Friday, October 1, 2010

Magnesium and the Brain

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.

I've spent much of the last evening and this afternoon (while the kids are napping) reading a bunch of magnesium and depression papers. Frankly, I'm blown away. 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.

Phew. It's been a few weeks since I linked a song. How about Crystallized, by the XX, acoustic version?


29 comments:

  1. Hey Emily,

    I'm really enjoying your blog as are many others over at the MDA forums.

    Magnesium has been very helpful in reducing my anxiety and eliminating muscle tension and menstrual cramps.

    Currently I'm using the rather pricey time released Jigsaw Health Magnesium w/ SRT. (SRT stands for sustained release technology) If I could tolerate sufficient doses of anything less expensive, I would but after a couple of years of experimenting, it was pretty clear that mg citrate, taurinate, aspartate and even glycinate were not going to work in for my system.

    After reading some of Davis' recent posts on calcium and optimal vitamin D levels, I decided to elimininate calcium supplementation. Over time, this (not suprisingly) has reduced my need for magnesium supplements. At one time, I was needing 500-1000 mg per day of my $$ magnesium. Now I'm taking 250-500mg per day in divided doses - and always with food.

    Best,
    Katherine
    (cillakat on MDA)

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  2. Hi Emily-

    I've been using the magnesium oil and have been surprised with the results... I put on 8-16 sprays about an hour before bed, then stretch and foam-roll for about an hour. By the time I'm done, I am distinctly "chilled out" and ready for bed. Sleep has been great, due to what I feel is a more relaxed mind. Maybe it's all placebo though...

    Also, I work in a Human Performance Lab and get BP's taken several times a week, and have experienced a consistent drop in resting BP since starting the magnesium. So far, a high-benefit/low-cost supplement..

    Tyler

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  3. Possible hijack alert Emily... no problems if you don't want this to go through. Some info there for you anyway!
    ___________

    I thought you & your readers might find these notes from my Nutritional Medicince course book of interest Emily:

    The adult human contains about 25 gm of magnesium (Mg) with 60-65% being found
    in bone, 27% in muscle and the remainder throughout the body

    Mg is involved in over 300 essential metabolic reactions within the human body.

    The predominant action of Mg within human physiology is related to ATP utilisation
    in the form of the Mg-ATP complex

    Mg and potassium are intricately involved within the human body and hypomagnesia
    will lead to potassium depletion

    Mg is known as nature’s calcium-channel blocker

    Ingested Mg is predominantly absorbed within the jejunum and ileum of the small
    intestine, although absorption can occur at other sites, including the colon.

    Both a passive paracellular and an active transport mechanism exist for Mg. It is
    queried that this may be the same vitamin D-dependent transport system as exists for
    calcium.

    Once within the serum, Mg is transported to target tissue where it is compartmentalised within the nucleus, mitochondria, cytoplasm and endoplasmic and sarcoplasmic reticulum.

    The kidneys play a vital role in maintaining Mg homeostasis within the filtration /
    reabsorption process.

    Beneficial Physiological Effects of Magnesium

    Energy production
    Synthesis of essential biomolecules
    Active transport of ions across cell membranes
    Cell signalling
    Cell migration

    Deficiency Signs and Symptoms for Magnesium

    Hypomagnesemia
    Hypokalemia
    Tetany (frequent cramping??)
    Cardiac arrhythmia
    Hyporeflexia
    Tremors
    Muscle weakness

    Principal Uses of Magnesium

    Magnesium is used therapeutically in the following conditions:

    Hypertension
    - Conflicting results, more likely to be useful in those with hypomagnesemia (which might be many people)

    Preeclampsia / Eclampsia
    - Magnesium sulfate is the treatment of choice for this condition

    Cardiovascular disease
    - Use of IV Mg after MI remains controversial
    - Improves endothelial function

    Diabetes mellitus
    - Improves glucose tolerance

    Osteoporosis
    - May reduce bone loss, further research needed

    Migraine
    - Hypothetical

    Asthma
    - IV magnesium may have a minimal role

    Magnesium is used preventively in the following conditions:

    Hypertension
    - Hypomagnesemia may play a role n the development of hypertension

    Cardiovascular disease
    - Theoretical link, but currently unclear

    Safety Issues for Magnesium

    Excess Mg supplementation causes diarrhoea

    Individuals with impaired kidney function are at higher risk of Mg toxicity

    Hypermagnesemia presents as hypotension, lethargy, confusion, cardia arrhythmia,
    muscle weakness, difficulty breathing and disturbed kidney function

    Interactions for Magnesium

    The use of Magnesium is impacted upon by the following:

    Mg interferes with the absorption of digoxin, nitrofurantoin, biphosphanates and
    certain antimalarials; thereby reducing their efficacy.

    Mg reduces the efficacy of chlorpromazine, penicillamine, oral anticoagulants and the
    quinolone and tetracycline classes of antibiotics

    Long-term furosemide and some thiazide diuretics may cause Mg depletion.
    ___________

    For me, I am intrigued by the relationship between Mg++ and vitamin D - especially that vitamin D may enhance absorption of Mg++ as it does with Calcium. So those in a vitamin D deficient state may struggle to absorb Mg. And grains increase our turnover rate of vitamin D. So - eat lots of grains - rapidly deplete vitamin D - low vitamin D status impairs Mg absorption (and likely other aspects within grains bind Mg) - low magnesium status.

    Some interesting links here:

    http://www.ncbi.nlm.nih.gov/pubmed/9140864

    http://wholehealthsource.blogspot.com/2010/04/magnesium-and-vitamin-d-metabolism.html

    http://www.thinkmuscle.com/articles/jalali/magnesium.htm

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  4. Hi Katherine - I don't eat a lot of dairy (other than pasture butter and ghee - cooking with those is the easiest way to get some K2 into the kiddos!), and I don't supplement with calcium. Magnesium supplementation appears to be a very personal thing. That said, the authors of the controlled trials mentioned that next time around they would use Magnesium citrate and a higher dose (maybe 250-350 mg). Thanks for commenting!

    Hi Tyler - magnesium oil is tempting to buy, just to see what it is like topically. Interestingly, the one I linked online is the magnesium chloride qualia commented about in the last post.

    Jamie - thanks for all the info. I made my post a bit brain central simply because there is SO MUCH that magnesium seems to do in the body. Want a cheap way to improve insulin sensitivity, decrease the chance of sudden cardiac death, and (perhaps) temper your anxiety, stress response, and mood? Try magnesium, which the entire western world, by the way, is deficient in. I have a whole ranty post brewing, probably for tomorrow.

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  5. Your post is extremely timely! I have just been thinking a lot about supplementing, and a month ago convinced myself to get back and take some pills. I haven't noticed any positive effects, but was ok with that. It's only now that I found out that the Oxide version I was taking is basically useless! Somehow I got confused (or misled) and thought that was teh best one.
    I just ordered a chelated so I hope it will be better.
    I struggle with anxiety, sleep issues and fibromyalgia, and have quite stressful work so it looks like Magnesium is really needed for my body.

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    Replies
    1. Natural Calm (magnesium citrate powder) has worked like a dream for my anxiety.

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  6. Robb Wolf suggests dosing in the 1.2-2 grams a day range (in his the Paleo Solution book)
    Any idea why the disparity in dosing suggestions?

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  7. Hi Jolly - my impression is that Robb Wolf usually has nuanced and well-researched reasons for what he recommends. If he did suggest the oxide, then perhaps that explains the high amount? I have to look at the book (I had read quite a bit of it, and then misplaced it!). In addition, usually you will find that physicians such as myself will be more conservative about this sort of thing. I'm not going to go too far afield of the RDA without some very good data (such as for vitamin D). The studies (aside from the case series at Eby and Eby) used smaller supplement amounts than Robb suggests. Also, 2 grams of magnesium seems like a major recipe for diarrhea...

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  8. I did not know mg oil was chloride. I take it orally but tastes awful.

    Tyler, do you know which other minerals has the oil?

    Isn´t it better to use mg sulphate topically?.

    Thanks.

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  9. I made a Mg Cl2 saturated solution and applied it to my legs. It is surprising and yes it feels kind of "oily".

    I am not sure how to dose it. If anyone has any suggestion please let me know.

    Thanks.

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  10. Dr. Dean, Thanks for providing the great blog. I would strongly recommend that you check out Dr. Mark Sircus (he has a blog) who is an expert on magnesium & has written a book about it. He advises that people take magnesium in the oil form but usually transdermally (sp?).
    Recently, I have been taking magnesium internally & my brain, which was seriously injured when I had a concussion (8 yrs ago), has been working better & feeling much more electrically connected. Magnesium oil taken internally is hard for the system to get used to so I would recommend that people interested it taking it start out with just a few drops at a time & over the course of a week or two (depending on tolerance) work their way up to a few droppers full at a time. Anyone taking it internally needs to dilute it in distilled or purified water because the taste of raw mag. oil is extremely strong. Also, gastric disturbances may occur & if they do then I take a calcium supplement as an antacid to offset stomach uneasiness.

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  11. Doc Dean,

    I’ve been avidly following your blog for about a year now. It’s been a tremendous help to me to help my bipolar son.

    The supplements scene in India is pretty limited. The largest dose of magnesium that I’ve been able to find is 100 mg of magnesium oxide in Riconia Silver that comes with a range of other minerals & vitamins. But I just realized that Epsom Salt is dirt cheap and readily available. So I mixed 3 g of ES and a sachet of WHO oral rehydration therapy electrolyte powder into 1 liter of water, let it dissolve for an hour, and drank 200 ml last night. Had another 200 ml this AM. No ill effects so far.

    But the question is, how much elemental magnesium am I getting? Wikipedia gives both mass & molar densities for ES but only mass density for elemental magnesium so I’m unable to calculate a conversion. And of course I also have no idea how much of the ES, or the magnesium in it, is actually finding its way into my blood.

    Any suggestions?

    Tim

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  12. Hi Emily,

    Just reading this post now, as it was mentioned in your latest article on depression. I'm newer to your blog, ultimately came across your name through C Kresser, K Harris, P Jaminet, etc. Your posts are so well written.

    Just a thought about Mg. I'm a naturopathic doc and I've switched the form of Mg I use to the bisglycinate form after hearing C Kresser talk about the better absorption of this form. Since the switch, both personally and with my patients, I have definitely noted better improvements in cramping symptoms, getting the bowels moving more effectively without overt diarrhea (unless dosed too high) and more of a calming effect when taking in the evening.

    Not sure if you have thoughts on the bisglycinate form but just thought I'd share that with you and your readers.

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  13. I'm always interested in brain health and take magnesium citrate regularly as well as eat dark leafy greens.

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  14. if you can only get the oxide form, you can make magnesium citrate by dissolving 10 grams of magnesium oxide in 1 liter of lemon juice. this provides 6mg elemental magnesium per ml. best to let it sit in the fridge overnight before using, to allow chelation to occur, and dilute with water when taking.

    it's worth noting that citrate is not an amino acid. the magnesium in amino acid chelates will be transported to different tissues depending on the specific amino acid used. glycinate goes mainly to the glands, liver, and skeletal muscle, and threonate has been shown to go to the brain and spinal fluid. see the albion patents and inna slutsky's paper for details.
    http://www.google.com/patents/US4863898
    http://basicmed.med.ncku.edu.tw/admin/up_img/990514-1.pdf

    another reason to drink bone broth!

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    Replies
    1. Surely to 'god' it's easier to just track down a supplement.

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  15. "It also is taken up by the same transporter as calcium and zinc, so they can fight with each other for absorption. "

    -So does this mean one should take zinc and magnesium at different times?

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  16. I need to know if possible,for people like me who had kidney stones in the past,is it safe to take magnesium with calcium in a powder supplement?Please help..

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  17. Please help...Magnesium supplements? Which one is healthy for me..:-)

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  18. Hi Emily,
    I've been reading your blog for a couple of weeks: plenty of food for thought!
    I loved your 'full-bore' approach of treatment (nutrition, exercise, relationships, not just drugs), as discussed in another of your posts, and the phrase 'I attempt to buttress the strengths and soothe and repair the weaknesses.' You sound like a really good doctor.
    Mg supplementation before and during periods was first recommended to me by my ORL, about a decade ago.
    It works in other situations too. My ORL actually prescribed it to me to help me deal with a tinnitus which had materialised out of nowhere, after a whole night of 'listening' to my neighbours' noisy hifi... The tinnitus vanished less than 24 hours after its apparition, partly thanks to my ORL's reassurance that it was purely neurological, that the stapedial reflex was still working normally and that my audition was unchanged (i.e. borderline hyperacousia + absolute pitch): as a former violonist, I am terrified of losing my audition.
    My ORL told me his wife (also an ORL) used it for her periods. It works a treat on levelling the mood and suppressing cramps, much better than the pill, and with lesser (and less dangerous) side effects. I get mild sedation and diarrhea, but with time and experience, you get better at finding a supplement with the right dosage, and when best to take it (usually before going to bed). I exceptionnally forewent the Mg last week as I was travelling and the bowel unreliability would have been unwelcome: as a result, my periods have spoiled my Easter bank holiday weekend!
    I find the warning about kidney disease a useful reminder. I am tested for renal function regularly (I get haematuria and proteinuria, possibly a runner's pseudo-nephritis) and grew up living next to 2 people who had to undergo dialysis. In France, the majority of patients on dialysis complain of depression and report mood swings, which seem closely correlated with how much time has elapsed since the last dialysis. Additionnally, some patients get depressed by how dialysis-unfriendly employers are: the French patient association Renaloo recently conducted a survey of 8K+ patients, and some of them hide their disease from their employer, taking days off work to undergo dialysis when they cannot find an evening slot... with the risk that the employer might think they've taken the day off to attend a job interview! It is ridiculous...
    Do you have any experience of this condition, and/or is that something you could look into?

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  19. Hi elaine. Can you please tell the type and dose of magnesium you use for tinnitus? Thanks.

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  20. Dr. Dean,

    I just found your blog.
    It's great!

    This is a link to a non-commercial resource site for anyone interested in finding holistic approaches for mental health conditions (including severe conditions). -

    http://discoverandrecover.wordpress.com

    My best,

    Duane

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  21. Hi Dr. Deans,

    When I've tried magnesium I found it made me very calm and greatly improved my night's sleep. Unfortunately the next day I felt REALLY depressed and just blah. I've tried taking a lower dosage and it definitely helped with the depressed crummy feeling but also resulted in less calm and restful sleep. I've taken anti anxiety meds and found the magnesium to have just as strong of an effect with no physical side effects. Do you know of a way around the depressed feeling? The magnesium seems much better than sleeping pills and anti anxiety meds.

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  22. great post & thanks for your efforts here :>

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  23. Magnesium oxide reacts with stomach acid to form magnesium chloride, which is highly absorbable

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  24. Thank you for this, I can honestly say that I've suffered severe bouts of depression and anxiety over the last few years due to trauma I suffered. No one could figure out what was wrong and docs wanted me on SSRI's which only gave me "flat affect" AND nothing else. Finally found a PCP who listened to me. My blood pressure was high, my anxiety was outrageous, so was my heart rate (inappropriate sinus tach 180 heart rate sometimes), and in addition to all this fear I couldn't get up off my couch I was so depressed. All I kept getting from the mental health profession is a diagnoses of PTSD and "take this SSRI." But my PCP put me on labetalol for the anxiety, heart rate and blood pressure and then she did bloodwork 3 months after this. I was still on the couch, depressed, but my bloodwork showed a severe Mg deficiency. She put me on several vitamins I seemed to be lacking B1, Iron, D3 and lots of Magnesium. About 3 days after I started taking the vitamins no more couch. About 5 days after I took them, I got up and cleaned my whole house. 10 days--I cleaned out my closets, I organized my kids rooms, I began to play with my kids again and not just hang out in the bed all the time, and I've also began dropping weight. I'm not a chemist, though Organic Chemistry was my favorite subject in school... not a doc...no studies on this stuff but we need them. I can attest personally that Mg probably--with the labetalol for blood pressure and anxiety--saved my life.

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  25. there are lot of magnesium citrate and potassium citrate combinations available in india:
    http://www.drugsupdate.com/brand/generic/Magnesium%20citrate%20+%20Potassium%20citrate/49107

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  26. whoever asked about kidney stones: excess calcium plays a role in some kind of stones so here magnesium actually prevents stone formation. also if using epsom salt as a bath, you would get the relaxing effects without it going through your digestive system. please rinse the epsom salt well after bathing in it as excess can be a problem too.

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  27. What about supplementing this way?

    http://www.afibbers.org/magnesium.html

    http://www.mgwater.com/laf.shtml
    "To address the growing problem of inadequate Mg intake, several Mg rich drinking waters have appeared on the market. These are mineral waters or their approximations. They include Unique Water (Australia), Noah's California Spring Water (110 mg Mg/liter) and Waller Water (developed by Erling Waller and containing up to 1500 mg of Mg/liter). All (and they are not alone) have pHs well over 8 and have the potential to cause urinary K wasting, due to bicarbonaturia (see GERD discussion above). However, a generous squeeze from a fresh lemon addresses nicely not only this concern but also adds a touch of taste. Hexahydrated Mg is otherwise especially beneficial, because it provides more bioavailable Mg. "

    I've made this water:
    http://www.afibbers.org/Wallerwater.pdf

    But only "half strength" (150ml of "concentrate" into a gallon of purified water):

    "To make 4 liters of magnesium bicarbonate drinking water with approximately 125 mg of
    magnesium and approximately 625 mg of bicarbonate per liter and a pH of
    approximately 8+
    To make 4 liters of magnesium bicarbonate drinking water with approximately 125 mg of
    magnesium and approximately 625 mg of bicarbonate per liter and a pH of
    approximately 8+ measure and transfer 1/3 liter of the concentrate (333 ml) into a 4-liter
    container. Fill the container with 3 2/3 liters of plain or purified water, as desired."

    There are a couple other high Mg natural sparkling waters out there in grocery stores. Chart on this page:

    http://www.lef.org/magazine/mag2007/feb2007_report_water_02.htm

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