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Zinc is an essential mineral that may be lacking in modern processed and strict vegetarian diets, as major sources are meat, poultry, and oysters. While beans and grains also contain zinc depending on the soils in which they are grown, phytates in grains, legumes, and nuts can interfere with its absorption. Since the body has no special zinc storage capability, its important to consume a bit of zinc on a regular basis (1).
What does zinc have to do with depression? It turns out that zinc plays a part in modulating the brain and body’s response to stress all along the way. I’ll review some tried and true information, but excellent new paper brings all the evidence together and sheds some new light.
300 or more enzymes in our bodies use zinc as a buddy to help them do their thing, making DNA, protein synthesis, cell division, all hugely important stuff. Zinc is also critical to cell signaling (a major receptor motif, the “zinc finger” is as famous as the G protein in cell biology circles). The highest amount of zinc in the body is found in our brains, particularly in a part of our brains called the hippocampus. Zinc deficiency can lead to symptoms of depression, ADHD, difficulties with learning and memory, seizures (2), aggression, and violence (3).
Back in the day, scientists did all sorts of horrible experiments on rats to see what zinc does in the brain. It is anti-inflammatory and anti-depressant on its own, and the combination of zinc plus modern antidepressant medication made rats more resilient in face of hopeless swimming and being restrained. Zinc increased the amount of the brain fertilizer BDNF in the hippocampus and reduced rat fighting behavior.
In humans, zinc has been found to be low in the serum of those suffering from depression. In fact, the more depressed someone is, the lower the zinc level (4). Low zinc also seems to affect inflammation and immunity. The T cells in our immune system, which hunt and kill infection, don’t work well without zinc and also release more calls for help (leading to more inflammation, via IL-6 and IL-1) in the case of zinc deficiency. Zinc supplementation has been shown to have antidepressant effects in humans, and successful treatment with antidepressants will increase serum zinc levels. That last bit of information tells us that low zinc levels are a biomarker for depression, zinc is not the whole story. Under conditions of major stress, we tend to get rid of zinc like gangbusters in our urine, sweat, and saliva.
If we want to get down to the super nitty gritty, we can examine the role of zinc in the hippocampus, which is the part of the brain central to memory and mood. Antidepressants work (when they do) by increasing the production of the nerve fertilizer BDNF in the hippocampus, which helps in nerve recovery, adaptation, and repair.
Zinc deficiency leads to decreased zinc in the nerve synapse, which results in an increase in the NMDA receptors. These receptors respond to glutamate, an excitatory neurotransmitter that can be responsible for toxic effects in the brain if there is too much.
At the same time, the inhibitory (in this case, neuroprotective) neurotransmitter GABA is decreased, along with BDNF and another nerve growth factor, NGF. The glutamate level in the synapse is higher, so calcium mediated stimulation of the nerves is primed. Do this too much, and you get "excitotoxicity." This same mechanism is thought (in acute vs chronic and in differing areas of the brain) to be responsible for seizures, migraines, dementia, anxiety, depression, and bipolar disorder (and is why pharmaceutical GABA receptor modulators, such as valium and anti-seizure medicines, can be effective for certain symptoms of any of those conditions).
To rephrase, zinc is a cog in the machine in pretty much every signal and second messenger system you might have learned about in molecular biology classes. So there are clear mechanisms by which absolute zinc deficiency can have a hand in all sorts of bad brain syndromes, and vegetarians, dieters, the elderly, those with malabsorption or intestinal issues, and the two billion people on the planet who (due to poverty) pretty much subsist on grains alone (rich in zinc-binding phytates) are all at risk for absolute zinc deficiency.
But the zinc-replete massive meat-eaters can get depression, diabetes, and all the Western diaspora of chronic disease, of course. Inflammation is the primary driving mechanism behind the whole shebang and may decrease brain zinc levels all on its own. Pancreatic beta cells, are on the front lines in diabetes, also run a lot of zinc-dependent pathways (5)(6).
Zinc plays a major role in the inflammatory response, increasing the body’s ability to fight viruses such as the common cold (7) and, at the same time, starts the domino chain in down-regulating the inflammatory response. IL-6, an inflammatory cytokine which needs zinc the be born, will activate a protein in the liver called metallothionein, a protein that holds on to zinc and keeps it in the liver, so that even if you eat a lot of zinc, it won't be available in your blood or brain for other uses. A lot of biochemical systems work this way—too little zinc (such as in people born without the ability to absorb it (8) and you get immune dysfunction and vulnerability to infection, as your protective inflammatory response won't work. But if inflammation gets high enough, it has its own down regulating systems (sequestering zinc via IL-6 and metallothionein, for example) that cool things off.
Our inflammatory and fight or flight systems were built for acute insults. Viruses, injury, bacterial invasion, angry lion attacking the camp. When the insults are chronic (unalleviated stress, gallons of inflammatory-promoting omega-6 fatty acids, weird glutens and lectins, chronic depression-causing viral infections such as herpes, HIV, or Epstein Barr), the whole system becomes dysregulated. What should be up is down. So zinc ought to be in the central nervous system, helping out with nerve repair and plasticity, and instead it is crusading with the inflammatory cytokines or stuck with metallothionein in the liver, and your poor hippocampus is shorting out on glutamate and calcium.
Extra zinc might help. As might antidepressants, GABA receptor modulators, and other neuroprotective chemicals. But those are bailing buckets. What we really need is to correct the problem causing the boat to sink. We need to reduce the inflammatory insults in the first place.
As always, there is a sweet spot of zinc consumption, and more is not always better. More than 50 mg a day can lead to improper copper metabolism, altered iron function, and reduced immune function. We need enough zinc in the right place at the right time…a typical zinc supplement pill of 25-50mg is probably best taken only every few days, unless you are an oyster connoisseur, in which case no supplementation is necessary.
*In a side note, when one is writing about zinc, there is always the question of Pyroluria, or a specific metabolic issue with absorbing and processing zinc (often in association with issues of vitamin B6). There was one researcher who was convinced pyroluria was the end all and be all of depression, chronic fatigue, etc. It seems plausible that some folks will have some genetic or gut issues in absorbing zinc and may need higher doses to maintain blood levels and be healthy. However I haven’t seen any evidence that a major part of the general population may have this affliction.
Copyright Emily Deans, MD
