27 replies to this topic

[eason]

Michael,

There are a few things that I see in your regimen that stand out to me. But one thing that particularly concerns me is your intake of 250mg of Vitamin B6 daily (for anti-glycation purposes).

I do not say this to point out flaws but rather to understand your reasoning behind supplementing this amount, particularly when we know that high doses of Vitamin B6 can lead to neurological problems in rats. For example, we have the following study in which they claim Vitamin B6 (I'm assuming they used Pyridoxine) caused neurological damage:

http://www.ncbi.nlm....pubmed/16201314

Effects of excess vitamin B6 intake on cerebral cortex neurons in rat: an ultrastructural study.
Demir R, Acar G, Tanriover G, Seval Y, Kayisli UA, Agar A.
Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya, Turkey. rdemir@akdeniz.edu.tr
The aim of this study was to investigate whether excess of vitamin B6 leads to ultrastructural changes in cerebral cortex of forty-eight healthy albino rats which were included in the study. Saline solution was injected to to the control groups (CG-10, n = 12 for 10 days; CG-15, n = 12 for 15 days; CG-20, n=12 for 20 days). The three experimental groups (EG-10, n = 12; EG-15, n = 12; EG-20, n = 12) were treated with 5 mg/kg vitamin B6 daily for 10 days (EG-10), 15 days (EG-15) and 20 days (EG-20). Brain tissues were prepared by glutaraldehyde-osmium tetroxide double fixation for ultrastructural analysis. No significant changes were observed in the control groups. The ultrastructural analysis revealed that the numbers of damaged mitochondria, lipofuscin granules and vacuoles were significantly higher in all the experimental groups than in the control groups (p < 0.05). However, synaptic density was significantly decreased in the experimental groups as compared to the control groups (p < 0.05). The results suggest that the excess of vitamin B6 intake causes damage to the cerebral cortex due to cellular intoxication and decreased synaptic density. Thus, careful attention should be paid to the time and dose of vitamin B6 recommended for patients who are supplemented with this vitamin.

Do you believe that pyridoxamine and P5P are immune to this problem, and if so, why?

[kismet]

I hope this is not the demise of another anti-gylcation supplement. I hope there's an explanation. I've read something along the lines, perhaps even more concerning a while ago, but was too lazy to follow-up. Now, maybe it's time... maybe I'm just getting forgetful because my brain is all mushy.

Quotation from:
Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin B6
EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL

Administration of doses of 100 or 500 mg B6 per day for 10 days to a group of 58 medical students resulted in significantly impaired memorisation at 500 mg/day, and a non-significant decrease at 100 mg/day (Molimard et al., 1980). This is a potentially important observation, given the dosage and the short duration of intake. The study was designed to investigate further an earlier unpublished observation of a decrease in “brain performance” from a double-blind study in medical students conducted in 1961. The study of Molimard et al. (1980) recruited 69 first year medical students who were randomly allocated to receive identical tablets of 50 mg or 250 mg pyridoxine or placebo to be taken twice per day for 10 days.

Those who declared that they did not take the tablets were treated as a separate group. The subjects were given a simple digit coding test prior to treatment, immediately after treatment and 14 days later. In addition the subjects underwent a test on the medical physiology that had been taught during the treatment period, plus some simple numerical problems at the end of the treatment period. A total of 58 subjects completed all 3 digit coding tests, which showed a highly significant improvement with time (a learning effect) in all groups. There were no significant differences in the uncorrected scores, but evidence of a dose-related decrease in the learning effect, with a highly significant difference between the placebo group and 500 mg/day group (P<0.002) but a smaller difference between the placebo and 100 mg/day group (P<0.07). There were no differences in the other tests of performance.

In a second trial as part of the same publication, a group of 30 obese patients were randomly allocated to receive placebo or 20 mg or 1000 mg of pyridoxine per day for 15 days, with subjects given a number of tests before and immediately after treatment. An adverse doserelated effect was found for word recognition (P<0.05) but not for word or visual memorisation, together with a decrease in the results for a visual retention test in the pyridoxine treated group after treatment. These studies reported effects after short-term treatment, and no studies have investigated the relationship between dose and duration of treatment for such effects.

Primary source:
Molimard R, Marillaud A, Paille A, Le Devehat C, Lemoine A and Dougny M (1980).
Impairment of memorization by high doses of pyridoxine in man. Biomedicine 32: 88-92.

Edited by kismet, 08 February 2010 - 01:14 AM.

[Sillewater]

Krillin had a post about it here, he's mentioned it in other threads too:
http://www.imminst.o...&...st&p=196418

[thatperson]

Vitamine b6 in the form of Pyridoxine Hydrochloride, has definatly had bad negative effects for me in the past lasting 2 months+. Muscle twitching poor memory etc.

[J_o_L]

Does P5P have these negative effects as well ?

[neogenic]

P5P does not have this issue. Pyridoxine actually has this issue because it is similar to P5P and binds at the receptor at higher doses blocking endogenous p5p... ironically. Very high doses of P5P have demonstrated zero toxicity and it is the coenzymated form. Moral of the story synthetic, crap versions of vitamins in your total cereal are not the same as what's found in food or your body. They can not and should not be lumped in together and to do so is quite erroneous. Pyridoxamine is the other coenzyme form available besides p5p. Both should have no neurotoxicity associated with them.

http://www.thorne.co...text/6/1/87.pdf
This is an older monograph and more research has been done since then, but it illustrates the points quite well.

[NDM]

so the bottom line: given what we know, what would constitute the upper limit of a reasonably safe supplementation with B6?

No more than...?... mg/day

[Blue]

Some of the information regarding the B6 vitamins by supplements resellers in favor of the more expensive P5P form seem dubious. The Thorne report which rather selectively cites the often ancient studies is one example.

First, P5P = PLP is converted to pyridoxal (PL) in the gut before absorption. So what is interesting is the differences between pyridoxal (PL), pyridoxine (PN), and pyridoxamine (PM).

Institute of Medicine : Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998):
"PN at high doses raises the plasma PLP concentration and is retained more effectively than is PL (Shane, 1978). Similarly, dietary pyridoxamine (PM) and PL are about 10 percent less effective than PN in raising the plasma PLP concentration, and slightly more of these vitamins is excreted in the urine as 4-pyridoxic acid (4-PA) (Wozenski et al., 1980). Most controlled B6 studies have used PN as the added B6 source, but requirements calculated from these studies would underestimate the B6 requirement by only 5 percent or less for individuals deriving most of their B6 as PLP and PMP from animal sources."

So PN is actually slightly better than the other forms at raising plasma PLP (P5P) in a normal population. That may be different in patients with severe disease, especially liver disease, as suggested by the studies mentioned in the Thorne report.

Pyridoxamine (PM) has some interesting research and looks better than the other forms at least in vitro. However, it has a rather short half-life before conversion to PLP. Not sure how much in vivo research, where it is taken intermittently, there are showing it is better than the other forms.

Now regarding the central question of toxicity. As far as I know there is no research showing that the non-pyridoxine forms are less toxic. That pyridoxine itself should be damaging as compared to PLP or its metabolities seems just to be an unproven speculation. That most cases of neurotoxicity have been seen from pyridoxine is only to be expected since it the commonly used form. Does anyone have an actual study showing less neurotoxicity for any of the non-pyridoxine forms?

Edited by Blue, 09 February 2010 - 11:49 AM.

[neogenic]

The study on a dephosphorylated form from the seventies is interesting (I'd like to look at it)...there is some compelling evidence, granted in those with liver damage that P5P was not only better...but 300% better. There are some that question differences of absorption (oral/sublingual), much like MB12, but much like MB12 I've seen bloodwork with sublingual impact being more significant.

The monograph from Thorne was easily discarded by you like its a musclemag ad-report. I find their monographs are far more reliable than any of the "referenced" LEF magazine "articles" as of late. AOR touts this form and being a clinician (Chief Clinical Dietitian) and a formulator I've seen the bloodwork on P5P be compelling.

I had some other research on it, but I will dig for it. In my mind there is no question, even with straight PO consumption, which is better. And I've none people to mega-dose P5P with absolutely zero side effects.

[neogenic]

http://neurotalk.psy...amp;postcount=4
After doing some digging around, and I am not at home to access my papers...this thread covers a lot on P5P and is very, very well referenced and thought out.

I

[Blue]

The study on a dephosphorylated form from the seventies is interesting (I'd like to look at it)...there is some compelling evidence, granted in those with liver damage that P5P was not only better...but 300% better. There are some that question differences of absorption (oral/sublingual), much like MB12, but much like MB12 I've seen bloodwork with sublingual impact being more significant.

The monograph from Thorne was easily discarded by you like its a musclemag ad-report. I find their monographs are far more reliable than any of the "referenced" LEF magazine "articles" as of late. AOR touts this form and being a clinician (Chief Clinical Dietitian) and a formulator I've seen the bloodwork on P5P be compelling.

I had some other research on it, but I will dig for it. In my mind there is no question, even with straight PO consumption, which is better. And I've none people to mega-dose P5P with absolutely zero side effects.

If you are talking about the 1977 study on patients with severe liver disease it is irrelevant to a normal population.

Do you have source regarding difference between oral/sublingual.? Never heard of that being important regarding B6 vitamins.

See no reason to differentiate AOR, LEF or Thorne. They are all more or less dishonest in their publications by using very selective positive only citations of various kinds to sell their products.

Oh, anecdotal evidence is not interesting. If wanting that you can find endless amounts for any substance, including homeopathic ones, on the customer reviews sections of iherb.

The main issue in this thread is neurotoxicity. I am still interested in knowing if anyone has a study showing less of this for the non-pyridoxine forms.

[Blue]

" In very high doses, pyridoxine is neurotoxic in humans and other animals. Using morphometry and a model system of dorsal root ganglion neurons in culture, we found that several analogs of pyridoxine were neurotoxic in vitro. Those that may be converted into active coenzymes— pyridoxal, pyridoxine, and pyridoxamine— were almost equal in, toxicity. Pyridoxic acid, which is not active, was nontoxic. Pyridoxamine 5-phosphate, which cannot enter cells, also was nontoxic. Several hypotheses that link coenzyme function to toxic effect are described."
http://www.springerl...515813n1473704/

As stated earlier P5P=PLP is converted to PL=pyridoxal in the gut before absorption. Which from this cell study is as toxic as pyridoxine. Which does not necessarily mean that pyridoxal is toxic in vivo if, for example, it is more rapidly converted PLP and this is less toxic. Any animal studies?

[kismet]

P5P is not the natural form. As far as I know pyridoxamine and P5P are experimental drugs and not found in food. Also, I don't see any reason to take speculation of why P5P might be safer than B6 over two (pre-)clinical studies of a very close analog (pyridoxin) showing significant neurtoxicity or neurologic problems. Blue's right in that regard...

See no reason to differentiate AOR, LEF or Thorne. They are all more or less dishonest in their publications by using very selective positive only citations of various kinds to sell their products.

I didn't know Thorne's selling any products? OTOH, you must be kidding about LEF. If AOR is bad (and, yes, they surely are - they have a vested interest so they must twist the evidence at least a lil') than LEF is beyond ridiculous.  In the end any, even the most unbiased, review on this planet is "more or less" selective in their citations. It's all fair game as long as you don't over do it (like supplement pushers).

The reason pyridoxamine and P5P are preferred is probably because only pyridoxamine is in clinical development in diabetics and backed by (weak) clinical safety and efficacy data and because P5P is - apparently - more effective in vivo (in rats) and was also clinically employed / or is in further development.

What is the interesting pyridoxamine reseach you mention? I thought the reason why people use P5P was actual in vivo research (in rats) showing superior efficacy over pyridoxamine. I am not sure there is in vivo research showing P5P and Pyridoxamine to be superior to pyridoxin, though.

For instance the MEND-CABG II RCT, n~3k & other trials; no evidence of neurotox. (but it was a very short trial):
"Selected prespecified adverse events are shown in Table 7. Overall rates of other serious and nonserious adverse events (including virtually all MedDRA system organ classes and preferred terms) were similar between patients assigned to receive MC-1 and placebo. Nausea and vomiting, the only known dose-related adverse effects of MC-1, were numerically more common among patients assigned to MC-1 than among those assigned to placebo."

The same goes for the other phase II trial(s), but obviously all of them are either too short and/or too small to give conclusive answers...

Skimming my notes, I do think P5P & pyridoxamine > pyridoxine, but I am not sure either is worth the risk. Pyridoxamine is superior in vitro and in clinical trials. P5P is/was in clinical trials and is more effective in vivo in rats. Both are less neurotoxic...

Skimming my notes further, I found a primary ref. that should be of interest: the vitamers -apparently- are less toxic than B6! (just how much?)

J Appl Toxicol. 2004 Nov-Dec;24(6):497-500.
Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet.
Levine S, Saltzman A.

Now if I only had time to more than skim all the refs. The last paper is the interesting one.

Edited by kismet, 09 February 2010 - 06:03 PM.

[OneScrewLoose]

Is P5P fully converted to pyridoxal, or just some of it?

[stephen_b]

PMID 15558839 was cited on Paul Wakfer's page on pyridoxamine:

Large doses of pyridoxine cause injury to the primary sensory neurons in trigeminal and dorsal root ganglia of animals and patients subjected to megavitamin therapy. The increased hazard to subjects with reduced renal excretory function has been explored previously. In the present work, the neurotoxicity of pyridoxine for rats was found to be increased by dietary protein deficiency. A mere 3 or 7 days of pretreatment with either of two protein-deficient diets were sufficient to accelerate and intensify the clinical neurological signs and histological lesions from pyridoxine injections. These results are caused, at least in part, by loss of body weight, decreased protein binding in serum and decreased consumption of water and decreased volume of urine, which reduce the urinary losses of the toxicant. The vitamers related to pyridoxine (pyridoxal, pyridoxamine) and the coenzyme (pyridoxal 5-phosphate) did not cause clinical signs or lesions similar to those produced by pyridoxine even when injected in maximum tolerated doses. Neither a protein-deficient diet nor bilateral nephrectomy changed the results with the vitamers.

StephenB

Edited by stephen_b, 09 February 2010 - 11:03 PM.

[neogenic]

The study on a dephosphorylated form from the seventies is interesting (I'd like to look at it)...there is some compelling evidence, granted in those with liver damage that P5P was not only better...but 300% better. [...] I've seen bloodwork with sublingual impact being more significant.

[...] being a clinician (Chief Clinical Dietitian) and a formulator I've seen the bloodwork on P5P be compelling. [...] In my mind there is no question, even with straight PO consumption, which is better. And I've none people to mega-dose P5P with absolutely zero side effects.

If you are talking about the 1977 study on patients with severe liver disease it is irrelevant to a normal population.
[...]
Oh, anecdotal evidence is not interesting.

Anecdotal? Bloodwork done with patients is irrelevant? Did you read the link I posted below my responses? There's tons of great info...disproving a lot of thoughts and concerns from a very well done and thought collection of sources. And I am not sure how you've wrote off completely the thoughts/hypothesis of binding/competition just because they're "thorne". Can you explain why you think that theory is erroneous? Is there newer data to the contrary when its study authors that concluded those statements that Thorne is merely passing along?

And no, I put AOR and Thorne, well, well, above LEF. LEF is just getting silly lately. I used to really love that company.

I fail to see how anything is just blanketly "irrelevant" like that. Please explain why there is such a difference? It at least makes one go, Hmmm. No? 300% is irrelevant? I'd like to know how so? Really.

Edited by Michael, 10 February 2010 - 04:02 PM.
Trim quotes

[neogenic]

PMID 15558839 was cited on Paul Wakfer's page on pyridoxamine:

Large doses of pyridoxine cause injury to the primary sensory neurons in trigeminal and dorsal root ganglia of animals and patients subjected to megavitamin therapy. The increased hazard to subjects with reduced renal excretory function has been explored previously. In the present work, the neurotoxicity of pyridoxine for rats was found to be increased by dietary protein deficiency. A mere 3 or 7 days of pretreatment with either of two protein-deficient diets were sufficient to accelerate and intensify the clinical neurological signs and histological lesions from pyridoxine injections. These results are caused, at least in part, by loss of body weight, decreased protein binding in serum and decreased consumption of water and decreased volume of urine, which reduce the urinary losses of the toxicant. The vitamers related to pyridoxine (pyridoxal, pyridoxamine) and the coenzyme (pyridoxal 5-phosphate) did not cause clinical signs or lesions similar to those produced by pyridoxine even when injected in maximum tolerated doses. Neither a protein-deficient diet nor bilateral nephrectomy changed the results with the vitamers.

StephenB

That's pretty solid evidence to me. The link I posted discusses some thoughts on impurity issues being highly significant with pyridoxine and that may play a part in the toxicity concerns. Its quite interesting.

Edited by neogenic, 10 February 2010 - 02:28 AM.

[neogenic]

" In very high doses, pyridoxine is neurotoxic in humans and other animals. Using morphometry and a model system of dorsal root ganglion neurons in culture, we found that several analogs of pyridoxine were neurotoxic in vitro. Those that may be converted into active coenzymes— pyridoxal, pyridoxine, and pyridoxamine— were almost equal in, toxicity. Pyridoxic acid, which is not active, was nontoxic. Pyridoxamine 5-phosphate, which cannot enter cells, also was nontoxic. Several hypotheses that link coenzyme function to toxic effect are described."
http://www.springerl...515813n1473704/

As stated earlier P5P=PLP is converted to PL=pyridoxal in the gut before absorption. Which from this cell study is as toxic as pyridoxine. Which does not necessarily mean that pyridoxal is toxic in vivo if, for example, it is more rapidly converted PLP and this is less toxic. Any animal studies?

This is covered in that link I posted as well. The "gut" idea may or may not be accurate. Hopefully some peruse it. Its quite the fascinating read.

Also, to quote Dr. Sahelian: Vitamin B-6 exists in different forms; one of those forms, pyridoxal 5'-phosphate (PLP), serves a cofactor in many enzyme reactions, including the transsulfuration pathway, in which homocysteine is converted to cystathionine and then to cysteine."

Wiki: "Pyridoxal-phosphate (PLP, pyridoxal-5'-phosphate, P5P) is a prosthetic group of some enzymes. It is the active form of vitamin B6, which comprises three natural organic compounds, pyridoxal, pyridoxamine and pyridoxine."

I am failing to see how a phosphate group make this not a coenzyme form when it does occur in the body (despite what is stated in this thread elsewhere) and no, coenzyme forms...none of them occur in food...that's a bizarre discussion (this was brought up in another post).

Also the deficiency related to enzymatic dysfunction issue is significant, not to the degree of 5-mthf, but significant nonetheless. Again, that link discusses this...and blacks in particular are at higher risk for this. P5P would certainly prove dramatically superior in those individuals.


P5P=PLP, should be readily clear, hopefully not a point of confusion for those reading along.

Edited by neogenic, 10 February 2010 - 02:39 AM.

[neogenic]

"Michael" from this forum discussed this in another thread with some interesting input:

does anyone have any info on p5p bioavailability? i was under the impression it would much higher serum levels of p5p than other forms of b6 but this suggests otherwise:

http://www.efsa.euro...f?ssbinary=true

As only dephosphorylated vitamers can be transported into the cells (Coburn et al., 2003) the bioavailability of intact pyridoxal 5’-phosphate upon oral intake would be low. Bioavailability of vitamin B6 from pyridoxal 5’-phosphate requires hydrolysis of the phosphate group before absorption through the intestinal layer may occur.

Almost all authorities agree on this point generally. But note, first that they say that "only dephosphorylated vitamers can be transported into the cells ", which is not the same as having it absorbed into serum; and remember that when they say that "Bioavailability of vitamin B6 from pyridoxal 5’-phosphate requires hydrolysis of the phosphate group before absorption through the intestinal layer may occur", and that such hydrolysis results in pyridoxal, not simple B6 (pyridoxine). Additionally, some preliminary evidence that while most P5P is indeed dephosphorylated before absorption, some remains intact and is absorbed, either by passive diffusion across the ECF, or perhaps active transport (1-3). Any of these mechanisms could lead to very different pharmacodynamics between B6 and P5P, irrespective of how many molecules of the core pyridoxine structure gets out of the intestinal lumen and into the serum (simple bioavailabiltiy). ...

Moreover, high-dose B6 has been reported to cause a reversible neuropathy, which has not been reported (as I would assume that it would be) for quite high dose P5P in the pharma trials ((6) and its Phase II precursor), which may also somehow involve the pharmacokinetics or pharmacodynamics; I'd say IAC it's wise to constrain one's total intake of all of forms of B6, and especially of B6 proper.

It's also worth noting that peak and total AUC bioavailability of P5P is higher from conventional rather than enteric-coated dose forms in humans (7), and when taken 15 mins after a meal rather than on an empty stomach or at the beginnning (8).

NB: there there is again an issue of possible vestigal CoI here, for which I again urge all readers to see my discl0sure, tho' I swear up and down that my comments are made in good faith and public interest, not out of any anticipation of personal gain.

[Refs at original post]

Edited by Michael, 10 February 2010 - 04:17 PM.
Cleanup & trim

[Blue]

P5P is not the natural form. As far as I know pyridoxamine and P5P are experimental drugs and not found in food. Also, I don't see any reason to take speculation of why P5P might be safer than B6 over two (pre-)clinical studies of a very close analog (pyridoxin) showing significant neurtoxicity or neurologic problems. Blue's right in that regard...

See no reason to differentiate AOR, LEF or Thorne. They are all more or less dishonest in their publications by using very selective positive only citations of various kinds to sell their products.

I didn't know Thorne's selling any products? OTOH, you must be kidding about LEF. If AOR is bad (and, yes, they surely are - they have a vested interest so they must twist the evidence at least a lil') than LEF is beyond ridiculous.  In the end any, even the most unbiased, review on this planet is "more or less" selective in their citations. It's all fair game as long as you don't over do it (like supplement pushers).

The reason pyridoxamine and P5P are preferred is probably because only pyridoxamine is in clinical development in diabetics and backed by (weak) clinical safety and efficacy data and because P5P is - apparently - more effective in vivo (in rats) and was also clinically employed / or is in further development.

What is the interesting pyridoxamine reseach you mention? I thought the reason why people use P5P was actual in vivo research (in rats) showing superior efficacy over pyridoxamine. I am not sure there is in vivo research showing P5P and Pyridoxamine to be superior to pyridoxin, though.

For instance the MEND-CABG II RCT, n~3k & other trials; no evidence of neurotox. (but it was a very short trial):
"Selected prespecified adverse events are shown in Table 7. Overall rates of other serious and nonserious adverse events (including virtually all MedDRA system organ classes and preferred terms) were similar between patients assigned to receive MC-1 and placebo. Nausea and vomiting, the only known dose-related adverse effects of MC-1, were numerically more common among patients assigned to MC-1 than among those assigned to placebo."

The same goes for the other phase II trial(s), but obviously all of them are either too short and/or too small to give conclusive answers...

Skimming my notes, I do think P5P & pyridoxamine > pyridoxine, but I am not sure either is worth the risk. Pyridoxamine is superior in vitro and in clinical trials. P5P is/was in clinical trials and is more effective in vivo in rats. Both are less neurotoxic...

Skimming my notes further, I found a primary ref. that should be of interest: the vitamers -apparently- are less toxic than B6! (just how much?)

J Appl Toxicol. 2004 Nov-Dec;24(6):497-500.
Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet.
Levine S, Saltzman A.

Now if I only had time to more than skim all the refs. The last paper is the interesting one.

Regarding Thorne, see
http://www.thorne.co...op_products.jsp

Having read some of the magazine articles of AOR and LEF I see no reason to differentiate them. (Well, LEF has a really evil system for abbreviating their references.) Both go through the literature with a microscope searching for anything positive regarding the substance discussed while avoiding null/negative results.

At least some time ago pyridoxamine had more research in done than PLP as likely supplement because pyridoxamine had better patent protection. Likely difficult to get pyridoxamine as a supplement these days because of this. Regarding better effect in rat for PLP compared to PM I guess you are referring to this?
http://ndt.oxfordjou...stract/gfm166v1

Thanks for the study regarding neurotoxicity in rats. Makes PLP and PM looks safer to use. Although rats are not humans.

Regarding the short-term study on the effect on cognition. There are several relatively long-duration studies where relatively high-doses of PN + other b vitamins have been given in an attempt to prevent cognitive decline in the elderly. While not improving compared to placebo, they did worsen either.

Edited by Blue, 10 February 2010 - 12:21 PM.

[kismet]

Yes, that is the study. Although, I rarely read AOR (or LEF), I wouldn't have thought it anyone could come close to LEF's defense of sucky multivitamins or dangerous megadoses (?) and whatnot.

There is still some unique research on pyridoxamine, I guess. You get for instance a new study in obese mice. While I haven't read the paper yet, it does not seem completely worthless (high dose PM apparently reduces serum AGEs and 8-OHdG below controls, which is kind of neat; although accumulation was merely normalised).

Metabolism. 2009 Jul;58(7):934-45.
Effects of pyridoxamine (K-163) on glucose intolerance and obesity in high-fat diet C57BL/6J mice.
Hagiwara et al.

Oh, yes, I uploaded the toxicity paper in the members section for those interested.

Edited by kismet, 10 February 2010 - 02:21 PM.

[Blue]

AOR's supplements are certainly better formulated than LEFs. But their magazine articles are about equal hagiographies. Although somewhat useful for looking up about almost everything positive about a substance.

Not really clear why PLP should be better than PM since PM is rather rapidly converted to PLP causing about equal blood concentrations of PLP in humans as per my first post. Is PM itself toxic, or is it due to different conversion between Bs in rats, or due to different conversion between Bs with diabetes, or something else?

[Michael]

All:

Sound of clicking pillboxes and rummaging ...

Well, looks like my pill regimen is about to get a lot cheaper ...

Thank you, eason and kismet.

Let's start at the beginning, by dispensing with the disputed study of P5P vs PN in liver disease patients.(5) Aside from the fact that one should always be extremely cautious in making leaps from results diseased people into healthy life extensionists (a theme to which we will shortly return), or the readily-discovered and somewhat predictable fact that people with liver disease have "Abnormal regulation of plasma pyridoxal 5'-phosphate" (5,10), no one has apparently noticed that the full article is available in free full-text thanks to American taxpayers: if someone had, s/he would have noted that this study involved intravenous delivery, not oral, which of course bypasses the dephosphorylation of P5P which (as noted in a previous post) is how the great majority of oral B6 as P5P is absorbed. And, although only available by subscription (and now to full Imminst members, thanks to K.....†), (12) while ambiguously worded seems to indicate that the substantial reduction in B6 neurotoxicity in PM an P5P vs PN was also for the injected vitamer or coenzyme.

So, how seriously should we take these newly-discovered reports? Very seriously, in my view.

As I hope everyone taking PM, P5P, or even megadose PN already knew, there is certainly plenty of evidence that higher-dose PN (>500 mg/d) does cause a reversible sensory neuropathy in humans. Molimard et al ((2), as summarized by (3)) observed subtle and apparently dose-dependent cognitive deficits in humans at 200 and likely 100 mg/d, despite a lack of any such symptoms; I note that this study was not reviewed by the Institute of Medicine in setting the No Observed Adverse Effect Level (NOAEL) of 200 mg/day for adults, nor the resulting tolerable Upper Limit (UL) of 100 mg. Effects on memory are consistent with the evidence of ultrastructural damage and in particular decreased synaptic density in the rodents (4), and to observe such effects on memory without overt neuropathy also seems quite consistent with other rodent studies, which showed evidence of abnormal startle response in overdosed rats despite a lack of overt neurotoxicity (at 100, 200 or 300 times -- but not 10 x -- the requirement (8); the same authors, in a short-term study, observed "A transient, but significant, elevation in acoustic startle response, a central nervous system reflex, was observed in rats fed excess vitamin B-6" at 20 x rat 'RDA.' (9) The range of 20-100 x the human DRI is just 34-170 mg -- still below what might be a clinically effective dose for AGE in diabetic humans. The free full text of (4) also says that:

Many studies dealing with administration of different daily doses of excess vitamin B6 have suggested that the excess of this vitamin affects the brain and serum concentrations of some amino acids and cortical serotonin receptors. ... The experiments on rats have demonstrated that dietary deficiency of vitamin B6 causes very important morphological changes such as dendrite loss, perikaryonal swelling, vacuolization of dendrites, neuropil degeneration in cortical layers, glial proliferation in the area of neuronal loss [ref], and decreased number of Purkinje cells in the cerebellum [refs]. Interestingly, we have observed similar changes in the cerebral cortex in the experimental groups receiving excessive vitamin B6 doses, in a time-dependent manner … ultrastructural changes observed in the perikaryons and neuropil of animals treated with excess vitamin B6 for short period were, however, less pronounced ... (4)

It is entirely reasonable to think that cognitive deficits and brain damage might manifest at lower doses than those required for neuropathy, depending on the disposition, storage, metabolism, and requirements of the brain vs the periphery.

The requirement of pyridoxine in the CNS is a 100-fold greater than in the peripheral organs. In humans, ... vitamin B6 ... is stored primarily in the liver and to a lesser extent in the muscle and brain. ... It is unclear at this time which of the forms [ pyridoxine, pyridoxamine, pyridoxal, or P5P] crosses the blood brain barrier (BBB) and what biochemical reactions centrally activate the vitamin. Considering the selective permeability of the BBB (a phosphorylated molecule cannot cross the BBB), PLP levels in the brain could substantially differ from the periphery. Imaging of brain vitamin B6 with radioactive tracers becomes possible only when they are available in the phosphorylated form (essentially by being trapped intracellularly), hence, the significance of a detailed pathway exploration ... [and] the need to develop a reference range for optimal levels of this cofactor, especially in the CNS, is important.(6)

In (7), rats fed 20x their 'RDA' showed (nonsignificantly) ~33% higher brain levels of PN (and, interestingly, PM), slightly lower levels of P5P, substantially (but still NS) higher levels of the metabolite PA, and a pretty dramatic increase in pyridoxal. This is, methinks, consistent with the idea of selective retention of B6 in the brain because of its critical dependence, and with the inability of intact P5P to enter or exit the brain.

Now, why are we taking this stuff in the first place? There is a great deal of animal evidence in diabetic and/or obese, hyperinsulinemic rodents that pyridoxamine lowers tissue AGE and prevents associated complications. There is one study supporting similar (and indeed larger) such effects using P5P.

The only data from human clinical trials is suggestive at best of a benefit for PM diabetic and renal disease patients, and showed no benefit of P5P for heart disease. The company advancing PM has put its best spin on the results, but has been in a rather stagnant bend in the clinical pipeline for years, having been unable to secure sufficient new investment to perform further studies.

Not only do we have no data whatsoever showing benefits (or risks) in normal, healthy humans: we have no such data on the key question (AGE levels) in animal models! We don't know if it would be of any benefit at all, even to a rat -- and let's remember that even targeting AGE as an intermediary in 'normal' aging is both a surrogate marker, and an unvalidated one (but see eg ()); indeed, while there is good correlative evidence for a relationship between AGE accumulation rates and species lifespan, and while CR (the most well-validated and until recently only intervention to retard aging in mammals) does lower AGE levels, selectively lowering blood sugar with transgenic GLUT4 (the insulin-regulated glucose transporter for muscle and fat) -- which, ceteris paribus, ought to lower AGE, tho' they didn't measure this -- had no effect whatsoever on lifespan in either normally-fed or Calorie-restricted rodents (1).

In addition to the lack of any strong reason to expect a benefit for these substances in healthy life extensionists, the risk side of the risk:reward calculus may very well be different for us than for the patients in human trials or their rodent analogs. For instance, to the extent that these agents' mechanism of action is as carbonyl traps, it is entirely reasonable to speculate that due to sheer stoichiometry between agent and target molecule, a similar dose to that used in diabetic and/or renally-impaired humans would leave much more of the molecule intact in circulation rather than being sequestered or modified by interaction with abundant substrate.

I already recognized that PM and P5P were by a substantial margin the most tenuous and risky of supplement gambles that I was making; this evidence clearly takes that calculus, straps it to an anvil, and pushes it over the edge. It is extremely clear to me that no healthy, normal life extensionist should continue taking these supplements as antiglycation agents.I would be inclined to counsel against it even in diabetic patients, pending further evidence on either risk or reward.

-Michael

1. Plasma glucose and the action of calorie restriction on aging.
McCarter R, Mejia W, Ikeno Y, Monnier V, Kewitt K, Gibbs M, McMahan A, Strong R.
J Gerontol A Biol Sci Med Sci. 2007 Oct;62(10):1059-70.
PMID: 17921417 [PubMed - indexed for MEDLINE]

2. Molimard R, Marillaud A, Paille A, Le Devehat C, Lemoine A, Dougny M.
Impairment of memorization by high doses of pyridoxine in man. Biomedicine. 1980
May;32(2):88-92. PubMed PMID: 7388119.

3. SCF (Scientific Committee on Food). Opinion of the scientific committee on food on the tolerable upper intake level of vitamin B6 (SCF/CS/NUT/UPPLEV/16 Final). 2000.

4. Demir R, Acar G, Tanriover G, Seval Y, Kayisli UA, Agar A. Effects of excess vitamin B6 intake on cerebral cortex neurons in rat: an ultrastructural study.
Folia Histochem Cytobiol. 2005;43(3):143-50. PubMed PMID: 16201314.

5. Labadarios D, Rossouw JE, McConnell JB, Davis M, Williams R. Vitamin B6 deficiency in chronic liver disease--evidence for increased degradation of pyridoxal-5'-phosphate. Gut. 1977 Jan;18(1):23-7. PubMed PMID: 838399; PubMed
Central PMCID: PMC1411256.

6. Yarlagadda, Atmaram, Clayton, AH. Blood Brain Barrier: The Role of Pyridoxine. Psychiatry, August 2007.

7. Schaeffer MC, Sampson DA, Skala JH, Gietzen DW, Grier RE. Evaluation of vitamin B-6 status and function of rats fed excess pyridoxine. J Nutr. 1989 Oct;119(10):1392-8. Review. PubMed PMID: 2685201.

8. Schaeffer MC. Excess dietary vitamin B-6 alters startle behavior of rats. J Nutr. 1993 Aug;123(8):1444-52. PubMed PMID: 8336216.

9: Schaeffer MC, Gretz D, Gietzen DW, Rogers QR. Dietary excess of vitamin B-6 affects the concentrations of amino acids in the caudate nucleus and serum and the binding properties of serotonin receptors in the brain cortex of rats. J Nutr. 1998 Oct;128(10):1829-35. PubMed PMID: 9772157.

10. Mitchell D, Wagner C, Stone WJ, Wilkinson GR, Schenker S. Abnormal regulation
of plasma pyridoxal 5'-phosphate in patients with liver disease.
Gastroenterology. 1976 Dec;71(6):1043-9. PubMed PMID: 992265.

11: Levine S, Saltzman A. Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet. J Appl Toxicol. 2004 Nov-Dec;24(6):497-500. PubMed PMID:
15558839.

12. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press. Washington, DC, 1998.

Edited by Michael, 11 February 2010 - 03:01 PM.
Note on NOAEL; link to posted study; unmashed refs 4 & 5

[Blue]

Again regarding the effect of cognition from pyridoxine, Molimard's two-week study on a total of 60 and 30 persons is interesting, but was very small och short-term. If the "low-dose" (compared to amounts required for neuropathy) cognitive effect was of the same origin as the neuropathy one would expect that it would worsen with time since the neuropathy only appears after many months or years of supplementation. However, there is no evidence for harmful effects on cognition in the many much longer studies on B6 and cognitive decline. One example:

"BACKGROUND: High homocysteine concentrations may be neurotoxic and contribute to cognitive decline in older persons. OBJECTIVE: The objective was to examine the effect of supplementation with folic acid, vitamin B-12, and vitamin B-6 on cognitive change in women with cardiovascular disease (CVD) or CVD risk factors. DESIGN: The Women's Antioxidant and Folic Acid Cardiovascular Study is a randomized placebo-controlled trial designed to test the effect of a combination of B vitamins (2.5 mg folic acid/d, 50 mg vitamin B-6/d, and 1 mg vitamin B-12/d) on secondary prevention of CVD. Female health professionals aged >or=40 y (n = 5442) with CVD or >or=3 coronary risk factors in 1998 (after folic acid fortification began in the United States) were randomly assigned to treatment. Shortly after randomization (mean: 1.2 y), a substudy of cognitive function was initiated among 2009 participants aged >or=65 y. Telephone cognitive function testing was administered up to 4 times over 5.4 y with 5 tests of general cognition, verbal memory, and category fluency. Repeated-measures analyses were conducted, and the primary outcome was a global composite score averaging all test results. RESULTS: Mean cognitive change from baseline did not differ between the B vitamin and placebo groups (difference in change in global score: 0.03; 95% CI: -0.03, 0.08; P = 0.30). However, supplementation appeared to preserve cognition among women with a low baseline dietary intake of B vitamins. CONCLUSIONS: Combined B vitamin supplementation did not delay cognitive decline among women with CVD or CVD risk factors. The possible cognitive benefits of supplementation among women with a low dietary intake of B vitamins warrant further study."
http://www.ajcn.org/...tract/88/6/1602

Older reviews:
http://archinte.ama-...stract/167/1/21
http://www.ncbi.nlm....pubmed/14584010

So any "low-dose" harmful effect on cognition from pyridoxine, if it exists at all, seems to be rather subtle. At least for a dose of 50 mg/day.

In addition we have, as mentioned previously, the rodent study showing no clinical signs or lesions similar to those produced by PN from PM or PLP. Also the human studies on PM or PLP, although not very long-term, which did not find increased neuropathy incidence.

Edited by Blue, 11 February 2010 - 09:00 AM.

[Sillewater]

This discussion combined with B6's effect on steroid receptors has just removed P5P from my regimen.

[Michael]

Again regarding the effect of cognition from pyridoxine, Molimard's two-week study on a total of 60 and 30 persons is interesting, but was very small och short-term. If the "low-dose" (compared to amounts required for neuropathy) cognitive effect was of the same origin as the neuropathy one would expect that it would worsen with time since the neuropathy only appears after many months or years of supplementation. However, there is no evidence for harmful effects on cognition in the many much longer studies on B6 and cognitive decline.

First, the animal data I cited suggested that the threshold for cognitive effects in humans would likely be somewhere above 34 mg but begin by about 170 mg, and in Molimard's study the defects at 100 mg were less clear than that at 200 mg. The AJCN study used only 50 mg, and others of the studies reviewed used less. Moreover, these were all studies in middle-aged or elderly people with CVD, and coadminstered folic acid and/or B12 which might have masked or blunted any negative effects of B6; and as Demir et al note,

Under normal conditions, oral intake of vitamin B6 is lower than recommended. Particularly in elderly people, it gradually decreases. The experiments on rats have demonstrated that dietary deficiency of vitamin B6 causes very important morphological changes ... Fairfield and Fletcher [15] have suggested that neuropathic cases resulting from a deficiency of vitamin B6 may be treated with vitamin B6 excess intake ["attack dose" -MR].

People with marginal or deficient B6 intake might be expected to be more tolerant to high B6 intake for some time; and again, IAC, one wouldn't expect 50 mg to have this negative side effect; and OTOH, 50 mg is not nearly enough PM to even potentially protect against AGE-related tissue damage.

Second, it's not clear to me that one would expect a time-dependent effect: again, we don't know much about the ADME of B6 in the brain, and PN and PL levels might reach a toxic steady-state level relatively early on.

In addition we have, as mentioned previously, the rodent study showing no clinical signs or lesions similar to those produced by PN from PM or PLP.

As I noted in my post,

although only available by subscription (and now to full Imminst members, thanks to K.....), (12) while ambiguously worded seems to indicate that the substantial reduction in B6 neurotoxicity in PM an P5P vs PN was also for the injected vitamer or coenzyme.[emphasis added]

To be clearer: they definitely tested PN both by injection and by oral gavage; they seem to have only tested the other forms by injection, bypassing the de- and re-phosphorylation in the gut and any additional metabolism in the liver.

Also the human studies on PM or PLP, although not very long-term, which did not find increased neuropathy incidence.

We wouldn't be expecting neuropathy, but subtle cognitive deficits; I doubt very much they would be testing for such.

-Michael

[Blue]

The AJCN study abstract indicates that they did look at the effect on people with different dietary B6 intake without seeing an harmful effect on those with adequate intake. Also, the study looked at people at high risk for CVD which did not necessarily include prior known CVD.

This study seems to indicate that the neuropathy is caused by a toxic effect in the CNS and not the periphery. So the ADME should be similar for sensory and any cognitive effects.
http://dx.doi.org/10...rol.2004.07.013

Regarding interaction with B12 and B6 at least some arms of the studies mentioned here do not seem to have that problem.
http://www.ncbi.nlm....pubmed/14584010

Sure, a dose higher than 50 mg may have shown a different effect as I stated.

On the other hand, if you do a very small study on a total of 58 persons and look at enough subtests then it will eventually become very probable that one of them will show a "significant" difference. Especially if you start doing various "corrections". In short, this is a rather dubious result.

Not sure what the point regarding injecting PM and PLP is. If injected PmMbypasses the first-pass metabolism in the liver to PL so if PM has a toxic effect it would be easier to see.

Not sure how many cases of neuropathy, if any, one would expect from giving 200 patients 500mg of PN for 24 weeks. Just noting that they did not occur in a study with PM, for example.

Edited by Blue, 11 February 2010 - 05:18 PM.

[Nobility]

Started taking a 'high potency' b-complex, 50mg of b6, and other very high % over the top b vitamins,etc.

noticed after a couple of days, that I think if in certain cases, it can cause problems such as memory/trouble breathing and what not.