Effects of Intranasal Applications of Zinc Salts

Background

In July of 2002 I received the following correspondence from a very distressed person: "Dear Dr. Wuensch, I am glad to have found your web site and maybe you have some information that can help. I used [an OTC product containing zinc gluconate], which is a homeopathic nasal gel used at the onset of a cold. I got it too far up my nose, as I found out everyone does, and have had no sense of smell or taste in 1 month. I called the company and it is a Zinc salt. That's all . I have seen an ENT and tried steroids, no luck. I have also seen an acupuncturist. No Luck. I now can smell coffee once in awhile, or taste sweet and sour sometimes. I am scheduled for a cat scan, which I think is unnecessary, but I guess will do. The minute I put in up by nose, my whole head filled up, like with a bad cold. When it finally cleared, no smell or taste. Do you think I will ever get it back or have any suggestions?"

According to the manufacturer, the active ingredient in this product is "Zincum Gluconicum." There is published evidence that this product can reduce the duration of the common cold: Ear Nose Throat J. (2000 Oct;79(10):778-780, 782). A report in the journal Clinical Infectious Diseases (2001 Dec 1;33(11):1865-70) indicated that intranasal zinc gluconate is not effective for preventing the common cold. Likewise, research reported in the American Journal of Medicine (2001 Aug;111(2):103-108) indicated that intranasal zinc sulfate did not reduce the duration of the common cold.

My initial reaction to the distressed correspondent was to suggest that his anosmia may have been produced by the infection for which he was using the intranasal zinc gel. That is, I suggested that he had a case of viral anosmia. I still believe that this is possible in cases like this, but there is some reason to suspect that the intranasal application of zinc salts may itself be troublesome.

Since this first report, several other correspondents have alleged that this product made them anosmic. I am aware of an association between intranasal zinc and anosmia. In graduate school, many years ago, I read several articles on the effects of temporary anosmia on the behavior of various animals. Researchers produced anosmia by the intranasal application of ZINC SULFATE.

One correspondent pointed me to a document (The Middle-Class Plague: Epidemic Polio and the Canadian State, 1936-1937) that mentions anosmia as a side effect of intranasal application of zinc sulfate in humans. It seems that Canadian researchers, back in the 1930's, experimented with the intranasal application of zinc sulfate as a prophylactic intended to prevent the polio virus from entering the brain through the olfactory neurons. The researchers expected the zinc solution to produce temporary anosmia, and not more than a quarter of the treated children reported having lost their sense of smell. Some of these children still had not regained their sense of smell months later. Whether they ever did I just do not know. One of the researchers tried the solution on himself and he also became anosmic. I really would like to know how long the anosmia in these children lasted. If you find a reference to this, please advise me.

I am also curious regarding the mechanism involved in zinc-produced anosmia. One researcher suggested to me that zinc solutions produce anosmia because they are caustic. I'd like to know more about this too.

Zinc Used to Produce Anosmia or Hyposmia in Laboratory Animals

I used Google to search for (+ZnSO4 + anosmia) and for (+"zinc sulphate" +anosmia) and for (+"zinc sulfate" +anosmia). I found several interesting references to the use of zinc sulfate for the experimental production of anosmia. The one that most captured my attention was an article listed on the online vita of Dr. Burton Slotnick. I found this article at the library of our medical school. It is the primary source for the information which I present below.

Researchers interested in the behavioral effects of anosmia have experimentally produced anosmia in laboratory animals and then compared their behavior to that of control animals. One technique which has been employed to produce anosmia in an experimental animal is olfactory bulbectomy, that is, destruction of the olfactory bulb in the brain of the experimental animal. This most certainly produces an animal that is anosmic, but it may also produce other changes in brain function which are not directly associated with olfaction (assuming that the olfactory bulb has functions that are not directly associated with olfaction).

For several decades now an alternative method has commonly been employed for producing anosmia in experimental animals. This method involves the application of solutions of zinc salts. Both zinc sulfate (a 5% solution) and zinc chloride have been employed and appear to be more effective than other salts which have been tested.

Burton Slotnick et al. (Slotnick, B., Glover, P., & Bodyak, N. Does intranasal application of zinc sulfate produce anosmia in the rat? Behavioral Neuroscience, 2000, 114, 814-829.) present a review of the research done with zinc sulfate along with the results of their own research.

Anatomical studies have shown that zinc sulfate quickly produces severe degeneration of the olfactory epithelium. Numerous behavior studies have show that intranasal application of zinc sulfate seriously affects animals' ability to solve an olfactory task. The olfactory task which has most commonly been employed involves finding a scented pellet of food which has been buried in sawdust. While normal rats have little problem finding the scented food, rats treated with zinc sulfate seem unable to do so for a period of 3 to 10 days following treatment. Do note that rats recover from the effects of the zinc treatment within a few days.

Despite the evidence of the effectiveness of zinc sulfate in producing behavioral effects attributed to anosmia, Slotnick et al. argue that zinc treatment is not a reliable method of producing anosmia. Their research and the results of research they reviewed indicate that zinc treatment may produce considerable hyposmia, but not complete anosmia, at least not in most rats.

The behavioral test employed by Slotnick et al. involved teaching rats to discriminate (on a go/no task) whether or not an olfactory stimulus (ethyl acetate, which has a pleasant fruity odor, or another odorant) was present. Bulbectomized rats performed at chance level on this task, but rats treated with zinc sulfate (with one exception) performed as well after treatment as they had before treatment, at least when the scent was presented at high concentrations. When the scent was presented at lower concentrations, some rats (3 of 7) showed behavioral deficits, suggesting that the zinc treatment had produced hyposmia (reduced but not abolished capacity to detect scents).

The evidence clearly indicates that zinc treated rats can discriminate between a strong scent of ethyl acetate and no scent -- but is the sensation still the same as it was before the experimental treatment? Regretfully, the rats cannot tell us. It could be that the experimental rats can detect scents but cannot discriminate one scent from another -- that is, that all things might smell the same -- but Slotnick et al. also have data that suggest that zinc treated animals can discriminate between different odors. Slotnick et al. tested three rats on a series of four odor discrimination tasks (for example, discriminating between the scent of bubble-gum flavored mouthwash and that of cinnamon flavored mouthwash). One of the three rats had difficulty making these discriminations after treatment, but improved to nearly normal levels after some practice. A similar pattern was shown by a second rat who was given a second treatment with zinc. These results suggest some detriment caused by the zinc treatment, at least in the short term, but certainly not complete loss of the ability to discriminate between different scents.

Anatomical results showed that when wheat germ agglutinin-horseradish peroxidase was applied to the olfactory sacs of control rats, all or nearly all of their glomeruli were subsequently found to contain high levels of the reaction product, indicating a normally functioning olfactory system. [Glomeruli are structures within the olfactory bulb, where incoming olfactory neurons connect with secondary neurons. Each glomerulus receives connections from several thousand olfactory neurons, all of the same type. From the glomeruli, the secondary neurons carry olfactory information to various parts of the brain, especially the limbic system, hypothalamus, and to the primary olfactory area of the cerebral cortex (the orbitofrontal cortex, on the underside of the frontal lobe).] With the experimental animals, however, there was evidence of disruption of olfaction, but not total lack of olfaction. On average, 53% of the glomeruli (range of 22% to 74%) of zinc treated rats had detectable levels of the reaction product.

The evidence presented by Slotnick has convinced me that intranasal application of zinc sulfate is not a reliable method of producing anosmia in laboratory rats. It is also clear, however, that such zinc treatment does affect the olfactory system, probably producing hyposmia. Such hyposmia seems not to affect the performance of rats in a simple task where they are asked to discriminate between scented and unscented air (unless the scent is of low intensity), but in more complex tasks, such as finding buried, scented food (a more ecologically valid task, one might argue), such hyposmia can produce behavioral deficits (as shown by past research).

It should be noted that treatment with zinc sulfate may be a reliable means of producing anosmia in some animals other than rats. For example, Slotnick et al. note that zinc treatment of laboratory mice produces both anatomical and behavioral evidence consistent with the production of anosmia. Furthermore, the anatomical evidence indicates that the effect of the zinc treatment persists for weeks or months after the treatment.

One confounding factor when comparing the mouse studies with the rat studies is that rats are typically anesthetized during treatment, but mice are not. It is possible that the anesthesia produces nasal secretions which reduce the effectiveness of the zinc sulfate treatment.

Dr. Slotnick (personal communication, 21. April 2003) has suggested that zinc sulfate may have a stronger effect on olfaction in humans and frogs than in rats. He related this to the fact that the structure of the turbinates in humans is less complex than in rats. He also suggested that zinc sulfate achieves its effect by caustic action, and that other metallic salts can have similar (generally lesser, according to research cited in his article) effects.

The article by Slotnick et al. has a number of references of potential interest to those who want to know whether or not intranasal application of zinc can produce anosmia or hyposmia in humans.

Does Intranasal Zinc Cause Anosmia in Humans?

Some in the medical community have recently expressed concerns about the use of intranasal zinc. In October of 2000 C. A. DeCook and A. R. Hirsch reported a case of a man who lost his sense of smell following use of this intranasal zinc preparation, and suggested further research on this product (225. Anosmia due to inhalational zinc: a case study. Chemical Senses, 25(5), 659).

In September of 2003 there was presented at a meeting of the American Rhinological Society, a paper on clinical problems attributed to the intranasal use of zinc gluconate (Bruce W. Jafek, Miriam R. Linschoten, and Bruce W. Murrow (Department of Otolaryngology, University of Colorado School of Medicine). A short case study of one patient was presented. This patient had treated himself with the OTC intranasal zinc preparation. He reported that he felt an intense burning upon treatment and immediately became anosmic. His sense of smell was reported to still be absent 23 months after this incident. His anosmia has been confirmed by chemosensory testing and sinus disease has been ruled out as a possible contributor to his condition. The authors then reviewed the records of patients at the Rocky Mountain Taste and Smell Center and found ten patients whose anosmia may have been caused by the intranasal application of zinc. This research has now been published in the American Journal of Rhinology (18, 137-141, 2004), and the article is available online.

In February of 2004, shortly after ABC ran their story on the association between intranasal zinc and anosmia, I received an email from a concerned father whose daughter had used such a product. He also had invested in a firm that markets such a product. He asked me a number of interesting questions, none of which I was able to address with any certainty. For example, he asked if the fact that zinc sulphate produces anosmia or hyposmia in nonhuman animals means that zinc gluconate does the same in humans. My response, in part, is reproduced here:

I remain agnostic regarding whether or not products containing zinc gluconate can produce anosmia in some individuals. Some highly regarded otorhinolaryngologists have presented clinical evidence that suggests that such products can produce anosmia, but nobody has, to my knowledge, provided experimental evidence that the zinc gluconate can cause anosmia. If it can, it clearly is a problem only for a very small minority of individuals, those who are at risk because of some unknown factor or factors (such as, for example, the morphology of their nose contributing to the solution reaching and staying on the olfactory receptors high in the nasal chamber). I think you should reassure yourself and your daughter that it is highly unlikely that she will react to the product in this way. I trust that she has noticed no reduction in her sense of smell. Those who have corresponded with me about their anosmia following use of Zicam told me it produced a very painful burning sensation, not the minor burning sensation you daughter mentioned.

Nobody has been able to answer to my satisfaction my questions regarding the mechanism of action involved when zinc sulfate produces anosmia or hyposmia. Slotnick suggested that it might be due to some "caustic" effect, but his answer was more than a little speculative.

I suspect that some researchers will do some experimental research on zinc gluconate now, but I doubt that it can be done with humans -- it might take a very large sample of subjects to be able to detect a problem that occurs (if at all) in only the very few who are at special risk, and that may be prohibitively expensive.

I understand all too well that products that are safe for most can be troublesome for a few. In early January of 2004 I lost vision (not complete loss) in my left eye, apparently due to an ischemic event involving the anterior optic nerve (see AION). Some of the recent research strongly suggests that this can be caused, in those persons who are at special risk, by taking blood pressure medication in the evening (as I had been doing, as directed by my physician). Taking blood pressure medicine in the evening may be a good idea for most persons with hypertension, but for me it may have been a mistake.