152 replies to this topic

[ajnast4r]

i've compiled the results & made some judgment calls where the discussions provided no real conclusions... please feel free to discuss and submit modifications as you see fit

http://spreadsheets....o...phWGc&hl=en

Edited by ajnast4r, 20 November 2009 - 06:44 PM.

[scottl]

i've compiled the results & made some judgment calls where the discussions provided no real conclusions... please feel free to discuss and submit modifications as you see fit

http://spreadsheets....o...phWGc&hl=en

My 3c (inflation):

Carotene: I take jarrow CarotenALL and would recommend a product that has lutein, lycopene and some astaxanthin (as does the jarrow product). Zeaxanthin also. A google search did not turn up the product ajnast4r is suggesting, so I cannot compare it.

B Vitamins: I defer to your choices.

Vitamin C; I would strongly advise you increase the dose e.g. 250 mg. WHy?
1. rapidly excreted
2. vit c is a six carbon sugar like glucose and only a few mammals including humans have lost the enzyme to convert glucose to vitamin c. Most mammals convert glucose
throughout the day (thus I recommend taking several doses throughout the day although not relevant to this product).
3. References near the bottom of this page http://lpi.oregonsta...minC/index.html
4. Fears of increasing oxidation in vivo are incorrect: from wikipedia:

Recent studies show that intravenous injection of 7.5g of ascorbate daily for six days did not increase pro-oxidant markers;[72] thus, ascorbate as a pro-oxidant is unlikely to convert metals to create ROS in vivo.


Vitamin D: agree.
Vitamin E:
Tocopherols: agree
Tocotrienols: OMIT. Tocotrienols do not meet the definition of vitamins i.e. the body can live without them. How much data is there really that these are beneficial in ALL
people?


MInerals:
1. Magnesium glycinate. Excellent form, but I wonder if this is going to drive the price of the multi up too much. I'm also curious as to why you've included any magnesium and no calcium. I could see including some of both, or none of either.
2. silicon: not sure if this is necessary.
3. manganese: interesting omission. ajnast4r and I have discussed this ages ago and including none may be a good choice (e.g. last I checked LEF was decreasing the amount in their multis).

Choline: I know this is listed in most B vitamin products, but does adding this really add anything? I have no idea.

Edited by scottl, 22 November 2009 - 03:45 PM.

[scottl]

Oh and do you plan on putting the carotenes, vit D and E is one capsule and the water soluble things in another... e.g. cap? The dry form of Vit D is not as good and the carotenes are I think best in a gelcap with oil as well.

And others said similar things as I in the tocotrienol thread.

Edited by scottl, 22 November 2009 - 05:28 PM.

[ajnast4r]

Carotene: I take jarrow CarotenALL and would recommend a product that has lutein, lycopene and some astaxanthin (as does the jarrow product). Zeaxanthin also. A google search did not turn up the product ajnast4r is suggesting, so I cannot compare it.

i believe the profiles are actually similar.. ide like to aim to mimic carotenALL's profile.

Vitamin C; I would strongly advise you increase the dose e.g. 250 mg. WHy?

i read up on C... i actually wouldnt mind seeing a 400mg dose.

Tocotrienols: OMIT. Tocotrienols do not meet the definition of vitamins i.e. the body can live without them. How much data is there really that these are beneficial in ALL

disagree... technically only alpha tocopherol has vitamin activity but balance is still preferable

[zoolander]

I posted a long reply but lost it......

in short

Lycopene = significant cost driver

Vitamin C = also significant cost driver
Vitamin C = know to leak into softgels so if we use a softgel this needs to be considered and an overage applied. Softgels should be dark

[scottl]

1. "i read up on C... i actually wouldnt mind seeing a 400mg dose."

Yes that would be a good idea. I was..hesitant to suggest it since there tends to be something of phobia of greater than RDA doses around here.

2. "disagree [on ditching tocotrienols] ... technically only alpha tocopherol has vitamin activity but balance is still preferable"

Balance =adding other TOCOPHEROLS in appropriate amounts which I strongly support. On what basis do you conclude adding tocotrienols is necessary for balance?

People would be far better off adding e.g. some omega 3 fatty acids (you can fight out the EPA/DHA business), small amounts e.g. 30 mg Co Q10 (which Michael has reversed his opinion on and has added to his regimen), or lipoic acid to the mix than they would be adding tocotrienols. I've been trying to avoid mentioning this, but I have some anecdotal evidence that tocotrienols...are not a great idea for some people. While one cannot advocate recommending something on the basis of positive anecdotal evidence, I feel comfortable based onthe quality of this negative anecdotal evidence saying that I don't think it is a good addition in a product meant for the general public. And again, compared to everything else in the mix, how much evidence is there really to support tocotrienols having added benefit to appropriately mixed tocopherols?

I see why ajnast4r thinks tocotrienols are necessary for balance but I am skeptical that the data is there, and there still remains my concerns (which I realize are little help to the board) above.

Edited by Michael, 07 December 2009 - 12:42 AM.
Trim quotes

[Mind]

Monday is November 30th, the hoped-for conclusion of this discussion, but I would like to have each expert weigh in before moving forward. Only about half the team has commented thus far. (Thank you for your analysis)

We will likely have to extend the discussion a week or more.

[niner]

A couple questions: Has anyone done an estimate of materials cost on the current formulation? I'd really like to see it come in at well under a dollar a day retail. Do we have an idea of the volume of our non-fat soluble compounds? It looks like a bit over a gram, and might fit in a single cap. Two caps gives people the ability to split doses if they are so inclined, and allows smaller caps which may matter to some people. It raises the cost some as well. We are still planning on formulating the A, D, E, K2, and lutein esters in a gelcap, right? Finally, do we know if 16mg of nicotinic acid is going to cause flushing? I've never experienced the niacin flush, but it sounds like people generally don't like it. If flushing is going to be a problem, why not inositol hexanicotinate?

[ajnast4r]

Monday is November 30th, the hoped-for conclusion of this discussion, but I would like to have each expert weigh in before moving forward. Only about half the team has commented thus far. (Thank you for your analysis)

We will likely have to extend the discussion a week or more.

i wont be able to participate significantly before tuesday, i have a research paper due... another week would be good

[scottl]

A couple questions: Has anyone done an estimate of materials cost on the current formulation? I'd really like to see it come in at well under a dollar a day retail. Do we have an idea of the volume of our non-fat soluble compounds? It looks like a bit over a gram, and might fit in a single cap. Two caps gives people the ability to split doses if they are so inclined, and allows smaller caps which may matter to some people. It raises the cost some as well. We are still planning on formulating the A, D, E, K2, and lutein esters in a gelcap, right? Finally, do we know if 16mg of nicotinic acid is going to cause flushing? I've never experienced the niacin flush, but it sounds like people generally don't like it. If flushing is going to be a problem, why not inositol hexanicotinate?

--Dose to cause flushing varies person to person (which should be a clue).

-- inositol hexanicotinate does not have the benefits of nicotinic acid (abstract posted online...perhaps sci.lifeextension ages ago).

[scottl]

inositol hexanicotinate :

Arch Sci Med (Torino). 1977 Oct-Dec;134(4):359-94.
[Comparative studies of the response of normolipemic and dyslipemic aged subjects to 2 forms of delayed-action nicotinic acid polyesters. Pentaerythrotol tetranicotinate and inositol hexanicotinate. Results of a controlled cross-over trial]

[Article in Italian]

Ziliotto GR, Lamberti G, Wagner A, Cima L, Genco G.

A cross-over trial was run to compare the effects of two delayed-action nicotinic acid polyesters (pentaerythritol-tetranticotinate, PETN, and inositol-hexanicotinate, MIEN) in 59 aged normo- and dyslipaemic subjects. PETN tended to normalise the lipid picture in much the same way as nicotin acid, without a drastic effect on circulating lipids and lipoproteins. MIEN, on the other hand, had only a slight effect on total blood lipids, and appeared to be ineffective or negative with respect to the other lipid parameters. PETN proved capable of releasing active concentrations of nicotinic acid in vivo for a period of time that was sufficient to correct hyperlipaemia in age subjects. The side-effects were slight, infrequent and quickly reversible.

PMID: 345998

[niner]

16 mg of nicotinic acid isn't enough for an anti-dyslipidemic effect is it? So the only issue would seem to be flushing, and perhaps cost or stability.

[kismet]

i wont be able to participate significantly before tuesday, i have a research paper due... another week would be good

I second that.

[edward]

I am jumping in here late, I apologize but I have been finishing up my last semester of school.

I would really love to see Methylfolate, though high doses (7.5 mg) are prescription (Deplin) it appears that there is no problem selling 1mg doses http://www.iherb.com...e...ium=f2&at=0
Folate (as 5-Methyltetrahydrofolic acid (5-MTHF), and calculated based upon the biologically Active 6S isomer)

This would compliment the methylcobalmin (the dosage I think is too small though) personally I would like to see at least 250-500 mcg methylcobalmin and 250-500 mcg methylfolate.

We also need some CoQ10, pantothenic acid, some more trace minerals and possibly a few goodies such as a small therapeutic dose of an herb or polyphenol or a good balanced red wine extract such a MR mentioned in his latest supplement update.

[maxwatt]

We also need some CoQ10, pantothenic acid, some more trace minerals and possibly a few goodies such as a small therapeutic dose of an herb or polyphenol or a good balanced red wine extract such a MR mentioned in his latest supplement update.

CoQ10, and polyphenols are not proven to be necessary, though they may be beneficial, they may, particularly CoQ10, have a down side. Would drive cost up. If research shows harm from an ingredient, one would have to dump entire inventory so the fewer things that may or may not have a benefit, the better. I see the muti as a good base, other things may be supplemented by those who wish.

Tocotrienols: is there really any research other than that sponsored by the manufacturers that shows a benefit? Not that they are harmful, they occur in the matrix one finds in food.

Overall, the spreadsheet looks like what I've been seeking and unable to find in a basic multi-supplement.

Edited by Michael, 07 December 2009 - 12:44 AM.
Trim quotes

[niner]

16 mg of nicotinic acid isn't enough for an anti-dyslipidemic effect is it? So the only issue would seem to be flushing, and perhaps cost or stability.

Flushing is off the table at 16mg. It's the basis for the UL, which I believe is 25mg. Jarrow B-right has 25mg niacin, and I've taken that a number of times without flushing.

I am extremely happy with the way the multi is shaping up. In its present form I would recommend it to all my family and friends. My biggest concern at this point is keeping the cost in the affordable range. A buck a day is way too much. That will push a lot of people away from it.

[ajnast4r]

http://spreadsheets....o...BnT3c&hl=en

unedited

[niner]

http://spreadsheets....o...BnT3c&hl=en

unedited

This one has access problems, at least for me. The other one can be cleaned up easily using the 'revert to previous version' feature. Takes about 8 or ten clicks on 'previous' to get back to a clean one.

[kismet]

I'll abstain from discussion, no time to look much into anything. Hope to contribute to other iteratios of the multivitamin if there should be any.

[Michael]

All:

I'm working now on a detailed reply. Sorry to come in late: Ajnast4r did ask me to participate early on, and Mind graciously invited me to come in as a late-stage expert reviewer, and I just lost track of the timing that was originally requested (by Nov 30). Thanks to Niner for the prod. Maybe I'll make up in length and disruptiveness what I've lost in timeliness. .

[Michael]

All:

First, I take it we agree we can safely ignore the comments on the spreadsheet ...?

Natural mixed carotenoids: of all available sources, I would rank CaroCare at the bottom, as containing little cis-beta-carotene and very little non-b-c carotenoids. I'd instead turn your attention to Alphabeads and/or Betatene. I wasted an ABSURD am't of time balancing out both of these, plus small am'ts of other carotenoids, to get the balance that seemed most reflective of the epidemiology in formulating OrthoCore; if the final supplement gets farmed out to them, you could ask them to replicate this, but honestly I don't think we have to micromanage it this much, I'd lean toward Alphabeads as having a more diverse profile plus a mixture of lutein + zeazanthin (from eg Xangold) and separate lycopene.

Lycopene: not on spreadsheet, but arguably the single most robustly-supported non-essential nutrient to protect against cancer and other diseases. One of very, very few nutrients well-justified enough to still get an indirect nod from AICR and WCRF:

Foods containing folate probably protect against pancreatic cancer, and there is limited evidence suggesting that these foods also protect against oesophageal and colorectal cancers. Foods containing carotenoids probably protect against cancers of the mouth, pharynx, and larynx, and also lung cancer. Foods containing the carotenoid betacarotene probably protect against oesophageal cancer; and foods containing lycopene probably protect against prostate cancer. Foods containing vitamin C probably protect against oesophageal cancer. There is limited evidence suggesting that foods containing quercetin protect against lung cancer.

Really oughta be there, in am'ts similar to OrthoCore (18 mg per daily dose). Yes, it's expensive.

Vitamin C: folks, PLEASE don't get distracted by metabolic and biochemical hypothesis-spinning!! The best actual outcome data we have suggests something in the ballpark of the current Institute of Medicine DRI RDA (90 mg); this Linus Pauling Institute Review, arguing for 120 mg, is about as far as it can be pushed on plausible grounds, except for smokers or people with specific conditions (for whose exceptional needs a general-purpose multi should not be tailored!).

B2/Riboflavin-5′-phosphate: I looked at the thread on this, and am totally unclear why it's even being considered (as vs. basic B2). I can think of no good reason to include it.

P5P: ditto. Yes, it's good against glycation-related damage -- but at MUCH higher doses, and such pharmacological and speculative stuff shouldn't be on the table for a basic multi.

Folate: Why are folinic and methylfolate on the table, and methyltetrahydrofolate noteven under discussion? The latter is the predominant food form of folic acid, and thus the basis for the original epidemiology etc etc. I would really advocate the latter. Also, why 100 mcg? I'd suggest 200 mcg "molar" bioequivalence (haven't done the math, & haven't determined how).

Methyl- and hydroxocobalamin: Again, why?? Nice 'special' uses for both at high dose. For a normal, healthy person, it's not a basic core essential, and if I were bothering (as I am ) with methyl- for neuroprotection (which is not an appropriate consideration for a multi!!) I would go with at least 1 mg. I would suggest, hesitantly (because of the population involved, but in light of (knocks on wood) the apparent safety of megadose B12) a dose of of 647 µg of cyanocobalamin, which is sufficient to achieve rapid 80% maximal reduction in the plasma methylmalonic acid concentration, even in frankly-deficient, elderly, B12-malabsorbing people; the DRI RDA is only 2.4 µg, but this study finds that in such folks, 30 d at even 80 µg doesn't normalize elevated homocysteine.

Vitamin K: should be at least the Adequate Intake (120 µg), and 500 µg seems epidemiologically-justified. I'd somewaht prefer the more expensive MK-4 over MK-7.

Glycinate minerals: expensive, no evidence they're any better, Mg glycinate actually lower bioavailability. For most nutrients, bioavailability is a bit of a bugaboo anyway, but that's another subject. Organic salts are fine.

Zn: 11 mg (current DRI RDA) is plenty.

Missing lithium: good evidence that this is an essential nutrient, with an RDA of ~1 mg, as discussed here:

No, this is not the pharmacological dose shown to be neuroprotective in rodents subjected to horrible pharmacological or genetic assault, nor in human disease victims, neither of which are reasonable justification for use (let alone for dosages) in normal, healthy humans. See instead ([(1) below]), which presents animal studies and a surprisingly large am't of (unfortunately, but of necessity, 'ecological' rather than truly prospective) epidemiology suggesting that Li is an essential nutrient, with an 'RDA' of ~ 1 mg, whose presence in the water is linked to having a much happier (less violent, criminal, suicidal, and generally "crazy") population; see also ([(2) below]), quite recently, in Japan. The source I used to use (guess who ?) has unfortunately quit the market, and most of the alternatives are fly-by-night operations; I would probably recommend VRP. Whatever the merits of the orotate salt specifically (and I'm skeptical, esp at this dose), there's a good chance that even these guys don't have real Li orotate: most of the material out there is just the chloride or carbonate in a blend with orotic acid in the suitable proportions; unfortunately, there's no positive test for the compound per se, and so you have to do a series of negative tests to exclude chloride and carbonate, and almost no one does this. In my former career I went looking for the real deal, and couldn't find it ANY materials suppliers that had it, despite their claims, and it had to be contract manufactured by a company that specializes in true chelates (and then, they dropped it).

No on CoQ, on the fence on wine polyphenols. Gut says to include tocotrienols and high-dietary (1 mg) Sr, but I can't back that up with rigorous evidence.


-Michael

References
1. Schrauzer GN. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr. 2002 Feb ;21 (1):14-21. PMID 11838882

2. Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N. Lithium levels in drinking water and risk of suicide. Br J Psychiatry. 2009 May ;194 (5):464-5; discussion 446. PMID 19407280

[Michael]

http://spreadsheets....o...BnT3c&hl=en

unedited

This one has access problems, at least for me.

I only just saw this post; I, too, can't access it. Is it different from the originally-posted one, outside of S****m's comments?

-Michael

[ajnast4r]

the spreadsheet should work now

...

i dont have time right now to formulate out a detailed response as its finals week for me. i will get more in depth later on if need be

i agree about C, lycopene & lithium.

b2 was to mimic food composition


folate, i also have no idea about how to do that conversion... 200mcg supplemental + food folate, which is high in the average LE'er seems high to me.

b12 mimic food composition, each has unique benefits.

k2... as far as i know mk4 has no research in small amounts and mk7 does

glycinates, there is evidence some are better, zinc for example. strongly disagree about organic salts... they are prone to complexing w/ fiber, phytates... destroyed by tannins & other polyphenols... antagonize one another because of ionization/transport sites & digestion. properly chelated minerals avoid most of these problems, most importantly being absorbed through different mechanisms, ie: AA transport vs mineral specific transport. i have no evidence on hand but i can provide it later if needed.

zinc, agree. what are your thoughts on excluding copper?

Edited by ajnast4r, 08 December 2009 - 12:58 AM.

[scottl]

If you are going to include several hundred mg of magnesium oxide ("Organic salts are fine") you are going to give some people diarrhea. I don't know if that is 1 in 20 people, 1 in 10, or more frequent. I believe magnesium glycinate (to pick one alternative form) does not have this problem.

Edited by scottl, 08 December 2009 - 05:50 PM.

[Michael]

All:

First, I'd somehow neglected how relatively high the vitamin E is. New DRI RDA is just 15 mg alpha-tocopherol, and we have real mixed to tocopherols. I certainly won't bitterly oppose so reasonable a dose, but is there a reason we're not just using the DRI RDA plus the fellow-travellers?

b2 was to mimic food composition

Don't bother . The Institute of Medicine report on Riboflavin sez,

Most dietary riboflavin is consumed as a complex of food protein with FMN and FAD (Merrill et al., 1981; Nichoalds, 1981). In the stomach, gastric acidification releases most of the coenzyme forms of riboflavin (FAD and FMN) from the protein. The noncovalently bound coenzymes are then hydrolyzed to riboflavin by nonspecific pyrophosphatases and phosphatases in the upper gut (McCormick, 1994; Merrill et al., 1981). [Flip, flip, flip ....:] There is considerable diversity of flavins in foods, but over 90 percent of riboflavin is estimated to be in readily digested flavocoenzymes (mainly flavin-adenine dinucleotide [FAD] and to a lesser degree flavin mononucleotide [FMN]), with lesser amounts of the free vitamin and traces of glycosides and esters that are also hydrolyzed during absorption from the gut (McCormick, 1994; Merrill et al., 1981).

P5P is similarly hydrolyzed (to PL), & tho' as discussed here, there is evidence for a minor residual absorption of the intact coenzyme, I can't imagine this has a meaningful impact at such low doses.

b12 mimic food composition, each has unique benefits.

Ditto -- certainly for methylcobalamin, and it's not actually clear to me (from teh IOM report or from Modern Nutrition in Health and Disease) that there is significant hydroxocobalamin in the diet (it's an intermediate form after absorption in the gut, converted to methyl- and adenosylcobalamin for coenzymatic use).

I realize that folks are prob rightly hesitant about using any but the form actually present in the diet, after the fiascos of synthtetic vitamin E, folate, and beta-carotene, but the case isn't the same here: it's the same core nutrient, with (overwhelmingly discarded) "decorations," not an actual difference in chemical form, nor (any but the smallest) difference in absorption and metabolism.

folate, i also have no idea about how to do that conversion... 200mcg supplemental + food folate, which is high in the average LE'er seems high to me.

Absolutely true, if someone is taking a full daily dose -- but they shouldn't be.

As to how to do the conversion: digging around a bit, food folates are mainly reduced methyl- and formyl- polyglutamates, and if "In human subjects, dietary folate polyglutamates are deconjugated at the mucosal epithelial cell brush border by folylpoly- glutamate carboxypeptidase (EC 3.4.17.21) to the corresponding monoglutamate forms" (1), which stripping would thus be unnecessary for folinic acid (formyltetrahydrofolate); oral bioavailability of leuvocorin seems to be damned near 100% at low doses (2), is readily converted to tetrahydrofolate, is almost completely metabolized rather than 'making expensive urine' at low doses and is said to have equivalent vitamin activity to folic acid. The dietary folate equivalents (on the now-discarded understanding of folic acid metabolism) give a rule of thumb of 0.6 of an unit of folic acid. So ISTM that we should treat it like folic acid in terms of proper physiological equivalents, on a molar basis; the molecular weights of folate and folinate are (respectively) 441.41 and 473.45, so we might say 214.5 µg is equivalent to 200 of folic acid (or half of that for 100 µg), based on that same original DFE equivalent.

That is extremely back-of-my-pants, and I have made no deep study of the matter. Does anyone have a better idea? Niner? Is Krillin 'out there,' and should we request his comment?

k2... as far as i know mk4 has no research in small amounts and mk7 does

I'm inclined to buy that, but MK7 is really only present in fermented foods (ie, to engage in a bit of superstition, not 'paleo,') whereas MK4 is both present in animal foods and is generated in vivo and selectively retained. But I don't think it's worth really quibbling about this, certainly at these doses.

glycinates, there is evidence some are better, zinc for example. strongly disagree about organic salts... they are prone to complexing w/ fiber, phytates... destroyed by tannins & other polyphenols... antagonize one another because of ionization/transport sites & digestion.

... Just like the stuff in food . In fact, there is no bioavailability advantage to Zn amino acid chelates, even the best-studied (monomethionate), except at low doses in high-phytate meals typical of Western or low-grain diets, & even there the difference is pretty marginal (eg., 4 h AUCs of "262 +/- 30 microgram/dl for zinc methionine, 225 +/- 9 microgram/dL for zinc polyascorbate, 210 +/- 33 microgram/dL for zinc sulfate." (3)). In fact,

There are, however, conflicting reports on the bioavailability of various zinc compounds. Bioavailability of zinc from inorganic and organic sources for pigs fed corn-soybean meal diets were assessed by Wedekind et al. [ref]. Bone and plasma zinc concentration increased linearly (p < 0.01) in response to supplemental zinc. The estimate of zinc bioavailability differed depending on the methods that were used in the calculation. Overall trends indicated the following rankings: ZnSO4.H2O>Zn-Met>ZnO>Znlys (Zinc lysine) [ref]. Same results were observed by Schell and Kornegay [ref] in a study conducted on weanling pigs. Zinc concentration in tissues fed pharmacological levels of zinc from ZnO, Zn-Met, Zn-lysine and ZnSO4. When high levels of supplemental zinc were fed, supplemental zinc sources were found to be less important in terms of zinc bioavailability [ref]. A twelve week study on zinc methionine and two inorganic zinc sources was reported by Rojas et al. [ref], 320 mg of supplemental zinc from Zn-Met, ZnSO4 and ZnO was fed daily to 32 cattle for four weeks, withdrawn for four weeks, and then resumed for another four weeks. There were no treatment differences (p > 0.05) in zinc concentrations. Equivalent uptake of organic and inorganic zinc by monkey kidney fibroblasts, human intestinal epithelial cells, or perfused mouse intestine was shown by Beutler et al. [ref]. (4)

The larger advantages seen in horse and lamb studies are likely due to the fact that they rely heavily on fermentation for digestion, and have teh Zn liberated by microflora.

Yes, I've seen (5), tho' the comparator is gluconate; IAC, you can always just take more zinc .

properly chelated minerals avoid most of these problems, most importantly being absorbed through different mechanisms, ie: AA transport vs mineral specific transport.

Mg glycinate, at least, is probably so relatively poorly absorbed precisely because it's so tightly bound that it can't be liberated from its chelate -- a bit too clawlike.

zinc, agree. what are your thoughts on excluding copper?

Madness! The average omnivore gets if anything too high a Zn:Cu ratio already. The inclusion of Zn and/or Cu is going to reinforce or exacerbate someone's imbalance no matter which way you go, but the great majority of folks need that Cu (and actually, we should if anything give a full mg or more).

If you are going to include several hundred mg of magnesium oxide ("Organic salts are fine") you are going to give some people diarrhea. I don't know if that is 1 in 20 people, 1 in 10, or more frequent. I believe magnesium glycinate (to pick one alternative form) does not have this problem.

MgO is an inorganic salt . IAC, the formula is not for " several hundred mg of magnesium" in any form, but 200 mg -- and that will, if people are sensible, be spread out thru' 2+ meals.

-Michael

1: Wright AJ, Dainty JR, Finglas PM. Folic acid metabolism in human subjects
revisited: potential implications for proposed mandatory folic acid fortification
in the UK. Br J Nutr. 2007 Oct;98(4):667-75. Epub 2007 Jul 9. Review. PubMed
PMID: 17617936.

2. Greiner PO, Zittoun J, Marquet J, Cheron JM. Pharmacokinetics of (-)-folinic acid after oral and intravenous administration of the racemate. Br J Clin
Pharmacol. 1989 Sep;28(3):289-95. PubMed PMID: 2789922; PubMed Central PMCID:
PMC1379947.

3. Rosado JL, Muñoz EC, López P, Allen LH. Absorption of zinc sulfate, methionine, and polyascorbate in the presence and absence of a plant-based rural Mexican diet. Nutr Res. 1993 Oct;13(10):1141–51.

4. Chien XX, Zafra-Stone S, Bagchi M, Bagchi D. Bioavailability, antioxidant and
immune-enhancing properties of zinc methionine. Biofactors. 2006;27(1-4):231-44.
Review. PubMed PMID: 17012778.

5. Gandia P, Bour D, Maurette JM, Donazzolo Y, Duchène P, Béjot M, Houin G. A
bioavailability study comparing two oral formulations containing zinc (Zn
bis-glycinate vs. Zn gluconate) after a single administration to twelve healthy
female volunteers. Int J Vitam Nutr Res. 2007 Jul;77(4):243-8. PubMed PMID:
18271278.

[kismet]

As to the vitamin K issue, I'd still strongly oppose MK-4-only. While admittedly I haven't managed reading your older posts on the topic, I think your concerns are overthrown by recent epidemiology.
Long chain menaquinones are a must, 3 out of 4 observational studies found 'em to be superior to MK-4* and only one suggested similar efficacy, w/ MK-4 coming out on top. (I am not sure w/o looking it up, but) Natto and high intakes of phylloquinone may be casually linked to improved BMD/quality, I don't think such data exists for dietary-level MK-4. There are hardly any human or animal studies using low amounts (dietary) of MK-4, so it's not superior in that regard, either. If anything, the epidemiology indeed supports a broad range of menaquinones (-4 and -7 & others).

While a priori the paleo angle makes sense we must additionally consider:
Long chain MK-ns are also found in human tissue, most likely we already have the ability to produce MK-4 (on an as need basis?) from menadione and thus any vitamin K. Furthermore, to engage in some speculation, there are several ways that our ancestors could have gotten their long chain MK-ns, coprophagy?, consumption of slightly putrid meat?, consumption of intestine, liver, bone marrow, etc.

*using some nifty statistical tests that I am not familar with.

This is in perfect agreement with, by itself not conclusive, mechanistic data (e.g. pharmakokinetics): Long chain menaquinones generally reach higher blood levels and are better activators of gamma-carboxylase (in vitro biochemical assay). Obviously, one can speculate to the contrary that they reach higher blood levels because they're not effectively used by tissues, but this ain't supported by the data we have.

I do think that 500mcg K1 would be a good idea, but I'd not consider it very well supported by actual epidemiology or even teh paleo angle (did they really eat that many greens?) Aren't highest quartile intakes generally in the 200mcg range e.g. in the Rotterdam study? Maybe there's direct or indirect evidence from vegetarian folks linking very high K1 intakes to better outcomes (e.g. "greens" being esp. beneficial in observational studies), but I don't know any high quality evidence as to a direct link.
The clinical data is much stronger (&1000 is likely better than 500mcg), but to me that's more "pharmacologic" supplementation so I originally did not suggest inclusion.

Absolutely true, if someone is taking a full daily dose -- but they shouldn't be.

This may be a source of confusion. So let's make sure: Michael recommends not taking a full multi (and designing this multi w/ that in mind). AFAIK Ajna intended the "full" dose of this multi to be optimal (or as good as possible). For instance the vitamin D amount was chosen with that in mind (and IMHO represents the most conservative sweetspot there is). But if we eventually recommend people to take a lower dose, I believe we should increase the vitamin D somewhat so that people will get ~1.1 - 1.2k IU when supplementing the multi at the most sensible or recommended dose.
I didn't see why anyone would need the DRI of most nutrients, especially zinc as mentioned in a recent thread (esp. omnivores who are not aware of their Zn/Cu intakes). So I guess you agree. On the flipside, this means that we should cut the amounts of several nutrients if we intend people to take the "full" dose.

So do we optimise the "full" dose or recommend people to adjust their intakes? (which many will fail to do...)

Edited by kismet, 10 December 2009 - 03:21 PM.

[Mind]

There was some discussion of splitting the full dose into 2 or 3 caps, so that people can adjust their intake. Imminst members who monitor their diet religiously, might only take 1/3 dose. Regular folks who buy it because all the "health-nuts" are taking it (and whose diets are probably lacking), could consume the full dose and get the benefits of a well-rounded best-current-science multi (no over-kill).

[Michael]

All:

Sorry for the long delay ... digging, and other responsibilities ...

On Mg form: just saw this study, which (using the most comprehensive and reliable methodology to establish actual systemic bioavailability (in rats, not humans, but as they say there's little reason to expect much interspecies difference), which compared Mg from

oxide, chloride, sulphate, carbonate, acetate, pidolate, citrate, gluconate, lactate or aspartate. After 10 days of Mg-repleted diet ... Mg absorption values obtained varied from 50% to 67%. Organic Mg salts were slightly more available than inorganic Mg salts. Mg gluconate exhibited the highest Mg bioavailability of the ten Mg salts studied

That surprised me. FWIW, they didn't specifically test citrate or glycinate, but (again) Mg glycinate actually hasn't fared all that well, and heretofore the aspartate (the closest second in this study) has seemed best. Alas, gluconate is only 5.4% elemental Mg! This study, in humans,

was a randomised, double-blind, placebo-controlled, parallel intervention, of 60 days duration. ["Subjects were only recruited if their dietary Mg intake was equal to the Reference Nutrient Intake (RNI) ± 20% ... 270 mg for women and 300 mg for men. "] Urine, blood and saliva samples were taken at baseline, 24 h after the first Mg supplement was taken ('acute' supplementation) and after 60 days of daily Mg consumption ('chronic' supplementation). Results showed that supplementation of the organic forms of Mg (citrate and amino-acid chelate [specific amino acid unspecified]) showed greater absorption (P = 0.033) at 60 days than MgO, as assessed by the 24-h urinary Mg excretion. Mg citrate led to the greatest mean serum Mg concentration compared with other treatments following both acute (P = 0.026) and chronic (P = 0.006) supplementation. Furthermore, although mean erythrocyte Mg concentration showed no differences among groups, chronic Mg citrate supplementation resulted in the greatest (P = 0.027) mean salivary Mg concentration compared with all other treatments. Mg oxide supplementation resulted in no differences compared to placebo [!]. We conclude that a daily supplementation with Mg citrate shows superior bioavailability after 60 days of treatment when compared with other treatments studied.

As I said, bioavailability is a bit of a bugaboo here, but citrate also has that much-more-reasonable 16% elemental Mg content.

I'd still strongly oppose MK-4-only. ... I think your concerns are overthrown by recent epidemiology. Long chain menaquinones are a must, 3 out of 4 observational studies found 'em to be superior to MK-4* and only one suggested similar efficacy, w/ MK-4 coming out on top. ... Natto and high intakes of phylloquinone may be casually linked to improved BMD/quality, I don't think such data exists for dietary-level MK-4. There are hardly any human or animal studies using low amounts (dietary) of MK-4 ... If anything, the epidemiology indeed supports a broad range of menaquinones (-4 and -7 & others).

Clickety-click ... PubMed ... clickety-click ... Google Scholar ... ... Yup, that does seem to be the best way to read the evidence on CVD, particularly since EPIC is a much bigger and more widely-representative study than the Rotterdam Study, tho' it looks to me like the apparent nonassociation in some cases is just ad silentio, and there is teh caveat that most MK-4 comes from cheeses, which confounds MK-4 intake with saturated fat and AGE, whereas MK-7 is a marker of relatively healthy diets. For osteo, the pattern is the same, or stronger, tho' much of it is cross-sectional rather than prospective; also, the data are almost all Japanese, who in some regions get a lot of MK-7 thru' natto, and little to no 4, so it could just be not meeting a (quite low) threshold dose. Even if that's all correct, however, then (as you say) "If anything, the epidemiology indeed supports a broad range of menaquinones (-4 and -7 & others)" rather than any actual advantage to using 4.

So, you go with what you've got, and clearly 7 is better-supported here at dietary intakes, caveats aside. Plus, it's happily much cheaper. And whoever picked 45 µg was doing hir homework, too. Good job, Kismet and Mystery (Wo)Man!

I do think that 500mcg K1 would be a good idea, but I'd not consider it very well supported by actual epidemiology or even teh paleo angle (did they really eat that many greens?)

Actually, yes, they did, but leaving that aside: I might suggest instead a small, DRI-level K1 (120 µg), which as you allulde is well below population intakes in both of the above studies and so should be both harmless and plenty for basic functions granted the DRI evidence base plus the inclusion of a high (population-level dietary) dose of MK-7.

Absolutely true, if someone is taking a full daily dose -- but they shouldn't be.

This may be a source of confusion. So let's make sure: Michael recommends not taking a full multi (and designing this multi w/ that in mind). AFAIK Ajna intended the "full" dose of this multi to be optimal (or as good as possible).

Well, you certainly can't have people taking 100% of their total daily nutritional requirements for most nutrients from a multi on top of what's in their diets, as would be the case with this multi if so, for the usual reasons. 100% of this multi would be a good idea for someone eating a diet composed entirely of protein powder, refined canola oil, and cornstarch -- but no one else.

For instance the vitamin D amount was chosen with that in mind (and IMHO represents the most conservative sweetspot there is).

Even there, some will not be getting enough -- but yes, it's a problem, and it's inescapable. As I've said many times, the whole multivitamin concept is fundamentally a very blunt instrument, and people shouldn't use them. If they "must," they still oughta use a part dose and then add on where still lacking, and vitamin D is the clearest case where that's just inescapable.

An even trickier case is iron: most males, especially omnivores, and postmenopausal women, get all the iron they need, and often too much, and certainly shouldn't be taking a supplement -- but many or even most women ≤ 55 and plenty of vegetarians could use (say) 50% DRI. Whatcha gonna do? (Happily, D and Fe are also amongst the few nutrients where there's a reliable functional marker to assess one's status).

On the flipside, this means that we should cut the amounts of several nutrients if we intend people to take the "full" dose.

I don't think that strategy quite makes sense, as no one will understand the label. The point of the multi should be to represent the perfect diet in a pill -- the old "Astronaut food" idea. You can't understand the targets and logic without seeing the pattern you're aiming for (which is revealed at the somewhat-misnamed "full daily dose").

So do we optimise the "full" dose or recommend people to adjust their intakes? (which many will fail to do...)

We can certainly can't force people not to take a full dose, but we can do our best to educate them, which should get at least a few people acting intelligently (if nothing else, by rubbing their neurons together for a moment). If we design the product (or the label) so that the formula looks, prima facie, somehow "incomplete" or "low-dose," they just won't buy it in the first place, ISTM.

There was some discussion of splitting the full dose into 2 or 3 caps, so that people can adjust their intake.

Well, first, we're not going to have any choice about splitting or no: if eg we're seriously going to put in 200 mg of mg as the glycinate, it's only 11% elemental, so that's 3 capsules right there. Even true citrate is only 16% (tho' a lot of shyster and/or ignorant suppliers will sell "blends," "complexes" etc that claim higher elemental Mg because they're mixed in with MgO), so that's 2. 550 mg choline (as bitartrate) will also take nearly 2 caps. This kind of thing is why A0R held our noses on the multis and used (and disclosed use of!) some MgO along with citrate and ascorbate (the latter largely to save a bit of space), and OrthoCore original was still 9 freakin' caps/d.

Imminst members who monitor their diet religiously, might only take 1/3 dose. Regular folks who buy it because all the "health-nuts" are taking it (and whose diets are probably lacking), could consume the full dose and get the benefits of a well-rounded best-current-science multi (no over-kill).

No, they won't, again for the op cit reason. Look, here is (some of) the nutrition in Mcdonald's Big Mac, French Fries (Large Serving), And Chocolate Triple Thick Shake, 21 fl oz:

General (83%)
=======================
Energy | 1820.5 kcal (!)

Vitamins (48%)
========================
Vitamin A | 1840.2 IU 61%
Retinol | 430.4 µg
Folate | 197.9 µg 40%
B1 (Thiamine) | 1.1 mg 90%
B2 (Riboflavin) | 1.5 mg 117%
B3 (Niacin) | 12.3 mg 77%
B5 (Pantothenic Acid)| 4.2 mg 83%
B6 (Pyridoxine) | 1.0 mg 61%
B12 (Cyanocobalamin) | 4.5 µg 187%
Vitamin C | 12.1 mg 13%
Vitamin D | 0.0 IU 0%

Minerals (66%)
========================
Calcium | 857.3 mg 86%
Copper | 0.6 mg 70%
Iron | 8.3 mg 103%
Magnesium | 168.8 mg 40%
Manganese | 1.0 mg 45%
Phosphorus | 967.1 mg 138%
Potassium | 2327.8 mg 50%
Selenium | 0.0 µg 0%
Sodium | 1692.8 mg 130%
Zinc | 7.2 mg 66%

Lipids (32%)
=======================
Saturated | 22.4 g
Omega-3 | 0.6 g 16%
Cholesterol | 145.1 mg 48%

This person clearly needs more nutrition, including ≥1000 IU of vitamin D, and might or might not need more Fe depending on gender and age, but should not throw 100% DRI of everything else on top of that, even if that's all s/he eats all day -- and presumably (Dog help hir!), s/he's going to eat more food over the course of the day.

We're just stuck with this; ISTM the best course of action is to design the perfect Astronaut Food, and provide instructions to get as many people to act responsibly as possible -- or alternatively, to wash our hands of the whole multivitamin project, as (again) was my initial instinct.

-Michael

Edited by Michael, 13 December 2009 - 11:02 PM.

[scottl]

Or just put in vitamins and trace minerals.

[ajnast4r]

finals are over :d

As I said, bioavailability is a bit of a bugaboo here, but citrate also has that much-more-reasonable 16% elemental Mg content.

glycinate is the only form i know of that wont induce diarrhea in higher amounts...which was one of the main reasons it was suggested. i'm not sure if this would be an issue @ 200mg. perhaps citrate would be the best choice. some people had complained in the original thread that aspartate was stimulating, so i think it would be best to avoid it.

I might suggest instead a small, DRI-level K1 (120 µg)

i agree with this totally... although it was voted down earlier in the process i still think k1 should be included. my original suggestion was 120mcg, 1/2 k1 & 1/2 k2-mk7... but 120mcg k1 and 45mcg k1 would work for me as well.

Ajna intended the "full" dose of this multi to be optimal (or as good as possible).

my original intent was to keep people in the 200-300%DRI range on most nutrients... assuming that the average LE;er is getting somewhere between 100-200% from the diet +100% from full dose of the multi.

but i would like to see it split into 2 or 3 pills, giving people the ability to titrate as they see fit.