61 replies to this topic

[Michael]

All:

Edits: Dietary nutrition report now appended; reference list fixed; details on Li rationale.
2010-02-21: Nixed pyridoxamine & P5P, for reasons in the thread Vitamin B6 (Pyridoxamine??) Neurotoxicity, Impaired Synaptic Density, Ultrastructural Damage; my comments here.
Corrected important link that was completely misdirected in earlier edition (2011-02-21)
Dropped R(+)-lipoic acid since it's now clear from multiple studies that it has no effect on LS (26-29) or insulin sensitivity(30,31), or AGE or ROS generation(31) in normal, healthy, nonobese, non-genetic-monstrosity AL or CR rodents, and is thus all long-term risk of a substance never tested in healthy humans for more than a few weeks at a time, with no meaningful prospect of reward. (Summer 2011).
Changed choline for phosphatidylcholine due to possible free choline supplement cardiovascular risk (2011-07-15)

First, please see my discl0sure here. I'd appreciate this fact not being discussed in open forum, as I value my privacy, but y'all should know.

Now:

I occasionally get requests for an update on my supplement regimen of 2 years ago. I've long put this off, first and foremost lack of time , but also because the life extension community (including Imminst) is way too focused on this stuff anyway. Moreover, while the Sysiphean cycle of the absolute latest supplement marketing hype scientific breakthrough has of course continued, very little of actual importance has happened in the field -- and most of what has, has been either:

(A) Debunkings: notably, the death (over which many of the bereaved remain in denial) of the whole resveratrol-as-sirtuin-activating-CR-mimetic fairy tale, now that it's been clearly shown not to do so in normal, healthy, well-cared-for mammals (1), contrary to the wild speculation derived from irrelevant test-tube nonsense and yeast studies, dubious Drosophila and C. elegans studies, and yet more studies in rodents fed high-lard, high-sucrose diets until they become morbidly obese and diabetic (whom huge doses of resveratrol partially restore some of their ruined health). Note the full context of the effects of resveratrol and EOD on lifespan in (1), includings confirmation of (2)'s finding that "Resveratrol Flunks Vs. Real-World Cancer"), as well as the many other "issues" with resveratrol; or:

(B) More reasons for extreme caution, such as the surprising new concerns about a potential cancer-promoting effect of folic acid, further evidence that supra-RDA selenium supplementation raises the risk of diabetes and some cancers, the dangers of multivitamins, hypothetical cancer risk from benfotiamine, etc.

I had long thought in any case that I hadn't made any major revision in my regimen since '06; of two changes that would have been major, one (a large increase in R(+)-lipoic acid intake in response to this study)) I soon thought better of and reverted to a lower dose [and have now (summer 2011 dropped altogether], and the other I never actually got started on: after brief time of enthusiasm where I -- yes, I! -- was seriously considering adding a "low" megadose of resveratrol, in response primarily to the apparent finding that the only group to benefit from resveratrol in (1) was precisely the animals given the lower dose of res and who were also on low-level (EOD) CR (ie, the group most like me!) in (1)):



Ultimately, however, I didn't even get started on this, after I realized that on top of everything else, and despite the diligent efforts of Niner and others, extrapolating a suitable dose from (1) was actually pretty much impossible -- a subject on which I've long intended to post, but doing so would take a long time.

However, looking back at it recently, I can see that I have, incrementally, actually made some pretty significant changes overall. So I'm finally getting around to posting this update

As background, please see this post about dietary supplement use in general [corrected this key link, previously totally misdirected (2011-02-21); this kind of reasoning should inform everyone's judgements about what supplements to take, and why, for them as individuals. Please do note the importance of actually using nutrition software to get a handle on your actual dietary intake of essential nutrients before deciding what to supplement, tho' this is less of an issue to the extent that your diet is (a) genuinely poor (& thus more likely to actually need 'everything' and not be overdosing on eg Mn, Cu, etc) and (b) you're not on CR (and thus have a lot of 'slop factor' and don't have the specific nutritional risks of CR folk). (Yes, ironically, health-conscious people actually have more need for caution in supplementation, because they often wind up on somewhat restrictive 'health food' regimens that limit the diversity of their nutrient sources, and because, as noted above, it's common for people eating quite well to get almost too much of some nutrients from diet alone, and then add supplements on top of that. Studies show, perversely, that the people who need vitamin supplements the most use fortified cereals the least -- and the converse).

On this point, let me emphasize the logical corollary which I've spelled out repeatedly but that people keep missing: unless your diet is composed entirely of fries, Coke, and fast-food burgers with the lettuce, ketchup, and tomato thrown out, no one should be taking a full daily dose of any commercial multivitamin. You are absolutely guaranteed to get too much of many nutrients, and to create or exacerbate imbalances in others.

I should also emphasize the other corollary: this is a regimen for a very specific individual: a very healthy, young(ish) CR practitioner with an excellent diet (which I've analyzed extensively, to understand its weaknesses and "excessive" strengths -- see a representative week's average appended to this post). As the links above indicate, a person must customize hir regimen based on hir own diet, and also age, specific risk factors, existing diseases, etc.

So: the regimen (notes on WHY I take various things at the end, when it isn't obvious from the link or other grounds):

UPON WAKING (5 AM or before), with 1/3 c pomegranate juice + 2/3 C diet Dr. Bob:
1 tsp (~5 g) CreaPure Creatine monohydrate (do not buy commodity creatine! See below).
314 mg Strontium (citrate)
50 mg Pyridoxamine

(Upon swallowing the above):
1 mg Methylcobalamin, sublingually

5:50 AM, with green tea:
100 mg R(+) Lipoic Acid (stable sodium salt)
1000 mg Lysine
1 Prostaphil defined pollen extract
0.5-1 g Beta-alanine (higher dose when doing resistance training)

6:30 AM, breakfast:
219 mg Wine Rx (authentic red wine concentrate)
15 mg Menatetrenone
250 mg Lactoferrin
30 mg CoQ10 (dissolved in oil carrier)
355 mg Choline
420 mg phosphatidylcholine

~15 min after breakfast (superior pharmacokinetics (17,18)):
50 mg P5P

While scrubbing teeth: 1 drop per eye N-acetyl-L-carnosine eyedrops

10:30 AM, with green tea:
50 mg pyridoxamine
500 mg ALCAR

11:10 AM, with green tea:
0.5-1 g Beta-alanine (higher dose when doing resistance training)
Brain nutrient (rotating one of: 800 mg piracetam ( why?) (once/wk), pyroglutamate (500 mg, thrice/wk) or the sadly-discontinued Turbo Tyro Tea (to provide tyrosine (4000 mg) & phenylalanine (800 mg)) (thrice/wk)

11:50 AM, with green tea:
500 mg lysine, 500 mg arginine (no, these do not interfere with one another's effects for this application).
100 mg R-LA

12:30 PM, lunch:
500 mg citicoline
1 mg lithium (orotate -- do see note below!)
1 Wine Rx

4:30, with green tea or other beverage:
500 mg IP-6
500 mg Inositol (possibly synergistic to IP-6)
50 mg pyridoxamine

5:10, with green tea or other beverage:
0.5-2 g Beta-alanine (higher dose when doing resistance training)
1 Prostaphil

5:50, with green tea or other beverage:
1000 mg lysine (1.5 g arginine when doing resistance training)
100 mg R-LA

6:30, dinner:
1288 IU (average) vitamin D3
675 mg taurine
15 mg Zn (citrate)

10 pm, bed, with green tea or other beverage:
50 mg pyridoxamine
0.5-1 g Beta-alanine (higher dose when doing resistance training)
5 g Glycine
300 mcg melatonin (as required)


Further on Rationales
Pomegranate juice: I want SOME source of relatively high-GI sugar without protein or fat to get glucose levels up first thing on rising, and for the possible benefit of taking creatine with a sugar source (tho' it's not at all clear that this is anything like enough glucose to meaningfully affect this, nor that the extra boost to tissue reserves as vs. water coadministration during the loading period is sustained with ongoing administration); I chose pom juice for the many promising-looking studies in disease states, tho' again the dose may be inadequate (studies typically use 1-2 C). Don't blow your bucks on POM Wonderful: Trader Joe's has it reasonably cheap, as does Georgian Nectar (a hard-to-find brand I sometimes find at a local Asian grocery store). I would "look" for brands that aren't syrupy or sickly-sweet, and still have some bitterness and residual granular material; Lakewood has the stuff genuinely fresh-pressed rather than from concentrate, which strikes me as likely preferable, but it's VERY expensive.

The diet Dr. Bob is 'cause I like it and it has zero Calories; it's cheaper and to my taste yummier than the brand name original. No, I am not worried about aspartame (or sucralose, for that matter). Indeed, the recent, much-hyped report of increased cancer in aspartame-dosed rodents (3) actually made me less nervous about aspartame: it (a) really didn't clearly show any increased cancer risk (they hyped up non-statistically-significant elevations in incidence of some cancers late in life, but also NS decreases in others), and indeed (b) reported identical survival curves between aspartame-treated and untreated animals (if anything, it looked like females given the highest dose lived LONGER on average than untreated animals); plus, there was massive mortality from inflammatory lung disease and other causes, showing that these people just can't raise healthy mice. Additionally, because aspartame has been on the market for a quarter century and is widely and selectively used, there's now been enough time for both additional direct human and animal research and decades of prospective epidemiology (4,5) showing no ill effects over a wide range of intakes in humans. If you were alarmed by a recent scary-sounding paper in an otherwise-respectable journal,(6) please see this post debunking the junk science on "Direct and indirect cellular effects of aspartame on the brain" by Humphries, Pretorius, and Naudé (5a).

To read a thoughtful, non-paranoid, non-"it's-just-not-natural!" argument for caution by a reputable and careful scientist, I refer you to Devra Davis' excellent (and disturbing) Secret History of the War on Cancer.

Creatine, beta-alanine, ALCAR, taurine, zinc: I'm ovolacto for my quotidian diet, and am therefore somewhat low on these, and Vegetarian Booster has been discontinued. Plus, I found during a period that I briefly ran out of Veg Booster that I felt better on the higher ALCAR and creatine combined with the concomitant (at the time, much smaller) increase in R(+) (to compensate for the increase in carnitine and use of ALCAR in particular); and, I actually exhibit symptoms of Zn deficiency (Beau's lines (more usually associated with iron deficiency), cracking fingertip skin, inability to taste zinc sulphate heptahydrate solution) when I don't, despite a fairly high dietary Zn, presumably due to high dietary copper. More on most of these below.

Creatine: don't settle for anything less than CreaPure (a branded raw material manufactured by Degussa AG Trostberg (formerly SKW) but used in several different retail brands). Years ago, Dr. N..... at A0R had raised concerns about contaminants in other creatine manufactrers, but I never looked into it at the time as the company wasn't marketing it and I wasn't taking it. A while back, however, I did do some digging after having bought some creatine from a company that I generally consider to be quite reputable and from whom I often buy commodity-item supplelments, and was disturbed by its very bitter and (surprisingly) soapy taste. The company insisted that it was fine; I did some digging and found that there are indeed reasons for caution, as outlined in these two very good articles on creatine by Will Brink: "What's in your Creatine?" and "What's Really in Your Supplements? - An Update on Creatine". I proceeded to order some CreaPure-sourced creatine and was surprised that, for the very first time, the stuff had absolutely no bitter taste to it: the suspicious supplement had been the only one with a soapy taste, but I'd taken a mild bitterness to be intrinsic to the supplement rather than a sign of impurity. There is still no proof that dicyandiamide or dihydrotriazine is harmful -- but why anyone (let alone a life extensionist!) would knowingly put high (relative to likely dietary intakes) levels of organoleptically-detectable impurities of unknown toxicity into hir body to save a few dollars is beyond me.

Strontium: I have low BMD typical of natural- and CR-induced low BMI; this is a fracture risk factor, tho' not as much as would be routinely assumed and even diagnosed, because of my overall risk profile: see the new FRAX fracture risk assessment tool developed by the WHO. See also this post on how CR appears to protect bone against age-related decline in bone quality/microarchitecture.

Prostaphil defined pollen extract: I have an idiopathic urinary urgency; definitely not BPH or bacterial prostatitis, conceivably related to alpha-adrenergic function. This is subjectively very helpful.

Menatetrenone: as with strontium. All the more likely useful for CR-related low bone mass, as my actual MASS of bone is constrained by low energy intake, whereas menatetrenone primarily appears to reduce risk by preseving QUALITY -- a more likely viable strategy.

Arginine and lysine: these have been found to be surprisingly effective in reducing AGE and AGE-induced complications of diabetes, especially in the kidneys but also apparently in the heart (6-12). (13) was negative, but the measurement of AGE was in skin, which not be reached by a significant concentration of these nutrients (vs the heart and kidneys, thru' which they would of course travel in the blood when they're taken on an empty stomach) (tho' (11) did find reductions in hexosyllysine), and their conclusion was (reasonably) that "treatment may need to continue for more than 1 year before clinical status improves."

Beta-alanine: I was previously taking carnosine, which is possibly anti-senescent cell, possibly anti-mitochondrially-mutant cell, and is deficient in vegetarian diet. However, I've now substituted beta-alanine, for which there is much better evidence of elevation of tissue carnosine levels (and, I happily anecdotally report, seemingly impressive muscle power gains, consistent with the surprisingly large number of clinical trials with the stuff, tho' this wasn't what got me interested originally). One thing to watch out for is the dose: bottle directions often suggest 2 g, 4 x daily, which is the final, ramped-up dose used in the trials; however, this is likely to cause you (as I shame-facedly admit, it caused me) maddening paraesthesia (pins and needles), as explained here. Instead, start at 500 mg 4 x daily, and work your way up as needed or desired; I only take a higher dose on days when I'm doing resistance training.

Wine Rx: Unlike the shaky-to-begin-with-and-now-disproven resveratrol hype, there is a quite solid body of epidemiological evidence of an association between a couple of glasses of wine a day and lower risk of a range of adverse outcomes, including total mortality and dementia. The epidemiology clearly indicates a U-shaped dose-response curve for alcohol consumption and heart disease, with the best outcomes associated with 1-3 drinks/d, but only wine (not beer or spirits) lowers total mortality and dementia. (No, despite the use of these findings as a justification for resveratrol supplements, there is no epidemiological evidence favoring red over white). The benefits for total mortality reach a nadir at <1 drink/d for total mortality:


Figure 1. Relative risk of total mortality (95% confidence interval) and alcohol intake extracted from 56 curves using fixed- and random-effects models. From (19); cf eg (20) for similar findings in wine specifically.

However, my working hypothesis is that the climbing risk is due to the toxicity of alcohol per se, and that additional benefits might be available from higher intake of the component(s) of wine responsible for these benefits, without the extra Calories and toxicity of drinking the stuff. However, we don't know which component(s) of wine exert these effects, so we should aim for a supplement that is a direct concentrate of the same spectrum of bioactives in actual, fermented wine -- ie, not just resveratrol, nor the grape-seed and/or -skin extract that is often mislabeled "wine extract," and whosee polyphenol mix is actually quite different from that in wine, due to complexation and biotransformation that the grapes undergo during fermentation. Seppic in France has done a great deal of work in characterizing these, and still the surface is only barely scratched and we don't know what might do what.

Therefore, I went looking for a genuine concentrate of actual red wine that did not rely on high temperature or extraneous chemicals which might also alter the original mix, and which did not come from China or another country with high levels of industrial contaminants or shady business practices.

I first hit on Provinols, which is a pioneering product in this field, but unfortunately it is damned near impossible to get in the Americas, except in low doses and mixed in with other junk, or at absurdly HIGH doses that I wouldn't take. (Europeans and Turks may be able to get it, however). A long convo with their USA biochemist convinces me that Wine Rx is the real deal, with each cap equivalent to a glass of red, and is from Chile, not China.

Pyroglutamic acid: VRP, my previous source, has discontinued pyroglutamic acid. I'm very annoyed: this is the SECOND time they've disc. something I use for which they're the only trustworthy source I know, and w/o notice ... And in fact, a quick Google suggests no other source (S*urce N@turals sucks (a couple of flunked consumerlabs.com tests, totally inappropriate tableting of R-LA, other bad behavior), and I don't want arginine pyroglutamate). Damn damn damn! Does anyone know of a reliable source for this supplement?? Or is anyone willing to sell me any sealed, non-expired bottles of VRP's? PM me if so, please).

Lithium orotate: I just do my best to spread the contents of a 5 mg cap evenly over 5 days. 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 (24), 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 (25), 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).

Zinc: my regular diet includes what should be quite adequate zinc, but my dietary copper intake is so high I get (copper-induced secondary zinc deficiency if I don't supplement (click on the "Research" tab; most people are more likely to have the converse problem). This was mildly symptomatic for much of the year for several years, and even the 7 mg/d in the Veg Booster isn't quite enough to keep it at bay.

Glycine: mostly for soundness of sleep (16).

Melatonin: for sleep when stressed, wide awake, or jetlagged. 300 mcg is sufficinet to raise levels to normal physiological youthful ones and apparently works as well as higher doses ((22,23), and see (21)) and doesn't produce the 'hangover' sleepiness sometimes seen with the supraphysiological 3 mg (and up) doses that became ubiquitous thanks to the recommendation of the once-notorious Melatonin Miracle.

And with that melatonin discussion, I symbolically put this thing to bed!

-Michael

===========================================
Nutrition Summary
October 25, 2009 to October 31, 2009
Daily Averages over 7 days
Report generated by CRON-o-Meter v0.9.5
===========================================

General (93%)
===========================================
Energy | 1756.3 kcal 275%
Protein | 99.9 g 208%
Carbs | 190.0 g 63%
Fiber | 65.4 g 218%
Starch | 0.5 g
Sugars | 51.6 g
Fat | 74.6 g 339%
Alcohol | 11.1 g
Caffeine | 0.0 mg
Water | 1885.3 g 126%
Ash | 19.8 g

Vitamins (88%)
===========================================
Vitamin A | 44126.9 IU 1471%
Retinol | 110.2 µg
Alpha-carotene | 1636.2 µg
Beta-carotene | 24683.6 µg
Beta-cryptoxanthin | 30.8 µg
Lycopene | 27549.6 µg
Lutein+Zeaxanthin | 38361.3 µg

Folate | 1285.7 µg 257%
B1 (Thiamine) | 4.3 mg 361%
B2 (Riboflavin) | 3.2 mg 244%
B3 (Niacin) | 55.7 mg 348%
B5 (Pantothenic Acid)| 22.4 mg 448%
B6 (Pyridoxine) | 3.6 mg 212%
B12 (Cyanocobalamin) | 3.4 µg 140%

Vitamin C | 483.1 mg 537%
Vitamin D | 63.3 IU 16%
Vitamin E | 26.9 mg 179%
Beta Tocopherol | 0.2 mg
Delta Tocopherol | 0.1 mg
Gamma Tocopherol | 3.1 mg

Vitamin K | 1182.0 µg 985%
Biotin | 0.0 µg 0%
Choline | 163.7 mg 30%

Minerals (100%)
===========================================
Calcium | 1337.8 mg 134%
Chromium | 0.0 µg 0%
Copper | 4.2 mg 467%
Fluoride | 18.6 µg
Iron | 23.2 mg 290%
Magnesium | 655.0 mg 156%
Manganese | 14.3 mg 621%
Phosphorus | 1865.0 mg 266%
Potassium | 5797.9 mg 123%
Selenium | 70.0 µg 127%
Sodium | 1654.0 mg 127%
Zinc | 33.4 mg 303%

Amino Acids (97%)
===========================================
ALA | 4.3 g
ARG | 5.0 g
ASP | 7.8 g
CYS | 1.2 g 84%
GLU | 12.0 g
GLY | 3.9 g
HIS | 1.7 g 156%
HYP | 0.0 g
ILE | 3.8 g 259%
LEU | 5.3 g 165%
LYS | 4.4 g 148%
MET | 1.3 g 90%
PHE | 3.4 g 135%
PRO | 4.0 g
SER | 3.9 g
THR | 3.7 g 239%
TRP | 1.0 g 259%
TYR | 2.2 g 88%
VAL | 4.0 g 1292%

Lipids (55%)
===========================================
Saturated | 9.5 g
Monounsaturated | 39.5 g
Polyunsaturated | 20.9 g
Omega-3 | 7.6 g 190%
Omega-6 | 13.2 g
Trans-Fats | 0.0 g
Cholesterol | 30.8 mg 10%
Phytosterol | 136.2 mg


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21: Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, Ford
I. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev. 2005 Feb;9(1):41-50. PubMed PMID: 15649737.

22: Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. Sleep. 1996 Jun;19(5):423-31. PubMed PMID: 8843534.

23: Zhdanova IV, Wurtman RJ, Lynch HJ, Ives JR, Dollins AB, Morabito C, Matheson JK, Schomer DL. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther. 1995 May;57(5):552-8. PubMed PMID: 7768078.

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

25. 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

26: Merry BJ, Kirk AJ, Goyns MH. Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span. Mech Ageing Dev. 2008 Jun;129(6):341-8. Epub 2008 Apr 22. PubMed PMID: 18486188. See my detailed discussion of this study here.

27: Spindler SR, Mote PL. Screening candidate longevity therapeutics using gene-expression arrays. Gerontology. 2007;53(5):306-21. Epub 2007 Jun 15. Review. PubMed PMID: 17570924. Lifespan data.

28: Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA. The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med. 2004 Apr 15;36(8):1043-57. PubMed PMID: 15059645. Lifespan data.

29: Ames BN. Personal communication. Used R-enantiomer.

30: Saengsirisuwan V, Perez FR, Kinnick TR, Henriksen EJ. Effects of exercise training and antioxidant R-ALA on glucose transport in insulin-sensitive rat skeletal muscle. J Appl Physiol. 2002 Jan;92(1):50-8. PubMed PMID: 11744642.

31: Midaoui AE, Elimadi A, Wu L, Haddad PS, de Champlain J. Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production. Am J Hypertens. 2003 Mar;16(3):173-9. PubMed PMID: 12620694.

Edited by Michael, 10 February 2012 - 06:34 PM.

[immortali457]

"no one should be taking a full daily dose of any commercial multivitamin. You are absolutely guaranteed to get too much of many nutrients, and to create or exacerbate imbalances in others."

Hogwash

[ajnast4r]

"no one should be taking a full daily dose of any commercial multivitamin. You are absolutely guaranteed to get too much of many nutrients, and to create or exacerbate imbalances in others."

Hogwash

not hogwash at all..its basically a universal truth. hence the imminst community supplement project.

michael, i cant remember if i emailed you or not... but i meant to. we would really appreciate your input on the community supplement project if youre interested.

http://www.imminst.o...esign-f365.html

Edited by ajnast4r, 30 October 2009 - 01:03 AM.

[rwac]

It's good to know Michael agrees with the rationale for Menatetrenone.

Any comments on MK-7 and the effectiveness thereof ?

Edited by rwac, 30 October 2009 - 02:08 AM.

[Blue]

Thanks for all the good advice!

There are some things I am curious about. There have been discussions here regarding the safety of carnosine/beta-alanine especially in high-dose. Niner has a nice post on this linked below. You see no problems with a long-term intake of several grams of beta-alanine per day?
http://www.imminst.o...o...st&p=245731

Another is that a high copper intake may be problematic.
http://www.imminst.o...showtopic=31198

Edited by Blue, 30 October 2009 - 02:07 AM.

[Matt]

Thank you Michael for your updated supplement regimen, much appreciated! I also noticed some Zinc issues since starting CRON which were corrected with 15mg zinc supplement. Also from your advice back a while ago I lowered my multi to just 1/3 of the normal full dose (essential mix). :-) I think i'll try out the Glycine and Red Wine extract, not sure I would need melatonin at my age ? hmmm..

thanks again for all those references too!

Edited by Matt, 30 October 2009 - 04:13 AM.

[nameless]

Thank you for posting your regimen.

Interesting you mentioned Provinols, as a couple of years ago I became interested in it, but it was nearly impossible to find. A UK company, Healthy Direct, used to sell it, but I never purchased due to shipping costs to the US. I even wrote the company, and after several months got a reply back, basically saying that UK company was the only place I could get it. As of now, I'm not sure who even sells it.

Wine Rx looks interesting, although I never heard of that company before.

Nature's Plus makes a red wine supplement --
http://www.vitacost....s-Plus-Red-Wine

How does that compare? I tried contacting Nature's Plus for info, but they never respond to emails.

Currently just going with a low dose of Masquelier's OPCs as my 'wine' replacement.

Edited by nameless, 30 October 2009 - 05:07 AM.

[pycnogenol]

"Pyroglutamic acid: VRP, my previous source, has discontinued pyroglutamic acid. I'm very annoyed: this is the SECOND time they've disc. something I use for which they're the only trustworthy source I know, and w/o notice ... And in fact, a quick Google suggests no other source (S*urce N@turals sucks (a couple of flunked consumerlabs.com tests, totally inappropriate tableting of R-LA, other bad behavior), and I don't want arginine pyroglutamate). Damn damn damn! Does anyone know of a reliable source for this supplement?? Or is anyone willing to sell me any sealed, non-expired bottles of VRP's? PM me if so, please)."

Hi Michael,

What other Source Naturals products have also failed on Consumer Labs besides pyroglutamic acid?

[Bacano]

Hey Michael

What about a sample day on your diet regimen?

Edited by Bacano, 05 November 2009 - 10:13 PM.

[tunt01]

thx for posting this michael. very thoughtful, as always.

one thing kind of struck me. you have regimented your daily routine to taking specific pills at 12 different specific times throughout the day. do you think this is overkill?

i mean when you stand back and look at it, is it really necessary to do this in such a time specific matter at 12 different points in the day? if you were to simplify it, how would you go about it?

thx & hope you are well

[Brain_Ischemia]

As someone relatively new to serious, monitored CRON, this is very useful indeed.

[Michael]

All:

[Grr ... hit the quote limit again ...]

its basically a universal truth [that "no one should be taking a full daily dose of any commercial multivitamin[/i]. You are absolutely guaranteed to get too much of many nutrients, and to create or exacerbate imbalances in others"]. hence the imminst community supplement project.

michael, i cant remember if i emailed you or not... but i meant to. we would really appreciate your input on the community supplement project if youre interested.

Sorry, you did PM me, and I didn't reply, mostly because I had explained here that while I certainly have my opinions, I'm really not very comfortable with the idea, and someone pointed this out early in the thread. However, to the extent that it's now focused on an RDA-ish, essentials-only formulation, I'm reconsidering ... I just have little time to spare, and as you can see, put off stuff way too long even when I do mean to reply ...

Any comments on MK-7 and the effectiveness thereof ?

I was initially skeptical, for reasons given here; subsequently, research has tended to support the idea that MK-7 should also work, but we still don't have the gold standard of a clinical trial showing reduced fracture risk, whereas we have multiple such trials for menatetrenone proper (MK-4). I strongly favor sticking with the tested nutrient; it's unfortunate that is so much more expensive ...

There are some things I am curious about. There have been discussions here regarding the safety of carnosine/beta-alanine especially in high-dose. Niner has a nice post on this linked below. You see no problems with a long-term intake of several grams of beta-alanine per day?
http://www.imminst.o...o...st&p=245731

Yeah, I came across this independently when I first started digging into beta-alanine supplementation. I went ahead for a couple of reasons. First, there has actually been a (relatively short-term) human study of "The absorption of orally supplied beta-alanine and its effect on muscle carnosine synthesis in human vastus lateralis" (Amino Acids 30: 279–289), which revealed only small, nonsignificant reductions in skeletal muscle taurine levels, and argued that the inhibitory effects observed in animal models are the result of the extremely high doses used and/or the route of administration (IV or even intracerebroventricular). But, of course, other tissues may have differential vulnerability to such an effect.

I also would have expected that since high-dose taurine supplementation has been shown in humans to have hypotensive effects, and the concern with beta-alanine is exactly impaired intracellular taurine transport, that if there were such an effect it would set in early in the game in a dynamic process like regulation of vascular tone. It's argumentum ad silentio, but no such reports have come forward, and BP is a pretty standard thing to monitor. That's a pretty weak argument, however, and I did email several researchers about this very concern, asking if, as a preliminary test for such effects, they had ever monitored blood pressure during their clinical trials. Unfortunately, almost none of them replied. A former graduate student in Dr. Roger Harris' lab advises me that in earlier "studies when beta-alanine was first used as a treatment (approx 8 years ago) cardiovasular health was assessed using a cardiograph pre and post treatment. There where no change in cardiac function pre-post treatment. This was before [he] was a reasearcher (I was an undergraduate and a subject!) so [he] do[es] not have access to data. Prof Roger Harris (r.harris@chiuni.co.uk) may be able to provide you with a more definative [sic] answer. However I know that it was important at that stage to rule out any negative effects on cardiac function, via a reduction in taurine, so as to contiune research in the area."

Unfortunately, from a search of PubMed, I cannot find such studies, and my repeated emails to Dr. Harris have not been answered. If anyone knows Dr. Harris and can get answers to these questions I'd be delighted for the information ...

Blue also wrote: Another is that a high copper intake may be problematic.

Indeed -- as I noted carefully in my post . I'm obviously not happy about a secondary Zn deficiency, and have tweaked my diet in various ways to bring it down, but the reality is that anyone eating a large amount of vegetables (and especially some very valuable foods, like mushrooms) inevitably winds up taking in several RDAs of copper. Crunch your diet .

Matt wrote: not sure I would need melatonin at my age ?

I don't take it because of my age, as some kind of piineal HRT, and wouldn't recommend that people do so: I take it on an occasional basis as a sleep aid.

Nameless wrote: Thank you for posting your regimen.

You're (all) welcome .
Nameless wrote: Interesting you mentioned Provinols, as a couple of years ago I became interested in it, but it was nearly impossible to find. ... Wine Rx looks interesting, although I never heard of that company before.

Nature's Plus makes a red wine supplement --
http://www.vitacost....s-Plus-Red-Wine

How does that compare? I tried contacting Nature's Plus for info, but they never respond to emails.

First, I should add a new discl0sure: after first posting on this product on CR Society, and while in the middle of writing my regimen post here, I got into an email discussion with the N American distributor and mentioned to her that I was probably responsible for the small surge in sales she'd observed in the 24 h after I'd made the former post (the N. American operation being tiny enough to notice such), and she gave me, unsolicited, a permanent discount on the product. So, I'm now grateful -- and compromised.

Now, endeavoring as always to be conscious of this conflict and speak in as objective a manner as possible: based on the provided info for the NP product, it's very hard to know absent any detailed info on sourcing and extraction procedures; by default, I'd assume that it's likely to suffer from some of the problems and deficiencies that I highlighted in my original post:

we should aim for a supplement that is a direct concentrate of the same spectrum of bioactives in actual, fermented wine -- ie, not just resveratrol, nor the grape-seed and/or -skin extract that is often mislabeled “wine extract,” and whose polyphenol mix is actually quite different from that in wine, due to complexation and biotransformation that the grapes undergo during fermentation. Seppic in France has done a great deal of work in characterizing these, and still the surface is only barely scratched and we don't know what might do what.

[I want] a genuine concentrate of actual red wine that did not rely on high temperature or extraneous chemicals which might also alter the original mix, and which did not come from China or another country with high levels of industrial contaminants or shady business practices.

If NP won't answer your questions, I would assume the worst. Plus, it's more epensive than WineRx!

Also, I wouldn't buy anything from VitaC0st, whose in-house brand has been nailed repeatedly by Consumerlab.com and others for quality problems from lead content to not meeting label claims, and labels many of their products misleadingly by putting " x mg" on the front of the label and in the product description, and only disclosing in the "supplement facts" that this is for the original material, and the active they're selling is actually only a fraction of X milligrams, in a way that doesn't seem intended to fairly represent the product. While this wouldn't affect their resale of other manufacturers' products (I hope!), I don't like giving money to companies of questionable ethical standards.

Nameless wrote: Currently just going with a low dose of Masquelier's OPCs as my 'wine' replacement.


Again, see above: not at all equivalent.

What other S0urce Naturals products have also failed on Consumer Labs besides pyroglutamic acid?

To be clear, I have no reason to think that their pyroglutamate failed, but that other products of theirs did. For examples, see the link I gave in the post to which you're responding .

one thing kind of struck me. you have regimented your daily routine to taking specific pills at 12 different specific times throughout the day. do you think this is overkill?

i mean when you stand back and look at it, is it really necessary to do this in such a time specific matter at 12 different points in the day? if you were to simplify it, how would you go about it?

When I'm forced to on a particular occasion by circumstances, I just do -- but usually by skipping a serving of something. There really are good reasons behind all of that. Lots of things have to be taken on an empty stomach and are in some way mutually incompatible; the lysine/arginine, PM, and lipoic acid are in large part to mitigate the adverse metabolic impact of the postprandial state, and have different pharmacokinetics, so this (along with water solubility) dictate their multiple doses per day (1 serving each per meal) and their different timing around a given meal; obviously, sleepy-time potions are taken at bed. [Insert, 2009/11/19]: Also, I'm skeptical that one can even absorb much more than I'm taking of a lot of these things at a given serving: eg, can one really expect the body to absorb more pills on top of 5 g of creatine or of tyrosine + phenylalanine, or more than 5 x 500-1000 mg pills of different composition, with a glass of water/tea, at once? We have of course no studies to answer the question in most cases.

I've just discovered that the EU monograph for the pharma Sr appears to have changed: it "should be administered at bedtime, preferably at least two hours after
eating, since the absorption of [the stuff] is reduced by food intake," so I may move this.

What about your a sample day on your diet regimen?

That's actually a good idea -- not just for my specific case, but to have as a dedicated subtopic, just like we do here for the much less important area of supplements ... of course, it's much easier to post a supplement regimen, which tends to be essentially the same thing from day to day than it is to give an accurate idea of a person's diet, unless s/he eats a diet with very little day-to-day variation. But I'll give a shot at this one way or t'other.

-Michael

Edited by Michael, 18 November 2009 - 06:31 PM.

[ajnast4r]

I'm reconsidering

i will shoot you an email when the project is finished and if you have time you can look it over and offer your input

[drmz]

Thanks for the post. Enjoyed reading it, very informative. Glad to hear a skeptical resveratrol sound on here. Not used to that on here.

Edited by drmz, 17 November 2009 - 09:17 PM.

[nameless]

Thanks for the followup info on WineRx. I agree that Masquillier's isn't equivalent... and I'm not fond of Vitacost/NSI either. I just used that link as it was the handiest one I had at the time for that product. I've also seen wine extracts from Swanson (no info available as for sourcing) and Doctors Best (Biovin Advanced, which I'm not entirely sure is from actual wine, or wine grapes, and is more resveratrol-heavy that I prefer).

I have a couple of questions on that product though. Does the WineRx distributor use 3rd party testing?
From what I can gather, the extract used is Uvamia --
http://www.uvamia.cl...dex ingles.html

But the website only supplies limited info. And the WineRx distributor looks to be rather smallish, so am not sure how much testing they do. I have corresponded a little with probably the same person you have at WineRx, and have been told the encapsulation process is GMP certified, but I don't know about the extract itself. I also suggested she look into getting it on iHerb, as it'd be easier to order there. I think she said it will be showing up in some Whole Foods soon, if anyone is interested in it.

Edited by nameless, 17 November 2009 - 10:48 PM.

[kodi]

15 mg Zn (citrate)

Zinc citrate and gluconate seem to have poor bioavailability compared to picolinate according to www.ncbi.nlm.nih.gov/pubmed/3630857:

Comparative absorption of zinc picolinate, zinc citrate and zinc gluconate in humans.
1987 Jun;21(1-2):223-8.
Barrie SA, Wright JV, Pizzorno JE, Kutter E, Barron PC.

The comparative absorption of zinc after oral administration of three different complexed forms was studied in 15 healthy human volunteers in a double-blind four-period crossover trial. The individuals were randomly divided into four groups. Each group rotated for four week periods through a random sequence of oral supplementation including: zinc picolinate, zinc citrate, and zinc gluconate (equivalent to 50 mg elemental zinc per day) and placebo. Zinc was measured in hair, urine, erythrocyte and serum before and after each period. At the end of four weeks hair, urine and erythrocyte zinc levels rose significantly (p less than 0.005, p less than 0.001, and p less than 0.001) during zinc picolinate administration. There was no significant change in any of these parameters from zinc gluconate, zinc citrate or placebo administration. There was a small, insignificant rise in serum zinc during zinc picolinate, zinc citrate and placebo supplementation. The results of this study suggest that zinc absorption in humans can be improved by complexing zinc with picolinic acid.

Another way to measure zinc sufficiency (besides the mouth rise test you mentioned) might be a zinc blood test. LEF offers it for $28 (even less during annual blood test supersale in April/May): www.lef.org/Vitamins-Supplements/ItemLC001800/Zinc-Serum-Blood-Test.html

However, the blood test might reveal only frank deficiency (not mild deficiency or toxicity) because the study above says, "There was [only] a small, insignificant rise in serum zinc during zinc picolinate, zinc citrate and placebo supplementation."

Edited by kodi, 04 December 2009 - 02:29 PM.

[TheFountain]

not sure I would need melatonin at my age ? hmmm..

Why not? You're 25 years old not 12 years old. But if you do not have trouble sleeping all the power to you.

[Sillewater]

Hi MR,

Why do you no longer take chlorofresh?

[Michael]

All:

15 mg Zn (citrate)

Zinc citrate and gluconate seem to have poor bioavailability compared to picolinate according to www.ncbi.nlm.nih.gov/pubmed/3630857:

Comparative absorption of zinc picolinate, zinc citrate and zinc gluconate in humans.
1987 Jun;21(1-2):223-8.
Barrie SA, Wright JV, Pizzorno JE, Kutter E, Barron PC.

First, in general, bioavailability is really a bit of a bugaboo. If I were really worried about it, I'd just take more . More importantly: this will sound to many (entirely reasonably!) to be a quite lame response, but I did some digging into this years back when I was at A0R, and concluded that there was no real advantage to the picolinate, despite a couple of more favorable studies.

Another way to measure zinc sufficiency (besides the mouth rise test you mentioned) might be a zinc blood test. ...

However, the blood test might reveal only frank deficiency (not mild deficiency or toxicity) because the study above says, "There was [only] a small, insignificant rise in serum zinc during zinc picolinate, zinc citrate and placebo supplementation."

It actually doesn't even show that: serum levels of Zn, like (nearly?) all minerals and nearly all vitamins, is totally useless as an indicator of functional status:

Evaluating the possible effects of marginal [Zn] deficiencies is difficult since sensitive biochemical criteria for detecting marginal zinc status have not been established. Changes in serum zinc are insensitive and may reflect a temporary redistribution of body pools ... Plasma zinc consequently provides only an insensitive index of zinc status. Although knowledge of the numerous biochemical and molecular roles of zinc has been developed extensively, mechanistic explanations for the nutritional functions revealed by severe zinc deficiency ... have not been established conclusively. ... [E]stablished functional or biochemical markers for the nutritional adequacy of zinc do not exist.(1)

Why do you no longer take chlorofresh?

First, I realized it was silly for a person getting as much greenage as I to be taking a chlorophyll supplement every day . Second, it really is loaded with copper, and it was even sillier to push my already-elevated need for zinc due to excess copper intake from vegetables into a supplement-induced deficiency. Finally, the only real known mechanisms for anticarcinogenic effects of the supplement are in neutralizing mycotoxins, which makes them very protective in places with poor hygeine and refrigeration (rural China, where the clinical trial was done), and likely of nearly no relevance to even an average Westerner, let alone a veggie-gobbler like myself.

-Michael

1. Title Mineral requirements for military personnel: levels needed for cognitive and physical performance during garrison training
Authors Institute of Medicine (U.S.). Committee on Mineral Requirements for Cognitive and Physical Performance of Military Personnel, National Academy of Sciences (U.S.). Committee on Military Nutrition Research, National Academy of Sciences (U.S.). Food and Nutrition Board
Publisher National Academies Press, 2006
ISBN 0309101263, 9780309101264

[tunt01]

michael:

i noticed you have no fish oil or flax/borage oil. any thoughts on this? do you get it through your diet?

thx

[VespeneGas]

Fish oil is certainly a notable absence. I'm also surprised not to see any probiotics on this list. Seems like a no-brainer. I do wish we could resolve the beta alanine/taurine issue in a satisfying way.

Thanks for the well-researched list, Michael.

[mikeinnaples]

A) Debunkings: notably, the death (over which many of the bereaved remain in denial) of the whole resveratrol-as-sirtuin-activating-CR-mimetic fairy tale, now that it's been clearly shown not to do so in normal, healthy, well-cared-for mammals (1), contrary to the wild speculation derived from irrelevant test-tube nonsense and yeast studies, dubious Drosophila and C. elegans studies, and yet more studies in rodents fed high-lard, high-sucrose diets until they become morbidly obese and diabetic (whom huge doses of resveratrol partially restore some of their ruined health). Note the full context of the effects of resveratrol and EOD on lifespan in (1), includings confirmation of (2)'s finding that "Resveratrol Flunks Vs. Real-World Cancer"), as well as the many other "issues" with resveratrol; or:

I guess I am a bit confused with your statement here and why you are so vehement. Reading the very paper you cited in (1) gives me good reason to supplement resveratrol. Is there something I missed in reading it that should lead me away from resveratrol?

[kismet]

I guess I am a bit confused with your statement here and why you are so vehement. Reading the very paper you cited in (1) gives me good reason to supplement resveratrol. Is there something I missed in reading it that should lead me away from resveratrol?

Yes, the study was an utter disaster. The primary endpoint was missed by a mile. Generally, we care about maximum life span; because it best reflects real aging and slowing thereof (so research on Rapamycin falls in the category of 'awesome', resveratrol does not as of yet).
The results on those secondary outcomes can be possibly explained (IIRC) by the general polyphenolic/phytoestrogenic nature of resveratrol (therefore hardly applying to human diets already high in those compounds, etc) and many completely useless compounds that fail in humans are known to improve such outcomes in rodents. So even those weak results have to be taken with a grain of salt until replicated in other cohorts* or humans.

With that being said, you'd be taking a substance of unkown benefits even on those select few endpoints in rodents (much less knowing whether any of the data translates to humans!) and the additional drawback of zero safety data for chronic use. High doses of resveratrol are basically untested. You'd be taking an experimental drug that was never tested in humans.

While resveratrol may do something it's as of yet unproven and taking it now is IMHO nothing short of russian roulette... the rest can be found via the search function.

*at least wait until the NIA tests resveratrol which is going to happen in the coming few years

Edited by kismet, 24 December 2009 - 08:49 PM.

[mikeinnaples]

With that being said, you'd be taking a substance of unkown benefits even on those select few endpoints in rodents (much less knowing whether any of the data translates to humans!) and the additional drawback of zero safety data for chronic use. High doses of resveratrol are basically untested. You'd be taking an experimental drug that was never tested in humans.

While resveratrol may do something it's as of yet unproven and taking it now is IMHO nothing short of russian roulette... the rest can be found via the search function.

*at least wait until the NIA tests resveratrol which is going to happen in the coming few years

To be honest, that can be said of most supplements people are taking. On the reservatrol subject though, there seems to be vastly more evidence for it having positive effect than negatives. Even if it isnt an actual CR mimetic or acts in to increase max lifespan, there is much to be said for aging gracefully as well... and doing so without starving yourself.

[kismet]

To be honest, that can be said of most supplements people are taking.

Perhaps there's an issue with "most supps" and "most people"? But let's pick for instance the following: vitamin D, menatretrenone, strontium, wineRx, creatine, taurine, etc have much, much more long term safety and efficacy data compared to resv. 

On the reservatrol subject though, there seems to be vastly more evidence for it having positive effect than negatives.

But unfortunately not in humans...

Edited by Michael, 29 December 2009 - 12:23 PM.
Misplaced quotation boxes

[mikeinnaples]

To be honest, that can be said of most supplements people are taking.

Perhaps there's an issue with "most supps" and "most people"? But let's pick for instance the following: vitamin D, menatretrenone, strontium, wineRx, creatine, taurine, etc have much, much more long term safety and efficacy data compared to resv.

On the reservatrol subject though, there seems to be vastly more evidence for it having positive effect than negatives.

But unfortunately not in humans...

I concede your point in regards to the supps you mentioned for the most part .....but wineRx? really?

Edited by Michael, 29 December 2009 - 12:24 PM.
Misplaced Quotation Boxes

[drmz]

With that being said, you'd be taking a substance [resveratrol] of unkown benefits even on those select few endpoints in rodents (much less knowing whether any of the data translates to humans!) and the additional drawback of zero safety data for chronic use. High doses of resveratrol are basically untested. You'd be taking an experimental drug that was never tested in humans.
While resveratrol may do something it's as of yet unproven and taking it now is IMHO nothing short of russian roulette... the rest can be found via the search function.

*at least wait until the NIA tests resveratrol which is going to happen in the coming few years

Amen, i cannot agree more.

Edited by Michael, 29 December 2009 - 12:25 PM.
Trim quotes

[maxwatt]

I guess I am a bit confused with your statement here and why you are so vehement. Reading the very paper you cited in (1) gives me good reason to supplement resveratrol. Is there something I missed in reading it that should lead me away from resveratrol?

Yes, the study was an utter disaster. The primary endpoint was missed by a mile. Generally, we care about maximum life span; because it best reflects real aging and slowing thereof (so research on Rapamycin falls in the category of 'awesome', resveratrol does not as of yet).
The results on those secondary outcomes can be possibly explained (IIRC) by the general polyphenolic/phytoestrogenic nature of resveratrol (therefore hardly applying to human diets already high in those compounds, etc) and many completely useless compounds that fail in humans are known to improve such outcomes in rodents. So even those weak results have to be taken with a grain of salt until replicated in other cohorts* or humans.

With that being said, you'd be taking a substance of unkown benefits even on those select few endpoints in rodents (much less knowing whether any of the data translates to humans!) and the additional drawback of zero safety data for chronic use. High doses of resveratrol are basically untested. You'd be taking an experimental drug that was never tested in humans.

While resveratrol may do something it's as of yet unproven and taking it now is IMHO nothing short of russian roulette... the rest can be found via the search function.

*at least wait until the NIA tests resveratrol which is going to happen in the coming few years

Amen, i cannot agree more.

Yet I have found nothing with as positive an effect for me on osteoarthritis. Even were celebrex to as effective, its long-term effects are even more worisome, and that is perhaps the safest of the high-power drugs in the rheumatoligists' arsenal. At least resveratrol did not shorten life expectancy in that study.

[FunkOdyssey]

I concede your point in regards to the supps you mentioned for the most part .....but wineRx? really?

To the extent that WineRX is simply dehydrated red wine, it is supported by good evidence in humans.

I am more interested in the rationale behind the 1mg sublingual methylcobalamin, an exponentially higher dose than the RDA combined with an unnaturally (compared with food) bioavailable route of administration.

[vines]

I concede your point in regards to the supps you mentioned for the most part .....but wineRx? really?

To the extent that WineRX is simply dehydrated red wine, it is supported by good evidence in humans.

I am more interested in the rationale behind the 1mg sublingual methylcobalamin, an exponentially higher dose than the RDA combined with an unnaturally (compared with food) bioavailable route of administration.

From the wikipedia article:

The sublingual route, in which B12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary or helpful. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 µg (micrograms) of cobalamin.[38] Sublingual methods of replacement are effective only because of the typically high doses (500 micrograms), which are swallowed, not because of placement of the tablet. As noted below, such very high doses of oral B12 may be effective as treatments, even if gastro-intestinal tract absorption is impaired by gastric atrophy (pernicious anemia).

So I guess the dose is not nearly as high as you might think...