Saturday, October 9, 2010

Zinc Revolution

Back in July, I wrote a number of posts about zinc.  There was Zinc! (which remains one of my most popular posts - perhaps it was the exclamation point?), Zinc, Depression, and Everything, and the optimistically titled Zinc Clarity.  By all means go back and dig in, but the summary here: rather like magnesium, zinc is wasted and sequestered during periods of inflammation, but zinc is also necessary for our brains to work properly.  Low serum levels of zinc have been measured in ADHD, depression, and anorexia, and zinc repletion has been shown to help the symptoms of those illnesses, at least in small studies (though for anorexia with need for weight gain, zinc supplementation should really be standard of care, as the data is good).  Hunter gatherers averaged 43 mg daily (above the RDA safety zone "upper tolerable limit" of 40mg daily, but below the lowest level where there begins to be issues with copper absorption, which is around 60mg daily, but is likely not a serious problem until 150mg daily).  A Standard American averages much, much less than all those numbers, somewhat below the RDA of 11-15mg daily, and as zinc is available mostly in egg yolks and other animal foods, a vegetarian has a serious risk of being deficient, as does anyone on a thiazide diuretic medication.

Cool.  Well, as always, it is not quite that simple.  As I mentioned in Zinc, Depression, and Everything, zinc deficiency doesn't necessarily cause depression (though it might play a role).  In fact, depression (inflammation) will cause low serum zinc.  Low serum levels of zinc are a biomarker for depression, rather like high C reactive protein is a biomarker for inflammation.  (Please, please, please do not take Crestor for the sole purpose of lowering your C reactive protein.  Don't do it!)

On Wednesday when I was tooling through the Journal of Affective Disorders, I found this new study from the same zinc-obsessed Polish group who have produced a slew of papers over the last several years, "Serum zinc level in depressed patients during zinc supplementation of imipramine treatment."

The researchers took 60 patients diagnosed with Major Depressive Disorder from inpatient units and outpatient clinics, and also recruited 25 healthy age- and sex-matched controls with no mental illness (and, interestingly, no family history of depression or mania).  The healthy controls had their serum zinc measured once, the depressed subjects four times (before, and 2, 6, and 12 weeks after starting antidepressant medication treatment). 

All the depressed patients were treated with an antidepressant (imipramine), but the 60 patients were divided into receiving placebo + imipramine or zinc + imipramine.  During the data analysis after the experiment, "resistant" and "non-resistant" groups were established by how the patients responded to the treatment (it also happened to line up with now long they had been depressed).  Got it?   So in the end, you have four groups of depressed patients:

Treatment resistant receiving imipramine + zinc
Treatment resistant receiving imipramine + placebo
"Non-resistant" receiving imipramine + zinc
"Non-resistant" receiving imipramine + placebo

Some results (all of these are statistically significant unless I note otherwise).  Serum zinc levels were 22% lower on average at baseline in the depressed individuals than in the healthy controls.  The serum zinc levels of the long-term "resistant" depressed patients were lowest of all.  Serum zinc over the twelve weeks increased in all the depressed patients except the treatment-resistant imipramine + placebo group.  Yes, that means that anyone who felt better by depression rating scales at the end of the 12 weeks had a higher zinc level, whether they were given placebo or zinc supplementation.  The treatment resistant group who received zinc also had a higher zinc level at the end of the treatment than at the beginning, but it was still much lower than both non-resistant groups.  Everyone remained lower than the normal controls, but the treatment responsive groups were fairly close.

Based on review of other zinc studies and the results of this study, the researchers concluded the following:  It is unlikely that low blood zinc level in depression is due to lack of appetite or from HPA axis hyper-stimulation that occur with depression.  They felt it was specifically due to inflammation (as zinc levels are negatively correlated with inflammatory markers, like IL-6 and neopterin), and even more specifically due to either a decrease in the protein that carries zinc around in the blood, or the increase in IL-6 leading to metallothionein sequestering zinc in the liver.  Therefore, "it can be inferred that normalization of the serum zinc level in treatment non-resistant patients was the result of the abatement of inflammatory processes during remission of the depressive episode."  (The entire paper reads like that.  It is thankfully quite short.)  In other words, inflammation causes depression and low zinc levels.  Successfully treat the inflammation and your depression gets better and your zinc levels rise.

Why did I call this post "Zinc Revolution?"  Well, here we have something heretofore unknown in psychiatry -- a simple blood test that could, if all this pans out in more studies,  monitor treatment resistance and treatment response.  In the old days they would do tedious dexamethasone suppression tests and even, sometimes, in research, spinal taps to measure serotonin levels and the like.  Certain features of depression would correlate with some of the measures, but there was nothing found that would give you a real physiologic clue for most patients with depression.

Not to mention here we have real proof that depression isn't all in your head.  It's in your blood, too, right there in the inflammation, measured by the biomarker zinc.

We can measure treatment resistance and response already, via diagnostic interviews and symptom scales.  All these are subjective, but similar to how a neurologist would measure treatment response to migraine medication.  An objective blood test could be a nice addition to the psychiatric armament, but it is the principle that matters, and I'll repeat it here:

Depression is not all in your head.


  1. This is fascinating! And I thought Zinc was good only for acne ;-)
    I do battle with depression, even though not severe. I just started taking mix-minerals caps, which have 15mg of Zinc (chelate). I am wondering now if that's enough of a kick or maybe I should get extra Zinc. I am already taking extra Mg (also chelate). I don't like taking too many pills, but prefer the supplements than serious anti-depressants and anti-anxiety meds I have to take now!

    Do you know if Zinc has similar positive influence on anxiety? Or other mental disorders?

    oh, and I feel good that such Zinc-obsessed people are coming from my country! :)

  2. Autsajder - in the experiments and papers where a zinc supplement amount is named or recommended, it is usually 12- 14mg or thereabouts. Assuming a non-vegetarian diet, total would be around 25mg daily? This would be higher than the RDA but not a mega -dose or anything. I haven't read anything about anxiety. Neurochemically it is extremely similar to depression. All the supplement studies were quite small, so nothing to hang your hat on. The overall lesson as I see it is to have enough zinc on board so you bounce back quickly from the stress-wasting, but there is no need for people without absorption problems or metabolic issues dealing with zinc to take mega doses.

  3. That's good to hear, thank you. I eat paleo, so enough animal sources, I think I will take the minerals only every other day, as I eat pretty well otherwise.

  4. Interesting numbers from one of Prof Cordain's looking at nutrient content in a modern diet based on Paleo foods;

    Magnesium - 643mg (207% of RDA)
    Zinc - 27.4mg (228% of RDA)

    In his book, The Paleo Diet, he gives the micronutrient intake numbers based on the typical American Diet;

    Magnesium - 128mg
    Zinc - 3.9mg

    And as the sample diet he uses still includes some meat, perhaps a poor vegetarian/vegan diet is lower still?

  5. Gads, the SAD numbers are low! There is a lot more data on zinc and depression, but there is a lot more theory to suggest at least having replete magnesium stores would be even more important than zinc. I know why magnesium hasn't been studied more - zinc can be tested with a simple blood test. With magnesium you have to follow serial 24 hour urines to make sure research subjects are compliant and magnesium levels are growing in the body, as the serum levels are nearly meaningless (outside an ICU situation).

    Anyway, I don't see anything wacky or out to lunch or particularly alternative about recommending at least adequate zinc and magnesium. And I hope that magnesium is studied more vigorously. (zinc too, but at least there are research factions doing their thing and churning out papers).

  6. Really interesting about the hunter-gatherer zinc intake. I'll up my own zinc intake, which previously I'd tried to keep away from the TUL. I'm curious as to where the figures come from, or how the hunter-gatherer's would have managed it though. 40mg+ of zinc a day requires more than 1kg of steak or liver (giving almost 250g protein).

  7. Hi DM - I orginally got the number 43 from "Primal Body, Primal Mind" but her primary source for the table was this paper:

    It's in table 3, and Eaton et al discuss their methods. I think the main thing to keep in mind is that HGs eat a lot more than we do. Average is 3000 calories. It is much easier to get plenty of vitamins and minerals when you eat a lot of nutrient rich whole real foods. On a modern calorie-restricted, less moving around sort of diet, it is easy to get deficient in something unless you are pretty meticulous.

  8. Thanks Emily that's great, although the mind still boggles at eating up to 3.5g protein/KG! It's also a shame that they recommend 7-8% SFA and no more than 25% energy from fat. I can't help but think that both of these odd conclusions would make more sense if they were to assume that HG's ate fattier game.

  9. DM - as I understand it Eaton revamped his conclusions in 2000 (according to Gary Taubes in GCBC) because, believe it or not, they didn't count organ meats or marrow in the earlier papers, which frankly boggles *my* mind. I've looked for the primary source on this correction(with a few google and pubmed searches, though not for too terribly long) and couldn't find anything. If anyone has a primary source on this correction, I'd love to see it! Maybe I should get cordain's updated Paleo Diet cookbook as it seems to be less fat phobic and would presumably include the correction. And I don't think most of us need quite so much zinc. I think 20-25 mg daily seems like a more reasonable number. Copper deficiency is a real issue with modern diets too, apparently.

  10. What about neuropathy caused by too much zinc in denture adhesives?

  11. There have been deaths from copper deficiency from zinc adhesives! I do not recommend huge overdoses of zinc.

  12. A very late question here, but I found this post by searching for zinc and copper on your site.

    Where do you stand on pyroluria (aka Kryptopyroluria (KPU)/pyroluria hydroxyhaemopyrrollactumuria (HPU))? People with this little-known condition are extremely deficient in zinc and B6 and are often helped by mega doses of both.


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