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Medical Forum / General / Nutrition / March 2005Implications of B1 absorption limits for lipid-soluble thiamin use
First-time poster to this group. I've been following the sporadic pockets of discussion on the allithiamin family(TTFD, benfotiamin, etc) and its proposed effects on AGE accumulation in the body. Intriguing, and the relevant abstracts on pubmed look promising, too. I also see that some of them are available OTC as supplements, in doses rather larger than found in natural dietary sources. This fact alone does not bother me - I can appreciate the argument that "ideal" doses (for optimum health, longevity, etc) are not necessarily equivalent to the nominal range we have adapted to as a species in order to survive long enough to reproduce. However. The oft-cited "asymptote" of B1's luminal absorption (approx 10 mg? per...what? day? meal?) as well as its rigorous excretion colors the case somewhat, from an adaptive standpoint. If our systems maintain such tight control of the water-soluble form, so that little more than this can be absorbed at any one time - say a single meal - and assuming a reasonable maximum of 4 meals per day (a meal every 4 hours to allow for gastric emptying, none during an 8 hour sleep period), it seems reasonable to extrapolate a daily absorption limit of 40-50 mg. Considerably above the current RDA, but much lower than many of the suggested daily doses I've run across, both here and elsewhere, proposed to reduce or maybe even reverse AGE formation. I know that there is some disagreement on the issue of absorption limits(e.g. Michael Price ), but let's play "what if" for a bit. I've not found any reliable references that consistently warn against thiamin toxicity even at hypothetically therapeutic doses (>>50 mg). So why are our bodies so keen to limit this particular vitamin? B6, by way of comparison, has a much more generous bioavailability profile than B1, and it has a known (if somewhat uncertain) toxicity. I'm just wondering if there's something being missed, maybe some adverse effect of "megadosing" that is so subtle that it might not be detected in typical studies, but just enough to offset any benefit it might have in the long term. Picture this: on the promise of anti-AGE properties of thiamin at supra-physiological doses - in whatever form - you supplement for decades only to find out later that you only broke even, longevity- or health-wise, at great long-term expense. Worse yet, maybe you lost a little ground; not much maybe, but wouldn't breaking even have been bad enough? I'd like to end my speculation on a positive note, by reiterating that the current weight of evidence and opinion is not entirely convincing, but encouraging. Like many of you here(I assume), I wouldn't be wasting calories thinking about it if it wasn't. Anyone like to weigh in? Educated guesses, clinching references and everything in between equally welcome :) Rob Hi Rob, speculate by all means, but it is rather a big "what-if", considering that all the evidence points towards non-plateaued passive absorption. Also > Picture this: on the promise of anti-AGE properties of thiamin > at supra-physiological doses - in whatever form - you supplement > for decades only to find out later that you only broke even, > longevity- or health-wise, at great long-term expense. Worse > yet, maybe you lost a little ground; not much maybe, but wouldn't > breaking even have been bad enough? Since we're playing "what-if", what if you *don't* megadose for decades and later find that it *does* slow aging? Wouldn't you be tiny bit gutted to die before immortality becomes available? Cheers, Michael C Price ---------------------------------------- http://mcp.longevity-report.com http://www.hedweb.com/manworld.htm > First-time poster to this group. I've been following the sporadic > pockets of discussion on the allithiamin family(TTFD, benfotiamin, etc) [quoted text clipped - 42 lines] > > Rob Ah, the old "traffic-light" argument. Good point. I sincerely hope our understanding of the effects of mega-dosing vitamins improves enough in the interim to make a more informed decision possible. However, I don't think ALL the evidence points towards non-plateaued passive absorption. While many studies demonstrate desirable effects of mega-dosing, many do not. Additionally, those that focus on absorption - especially measuring serum levels following oral doses - seem to indicate that there IS an asymptote. I would LOVE to see equivalent references to the contrary, or informed criticism as to why such studies might be flawed. But so far, I haven't. Rob "Rob Capps" <rccapps@hotmail.com> wrote in message > Ah, the old "traffic-light" argument. Eh? I not familiar with this description. Care to explain? > Good point. Thank you. > I sincerely hope our understanding of the effects of mega-dosing > vitamins improves enough in the interim to make a more informed > decision possible. I hope that you realise that not megadosing is as much of a decision as megadosing. Therefore you should require the same level of proof -- expected Bayesian balance of probability -- for either course. > However, I don't think ALL the evidence points towards non-plateaued > passive absorption. While many studies demonstrate desirable effects of > mega-dosing, many do not. I don't know of any credible studies that demonstrate the harm of megadosing with enzymic cofactor precursors (such as the B-vitamins and some minerals) at sub-toxic levels -- with the possible exception of riboflavin & selenium (which I still take because the balance of prob' looks good). Nor can I find any credible null results for many supplements tested over the long term. (And any anti-aging effect would only be apparent over the long term.) > Additionally, those that focus on absorption - especially measuring > serum levels following oral doses - seem to indicate that there IS an > asymptote. I would LOVE to see equivalent > references to the contrary, or informed criticism as to why such > studies might be flawed. But so far, I haven't. Well, a number of studies have shown that serum levels do not correlate with bioavailability or throughput. The blood is a just a transport system. Cheers, Michael C Price ---------------------------------------- http://mcp.longevity-report.com http://www.hedweb.com/manworld.htm > "Rob Capps" <rccapps@hotmail.com> wrote in message > > > Ah, the old "traffic-light" argument. > > Eh? I not familiar with this description. Care to explain? A common, if fallacious, argument against speeding is that the fast driver is very likely to be "caught" by a traffic light, giving the slower driver a chance to catch up and remove whatever advantage the speeder had in terms of ETA. The flip side of this reasoning is that if the speeder makes it through the light, but the slow driver is "caught", the gap is widened further, the advantage improved. If the former scenario occurs roughly as often as the latter, as it should, the speeder will still have a net gain over the slower driver in the long run, unless stopped by the traffic cops. Not EXACTLY analogous to our discussion, but the framework is similar, in that ALL potential consequences, negative, neutral and positive, of any given action must be considered in the aggregate to decide on its desirability. That's all - nothing more exotic than a colloquial term for risk/benefit analysis :) > Well, a number of studies have shown that serum levels do not > correlate with bioavailability or throughput. The blood is a just > a transport system. Can you name one or two of these studies? Preferably one(s) including thorough explanations of their results, especially the HOW/WHY. I can accept the possibility that different water-soluble compounds are sucked out of the blood into the cells fast enough to keep serum levels relatively low, but I got the impression that this is due to INPUT limits (GI absorption) not "OUTPUT" limits (from the blood to the rest of the cells). So I guess what I'm looking for is studies that specifically contradict this. Rob Hi Rob, thanks for the explanation re traffic lights -- yes not EXACTLY analogous, I'm sure we can both agree. Actually I rather thought my argument was the reverse, but no matter. I'm bit rushed at the moment but I'll get back to you with references for the sera levels not being indicative of absorption. Cheers, Michael C Price ---------------------------------------- http://mcp.longevity-report.com http://www.hedweb.com/manworld.htm > > "Rob Capps" <rccapps@hotmail.com> wrote in message > > [quoted text clipped - 32 lines] > > Rob Hi Rob and Michael, > First-time poster to this group. I've been following the sporadic > pockets of discussion on the allithiamin family(TTFD, benfotiamin, etc) [quoted text clipped - 9 lines] > The oft-cited "asymptote" of B1's luminal absorption (approx 10 > mg? per...what? day? meal?) Never heard of it. Maybe you have some refs. Make 'um good. :>) Below I post some showing efficacy in the three to eight gram range. > as well as its rigorous excretion colors > the case somewhat, from an adaptive standpoint. If our systems maintain [quoted text clipped - 11 lines] > against thiamin toxicity even at hypothetically therapeutic doses (>>50 > mg). So why are our bodies so keen to limit this particular vitamin? They're not. It takes specific transporters to absorb it, and then to reabsorb it every 20 min when it passes thru the kidneys. M. Nature thinks we get enough, but she doesn't care if we live past 60 or not. We're going to have to make the last leg of the journey on our own. > B6, by way of comparison, has a much more generous bioavailability > profile than B1, and it has a known (if somewhat uncertain) toxicity. [quoted text clipped - 7 lines] > maybe you lost a little ground; not much maybe, but wouldn't breaking > even have been bad enough? Each individual is best placed to make financial decisions for themselves, but I will point out that for those who want to supplement with large quantities of different vitamins, it's cheaper to take large doses of B1 than it is not to. As for the toxic possibilities, I have some and post them below. We all know that some people see a glass as half full while others see it as half empty. I've noticed that some see 95% full glasses as five percent empty. > I'd like to end my speculation on a positive note, by reiterating > that the current weight of evidence and opinion is not entirely [quoted text clipped - 4 lines] > > Rob Yes, I agree completely. The big question is whether or not to supplement while continuing your studies. I do. If I were I lot younger, I might not. Rob also wrote; > However, I don't think ALL the evidence points towards non-plateaued > passive absorption. While many studies demonstrate desirable effects of > mega-dosing, many do not. I was at an Easter egg hunt last September, and some kids were bringing in loaded baskets. Some were coming back empty. A neighbor commented, "Look's like they didn't put out any eggs this year." I saw he was serious, thought a minute, then said. "Hey, you must be a doctor, medical research, maybe. He said, "Yeah, that I am. How did you guess?" If you're going to claim there may be no eggs in the field, you HAVE to have a theory that explains all those studies showing mortality, cancer, stroke, and cardiovascular benefits for things like the B vitamins, vit C, fish oil, nut consumption, etc. The few empty baskets are quite easy to explain. Yes, I'm encompassing a bit more than B1. The case is easier to argue because there isn't really that much on mega dosing of B1 in isolation. The principle is clearly the same tho. One paper for and one against doesn't mean there's a fifty/fifty chance. It means the circumstances of one study were probably not right. The most common failures of the null studies are too short, too small a dose, and wrong cohort. The kids with empty baskets walked too slow, came back too soon, and like all too many adults looked with their minds closed. > Additionally, those that focus on absorption > - especially measuring serum levels following oral doses - seem to > indicate that there IS an asymptote. No, the only indication is reduced percentage of absorption and retention. Consider the difference between asymptotic and logarithmic curves. Then guess whether or not a particular paper is empowered enough to differentiate between the two. >I would LOVE to see equivalent > references to the contrary, or informed criticism as to why such > studies might be flawed. But so far, I haven't. Post one. I'll be happy to rip it to shreds. :>) Rob, your belief appears to be just what mine was about 15 years ago when I started reading my wife's subscription to Prevention magazine. However, I soon noticed that it seemed vit. C was more likely to help than hurt. I started taking it while studying more and more. I was and am ready to stop at the first sign of a poor risk/benefit ratio. In fact I have stoped some supplements and reduced amounts of others. Michael C Price wrote: > Hi Rob, > speculate by all means, but it is rather a big "what-if", > considering that all the evidence points towards non-plateaued > passive absorption. Michael, did you know there is now recent evidence of active B1 absorption by one of the folic acid transporters? The one for the reduced dihydro form IIRC. I didn't save the reference. Thomas Here's what I have on B1. DEF: Vitamin B1 also see B vitamins Also see Benfotiamine Thiamin, a water-soluble vitamin, found in association with other B Complex vitamins in wholemeal products, brown rice, many vegetables, meat, nuts and dairy, is unstable and frequently destroyed by cooking or by preservatives. B1 is needed for carbohydrate metabolism and may be deficient in those on a high sugar diet. Helps maintain appetite, normal functioning of the nervous system, eyes, hair, heart and other muscles. Helps keep mucous membranes (digestive lining, lungs, etc) healthy. It is needed for digestion, growth and maintenance of muscle tone. Thiamine. Monograph. Altern Med Rev. 2003 Feb;8(1):59-62. Review. No abstract available. PMID: 12611562 The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003 Feb;8(1):7-19. Review. PMID: 12611557 1: Haupt E, Ledermann H, Kopcke W. Related Articles, Links Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther. 2005 Feb;43(2):71-7. PMID: 15726875 [PubMed - in process] 2: Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Related Articles, Links Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes. 2003 Aug;52(8):2110-20. PMID: 12882930 [PubMed - indexed for MEDLINE] 3: Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Related Articles, Links Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9. Epub 2003 Feb 18. PMID: 12592403 [PubMed - indexed for MEDLINE] 4: Stracke H, Lindemann A, Federlin K. Related Articles, Links A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6. PMID: 8886748 Ann Neurol. 1993 Nov;34(5):724-6. Related Articles, Links Evidence for a central cholinergic effect of high-dose thiamine. Meador KJ, Nichols ME, Franke P, Durkin MW, Oberzan RL, Moore EE, Loring DW. Department of Neurology, Medical College of Georgia, Augusta 30912-3280. In vitro animal studies have suggested that thiamine is involved in the presynaptic release of acetylcholine. Total thiamine content in cholinergic nerve terminals is comparable with that of acetylcholine, and the phosphorylation state of thiamine changes with release of acetylcholine. Thiamine binds to nicotinic receptors and may exhibit anticholinesterase activity. Based on these observations, we investigated the effects of pharmacological doses of thiamine on the cognitive deficits induced by the anticholinergic scopolamine in healthy young adults using a randomized, double-blind, placebo-controlled, double-crossover design. Drug effects were assessed by P3 event-related potential, quantitated electroencephalography, and free recall memory. Conditions included (1) baseline, (2) thiamine 5 gm p.o. and scopolamine 0.007 mg/kg IM, and (3) lactose PO and scopolamine 0.007 mg/kg IM. Thiamine significantly reduced adverse effects of scopolamine on P3 latency, spectral components of electroencephalography, and memory recall. The results are consistent with a cholinomimetic effect of thiamine in the central nervous system. Additional studies are needed to delineate the basic mechanisms and possible therapeutic efficacy of thiamine at pharmacological dosages. PMID: 8239567 [PubMed - indexed for MEDLINE] -------------------------------------------------------------------------------- 2: Psychiatry Res. 1997 May 30;70(3):165-74. Related Articles, Links Beneficial effects of thiamine on recognition memory and P300 in abstinent cocaine-dependent patients. Easton CJ, Bauer LO. Department of Psychiatry, University of Connecticut Health Center, Farmington 06030-2103, USA. The present study evaluated the effects of thiamine vs. placebo on memory task performance and event-related electroencephalographic potentials in eight abstinent cocaine-dependent patients. Patients orally ingested 5 g of thiamine and 5 g of a lactose placebo on two separate days scheduled approximately 1 week apart. The order of administration was randomized. Double-blind procedures were followed. Approximately 3 h after ingesting the capsules, patients completed Sternberg's (1975) memory scanning task during which performance and event-related potentials (P300) were recorded simultaneously. Thiamine was found to significantly improve recognition accuracy and P300 amplitude, at the midline parietal (Pz) electrode. The improvement was most reliable under conditions of increased memory load. These preliminary findings justify a further examination of the relation between thiamine's hypothesized effects on central nervous system cholinergic function, and the direct and indirect effects of cocaine abuse. PMID: 9211578 [PubMed - indexed for MEDLINE] -------------------------------------------------------------------------------- 3: J Geriatr Psychiatry Neurol. 1993 Oct-Dec;6(4):222-9. Related Articles, Links Preliminary findings of high-dose thiamine in dementia of Alzheimer's type. Meador K, Loring D, Nichols M, Zamrini E, Rivner M, Posas H, Thompson E, Moore E. Department of Neurology, Medical College of Georgia, Augusta 30912-3200. Thiamine is important not only in the metabolism of acetylcholine but also in its release from the presynaptic neuron. Pathologic, clinical, and biochemical data suggest that thiamine deficiency is detrimental to the cholinergic system and that thiamine-dependent enzymes may be altered in Alzheimer's disease. Two previous studies reported contradictory results in patients with dementia of Alzheimer's type treated with 3 g/day of thiamine. In the present study, we examined the effects of 3 to 8 g/day thiamine administered orally. Our results suggest that thiamine at these pharmacologic dosages may have a mild beneficial effect in dementia of Alzheimer's type. The mechanism of the observed effect is unknown, but the findings warrant further investigation, not only for their therapeutic implications but for their possible etiologic clues. In addition, the results suggest long-term carry-over effects that should be considered in the design of future studies.PMID: 8251051 [PubMed - indexed for MEDLINE] -------------------------------------------------------------------------------- 4: Acta Anaesthesiol. 1968;19:Suppl 4:1-14. Related Articles, Links [On probable interference between thiamine and the cholinergic system. (Experimental study)] [Article in Italian] Gritti G, Manzin E, Manani G, Gasparetto A. PMID: 5757017 [PubMed - indexed for MEDLINE] -------------------------------------------------------------------------------- 5: Zasshi Tokyo Ika Daigaku. 1967 Sep;25(5):605-20. Related Articles, Links [Experimental study on toxicity and pharmacological action of thiamine derivatives. 2. Study of the effect of thiamine derivatives on the central nervous system] [Article in Japanese] Sato S. PMID: 5625988 Hi Thomas, Rob; Nice anecdote about the (non) implications of the empty Easter egg baskets! Yes, some doctors really are that stupid. > Michael C Price wrote: >> Hi Rob, [quoted text clipped - 5 lines] > absorption by one of the folic acid transporters? The one for the > reduced dihydro form IIRC. I didn't save the reference. No, I didn't know that. BTW, I didn't mean to imply that B1 isn't actively absorbed at lower concentrations, just that whilst the active transport mechanisms tend to plateau the passive ones (e.g. diffusion, osmosis) do not. And when taking megadoses passive absorption is often more significant overall. To return an earlier point of Rob's, the absence of active transport at higher concentrations indicates that M Nature doesn't often encounter said concentrations, not that the higher concentrations are not beneficial. Cheers M > Thomas > [quoted text clipped - 133 lines] > [Article in Japanese] > Sato S. PMID: 5625988 Hi Michael and Rob, > Hi Thomas, Rob; > > Nice anecdote about the (non) implications of the empty Easter > egg baskets! Yes, some doctors really are that stupid. When smart people exibit stupid behavior, if not a simple oversight, it's almost invariably due to bias. When analyzing drug studies they do a much better job of interpretation. When dealing with studies on natural medicine many of the same people display a simply incredible level of stupidity. > > Michael C Price wrote: > >> Hi Rob, [quoted text clipped - 11 lines] > (e.g. diffusion, osmosis) do not. And when taking megadoses > passive absorption is often more significant overall. Thiamine does of course use dedicated transporters for it's "passive" diffusion. So there is a noted tendency towards a plateau. But studies that show effects at very hi doses such as the ones I posted demonstrate that no physiological plataeu has been found. I have several problems with the methodology of just about all micronutrient absorption papers. One that I haven't previously mentioned is that after prolonged consumption of a particular substance the dedicated transporters for it are usually transcribed at a higher level. So short term studies of absorption done on people taking hi levels of a substance are not necessarily indicative of the absorption of someone who has been magadosing for years. There is also a tendancy for such a person to develope better methods of dealing with potential downsides of such mega dosing. Constituent transcription of phase I (CYP450s) and phase II enzymes come to mind. Another possibility that Tim has addressed extensively in recent posts is that of the Nrf2 master controller of many coordinated antioxidative proteins. A constantly active hormetic effect on this system by chronic megadosing can not be ruled out. > To return an earlier point of Rob's, the absence of active transport > at higher concentrations indicates that M Nature doesn't often [quoted text clipped - 3 lines] > Cheers > M Yes, very true, as Rob himself acknowledged. Such instances would tend to be very rare, but the very nature of modern science is that it identifies these rare substances so that they become widely known and available for those who wish to take advantage of them. Thomas |
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