graphics of the inner nose.

Evidence that Intranasal Zinc Can Cause Extreme Pain and Anosmia

Extreme intranasal pain immediately after instilling into the nose soluble and ionizable zinc compounds like zinc sulfate and zinc gluconate is an indicator that the olfactory region has been contaminated with rhinotoxic amounts of zinc. If this pain occurs and does not rapidly resolve, it may be treated by nasal irrigation in an attempt to remove the zinc as described here. Although incidence of anosmia from intra-nasal zinc administration of common cold remedies (the only commercial products that use intranasal zinc) is quite rare, extreme intranasal (olfactory region) pain is a universal precursor, and must be treated immediately in the hope of preventing persistent, perhaps permanent, anosmia. Anosmia in children and animals seems reversible within several weeks in most cases, treated or not, but there is concern that anosmia induced by intranasal zinc in adults may become persistent and perhaps permanent.

Intranasal zinc solutions have been known to kill the ability to smell by both animals and people for many years. However, there has been no use of intranasal zinc in humans since its brief use in 1938 in an attempt to prevent polio (see below). Due to homeopathic provisions of U.S. Food and Drug Administration laws, these new homeopathic common cold remedy products containing soluble zinc such as zinc sulfate or zinc gluconate have not been required to be approved by the FDA for either safety or efficacy.

There is some medical literature evidence that the problem has occurred in people both in history and today as:

• In PERSISTENT ANOSMIA FOLLOWING ZINC SULFATE NASAL SPRAYING, F.F. Tisdall, M.D., Alan Brown, M.D. and R.D. Defries, M.D. in Toronto, Ontario at the Hospital for Sick Children and the School of Hygiene and Connaught Laboratories, University of Toronto published in the Journal of Pediatrics, Vol. 18, No. 1, Pages 60 - 02, July, 1938, the authors found that about 15 percent of the children treated with intranasal zinc sulfate (for polio prevention) developed anosmia. See original 1938 report as graphics here (page 1, page 2, page 3, page 4).
• In THE USE OF ZINC SULFATE SOLUTION FOR THE PREVENTION OF POLIOMYELITIS IN MAN, E.W. Schultz and L.P. Gebhardt of Stanford University published in Journal of the American Medical Association (JAMA), 1938, Vol 110, page 2024 correspondence showing their concern that intranasal zinc sulfate nasal treatment to prevent polio might be producing permanent anosmia in adults, although anosmia often seemed to abate within 2 weeks in children. They reported that both the duration and severity of pain and anosmia were much greater in adults than in children.
• In ANOSMIA DUE TO INHALATIONAL ZINC: A CASE REPORT, C.A. DeCook, Hirsch, A.R. Chemical Senses. 25 (2000) 659 (graphic image here) or PDF version, see abstract 225.
• In ANOSMIA ASSOCIATED WITH [censored word] USE, a Power Point poster presented at the Fall 2003 meeting of the American Rhinologic Association by Bruce W. Jafek, Miriam R. Linschoten, and Bruce W. Murrow, Department of Otolaryngology, University of Colorado School of Medicine. The image " jafek.jpg" is presented here. See pages 48 and 49 of the Association's Fall 2003 program here.
• The work by Jafek, Linschoten and Murrow has been published in a peer reviewed medical journal, the American Journal of Rhinology, a leading nose research journal in 2004 in volume 18, pages 137 - 141. Their work expands on their 2003 work and their abstract reads: BACKGROUND: Zinc is an essential mineral. Beneficial zinc absorption takes place via enteral, parenteral, or cutaneous routes. However, direct application to the olfactory epithelium has been reported to cause loss of smell. Recently, intranasal zinc gluconate has been recommended as a treatment for the common cold. Severe posttreatment hyposmia and anosmia have been observed. METHODS: The case report of a typical patient is presented and analyzed in detail, followed by a series of patients with severe hyposmia or anosmia after the use of intranasal zinc gluconate. RESULTS: Although interindividual variation in drug response and drug effect is apparent, the severe hyposmia or anosmia appears to be long lasting or permanent in some cases. The mechanism of olfactory loss is thought to be the direct action of the divalent zinc ion on the olfactory receptor cell. CONCLUSIONS: Zinc ions are toxic to olfactory epithelium. Reports of severe hyposmia with parosmia or anosmia have occurred after intranasal use of zinc gluconate. The full text of the article is here. The graphic images of this report are as follows: Page 137, page 138, page 139, page 140, and page 141. Of extreme importance in this article is the statement in the lower left corner of page 139, which reads '...By 1982, Cancalon attributed the "necrotic effect" of various salt solutions to the divalent "zinc cation" in irrigation experiments on the catfish olfactory mucosa, using concentrations of 6 to 960 mM of zinc sulfate. He noted that ZnSO₄ (zinc sulfate) and ZnCl (zinc chloride) were "equally effective in destroying the olfactory epithelium, offering proof that it was the zinc cation that produces the toxic effects. He reported that the damage was very reproducible, largely concentration independent, and almost completely specific for the olfactory receptor cells...'.
• Alexander and Davidson wrote an article titled "Intranasal zinc and anosmia: the zinc-induced anosmia syndrome." in the September, 2006, edition of Laryngoscope. this is their abstract, or central findings: "OBJECTIVE: Commercial preparations of intranasal zinc gluconate gel are marketed as a remedy for the common cold. However, intranasal zinc has been reported as a cause of anosmia in humans and animals. Seventeen patients presenting with anosmia after the use of intranasal zinc gluconate are described. METHODS: The authors conducted a retrospective case series of patients presenting to a nasal dysfunction clinic and conducted complete history and physical examination on all patients, including nasal endoscopy. All patients underwent detailed odor threshold and identification testing. RESULTS: Threshold and identification testing revealed impaired olfaction in all patients. Inflammatory and traumatic causes of anosmia were excluded based on history, physical examination, and imaging. All patients diagnosed with zinc-induced anosmia or hyposmia reported sniffing deeply when applying the gel. This was followed by an immediate sensation of burning lasting minutes to hours. Loss of sense of smell was then perceived within 48 hours. Seven of 17 patients never developed symptoms of an upper respiratory infection. CONCLUSIONS: The zinc-induced anosmia syndrome, characterized by squirt, sniff, burn, and anosmia, occurs after the exposure of olfactory epithelium to zinc cation. It can be distinguished from postviral anosmia based on history."

The intranasal zinc as cause of anosmia observations are part of a more general problem caused by several metals in solution when in contact with the olfactory receptors of the nose. In F. W. Sunderman's year 2001 review article "NASAL TOXICITY, CARCINOGENICITY, AND OLFACTORY UPTAKE OF METALS", he reviewed the evidence for injury from intranasally introduced metals (eg, Al, Cd, Co, Hg, Mn, Ni, Zn) in a wide variety of species including man. He also reviewed the evidence that these metals pass via olfactory receptor neurons from the nasal lumen through the cribriform plate to the olfactory bulb of the brain. Furthermore, he reviewed the evidence that some metals (eg, Mn, Ni, Zn) can cross synapses in the olfactory bulb of the brain and migrate via secondary olfactory neurons to distant nuclei of the brain. Some of these metals, such as cadmium and nickel, can produce carcinogenic effects, but not zinc. Graphic images of each page of Sunderman starts here, while a scanned OCR file of Sunderman is here.

Nasal congestion, excessive nasal mucous (particularly from goblet cells in and adjacent to the olfactory receptor tissue) and swelling of the nasal turbinates occurring during a common cold may physically protect olfaction, helping to explain the low incidence of anosmia resulting from administration of doses of intranasal zinc that would otherwise produce extreme intracranial pain and anosmia in as many as 15% of people not having severe nasal congestion.

Some have questioned the importance of olfaction, perhaps in an effort to defuse the intranasal zinc as cause of anosmia issue. Let all be aware that the science of olfaction has strong support in science and medicine. In fact, the 2004 Nobel Prize for medicine and physiology went to Richard Axel, and Linda B. Buck for their discoveries of odorant receptors and the organization of the olfactory system.

George Eby's Common Cold Research

As the inventor of zinc lozenges for common colds, George Eby does not use, and does not recommend intranasal zinc sprays or pumped gels to treat colds or for any other purpose in humans because his research showed that intranasal zinc sprays did not shorten the duration of colds, and because they caused excruciating intracranial pain if contact with the olfactory region occurred. More recently others have also found poor or null results using intranasal zinc sprays and gels to shorten the duration of colds. Zicam® zinc gluconate nasal gel was found to have no effect in preventing rhinovirus-induced experimental common colds by Turner, a leading U.S. common cold researcher, a finding that only one person challenged, which was easily countered. Even though the positively charged zinc ion has many in vitro effects useful in treating colds, the only report to show intranasal zinc shortened common colds in over 100 years of treating colds with zinc, starting with Merck's 1901 "Manual of the Materia Medica", New York:Merck and Co., page125 and in Merck in 1923, is the report of Hirt. Consequently, the report of Hirt remains unconfirmed and suspect.

All zinc for common cold research articles were reviewed in the first accurate meta-analysis of the subject by Eby, as reported in the February, 2004, issue of Bioscience Reports, in an article entitled "Zinc Lozenges: Cold Cure or Candy? Solution Chemistry Determinants". The abstract reads: Common colds were shortened by 7 days in a 1984 clinical trial using zinc gluconate throat lozenges each 2 h. Between then and 2004, 10 other double-blind, placebo-controlled clinical trials showed widely varying results. This re-analysis of these trials presents solution chemistry methods to elucidate differences in efficacy. Statistically significant correlation was shown between total daily dosages of positively charged zinc species and reductions in median (p = 0.005) and mean duration (p < 0.02) of common colds in these trials. Part of the discussusion section concerns intranasal zinc for common colds, and it reads in part: "On the other hand, positively charged substances, such as zinc ions, applied on top of the nasal mucous are repelled by electrons flowing from the mouth outward through the nasal and nasal pharyngeal tissues, causing them to be expelled by the mucous and down into the throat. The mouth–nose BCEC also suggests no possibility for meaningfully reducing the duration of colds using intra-nasal zinc without electricity to reverse the mouth–nose BCEC."

George Eby's Painful Experience with Intranasal Zinc

As part of George Eby's research in 1979 using various zinc-related techniques to shorten colds, he prepared a 150 milliMolar solution of zinc gluconate and sprayed it into his nose using an emptied nasal spray bottle. He immediately developed excruciating intracranial pain, a sensation that filled his entire head with the greatest, sharpest, most intense pain he had ever experienced - even to this day over 25 years latter. The pain was worse than passing a kidney stone! It was worse than fire! He immediately and repeatedly irrigated his nose with plain tap water and the pain resolved in about an hour, leaving him in a state of near shock. He used a zinc gluconate concentration 5 times higher than the main U. S. commercial intranasal zinc product, Zicam® zinc gluconate nasal gel .

Only because he irrigated his nose with water to remove the rhinotoxic zinc, did he not become anosmic or develop anosmia or develop any other smell loss or taste loss sensory problem.

In the Quigley vs. Gum Tech (now Matrixx Initiates) patent infringement trial in 2000 in Philadelphia, PA., he testified under oath that more than 10 milliMolar zinc gluconate concentration intranasally sprayed caused nasal pain. My findings of "extreme nasal pain" from 150 mMol intranasal zinc gluconate were read into this Judge's Memoranda before the trial. Also see these archived copies of for the March 9, 2000 and the April 19, 2000 memoranda. In my no-effect clinical trial of 10mMol zinc gluconate isotonic nasal spray and zinc orotate lozenges in 1981 (published in brief in my handbook), some patients complained of nasal pain from the nasal spray. The full 1981 report was recently resurected from CPM files, updated to include these anosmia issues and published in 2006 as shown in the full article located here. However, not until Dennis Christensen notified George Eby in 2003 of his lawsuit against the manufacturer of the intranasal zinc gel product as cause of his anosmia, did he begin to suspect how close he came to causing himself to become anosmic.

Irrigate the Nose! How George Eby Removed Intranasal Zinc Gluconate

See various pages on the Internet for "nasal irrigation". A simple isotonic solution can be made using a teaspoon of table salt (sodium chloride) and a teaspoon of baking soda (sodium bicarbonate) in a liter of warm water. Here is a page for a high-quality, home-made nasal irrigation formula. In retrospect, he probably should have used isotonic water to treat the astonishing pain of intranasal zinc gluconate, but the pain demanded immediate attention. He certainly could not wait until he traveled to a doctor's office. Nasal irrigation is exactly like it sounds. From the tiny bit of experience collected, it seems imperative to irrigate promptly before permanent damage to the olfactory apparatus occurs. How long is "promptly"? George Eby has no idea, but the pain in his case from 150 mMol zinc gluconate forced him to do it immediately. Here is a page showing various nasal irrigation techniques including the use of a Water-Pic®. George Eby used a Water Pic® daily to rinse out his nasal cavity as part of his normal daily hygiene, although the tip was enlarged by cutting off the end to reduce the pressure but maintain the high flow rate.

Treatment for Intranasal Zinc Induced Anosmia

At this time, George Eby knows of no cure for anosmia due to intranasal zinc after it occurs. The anosmia may be transient, which appears to be the case in small children, or anosmia may be persistent, which appears more likely in adults. In other words, he doubts that permanent anosmia can be prevented or anosmia reversed by any specific medical treatment or procedure if nasal irrigation to remove the zinc gluconate is not immediately performed by the victim.

On the other hand, since George Eby is the only known person to have tried to remove intranasal zinc gluconate through nasal irrigation, who knows if it will or will not work in other people. Schultz and Gebhardt in 1938 suggested, "The risk of inducing a lasting anosmia may possibly be reduced if the zinc sulfate solution is followed within a few minutes by drops of physiologic solution of sodium chloride (meaning isotonic salt water) instilled by the Shahuinian method. This would have the effect of reducing the length of time that a full strength solution of zinc sulfate would be permitted to act, should it tend to be held by capillary attraction in the superior common nasal meatus".

There is no ethical scientific way to experiment with intranasal zinc to see what actually happens in human adults due to the severity of the zinc-anosmia reaction. Judging from the reports of others, the damage in adults appears to last many months or years, and is likely to be life-long in duration. Patients that have become anosmic from intranasal zinc should remain the subjects of investigation and reporting for at least 10 years to generate actual data. Realistically, anosmia from intra-nasal zinc sprays and gels lasting longer than several months in adults or children appears likely to be permanent.

Side effects from drugs are not always seen in clinical trials and are often seen only in large populations. To protect the public concerning these rare events, the U.S. Food and Drug Administration has set up the "Safety Information and Adverse Event Reporting Program", which should be used to document unexpected adverse reactions, such as anosmia from intra-nasal zinc products.

Capsaicin nasal sprays (Sinus Buster®) are being touted by the manufacturer, SiCap Industries, to restore the sense of smell in people rendered anosmic from various causes, usually inflammation, and that it might help people with intranasal zinc-induced anosmia. Is there clinical evidence? Not yet. None. Not even a single case report for intranasal zinc-induced anosmia. Capsaicin is considered to be a strong neurotoxin by a manufacturer. Capsaicin seems to have quite complex neurochemical effects. While it deceases pain by decreasing substance P levels, and it is frequently used as a treatment of neuropathic pain, it works by differentially modulating substance P in pain pathways. Thus, it is the interaction between substance P and the particular receptor sites that causes either nociceptive (pain causing) or anti-nociceptive (anti-pain causing) effect. In other words, in high doses it causes pain, and at low doses it prevents pain. Yet, no documented evidence that capsaicin has any beneficial effect on anosmia exists, and certainly not for intranasal zinc-induced anosmia.

Zinc Gluconate Chemistry

Distribution of zinc ionic species in the Zn2+ and gluconic acid system. Curves were constructed from pK values shown after the reactions: Zn2+ + L_ <=> ZnL+ (1.62) and ZnL+ + OH_ <=> ZnL(OH)0 (8.14) at a concentration of 30 mMol zinc. The pK values are courtesy of Gerritt Bekendam, Akzo Chemicals BV Research Centre, Deventer, The Netherlands, 1989. The Zn2+ fraction over pH 6 is strongly affected by the second pK value [hydroxide (OH)]. Precipitates of hydroxides of zinc result in supersaturated solutions. Computer-simulated distribution of zinc ionic species is courtesy of solution chemist Guy Berthon, 1992. Zinc gluconate is highly soluble in water, and this computation is directly applicable to Zicam® Zinc gluconate Nasal Gel (Zicam).

The Zicam® Zinc Gluconate Nasal Gel Problem