New Zicam study shows possible mechanism for anosmia

Remember the Zicam debacle? To catch you up, Zicam has been promoted for years as a "homeopathic cold remedy". It is of course neither. Since it contains measurable amounts of zinc, it isn't "homeopathic", and since there is no cure for the common cold, it's not a remedy. In addition to having neither of it's promoted qualities, the FDA has received hundreds of reports of people losing their sense of smell (became "anosmic") after using intranasal Zicam. As Steve Novella has pointed out, there is some scientific evidence pointing to a causal connection between zinc and anosmia. Now evidence is pointing toward possible mechanisms.

Adverse drug events are reported all the time. Nailing down whether they are significant can be difficult. First, there must be a plausible connection between the drug ingestion and the adverse event. Then cases have to be studied statistically to see if there is a true causal relationship. This is more difficult for Zicam since it has historically been more or less unregulated, being part of the homeopathic pharmacopoeia and not subject to the same regulation as other drugs (despite not being truly homeopathic).  Despite this, the number of reports about Zicam was concerning enough for the FDA to issue a warning.

BiochemBelle tipped me off to a fascinating new study in PLoS One. This new study did a lot of things right in trying to illuminate this issue. For one thing, they used Zicam itself rather than a generic zinc preparation. They then tested Zicam in a mouse model and found loss of smell. Then the took human nasal tissue and exposed it to Zicam and found significant cell death. In both models, they also exposed the subjects (either mice or human olfactory neurons) to other substances commonly used with Zicam, such as nasal corticosteroids, vasoconstrictors, and saline.  Not only did Zicam cause damage that other common cold medications did not, the damage was severe enough to be permanent.  

This is a damning report.  Given the lack of benefit of zinc preparations and the risk of serious neurologic damage, they should be taken off the market.  It also points to the wider problem of medicines being classified as "homeopathic", despite having measurable amounts of an active ingredient.  The homeopathic pharmacopoeia is a bad joke---it contains unregulated fake medicines, and unregulated, untested, and potentially unsafe real medicines.    This loophole for quackery needs to be closed before people suffer worse fates than loss of one of their primary senses.


Lim, J., Davis, G., Wang, Z., Li, V., Wu, Y., Rue, T., & Storm, D. (2009). Zicam-Induced Damage to Mouse and Human Nasal Tissue PLoS ONE, 4 (10) DOI: 10.1371/journal.pone.0007647

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Some mothers my wife knows use "homeopathic teething tablets" on their infants. They find anecdotally that it works quite well, which is of course not evidence, but it was enough to pique my interest.

So she borrowed a box and tried a few. They do seem to soothe the infant a bit, but of course it's not possible that's homeopathy working, since that's just absurd. My wife thinks that basically works because it's a sweet-tasting quick-dissolving tablet -- which it makes sense might be momentarily soothing for gum pain. (That also matches the anecdotal experience of the woo-believing moms she knows, since they report it only really works while the tablet is in the mouth)

This seems innocent enough, but reading the label, I came up with a much more sinister hypothesis: One of the ingredients is the homeopathic name for coffee beans. In addition, these tablets are solid, not liquid. Depending on the "strength" of the dilution, it's possible that there was still a non-trivial amount of coffee left before they did whatever process they used to concentrate it back into a solid. It's just conceivable that, despite being "homeopathic", these tablets might work because they are a mild stimulant. Not something you really want to be giving an infant...

It probably is just the sugar-pill effect after all, but it's worrisome nonetheless. This shit is completely unregulated, and it's being given to babies. Yeesh...

I wish that the authors would have put a more detailed description of the product used in their Materials and Methods. Zicam sells a ton of different products, some homeopathic, some not. If they were using the product I think they were, it contains 33 mM Zn gluconate (yes folks, that's 33 MILLImolar - I didn't screw up a mu). That is a royal bungload of zinc and, therefore, not homeopathic. It only takes zinc at concentrations above 100 mM to kill cells in culture. How this product was marketed as a homeopathic remedy is beyond me.

The lawsuit launched in summer, 2009, (and detailed at Zicam's lawsuit site) speaks of what I believe the tested product to be: the Zicam ColdRemedy Nasal Gel, a product that is no longer on the market. They still sell a couple of other Zicam nasal gels under different names (as seen on their US website) but none of these appear to contain the high zinc concentrations any longer.

Otherwise, this is a terrific paper. Many thanks to you and BiochemBelle for bringing it to my attention.

Any product containing 10% zinc gluconate should never have been classified as homeopathic. But Zicam should not be compared with other zinc preparations. There haven't been any reports of Anosmia when zinc is taken orally, topically, or by injection. Here are just three of many studies demonstrating zinc's benefits:

1. Efficacy of zinc against common cold viruses: an overview
This meta-analysis concluded, "Clinical trial data support the value of zinc in reducing the duration and severity of symptoms of the common cold when administered within 24 hours of the onset of common cold symptoms."

2. Serum zinc and pneumonia in nursing home elderly
Study conclusion: "Normal serum zinc concentrations in nursing home elderly are associated with a decreased incidence and duration of pneumonia, a decreased number of new antibiotic prescriptions, and a decrease in the days of antibiotic use. Zinc supplementation to maintain normal serum zinc concentrations in the elderly may help reduce the incidence of pneumonia and associated morbidity."

3. Zinc and Immunity

This was published in the medical literature in 1938 if not before then (I haven't done a full literature search). It boggles the mind that this is just now being rediscovered 71 years later.

Persistent anosmia following zinc sulfate nasal spraying
The Journal of Pediatrics
Volume 13, Issue 1, July 1938, Pages 60-62

I don't recall the exact details, but in the mid 1930s it was believed that a zinc sulfate nasal spray would prevent polio by killing any virus that was inhaled into the nose. This led to many children losing their sense of smell.

There are a lot of true believers posting comments over at CBS MoneyWatch to the effect that this is some sort of FDA conspiracy.;blog-river#comments

One other skeptic and I posted a few comments seeking to inject a dose of reality into the discussion, but I'm exasperated at this point. The posters seem to be more concerned with the impairment of their stock portfolios than anybody's sense of smell.

By JimfromHartford (not verified) on 02 Dec 2009 #permalink

James Sweet,

It seems to be the standard party line within the recovery (alcohol/drug/addiction) community here in Massachusetts to advise against all use of "natural" and homeopathic products because "you couldn't tell what was in them." Whether this was just a rule for simplicity (grouping homeopathic medicines with things like, say, St. John's Wort) or whether there was some evidence or suspicion of active ingredients or even deliberate adulteration (something which may have been a problem in bodybuilding supplements) I don't know.

The "homeopathic" zicam was covered by Orac and undoubtedly others, and I vaguely remember it may have taken multiple posts and comments to tease out the information but it may have been like a "2X" or "2C" dilution which is ridiculous. I assume that the teething pills should list a dilution, but then I wouldn't purposely buy anything homeopathic. (36 years ago I was winning chemistry competitions in high school, and was the kind of person who, asked what a mole was, would recite Avogadro's number (I *might* have said an insectovore when asked what a shrew was, if you remember that recent kerfuffle)). I think I once mortally offended someone who, while I was at my vet (this was a customer, not employee) very smuggly noted he had the flu but was taking a homeopathic remedy.

Nice try, but Rush Limbaugh already revealed that the Zicam recall was a dastardly plot to undercut his show by getting rid of one his sponsors.

Nitpick: Zicam really is homeopathic. This is because the legal definition of "homeopathic" (and the one which binds the FDA) is "appears in the official homeopathic pharmacopoeia." And guess what? After the kerfluffle about it being not really homeopathic a few years ago, the homeopaths changed the documentation so that a "2X" dilution is now officially homeopathic.

The mind-boggling arrogance required to do something like this is staggering. At some level, the homeopaths have to know what they're doing, and just not care. They must think their customers are incredibly stupid, or at least totally oblivious to these shenanigans. Sadly, for the most part, they seem to be *right*.

By Calli Arcale (not verified) on 03 Dec 2009 #permalink

So Rush Limbaugh pushed Zicam... so his listeners wouldn't be able to smell his giant stink... wow it is all so clear to me now!

Thanks for the clarification, Calli.

p.s I read all of the Hep B article at SBM last night. It was ... something. You have great patience. Also loved the salmon/fMRI experiment.

Observation on Calli's nitpick: At least one homeopathy group tried to distance itself from the recalled nasal spray. Following the FDA action last June, Bloomberg's reporting on Matrixx's exploitation of the homeopathic medicine loophole in the Food, Drug and Cosmetics Act noted that the company's claim its intranasal products qualify as "homeopathic" is, at least, questionable:
"Zicam's recall has raised concerns among homeopathic industry officials. According to [Homeopathic Pharmacopeia Congress of the United States spokeswoman Mary] Borneman, the Zicam nasal products, because the medicine is inserted into the nose rather than taken orally, doesn't meet the guidelines of the homeopathic congress. Applying zinc in the nose hasn't been tested by the industry group, she said." See

By JimfromHartford (not verified) on 03 Dec 2009 #permalink

I assume that the teething pills should list a dilution, but then I wouldn't purposely buy anything homeopathic.

It did, but I can't remember what it said. I seem to remember it was in the range where it was pretty diluted, but not "There could not possibly be a molecule of the solute remaining"-diluted. I won't be checking because I also wouldn't purposely buy anything homeopathic :)

Oh, and BTW, it was Orac's early coverage of the Zicam debacle that originally made me wonder if the teething tablets might be more than sugar pills... :)

Interesting; so some of them are aware of the internal inconsistencies of homeopathy. It must be frustrating, to be a homeopath and attempting to practice rationally. (Note: you can be a homeopath and practice rationally, as long as you know bupkis about chemistry and biology.)

Even more interesting that their criticism focused not on the rather *high* concentration but rather on the route of administration. There are plenty of homeopathic remedies sold for routes other than oral. I've seen eyedrops, eardrops, and lotions. The industry must be a bit schizophrenic, much like chiropractic.

By Calli Arcale (not verified) on 04 Dec 2009 #permalink

Uncle Glenny: thank you for the kind words! It was an interesting thread, but the always-hilarious Th1Th2 has kinda ruined it now. :-( (He's kind of like SBM's H@ppeh.)

By Calli Arcale (not verified) on 04 Dec 2009 #permalink

Dr Lipson- I have not been able to tell from what I have read. Is reported the loss of smell as it relates to Zicam use permanent or temporary?

By DrWonderful (not verified) on 08 Dec 2009 #permalink

It's seems it can be permanent.

Seconding Calli Arcade, sort of, Zicam is homeopathic if it has been banged against a leather bound bible, or some facsimile of that process. Just because they only did it twice doesn't stop them claiming the magic. The legal position I'll leave to Calli, and your earlier Zicam posts.

By the way, the Science Based Medicine link in the blogroll is wrong - the URL should end in .org not .com

1. It's obviously not homeopathic by any conventional definition, because it has something in it.

2. I t does work, by double-blind clinical trial.

3. The instructions specifically warn not to snort it, but only to wipe it around in the outermost nostril cavity.

4. It betrays a fundamental confusion to insist something can't work just because the word "homeopathic" appears on the box, and also insist it is necessarily harmful.

Hasn't anybody ever heard of "Use as directed"? Sheesh.

By Nathan Myers (not verified) on 09 Dec 2009 #permalink


1. You can try telling the homeopaths that.

2. It does? I'd be very interested to see that study. You may be confusing it with the nonblinded studies which showed a modest effect for zinc lozenges, though the results didn't reproduce well. At best, the net result is inconclusive. (Note: Zicam is not a zinc lozenge.)

3. You're right; nobody is snorting Zicam swabs, as this would lead to a rapid increase in ER visits to have the swabs removed. But the people who have lost their senses of smell after using Zicam were in fact using it as directed.

4. This is exactly why the legal definition of "homeopathic" is such a problem. People who know homeopathy is bunk assume that at least it's just water, and therefore harmless. But this assumption is clearly not warranted. Not only may homeopathic drugs be adulterated, but even those prepared according the the standards of the homeopathic pharmacopeia may contain actual active ingredients, in direct contradiction to the principles of homeopathy. Frankly, the only word I can think of to describe this is "fraud". The makers of Zicam and the homeopaths who got "2X zinc" added to the pharmacopoeia have to know that what they are doing is complete BS by anybody's standards, even those of Hahnemann.

Note: the FDA does have *some* power over homeopathic remedies. If there is evidence of harm, they can intercede. So far, they have limited themselves to issuing warnings to the general public. The most recent was in June of this year. Matrixx responded that the results weren't produced in a controlled trial, therefore should be ignored, but if we were to follow that model, Fen-Phen and Vioxx would still be on the market, because their manufacturers were every bit as eager as Matrixx to brush aside inconvenient side effects reported by actual users.

By Calli Arcale (not verified) on 10 Dec 2009 #permalink

I just had an idea. A major problem that lead to the loss of smell in these many victims is the reckless negligence of those that regulate what is listed in the Homeopathy Pharmacopeia. They allowed zinc 2x to be added without testing. It seems to me that the Homeopathy regulatory body carries significant culpability in the injury of these victims and should be held responsible.

I very much doubt if the Homeopathy regulatory body has deep enough pockets or carries enough insurance to compensate all the victims sufficiently. Going forward, I would like to see at least two outcomes:

1. Regulators, manufacturers, and sellers of homeopathic remedies should be required to carry enough insurance to compensate victims of any future malpractice.

2. Substances listed in the Homeopathy Pharmacopeia need to be tested for safety and efficacy, just like any other treatment, and with no âgrandfatheringâ.

Because those who regulate the Homeopathy Pharmacopeia donât have deep enough pockets to satisfy the claims of the victims, they will have to negotiate with those victims and come to a settlement. I think that settlement should at the least include the two above provisions.

I appreciate that implementing provisions 1 and 2 may make homeopathic preparations unavailable because they canât meet minimum standards of safety and efficacy. I donât see that as a bad thing.

Calli: Who cares what homeopathists think? Obviously the label on the box is just there to take advantage of a loophole in FDA regulations. Without that loophole, I would be unable to buy it at all, and it's the only thing that actually works. (Zinc lozenges don't.)

The original delivery mode of the Zicam zinc gel was in a little squeeze pump bottle with a nozzle. People who gave themselves anosmia were manifestly not using it as directed, because the directions specifically said not to snort it, but they did anyway. My family and I have used it for years, and we smell fine. I pump a drop onto my finger, or my kid's finger. You can drive your car off a cliff, but that doesn't make cars unsuitable for getting you to work. Don't drive off cliffs.

The swabs vehicle was a response to the misuse problem. Probably few people have got asosmia that way. It has the additional advantage (to Zicam) that customers have to pay enormously more to get the same number of treatments. I haven't had to buy swabs yet, because I stocked up on the last run of pump bottles.

The fundamental problem is that any treatment that can't be patented will never get FDA approval, because only patented treatments stand a chance of generating enough revenue to pay for the $100M trials needed. The FDA should be performing these trials for promising unpatentable treatments. That they don't is an almost criminal dereliction of their duty to the public. Solutions to pharmacological problems that include making zinc gel unavailable to me are actively harmful.

By Nathan Myers (not verified) on 10 Dec 2009 #permalink