Magnesium, we know magnesium like so many other minerals are really needed and very important, and the question here is, while spending so much time and effort trying to solve what we call the magnesium issue... Right. So why magnesium as compared to other minerals... What was special about magnesium? Now, we know magnesium is somehow special because we have a large amount of magnesium in our body, most of it are stored in bone, other tissue, and the fraction of it is actually free ionic magnesium, that what we think it is actually, it's a functional magnesium because able to actually be part of an enzymatic reaction as a cofactor, as Ionic channel modulation and so on. And we also have an issue with magnesium is because magnesium in our food is a kind of continuously declining and to make things even worse, they showed that magnesium, beyond that, the diet intake is... We have low dietary intake of magnesium and we don't know if a patients have magnesium deficiency or not, there's no clear biomarker for us to know if you're deficient of magnesium or you're actually fine... And then when you're looking at magnesium, different tissue in your body, you have a different level of magnesium, and if you look at the sample from blood from RBC or from serum, you might find magnesium level is fine, but does not reflect magnesium level in a different tissue especially in the central nervous system and so on. So let's go step by step and discuss with you what's the really issue with magnesium. First, I want to tell you that there's two type of deficiencies, one is subclinical deficiency, where the patient looks largely fine, and the other type is the clinical deficiency, so when you look up for the clinical deficiency like hypo-magnesium, where we have low magnesium in the serum this is really clinical deficiency where we have all the overt symptoms of magnesium, and this would actually be a quick intervention to supplement with magnesium, the... The other type of magnesium deficiency is the subclinical magnesium deficiency, where the patient does not present a clear clinical symptoms deficient in magnesium, but yet there's some deficient magnesium, and this type of magnesium is very hard to actually to detect, and this type of magnesium deficiency, the subclinical magnesium is long term and can predispose the patient to different risk factor for cardiovascular, neurological and so on, so it becomes more increasing vulnerability for the patient to be actually at the risk factor for different conditions. In the general population, as I mentioned before, we have what we call an epidemic of magnesium deficiency, and so different study... This is only one of them, shows that. It's really 50 to 80% of males are somehow have low dietary intake of magnesium, and the same is true for the female, so in this room, around half of you are not having enough magnesium from the diet, so we have diary magnesium deficiency, and this deficiency is not like a huge deficiency compared to the RDA, we're looking for 80 to 100 milligram less than RDA, most of us, we just need extra 80, 100, 150 for us to meet our RDA requirement for magnesium, and yet we're not meeting this, and people would say, okay, 100 mg, 120 milligram, less than RDA how serious is that? We conducted some studies to show that even 10% less than RDA will become an issue. So we know the best way to take magnesium is the diet, and the question here is, we are trying to have a good diet, so what's the issue why we're not getting enough magnesium in the diet where there's different issue why this is happening? First, we're consuming more and more processed food and processed food is deficient in magnesium. The way we process our food, fast food and other canned food and so on, we actually leech magnesium out of their food, so we have really low magnesium in this food we consume, and we don't eat enough fruit and vegetable, or we keep saying fruit and vegetable should be part of your diet, but most of us don't even meet the requirement for fruit and vegetable. And for those of us who actually need the requirement of fruit and vegetable, our fruit and vegetable, the level of magnesium and this vegetable is also declining. So even when you try to eat our six, seven, eight serving of vegetable, we're getting less magnesium than we were if we're eating 5, 6 serving of vegetable 50 or 100 years ago, so there's so many kind of the perfect storm that actually prevent us to acquire enough magnesium from the diet, let alone that some patient require more magnesium than other, there's so many physiological condition that actually accelerate the loss of magnesium from your body, so this patient require more magnesium and the other, and the RDA does not really address that. To show you some data, really evidence, like when I said the magnesium, when our food is on the decline, so when you compare data from magnesium content from fruit and vegetable, let's say 50 years, 80 years compared to now, if you look at the case of magnesium, it's around 20%, 25% decline, and you see other data showing magnesium decline as much as 30 and 40%. So basically, we're looking for 40% less magnesium and fruit and vegetable, and we're eating less fruit and vegetable, so you can really see why 50, 60, 70% of some populations are deficient and magnesium. This is another data set showing not only vegetable, but also fruit, so we have the fruits and vegetable, and you see not only magnesium is on the decline, but also other minerals, also on the decline. So why our fruit and vegetables have less magnesium and so I'm not int9=o farming, but we all can have an idea, more use of chemical insecticides, pesticide and fertilizer, we're over using our land, we're not really a replenishing, we're not using organic technique, there's long list of why this is happening, and he's just like a few idea, so depletion occurred and lack of plant rotation of a production, pesticide use and so on. So basically, it is a serious problem and a problem of industrialization that actually accelerate the loss of magnesium as well as other minerals, and when you're looking at these plants, when you say this plant have less magnesium, we always think that this plants are just a vehicle carrier of magnesium, but that's not true. The reason why plant have magnesium is because magnesium is so important for the plant health... So when magnesium in this plant is on the decline, the whole plant health is also on the decline, which means other bioactive polyphenols, other vitamins could also be on the decline, we're not eating healthy plants. So not only a matter of magnesium is low and everything else is fine - no, when magnesium is low other polyphenols, other nutrients in the plants become lower and lower, and when the plant has is on the decline, the plant becomes a little less resistant to insects and diseases, so which means you have to use more insecticide, more pesticide, and so on and so on become like a vicious cycle. So the problem is really there... This is an example to tell you that magnesium in the plant, around 35% of magnesium in the plant is bound to chlorophyll in the chloroplast. So needless to say, then when the plant have less magnesium, whether the soil has poor magnesium or the magnesium in the soil cannot be properly ab- sorbed by the plan because it's interfering, it's interacting with other compounds were adding into the soil like increase in potassium increasing in other fertilizer, nitrite, and so on will prevent magnesium absorption. So when this happened, you see a comparison on plant with the low magnesium versus a plant with the normal magnesium, you can see how it was not healthy, and which mean the plant's other bioactives also not health with them. So again. What are the sub clinical or clinical symptoms of magnesium Why is magnesium such a hot topic. Why we're really interested to make sure that we have enough magnesium, it's a long list of symptom, I just took like a summary of them, the most important one. And you can see we have headache, brain fog, memory issue, cognitive issues, we have muscles twitching with cramps or muscle, and a lot of people think about muscle as just muscle, but you have to think about muscle as a neuro muscular system, it's like a neuromuscular system. When the newest part of it, muscle does not work in vacuum, so there's a neural support of the muscle, we have so many intervention to strengthen the muscle, and you can see the muscle to all remain weak, and you say, We're giving all the nutrients for the muscle but because you're forgetting the center nervous system that control the muscle and control muscle tone, so both had to work in synchrony for us to get clinical benefit. Changing mood, and then we have muscle weakness, fatigue, when you look at all of these guys, almost most of the symptoms that relevant magnesium. You'll be surprised they are central nervous system related one way or the other. And that was very interesting question, when we take our magnesium or when we are deficient in magnesium, how our data intake of magnesium is sub optimal, that question here is what happened to central nervous system function, and when we make sure that our tissue have enough magnesium are we really ensuring the central nervous system have enough magnesium, and I'm saying that is because of the presence of the blood brain barrier that prevent and separate the periphery from the center nervous system. So in many cases, we have to ensure that when we feed the peripheral system, we have to keep an eye, are we feeding the central nervous system? And this concept is so clear with magnesium is because a lot of magnesium forms out there do not really deliver magnesium to the brain at the rate that's required to maintain proper level of magnesium in the central nervous system. So in this way, we're really having this dichotomy between the peripheral nourishment of magnesium and magnesium with the bone and other tissue versus central nervous system. So we are kind of for working deficiency in the central nervous system despite we're having enough magnesium from different supplements and so on and our periphery's fine, but our central system is suffering, and most of the system, you have symptoms, you see them persistent, even though we're giving this patient a mega dose of magnesium and the patient is living with some GI issue, but you tell them It's fine, it's good for you because you need your magnesium, but even then the central nervous system to remain deficient in magnesium and most of the symptoms relevant to magnesium remain there, which is frustrating in so many case... Let me bring the case of magnesium back. We all known magnesium is important for more than 300 enzymatic reaction. But what does it really mean? 300, 400, 200. Let me just bring it home to something that functional medicine we're really interested in, and this is the three key functions of magnesium, one of them is ATP, adenosine triphosphate , so ATP, we know ATP for energy, but what... Sometimes we don't realize that ATP cannot function - ATP is not stable - without the magnesium ion. The magnesium ion will stabilize an ATP molecule. So every ATP molecule, a functional ATP molecule is actually called ATP - magnesium, it's not ATP, and that's what we mean. Without magnesium, to stabilize the two phosphate groups, ATP just become ADP, not a triphosphate. Basically, magnesium is so crucial to bind to ATP, and you cannot steer the magnesium that's binding to ATP is an ionic magnesium, it's not magnesium glycinate or magnesium citrate, it is a free ion of magnesium that's required to be... To actually do its function. Other one is an enzyme called C OMT, this enzyme, MT so COMT is a methyl transferase, So COMT is a metal transferase which means transfer a methyl group to different enzymatic reaction. This enzyme is important for different neurotransmitter metabolism, including dopamine, serotonin, norepinephrine, and so on, and also this enzyme required magnesium as a co-factor. So under magnesium deficiency, what do you expect? This co factor become deficient, the COMT key function might be affected, and when the COMT function is affected, the consequence would be mood issue, sleep issue, irritability, serotonin, dopamine, norepinephrine, and the list goes on for all the mood changes and so on. Also, COMT is a, we call it Phase II enzyme. We can talk more about that in the next session. Phase two enzymes are so important for detox, and magnesium is actually a Cofactor of COMT, which is a Phase II enzymes, which means under magnesium deficiency, what we expect to see is deficiency in your body ability to detox toxin, and one of the toxin is estrogen, so we all know estrogen is required to be detoxed from your body, and one way for us to detox estrogen is to use methylation and the enzyme required to methylate estrogen molecule is COMT, that require magnesium. So and under mechanism deficiency would expect that estrogen detox would be affected. A lot of scientists out there, they keep pushing about estrogen metabolism, they use of them is of broccoli and other similar vegetable to improve the ratio of estrogen, the good and the bad estrogen, but a lot of them miss the point that this is not enough for estrogen. You just make less bad and more good estrogen form, but without the toxin estrogen, that good estrogen build up and become bad, so what you really have to think about is to shift the bad to good estrogen and to detox estrogen from your body and to detox estrogen, you require methylation and one enzyme is COMT that require magnesium. So under magnesium deficiency, you're gonna have a build up of the good estrogen and actually will create a large amount of good... Become bad. Last point here is glutathione. So glutathione, the master intracellular antioxidant, and it's very important to repeat that its intracellular antioxidant, what makes it so special is because intracellular, most of antioxidant, polyphenols vitamin C, vitamin A - a lot of vitamins - vitamin C, and all the water soluble antioxidant don't get inside the cell, so they all work outside the cell, but most of the oxidative stress that occur in mitochondria is intracellular, so how can we actually scavenge these free radicals if we don't have an anti oxidant that'll get inside the cell? One of them is Vitamin E and other lipid soluable antioxidant, but the most important one is a Glutathione, and we all know why because glutathione is more like an enzyme, so it keeps producing, keeps regenerating as compared to vitamin E. One molecule of vitamin E can actually neutralize one molecule of free radical where glutathione can neutralize hundreds and hundreds of thousands of molecule and the demand going and going and going, so you have to take a larger amount of vitamin E to have an effect, but it's more amount of glutathione generation inside your body, intracellularly can actually help you way more, that's why we call it the master intracellular oxidant, but for this enzyme to be produced, you need magnesium, so under low magnesium, you expect the intracellular antioxidant capacity of your body to be somehow affected and when this is a factor, what you expect to see free radicals creating more damage, more damage, creating more inflammation, and become like a cycle: inflammation, more free radical damage and more free radical damage more inflammation, and magnesium could play a role in all of that, if you have magnesium deficiency, you feed into this vicious cycle of inflammation and antioxidant. As I mentioned before, when you say, Okay, we're only 80 milligram, 100 milligram less than RDA So we're not too far from it, but the answer is yes, you are too far as other people, they've done this study in rats, what we did here, the data I'm showing right now, as we took this rats and we put them on magnesium deficient diet and magnesium deficient diet was only 10% less than RDA for the rats - not much... Will not put them at 50% less diet only 10%. I wanna see what happens. And what happens for us is we want to see what happened, in the central nervous system, because in the periphery, okay, we know it might do X, Y, Z, but our interests really is magnesium in the central nervous system because very hard to get magnesium to central nervous system and most of symptom of magnesium deficiency are CNS related, so let's see what happens if you just 10% less of RDA And we know magnesium in the central nervous system, the functional magnesium is ionic magnesium says, Okay, let's put this rat at low magnesium, 10% just diet. Only for 30 days, not too long, 30 days. And what happened to the cerebrospinal fluid level? Concentration of free ionic magnesium, we can measure that, and that's what we did. And here's the data clearly show that only 30 days with 10% less magnesium in the diet, in the rat, we see around 10% decline in free ionic magnesium. Okay, so it doesn't take long of low or below RDA to have a significant functional impact on the central nervous system magnesium level, a Functional magnesium level, which is very good insights and this has been published before, but never on 30 days and not ever in this context, I'm just telling you right now. Alright, so one concept I would like to put here today is the concept of whole food matrix support biochemical pathways in your body, so we say we're low on calcium, we're low on vitamin B6. So take vitamin B6. Fine, so the patients take vitamin B6, you measure serum and blood, and you find B6 is back to normal, everything is fine, but the symptoms did not change, you still have the same symptoms before B6 as well as after B6 supplementation. And you can go for a vitamin B12, you might relieve some of the symptoms of B12 deficiency, but other symptoms remain and question here is, what's going on, because in so many time you're treating kind of the deficiency but not the pathway, were that this vitamin is essential. So for example, B12 have so many function... One of the function of B12 is to lower homocysteine, which is part of the methylation pathway, but B12 alone will not lower homocysteine. You require the other player, you require vitamin B6, you require zinc, molybdenum require magnesium. You require vitamin B1, vitamin B2 and so on. So basically by you see a deficiency in B12 and you give B12, you actually fix the B12 deficiency, but you did not fix the homocysteine problem, which is give you some of the symptoms of B12 deficiency and some of the risk factor relevant to B12 deficiency, so you really have to feed the whole pathway, or rather than just supporting one player or the other player, I'm gonna spend five, 10 minutes talking about the methylation concept because so much relevant to magnesium and to detox down the road... So methylation , when we have methylation capacity issue, you have mood, brain fog, metabolic issues, estrogen metabolism issues, cardiovascular and so on, there's a lot of conditions associated with low methylation capacity, and homocysteine is a by product of methylation pathway, is an endotoxin and its associated with many health condition, neurological problem, cardiovascular problems and so on. So homocysteine to be cleared from your body, it could be cleared by four different pathways, one of them, folate-dependent pathway, folate-independent pathway, and transsulferation pathway as well as by your kidney, and each of the parts we require different vitamins and cofactors. So here's at a glance, you see homocysteine to be clear, you need vitamin B12, you need the folate for the folate pathway... you need betaine, you need choline, you need B6, and so on. So if you have B6 efficiency and you give B6, you say, okay, what is the symptoms effect? Not much change in the symptoms relevant to homocysteine and to methylation, you still have methylation problem, even though you give B6, because B6 is only one compound and will not actually impact homocysteine. When you give whole food matrix, such as a Swiss chard, what we're giving is one complex whole food matrix and contain different nutrients and for example, as Swiss chard, it's rich in folate, choline, B6, B2, B3 and magnesium as well as vitamin K and so on. And vitamin C. So when you're looking at here, you're looking at one ingredient, and the same time you're getting support of a pathway more than support of one deficiency and the other, just a concept to keep in mind as we move forward to understand What is the advantages of magnesium from whole food matrix, it's not magnesium working by itself. We're feeding the whole system relevant to magnesium, so there are different advantages of whole food matrix and having nutrients coming from whole food matrix versus nature and coming and synthetic or one form supplementation. First, there's a bioavailability of nutrients, really change between matrix and between just a single molecule and proportion of various nutrients and vitamins in whole food matrix are different, as well as the form... There's so many debates. What form is better? Is it methylated B12, cyanocobalamin, looking for methylcobalamin? Is it folate? Is it folic acid? Is it formyl folic acid? Whatever it is, what are the forms [that are] good for us? Well, from the whole food matrix, the form is set for you, that's what our body evolved to have. Whole food matrix stands to support a system, a biochemical pathway, more than just one deficiency here and there, in many cases, solving deficiency in one nutrient does not translate [to] solving the whole symptoms or have any meaningful clinical output, having this... so now we know that in the whole food matrix, there's different forms sometimes of the same molecule like magnesium. So magnesium in a pill could be one or two or three forms: magnesium, citrate, magnesium oxide, magnesium glycinate. In the whole food matrix, it's a mix of different form of magnesium - why? Because magnesium - only 2% is a free ionic magnesium in nature, 98% should be bound to something because magnesium is very reactive. Have you seen pure ionic magnesium? It's just very combustible. Just explode in your face. So magnesium, very active molecule, so it has to be bound to something, so in nature, in plants, 98% of magnesium is bound to something. And what is this something in the plant? Almost so many things, right? So it bind to magnesium malate, magnesium citrate, bound to chlorophyll, bound to polyphenols, bound to inorganic and organic molecules, bound to peptide protein, and the list goes on and on. It binds to something right? So It's what we call, it's like multi form, there's magnesium bound to so many different molecules, so one form of molecule, like you see in supplement is magnesium citrate, that's one form. In plants, it's a multi form, it's really a mix, a soup of so many forms of magnesium. So since we have different forms of magnesium, the question here is, how can we choose which form is good for what person and when? Because we all know our GI system relevant to magnesium, it's not always the same every day. Some day it changes and other day you can absorb this form of magnesium, but next two weeks or one month, we have some GI issue, and this particular form cannot be a properly absorbed; we need another form. One example is stomach acid, when your stomach acid change for different reason, if you're taking medicine, you're taking a different meal, and so on - your stomach, acidity will change, which mean different magnesium... form that have poor solubility in water that require acidic environment for it to be soluble would not be properly dissolved and will not be properly absorbed. So all forms of magnesium are useful. There's no good or bad magnesium form. Selection of magnesium should be based on condition specific, and that's the key point - condition specific, some patients know what their condition, so many patients have no clue with their condition, they're not aware they have a condition, a magnesium form that's good for constipation may not be good for diarrhea and so on, and the magnesium complex is only half of the story, so when you say magnesium lactate, magnesium glycinate... We're not only taking magnesium, we're taking glycine with it, we're taking lactic acid with it. And this ligand So many times they are bioactive, right? So as you're taking your magnesium citrate, you're taking a lot of citric acid, you take a lot of lactic acid. Some patient cannot... cannot recommend them to take lactic acid. They have issue that forbid them to take lactic acid or to minimize lactic acid. Some patients have a problem with orotic acid for magnesium orotate and so on. So basically, magnesium form is a magnesium part as... As a ligand part. So let me spend two minutes, talk about some physiology so you can kind of understand more the magnesium story relevant to GI... To the gastrointestinal issue. So first, the magnesium form you're taking need to be soluable, you have to dissolve this magnesium form... That's the first step. Second step, the magnesium chelated forms have different absorption profile than free magnesium, if you're looking at the chart here, you see when you take your magnesium, proportion of magnesium is up, so magnesium ion is absorbed and jejunum, ileum in the colon 5%, 10%, 25%, 5%. When magnesium is bound to citrate molecule, glycine molecule, it's no longer absorbed based on these percentages, so magnesium glycinate is a magnesium bound to two glycine molecule, which means this magnesium glycinate is absorbed as a dipeptide, and the dipeptides' absorption have different profile in different area in the small intestine than free ionic magnesium so you shift the absorption away from the physiological absorption of free ionic magnesium and the same for different forms, they are really absorbed with the ligand mode of absorption. So which means that if you have any issue in the lower small intestine, if you have any inflammation or condition like Crone's disease or ileum resection, you have any surgery in the ileum or problem with the colon microbiota and so on... You see around 30% uo to 40% of magnesium absorption could be affected, and that's why you see a lot of patients with Crone's disease, they suffer from magnesium deficiency disease, they suffer from magnesium deficiency as well as other nutrient deficiency. So in these cases, why not selecting a form that could be more absorbed in the upper lower intestine and to avoid absorption the lower intestine, that's why magnesium glycinate become a good option for patients who have issue in the ileum and so on. And we have so many clinical studies showing that magnesium oxide, Magnesium citrate will fail to reverse deficiency after ileum resection, but magnesium glycinate actually can be properly absorbed in this patient, that kind of evidence and very nice data showing the different side of small intestine could be absorbed Is different form of mechanism are absorbed in different site of the GI issues, which means how many of you know the state of every section of the lower intestine, how this change between month and month and month, you sell at magnesium glycine thinking this is the best form for you... Maybe it is, but if you have any issue with the upper lower intestine and magnesium glycinate start to be less and less absorbed and so on. Other issue then we say, Okay, different form of magnesium have a different strength of the bond between magnesium and the ligand. The weaker the bond, the less stable is the molecule, so which means we have a more total dissociation of magnesium from the ligand. One example is Magnesium oxide have almost 100% dissociation, so you when you take Mg-oxide in case it's properly dissolved in your stomach - assuming we have no stomach issue - because magnesium oxide and water is insoluble, that's the problem with magnesium oxide, but magnesium oxide in the acidic environment is quite soluble. So if your stomach acidity is okay, you can actually dissolve and magnesium oxide should be okay with you, and then you can give you 100% dissociation of magnesium ion and magnesium ion would be absorbed based on the different percentage... Normal physiological absorption of magnesium. But magnesium oxide, at higher dose will actually... will not be properly absorbed fast enough and magnesium ion as this form to give you a large amount of magnesium ion, it will actually draw water into the colon and that will create diarrhea, GI issue and so on. So to prevent that, we say, Okay, let's give you a form that have a stronger bond, lets go for magnesium citrate, magnesium malate or glycinate, you can see they have a stronger bond between the ligand and the magnesium, having this, which means this form magnesium, glycinate will not liberate a lot of magnesium ion when you ingest it, most of magnesium ion will remain bound to glycinate and this will be absorbed as dipeptide, and we have... That's what the positioning of this kind of products, lower GI issue, in so many patients, patients love it because I can take large dose and have lower GI issue, so lower GI issue because the magnesium is not liberated, is still bound to glycinate and absorbed as bound chelated to a glycine molecule. Then what happened after that, your body need to break the bond to liberate free ionic magnesium, which is a functional magnesium, so your body is unable to break the bond, if your digestive system failed to break the bond, do you think the tissue might... Some might, but you can see from magnesium glycinate, almost large dose that has been absorbed is excreted into the urine, so you body did not really use magnesium. Okay, so it's gonna be a balance between GI issue and the stability of the molecule and less GI issue, but less benefit. Okay, that's bringing us back to the multi form magnesium, so instead of trying to select different form for all this issue about the stability, solubility, about the absorption, about the ligand, about the different optic side of the intestine, and by going for a whole food source of magnesium, we have a multi form, if you have any issue of, Oh, what I mentioned before, some form will sneak in with contain like a minute amount of so many form. So if you have any issue with any form other form comes in, if you have any issue with one form being too much for you, none of this form is too much for you because all of them are minute or coming in and kind of... circumvent a lot of issues that face by so many supplements, so many uni-form of magnesium. But this does not mean that we don't need magnesium coming from supplement, and so many times, some patients require high dose of magnesium despite some GI issue, the doctor does not care much at some GI issue and some distress, because the risk and benefit, you have to really look at this in such a way that any side effects actually is not too important when there's a large risk, we have to actually tackle this issue right now. So for some patients, we really have to go for synthetic one-form, and again, the whole food matrix sometimes contains so many other bioactives that some patient cannot have. So for example, some food like green leafy vegetable, they are rich in vitamin K1. So if you have any medicine for blood thinners and anticoagulants and so on, maybe you should avoid this leafy vegetable rich in vitamin K1 and so on. So in this case, then the patient need to take a more pure form despite it could have some disadvantage, but you have to weight the risk and the benefit, and sometimes you have to go for a really high dose of magnesium to quickly fix a hypomagnesia or severe magnesium deficiency and so on, but then you have to go from what I said, selection of which form, so first, the best approach to take your magnesium is whole food diet based magnesium, and now we know that this magnesium symptoms and clinical symptoms, we didn't have as much 50, 100 years ago, this become much more like... We see it more and more because we were really able to take our magnesium from the diet and there was no issues, and then when the food level of magnesium drop, what we try to do, so, okay, we have an issue, let's go find this form of magnesium and give it to the population, and when we do that, we still have the same issue. So first things, the best way for magnesium intake is from the diet, and if not, then you go for the synthetic one form or two form of magnesium, and when you go to this world selection of what form become important and magnesium lactate, magnesium glycinate have advantages and disadvantages in this world. Okay, so as I just said, best way to teach magnesium is from the diet. Okay, what are the proof? Well we give magnesium we see it in the blood, we see it in the tissue, it's there... I just mentioned that magnesium have kind of poor penetration to the brain, the blood brain barrier kind of resist against the flood of magnesium to the brain, and there is good reason for that because magnesium ion play a role in ion channels, and we don't want to have... Imbalance in ion channel in the brain, that's why blood brain barrier block the magnesium influx to the brain, but does allow some magnesium to get in, but in so many time, magnesium leach out of the brain faster than magnesium can get to the brain, especially if we don't have the proper form they can get to the brain, that's why people try to figure out what form can get to the brain fast enough to actually counteract the loss of magnesium from the brain, as I just show you with the rat study, 30 days of low magnesium will affect the brain, and actually even 15 days might have an impact on the brain, we've seen in human studies actually in in vivo imaging because very fascinating. Now, we can have - not now, 20 years ago, since 20 years ago, we can do in vivo neuro imaging and we can measure free ionic magnesium in the live subject and can see if your central nervous system is deficient in ionic magnesium, and we've done that with so many patient population including migraine, including Parkinson, Alzheimer. And so we can see in so many time we have deficiency in ionic magnesium in the brain, and we're looking for all the five different biomarker tests for magnesium was an RBC or serum magnesium's fine, but the brain has significant decrease in free ionic magnesium and we have all the symptoms of magnesium deficiency. Very fascinating work. So by having this... Okay, does it deliver free ionic magnesium to the brain in rats that have been put on low magnesium diet for 30 days. Can we reverse that? And we say, Okay, maybe we can reverse that, but can we actually reverse it better than some form available in the market? Just a proof of concept? So we put the rats on low magnesium, 10% decrease in magnesium in the diet, and after 30 days, we saw low magnesium ion in the cerebrospinal fluid, and then we start intervention, only for14 days. Along with another group of rat, we give the magnesium glycinate, magnesium citrate, magnesium threonate, and we compare the ability and of these forms to deliver magnesium to the brain in this model with low ionic magnesium that we induced in the rat brain. Here's the design, as I just mentioned. So we put them at low magnesium diet for all the different form of magnesium including plant based magnesium, and we have one group of rats, 15 rats, where we kept them at low diet as a comparison control group. No treatment, no low magnesium diet. Just as a control to see how the low magnesium diet compared to control and how the intervention compared to rats with low magnesium diet versus the control, normal diet. So 30 days, low magnesium diet. We have the first CSF collection at baseline, after 30 days, what happens, the data I just show you, we see 10% decrease in the CSF ionic magnesium. We give them seven days to recover and we start the treatment with a different form of magnesium and then the intervention went on for 14 days, two weeks, and on the 15 days there was no treatment, would just collect CSF sample and we analyze them for free ionic magnesium and the control... Just no treatment, just CSF collection for comparison. When we did that, what we find is the plant based magnesium, this is percentage increase of free ionic magnesium in the CSF, so you see in the control, this is the control, whether on low diet or whether normal diet, and you see that the baseline versus 15 days we have a decrease of 5% and the free ionic magnesium in the CSF and rats that has been put on normal diet or put at low magnesium diet - percentage difference, and one reason for that this had been published same finding in the paper on magnesium threonate they found the same things, and we know why is because by just taking a CSF sample from the animal, even at the baseline after two weeks, the brain is unable to replenish the magnesium you took. Right, so you can just tell you that would take more than two weeks if you have any incident that make magnesium leach out of the brain, and there's so many reason why magnesium could leave the brain, one of them is taking CSF sample, the brain is unable to actually replenish the small amount of CSF containing magnesium, and you can see still low on magnesium when you go for this magnesium citrate, magnesium glycinate, and this is magnesium threonate. Magnesium threonate improve 5%. And if you remove this 5% that we remove, so basically there's an around 10% increase in free ionic magnesium, so we replicate, what magnesium threonate paper show that actually, by giving magnesium threonate. Magnesium threonate is better than the other form to deliver free one magnesium. But look how the diet based magnesium delivery to the central nervous system is kind of as good as magnesium threonate, even better than that. So a kind of a very clear proof of concept that this multi form magnesium found in plant or diet based magnesium remain the best way to deliver magnesium to so many tissue, and it looks like it's a very interesting way to prove that we can deliver magnesium to the central nervous system, which is very hard to bring magnesium to the central nervous system, so the implication for that are large, and because of that, we're currently replicating this data and we're extending the study in such a way we can have... We started a new study, we're gonna get data by January, and this study goes one step more beyond just an application of what we found, we can... We went actually collecting the first set of data on the rats that we put them at low magnesium for 30 days, and then we have some behavior tests, cognitive test, test for mood, depression, anxiety and so on, to see if this 10% decrease in diet in magnesium level in diet does actually translate to emergence of some symptoms, and we're looking for magnesium ion in the CSF at baseline, and we can go for two weeks, collect data, go for another month, and then do another behavior task to see can we reverse this symptom that we induce in the rat and which form can reverse the symptom more and which form can deliver magnesium to the brain more so in this way, replication plus extension of the study. So as I mentioned before, one other problem with magnesium is very hard to assess if you have magnesium deficiency, and it's even harder to assess if you have central nervous system magnesium deficiency, very hard to find biomarker other than taking a CSF sample from your patient or send the patient to in vivo neuroimaging to see if you have low magnesium... Most of us can't do that. Right. And we know that if your patient is fine, you send them for neuro imaging and the patient came up normal in magnesium, but does not mean two weeks after he can remain normal magnesium, as you can see if the... Anything changed within 15 days to one month, your brain will go back to the magnesium deficiency - it's so quick. So basically, how can we approach that, how can you assess magnesium deficiency? So It's difficult to assess because most magnesium is inside cells or in bone and most tissue we take, they are not really cell or bone, you go for serum or RBC, serum is not cellular; RBC is, but RBC is just like looking for magnesium. RBC, how about magnesium in your kidney tissue, how about magnesium in your liver tissue and the bone tissue and your teeth and in your brain. It's not the same. There's no one method considered satisfactory to say that you have a magnesium deficiency, and here's the list of some of these tests that we can apply. Most physician, they use or RBC is cheap, quick, and we don't want the patient to pay a fortune to know if they have magnesium deficiency, unless if they really, really need, then we can go and spend more, but most of us say serum is fine RBC is fine, go home, you're okay. And then so many times when you see that serum is fine, RBC is fine, but we're measuring total magnesium, not free ionic magnesium, and so many in rat model, even in human, you see that under stress and under some environmental change, there's a shift between bound magnesium to ionic magnesium even with the same day, so sometimes this is really change between bound and not bound, and so there's a lot prolong stress and other issue you see there is less free ionic magnesium. And so many times we have other molecules that prevent function of magnesium, one of them is calcium, so if you have high calcium and less than... also if you have the normal magnesium, but you have higher than usual calcium, like most of our diet is really high and rich in calcium. So calcium will actually antagonize the effect of free ionic magnesium, so you have a functional deficiency of magnesium, even though you have enough magnesium, because calcium competes with magnesium for the ion channel and other reaction because both of them are similar molecules, cations. So the take home message. The whole food tend to support biochemical pathway and better clinical outcome... This was more important, we don't want just to treat deficiency, we try to treat the whole clinical symptom that the patient is presenting, right? And one ingredient or one nutrient deficiency is one factor that we need to fix, but it's not enough to fix the pathway, than actually is what giving you these symptoms. Right? It's easy to reverse deficiency in nutrients, it's harder to reverse functional deficiency. It's the reversal of the functional deficiency that has better chance to translate into a meaningful clinical benefits, it's very important this work, and meaningful clinical benefit, you see so many publication about clinical benefit, but we can see the change that's meaningful. Really, if you changed by this percentage or whatever, so what's really important in clinical practice is meaningful clinical benefit. And to achieve that, you start to see it's very hard to achieve that by just reversing one nutrient deficiency here, one nutrient deficiency there. One clear example was the homocysteine methylation pathway, it's very hard to fix methylation related symptoms without actually supporting the whole pathway with all the nutrients required.
