Wednesday, October 6, 2010
Time Crunch
Busy around here. I'm preparing for a podcast with Dr. Su at Carbohydrates Can Kill and a radio show with Leslie Irish Evans at Peeling Mom Off the Ceiling in addition to all the usual day to day. However, I've found a (new to me) dietary study, and interesting tidbits came though in one of this weeks' American Psychiatric Association emails - just have to get an hour or two to dig up and paw through the papers so I can make sense of the news. Likely to happen tomorrow!
Sunday, October 3, 2010
Temple Secrets
The song for the day is Finlandia (right click to open in new tab) by Sibelius, one of my favorite composers.
At first, evolutionary medicine and a paleolithic diet was a great way to take off the baby weight. I'd never needed to lose so many pounds before, though I'd spent some time in the past (like many modern people) pursuing a smaller jeans size, and in that quest had studied quite a lot of sports nutrition. Even back then the sports nutrition folks outside the endurance sphere were encouraging lower carb intake and carbohydrate cycling. They were, however, very fat phobic and into eating 5-6 times a day, so the recommendations were too high in protein, not satisfying due to a reliance on fiber rather than fat to fill you up, difficult to maintain, and required lugging around lots of food everywhere. The minute you relaxed and went out for a nice dinner, it seemed those goal jeans were tight again. It also required about 6 hours of running and gym time a week - something I could usually squeeze in back in the day, but would require a lot of sacrifices I'm not willing to make in my life now. That's not to say I don't exercise a lot now - just not in the time-intensive or planned way that I used to.
All that effort over years kept me a normal weight, with a BMI smack in the middle of the "normal" range. And that effort - calorie counting, fat restriction, monitoring nutrient ratios, and a cardio-intensive exercise regimen - is pretty much exactly what the government recommends for maintaining a normal weight or losing weight at a healthy slow pace. If you look around, you'll notice the "20 minutes a day" exercise recommendation for weight maintenance and loss fell by the wayside in 2005 and was replaced with 30 minutes a day for weight maintenance, and 60-90 minutes a day if you wanted to lose weight (1). So there you have it. If you want to lose weight on the government-recommended diet, you can possibly do it by becoming an endurance athlete.
Enter the reality of having two little kids, and the resultant long periods of sleep deprivation, which, being every single night, was more difficult than the periodic sleep deprivation of medical training. There was no human possibility of long runs 4 times a week and long sessions at the gym in between. There were plenty of walks, but do the math - if you are counting calories, walking is a depressing way to take off the pounds. And I don't know if any of you have tried to count calories while breastfeeding - it's nearly impossible. The hunger is unbelievable. While pregnant, I could smell if someone brought powdered donuts into the office 4-5 rooms away, but, in general, I could limit myself to one little donut hole, as long as I was eating plenty of real food from home. While breastfeeding, I would fight the urge to rifle through other people's desks to find a snickers bar, and I could leap over tables to sample the office donut holes.
Enter a paleolithic inspired diet. Despite the above rare indulgences, I did limit vegetable oils, high fructose corn syrup, and processed food for the past 3-4 years. The main difference was dropping carbs by avoiding grains and low-fat dairy, skipping a meal 2-3 times a week and pretty much eliminating snacks, and increasing the fat. No counting. No nutrient ratios. The recommended exercise (which I followed) was a 20 minute sprint session once a week, lots of hiking and running around (with the kids, which gave me the time to do it), and mostly body weight lifting I could do at home, quickly, in the morning before everyone else woke up. Or tabatas in the back yard while the kids are digging around in the sandbox. It was, compared to the old days, extremely simple and easy, and the transition was accompanied by a much-needed increase in energy levels and even increased mental clarity and serenity. I was back into my old pre-baby jeans after 3 months. Now I'm having to buy smaller jeans.
It worked so well, and my reading had dug up so many links between the modern disastrous diet and chronic Western disease, that I felt obligated to start up this blog, looking for connections between the modern diet and poor mental health. It's a simple approach. I keep an eye out for nutrition-related research articles, follow the tips from blog readers who have seen interesting related case studies or papers, and I also look specifically at known differences between modern diets and past ones - daily amount of magnesium being one of those.
It seems that everywhere I look, I find something that has the potential to be major (fructose, magnesium, omega 3/6 ratio, vitamin D, phospholipids), and enough is already known about it to have a very solid basis for further meaningful research, even on a piecemeal basis. And the pleiotropic effects of adding back all the "real food" minus all the poisons we so regularly consume could be simply staggering on a public health basis. This is what evolutionary medicine and evolutionary psychiatry means to me now.
Last week, while researching magnesium, I stumbled on this news bit from Science in April of 2009 - "Darwin Applies to Medical School." It discusses a recent push to add more evolutionary training to medical school, a classic example being a better understanding of the development of antibiotic resistance. (I don't quite understand this example - does it really require extra evolutionary training to understand the concept of generations of microbes being exposed to antibiotics so some develop resistance and live on, taking over the population assuming vast exposure to the antibiotics? I think it takes about 30 seconds to understand that concept, assuming a basic knowledge of genes and biology.) The evolutionary training that is needed is the comparison of the health of our paleolithic ancestors, an understanding of natural selection as it pertains to human populations (including a discussion of K-type selection and grandmothers), and, frankly, reading Stephan Guyenet's entire blog archives.
Here's what James Lupisky, of Baylor College of Medicine said in the Science article: "Medical schools have a lot on their plate." (Next is from the article, but not Dr. Lupisky's quote) They are "already straining from an explosion and information and technology, and clamors for change come from many directions." And Harvard evolutionary biologist David Haig says, "Evolutionary thinking is not going to give cheap medical solutions."
On that, I think he is dead wrong. In fact, I know we can't afford to go forward as we are, pursuing more and more pharmaceuticals and technology to slow down our dying. Maybe David Haig should check out the cost of grassfed beef liver once a week, sunlight, sardines, and magnesium pills.
Again, I don't understand. Why doesn't even the evolutionary biologist get it? Granted, I had an interest in anthropology and evolution and a solid grounding in molecular biology prior to medical school, and the field of psychiatry lends itself, perhaps counter-intuitively, to look for holistic solutions to human problems. Still, I don't understand why just a few of us, in 2010, are pulling together this information and trying to work the biggest problem in human health in the evolutionary way. I'm simply baffled by how easy it is to find enormous clues as to the pathogenesis of biologic mechanisms of modern mental health problems with this ridiculously simple approach. It used to be exciting - I knew the secret to weight loss and metabolism. I knew the secret to good health and reducing the ravages of stress. The temple secrets were right there, within reach. At the same time, the work is frustrating. I feel a bit like Cassandra, blessed (I hope) with knowledge but knowing that no one in charge who could make some real difference would believe me.
Here is the orchestral version of Finlandia. Those who misspent a childhood watching the Smurfs might recognize the introduction.
At first, evolutionary medicine and a paleolithic diet was a great way to take off the baby weight. I'd never needed to lose so many pounds before, though I'd spent some time in the past (like many modern people) pursuing a smaller jeans size, and in that quest had studied quite a lot of sports nutrition. Even back then the sports nutrition folks outside the endurance sphere were encouraging lower carb intake and carbohydrate cycling. They were, however, very fat phobic and into eating 5-6 times a day, so the recommendations were too high in protein, not satisfying due to a reliance on fiber rather than fat to fill you up, difficult to maintain, and required lugging around lots of food everywhere. The minute you relaxed and went out for a nice dinner, it seemed those goal jeans were tight again. It also required about 6 hours of running and gym time a week - something I could usually squeeze in back in the day, but would require a lot of sacrifices I'm not willing to make in my life now. That's not to say I don't exercise a lot now - just not in the time-intensive or planned way that I used to.
All that effort over years kept me a normal weight, with a BMI smack in the middle of the "normal" range. And that effort - calorie counting, fat restriction, monitoring nutrient ratios, and a cardio-intensive exercise regimen - is pretty much exactly what the government recommends for maintaining a normal weight or losing weight at a healthy slow pace. If you look around, you'll notice the "20 minutes a day" exercise recommendation for weight maintenance and loss fell by the wayside in 2005 and was replaced with 30 minutes a day for weight maintenance, and 60-90 minutes a day if you wanted to lose weight (1). So there you have it. If you want to lose weight on the government-recommended diet, you can possibly do it by becoming an endurance athlete.
Enter the reality of having two little kids, and the resultant long periods of sleep deprivation, which, being every single night, was more difficult than the periodic sleep deprivation of medical training. There was no human possibility of long runs 4 times a week and long sessions at the gym in between. There were plenty of walks, but do the math - if you are counting calories, walking is a depressing way to take off the pounds. And I don't know if any of you have tried to count calories while breastfeeding - it's nearly impossible. The hunger is unbelievable. While pregnant, I could smell if someone brought powdered donuts into the office 4-5 rooms away, but, in general, I could limit myself to one little donut hole, as long as I was eating plenty of real food from home. While breastfeeding, I would fight the urge to rifle through other people's desks to find a snickers bar, and I could leap over tables to sample the office donut holes.
Enter a paleolithic inspired diet. Despite the above rare indulgences, I did limit vegetable oils, high fructose corn syrup, and processed food for the past 3-4 years. The main difference was dropping carbs by avoiding grains and low-fat dairy, skipping a meal 2-3 times a week and pretty much eliminating snacks, and increasing the fat. No counting. No nutrient ratios. The recommended exercise (which I followed) was a 20 minute sprint session once a week, lots of hiking and running around (with the kids, which gave me the time to do it), and mostly body weight lifting I could do at home, quickly, in the morning before everyone else woke up. Or tabatas in the back yard while the kids are digging around in the sandbox. It was, compared to the old days, extremely simple and easy, and the transition was accompanied by a much-needed increase in energy levels and even increased mental clarity and serenity. I was back into my old pre-baby jeans after 3 months. Now I'm having to buy smaller jeans.
It worked so well, and my reading had dug up so many links between the modern disastrous diet and chronic Western disease, that I felt obligated to start up this blog, looking for connections between the modern diet and poor mental health. It's a simple approach. I keep an eye out for nutrition-related research articles, follow the tips from blog readers who have seen interesting related case studies or papers, and I also look specifically at known differences between modern diets and past ones - daily amount of magnesium being one of those.
It seems that everywhere I look, I find something that has the potential to be major (fructose, magnesium, omega 3/6 ratio, vitamin D, phospholipids), and enough is already known about it to have a very solid basis for further meaningful research, even on a piecemeal basis. And the pleiotropic effects of adding back all the "real food" minus all the poisons we so regularly consume could be simply staggering on a public health basis. This is what evolutionary medicine and evolutionary psychiatry means to me now.
Last week, while researching magnesium, I stumbled on this news bit from Science in April of 2009 - "Darwin Applies to Medical School." It discusses a recent push to add more evolutionary training to medical school, a classic example being a better understanding of the development of antibiotic resistance. (I don't quite understand this example - does it really require extra evolutionary training to understand the concept of generations of microbes being exposed to antibiotics so some develop resistance and live on, taking over the population assuming vast exposure to the antibiotics? I think it takes about 30 seconds to understand that concept, assuming a basic knowledge of genes and biology.) The evolutionary training that is needed is the comparison of the health of our paleolithic ancestors, an understanding of natural selection as it pertains to human populations (including a discussion of K-type selection and grandmothers), and, frankly, reading Stephan Guyenet's entire blog archives.
Here's what James Lupisky, of Baylor College of Medicine said in the Science article: "Medical schools have a lot on their plate." (Next is from the article, but not Dr. Lupisky's quote) They are "already straining from an explosion and information and technology, and clamors for change come from many directions." And Harvard evolutionary biologist David Haig says, "Evolutionary thinking is not going to give cheap medical solutions."
On that, I think he is dead wrong. In fact, I know we can't afford to go forward as we are, pursuing more and more pharmaceuticals and technology to slow down our dying. Maybe David Haig should check out the cost of grassfed beef liver once a week, sunlight, sardines, and magnesium pills.
Again, I don't understand. Why doesn't even the evolutionary biologist get it? Granted, I had an interest in anthropology and evolution and a solid grounding in molecular biology prior to medical school, and the field of psychiatry lends itself, perhaps counter-intuitively, to look for holistic solutions to human problems. Still, I don't understand why just a few of us, in 2010, are pulling together this information and trying to work the biggest problem in human health in the evolutionary way. I'm simply baffled by how easy it is to find enormous clues as to the pathogenesis of biologic mechanisms of modern mental health problems with this ridiculously simple approach. It used to be exciting - I knew the secret to weight loss and metabolism. I knew the secret to good health and reducing the ravages of stress. The temple secrets were right there, within reach. At the same time, the work is frustrating. I feel a bit like Cassandra, blessed (I hope) with knowledge but knowing that no one in charge who could make some real difference would believe me.
Here is the orchestral version of Finlandia. Those who misspent a childhood watching the Smurfs might recognize the introduction.
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?
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?
Thursday, September 30, 2010
Magnesium!
I'll get back to Alzheimer's Dementia and fats. But I'm left-handed, and it is more interesting for me to multitask than to stay on one topic in a particularly organized fashion. I have a right-handed accountant for that sort of thing. Ooh, a butterfly fluttered by the window! Pretty!
Ahem. Magnesium is another one of those minerals that our ancestors got lots of, but now we don't. Eaton, Eaton, and Konner figure that an average hunter-gatherer intake is 700mg daily. The RDA is 350mg, and the average US intake is 250mg (Update - these numbers are from "Primal Body, Primal Mind" page 42 - paperback version, and Gedgaudas cites the following paper as the source, but as MM rightly points out, there is no magnesium in this paper! Sorry to mislead - I had double checked the same source for my zinc posts a few months ago and the numbers were correct, right from the paper, so I didn't bother to double check the magnesium numbers. Oops! Fortunately in the internet age everything is double-checked for me. I have no clue where Nora Gedgaudas obtained the magnesium numbers for her table in the book)(1)(This is an Eaton paper before the addition of the marrow and all the organ meats into the equation, looks like, so one might think the magnesium would be even higher). Who cares? Well, your cells, for one. Magnesium is involved in a lot of cell transport activities, in addition to making energy aerobically or anaerobically. Your bones are a major reservoir for magnesium, and magnesium is the counter-ion for calcium and potassium in muscle cells, including the heart. If your magnesium is too low, your heart could go pitter-patter in some unfortunate ways (2). Ion regulation is everything with respect to how muscles contract and nerves send signals. In the brain, potassium and sodium balance each other. In the heart and other muscles, magnesium pulls some of the load.
That doesn't mean that magnesium is entirely unimportant in the brain. Au contraire! In fact, there is an intriguing article entitled Rapid recovery from major depression using magnesium treatment, published in Medical Hypothesis in 2006. Medical Hypothesis seems like a great way to get rampant speculation into the PubMed database. Fortunately, I don't need to publish in Medical Hypothesis, as I can engage in rampant speculation in my blog, readily accessible to Google. Anyway, this article was written by George and Karen Eby, who seem to run a nutrition research facility out of an office warehouse in Austin, Texas. They might sell zinc supplements for the common cold, but I haven't looked closely enough to say for sure. I must admit to being a zinc fan.
But back to magnesium! Magnesium is an old home remedy for all that ails you, including anxiety, apathy, depression, headaches, insecurity, irritability, restlessness, talkativeness, and sulkiness. In 1968, Wacker and Parisi reported that magnesium deficiency could cause depression, behavioral disturbances, headaches, muscle cramps, seizures, ataxia, psychosis, and irritability - reversible with magnesium repletion.
Stress is the bad guy here, in addition to our woeful diets. As is the case with zinc, stress causes us to waste our magnesium like crazy.
Let's look at Eby's case studies from his paper:
A 59 y/o "hypomanic-depressive male", with a long history of treatable mild depression, developed anxiety, suicidal thoughts, and insomnia after a year of extreme personal stress and crappy diet ("fast food"). Lithium and a number of antidepressants did nothing for him. 300mg magnesium glycinate (and later taurinate) was given with every meal. His sleep was immediately restored, and his anxiety and depression were greatly reduced, though he sometimes needed to wake up in the middle of the night to take a magnesium pill to keep his "feeling of wellness." A 500mg calcium pill would cause depression within one hour, extinguished by the ingestion of 400mg magnesium.
A 23 year-old woman with a previous traumatic brain injury became depressed after extreme stress with work, a diet of fast food, "constant noise," and poor academic performance. After one week of magnesium treatment, she became free of depression, and her short term memory and IQ returned.
A 35 year-old woman with a history of post-partum depression was pregnant with her fourth child. She took 200mg magnesium glycinate with each meal. She did not develop any complications of pregnancy and did not have depression with her fourth child, who was "healthy, full weight, and quiet."
A 40 year-old "irritable, anxious, extremely talkative, moderately depressed" smoking, alchohol-drinking, cocaine using male took 125mg magnesium taurinate at each meal and bedtime, and found his symptoms were gone within a week, and his cravings for tobacco, cocaine, and alcohol disappeared. His "ravenous appetite was supressed, and ... beneficial weight loss ensued."
Interesting, anyway. No one mentioned magnesium (or zinc) during my psychiatry residency, that I recall. Eby has the same questions I do - why is depression increasing? His answer is magnesium deficiency. Prior to the development of widespread grain refining capability, whole grains were a decent source of magnesium (minus all that phytic acid, of course). Average American intake in 1905 was 400mg daily, and only 1% of Americans had depression prior to the age of 75. In 1955, white bread (nearly devoid of magnesium) was the norm, and 6% of Americans had depression before the age of 24. In addition, eating too much calcium interferes with the absorption of magnesium, setting the stage for magnesium deficiency. In Paleolithic times, we drank a lot of magnesium with our natural mineral water, but modern water treatment systems tend to remove the magnesium. Go San Pellegrino!
Magnesium is not readily available in a normal multivitamin, as it is too bulky to fit into the small pills. Therefore you have to go a little out of your way to supplement. Most supplements are also magnesium oxide, which isn't biologically available to the human body. Magnesium glutamate and aspartate can worsen depression (recall that glutamate and aspartate are thought to be neurotoxic in excess). I know, nutrition can be a tricky business.
Next up will be more about the different magnesium supplements, more about magnesium and the brain, and the side effects of robust magnesium supplementation! Yee haw!
Ahem. Magnesium is another one of those minerals that our ancestors got lots of, but now we don't. Eaton, Eaton, and Konner figure that an average hunter-gatherer intake is 700mg daily. The RDA is 350mg, and the average US intake is 250mg (Update - these numbers are from "Primal Body, Primal Mind" page 42 - paperback version, and Gedgaudas cites the following paper as the source, but as MM rightly points out, there is no magnesium in this paper! Sorry to mislead - I had double checked the same source for my zinc posts a few months ago and the numbers were correct, right from the paper, so I didn't bother to double check the magnesium numbers. Oops! Fortunately in the internet age everything is double-checked for me. I have no clue where Nora Gedgaudas obtained the magnesium numbers for her table in the book)(1)(This is an Eaton paper before the addition of the marrow and all the organ meats into the equation, looks like, so one might think the magnesium would be even higher). Who cares? Well, your cells, for one. Magnesium is involved in a lot of cell transport activities, in addition to making energy aerobically or anaerobically. Your bones are a major reservoir for magnesium, and magnesium is the counter-ion for calcium and potassium in muscle cells, including the heart. If your magnesium is too low, your heart could go pitter-patter in some unfortunate ways (2). Ion regulation is everything with respect to how muscles contract and nerves send signals. In the brain, potassium and sodium balance each other. In the heart and other muscles, magnesium pulls some of the load.
That doesn't mean that magnesium is entirely unimportant in the brain. Au contraire! In fact, there is an intriguing article entitled Rapid recovery from major depression using magnesium treatment, published in Medical Hypothesis in 2006. Medical Hypothesis seems like a great way to get rampant speculation into the PubMed database. Fortunately, I don't need to publish in Medical Hypothesis, as I can engage in rampant speculation in my blog, readily accessible to Google. Anyway, this article was written by George and Karen Eby, who seem to run a nutrition research facility out of an office warehouse in Austin, Texas. They might sell zinc supplements for the common cold, but I haven't looked closely enough to say for sure. I must admit to being a zinc fan.
But back to magnesium! Magnesium is an old home remedy for all that ails you, including anxiety, apathy, depression, headaches, insecurity, irritability, restlessness, talkativeness, and sulkiness. In 1968, Wacker and Parisi reported that magnesium deficiency could cause depression, behavioral disturbances, headaches, muscle cramps, seizures, ataxia, psychosis, and irritability - reversible with magnesium repletion.
Stress is the bad guy here, in addition to our woeful diets. As is the case with zinc, stress causes us to waste our magnesium like crazy.
Let's look at Eby's case studies from his paper:
A 59 y/o "hypomanic-depressive male", with a long history of treatable mild depression, developed anxiety, suicidal thoughts, and insomnia after a year of extreme personal stress and crappy diet ("fast food"). Lithium and a number of antidepressants did nothing for him. 300mg magnesium glycinate (and later taurinate) was given with every meal. His sleep was immediately restored, and his anxiety and depression were greatly reduced, though he sometimes needed to wake up in the middle of the night to take a magnesium pill to keep his "feeling of wellness." A 500mg calcium pill would cause depression within one hour, extinguished by the ingestion of 400mg magnesium.
A 23 year-old woman with a previous traumatic brain injury became depressed after extreme stress with work, a diet of fast food, "constant noise," and poor academic performance. After one week of magnesium treatment, she became free of depression, and her short term memory and IQ returned.
A 35 year-old woman with a history of post-partum depression was pregnant with her fourth child. She took 200mg magnesium glycinate with each meal. She did not develop any complications of pregnancy and did not have depression with her fourth child, who was "healthy, full weight, and quiet."
A 40 year-old "irritable, anxious, extremely talkative, moderately depressed" smoking, alchohol-drinking, cocaine using male took 125mg magnesium taurinate at each meal and bedtime, and found his symptoms were gone within a week, and his cravings for tobacco, cocaine, and alcohol disappeared. His "ravenous appetite was supressed, and ... beneficial weight loss ensued."
Interesting, anyway. No one mentioned magnesium (or zinc) during my psychiatry residency, that I recall. Eby has the same questions I do - why is depression increasing? His answer is magnesium deficiency. Prior to the development of widespread grain refining capability, whole grains were a decent source of magnesium (minus all that phytic acid, of course). Average American intake in 1905 was 400mg daily, and only 1% of Americans had depression prior to the age of 75. In 1955, white bread (nearly devoid of magnesium) was the norm, and 6% of Americans had depression before the age of 24. In addition, eating too much calcium interferes with the absorption of magnesium, setting the stage for magnesium deficiency. In Paleolithic times, we drank a lot of magnesium with our natural mineral water, but modern water treatment systems tend to remove the magnesium. Go San Pellegrino!
Magnesium is not readily available in a normal multivitamin, as it is too bulky to fit into the small pills. Therefore you have to go a little out of your way to supplement. Most supplements are also magnesium oxide, which isn't biologically available to the human body. Magnesium glutamate and aspartate can worsen depression (recall that glutamate and aspartate are thought to be neurotoxic in excess). I know, nutrition can be a tricky business.
Next up will be more about the different magnesium supplements, more about magnesium and the brain, and the side effects of robust magnesium supplementation! Yee haw!
Monday, September 27, 2010
Alzheimer's and Omega 3s
Let's continue on our journey deconstructing and reverse engineering psychiatry from an evolutionary medicine perspective. That is, I assume the correct answer and see how the many pieces fit. There is a danger from this approach - if the main hypothesis is incorrect, I might be wasting a lot of time. But I'm having a bit of fun in the process, and it's quite remarkable just how many connections can be made using the intuitive evolutionary framework to lay out the data.
To date there are a large number of studies covering the topic of dementia and omega 3 fatty acids (1)(2). There are a couple of reasons omega 3s have been so thoroughly studied, and if you have the stamina, I'll take you through a bit of molecular biology.
First off, inflammation and Alzheimer's are linked, and omega 3s are basically anti-inflammatory. DHA is modified by phospholipases to become neuroprotectin 1 (your neurons' superhero - neuroprotectin!) Alzheimer's patients have lower phospholipase activity in brain tissue, CSF, and in platelets. All sorts of inflammatory stressors (lack of oxygen, exposure to amyloid, and IL-1b) cause the up regulation of phospholipase, leading to the formation of neuroprotectin from DHA, which then reverses the inflammatory cascade. Perfect negative feedback inhibition - which works best no doubt if the omega 3s and 6s are balanced in a more evolutionary style diet.
Secondly, an imbalance of AA (derived from omega 6) vs DHA (omega 3) may be critical to the formation of amyloid plaques in the first place. Amyloid precursor protein has to be cut in particular ways to make the toxic fragments that eventually aggregate into amyloid plaques. It seems that if brain cell membranes are rich in DHA, the squiggles and wiggles of DHA hide and protect the bad cleavage sites on amyloid precursor protein. AA squiggles and wiggles seem to expose the bad cleavage sites, making it easier to make plaque from amyloid precursor protein. DHA also seems not only to make it physically harder to cut amyloid precursor protein in the bad way, but DHA also chemically cripples the action of the amyloid-creating enzyme, gamma secretase. All this in addition to reducing the inflammatory action of plaque once DHA is formed into neuroprotectin!
So what about those studies of omega 3 and dementia? 17 reasonably good cross-sectional, epidemiological, and prospective cohort studies have been done over the years. Some of better quality than others, of course. 2/3 used food frequency questionnaires, the other 1/3 lab measurements of fatty acid ratios (from serum or plasma). Overall, the studies followed some 24,000 or so people in Japan, the US, Canada, and Europe, both those with dementia and regular population cohorts.
Results time! Some studies found no correlations, but for the most part, diets high in fish were associated with less dementia. Diets high in omega 6, saturated fat, total fat, and cholesterol were associated with more dementia. The association was especially strong for those people without the genetic predisposition for Alzheimer's - people without the ApoE4 allele. (ApoE is short for apolipoprotein E, by the way - yes, just like high density lipoprotein (HDL) and low density lipoprotein (LDL), apolipoproteins carry around fat and cholesterol, but in the brains. More about this in a later post).
The overall trend was enough to cause researchers to try prospective controlled trials with omega 3 supplementation in dementia. 6 have been done to date. The first one, in 2004, was badly designed at the beginning. 20 Alzheimer's patients were treated with 500 mg of the omega 3 EPA. Since EPA is not an important fatty acid in the brain as far as we know, there was no effect in cognitive decline between the supplement arm and the placebo arm of the studies. In Japan in 2006, 240mg of AA+DHA was compared to 240mg of olive oil daily for 90 days. The mild cognitive impairment group with the PUFAs showed some improvement, whereas the olive oil group had no improvement.
Also in 2006, a large (204 subjects) double blind randomized controlled trial was done with 1.7 grams DHA and 0.6 grams EPA or placebo for 6 months, followed by an additional 6 months of "open label" where everyone got the omega 3 treatment. Overall, there was no difference between the two groups, except one subgroup of mild cognitive impairment did better on the omega3s. Another small study in 2008 had similar results.
In 2009, 485 cognitively normal elderly folks were randomized to 900 mg DHA a day or placebo for 6 months. The treatment arm doubled their plasma DHA levels and showed improvement in some of the learning and memory tests (but not in the main study objective, the "global battery score") while the controls didn't improve. A second trial of 402 subjects with mild to moderate Alzheimer's dementia and 2 grams of DHA vs placebo did not meet the primary objective despite healthy increases in serum and CSF levels of DHA in the treatment arm.
Whew. So here we have science. Plausible molecular mechanism, followed by epidemiological studies, followed by randomized controlled trials. Overall, the science tells us that omega 3 is probably protective against amyloid and helpful in memory. Why? Because non-demented and mildly demented individuals benefited, while the more severe cases did not. In my last Alzheimer's post, I discussed how amyloid builds up over decades, and amyloid-zapping interventions in the end stage is like dousing a fire just after the house is burned down. Theoretically, omega 3s should have some benefit at the inflammatory stage too - I wonder what the outcome in more severe cases would be if the omega 6s and 3s where held to an evolutionary ratio of 2:1 or 1:2 or 1:1?
In general we are not talking about mega doses here. In the epidemiological studies, DHA intakes of 180mg a day correlated with a 40% reduction in dementia. Average Western diet intake is 80mg a day. Fatty fish three times a week or so would do the trick.
There are two schools of thought about getting the 3/6 ratios correct in the paleosphere. One way is to let time be on your side, avoid excess omega 6, and supplement prudently with Omega 3. DHA is easily oxidized, so you would want to supplement with oil you can taste - in fish, for example, or teaspoons. Another way is to take in high amounts of omega 3 to more or less wash out the omega 6. This method might make more sense if you are in a more desperate situation - mild cognitive impairment already, active heart disease, bad autoimmune stuff going on. The risk is that high amounts of PUFAs are tough on the liver and are bad to combine with sugar and alcohol, and likely cancer promoting. My perspective - if you can get away with it, take it slow. But compared to a number of other medical treatments for our various diseases of civilization, even higher doses of PUFAs for a short term is likely safer and possibly more beneficial.
(did this post on the iPad so I'm adding references later, when I get a moment at the bigger computer! - Done!)
To date there are a large number of studies covering the topic of dementia and omega 3 fatty acids (1)(2). There are a couple of reasons omega 3s have been so thoroughly studied, and if you have the stamina, I'll take you through a bit of molecular biology.
First off, inflammation and Alzheimer's are linked, and omega 3s are basically anti-inflammatory. DHA is modified by phospholipases to become neuroprotectin 1 (your neurons' superhero - neuroprotectin!) Alzheimer's patients have lower phospholipase activity in brain tissue, CSF, and in platelets. All sorts of inflammatory stressors (lack of oxygen, exposure to amyloid, and IL-1b) cause the up regulation of phospholipase, leading to the formation of neuroprotectin from DHA, which then reverses the inflammatory cascade. Perfect negative feedback inhibition - which works best no doubt if the omega 3s and 6s are balanced in a more evolutionary style diet.
Secondly, an imbalance of AA (derived from omega 6) vs DHA (omega 3) may be critical to the formation of amyloid plaques in the first place. Amyloid precursor protein has to be cut in particular ways to make the toxic fragments that eventually aggregate into amyloid plaques. It seems that if brain cell membranes are rich in DHA, the squiggles and wiggles of DHA hide and protect the bad cleavage sites on amyloid precursor protein. AA squiggles and wiggles seem to expose the bad cleavage sites, making it easier to make plaque from amyloid precursor protein. DHA also seems not only to make it physically harder to cut amyloid precursor protein in the bad way, but DHA also chemically cripples the action of the amyloid-creating enzyme, gamma secretase. All this in addition to reducing the inflammatory action of plaque once DHA is formed into neuroprotectin!
So what about those studies of omega 3 and dementia? 17 reasonably good cross-sectional, epidemiological, and prospective cohort studies have been done over the years. Some of better quality than others, of course. 2/3 used food frequency questionnaires, the other 1/3 lab measurements of fatty acid ratios (from serum or plasma). Overall, the studies followed some 24,000 or so people in Japan, the US, Canada, and Europe, both those with dementia and regular population cohorts.
Results time! Some studies found no correlations, but for the most part, diets high in fish were associated with less dementia. Diets high in omega 6, saturated fat, total fat, and cholesterol were associated with more dementia. The association was especially strong for those people without the genetic predisposition for Alzheimer's - people without the ApoE4 allele. (ApoE is short for apolipoprotein E, by the way - yes, just like high density lipoprotein (HDL) and low density lipoprotein (LDL), apolipoproteins carry around fat and cholesterol, but in the brains. More about this in a later post).
The overall trend was enough to cause researchers to try prospective controlled trials with omega 3 supplementation in dementia. 6 have been done to date. The first one, in 2004, was badly designed at the beginning. 20 Alzheimer's patients were treated with 500 mg of the omega 3 EPA. Since EPA is not an important fatty acid in the brain as far as we know, there was no effect in cognitive decline between the supplement arm and the placebo arm of the studies. In Japan in 2006, 240mg of AA+DHA was compared to 240mg of olive oil daily for 90 days. The mild cognitive impairment group with the PUFAs showed some improvement, whereas the olive oil group had no improvement.
Also in 2006, a large (204 subjects) double blind randomized controlled trial was done with 1.7 grams DHA and 0.6 grams EPA or placebo for 6 months, followed by an additional 6 months of "open label" where everyone got the omega 3 treatment. Overall, there was no difference between the two groups, except one subgroup of mild cognitive impairment did better on the omega3s. Another small study in 2008 had similar results.
In 2009, 485 cognitively normal elderly folks were randomized to 900 mg DHA a day or placebo for 6 months. The treatment arm doubled their plasma DHA levels and showed improvement in some of the learning and memory tests (but not in the main study objective, the "global battery score") while the controls didn't improve. A second trial of 402 subjects with mild to moderate Alzheimer's dementia and 2 grams of DHA vs placebo did not meet the primary objective despite healthy increases in serum and CSF levels of DHA in the treatment arm.
Whew. So here we have science. Plausible molecular mechanism, followed by epidemiological studies, followed by randomized controlled trials. Overall, the science tells us that omega 3 is probably protective against amyloid and helpful in memory. Why? Because non-demented and mildly demented individuals benefited, while the more severe cases did not. In my last Alzheimer's post, I discussed how amyloid builds up over decades, and amyloid-zapping interventions in the end stage is like dousing a fire just after the house is burned down. Theoretically, omega 3s should have some benefit at the inflammatory stage too - I wonder what the outcome in more severe cases would be if the omega 6s and 3s where held to an evolutionary ratio of 2:1 or 1:2 or 1:1?
In general we are not talking about mega doses here. In the epidemiological studies, DHA intakes of 180mg a day correlated with a 40% reduction in dementia. Average Western diet intake is 80mg a day. Fatty fish three times a week or so would do the trick.
There are two schools of thought about getting the 3/6 ratios correct in the paleosphere. One way is to let time be on your side, avoid excess omega 6, and supplement prudently with Omega 3. DHA is easily oxidized, so you would want to supplement with oil you can taste - in fish, for example, or teaspoons. Another way is to take in high amounts of omega 3 to more or less wash out the omega 6. This method might make more sense if you are in a more desperate situation - mild cognitive impairment already, active heart disease, bad autoimmune stuff going on. The risk is that high amounts of PUFAs are tough on the liver and are bad to combine with sugar and alcohol, and likely cancer promoting. My perspective - if you can get away with it, take it slow. But compared to a number of other medical treatments for our various diseases of civilization, even higher doses of PUFAs for a short term is likely safer and possibly more beneficial.
(did this post on the iPad so I'm adding references later, when I get a moment at the bigger computer! - Done!)
Saturday, September 25, 2010
Your Brain on Omega 3s
Nitty gritty time. I've been touting the benefits of omega 3 fatty acids from the beginning of the blog, but I haven't really gone into exactly what those marine-animal derived PUFAs are doing up there, and why they are so important. Fortunately, one of the papers I'm reading for the Alzheimer's series has an excellent discussion. (1)
If you recall, the brain has a heck of a lot of cell membranes, and cell membranes are made out of fat. The fat content of the brain is a little different than the rest of the body - the only PUFAs allowed into the healthy brain in any appreciable amount are the omega 3 DHA and the omega 6 derived (or obtained directly from animal foods) arachidonic acid (AA). In addition, while AA is found in equal amounts all over the brain, DHA is found predominately in the gray matter. That's where our thinking takes place.
Let me explain a bit about the actual structure of these molecules, and that may clarify some things. It will be helpful for you to consume some wild-caught salmon before reading this as the DHA helps the transcription factors of your hippocampus in the process of making new memories.
Saturated fats and cholesterol make rather boring cell membranes all on their own. Their structure is pretty straight, and they line up rather like this:
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii
PUFAs have unsaturated bonds, which make them rather kinky. Add some PUFAs to a cell membrane and you suddenly get this:
iiiiiiLiiiiiiiiiLiiiiiiiiiiiiiLiLiiiiiiiLiiiiiiiiiLiiiiiiiiiiL
The unsaturated bonds break up the structure a bit, and molecular biologists call this "increasing membrane fluidity." Important membrane proteins, such as ion channels, depend on the presence of PUFAs to be incorporated correctly into the membrane. If all is well, the PUFAs serve as part of "lipid rafts" that are required for transport of protein and signals through the membranes, the formation of synapses, and maintaining the integrity of the neuronal membranes. Lipid rafts. Whee!!
We can make a bit of DHA from ALA (an omega 3 found in plants, such as flax), but the process is horribly inefficient. Otherwise, DHA is made by photosynthetic algae eaten by krill or fish or oysters, etc. - which we eventually consume. We cannot make DHA ourselves in useful amounts. The amount and ratios of PUFAs in our brain are dependent upon what we consume in our diet.
AA is important in the brain - it initiates and maintains the inflammatory cascade, which is a critical function. But AA is a different kinky shape than DHA and the overall membrane functioning is quite different if we have a ton of AA compared to DHA. The paper notes here that "it is intriguing that the dramatic increase in the prevalence of [Alzheimer's disease] in the last century not only parallels the increase in average lifespan, but also an increase from 2 to more than 20 of the ratio of omega 6 to omega 3 PUFAs in the average Western diet."
Our brains are designed to run on fish oil. We really shouldn't be operating the all-important noggin too far outside the design specs, or nasty things tend to happen.
In the next couple of posts we will explore a bit more about DHA vs AA in the pathology of Alzheimer's, and also figure out why the randomized controlled trials of omega 3 fatty acids in dementia have, so far, been a bust.
(PS - Dr. BG had a couple of recent blog posts on the topic of our fish-eating ancestors - similar points to mine though made with considerably more flair!)
If you recall, the brain has a heck of a lot of cell membranes, and cell membranes are made out of fat. The fat content of the brain is a little different than the rest of the body - the only PUFAs allowed into the healthy brain in any appreciable amount are the omega 3 DHA and the omega 6 derived (or obtained directly from animal foods) arachidonic acid (AA). In addition, while AA is found in equal amounts all over the brain, DHA is found predominately in the gray matter. That's where our thinking takes place.
Let me explain a bit about the actual structure of these molecules, and that may clarify some things. It will be helpful for you to consume some wild-caught salmon before reading this as the DHA helps the transcription factors of your hippocampus in the process of making new memories.
Saturated fats and cholesterol make rather boring cell membranes all on their own. Their structure is pretty straight, and they line up rather like this:
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii
PUFAs have unsaturated bonds, which make them rather kinky. Add some PUFAs to a cell membrane and you suddenly get this:
iiiiiiLiiiiiiiiiLiiiiiiiiiiiiiLiLiiiiiiiLiiiiiiiiiLiiiiiiiiiiL
The unsaturated bonds break up the structure a bit, and molecular biologists call this "increasing membrane fluidity." Important membrane proteins, such as ion channels, depend on the presence of PUFAs to be incorporated correctly into the membrane. If all is well, the PUFAs serve as part of "lipid rafts" that are required for transport of protein and signals through the membranes, the formation of synapses, and maintaining the integrity of the neuronal membranes. Lipid rafts. Whee!!
We can make a bit of DHA from ALA (an omega 3 found in plants, such as flax), but the process is horribly inefficient. Otherwise, DHA is made by photosynthetic algae eaten by krill or fish or oysters, etc. - which we eventually consume. We cannot make DHA ourselves in useful amounts. The amount and ratios of PUFAs in our brain are dependent upon what we consume in our diet.
AA is important in the brain - it initiates and maintains the inflammatory cascade, which is a critical function. But AA is a different kinky shape than DHA and the overall membrane functioning is quite different if we have a ton of AA compared to DHA. The paper notes here that "it is intriguing that the dramatic increase in the prevalence of [Alzheimer's disease] in the last century not only parallels the increase in average lifespan, but also an increase from 2 to more than 20 of the ratio of omega 6 to omega 3 PUFAs in the average Western diet."
Our brains are designed to run on fish oil. We really shouldn't be operating the all-important noggin too far outside the design specs, or nasty things tend to happen.
In the next couple of posts we will explore a bit more about DHA vs AA in the pathology of Alzheimer's, and also figure out why the randomized controlled trials of omega 3 fatty acids in dementia have, so far, been a bust.
(PS - Dr. BG had a couple of recent blog posts on the topic of our fish-eating ancestors - similar points to mine though made with considerably more flair!)
Thursday, September 23, 2010
ADHD, Food Additives, and Histamine
I'll get back to the wild world of Alzheimer's research in a day or two. My September issue of the Green Journal arrived via USPS this afternoon, and of course this paper caught my eye:
"The Role of Histamine Degradation Gene Polymorphisms in Moderating the Effects of Food Additives on Children's ADHD Symptoms."
A colleague rolled her eyes at me when I squeaked while reading the title. But do you know how many diet-related articles are published in my specialty journal (the oldest specialty journal in publication, by the way) every year? Maybe one or two. And I've laid out the groundwork for evaluating this study. If you didn't read them the first time around, maybe take a moment now to go back to the archives to look at Hyperactivity and Diet and A Closer Look at Tartrazine. The recap is that some food additives have been shown to worsen the symptoms in ADHD (or hyperactivity) in some children, but other children seem to be impervious.
ADHD in children is diagnosed when kids have symptoms of inattention, impulsivity, and hyperactivity, to the point where severe problems interfere with daily functioning. The disorder is highly inherited, and a few genes have been found in some families that seem to explain the symptoms - the dopamine transporter genes and dopamine receptor genes, among others. Issues with these genes make sense for the symptoms you would see in ADHD - dopamine is the neurotransmitter, in our frontal lobes, especially, that is responsible for helping us pay attention and keeping us from saying things we shouldn't. If our dopamine system doesn't work efficiently, then you could see how someone could have ADHD.
But what in the world does this have to do with food dyes? Azo food dyes like yellow number five are known to cause allergic reactions in susceptible people, typically hives. That means artificial food colorings may result in the release of histamine, a chemical we let loose during an allergic reaction. The theory the researchers are working with here is that exposure to food dyes may cause some kids to release histamine, maybe not to a degree to where there is a full-on allergic reaction and hives, but where it could possibly affect behavior or impulsivity. Since the H3 receptor is prevalent in the human brain, histamine could certainly have a behavioral effect.
Researchers took the same kids who were involved in the Southampton study and checked the their genes for dopamine transporter, dopamine receptor, COMT, and ADRA2A genetic polymorphisms. All these genes have been associated with select groups of families with ADHD. In addition, the researchers tested for differences in the histamine N-methyltransferase (HNMT) genes to check out the histamine hypothesis. An efficiently functioning HNMT system means you clear histamine from the body in a timely manner. If your gene codes for a protein that is less efficient, you might be more vulnerable to allergy and other histamine-mediated problems. These kids were a random community sample and didn't necessarily have ADHD, and had gone through a double-blind crossover placebo controlled trial of two mixes of food dyes and preservatives and a control. The kids' behavior overall worsened significantly in the eyes of the parents and independent observers during the weeks they drank the additive-laden juice compared to the additive-free control juice. But, once again, individual reactions to the hyper juice were highly variable. Individual reactions were checked against the individual genotype to see if any connections could be made.
Of the 297 kids, about half were three years old, and the other half were eight and nine. Among the three year-olds, certain histamine and dopamine gene polymorphisms were associated with higher baseline hyperactivity - prior to drinking any hyper juice. That is to be expected if the genetic theory is sound. Among the 8/9 year-olds, there wasn't a connection found.
But what about when we added the additives? Overall, the three year-olds had significant reactions to the hyper juice (more Mix A than Mix B) if they lacked certain alleles of the histamine N-methyltransferase (HNMT) gene. There seemed to be no differences in the reactions depending on the dopamine or other checked genotypes. In the 8/9 year-olds, the results were quite similar. Not too much difference when dopamine may be off, but a significant difference depending on the HNMT gene allele.
The study was relatively short term, and obviously should be replicated before we jump up and down too much. But genetic differences in our histamine systems may explain why some kids react very badly to azo food dyes, and others don't seem to bat an eye. And this would mean that ADHD, in some people, is very likely a food allergy. Those kids might also be vulnerable to environmental allergies that affect the histamine system. There is also some evidence that methylphenidate (ritalin) and atomoxetine (strattera), medications used for ADHD, work not only via dopamine but also via histamine interactions.
The editorial in the same issue says it all: "The links are clear, and the paper is a watershed, although still falling far short of definitive proof. As with every breakthrough, more questions emerge than are answered...[the Southampton study didn't separate preservatives from additives which is an issue, as removing preservatives has economic and food safety issues] but there is no cost to health or safety in giving up artificial food colors. It certainly appears that over and above this set of studies, the cumulative evidence is sufficient for society to demand adherence to the precautionary principle and to... restrict the use of artificial dyes, at least in foods that target children."
From the conservative American Journal of Psychiatry, that is a clarion call. Amen.
"The Role of Histamine Degradation Gene Polymorphisms in Moderating the Effects of Food Additives on Children's ADHD Symptoms."
A colleague rolled her eyes at me when I squeaked while reading the title. But do you know how many diet-related articles are published in my specialty journal (the oldest specialty journal in publication, by the way) every year? Maybe one or two. And I've laid out the groundwork for evaluating this study. If you didn't read them the first time around, maybe take a moment now to go back to the archives to look at Hyperactivity and Diet and A Closer Look at Tartrazine. The recap is that some food additives have been shown to worsen the symptoms in ADHD (or hyperactivity) in some children, but other children seem to be impervious.
ADHD in children is diagnosed when kids have symptoms of inattention, impulsivity, and hyperactivity, to the point where severe problems interfere with daily functioning. The disorder is highly inherited, and a few genes have been found in some families that seem to explain the symptoms - the dopamine transporter genes and dopamine receptor genes, among others. Issues with these genes make sense for the symptoms you would see in ADHD - dopamine is the neurotransmitter, in our frontal lobes, especially, that is responsible for helping us pay attention and keeping us from saying things we shouldn't. If our dopamine system doesn't work efficiently, then you could see how someone could have ADHD.
But what in the world does this have to do with food dyes? Azo food dyes like yellow number five are known to cause allergic reactions in susceptible people, typically hives. That means artificial food colorings may result in the release of histamine, a chemical we let loose during an allergic reaction. The theory the researchers are working with here is that exposure to food dyes may cause some kids to release histamine, maybe not to a degree to where there is a full-on allergic reaction and hives, but where it could possibly affect behavior or impulsivity. Since the H3 receptor is prevalent in the human brain, histamine could certainly have a behavioral effect.
Researchers took the same kids who were involved in the Southampton study and checked the their genes for dopamine transporter, dopamine receptor, COMT, and ADRA2A genetic polymorphisms. All these genes have been associated with select groups of families with ADHD. In addition, the researchers tested for differences in the histamine N-methyltransferase (HNMT) genes to check out the histamine hypothesis. An efficiently functioning HNMT system means you clear histamine from the body in a timely manner. If your gene codes for a protein that is less efficient, you might be more vulnerable to allergy and other histamine-mediated problems. These kids were a random community sample and didn't necessarily have ADHD, and had gone through a double-blind crossover placebo controlled trial of two mixes of food dyes and preservatives and a control. The kids' behavior overall worsened significantly in the eyes of the parents and independent observers during the weeks they drank the additive-laden juice compared to the additive-free control juice. But, once again, individual reactions to the hyper juice were highly variable. Individual reactions were checked against the individual genotype to see if any connections could be made.
Of the 297 kids, about half were three years old, and the other half were eight and nine. Among the three year-olds, certain histamine and dopamine gene polymorphisms were associated with higher baseline hyperactivity - prior to drinking any hyper juice. That is to be expected if the genetic theory is sound. Among the 8/9 year-olds, there wasn't a connection found.
But what about when we added the additives? Overall, the three year-olds had significant reactions to the hyper juice (more Mix A than Mix B) if they lacked certain alleles of the histamine N-methyltransferase (HNMT) gene. There seemed to be no differences in the reactions depending on the dopamine or other checked genotypes. In the 8/9 year-olds, the results were quite similar. Not too much difference when dopamine may be off, but a significant difference depending on the HNMT gene allele.
The study was relatively short term, and obviously should be replicated before we jump up and down too much. But genetic differences in our histamine systems may explain why some kids react very badly to azo food dyes, and others don't seem to bat an eye. And this would mean that ADHD, in some people, is very likely a food allergy. Those kids might also be vulnerable to environmental allergies that affect the histamine system. There is also some evidence that methylphenidate (ritalin) and atomoxetine (strattera), medications used for ADHD, work not only via dopamine but also via histamine interactions.
The editorial in the same issue says it all: "The links are clear, and the paper is a watershed, although still falling far short of definitive proof. As with every breakthrough, more questions emerge than are answered...[the Southampton study didn't separate preservatives from additives which is an issue, as removing preservatives has economic and food safety issues] but there is no cost to health or safety in giving up artificial food colors. It certainly appears that over and above this set of studies, the cumulative evidence is sufficient for society to demand adherence to the precautionary principle and to... restrict the use of artificial dyes, at least in foods that target children."
From the conservative American Journal of Psychiatry, that is a clarion call. Amen.
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