Time to go back to Eby and Eby. I have an inexplicable fondness for this paper. The information is decent if a touch unorganized, and the reliance on case studies reminds me (in a pleasing way) of old fashioned papers, such as this one by John Cade about the use of lithium in mania.

When you start to untangle the effects of magnesium in the nervous system, you touch upon nearly every single biological mechanism for depression I've described so far in the archives of my blog. The epidemiological studies (1) and some controlled trials (2)(3) give us good reason to suspect that most of us are at least moderately deficient in magnesium. The animal models are promising (4). If you have healthy kidneys, magnesium supplementation is safe and generally well-tolerated (up to a point)(5), and many of the formulations are quite inexpensive. Yet there is a woeful lack of well-designed, decent-sized randomized controlled trials of various psychiatric disorders and magnesium supplementation.

Let's look at the mechanisms first. Magnesium hangs out in the synapse between two neurons along with calcium and glutamate. If you recall, calcium and glutamate are excitatory, and in excess, toxic. They activate the NMDA receptor. Magnesium can sit on the NMDA receptor without activating it, like a guard at the gate. Therefore, if we are deficient in magnesium, there's no guard. Calcium and glutamate can activate the receptor like there is no tomorrow. In the long term, this damages the neurons, eventually leading to cell death. In the brain, that is not an easy situation to reverse or remedy.

And then there is the stress-diathesis model of depression. The idea that chronic stress leads to hormonal imbalances of excess cortisol, which eventually damages the hippocampus of the brain, leading to impaired negative feedback and thus ongoing stress and depression and neurotoxicity badness. Murck shows that magnesium seems to act on many levels in the hormonal axis and regulation of the stress response. Magnesium can suppress the ability of the hippocampus to stimulate the ultimate release of stress hormone, it can reduce the release of ACTH (the hormone that tells your adrenal glands to get in gear and pump out that cortisol and adrenaline), and it can reduce the responsiveness of the adrenal glands to ACTH. In addition, magnesium can act at the blood brain barrier to prevent the entrance of stress hormones into the brain. Magnesium is the original chill pill.

If the above links aren't enough to pique your interest, depression is associated with systemic inflammation and a cell-mediated immune response. Turns out, so is magnesium deficiency. In addition, animal models show that sufficient magnesium seems to protect the brain from depression and anxiety after traumatic brain injury (10), and that the antidepressants desipramine and St. John's Wort (hypericum perforatum) seem to protect the mice from the toxic effects of magnesium deficiency and its relationship to anxious and depressed behaviors (4).

There are a few tricky things about magnesium, though. First of all, the overall levels are hard to measure. Most of our body's magnesium is stored in the bones, the rest in the cells, and a very small amount is roaming free in the blood. (Here's an excellent review at EvMed Forum) One would speculate that various mechanisms would allow us to recover some needed magnesium from the intracellular space or the bones if we had plenty on hand, which most of us probably don't. Serum levels may be nearly useless in telling us about our full-body magnesium availability, and studies of levels and depression, schizophrenia, PMS, and anxiety have been all over the place (6). There is some observational evidence that the Mg to Ca ratio may be a better clue. Secondly, the best sources of magnesium in the normal Western diet are whole grains (minus all those phytates), beans, leafy green veggies, and nuts. These happen to be some of the same sources as folate, and folate depletion is linked with depression, so it may be a confounding factor in the epidemiological studies.

Finally, magnesium is sequestered and wasted in times of stress. I'm speculating here, but in a hunter-gatherer immediate stress sort of situation, maybe we needed our neurons to fire on all cylinders and our stress hormones to rock and roll through the body in order for us to survive. Presumably we survived or didn't, and then the stress was removed, and our magnesium came out of hiding. However, it may not be overall magnesium deficiency causing depression and exaggerated stress response - it may just be all that chronic stress, and magnesium deficiency is a biomarker for chronic stress. But it doesn't hurt to replete one's magnesium to face the modern world, and at least the relationships should be studied thoroughly. Depression is hugely expensive and debilitating. If we could alleviate some of that burden with enough mineral water... we should know whether that is a reasonable proposition.

As I mentioned before, there are only a few controlled trials of magnesium supplementation and psychiatric disorders. A couple covered premenstrual dysphoria, cravings, and other symptoms (2)(3). Another small study showed some improvement with magnesium supplementation in chronic fatigue syndrome (7). Two open-label studies showed some benefit in mania (8)(9). There is another paper that postulates that magnesium deficiency could exacerbate the bad symptoms of schizophrenia. But nothing definitive. Which is, of course, ridiculous. How many gazillions of dollars have we spent on drug research for depression, bipolar disorder, and schizophrenia, when here is (possibly) a cheap and plausible helpful natural remedy that hasn't been properly studied?

Well, the EvMed Forum post I linked before shows the different bio-availability of the various magnesium supplements. The easiest and cheapest to find in magnesium oxide, which isn't very bio-available, but tests or urinary excretion show that you can top yourself off with magnesium after a month or so of 200 mg daily of the oxide (3). Also, if you can find the effervescent magnesium oxide tablets, they seem to be just as bio-available as the organic amino-acid chelates (11). I did a google search, though, and didn't find any magnesium oxide effervescent sources. Of the other amino-acid chelates, magnesium citrate seems to be both inexpensive and easy to find. Magnesium taurinate has the advantage of supplying taurine and magnesium in one formulation.

Different blood pressure medicines, psychiatric medications, heartburn medicines, and other medical conditions can affect the absorption and metabolism of magnesium. Those with short bowels (typically due to surgery that removes a large section of bowel) may want to supplement with magnesium oil. This formulation is also not going to cause the diarrhea that the oral supplements can cause (though I would say constipation is more common in the Western world, making magnesium a safe, cheap and easy cure). The EvMed Forum review also mentions that, in addition to those with kidney disease, people with myasthenia gravis, bowel obstruction, and bradycardia should avoid supplementation. In addition to diarrhea, magnesium can cause sedation, so it should be broken up into small amounts throughout the day, or taken at night. It also is taken up by the same transporter as calcium and zinc, so they can fight with each other for absorption. Jaminet and Jaminet recommend total daily levels between 400-800mg. Most people can safely supplement with 200-350mg daily without any problems (again, don't proceed without a doctor's supervision if you have known kidney disease or if you are elderly). If you do take extra or an expensive, highly bio-available form, you will eventually pee out any excess as long as your kidneys are going strong. I have a magnesium oxide supplement (I hadn't looked into it and just grabbed what was available at Target), but next time around I might try the citrate. Though the oxide is cheap, and, as mentioned above, even the oxide eventually results in increased urinary excretion of magnesium (suggesting full body repletion).

People looking for good (but not all paleo) food sources can go here, here, and here.