Vitamin D3 supplementation to prevent and treat Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)

This page is not for the public.  It is an early draft of a future web page and is only intended for particular people.  The final version will be better formatted, with headings, table of contents etc.

This site 5nn.info - 5 Neglected Nutrients - is not yet developed.  Please see https://vitamindstopscovid.info and https://nutritionmatters.substack.com.

../ To the main page of this site.

Robin Whittle rw@firstpr.com.au  2 October 2022 



Here is an account of how a few hours searching, with Google and Google Scholar, led me to believe:
1 - Most mainstream doctors, including most rheumatologists and other specialists, do not understand about vitamin D's importance for the immune system. 

2 - It is easy to show, beyond reasonable doubt, that their statements about Parkinson's Disease (PD) being incurable - with no method of stopping or slowing its progression - are ill-informed and almost certainly wrong. 

2 - There are good reasons to believe that with suitable - perhaps quite high - levels of vitamin D3 supplementation, the progression of PD and other such diseases can be slowed, and perhaps stopped.  There are likely to be multiple mechanisms by which the weak innate and adaptive immune responses, and the dysregulated inflammatory responses, caused by low 25-hydroxyvitamin D levels might drive the progression of PD, DLB and MSA.

3 - There is also evidence that over time, lost motor functions may be recovered to some degree at least.  This implies that the brain is able to either grow new neurons to replace those which have been destroyed, or that other neurons are somehow able to adapt and to some extent at least restore functions which were previously lost to the disease. 

If this is so for the best known neurons which are damaged in PD (dopaminergic neurons in the substantia nigra), this does not necessarily mean that the same longer-term recovery will happen with other populations of neurons which are harmed or destroyed in PD, DLB or MSA, but it is a reason for cautious optimism about regaining health and happiness.
After this searching, I also did a more thorough search for information on vitamin D and PD.  What I found confirmed my initial findings.

Here, for brevity, I focus on PD [WP <<< Wikipedia link] and a rare PD-like neurodegenerative disease Multiple System Atrophy (MSA) [WP], with some mention of Dementia with Lewy Bodies (DLB) [WP].  According these Wikipedia pages, PD is not at all rare - it affects about 1% of people over 60 - and DLB affects 0.4% of people older than 65, with an average survival time from diagnosis of 4 years.  MSA is rare - it affects about 0.005% of people.

Similar outcomes can probably be found by researching vitamin D and Alzheimer's disease (AD) [WP] and in many of the neurodegenerative diseases [WP], though some are caused directly by genetic problems and so may not be affected much by nutrition or the immune system.

There is a general pattern of:
1 - Not understanding the importance of nutrition, especially vitamin D, for the immune system, and so not understanding that most people's immune systems are weak and/or dysregulated.

2 - Researchers and doctors being overly attracted to fussy details rather than the most important things which are to inform the public about nutrition to largely prevent these diseases, and to suppress or cure these diseases once they start by the simplest, safest, least expensive means possible.

3 - Researchers and doctors being vastly over-interested in expensive, complex, patented, treatments which seem to fit their notion that they are brave, smart, priest-like workers tackling difficult or insoluble problems - hence the need for all the qualifications, millions of dollars in research funding, years and years of work, endless tests and lifelong regular consultation with patients.
There has been research on PD and vitamin D, but there is no mention of vitamin D in the extensive Wikipedia page for PD, which broadly reflects the views of mainstream doctors, including specialists who treat PD.




Ideally, every researcher in a given field, or intersection of fields, would be fully acquainted with all prior research in these fields, and with critiques of such research.  I have never seen evidence that this is the case.  Quite to the contrary, especially with vitamin D, there is a vast number of research articles, many of low quality, and it seems that the average researcher is only familiar with a small subset of the research - and probably not with the most important, reliable, articles in the field.

If every researcher was fully abreast of all prior research, most research would be a lot better than it is today.  If this was the case, and if doctors were up to speed on the most pertinent research, patients and the public would be reasonably well informed about all aspects of diseases, including especially nutritional improvements which reduce the chances of developing such diseases.

The current reality is the hellish opposite.  It is most briefly described as corrupted groupthunk ineptitude, with corruption coming from multinational pharmaceutical companies who make billions of dollars from patented drugs and vaccines which supposedly prevent or treat diseases which arise to a very large degree from nutritional inadequacies.

Please remember that no research article I have ever seen regarding vitamin D is fully informed.  Every research article I have read could have been improved in the light of the set of articles I cite at:
https://vitamindstopscovid.info/00-evi/
So if you are up to speed, even tentatively with the research articles I cite, then when you read research articles by eminently qualified PhDs, MDs, you know some important things they don't.


This particular, relatively short, sequence of article discoveries began when I read of a rare disease called Multiple System Atrophy.  It sounded to me much like PD, AD etc. etc.  It too is (conventionally) regarded as incurable - with no known treatment which will even slow the degenerative process, which always ends in death. 

First I searched Google Scholar for MSA (I spelled it out, in quotes) and "inflammation".  Sure enough, as I expected, there was lots of research on this.  Please see https://vitamindstopscovid.info/00-evi/ and https://vitamindstopscovid.info/06-adv/ .  When you review the articles cited there, you will learn about the two primary causes of excessive inflammatory responses.  For now, here is the summary, but please read or at least look at the cited articles yourself before making any decisions about nutrition, supplements or how to treat diseases.  If you can't understand this stuff, get a medical professional to read the research I cite and then advise you.

My summary of the etiology (causes) of numerous auto-immune inflammatory diseases:
1 - Helminths (intestinal worms [WP]) infested our ancestors, apparently ubiquitously, and long ago evolved the ability to exude compounds which downmodulate the inflammatory (indiscriminate cell destruction, such as by eosinophils [WP] - the suicide bombers of the immune system) immune responses which target such multi-cellular parasites.  Our ancestors' immune systems evolved to mount a stronger inflammatory response than would be healthy in the absence of this downmodulation, but was about right in the usual condition of being downmodulated by a number of compounds produced by possibly multiple species of helminth.  Now, without helminths, our immune responses are generally excessively inflammatory.  The same is true of our dewormed companion and agricultural animals.

2 - Considerable individual variation leads to some individuals being particularly prone to excessive, self-destructive, immune responses, such as those which drive the various diseases, not least Crohn's disease [WP], cluster headaches and migraine. The causes of the variation include genes and exposure to particular diseases or toxins.  For instance, exposure to some pesticides increases the risk of developing PD. 

Please see the research on - and Coimbra, Batcheller and McCullough protocols for - numerous inflammatory diseases at: https://vitamindstopscovid.info/06-adv/ .

Sidebar on HSCT:

One cause of this individual variation is the adaptive immune system developing in ways which target the body's own proteins, for instance the myelin which provides electrical insulation to speed the transmission of electrical signals in neurons - as in MS (multiple sclerosis).  There is a difficult, dangerous, technique known as HSCT (Hematopoietic Stem Cell Transplantation) [WP] which was developed for other reasons, but is apparently highly effective at ending MS permanently, without any changes in vitamin D intake or diet.  As explained here: https://www.hsctstopsms.com/hsct-for-ms/what-is-hsct/ some of the patient's hematopoietic stem cells are extracted.  These cells can differentiate (change their functions as they divide into daughter cells) to become a variety of bone-marrow cells which produce all the types of blood cell, including multiple types of immune cell.  The patient's existing hematopoietic in their bone marrow are then destroyed with chemotherapy and the stem-cells implanted.  This is effectively rebooting the immune system, and it apparently develops in healthy ways which do not involve generating antibodies to myelin.   This costs USD$54k or so and is only available in a few countries.   Perhaps this would help with PD, DLB and MSA.  I have not pursued this since it is a drastic move - more drastic than helminthic therapy and far more drastic than using higher than usual amounts of vitamin D3.

The above site supports the use of HSCT, but it also recommends the Coimbra protocol of high vitamin D3 intake, as a less expensive and less difficult alternative.

4 - Most people have only 5 to 25 ng/mL circulating 25-hydroxyvitamin D when they need 50 ng/mL (125 nmol/L, using the units preferred in the UK, Canada and Australia) or more to mount full strength innate and adaptive immune responses to the primarily bacterial pathogens which cause post-operative infections.  See Quraishi et al. 2014: https://jamanetwork.com/journals/jamasurgery/fullarticle/1782085, the graph of which is the frontispiece of: https://vitamindstopscovid.info/00-evi/ .

This lack of 25-hydroxyvitamin D means immune cells cannot respond properly to their changing circumstances, since their vitamin D based intracrine (internal to each cell) signaling systems cannot work.  See: https://vitamindstopscovid.info/00-evi/#02-compounds for an explanation. 

Low 25-hydroxyvitamin D levels also lead to poor regulation of inflammatory responses. See Chauss et al. 2021: https://www.nature.com/articles/s41590-021-01080-3 (my summary of this dense article: https://aminotheory.com/cv19/icu/#2021-Chauss) in which Th1 lymphocytes [WP] from the lungs of hospltalised COVID-19 patients are unable to respond to the signal (a high level of a complement [WP] protein) which should make them turn off their pro-inflammatory cytokine producing start up program and switch to their anti-inflammatory shutdown program.  The sole or major reason for this is that they lack sufficient 25-hydroxyvitamin D to run their vitamin D based intracrine signaling system (though it is called "autocrine" in this article, which is not quite correct).

If you have read and understood this summary, then you tentatively understand my position as I researched PD and MSA.  If you have read the articles I cite, then you will have a genuine understanding of my position.

In either case, you tentatively or genuinely understand the etiology of inflammatory diseases better than any of the researchers who wrote the many hundreds of research articles on this subject which I have ever read.  This is a bold statement, but it follows from the following observations:
1 - Most articles on inflammatory diseases do not mention vitamin D or lack of helminths.  These represent the mainstream medical establishment's best understanding of these diseases, with individual researchers and doctors comprehending some subset of this knowledge.  This knowledge is fundamentally flawed since it ignores the two most important causes of these diseases.  The fact that the sprawling research literature on PD and other autoimmune inflammatory diseases is endlessly detailed, with vast amounts of detective work on various molecules and cell types, does not alter this bleak fact.

2 - Some articles mention vitamin D.  However, almost none of them reflect a full understanding of many types of immune cells' need for 50 ng/mL 125 nmol/L circulating (in the bloodstream) 25-hydroxyvitamin D, so they can run their intracrine (and perhaps paracrine) signaling systems - which are crucial to each cell's ability to respond to its changing circumstances.

Most vitamin D articles refer to "vitamin D" as a "hormone", which it is not, and some assume that the circulating level of 1,25-dihydroxyvitamin D (calcitriol https://vitamindstopscovid.info/00-evi/#2.3)  affects immune cells, which is not the case.

3 - Very few articles mention lack of helminths.  There is, however, a more common, generalised, insufficiently detailed notion of the "hygiene hypothesis" [WP], which, if fully developed, would include a proper understanding of helminths and the impact of no longer being infected by them.

4 - I have not seen a single article about inflammatory diseases which mentions both vitamin D and helminths - let alone one which embodies the knowledge summarised above.  If you find such an article, please let me know!
Now you are at least tentatively up to speed with my perspective as I did these searches, you will perhaps understand why I glanced at the first page of titles of these "Multiple System Atrophy" and "inflammation" articles:  I have seen all this before.  Endless hand-wringing by people who don't really understand what is going on, wondering what to do about all this inflammation - usually by proposing the use of exotic drugs, monoclonal antibodies etc.

My next Google Scholar search was for MSA and "vitamin D".  I was not surprised to find many fewer articles with this combination, since MSA is a rare disease.  The second hit was for a depressing article which only vaguely mentions vitamin D and which details the work of two Mayo Clinic doctors who (as best I understand it) work primarily or exclusively with MSA patients.  Since they believe (as most people do) that the progression of MSA cannot be slowed or arrested with any known treatment, all their work concerns making life as comfortable for people as their brains and bodily functions degenerate and they live out their final years, certain of their impending death due to this disease, if nothing else kills them first.
My Treatment Approach to Multiple System Atrophy
Elizabeth A. Coon and J. Eric Ahlskog
May Clinic Proceedings 2021-03-02
https://www.sciencedirect.com/science/article/abs/pii/S0025619620311836
This indicates that the article is paywalled, but Unpaywall helpfully links to the article there, which is freely available:
http://www.mayoclinicproceedings.org/article/S0025619620311836/pdf
If you don't already know about MSA, please take a look at this to appreciate the grim fate these people and their families and friends face as the disease progressively disables them and eventually kills, with the best doctors unable to do anything which slows its progression.  There is a PD like form of MSA and another form which does not directly include PD symptoms and which cannot be relieved by the use of levodopa.  However, the differences in symptoms between PD, DLB and MSA are of marginal interest in the context of all three diagnoses being for closely related disease processes.  If there is a way of halting disease progress with one of these, it will almost certainly be effective with the other two.

I only glanced at this article, because I had recently become acquainted with the conventional overview of MSA.  I later found another article which gives the same outlook in greater detail:
https://rarediseases.org/rare-diseases/multiple-system-atrophy/
About three minutes into my MSA vitamin D sleuthing (it takes you longer to read about this than the events I describe) I came across this most intriguing article, which Google Scholar (salute!) presented as the third hit: 
Circulatory 25(OH)D and 1,25(OH)2D as differential biomarkers between multiple system atrophy and Parkinson's disease patients
Hiromu Ogura, Izzettin Hatip-Al-Khatib, Midori Suenaga, Funda Bolukbasi Hatip, Takayasu Mishima, Shinsuke Fujioka, Shinji Ouma, Yoichi Matsunaga and Yoshio Tsuboi.
eNeurologicalSci 2021-09-17
https://www.sciencedirect.com/science/article/pii/S2405650221000617
25(OH)D is 25-hydroxyvitamin D (calcifediol AKA calcidiol https://vitamindstopscovid.info/00-evi/#2.2), needed by immune cells.  1,25(OH)2D  is1,25-dihydroxyvitamin D (calcitriol) - the signaling molecule which combines with the vitamin D receptor (VDR) [WP] molecule, with the combined pair traveling to the nucleus where it up-regulates and down-regulates the transcription of dozens or hundreds of genes to messenger RNA, and so alters the behaviour or the cell.  The exact details of which genes are up- and down-regulated varies from one cell type to the next.

The researchers measured the blood (AKA serum - what ls left after centrifuging out the cells, AKA, loosely, plasma) levels of these two compounds.  They were not concerned about vitamin D3 (cholecalciferol) levels, since this compound, in the bloodstream, is converted in the liver, over 4 days to a week, into circulating 25-hydroxyvitamin D, which is needed both by the kidneys and by many types of immune cells as well as other cell types, including some which are involved in neurodevelopment.

The very low level of circulating (in the bloodstream) level of 1,25-dihydroxyvitamin D is created and maintained by the kidneys.  This acts as a hormone (the sole hormonal function of the three vitamin D compounds) to regulate calcium-phosphate-bone metabolism.  In mammals, a hormone is a blood-borne substance, the concentration (level) of which is controlled by some organ - here the kidneys - for the purpose of altering the behaviour of one or more cell type (and so, perhaps, one or more organs) anywhere in the body.  Contrary to widespread misunderstanding, this low level of circulating 1,25-dihydroxyvitamin D does not affect the immune system to any significant degree.

Ogura et al.'s observations about circulating 25-hydroxyvitamin D are of the utmost significance.  The healthy controls averaged 26.8 ng/mL.   Although 50 ng/mL is needed for proper immune function, this is actually a pretty good level for ordinary people not living near the equator and getting around for much of the day with little or no clothing.  The research was in Japan, and I attribute the 26.8 ng/mL level - 5 or 10 ng/mL better than what I think we would fine in the UK, Australia or the USA, as being due to the Japanese eating quite a lot of oily fish, which contains at least some vitamin D3.  Supplementation would also have played a role.

I am taking a while to explain this, but within seconds of finding the article I read the 25-hydroxyvitamin D figures in the abstract and Table 1.  "HS" means "Healthy Subjects".  (They can't be fully healthy with just 26 ng/mL 25-hydroxyvitamin D, but in this context they are healthy, since they are aged matched people who have neither MSA nor PD.)
HS  26.85 +/- 7.62
MSA 10.53 +/- 3.82  (p = 0.0001)
PD  13.36 +/- 4.76  (p = 0.0001)
Readers who have read lots of research articles probably gasp at these figures.  Here is a supposedly incurable disease (MSA, PD too) in which sufferers average 60.8% lower circulating 25-hydroxyvitamin D than age-matched controls.

This is a drastic difference, especially considering the second figures, which are (I assume) the standard deviation [WP] of the levels observed.  If the levels exhibited a reasonably bell-curve-like "normal" distribution, then about 68% of the HS people's levels would be within the range specified by "+/- 7.62": 19.23 to 34.47 ng/mL.  Only 2.2% of these levels would have fallen two standard deviations below the mean - below 11.61 ng/mL.  Yet more than half of the MSA sufferers have 25-hydroxyvitamin D levels below this.

The third figure is the significance.  "p = 0.0001" means that if there were, in fact, no underlying relationship between MSA and 25-hydroxyvitamin D levels, then in the samples of the size used in this study, with their particular distributions (roughly described by the standard deviations) then, due to random variation, a research study with this deviation would only occur once in every 10,000 or more studies.

Most scientific articles adopt 0.05 (one in 20 chance of the deviation occurring due solely to chance) as being "significant".  So these MSA and PD deviations are statistically highly significant.

Again, I am taking hundreds of words to explain what goes on, in a second or two, in the minds of a researchophile reading these figures.  Here is the graph of these figures, with a more detailed representation of the upper and lower standard deviations as the tops and bottoms of the boxes.  The upper and lower bars represent the top and bottom of the range of all observations.



The Parkinson's disease deviation is similar, and also highly significant.

This immediately (in the minds of anyone who is paying attention) raises the question of causality.

To what extent does MSA / PD lower 25-hydroxyvitamin D levels and to what extent does low 25-hydroxyvitamin D cause MSA / PD?

Before we get into that, we should consider a third path of causality, which might contribute something to the observations.  Suppose there is an unobserved condition XXX which to some extent causes both low 25-hydroxyvitamin D and MSA / PD.   We can't rule this out, but it is exceedingly unlikely to explain most of the dramatic deviation we observe. 

It is reasonable to expect that people's 25-hydroxyvitamin D levels drop somewhat as MSA / PD progresses, since their mobility decreases and they are less likely to spend time outdoors, and so less likely to have short-wavelength UV-B skin exposure when the Sun is high in the sky.  However, this could only explain a small fraction of the deviation as "reverse causality" - the disease causing the low 25-hydroxyvitamin D level.  Another "reverse causation" mechanism is the disease process - lots of inflammation, and so lots of immune cells working, albeit self-destructively.  This can in principle consume 25-hydroxyvitamin D, and it is not out of the question (though I have read of no research to this effect) that this inflammation might reduce absorption of vitamin D3, its creation in the skin and/or how efficiently it is converted in the liver to circulating 25-hydroxyvitamin D.  (By the way, this conversion process is normally, very roughly, 25% efficient.)

It is impossible for me to imagine more than a small fraction of this deviation being due to one or more XXX conditions and/or reverse causation.

I later found this 11 year old article, which shows that the low 25-hydroxyvitamin D status of PD patients has been known, at least to some researchers, for a long time. 
High Prevalence of Hypovitaminosis D Status in Patients With Early Parkinson Disease
Marian L. Evatt et al.
JAMA Neurology 2011-03-??
https://jamanetwork.com/journals/jamaneurology/fullarticle/802599 (Paywalled PDF.)
https://sci-hub.se/10.1001/archneurol.2011.30
The observations of this study indicate zero or perhaps only a very slight degree of reverse causation:
Vitamin D concentrations did not decline during progression of PD.
This means that the great majority of the causation flows from the low 25-hydroxyvitamin D to the the disease state.  Since it is easy to boost 25-hydroxyvitamin D levels to 50 ng/mL or more, why not do this?  We can reasonably expect a reduction or even cessation in the disease processes which are condemning (in the minds of conventional doctors) these people to an increasingly miserable life, ending in death with a handful of years, on average.


If the clinical and research aspects of medicine were working properly, this article - now just a year old -would have been trumpeted in the mainstream media and in research journals and medical conferences as being very strong evidence that the progression of MSA and PD could be reduced, and perhaps stopped, simply by the use of vitamin D3 supplements.

However, the whole system is broken in ways which are too complex and distressing to discuss here. 

I later found a Wikipedia page:
https://en.wikipedia.org/wiki/Amyloid
Please take a look at this.  "Amyloid" refers to a particular structure in which multiple naturally occurring proteins can aggregate, in a fibrillar structure - long strands grow as the agglomeration proceeds.  37 separate human proteins are now known to be follow this pattern, in a larger number of diseases, most or all which involve neurodegeneration.  There are healthy amyloid structures as well.   The "amyloid" structure is a general pattern.  The exact atomic details of a particular amyloid agglomeration of proteins depend on the exact structure of that protein - and as mentioned below, a single normal protein can fold in different ways in the agglomeration process.  All these resulting proteins agglomerations are classified as "amyloid', even though they differ in some ways at an atomic level.

Amyloid diseases are a subset of prion diseases, in which naturally occurring, individual molecules, of protein find their way to an agglomeration of such proteins, in a mis-folded (compared to the protein's folded shape when it is functioning healthily) structure and are attracted to this structure, adding to it by the molecule misfolding in the same pattern.   These agglomerations can grow bigger and bigger, and if there was just one of them, it would eventually grow so big it could be identified and surgically removed.  Instead, the agglomerations break up (I suggest, perhaps by excessive inflammatory processes) and so millions of these agglomerations spread to parts of the brain, eventually killing cells and destroying neural function.

Prion diseases https://en.wikipedia.org/wiki/Prion are considered incurable, since no-one (so most people think) has a way of slowing or halting the agglomeration. 

Mad Cow disease is the best known prion disease, in which a protein - confusingly known just as the "prion protein" PRNP [WP] called "beta amyloid peptide" folds in a prion configuration agglomeration.  The normal, healthy, function of this protein is apparently unknown.  (I don't necessarily believe anything I read like this - maybe someone knows and the mainstream researchers don't know this, or may even be resistant to the idea that is normal function is known.)

The same disease process can be spread among head-hunters by consuming the brains of people they killed, who had this particular prion agglomeration in their brains.

The same process - in these instances, known as Creutzfeldt–Jakob disease [WP], can start spontaneously - a single or two molecules of the protein folding in the particular prion pattern, and then other molecules folding according to this pattern and so joining the agglomeration.  This always (according to all reports I have read) kills people within a few years.  So a single molecule of this protein in a person's brain can misfold to form the initial prion, with more and more molecules misfolding onto it, and the agglomeration presumably being split into pieces and so giving rise to more and more such agglomerations.

The table in the Amyloid Wikipedia page shows that a single specific human protein - alpha-synuclein [WP], which plays a crucial role in many neurons - misfolds in the following prion diseases, which are collectively known as synucleinopathies [WP].  These diseases are:
Trying not to be distracted by Alzheimer's disease and many other types of neurodegeneration, my search continued regarding PD, MSA and vitamin D.

Sidebar on 1996 and 2004 research which should have prompted everyone to suspect that inadequate 25-hydroxyvitamin D might be a significant causative factor in PD and MSA.
I later found this article:
1,25-dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor
Philippe Naveilhan, Isabelle Neveu, Didier Wion and Philipp Brachet.
Neuroreport 1996-09-02
https://journals.lww.com/neuroreport/Abstract/1996/09020/1,25_Dihydroxyvitamin_D3,_an_inducer_of_glial_cell.23.aspx (Paywalled, but available at Alexandra Elbakyan's SciHub [WP].)
https://sci-hub.se/10.1097/00001756-199609020-00023
which reports that glial [WP] cells in the brain can absorb 25-hydroxyvitamin D from the bloodstream, that this can be 1-hydroxylated to 1,25-dihydroxyvitamin D (calcitriol, which binds with the vitamin D receptor (VDR)) and causes the glial cell to produce a compound GDNF https://en.wikipedia.org/wiki/Glial_cell_line-derived_neurotrophic_factor  "Neurotrophic" means it can induce growth of neurons. 

The most prominent type of glial cell are the astrocytes [WP] which physically support neurons and engage in numerous chemical exchanges with them.  In Multiple System Atrophy, the alpha-synuclein prion agglomerations build up in astrocytes.

The concept of vitamin D based intracrine (AKA, rather loosely, autocrine) internal signaling and paracrine (to nearby cells) signaling was not know when this article was written.  Now we know that this 1996-reported conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in glial cells - assuming this includes astrocytes  - shows that astrocytes have their behaviour changed when their vitamin D based intracrine signaling system is activated.

Astrocytes are not classed as part of the immune system, but the interact with immune cells.  This alone - ignoring all I write here about the need of many types of immune cell for at least 50 ng/mL circulating 25-hydroxyvitamin D - means we should consider inadequate supplies of 25-hydroxyvitamin D to astrocytes as likely to cause problems for neurons.  In MSA, it is the astrocytes which we clearly observe to be suffering as well as, no-doubt, many other types of cell

Blue text is quotes from the most recently mentioned article:
GDNF was later shown to exert neurotrophic effects on several neuronal populations in vivo, including dopaminergic neurones of the substantia nigra [These are the most important neurons killed by Parkinson's disease - and presumably in the PD type of MSA.  "Dopaminergic" means that the neurotransmitters their output axons release when the cell fires, is dopamine.], and noradrenergic neurones of the locus coerulus [These release the neurotransmitter noradrenaline, AKA norepinephrine.].  GDNF also prevents axotomy-induced motoneurone atrophy [degeneration of neurons involved in driving muscles, due to their output terminals - axons - being severed].  GDNF transcripts have been identified in several areas of the brain, supporting the concept that GDNF is a physiological neurotrophic factor which may have potential therapeutic applications in degenerative disorders affecting target neuronal populations, such as Alzheimer’s, Huntington’s, Parkinson’s or motoneurone diseases.
According to this, GDNF can enable neurons to survive even when one or more of their output terminals is damaged or somehow cut:

https://en.wikipedia.org/wiki/Glial_cell_line-derived_neurotrophic_factor

Glial cell line-derived neurotrophic factor (GDNF) is a protein  that, in humans, is encoded by the GDNF gene.  GDNF is a small protein that potently promotes the survival of many types of neurons.

So, with our current understanding, we learn from this 1996 research that vitamin D based intracrine signaling in glial cells - presumably including astrocytes - produces a compound which promotes the survival of these neurons.  This information is obviously of first-order importance for many types of disease, especially MSA.

This article Eyles et al. 2004 (co-written by Martin Hewison, whose team discovered vitamin D based intracrine and paracrine signaling in macrophages [WP] and dendritic [WP] cells (both are immune cells)) confirmed that VDR and 1-hydroxylase enzyme (both of which are produced in a cell when its intracrine/paracrine signaling system is activated) are found in many cells in the brain, including:
 in the large (presumably dopaminergic) neurons within the substantia nigra.
which are the ones best known for being killed in PD, and so causing the motor symptoms - tremors and poor control of limb movement.

Thus we see that an observant person searching a bunch of web pages and journal articles can learn, in a few minutes, vital information about deadly diseases which it seems most conventional researchers and doctors do not learn from one decade to the next.

20 or so minutes into my initial search I found this most interesting article:
Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy
Jacob I. Ayers, Joanne Lee, Amanda L. Woerman, Ann A. Lazar, Carlo Condello, Nick A. Paras, and Stanley B. Prusiner.
PNAS Neuroscience 2022-02-03
https://www.pnas.org/doi/abs/10.1073/pnas.2113489119
The researchers used a variety of subtle in-vitro (cell culture in test tubes) techniques to determine that the precise misfolded structure of alpha-synuclein in Parkinson's disease, dementia with Lewy bodies and Multiple System Atrophy, while unknown, were all different.

So - even before I read the above material about prion disease and synucleinopathies, I knew that these three diseases are prion diseases (and so extremely serious) and very similar to each other.   I assumed, I think reasonably, that a particular pattern of misfolding X gives rise to patterns of agglomerations which result in one pattern neural impairment and damage, and so of disease symptoms, while a slightly different pattern of misfolding Y results in agglomerations in different cells, giving rise to another pattern of damage and symptoms.

On this basis it is reasonable to assume that if we find that a particular intervention - such as correcting the statistically diabolically low pattern of 25-hydroxyvitamin D levels - will slow or arrest progression of one of these diseases, then it will probably do the same for the other two.  There is perhaps a greater commonality between the disease processes and their diagnostic criteria in that two types of MSA are recognised, one with many PD like symptoms.  Those with the PD type respond positively to levodopa.  This would be because, as is well known, PD's most obvious motor (muscle driving) control ill effects result primarily from the destruction of a particular population of neurons in the substantia nigra [WP], a small structure in the mid-brain which is involved in descending (from the upper, outer, parts of the brain) motor neuron pathways to the spinal cord, which drive lower motor neurons there which directly drive skeletal muscle.

As best I understand it, the overall function of this population of dopaminergic neurons is to inhibit signals emanating from the higher motor parts of the brain, to produce more finely controlled movements.  As these neurons decrease in number, voluntary muscle movements become less precise.  The dopamine these neurons release, at particular times, into the synapses [WP] between their output axons and the neurons they potentially inhibit, acts as an inhibitory neurotransmitter. 

The benefits of giving people oral levodopa are believed to result from increasing the levodopa levels in the remaining neurons.  Levodopa is normally produced in the output terminals of these dopaminergic neurons from the common amino acid tyrosine.  It is then converted in a not always so efficient process into dopamine, which is stored in vacuoles ready for release when the neuron fires.  By increasing levodopa levels inside the remaining cells (by ingesting levodopa, which goes into the bloodstream and diffuses into cerebro spinal fluid [WP] and then into these output axons), marginally more dopamine is produced there and stored in the vacuoles so that when the neuron fires, it releases more dopamine into the synapses with  motor neurons.  So the remaining neurons are able to marginally improve their limited inhibitory abilities, resulting in some reduction in PD motor control symptoms.  However, as far as I know, the levopdopa does not slow the fundamental progression of the disease.

On this basis, assuming that all MSA prions have the same structure, it seems that this structure can result in two patterns of disease progression - one which kills the same dopaminergic neurons in the substantia nigra as PD, and another one which does not do this to any significant degree.  Perhaps the PD type of MSA involves both the distinctive MSA prion structure and the PD prion structure.  If so, then there would be two similar looking, but in detail different, patterns of protein misfolding in the PD-like form of MSA.

This is further evidence that PD, DLB and MSA are very similar diseases.  While there is a great deal of fussing around about the differences, overall, according to conventional "wisdom", they are much of a muchness.   Low level and higher level brain functions turn to crap in various ways and death follows inexorably, sooner or later - so most doctors think.



Before long, I found:direct, incontrovertible, evidence that vitamin D supplementation slows the progression of PD:
Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease
Masahiko Suzuki, Masayuki Yoshioka, Masaya Hashimoto, Maiko Murakami, Miki Noya, Daisuke Takahashi, Mitsuyoshi Urashima
The American Journal of Clinical Nutrition 2013-03-13
https://academic.oup.com/ajcn/article/97/5/1004/4577000
This article has been cited 217 times in the 9 years since it was published.  I have not yet tried to survey these articles, but more below on a few instances of how it has been cited - including by it being unreasonably dismissed.

Suzuki et al.'s RCT involved Japanese PD patients, with baseline 25-hydroxyvitamin D levels of about 22 ng/mL.  The intervention group received 0.03 mg 1200 IU of vitamin D3 a day, for 12 months, with compliance estimated as 89%.  This is a fraction of what is required to get most people's level above 50 ng/mL, at the end of the 12 months, the intervention group's mean 25-hydroxyvitamin D level was 41.7 ng/mL from baseline 22.5.  The placebo group's mean level was 21.4 ng/mL from a baseline of 21.1.

The mean disease duration at the start of the RCT was 24 months for the vitamin D group and 13 months for the placebo group.  (I don't know how this would affect their measurements of disease progression, but I assume it was not significant, since they don't mention it.)

Some of their observations concern differences in disease progression which correlated with particular genetic variants of the vitamin D receptor (VDR) [WP] and vitamin D binding protein [WP] which binds to most circulating 25-hydroxyvitamin D.  Here I am concerned with their overall results.  They found (3rd column of Table 2) reasonably statistically significant (0.028 and 0.036 respectively, increases, in the vitamin D group, of the number of patients who showed no worsening or improvement (I would have thought no worsening on its own would be more pertinent) in two of 18 measures of disease progression: Hoehn and Yahr stages 1 - 5 [WP] and UPDRS part II [WP].

13 of the 18 measures showed improvement:with an RR (Relative risk) [WP] greater than 1.00, meaning a greater proportion of people in the vitamin D group did not get any worse (or better??) in the 12 months compared to those in the placebo group.   I have no knowledge of these measures, but I calculated the mean RR for all measures was 1.2.  This means that on average, over all these measures, 20% more patients who took the 1200 IU per day vitamin D had no change in symptoms, compared to those who did not take any vitamin D.

It is reasonable to assume that if more vitamin D3 was supplemented, higher 25-hydroxyvitamin D levels would have been reached, and further reductions in disease progression would have been attained.  This leads to the Coimbra protocol - which raises 25-hydroxyvitamin D very substantially over 50 ng/mL - which I discuss later.

Despite the length of my writing here, so far I am describing a very small amount of research - an hour so far, not counting some items above which I discovered later.

My next move was to find a few citations of Suzuki et al. to see how other researchers used their observations.  First up was a big review article which constitutes guidance for doctors treating PD patients:
International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson's disease
Susan H. Fox, Regina Katzenschlager, Shen-Yang Lim, Brandon Barton, Rob M. A. de Bie, Klaus Seppi, Miguel Coelho, Cristina Sampaio on behalf of the Movement Disorder Society Evidence-Based Medicine Committee
Movement Disorders 2018-10-30
https://movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.27372
A total of 143 new studies qualified. There are no clinically useful interventions to prevent/delay disease progression.

Dietary/nutritional supplements, including coenzyme Q10, creatine, and vitamin D remain popular among PD patients because of widespread availability, ease of use, and good tolerability, but the EBM review shows that there is no evidence of clinical benefit.
Here is their their dismissal of Suzuki et al. 2013:
One new study using vitamin D had unclear conclusions; thus the efficacy conclusion is “insufficient evidence” and the practice implication is “investigational.”
This is typical of the generalised dismissal and ignorance concerning vitamin D and numerous health conditions.

These mainstream doctors should be trying much harder to understand the conditions the immune system needs for proper operation, including especially the need for 50 ng/mL 25-hydroxyvitamin D. They should also pay much more attention to the other cause of generalised excessive inflammation: genetic variations on a theme set by lack of helminths when our immune system evolved to work best with them.

An earlier review article cites Suzuki et al.:
Systematic Review of the Relationship between Vitamin D and Parkinson’s Disease
Lisanne Rimmelzwaan, Natasja van Schoor,  Paula Lips, Henk Berendse and Elisabeth Eekhoff
Journal of Parkinson's Disease 2016-03-30
https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd150615
While this is potentially a pro-vitamin D article, the authors do little more than summarise Suzuki et al.'s findings (page 32).  They don't seem to think creatively or constructively at all, such as noting that the 1200 IU a day vitamin D intakes was low, and that the compliance rate and the long time it surely took at this rate to raise 25-hydroxyvitamin D levels to the marginal level of 41.7 ng/mL means that the rather marginal benefits could surely have been improved upon with much higher vitamin D3 intakes.  They show themselves to be unfamiliar with the fundamentals of vitamin D metabolism by mistakenly stating (page 30, para 2) that 25-hydroxyvitamin D is synthesized in the skin (it is vitamin D, cholecalciferol) and needs to be hydroxylated twice.  Their "ug/mL" mistake (page 30 last para - should be "ng/mL") is sloppy or indicative of limited knowledge of the field.

There are far too many of these next-to-useless, partly misleading, articles among the many vitamin D articles which are published every year.   So Suzuki et al.'s work, which should have been properly appreciated in an article with this impressive title, is not used for any constructive purpose, such as suggesting trials with much higher vitamin D3 intakes.

Ideally I would chase more citations of Suzuki et al. 2013.

Instead, I followed the limited citations, in the last year, of Ogura et al. 2021.  This article, according to my way of thinking - and, I think, of any alert person who reads it - should be the basis of analysis and recommendations to use proper vitamin D supplementation to get these poor PD people, declining into dysfunction and death, out of their downwards spiral by lifting their 25-hydroxyvitamin D levels out of the gutter, such as by attaining, generally, at least 50 ng/mL.  On 2022-09-29, Google finds only 3 citations.

Firstly, the same team https://www.sciencedirect.com/science/article/pii/S2590112522000330 pursue a misguided research direction by analysing the levels of certain enzymes which catalyse  25-hydroxylation of vitamin D3 to 25-hydroxyvitamin D and 1-hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D.  However, the researchers looked for the level of these enzymes in the bloodstream.  The presence of these enzymes in the bloodstream is irrelevant to their real functions in the body.  I have never heard of anyone measuring such levels. 

While the Ogura et al. team made very important, highly significant, observations, it seems they were generally clueless about vitamin D - having no idea about how the immune system depends on 25-hydroxyvitamin D to supply each cell's intracrine (internal) and paracrine (to nearby cells) signaling systems.  They seem to be looking for reverse causation - such as PD causing lower levels of one or both enzymes, which would lower 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in the bloodstream - an example of the disease causing the observed lower 25-hydroxyvitamin D levels.  If they could show such reverse causation is minimal, then the observations in their first article would be a strong argument for easily fixed low vitamin D strongly causing PD and MSA.

Secondly some of the same team have an article on constipation and MSA: https://www.mdpi.com/2075-4426/12/5/838 .  Who cares about such minutiae??  People are dying and we have good reason to believe that low vitamin D is a - or the - primary reason. So lets get on with boosting vitamin D intakes.

Thirdly and finally, a big article about autophagy (an interesting field concerning the healthy - or not - degradation of cellular components) [WP]), "nutraceuticals" and PD  https://www.mdpi.com/1422-0067/23/7/3625 .  Despite the pseudo-impressive diagrams (bewildering even to me - and I am a C++ programmer who designs printed circuit boards), 35 pages and 219 references, this article has nothing to say about using higher intakes of vitamin D to slow or halt PD progression.  The researchers are much more interested in gassing on about their beloved autophagy than in helping people survive a disease, which with current medical practices is invariably fatal.

So in a year, there's no sign at all from professional researchers that Ogura et al.'s dramatic observations are leading to better treatment decisions about PD or MSA.


What we need is a more adventurous researcher doctor to take action which to me looks sensible and obvious, but - as far as I can tell - appears to most doctors as wild, and perhaps crazy: give the poor patients enough vitamin D3 to get their immune systems working properly.

This has in fact happened, for PD.  Dr Cicero Coimbra, in Brazil, tried to cure (AKA halt the progression of) Parkinson's disease, in 2001, with 0.1 mg 4000 IU vitamin D3 a day, according to this account:
https://www.coimbraprotocol.com/the-protocol-1
It is not clear to what degree he succeeded, or how often he and the doctors he trained, now use his protocol for people suffering from PD, DLB or MSA. 

My initial, quick searching lead to the items above, and some Facebook and forum reports from, or about, PD patients who have apparently been cured with the Coimbra protocol.  I decided it was time to do more intensive work to understand the Coimbra protocol, and the early history of using vitamin D to tackle PD.  This is not a definitive literature review, but it goes well beyond the simple searching mentioned above, which any interested person could do, including for other inflammatory diseases, such as multiple sclerosis, Alzheimer's disease etc.

The earliest report I could find of using vitamin D to tackle PD or something like it is Derex et al. 1995 "Calcifications striato-pallido-dentelées et atrophié faciale acquise" Revue neurologique 1995, Vol 151, Num 10, pp 559-562, which does not seem to be available online.  It is mentioned in the quote below from the next article, which is the only vitamin D article which cites it::
Reversible parkinsonism, hypophosphoremia, and hypocalcemia under vitamin D therapy
L. Derex and P. Trouillas
Movement Disorders 1996-11-21 Volume 12, Issue 4 p. 612-613 (Often cited as 1997.)
https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.870120424
The description of Derex et al. 1995 is:
We described a family with two siblings suffering from action tremor and rigidity and presenting striopallidodentate calcifications [extensive calcification in the brain]. These two patients showed reduced level of 25-(OH) vitamin D3 [25-hydroxyvitamin D], which normalized under vitamin D2 supplements [vitamin D2 comes from plant sources and works similarly to vitamin D3, but not quite as well], thus excluding a defective activity of the enzyme that catalyzes hydroxylation of vitamin D in the liver.
I understand the reported movement disorders were regarded as PD or akin to it, in part because Derex 1996 cite an earlier article concerning similar calcification and PD / PD-like symptoms due to genetic abnormalities in a family, in which 25-hydroxyvitamin D levels were low: Martinelli et al. 1993: https://movementdisorders.onlinelibrary.wiley.com/doi/abs/10.1002/mds.870080221 .

Derex 1996 report on a 50 year old patient who was diagnosed with PD 13 years earlier, with low serum calcium and phosphate, normal parathyroid hormone [WP] and "rather low" 25-hydroxyvitamin D: 13.2 ng/mL 33 nmol/L.  This patient's extensive movement disorder symptoms largely resolved after a year taking 0.1 mg 4000 IU vitamin D3, and 1 gram calcium, supplements:
After the addition of 25-(OH) * vitamin D, (4,000 IU daily) and calcium supplements (1 g daily) to the ongoing conventional antiparkinsonian therapy, serum and urinary calcium and phosphorus values progressively normalized as well as serum 25-(OH) and 1,25-(OH), vitamin D,. The parkinsonism improved significantly during the following year with decreased rigidity and akinesia, and the antiparkinsonian drugs could be restricted to levodopa 375 mg daily. At 1-year follow-up, neurological examination revealed moderate rigidity without tremor.
*  See my notes below under McCullough et al. 2021.  I wonder whether the "25(OH)" was a typo.  If it is not, then they used 25-hydroxyvitamin D AKA calcifediol.  There is no recognised conversion to specify what mass of this constitutes an IU.  Also, it would have been difficult to obtain at all, let alone for daily dosing for a patient.  I suspect this is a typo and that they used vitamin D3 cholecalciferol.  Either way, the effect would have been the same - to boost circulating 25-hydroxyvitamin D levels, so my doubts about what compound they use do not detract from the validity or importance of their experiment.   
This is clear evidence of the ability to reduce or stop PD progression, in part with supplemental vitamin D3, with the benefits, in my interpretation, including some recovery of the neural functions which (as far as I know) would normally in PD have been assumed to be lost due to neural destruction.

This was 26 years ago.  We might reasonably have hoped that doctors all over the world would want to know about a simple, safe, apparent treatment for a common, devastating and ultimately deadly disease which was, and still is, regarded being impossible to treat, except regarding symptoms, by any known method.

Google Scholar reports 53 articles which cite Derex 1996.  I looked at them all to see if any of them seemed to concern vitamin D3 supplementation to treat PD.  I found:
Vitamin D and Parkinson's disease - A hypothesis
Harold L. Newmark and Jonathan Newmark
Movement Disorders 2007-03-27
https://movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.21317
I did not chase the 228 articles which cite this, but at first glance they seem to be a good set of articles on vitamin D and the brain.
They report that Derex 1996 is the only instance they are aware of in which PD was successfully treated with vitamin D3.  (There are non-human animal models of PD, but I don't trust experiments with these, since at least in some cases their supposed Parkinsonian conditions do not result from the pathological processes as in humans, but in deliberate destruction of the population of dopaminergic neurons which are destroyed in PD.)

This indicates that after Derex 1996, no-one seems to have used vitamin D supplementation to treat PD by 2007 = 11 years.  However, Cicero Coimbra was.  They also suggest an RCT (Randomised Controlled Trial) [WP], but the long term quantity of vitamin D3 they suggest (0.01 mg 1000 IU) is too small to make a decisive difference, being 1/5 of the amount needed to get most average weight adults' 25-hydroxyvitamin D level over 50 ng/mL.

Newmark et al. 2007 suggest:

Clinical intervention studies.

  • a High dietary supplementation of vitamin D (1,000–2,000 IU/day), but not over the upper limit (UL) of safe, well-tolerated daily intake of 2,000 IU/day established in the current Dietary Reference Intake, to be used as ancillary to current PD therapy with dopaminergic and/or adrenergic drugs. On prolonged use, this safe vitamin D supplementation may “stabilize” PD patients and retard, or even stop, further decline.

  • b  Attempt to reproduce, or expand into larger, placebo controlled studies [RCTs], on the single case-report of Derex and Trouillas in which a high dose (4,000 IU/day) of 25-hydroxy vitamin D was used daily.  A goal may be to use short-term, high-dose oral vitamin D such as 4,000 IU/day for 8 to 12 weeks to achieve 80 nM serum 25-OHD followed by long term 1,000 IU daily.  [0.1 mg 4000 IU / day is not high dose, once one recognises that, very approximately, 5000 IU / day is needed by 70 kg adults for proper immune function.]

  • c  Use of high dietary vitamin D supplementation as in (b) above, to aid in the repair and healing of damaged brain cells, including stroke, physical injury, toxic damage, and neuralgic damage, based on the animal studies reviewed earlier.

Dietary Factors in the Etiology of Parkinson’s Disease
Zeynep S. Agim and Jason R. Cannon
Biomed Research International 2015-01-20
https://www.hindawi.com/journals/bmri/2015/672838/
Similarly they indicate that after Derex 1996, no-one seems to have successfully used vitamin D supplementation to treat PD by 2015 = 19 years:
(Derex 1996) represents a single case and more additional robust studies have either not been conducted or have failed to show a direct protective effect of vitamin D in PD.
They do not seem to cite research in which vitamin D was used unsuccessfully to treat PD.  Given the prevailing notions of what constitutes a "high dose" of vitamin D3, it is not surprising of such trials failed.

Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience
Patrick J McCullough, Douglas S Lehrer and Jeffrey Amend.
Journal of Steroid Biochemistry and Molecular Biology 2019-01-04
https://www.sciencedirect.com/science/article/abs/pii/S0960076018306228 (Paywalled.)
https://sci-hub.se/10.1016/j.jsbmb.2018.12.010
Dr McCullough is one of the pioneers of higher than usual vitamin D3 intakes to suppress autoimmune inflammatory diseases.  He does this himself to suppress psoriasis, as mentioned in this article, which is one of the key articles in the field and which I cite alongside the work of Cicero Coimbra and Peter Batcheller (cluster headaches and migraine): https://vitamindstopscovid.info/06-adv/#01-higher .
This article also mentions Derex 1996 as the only attempt to treat PD with vitamin D.

This article indicates that after Derex 1996, no-one seems to have used vitamin D supplementation to treat PD by 2017 = 21 years:


A Review of the Relationship Between Vitamin D and Parkinson Disease Symptoms
Michelle E. Fullard and John E. Duda
Frontiers in Neurology 2020-05-27
https://www.frontiersin.org/articles/10.3389/fneur.2020.00454/
I found this to be a most valuable review article.  There are lots of items of interest, including regarding low vitamin D levels being correlated with orthostatic hypotension, a common problem for PD sufferers, in which blood pressure drops when standing.  So why don't conventional doctors prescribe decent amounts of vitamin D3 to their PD patients, for whom orthostatic hypertension, and so the risk of losing conciousness and falling when they stand up, represents a serious risk of injury and death?

Regarding vitamin D supplementation trials with PD patients, this article cites:
  1. Derex 1996, as noted above, which was a vitamin D3 or 25-hydroxyvitamin D supplementation intervention with a single subject.

  2. Suzuki et al. 2013, mentioned above.

  3. (Page 4.) An Iranian RCT involving only 0.025 mg 1000 IU vitamin D3 a day for 3 months.  This is far too low a dose and too short a time to show significant benefits.  (I have read lots of excellent research from Iran - this is an exception to that pattern.)

  4. (Page 5.) An RCT involving vitamin D supplementation and balance in PD subjects - Hiller et al. 2018, see below.

  5. Multiple vitamin D supplementation trials with PD patients aimed at improving cognition.  None produced improvement.  Ideally I would look at these - in refs 110 to 119 - but there is not enough time now.   It is very common for vitamin D supplementation trials to have a short time frame and use doses far too low to raise 25-hydroxyvitamin D levels safely over 50 ng/mL.

Oral and Topical Vitamin D, Sunshine, and UVB Phototherapy Safely Control Psoriasis in Patients with Normal Pretreatment Serum 25-hydroxyvitamin D Concentrations: A Literature Review and Discussion of Health Implications
Patrick J McCullough, William McCullough, Douglas Lehrer, Jeffrey Travers and Steven Repas.
Nutrients 2021-04-27
https://www.mdpi.com/2072-6643/13/5/1511
Similarly they indicate that after Derex 1996, no-one seems to have used vitamin D supplementation to treat PD by 2021 = 25 years: 
A 1997 case report of chronic Parkinson’s disease symptoms over the course of a year using 4000 IU/day of 25(OH)D [Derex 1996], roughly equivalent to 20,000 IU/day of vitamin D3.

Following on from my notes above on Derex 1996: McCullough et al. interpret the Derex 1996 mention of "4000 IU" of "25-OH vitamin D3" as meaning that this was 0.1 milligrams of 25-hydroxyvitamin D (AKA calcifediol) which is about as effective at raising circulating 25-hydroxyvitamin D levels as 5 times this amount of vitamin D3 cholecalciferol. So they interpret the effectiveness of this intervention as being equivalent to 20,000 IU of vitamin D3.

I question whether Derex 1996 really used calcifediol.  It is hard to obtain now, and would have been harder still then, especially in quantities such as 0.1 mg which would have been quite expensive.  If so, they might have known that it is more  effective per unit mass as vitamin D3 at raising circulating 25-hydroxyvitamin D levels.  So if they used calcifediol, we can't reliably know how much, in milligrams, they used.  There is no recognised conversion factor, but 3 to 6 seems reasonable based on my interpretation of various research articles.  I assume 4.  McCullough et al. assume 5, which is fine too.

I wonder whether the "25-(OH)" in the Derex article is a typo.  I can easily imagine them using 0.1 mg 4000 IU vitamin D3 cholecalciferol a day for a year.
This is the end of my review of the 53 articles which cited Derex 1996.  I noticed several things:
  1. Patrick McCullough et al. were the only researchers who used vitamin D supplemental quantities which were sufficient to get circulating 25-hydroxyvitamin D levels above 50 ng/mL in most subjects.  However, they did not work with PD patients.

  2. There is no mention of the work of Cicero Coimbra in the above, mainstream, research literature, which spans 26 years.  More on this below.

  3. In these 26 years - except for the work of Cicero Coimbra, nothing substantial happened regarding proper, substantial, long-term use of vitamin D3 to tackle Parkinson Disease progression or symptom severity.

    What is wrong with these people?   In electronics and computer programming I am constantly detecting and solving problems no--one has ever seen before or will see again.  Here is a problem: According to the Global Burden of Disease Project: https://www.sciencedirect.com/science/article/pii/S1474442218302953 in 2016, 6.1 million people had Parkinson's Disease and 211,296 of them died.  That is one death every 3 minutes.  There are strong mechanistic, observational and experimental reasons to believe that boosting PD patients' 25-hydroxyvitamin D levels substantially, such as over 50 ng/mL, will reduce disease progression.  So why not do this?  It is safe, easy and inexpensive. 

    The profound ignorance and lack of interest in vitamin D by most doctors has many causes.  However, one of them is probably that they didn't spend a decade or so training to become doctors to tell people to take more of a vitamin they can buy at the supermarket.  It seems that doctors and researchers are much more interested in complex interventions, and researching all sorts of potentially interesting details, than finding a simple way of saving millions of people from an otherwise deadly neurodegenerative illness.


As noted above, there was a vitamin D supplementation trial for PD, of potential interest:

A randomized, controlled pilot study of the effects of vitamin D supplementation on balance in Parkinson's disease: Does age matter?
Amie L. Hiller, Charles F Murchison, Brenna M Lobb, Susan O’Connor, Morgan O’Connor and Joseph F Quinn.
PLoS ONE 2018-09-26
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203637

The intervention group supplemented 0.25 mg 10,000 IU vitamin D3 a day, for only 16 weeks.  Mean 25-hydroxyvitamin D levels rose from 30 ng/mL to 60 ng/mL and were still rising at the end of the trial.  Those aged 67 to 86 did not show a significant improvement in balance, but those aged 52 to 66 did.

This is far too short to measure genuine reduction in disease progression, and the researchers measurement of PD severity focused on only one aspect of the disability it causes.

This indicates vitamin D3 supplementation can be helpful, but it is far from a proper trial of vitamin D for long-term suppression or prevention of disease progression.

I also found a low key trial:
A 2011 thesis involved PD patients supplementing 0.1 mg 4000 IU vitamin D3 a day for just 12 weeks, which improved the ability to lift weights.  No 25-hydroxyvitamin D measurements.  A short time, a modest dose and the possibility that the supplementation had benefits other than reducing the effects of PD: https://digitalcommons.memphis.edu/etd/214/ .

Here is a recent, extensive review article:
Vitamin D and Parkinson’s Disease
Antonio Pignolo et al.
Nutrients 2022-03-14
https://www.mdpi.com/2072-6643/14/6/1220
This notes that vitamin D compounds are well known to be important for brain development and neuroprotection.  This would all be via intracrine and paracrine signaling.
The presence of a high concentration of VDR and 1-α-hydroxylase in the substantia nigra (SN) provides evidence of a possible relationship between PD and vitamin D.

. . . a lower concentration of vitamin D correlates with high levels of C-reactive protein (CRP), a marker of inflammation.  Overall vitamin D role appears fundamental in the prevention of brain aging, considering also its function in the production of growth factors, including nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT3).
As mentioned in Fullard et al. (above) there is conflicting research on whether or not low 25-hydroxyvitamin D levels increase the risk of PD. For instance Shrestha et al. 2016 found that levels recorded in 1990 to 1992 were not correlated with the risk of PD by 2008.  Compared to the risk for those with 20 ng/mL or less 25-hydroxyvitamin D, the risk for those with 20 to 30 ng/mL and 30+ ng/mL were 5 and 14% higher, respectively.  I find this hard to reconcile with the very significantly lower levels of PD sufferers, unless in the intervening years, including perhaps before PD was diagnosed, behavioural or other PD-related changes lowered 25-hydroxyvitamin D levels.  This argues for a greater reverse causality than I can currently imagine.  Conflicting research is common, and it is important to scrutinise each study and consider all other studies, many of which do report that lower 25-hydroxyvitamin D levels (at least after diagnosis) strongly correlated with the incidence of PD.  The authors cite a similar, earlier study Knekt et al. 2010 which did find that lower 25-hydroxyvitamin D levels in 1978 to 1980 were correlated with increased risk of PD detected by the end of 2007.
Vitamin D administration reduces dopaminergic toxicity of 6-hydroxy dopamine. [This is a toxic compound known to kill dopaminergic neurons in the substantial nigra, causing PD.]
There are several functionally different variants of the gene for the Vitamin D Receptor (VDR) molecule.  This is a large field of research I have not paid much attention to since we can't change which variations each person has.  However, it is worth remembering since the incidence and/or severity of many health and disease conditions has been found to correlate with individual variations in VDR genes, and so the molecular structure and function of VDR molecules.  Research has shown that people with some forms of VDR are at higher risk for PD than are those who have other forms.

The authors provide a simplified account of the findings of several complex research studies, which indicate that not every person will respond equally, or perhaps at all (so they say - I think everyone will respond to some significant degree with sufficient intake quantities) to vitamin D3 supplementation regarding PD progression or some other measure of symptom severity. 
Therefore, as shown in some studies, response to vitamin D administration in PD patients depends upon the genotype of VDR.  VDR CC allele (FokI) is associated with PD, and subjects with FokI CC demonstrated no significant response to vitamin D administration with respect to placebo compared with other VDR genotypes. Specifically, subjects with FokI TT allele had a significant response to vitamin D administration compared to individuals with VDR FokI CT, who had a moderate response. FokI CC was also associated with milder form of PD.
Just because some studies, with some people, showed no benefits to vitamin D3 supplementation does not mean that those PD sufferers would have no benefit with longer-term, more substantial, vitamin D3 supplementation, especially if other commonly deficient nutrients were supplemented too, including magnesium, boron, omega 3 fatty acids etc.

Genetic variants of the Vitamin D Binding Protein (DBP) are also frequently found to correlate with disease incidence and severity, and this has been found with PD too. DBP exists in the blood plasma and strongly binds most circulating 25-hydroxyvitamin D, with most of the remainder being bound less tightly to albumin proteins, and only about 1% remaining unbound and so, as best we know, free to diffuse into tissues.  (The exact details of this all-important diffusion into cells such as immune cells are the subject of ongoing research and debate.)

These genetic and so structural and functional variations in DBP - which presumably affect how tightly DBP binds 25-hydroxyvitamin D - in combination with individual and racial variations in the quantity of DBP in the bloodstream, would explain, for any given total circulating 25-hydroxyvitamin D level (which is what vitamin D blood tests measure) different levels of 25-hydroxyvitamin D in various cells, including immune cells, and in the Cerebro Spinal Fluid (CSF) [WP] in which all neurons and support cells such as astrocytes are bathed. 

These variations in intracellular 25-hydroxyvitamin D surely exist, but as far as I know, no-one has been able to measure the level of 25-hydroxyvitamin D in individual immune cells, or in a small sample of such cells of a single type.  Such variations alter the amount of  25-hydroxyvitamin D these cells can hydroxylate when their vitamin D based intracrine or paracrine signaling systems are turned on by the cell detecting a specific external condition.  This would alter the amount of 1,25-dihydroxyvitamin D produced in each cell when the intracrine signaling system is activated, which would affect how strongly these systems can alter the behaviour of the cell, by altering the rate at which dozens or hundreds of genes are transcribed into messenger RNAs [mRNA] which control the cell's protein synthesis and so its overall behaviour.

This article mentions non-human animal models of PD. I don't trust such research, since they typically induce PDilike symptoms by using neurotoxins to kill specific populations of dopaminergic neurons.  We are interested in how vitamin D supplementation might reduce the actual PD disease processes in humans, including especially those which kill these cells in the substantia nigra.

Pignolo et al. cite Evatt 2011 (above), who report that 25-hydroxyvitamin D levels did not decline as PD progressed. This is an important argument against reverse causation being a significant reason for the observed, generally low, 25-hydroxyvitamin D levels of PD sufferers.

Regarding observations of levels, rather than vitamin D supplementation interventions:
Among non-motor symptoms, depression and cognitive impairment seem to be influenced by 25(OH)D3. Better scores in neuropsychiatric testing, especially verbal fluency and verbal memory, are associated with higher 25(OH)D3 serum levels, and 25(OH)D concentration was correlated with depression and anxiety scores.
On page 7 is a section "Vitamin D Supplementation and Parkinson's Disease".  This begins with discussion of adding 1,25-dihydroxyvitamin D to cells in the lab, and potentially doing so to an entire human being by injecting, or having them ingest, 1,25-dihydroxyvitamin D calcitriol.  This is an example of the misleading and uninformed statements or assumptions which are common in the vitamin D research literature, due to the authors not understanding vitamin D based intracrine and paracrine signaling.  Most articles don't mention these so it is reasonable to assume the authors have never heard of them

It is a  very common mistake is to think that circulating 1,25-dihydroxyvitamin D levels affect immune cells.  This very low, hormonal, level only affects calcium-phosphate-bone metabolism. 

When the vitamin D based intracrine signaling process is activated AND the cell has plenty of 25-hydroxyvitamin D in its cytosol (main body of the cell) [WP] substantial amounts of 1,25-dihydroxyvitamin D is produced, at levels much higher than the (usually hormonal) very low external levels.  It is this intracellularly produced 1,25-dihydroxyvitamin D, acting as an intracrine agent - not the low, stable, external level of hormonal 1,25-dihydroxyvitamin D - which alters the cell's behaviour. 

The exception to the above principle is vitamin D based paracrine signaling, in which multiple cells of some type X in a particular part of the body produce enough 1,25-dihydroxyvitamin D and let this diffuse into the interstitial fluid between cells, raising the local level well above the low, stable, hormonal level, and this does alter the behavior of other nearby cells, usually of types other than X.  I have never read an account of the distance vitamin D based paracrine signaling can work over.  I guess millimetres.

It is valid to add 1,25-dihydroxyvitamin D to cell cultures to see how it affects cells as it diffused into them.  Unfortunately some experimenters think this tells them about how such cells in the body would respond to externally applied 1,25-dihydroxyvitamin D.  Except in the case of them being on the receiving end of vitamin D based paracrine signaling, this is not so.  Most often, in vivo (in the cells in living human bodies) the cell changes its behaviour due to the successful operation of the vitamin D based intracrine signaling system in that particular cell, which has been activated by particular circumstances, and has worked well due to the cell having sufficient 25-hydroxyvitamin D to hydroxylate into 1,25-dihydroxyvitamin D.  

Some researchers think that because in-vitro addition of 1,25-dihydroxyvitamin D causes particular, desirable, changes in cell behaviour that this can be brought about in an entire human by feeding (or injecting) them with 1,25-dihydroxyvitamin D calcitriol.  This is not the case, since successful operation of immune and other cells depends on the per-cell operation of the vitamin D based intracrine signaling system - and for cells in a general area, paracrine signaling.

We are only interested in supplemental vitamin D3 cholecalciferol to raise 25-hydroxyvitamin D, or, in clinical emergencies, supplemental calcifediol, which is 25-hydroxyvitamin D, to raise the level in a few hours.

They mention Suzuki et al. 2013's research with the very small 1200 IU a day vitamin D3 supplemental intake.  The only other article they mention regarding vitamin D3 supplementation is a 2018 article by Luthra et al. which I could not be bothered looking at, since it involved only 0.01mg 400 IU of vitamin D3 - and no benefits were found.  To their credit, the trial period was 3 years.

So this very recent article does not list any further significant attempts to tackle PD with vitamin D3 supplementation (none have involved calcifediol == 25-hydroxyvitamin D) other than Suzuki 2013. This indicates that, after Derex 1996, no-one seems to have used vitamin D supplementation to treat PD by 2022 = 26 years:

So, according to this reasonably intensive search of the mainstream vitamin D Parkinson's disease, nothing substantial was done over 26 years to test robust vitamin D3 supplementation for the long-term benefit of PD sufferers, other than Suzuki et al. 2013, which was for a half-way decent 12 months, but crippled by such a small quantity: 0.03 mg 1200 IU a day.

This is a terribly slow rate of experimentation on the crucial, easy to fix, nutritional deficiency which clearly has a strong causative role in PD - and likewise DLB and MSA - which collectively affect millions of people.

Most people like to think that their doctors are well informed by the vastly expensive industry of medical research - but in this case, nothing could be further from the truth.

The other thing worth noting about the above-mentioned research and review articles is that none of them mention the Coimbra protocol - though I am sure that Patrick McCullough and colleagues are fully aware of it.

My best guess is that this is because Dr Coimbra and those who use his protocol, publish very little about their work in mainstream research journals. 

Google Scholar reports that about 69,000 journal articles were published on Parkinson's disease in 2020 and 2021.  I clicked through the first 1000 of them - which is all the system presents - and every one of them had "Parkinson's disease" in their title.  So these are articles directed at this disease, not citations or articles which mention it in passing.

This is an article every 15 minutes, 24 hours a day.   There is a vast industry of medical research directed at PD, and another vast industry treating it.   This is about one article for every 5 deaths from PD.

In all time, Google Scholar finds only one item which mentions both "Parkinson's disease" and "Coimbra protocol" - an obscure thesis for which the full text does not seem to be available.

Google Scholar lists 12,400 articles since the start of 2020 in a search for "Parkinson's disease" "Vitamin D", but I have already searched, as shown above, for articles which mention using vitamin D3 supplementation to prevent or treat PD.

The vast majority of this river of research and analysis is pointless.  While all sorts of biochemical mysteries and intrigues can be sleuthed - and while some of these are useful basic research - none of this effort directly pursues the goal of preventing of treating Parkinson's disease, which can only be done once everyone, before disease onset - or everyone who has been diagnosed with PD - has their 25-hydroxyvitamin D level raised to at least 50 ng/mL 125 nmol/L.  There are surely other nutrients which are important, but none or worth worrying about until we attain at least 50 ng/mL 25-hydroxyvitamin D.


Parallel to the Coimbra protocol, Pete Batcheller and Patrick McCullough and colleagues were both working with protocols similar to the Coimbra protocol, but as far as I know they were not working with people suffering from Parkinson's disease, dementia with Lewy bodies or Multiple System Atrophy.

This leaves us to enquire into the Coimbra protocol.

I was only roughly familiar with this work until late September and early October 2022 when I did this intensive research.  What I found out about it makes me think:
  1. The Coimbra protocol, or any broadly similar protocol, is likely to be highly effective in stopping disease progression of PD, DLB and MSA - just as it is with a plethora of other inflammatory disorders.  If this is true, as I am sure it is, then the guidance currently offered by mainstream medical professionals - that PD (and DLB and MSA) is untreatable - is harming and ultimately killing millions of people.

  2. The Coimbra protocol itself, and generally the work of Cicero Coimbra regarding his protocol, does not seem to have been published in peer reviewed journals or anywhere else.  I think they should publish more.  If anyone has a good therapeutic technique, it is incumbent upon them to make all the details fully available to medical professionals and the public, for the purposes of general education, criticism, improvement and wider dissemination.

  3. Moderate versions of the Coimbra protocol - broadly speaking - can probably be done by well-educated people with a good safety margin. However, the more intense interventions surely do require medical expertise to direct the vitamin D and other intakes of supplements, to ensure other dietary goals are maintained (such as minimising calcium intake) as well as to run and interpret blood tests for calcium and parathyroid hormones.  One would think that 25-hydroxyvitamin D measurements would be a crucial part of monitoring each patient, but Amon et al. 2022 don't bother having this tested.

Enough preambling - lets find out what we can about the Coimbra protocol!  I am not suggesting that no other aspect of nutrition than vitamin D is important for suppressing PD and numerous other diseases - but it is the most important deficiency which should be corrected, before any other interventions are considered.  There are surely all sorts of genetic details which are important to the various diseases, and it is possible or likely that particular drugs, or special nutritional arrangements, may help with various diseases.  My focus here is on vitamin D, while assuming that people are also getting sufficient magnesium, zinc, omega 3 fatty acids and other nutrients.  Ideally more people would supplement boron as well.



Dr Coimbra published another protocol, specifically for Parkinson's disease patients in 2003.  It does not mention vitamin D:

High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson's disease patients
C.G. Coimbra and V.B.C. Junqueira
Brazilian Journal of Medical and Biological Research 2003-08-27
https://www.scielo.br/j/bjmbr/a/BM4WLJBtjxF8Cx3wFsjFhKb/?lang=en

This reports on a 6 month RCT which apparently produced significant benefits.

I read somewhere that Dr Coimbra started with this approach, and then switched to vitamin D with other nutrients, I think including riboflavin (vitamin B2). So this article, presented for publication in early 2003, may report on an RCT which was planned one or a few years earlier.

For further research, the articles which cite this one are likely to be of interest - such as this one in 2017 concerning PD, migraine, mitochondria and inflammation.

This website:

https://www.coimbraprotocol.com
is "created and maintained by patients who follow the Coimbra Protocol". So it is not the site of Dr Coimbra.  As far as I know, he has no website.
https://www.coimbraprotocol.com/the-protocol-1

The protocol has apparently been stable since 2012.

https://www.coimbraprotocol.com/general-information

This page has some details of the protocol.  25-hydroxyvitamin D levels are tested, but are not used as part of the decision about how much vitamin D3 to take.  I think they rely on parathyroid hormone levels to determine limits to vitamin D3 intake.

It seems that the Coimbra protocol is most often used to treat MS (multiple sclerosis).  However, the protocol  is apparently useful with a very wide range of diseases, as I list below.

A low calcium diet and 2.5 litre a day water consumption are mandatory.

There is no mention of helminths, intracrine/paracrine signaling or even of inflammation.  The mechanistic theory underlying the protocol seems to involve a vaguely defined "vitamin D resistance" which can be overcome with suitably high levels of circulating 25-hydroxyvitamin D.

With adequate levels of vitamin D, essential cellular processes will unfold properly; however, the majority of patients with autoimmune diseases have an increased resistance to the effects of vitamin D. This resistance is mostly due to genetic polymorphisms, and may also be influenced by factors such as body weight, body mass index, and age. Consequently, patients with autoimmune disorders require higher levels of vitamin D to overcome this resistance and unlock the beneficial effects of this important substance at their cells and tissue.

Vitamin D suppresses autoimmunity by suppressing the Th17 (T helper 17 cell) [WP] reaction, which is caused by overproduction of an "immune messenger" (cytokine) called "interleukin 17". Production of interleukin 17 is a natural phenomenon and is beneficial in adequate, regulated amounts. However, overproduction of interleukin 17 is not a natural phenomenon. So, autoimmune disease is the result of a dysregulated immune system that produces an aberrant immunological Th17 reaction, and Vitamin D is the substance needed to modulate this process.

At the same time, vitamin D also induces the proliferation of regulatory immune cells called "T lymphocytes".

It's also important to mention that vitamin D does not suppress the immune system; quite the contrary, it empowers the immune system against viruses, bacteria and other microorganisms.

I think the Coimbra protocol is effective and probably safe if medical monitoring is done properly.  I think the Coimbra protocol has been developed by experiment, without an accurate mechanistic theoretical basis.

According to this description:

If PTH is not at its minimum normal limit, vitamin D daily doses are increased until the desired PTH level is achieved.  During the treatment, PTH levels are expected to go down to their lowest normal limit and stay there. When this happens, the resistance to vitamin D is overcome and the patient starts benefiting from its powerful immunomodulatory effects. It usually takes two years to adjust the doses of vitamin D. After this period, the treatment consists in maintenance of the proper levels of PTH and calcium.

every patient has their 25-hydroxyvitamin D level pushed as high as possible, using some lower limit of PTH as the observation which indicates this has been attained.  However, given the risks of doing this, it seems unlikely that clinicians would seek to attain any higher 25-hydroxyvitamin D level than is necessary to substantially suppress the disease process they are tackling.

Amon et al. 2022 (below) report differing mean 25-hydroxyvitamin D levels for patients tackling different diseases, with higher levels for their MS patients.  So they must be moderating the boosting of 25-hydroxyvitamin D levels to whatever is needed to suppress the disease in each patient rather than to maximise it for every patient.  This would have important benefits in reducing the risks for most such patients.

Their description of risks, here in red since they are serious, is:

The possible side effects of taking high doses of vitamin D for extended periods of time are an excess of calcium - in the blood (hypercalcemia) or in the urine (hypercalcuria), and loss of bone mass. Excess calcium can be easily avoided with a diet free of dairy and calcium-enriched foods, and regular lab tests to ensure calcium levels are kept under control.

To avoid loss of bones mass, patients on the protocol are instructed to practice a daily routine of aerobic exercises, like a 30 minute fast walk, for example. Those who cannot practice aerobic exercises might need medication with time, such as bisphosphonates, to prevent osteoporosis.

Osteoporosis [WP], hypercalcemia [WP] and hypercalcuria [WP] - which can lead to calcification of the arteries and heart valves - are serious, potentially deadly, problems.

However, if these problems can be prevented, and the protocol protects from the suffering, harm and possible death which would occur with the untreated MS or other disease, then it is a good deal.

Recommended supplements can vary from physician to physician. Some of the supplements prescribed include, but are not limited to:

    Magnesium (Glycinate, Malate, Citrate*, etc.)
    Magnesium Chloride
    Vitamin B2 - Riboflavin
    Omega 3
    Vitamin B12
    Chromium Picolinate
    Selenium
    Choline
    CoQ10

* Magnesium citrate is a laxative - best to use a chelated form, bound with a protein, including malate, glycinate etc. See Patrick Chamber's September 2022 article on calcium, magnesium and vitamin D: https://www.oalib.com/paper/6781033.

At the bottom of the page is a link to a map listing all the doctors who practice the Coimbra protocol - or at least those who do and have trained with Dr Coimbra.  There are:

58 in Europe.
9 in North America.
77 in South America.
2 in Iran.
1 in Algeria
1 in India

For people in China, Taiwan, Japan, Korea, Indonesia, Australia etc. the closest is a doctor on the west coast of India. To the east, the nearest doctors are on the west coast of the North American continent.  I wonder if any of them treat patients by video-conference.

There is an 89 minute video at https://www.coimbraprotocol.com/book from 2014 of Dr Coimbra explaining his treatment and how he arrived at it.

[I will listen to this properly and comment on it before I make this text into a web page.]

There are links to 113 pages, each a testimony with photographs of a person who benefited from the Coimbra protocol. 

https://www.coimbraprotocol.com/testimonials-1

The diseases include:

71 Multiple sclerosis
7 Rheumatoid arthritis
7 Atopic dermatitis
4 Myasthenia gravis
3 Vitiligo
3 Psoriasis
2 Neuromyelitis Optica (NMO) or Devic's disease
2 Lupus
2 Lyme disease
2 Sjogren's syndrome
1 Spongiotic dermatitis
1 Fibromyalgia
1 Alopecia
1 Schleroderma
1 Sjogren's syndrome
1 Psoriatic arthritis
1 Idiopathic thrombocytopenic purpura
1 Type 1 diabetes  (This is extraordinary.)
1 Autoimmune polyneuropathy
1 Ichtyosis
1 Crohn's disease

It is worth reading some of these, such as from Ludi Caneiro, with MS:

"When I first got sick I had so many symptoms; weakness, fatigue, tingling, and several others that I do not even remember after my treatment. I'm so grateful to Dr. Coimbra for seeing me right away despite his busy schedule, I went to his office with a heart full of hope, and once I met him in person, I knew I was following the right path.

Today, five years later, I have a completely normal life and two beautiful children, I've had two easy, great pregnancies without the need to interrupt my treatment. My children are so strong, healthy and beautiful. The only memory I have of MS is a slight weakness in my left leg, which does not prevent me from doing anything; walking, running, jumping, practicing sports and lifting weights, everything I used to do before my diagnosis.

Today I take 60,000 IU a day and live a normal, healthy life."

These reports are a good contrast to reading all the relatively bleak academic journal articles.

A German site devoted to the Coimbra protocol has 58 testimonials: https://coimbraprotokoll.de/erfahrungen/.  This link is to the Google Translate version so following the links leads to English translations of each report, such as this one on Crohn's disease.

Doctors associated with this site wrote the Lemke et al. 2021 article I discuss below.  This page https://coimbraprotokoll.de/en/scientific_principles/ features a 2018 video https://youtu.be/w1XT0btvVSg of Dr Coimbra explaining his protocol, in English. 


There seem to be few academic journal articles concerning the Coimbra protocol.  Here are my notes on three of them.  :

A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis
Danilo C Finamor, Rita Sinigaglia-Coimbra, Luiz C. M. Neves, Marcia Gutierrez, Jeferson J. Silva, Lucas D. Torres, Fernanda Surano, Domingos J. Neto, Neil F. Novo, Yara Juliano, Antonio C. Lopes and Cicero Galli Coimbra
Dermato Endocrinology 2013-01-01
https://www.tandfonline.com/doi/full/10.4161/derm.24808

Brazilian patients with psoriasis and vitiligo were given 0.975 mg 35,000 IU of vitamin D3 a day, for 6 months.  25-hydroxyvitamin D levels rose for two months and then stabilised.  For the psoriasis patients, the mean baseline was14.9 ng/mL, rising to a mean of 106.3 ng/mL.  For the vitiligo patients, the mean baseline was  18.4 ng/mL, rising to 132.5 ng/mL.  No calcium supplements were allowed.  Patients were instructed to avoid foods rich in calcium, and to drink 2.5 litres of water a day.  No other nutrients were mentioned, but existing medications for the conditions were continued.

The treatment benefited all 16 psoriasis patients and 14 of the 16 vitiligo patients.

The researchers state that with sufficiently restricted calcium intake, there are no problems with bloodstream calcium levels rising excessively.  Serum calcium levels need to be within a narrow range since most or all cells rely strongly on the concentration of calcium, sodium and potassium ions internally and in the extracellular fluid, which may be the bloodstream.  ("serum" broadly means the liquid, plasma, part of the blood.)

They acknowledge that high circulating 25-hydroxyvitamin D levels cause excessive osteoclast [WP] activity, though they do not provide a mechanistic explanation for this.  I guess that this is due to 25-hydroxyvitamin D (calcifediol) molecules, which have a lower affinity for the vitamin D receptor molecule than 1,25-dihydroxyvitamin D (calcitriol) but nonetheless may activate VDR molecules in osteoclasts if the 25-hydroxyvitamin D level is high enough.

Osteoclasts are cells which destroy bone calcification.  Osteoblasts [WP] build bones, in part by raising calcium levels (mainly as calcium hydroxyapatite) in bone.  Healthy bone requires continual and finely balanced activity of both osteoclasts and osteoblasts.

I do not understand how the combination of low calcium intake with increased osteoclast activity does not risk long-term de-mineralisation (weakening, due to less calcium compounds) of bone.  It takes years for this to occur and precise testing of an individual's bone mineral density requires special techniques, with the same X-ray machinery, in precisely the same piece of bone, over multiple years.

I regard this potential long-term bone weakening as a serious concern.  Hopefully many people will find their autoimmune inflammatory disease suppressed without pushing 25-hydroxyvitamin D levels as high as to cause significant loss of bone mineral density.

The authors suggest 300 ng/mL circulating 25 hydroxyvitamin D is safe for most people.  This may be the case, but they acknowledge the need for long-term research studies to assess the impact on bone and on other so-far unknown potential ill effects. 

Their theoretical framework is of higher 25-hydroxyvitamin D levels compensating for genetically determined "vitamin D resistance" in particular individuals, such as due to genetically determined inefficiencies in the 1-hydroxylase enzyme which converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D.  I am not sure to what extent such differences have been found, but it is well established that genetic variations in the vitamin D receptor and the vitamin D binding protein are correlated with a large number of disease conditions.

See below for my critique of their theoretical framework.

While they mention vitamin D based intracrine and paracrine conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in immune cells, they do not explain this as internal and to nearby cell signaling systems, which are completely distinct from hormonal signaling, which enable the cells to respond to particular circumstances and which are only activated when the cell detects those circumstances.

They repeatedly state, as most vitamin D researchers do, that "vitamin D" "regulates" the immune system, immune responses and/or immune cells.  A proper understanding of vitamin D based intracrine and paracrine signaling shows that this is absolutely not the case.  High circulating levels of 25-hydroxyvitamin D, diffusing into immune cells, enable the cells to work properly by producing the required amount of 1,25-dihydroxyvitamin D when required . This causes immune responses to be better regulated. 

These cells use 1,25-dihydroxyvitamin D as an important part of their intracellular (intracrine) and to nearby cell (paracrine) signaling - but it the cells regulating themselves and other cells, not the higher levels of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D regulating anything.

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol
Dirk Lemke, Rainer Johannes Klement, Felix Schweiger, Beatrix Schweiger and Jörg Spitz
Frontiers in Immunology 2021-04-07
https://www.frontiersin.org/articles/10.3389/fimmu.2021.655739/

This article is from  the German Coimbra protocol team associated with https://coimbraprotokoll.de .  They extend their theoretical framework to include acquired problems in vitamin D signaling:

The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance.  Its etiology is based on the one hand on polymorphisms (variations) [WP] within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections.

I will read this carefully in the future.  There are indeed genetic variations and I guess there are some infection-induced or otherwise acquired difficulties with vitamin D metabolism.  I am sure these play a role in the incidence and severity of numerous inflammatory disorders, even with healthy - such as 50 ng/mL - 25-hydroxyvitamin D levels.  However, I argue below that the most important single cause of these diseases is lack of helminthic downregulation of inflammatory responses.


Safety Data in Patients with Autoimmune Diseases during Treatment with High Doses of Vitamin D3 According to the Coimbra Protocol
Ulrich Amon, Raul Yaguboglu, Madeleine Ennis, Michael F. Holick and Julian Amon
Nutrients 2022-03-06
https://www.mdpi.com/2072-6643/14/8/1575

There's no mention of intracrine or paracrine signaling.

The theoretical framework here seems to exclude genetic variations, includes acquired difficulties in the metabolism of the three vitamin D compounds and adds to - or perhaps expands on - this, by mentioning "insufficient biological activity" of 1,25-dihydroxyvitamin D:

Underlying the CP is the hypothesis of the non-hereditary, but acquired form of vitamin D resistance and insufficient biological activity of 1,25(OH)2D3, which both may be overcome by high doses of vitamin D3, compensating the resistance.

This article reports:

a retrospective analysis of almost 300 patients monitored with respect to their treatment according to the CP as well as an analysis of gene polymorphisms (SNPs) [WP] of the vitamin D metabolism in a subgroup of patients.

They outline the Coimbra protocol, including their starting vitamin D3 doses for different conditions - something which was not mentioned at https://coimbraprotocol.com.

1000 IU/kg body weight for MS; 300 - 1000 IU/kg body weight for the majority of other autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, connective tissue diseases, plaque psoriasis, inflammatory bowel diseases; and 150–300 IU/kg body weight for autoimmune inflammation of the thyroid gland. The latter dosage was usually the starting dose in children for all diagnoses.

I get the impression that MS is the toughest disease they generally deal with, and that their aim is not to push for the highest possible 25-hydroxyvitamin D levels, at least initially, for many of the other diseases they treat.  They provide a partial list of diseases they treated in their 319 patients in Germany, Austria and Switzerland:

36% vitiligo
23% multiple sclerosis
15% other diseases
7% alopecia areata, psoriasis
2% scarring alopecia, rheumatoid arthritis, atopic dermatitis, ulcerative colitis, autoimmune thyroditis
1% Crohn's disease, "psoriasisarthritis"

In the long term, the mean vitamin D3 dose was 52,955 IU/day for MS patients and 29,791 IU/day for patients with all other diseases.  (I use the term "supplemental intake" for vitamin D general nutrition, but these are medicinal doses intended to suppress or cure disease.)

These doctors do not require that 25-hydroxyvitamin D levels be tested.  However they present some data from such tests done by the patients' primary care doctors.

440 values of 25(OH)D in 186 different patients with a mean of 141.4 ± 75.6 (SD) ng/mL (data not shown). The maximum value of 806 ng/mL 25(OH)D in a single female patient with MS was not paralleled by abnormal results in renal function or serum and urinary calcium levels.

In addition to a low calcium diet, and 2.5 litres of water a day, patients are required to "manage stress" (This always makes me wonder - such an instruction is just another stressful constraint!  "Meditation, yoga, qigong, tai chi, and psychotherapy" are recommended. I think they should tell people to minimise or eliminate caffeine and go easy on the dark chocolate.)

In order to avoid osteopenia or osteoporosis following strict calcium restrictions, frequent and regular exercise (jogging and walking) or where physically applicable daily use of a vibration plate was strongly recommended as prophylaxis.

(A "vibration plate" is a strongly vibrating platform which supposedly increases the benefit of exercise including holding muscles taut, by cyclic increases in tensile stress on these muscles.)

They prescribe magnesium, a form of vitamin A and vitamin K2.  (I will write about vitamin K2 after I have read more research on it - there are multiple forms of it, and it occurs already in some plant foods.)

In addition to exercise, they use vitamin K2 to reduce the degree to which high 25-hydroxyvitamin D levels may weaken bones:

Vitamin K2 (menaquinone) has been described as a protective factor for bones (cofactor for mineralization in synergy with vitamin D and vitamin A), the circulatory system and endothelium (cofactor for demineralization, also in synergy with vitamin D and vitamin A).  In addition, antioxidative effects have been described.  As recently shown, MS patients have much lower blood levels of vitamin K2 than healthy controls.  Since high doses of vitamin D may increase the risk of artery calcification following the elevation of serum calcium, we add vitamin K2 to the CP in daily concentrations between 100 µg and 800 µg depending on the starting dose of vitamin D3 and the levels of serum calcium and urinary calcium excretion.

Further dietary supplements depend on many different aspects, such as type and disease activity, blood analysis, degree of inflammation, oxidative and nitrosative stress, results from gut microbiome analysis and many others.

Further to a bunch of tests I won't list here, there is additional monitoring of bone and kidney health:

Depending on baseline levels, bone densitometry as well as bone metabolizing parameters (such as bone-specific alkaline phosphatase, P1NP or osteocalcin, and urine for serum crosslinks) should be monitored individually. Additionally, ultrasound examination of the kidneys once a year is very valuable.

I assume they are concerned about kidney stones.  Supplemental boron would probably reduce or eliminate the risk of this.  See the research of M. R. Naghii https://aminotheory.com/cv19/#boron-kidney-stones .

The results and safety analysis they present are too detailed to summarise here, but they found no problems with hypercalcemia (excessive calcium in the bloodstream) or with kidney function.  They did not mention any detailed, precise, long-term measurements of bone mineral density.  The article was finished in March 2022, four years after the began using the Coimbra protocol.

. . . increases in dosages are - under appropriate doctoral supervision - only moderately correlated with the subsequent serum and urinary calcium measurements.

However, with respect to all single measurements in 319 patients in over 3.5 years, we temporarily stopped vitamin D3 only in 27 situations, when calcium excretion exceeded more than 10 mmol/24 h (normal values: 2.50–8 mmol Calcium/24 h).  In almost all cases, the dietary calcium intake was reviewed with the patient with emphasis on reducing calcium intake to less than 500 mg daily and they were encouraged to increase fluid intake.  As a result, the patients were restarted on the CP four-to-eight weeks later  without any further disruptions in their treatment.

In 16 cases (13 f, 3 m, mean age 39.1 years), the CP treatment was stopped due to different reasons (e.g., non-compliance, no clinical effect, increase in symptoms, food supplements too expensive, diet too complex, daily fluid intake too stressful, pregnancy, familial hypocalciuric hypercalcemia, and significant increase in parameters of bone metabolism).

They analysed the prevalence of various gene mutations in their patients.

We strongly recommend that CP is always used in the hands of qualified and experienced physicians and strongly advise against the use of CP by patients themselves based on Internet information.

My critique of the "vitamin D resistance" hypothesis which is used to explain the mechanisms by which the Coimbra protocol works:

This is a simple and - I think - robust critique of the hypothesis presented by Dr Coimbra and other doctors using his protocol, as just described, which, in summary, is that the etiology of auto-immune diseases is primarily or wholly due to genetic and/or acquired "vitamin D resistance".

Many of the diseases which the Coimbra protocol is effective for treating can also be successfully treated by helminthic therapy: introducing a relatively benign intestinal worm infection, without any other intervention regarding vitamin D3 or other nutrients.

Crohn's disease patients have gone into remission after treatment with pig whipworm: PMC1774382

https://helminthictherapywiki.org/wiki/Special:AllPages

Crohn's disease

Lyme disease

Parkinson's disease  *

fibromyalgia

lupus

Lupus patient abandons wheelchair to run nine miles a week after getting hookworms 

multiple sclerosis 

neurodegenerative disease

psoriasis

rheumatoid arthritis

lupus and Sjogren's disease

fibromyalgia, IBS and rheumatoid arthritis

Crohn's colitis

13 years of remission for Crohn's disease and IBD-related arthritis

* This leads to a video reporting success in suppressing PD and an article PMC5626019 about cytotoxic T cells recognising alpha-synuclein in PD patients.  I guess that such activity might drive disease progression - such as by breaking up single agglomerations into multiple smaller agglomerations which continue to grow - and be amenable to better regulation by helminthic therapy and/or higher 25-hydroxyvitamin D levels.  An article in a non-PubMed-indexed journal collates reports of helminthic therapy being effective for dozens of illnesses, though I suspect some of these reports are spurious.

Since there is no reason to believe that helminthic therapy significantly alters the operation of the three vitamin D compounds, and the results are the same, it follows that the fundamental etiology of these diseases cannot be due to problems with vitamin D compounds.

I propose, as in my summary above, that while genetic variations of many types - including those affecting vitamin D - play some role in the etiology of all these disorders, the primary problem is lack of helminths.

Helminthic therapy is not out of the question for any deadly and supposedly untreatable disease.  Ideally, we would be able to use helminthic compounds as pharmaceuticals and so downmodulate our excessive inflammatory responses to any degree we choose, without actual helminths.  However, none are currently available for use, and I am not sure to what degree they are being used in human trials.

For reasons unknown, very high 25-hydroxyvitamin D levels are highly capable of down-modulating excessive inflammatory responses even in the absence of helminths - but we must remember that this also enables much stronger innate and adaptive responses than are possible with the typically low, 25 ng/mL or less, 25-hydroxyvitamin D levels most people have today, without proper vitamin D3 supplementation.


Without helminths or their compounds, my suggestion for the best approach to all these diseases, in particular Parkinson's disease, dementia with Lewy bodies and Multiple System Atrophy:

These three diseases have virtually identical etiologies.  Alpha synuclein folds to a prion pattern in all three.  The exact folding details are slightly different and the pattern of where in the brain this occurs is also somewhat different, but the end result is the same - declining health and death - according to conventional "wisdom".

However, we know that people generally only get these diseases if their 25-hydroxyvitamin D levels are (on average, across PD sufferers) even lower than the lousy levels of the general population.  This is easy to fix - and we need to fix it anyway for numerous other health reasons.

There's good reason to believe (see Coimbra Parkinson's disease testimonials below) that higher than 50 ng/mL 25-hydroxyvitamin D levels can suppress PD.   Many people get rapid relief from, for instance, rheumatoid arthritis within days or weeks of taking 10,000 IU vitamin D3 a day - I know one such person who was hospitalised with RA and was largely recovered within days or a week of, just beginning to take Coimbra-like vitamin D3 quantities.

I think there is a good chance of suppressing PD, DLB and MSA with higher than 50 ng/mL 25-hydroxyvitamin D, such as in the 80 to 140 ng/mL range (which raises fewer bone-health concerns than the more intense Coimbra levels) provided several other things are done - only some of which are in the Coimbra protocol:


Testimonials from people who claim to have recovered from Parkinson disease through the use of the Coimbra protocol:

It would be great if vitamin D3 and the above nutritional factors were able to slow the progression of PD / DLB / MSA. 

People would naturally feel better having these nutritional deficiencies fixed even if the main disease was unaffected, but it is surely going to be suppressed to a significant degree just by lifting the person's 25-hydroxyvitamin D level out of the gutter and making it probably well above 50 ng/mL.


It would be even better if these nutritional interventions completely, or almost completely, halted disease progression. 

I think this may well be possible, at least for some people.


If the disease progression was actually stopped - meaning that no more neurons were killed and that all the other likely debilitating processes in the brain (such as inflammation causing all sorts of trouble not so clearly recognised as the disease's distinctive symptoms) - then what are the chances that the brain can restore some or all of the lost functions.  This is something we can only speculate about.  Maybe some new neurons can grow - or other existing neurons can take over some of the functions of those which no longer exist.  The motor cortex of the brain is well known to allow whole sections to adapt to new skills, such as playing a musical instrument, or taking over control of somewhat different parts of the body than they previously controlled, to cope with brain injury or the need to develop new skills.

I have no idea to what extent this might happen - and the damage is likely to be in multiple populations of different types of neurons in different parts of the brain, brain stem and spinal cord.

However, these testimonials make me think that, at least for some people - including elderly people - recovery of lost function is possible to a significant degree.

This forum page has two of reports from, or about, PD sufferers who found relief with the Coimbra protocol:

https://www.thisisms.com/forum/viewtopic.php?p=253992 


A Facebook video of a man playing piano:

This is one of the first patients of Dr. Coimbra, 16 years with PARKINSON'S DISEASE and the COIMBRA PROTOCOL! André Linn's post in the group Protocolo Coimbra - Brasil.

"To the beginners in the Coimbra Protocol for Parkinson's, I publish here a video made today on my godfather's 80th birthday who, since 2004, when diagnosed with the pathology, has had the blessed doses of D3. He's the pianist.

Cheers to all!"

This patient is currently taking 50,000 IU a day.



A Facebook video of a man riding his bike.

Adriano Chagas's post:

"About 4 years ago I started with the first symptoms of Parkinson's. And slowly the symptoms got worse. But still I chose not to treat by conventional treatment.

I prioritized supplementation and not stop exercising, even if it got harder and harder. But faith in God was always my forte!

About 4 months ago I started with the Coimbra protocol with Dr Claudio Urbano. It seems like a miracle! Sometimes I feel back to normal. I'm even back to riding my bike daily!

Thank God and the protocol !! "


A not very well educated report of some success with the Coimbra protocol and PD:

https://healthunlocked.com/cure-parkinsons/posts/141649499/coimbra-protocol-3




© 2022 Robin Whittle   Daylesford, Victoria, Australia