Sunday, September 22, 2013

More Zinc Nitty Gritty

On the personal front we are going full speed ahead into fall, school, apple picking, corn mazes, and sweater weather. I also decided to participate in a little n=1 experiment of caffeine elimination for 24 days along with Dallas Hartwig, who apparently does an elimination of this sort at least once a year. He drinks quite a bit of coffee and the occasional detox seems prudent. For me, I figured there wouldn't be much difference in my life with or without caffeine. I rarely drink coffee, and a typical day will see me drinking 0-3 cups of tea, most days one. Since I could skip a day of caffeine without even noticing, I imagined there wouldn't be caffeine withdrawal.

I was surprised about 52 hours after my last dose when the classic headache and a combination of irritability and cognitive fog set in. (Withdrawal can begin as early as 12 hours, typically peaks at 48 hours, and can last 2-9 days total). Mine lasted about 6 hours until I went to bed, and it was gone the next morning. Over the next three weeks, I noticed my sleep was improved, muscle tension was noticeably decreased at the end of a clinic day, and I missed caffeine the most on Monday mornings, Wednesday afternoons (not surprising, my longer clinic day), and, unexpectedly, Sunday mornings. For the first week and even into the second I still didn't feel quite as "sharp," though that feeling began to pass a little by the third week. The experiment ends in a couple of days, and I have plans to moderate my caffeine intake a little more than I did before. Maybe 3 days a week instead of most days a week (thinking of those "most missed" times), and probably won't exceed a single cup of tea. All told, I learned some things, and I'm glad I did the experiment. Probably a worthy one for most people to do, as long as the withdrawal isn't too debilitating.

Last week we left off with some review of zinc, before that a bit of a review of the pathophysiology of depressive disorders in the brain. Today I would like to tie that together from the most recent review article and then discuss the overall human clinical data about zinc as an antidepressant.

Damage to the brain in major depression in the hippocampus seems to occur in part due to overstimulation of the NMDA receptors (by glutamate or similar substances). The overstimulation leads to a large influx of calcium molecules into the cells which results in damage to the neurons and can stimulate programmed cell death. Zinc can turn off this cascade to some extent, because it is a non-competitive inhibitor of the NMDA receptor, which means it keeps the receptor from being quite as easily activated. Thus it could potentially decrease the amount of damage done during a period of high stress.

In addition, zinc spurs the production of the brain fertilizer, BDNF, in the hipocampus, leading to recovery, nerve regeneration, and repair. Below is a modified diagram from the review similar to the ones I posted a couple of weeks ago with much of the zinc penciled in (IN COLOR. hah). For more step by step explanation, please go back to my previous post. Click the diagram to make it larger.

So now, the human data, which works better as a list:

1) In healthy humans, zinc levels in the central nervous system and in the serum tend to be equivalent with free passage through the blood brain barrier.
2) A post-mortum study of schizophrenic patients showed 50% reduction in brain zinc (particularly in the hippocampus) compared to controls.
3) In neurodegenerative diseases, reductions in brain zinc tend to be higher than reductions in serum zinc.
4) Numerous studies link lower serum zinc levels to increased depression scores on a rating scale (there is even some linear correlation, making zinc a reasonable candidate as a biomarker for depression).
5) Zinc levels are lower in treatment resistant patients (in some but not all studies).
6) Patients whose depression improves also have recovery of zinc levels.
7) People who are depressed tend to have lower zinc levels and lower zinc intake (eating less meat, fish, and legumes, and I'm assuming oysters), but hospitalized depressed patients fed the same diet as controls also had lower zinc levels than the controls.
8) Intense, competitive, anxious "Type A" personalities tend to excrete more zinc under stress than the more laid back, "Type B" sort of person.
9) Zinc is excreted in hyperactive kids exposed to artificial food dyes but not in kids who weren't hyperactive in a small study.
10) Zinc supplementation can increase testosterone in zinc-deficient men, and low testosterone is associated with depression.
11) In several (small) randomized trials, zinc (25mg) plus an antidepressant elicited a more robust recovery than antidepressnt alone. Similar results have consistently been found in animal models.

Still, more data is needed, and more information is needed about the genetic differences in people in zinc absorption, sequestration, and secretion in healthy and unhealthy states. The upper limit of recommended zinc intake is 40mg daily, the recommended daily allowance is around 11-12. Temporary supplementation of less than the upper limit during a stressful period seems low-risk, but there is still much to learn.


  1. All of my hands-on clinical work is in the hospital setting. I never see other docs order serum zinc levels, nor do I order them. Perhaps that should change.

    BTW, I like the background of your diagram.


    1. @Steve zinc behaves in a stressed system very much like magnesium, and of course the first thing we do in the ICU (or maybe the second) is grab a magnesium level and then replete that sucker by the bagful because the super sick waste magnesium like crazy, and you die very quickly when the levels drop. Zinc depletion won't kill you quite that fast…but it would stand to reason that it should be dropping like a rock, and supplementation might help. I haven't even looked for these sorts of studies.

  2. Ketogenic diets seem to increase neuroprotective kynurenic acid as well:
    (at least in rats that is). Potatoes also seem to be a good source of nutritional kynurenic acid:

  3. Do you have any thoughts/ideas on how to take both iron and zinc without one "outsmarting" the other, by chance? I take multi-minerals, including extra zinc picolinate and p5p with some folinic acid, as I am a high zinc user (perhaps something to do with my hyperhydrosis). I also tend to become low in iron (likely to do with my frustrating menstrual cycle), so I take extra iron bisglycinate to try compensating. Feeling like I'm defeating myself taking both ........

    1. Iron diminishes zinc absorption, so either don't take the supplements at the same time, or as long as the zinc supplements are somewhat robust absorbing less wouldn't make too much difference.

  4. Emily, do you think it is completely clear that the brain pathologies seen in depression, schizophrenia, etc. are not due, in part at least, to the medications now used so quickly and universally? Have completely unmedicated people been shown to have the same pathologies as the medicated ones? Having read some of Dr. Peter Breggin's work, I wonder if psychiatric drugs could be a huge potential confounder in psychiatric research.

    1. A month or two ago I met a woman who had been a psych nurse in the 1940s and for the next 25 years. She remembers insulin shock therapy and how long everyone stayed in the hospital and how sick they got when there were no medications to work with. I must say the sickest, most psychotic individuals I have seen were medication naiive. Schizophrenia has changed quite a bit, far less hebrephrenia, catatonia is extraordinarily rare, probably because the medications work well to stop those particular pathologies, though the medicines have severe shortcomings as well. I think the meat of the question you pose has to do with antidepressants and stimulants. If these medicines are applied early and/or incorrectly to you risk kindling a bipolar disorder? Some of the confounds can be answered by comparing different regions. In Europe people tend to be dosed lower and for shorter periods. I had a patient treated in Europe for a psychotic break with a 5 day course of a low dose antipsychotic, which is not what would happen, in general, in America. And on the West coast they tend to use aggressive doses (in fact our smaller doses are called "East Coast Doses" by the cowboys out west.) The serious confound is that people who get more treatment, more contacts, more attention and all the little bits of therapy that come with each contact tend to do better (on a large scale, there are always individuals who have had crappy treatment that makes things much worse), and people who utilize medical services more are more likely to be medicated. So that confound makes medicine look better than it probably is.

    2. Thanks, Emily, very interesting. What about the biochemical/physiological findings (inflammation, zinc, etc.) associated with depression and other psychiatric diagnoses? I wonder if they have been convincingly demonstrated in unmedicated people. Even then, cause and effect would require unravelling, but in medicated people could such associations be confounded, in part at least, by toxic effects of psychiatric drugs?

  5. Thanks for the write up, I always love learning more about zinc. I have pyroluria, so I have very high zinc needs. It is incredibly difficult to also balance zinc with copper - I'm almost balanced now after 2 years but I take quite a high dose of zinc at 150mg/day of picolinate. Otherwise, I have no improvements to zinc levels and no decrease in copper. I am monitored by my doctor by the way and test plasma zinc and serum copper every 3 months to check what is happening. I do feel much more mentally balanced (and less crazy PMT) with my copper and zinc balanced, but sometimes it feels like a losing battle to try to get copper levels down - my doctor believes it is leeched from the water pipes in to the drinking supply. Plasma zinc is the preferred measure, rather than serum zinc - serum zinc result is always higher, so the doctors that treat pyroluria always use plasma zinc and also check serum copper at the same time to assess the ratio.

    Will share this article with my doctor.

  6. Zinc can deplete Magnesium, so it's important to supplement them at different times of the day.


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