Zicam and your Nose

Sci saw this post recently at Dr. Pal’s place, and it rang some major bells in her head. So, I figure, I’ve got to cover it myself, now don’t I.
ResearchBlogging.org Lim et al. “Zican-induced damage to mouse and human nasal tissue” PLoS ONE, 2009.
So let’s start with a couple of things:
1) What is Zicam?
2) Why was it recalled?
3) What are the possible effects of zinc on the common cold?


First, I would like to state for the record that Sci has used Zicam. She had a cold, someone in her lab swore up and down that Zicam worked. Sci tried it (used the oral spray, not the nasal one that has been recalled. It tasted AWFUL). Didn’t get any benefit, but thankfully also did not lose her sense of smell (though since it was sprayed in my mouth, I wouldn’t expect to), which would have been very sad, as Sci has a VERY strong sense of smell (though I’ll admit this is more often a curse than a blessing, actually).
So anyway, most of you might know that a bunch of Zicam has been recalled, due to reports of anosmia following use of the nasal spray version. That would be the loss of your sense of smell, either temporary or permanent. Loss of smell can be a pretty big problem, actually. A lot of what you taste is dependent on your sense of smell, so losing it for a long period of time could make for a very very boring existence. Loss of the ability to taste things like pumpkin and chocolate honestly might make Sci a bit suicidal.

1) So what is Zicam?

Zicam is a nasal spray (comes in swab form, but most people have used the spray) marketed to reduce or eliminate the common cold. Zicam is marketed as a “homeopathic” remedy, containing zinc in homeopathic amounts. If this were in fact the case, it wouldn’t contain any zinc at all (Sci has an old post on homeopathy that she might post soon to clarify what we mean by homeopathy), but the website (I could only come up with the oral mist, they obviously don’t have the cold remedy nasal spray on there anymore) says that Zicam contains “Zincum Aceticum and Zincum Gluconicum as active ingredients” (sadly, I cannot seem to find HOW MUCH, though I did find some reports that the dilution was 1:100, which is a good bit of Zinc, but that’s unsubstantiated. Sources, anyone?), and presumably this means they are there in more than homeopathic amounts.

2) Why was it recalled?

Recently, the FDA issued a warning, and the nasal spray was recalled, following 130 reports of anosmia. That doesn’t sound like a lot, but this study (which came out in October), doesn’t help. The authors gave various nasal sprays to mice (saline, Afrin, Nasacort, epinephrine, lidocaine, or Zicam), and then looked 3 and 9 days later at the mouse’s noses, specifically the main olfactory epithelium (MOE). This is a layer of cells in your nose (or the mouse’s nose), which contain olfactory receptors, making them sensitive to odors. Not only that, these cells are long, and join directly together to make the olfactory NERVE, going straight up into the brain! Yes, folks, they’re neurons. This means you have cells in the brain connected to your nose and DIRECTLY to the outside world! (Let us all pause to contemplate how cool this is…w00t).
Anyway, so they looked as the MOEs of the mice following exposure to all of these agents, including Zicam. What they were looking for was an electro-olfactorgam response, implying that the cells fired in response to a sensory stimulus.
zicam1.png
And it…don’t look so good. you can see the responses following exposure (drug exposure listed on the top), and then the response to various things (listed on the side), including water, mineral oil, vanilla, citrus smell, and isoamyl acetate, a compound that smells heavily of juicy fruit. You can see the electro-olfactogram response as a deflection in the line of the measurement. For all of these stimuli…the Zicam treated epithelia are ominously silent.
So the question was WHY. Is it that the epithelia are just desensitized, or what? The scientists looked for several proteins expressed only in MOE.
zicam2.png
Oh, dear. You can see here the treatments, and on the left side what they were staining for. In all the cells, they found Adenylyl cyclase 3, beta-tubulin (a protein specific for neurons, and since MOE ARE neurons, you’d look for that), and olfactory market protein. You’re looking for the green stains in all of these. And again, only with Zicam was there a big reduction in detection of these proteins.
This isn’t happy, because this means the cells aren’t just insensitive. It implies that they’re dead. However, the MOE is known to regenerate, so they looked in the mice at 31 and 65 days following treatment, to see if function would return.
zicam3.png
Yikes. On the right you can see that, even following 65 days, the MOE function is NOT restored, and to Sci what is scariest is how the MOE actually LOOK different (on the left). They did further cell staining. Still no dice.
Finally, they did what seals it for being a good paper (to Sci, anyway), they linked it all with a behavioral experiment.
zicam4.png
This was a sniff test, measuring how long the animals sniffed something cool (believe me, to mice, other mouse urine is the ULTIMATE cool). The mice treated with Zicam showed no response, implying that they just couldn’t smell it.
Already, to Sci, this is a good study. Multiple treatments, multiple tests, behavior and cell. The only thing I would have liked to see is a dose response curve. Are these clinically relevant doses? Is there recovery following lower dose treatment?
And then they went me one better and did the thing in HUMANS. They took tissue culture from human noses and applied Zicam, and then looked for something called lactate dehydrogenase, a chemical that is an indicator of cell damage. Lactate dehydrogenase was increased significantly in Zicam-treated tissue. Tissue analysis looked even worse:
zicam5.png
Here’s the human nasal tissue, treated with saline (top), and Zicam (bottom). Ouch. None of the other agents tests produced this kind of damage.
So this study doesn’t make Zicam look very good. I’m glad they did it in humans, but I do still wish they had done a dose-response with lower doses. Mice were give 15 microliters into the nasal cavity, which is a tiny amount, but in a mouse nose that’s still a pretty hefty load. A small dose might result in less damage or possible recovery. But still, looks like that’s it for snorting Zicam. Or at least, I won’t be doing it.
3) So what’s up with zinc and colds?
Colloquial wisdom has had it for a while that zinc can cure the common cold. Or at least make it last for a shorter time. It’s been thought that this might be due to things like reducing inflammatory cytokines. Unfortunately, a lot of other studies say otherwise, and efficacy has yet to be established. Zinc is regulated as a dietary supplement in pill form, and so far the FDA warning apply only to those zinc applications taken as sprays through your nose. So it’s possible that zinc as a pill or lozenge is fine, but I won’t be spraying that stuff up my nose any time soon.
Lim JH, Davis GE, Wang Z, Li V, Wu Y, Rue TC, & Storm DR (2009). Zicam-induced damage to mouse and human nasal tissue. PloS one, 4 (10) PMID: 19876403
Link try number 2…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

16 Responses

  1. Ouchie. My nose hurts just looking at those graphs and pictures.
    Quite interesting though, a homepoathic snake oil which actually has snakes in it, something else my friends who use homeopathic stuff won’t believe me I guess.

  2. Actually homeopatic remedies might contain measurable amounts of stuff. Only ‘high potency’ remedies contain nothing. ‘Low potencys’ can have stuff like atropine in medically active amounts

  3. Strange, this post does not show up on ResearchBlogging.org as a PLoS ONE paper. Perhaps the Ref/DOI at the end should be in this form?
    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

  4. There was a big to-do over at Almost Diamonds when the FDA first recommended pulling Zicam. Some astroturfers showed up, not realizing they’d be found out in short order. It was epic.
    http://almostdiamonds.blogspot.com/2009/07/who-has-profit-motive_01.html

  5. …what is an astroturfer…?

  6. …what is an astroturfer…?

  7. You know how when real people organize “grassroots efforts” to counter something they find to be bad, e.g. in politics or what have you, and there’s a public outcry about it (on the internet or otherwise)? Well, when a corporation pays people to do the same thing, only in a manner beneficial to their company, it’s called “astroturf” — fake grass roots. Sort of like the recent response and amplification to the hacked climate emails, where people were springing up on blogs everywhere someone debunked them and posted things like “spin baby spin”.
    Swanson Vitamins carried Zicam and, after the FDA went after Zicam, people from Swanson invaded Stephanie’s blog spouting nonsense. I’m guessing it’s because her blog post on Zicam hit Google and the astroturfers were just doing the rounds.

  8. Sorry, I messed up the history on that. Greg had a post up first — http://scienceblogs.com/gregladen/2009/06/fda_limits_on_acetaminophen.php — then Stephanie wrote a reply to one of the astroturfers at her blog. The “who has the profit motive” post I linked is a follow-up exposing the astroturfers for what they are.

  9. Sorry, I messed up the history on that. Greg had a post up first — http://scienceblogs.com/gregladen/2009/06/fda_limits_on_acetaminophen.php — then Stephanie wrote a reply to one of the astroturfers at her blog. The “who has the profit motive” post I linked is a follow-up exposing the astroturfers for what they are.

  10. Sci: “Sci has a VERY strong sense of smell (though I’ll admit this is more often a curse than a blessing, actually).”
    I wonder if you’ve read this book. I don’t have a good sense of smell, and that novel gave me a different perspective of what could be to have a really good one. Highly recommended.
    Cheers.

  11. hazur: actually, Sci always thought she’d be a good sommalier, if she weren’t a scientist. Good smell and taste buds, you know. Now, though, they do COFFEE TASTINGS. I think I’ve found my calling.
    Jason: Ah! Excellent. Sadly, I think the person who just described this post as “f**kwitted” on Twitter just doesn’t agree with me. Doesn’t appear to be affiliated with a company.

  12. Yikes, excellent post, Sci. And Hazur, while I’ve yet to read the book (didn’t know there was one), I have seen the movie, and it was definitely fascinating. To the meat of this comment, I was born with congenital anosmia. I’ve never had a sense of smell, at least not as a result of proper olfaction. For Sci’s benefit, here’s what it’s like: Having never used a sense of smell, my sense of taste is actually intact. I doubt this would be true for anyone who loses an already established sense of smell, since their brains would be wired to make use of both senses. But in my case, it was never there to begin with, so my sense of taste evolved without it. I can differentiate many simultaneous flavors, but there are some differences. I love chocolate, olive oil, fruits, veg, and meat, and especially love cod liver oil (huh?). Yep, I even pour it over spaghetti. On the other end, I cannot stand flavored chips (like Doritos), Kool-Aid, candy corn, ketchup or mayo. Just about anything with fake flavoring drives me up the wall (can’t tolerate flavored coffee creams, for example, or fake strawberry). I cannot smell fresh baked bread or cookies, pine trees, or perfume, but I also can’t smell flatulence, BO, poop, cat pee, or old garbage. So that’s a plus.
    On the other hand, it appears that the olfactory section of my brain works just fine… I have pronounced synesthesia where other senses tend to “bleed over” into where I should be processing smells. Books, for example, have a distinctive smell. If I were to read Perfume at my home, then pick up a different copy at a friend’s place or library a year later, I would start to “smell the story” within a few minutes, and it would match the one in my home. Deja Vu also has a smell, as do some color combinations, co-incidental situations, music, and “spatial-temporal arrangements” (like if I enter a room in someone else’s house that is arranged in a very similar way as a different room I’d been in, or if something happens now that shares a pronounced similarity with a past event that occurred in close proximity to a shared reference point). Apparently, with no smells to link my memories together, my brain decided to invent a way of creating phantom scents to serve as memory reference points. I’m used to it, but it’s weird trying to explain it to other people. Do you happen to know of any studies that look into this sort of thing? I’ve been meaning to subject myself to scrutiny for the sake of science, but I don’t really know where or how to start. Thanks!
    (Oh, and I’ve used Zicam sticks, didn’t do squat IMHO, but you can’t disprove a negative either. Could the cold have been worse? Maybe, but it was as bad as I was expecting, so no real use to me there.)

  13. In November there was an article on the CBS Moneywatch site, based largely on an opinion piece in the National Law Journal, bemoaning the FDA’s action against Zicam intranasal products and what was perceived as a weak response by the manufacturer’s management. There have now been dozens of comments posted (including a few of mine) from a range of viewpoints, some of which are probably astroturf, some of which seem to be from a corporate gadfly who has sued the manufacturer’s management for its lack of disclosure of adverse events and some from people who defend the product based on personal anecdotes; the comments have included links to or excerpts from articles on the subject, including the Lim et al. study discussed in this blog.
    The anti-regulation comments keep coming back to an assertion made in a couple of court opinions regarding proposed expert testimony in cases where the manufacturer was sued by anosmia patients: the relevant tissue consists of olfactory neuroepithelial cells that are nearly “anatomically inacessible” and, therefore, there is no credible mechanism by which they can be directly exposed to a nasal spray.
    Are there any scientists or physicians who can provide the counterargument for this assertion? If you care to post on the CBS site, here’s the link: http://moneywatch.bnet.com/saving-money/blog/devil-details/zicam-addicts-and-shareholders-were-ripped-off/968/?tag=active-mw
    If you are interested in looking at a couple of the court opinions I refer to, they can be found here:
    http://zicamlawsuits.com/Sutherland%20-%20Brief%20re%20Motion%20to%20Exclude%20Dr%20Jafek_Daubert%20Decision.pdf

  14. Is there ever any pain associated with this nerve damage(other than the initial burning from using the product)? My husband has been having a strange tingling and sensitivity in his tongue and teeth on the left side of his mouth. The doctors say it appears to be nerve related but none have mentioned the Olfactory Nerve as a possibility.

  15. Any oral cold product with zinc or zincum temporarily destroys my sense of TASTE. That’s why I chose zicam nasal 10 years ago (only two colds since). I’m motivated enough to use the oral but wish I could have stocked up on the original. Why can’t they would lift the ban with a WARNING. Why can’t I CHOOSE? Think about the litany of much worse side effects by other drugs.
    No astroturfer. I’ve got to admit, I came upon this site looking to see if anyone was using the oral mist in their nose!🙂 (I’m not going to be the first; still looking)

  16. Please note that the directions tell you NOT TO SNORT the Zicam. You are to spray some into the front cavity and then rub for several seconds. I have followed the directions, not snorted and not taken it more than recommended. I have had no adverse affects re: smell (not always a good thing :)) and it has reduced the length of cold symtoms to 2-3 days instead of 7-10. I will take my Zicam and use it properly, thank you.

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