A more physiologically relevant observation was discussed by Peacock (see above link, NY annals paper), where their controlled trial found that the beneficial effect of calcium supplementation was blunted in those with higher 25-D.

The second, 1976 reference you mention is quite old –more current researchers state that 1,25-D is the only active metabolite. Overall, I think the modelling and our clinical data is a viable alternative to what others propose.

You are right that we don’t yet have enough corraborative data of the sort that you require, but hopefully we will in future.

If you read the article at this link: http://synergyhn.com/lesions you will see that the PTH issue isn’t nearly as simple or clear as many portray it. Look at the paper by Aloia that is discussed there. Many people have extremely low 25-D and do not have elevated PTH. If you look at his graph, they are by far the majority (probably 85%). I give an alternative explanation for the PTH — 25-D relationship that is often discussed.

If you observe the types of responses people have to Benicar, you will see that they really are not particularly similar to low aldosterone symptoms in most cases. In fact, the majority of patients feel no worse or feel considerably better on Benicar and raising the dosage of Benicar can reduce symptoms more in some patients due to its effects on receptors other than the VDR.

In those who do experience symptoms similar to hypoaldosteronism, the symptoms usually closely parallel antibiotic dosage increases rather than Benicar dosage and resolve as the treatment progresses, thus they appear to be primarily due to bacterial die-off.

Also, healthy people, typically feel no negative effect from very high dosages of Benicar and other ARBs.

As to the 32 ng/ml vs. 20 or less, I believe the 32 ng/ml was the level Dr. Marshall found that the modelling indicated the VDR blockage was more or less complete. The lower levels unblock it more and are preferred, leading to statements that you mention. You also have to consider that the VDR is also blocked by bacterial ligands, which would probably mean that an even lower 25-D level would be desirable in infected patients. In addition, Dr. Marshall has identified other means by which there is a blockage of the immune system when 25-D is high, via the very high 1,25-D levels that often occur.

Our work is so new that one isn’t likely to find adequate support in other’s work yet. For more support, I can only refer you to our data (Tom Perez’ presentation, the interviews on this site, the alumni forum on the MP site, also the case histories in part two of this article: http://winmlm.neostrada.pl/mp/townsend/Townsend_Apr07.PartOne.pdf
http://winmlm.neostrada.pl/mp/townsend/Townsend_Letter_May2007.Part2.pdf and our future work).

If you really spend time reading on the site and the above links, then you can judge whether your hypotheses that IP reactions are hypoaldosteronism and that lowering 25-D is crippling immune function are really the better explanation for patient’s responses. I don’t see how it could be consistent with the data.

Best wishes to you in your research and to your sister,

Joyce Waterhouse, PhD

I was a bit harsh. Sorry for that. You really care about this, and you’re looking for answers. That’s admirable.

Best,
Paul

Joyce – I’d be careful with using data based on lifeguards, since exposure to chlorine compounds is a complicating factor. http://en.wikipedia.org/wiki/Pool_chlorine_hypothesis

(Yes, I know wikipedia isn’t authoritative. But it’s a good starting point for those who need more info.)

Bill – Be aware that the ‘in silico’ computer modeling data often referred to by supporters of the Marshall Protocol in support of the immunosuppressive properties of 25D above a certain threshold is, to the best of my knowledge, not peer reviewed.

As a side note; Production of cholecalciferol is not the only biological result of exposure to light. Sunlight can kill microbes, break down bilirubin, increase serotonin levels, and so forth.

that there may be something to higher vitamin D supplementation and immunity to flu.

I agree. For what it’s worth, I’ve known a few people who take oral cholecalciferol (D3) in response to specific temporary sicknesses like the flu and seem to have good results. I think you hit the nail on the head in that AMP levels need to be studied in various people with different 25D3 levels to see what’s actually going on. As of about a year ago, I couldn’t find any studies which really spoke to that point.

It seems to me like several different groups; those who cannot produce enough cholecalciferol, those who use up cholecalciferol too rapidly and those with a dysregulated VDR are being lumped into a single group when 25D3 is measured.

The weakest point of the dominant paradigm and the easiest to support with in vivo and in vitro studies seems to be 25D3 and its relation to heart disease. Many studies assert that high 25D3 is associated with lower cardiac risk. But D3 supplementation (particularly when K1 is suppressed and in the absence of K2 or menaquinone) can lead to arterial calcification (which would require activation of the VDR.) That does support the notion that low 25D3 in some cases is the result of an infection rather than a ‘deficiency.’ But I’m not sure whether those studies concerned levels of 25D3 high enough to test the assertion that high levels of 25D3 blocks the VDR.

Here is a reply I made to Mr. Albert’s response to me, but it contains questions I have for you after your response as well, so I will repost it here and hope I do not offend anyone. You may want to read Mr. Albert’s response to me linked above, as some of the points pertain directly to it:

I have some genuine, sincere, objective questions and I need straight forward, compassionate answers.

“As for the relative lack of data supporting our claims, we are not the ones making the non-conservative recommendation to supplement with a secosteroid.”

1. Not all cholecalciferol is converted to 25D. Some is stored. Cholecalciferol is not a secosteroid (at least I don’t think, correct me if I am wrong, it is a pre-hormone, 25D is a secosteroid after cholecalciferol is converted).

2. If your recommended level for MP people to get below is 32ng/ml, this is not what I have seen on the forums. I have seen people well under 20, even 10-12 or lower. If it is not your intention for people to go this low then there needs to be better information. If it is intended for people to go this low, I would say this is not a “conservative” recommendation– just as you say the pro-D side, I belive there is a general lack of data supporting people avoiding D until their levels are in the low teens or lower. The only data you have supporting this is ‘in silica’. This is far from ideal data to base recommendations on.

Another common theme I see in MP anecdotes is the ‘IP’ reactions that used to be referred to as ‘herx’ reactions. It seems any adverse effects from this treatment are all attributred to these ‘IP’ reactions, almost encouraging the patient that the treatment is working and to move forward, and rarely if ever attributed to side effects of medication like the high and frequent dosing of Benicar– ARB’s are known to cause low aldosterone levels, especially at higher doses and this can produce many of hte same symptoms that are being classified as ‘IP’.

Maybe the pro-D side doesn’t have as long term data as you would like, but there certainly are some long term studies. The MP has none. At least not that I am aware of. No long term, randomized, controlled trials, just anecdotes. I do not doubt that some people are getting better, but no one, not even you, Amy Proal or even Trevor Marshall can tell me or anyone else exactly why. Is it perhaps the Benicar alone? Is it the long term dosing of antibiotics alone? As some people are on MP for years, with multiple variable like changes in diet, awareness of health, fitness, etc., you simply cannot say for sure what is helping them. You have no in vitro, much less in vivo data to prove any part of the MP protocol theory. No data besides ‘in silica’ to prove Benicar activates the VDR, and likewise to prove 25D is immunosuppressive.

Further, correct me if I am wrong, but I believe that your reference range for 1,25D is outdated at 45 for the upper limit. It seems more current lab tests and studies show this to be closer to 60-65.

Also, I’ve not seen any evidence in your protocol testing recommendations that takes into account the effect of calcium, PTH, Phosphate and others on 1,25D levels.

Correct me if I am wrong, but the studies I’ve seen show that levels of 25D below 20ng/ml tend to cause marked increases in PTH, which can precipitate bone loss.

To get back to a point I alluded to earlier. I’ve not seen sufficient evidence from your MP information that 25D or other inactive forms can effect the function of the VDR. Here are some references I found to support the opposite:

http://www.ncbi.nlm.nih.gov/pubmed/9398723?dopt=Abstract

This one is on the binding affinity of 25D compared to 1,25D, one showing 25D’s is at least 500x lower than 1,25D’s binding affinity for the VDR:

http://www.ncbi.nlm.nih.gov/pubmed/1084355?dopt=Abstract

I’ve heard reports of even 1000x lower, but I am still searching for an adequate reference.

To be fair, I had the common sense thought that 25D levels are many times higher in the serum versus 1,25D, given that 25D levels are measured in ng/ml and 1,25D levels are measured in pg/ml, and perhaps the relative abundance of 25D to 1,25D might overcome this binding deficit. However, when I explored this angle, it seems that 25D has a higher tendency to remain protein bound in the serum versus 1,25D by a nearly 10-fold amount. Even with ng being 1000x concentration vs pg, 25D (in ng) is about 10x more protein bound than 1,25D and 1,25D appears to have at least 500x binding affinity for the VDR than 25D, so it would seem 1,25D would win this battle– maybe this is too simplistic an assessment?

Further, I found a study on sarcoidosis where they bound radioactive 1,25D to VDR receptors on T cells. They found that 25D was not able to displace the radioactive 1,25D but that non-radioactive 1,25D was able to displace it:

http://www.ncbi.nlm.nih.gov/pubmed/1646583?dopt=AbstractPlus

I cannot seem to find one study that demonstrates that 25D affects the VDR and inhibits 1,25D’s ability to turn it on. Further, correct me if I am wrong because I am just learning about all of this, but from what I have read and understand so far about the relationship between 25D and PTH, if 25D did block the activity of 1,25D on the VDR, then wouldn’t PTH levels increase? Rather, it seems that the higher 25D goes, PTH is decreased.

What I would believe is if you had a study in human volunteers that took baseline 25D, 1,25D, PTH, Calcium, and antimicrobial peptide levels at baseline, then randomized and groups to receive D supplementation at a level targeted to get 25D levels into the 40-60ng/ml range. A placebo group, and a group for D-avoidance targeting low 25D levels and see what happens to antimicrobial peptide production and perhaps other immune markers. This would show id low 25D would indeed boost immune response, allowing 1,25D to active the VDR, or perhaps show that increased 25D levels decrease AMP production or other immune markers.

Also, to allude to an earlier point, to prove MP works, you need studies with multiple arms– perhaps a benicar only arm, a low D only arm, low D + abx, Benicar + abx, etc., etc. Perhaps Benicar and abx is enough? Perhaps low D is harmful long term? (You have no long term data, certainly no where near the number of years as some of the D-supplementation studies). MP and D-Avoidance simply have not been around long enough to bear out an potential long term health effects.

Now, after all this, this is not to say I am going to go out an gob down oodles of cholecalciferol, but I don’t think I’m going to recommend my sister starve herself of sun exposure or dietary D intake either.

I also don’t mean to be at all hostile, though your email (Mr. Albert’s) to me certainly seemed to be. I am just a brother who loves his sister very much and would genuinely like to help her. I am looking for conrete answers, and any information or clarification you can provde me on the points I have made here will be most helpful. I appreciate your time and that of the other volunteers on this and other sites.

Let me get this straight – you posted your book-length comment in three places??? Not cool.

Well, anyway I responded to one of them here:
http://bacteriality.com/about-2/

Paul

http://autoimmunityresearch.org/preprints/WaterhouseAnnals2009Preprint.pdf

http://www.townsendletter.com/Jan2009/vitaminD0109.htm
We have confidence that in the next few years we will get the funding to do the sort of in vitro work you describe (we have plans to do much in vitro and in vivo work of various sorts).

The briefest answer is that our current data on patient responses is supportive of the in silico data as described in the above articles and others.

A couple other points that have not yet been covered are below may be relevant to your concerns (from an unpublished manuscript):

17. Skin color. The idea that white skin color evolved to allow more vitamin D production has been critiqued by Robins (48). One of several alternative explanations (49) is that white skin offers an evolutionary advantage by decreasing the risk of frostbite. A possible frostbite link has received support from the higher prevalence of frostbite in African-American soldiers in the Korean War.

18. Subtle influence of evolutionary argument. What appears in some cases to cause some researchers to give vitamin D supplementation the benefit of the doubt is the supposition that early man had high levels of 25-D due to high sun exposure. A number of problems exist with this argument, which nevertheless often has an overt or subtle effect on conclusions that are made.

First, it is currently unknown what the 25-D levels for early man were. It is highly doubtful that we can extrapolate from aboriginal people living today, for whom there is little, if any data, in any case. We can not assume that the most important time for evolutionary change related to vitamin D was even accompanied by high sun exposure, since the level of forestation was often much greater in the past and very dense forests allow little light penetration. Cases of lifeguards or other outdoor workers with high 25-D levels cited by some researchers have not been studied adequately for long-term effects on health, and in any case, they are a self-selected population.

Furthermore, even if we could know that early man had high 25-D levels, far too many things have changed to extrapolate to current needs/benefits, particularly for oral supplementation. And even if high 25-D was beneficial for ancient man, a level that may have aided reproductive success for our ancient ancestors may have little bearing on the health of people living in the type of environment we live in, with its pathogen exposures, diet, calcium intake and other factors too numerous to mention. This is particularly true for people over 60 years of age, an age that many people living a hunter-gatherer lifestyle would not even reach. Thus, it is important to take the approach of looking at the highest quality published data regarding vitamin D rather than be influenced by suppositions regarding vitamin D levels in the evolutionary past.

48) Robins AH. The Evolution of light skin color: role of vitamin D disputed. Comment in: Am J Phys Anthropol. 2009. 139(4):447-50.
(49) Juzeniene A, Setlow R, Porojnicu A, Steindal AH, Moan J. Development of different human skin colors: A review highlighting photobiological and photobiophysical aspects. J Photochem Photobio B. 2009. 96(2):93-100.

Naturally, people need to evaluate the arguments on both sides and make their own decisions about treatment.

Joyce Waterhouse, Ph.D.

I have CFIDS and Fibromyagia (Diagnosed around 1988, 21 y ago).
I am going to get more testing for Lyme (and Chlamydia) and use a natural approach if positive: Samento seems to be very effective based on recent studies (not peer-reviewed yet).

I’d love to talk to you directly about that but I believe we can’t share e-mail on the site.
I’ll try anyway giving permission to moderator to delete it if necessary.
PS:I don’t have any link with, or interest in, Vit D business.
chrisddd40@yahoo.com

I personally have only been taking higher vitamin D for about 3 weeks, but there has been a marked improvement in my scalp eczema.

I read one of the other posts here on the 14 misconceptions about Vitamin D and that 25D is actually immunosuppressive. Your information seems well referenced and very plausible, so you can understand my confusion now after having read through the information from Heaney, Vieth and others on the benefits of D3 supplementation.

It seems both sides have credible arguments and data. Yours especially seems very convincing, but I have some questions:

1. In reading your information, I saw that you have identified the bllod level at which 25D becomes immunosupressive ~32ng/ml. What basis do you have for this conclusion? I would very much like to read the actual paper this is drawn from to see the methods used in the study.

2. While your arguments seem very credible, in fact maybe more credible to me now than that from Heaney, Vieth and other D supplementation proponents, there is one logical barrier I cannot seem to get past with your arguments. We’ve evolved as humans through the millennia with this innate system for Vitamin D production from the sun. Prior to industrialization, or even civilized society, presumably hominids and early humans spent quite a lot of time out in the sun, and no doubt produced a lot of their own vitamin D. Even today, in tropical climates, studies I have seen on blood levels show them to be around 40ng/ml or higher for people who live in these areas while people from northen climes tend to have much lower levels, especially during winter. If 25D is indeed immunosuppressive, then why is there not a higher level of chronic disease and cancer, flu mortality, etc. in these tropical areas? Also, how can you explain away the seasonality of flu and the higher morbidity and mortality rates throughout the fall and winter months? I know your information says that some of these epidemiological studies showing higher incidence of some of these diseases in northern climates are technically flawed– if they are, how so?

3. With regard to the Marshall protocol, or just restriction of Vitamin D intake in general, do you have any data on long term health effects of this popultion wide, or even in specific disease states? This is one of your criticisms of Heaney/Vieth/Cannell/Vitamin D Council et al. You pose the question that since they have no real long term data, i.e. 1-2 decades or more that we cannot really know the true health implications of higher vitamin D supplementation. I would ask the same question– if you have no long term studies regarding the health implications of restricting D3 intake and thus keeping 25D levels low, we cannot really know the true health implications of that either, can we?

4. To expand on point #2, how can something that we’ve evolved with over millennia– our innate ability to produce D3 and thus 25D from the sun, and given that a human can produce nearly 10,000IU per day from sun exposure, how can it be that 25D is deleterious to us? Perhaps there is an optimal level for both sides? i.e. something below the 32 ng/ml threshhold where you suggest 25D is immunosuppressive? Or would people with certain chronic diseases need to be even lower due to the L form bacteria produced proteins also occupying the VDR? If so, how LOW should someone with chronic disease go? To undectable levels of 25D? If so, what are the health implications non related to their chronic disease? Could we help their chronic disease on one hand, but cause other problems on the other? What is the risk/benefit ratio here?

5. From reading your misconceptions on vitamin D page, it was difficult to determine if the studies done demonstrating the immunosuppressive nature of 25D above 32ng/ml were in vitro or in vivo. If they were indeed in vitro studies, is it possible that if you had isolated only the VDR in vitro and introduced 25D that the response could be markedly different than that found in vivo, with the living system and all other substances and enzymes, etc found in the human body? Or do you actually have a double blind placebo controlled study that measured baseline blood levels of anti-microbial peptides as well as baseline 25D and 1,25D levels prior to, during and after supplementation, and do you have concrete proof that 25D above 32ng/ml in humans suppresses the expression of anti-microbial peptides and actually causes their production and blood levels to go down? I don’t believe the other side (Heaney/Vieth/Cannell et al) has a study showing that the levels actually do increase. However, the case reports in facilities and patient populations where patient’s 25D levels are checked and they are supplemented to the other side’s “optimal” levels of 40-60ng/ml are interesting. It does seem like the supplemented populations have less incidence of flu infection compared to surrounding counterparts in the same facility. I know these are clearly not scientific studies, but rather observations that may not even be statistically significant, but there seems to be enough of these case reports independent of each other to show that there may be something to higher vitamin D supplementation and immunity to flu.

6. Your information points out connections of some of the researchers invovled in the D supplementation proponent studies to those in the supplement and/or dairy industries. Some of which disturbed me. However, I believe it is a fair question to ask, what kind of market exists for the Marshall Protocol (independent of the patients actually enrolled in the formal study protocol under the study’s superision), i.e. books, foods, supplements, etc? And if so, what financial benefit if any do Marshall, you and others involved in this work have to gain? Perhaps if not commercial, then maybe private and/or government grants, continued employment, etc.? Your information points out that studies have a funny way of providing the information that is sought by the funder when speaking of those done by Heaney, Vieth et al. I think it is fair to say the same about your work too– could the results of your work be driven to provide information contrary to the other side of the D argument to be different and feed an alternative market?

Please don’t misunderstand me, I don’t mean to be antagonistic. From what I have read, the work you have done looks great and your motives seem genuine– perhaps more genuine than Heaney, Vieth et al. However, I am just trying to get to the truth for me and my sister and others I know that this issue can effect. Guaranteed someone is wrong on either side of this argument and no question there will be damage done. The question is, what side?

Also, you should know, I am not involved at all in supplement production or sales, though I did work for GSK for 6 years up til 2005, primarily selling antibiotics and antidepressants. I now own a business selling medical software– completely unrelated to pharma or supplements. I have been a paramedic for 20 years and have a keen interest in pharmacokinetics and pharmacodynamics, so that is where my medical knowledge and knowledge of study design/methods comes from.

I am really just looking for the truth, and your answers to my questions will help me to get that much closer.

Sincerely,

Bill Kelleher

For instance, sometimes the 1,25-D may not be elevated, but this does not necessarily mean the MP may not benefit them. There is lab error and there is the issue of serum 1,25-D not necessarily reflecting the level in tissues.

In any particular case I suppose one can’t necessarily rule out a viral infection being present, even if one tested for all known viruses. But even if a viral infection is present, it may respond to treatment of bacteria that the MP targets — apparently by reversing immune dysfunction. This has been found in a number of instances.

I suppose if one wants stronger evidence, one will have to wait for further research, which may be several years or more.

Joyce Waterhouse