Advanced vitamin D topics - some people need much more D3 than normal, to suppress rheumatoid arthritis, multiple sclerosis, psoriasis, cluster headaches, migraines etc.; Newly discovered vitamin D compounds; The impact of lack of helminths on inflammatory responses, including severe COVID-19

This page is a work in progress..

../ To the main page of this site.

Robin Whittle  23 June 2023    Twitter:
(First established 2021-07-16.)


You are reading the best efforts of an electronic technician and computer programmer.   What I write will hopefully help you understand the research, but should not be mistaken for medical advice.  Medical advice is what you get after a doctor has examined you.  Even if I was a doctor, I haven't examined you!

Don't take my word for anything.  Please read the research articles I cite - or at least their abstracts and my summaries.  If you don't understand them, please ask your doctor or other healthcare professional to read them and advise you. 

Before reading this page, please familiarise yourself with the research articles I link to and discuss at:

This is the most extensive set of links to and discussion of research articles concerning vitamin D and the immune system.

An article co-written with Simon Goddek, at the Brownstone Institute site:

This is shorter, and covers a subset of the above material, plus some new items, such as Dror et al. 2022 on COVID-19.   There is an upbeat robotic narration if you wish to listen to it, but the main purpose of both these pages, and what you will read below, is to encourage you to read the research yourself.

This page assumes a strong interest in biology and treatment arrangements which go not only beyond many MD's limited knowledge of vitamin D, but also beyond a properly informed knowledge of the needs for most people for D3 supplementation to enable the immune system to work well, as described in the above-mentioned page.

If you have this strong interest, a reasonable knowledge of biology and the ability to make your own decisions, even tentatively so, about your own and your family's health, then you might like to join the Nutrition for Immune System Health (NISH) email discussion list: .  This is a high-signal-to-noise ratio discussion group with MDs and nurses (only one so far), leading vitamin D researchers (many of whom are MDs), nutritionists, as well as autodidacts such as myself with no formal qualifications.

On 2021-10-02 I added mention of new research on helminths (intestinal worms) including how active helminth infections in Ethiopia are associated with a 77% reduction of incidence of severe COVID-19.  This is really interesting and makes good sense once the evolutionary history of helminth infections and the immune system is understood.


Last update
#00-intro Introduction.
#01-higher Higher than normal 25-hydroxyvitamin D levels to suppress chronic inflammatory disorders: the (Cicero) Coimbra, (Patrick) McCullough and (Pete) Batcheller protocols.
#02-helminths Lack of intestinal worm infections leads to self-destructively strong immune responses, including auto-immune disorders and much greater risk of severe COVID-19.
#03-ra Other mechanisms related to rheumatoid arthritis and other autoimmune disorders.
#04-novel Compounds beyond D3, 25OHD and 1,25(OH)2D which are in the early stages of being researched.
#05-25ohdreg Regulation of 25-hydroxyvitamin D levels.
Review articles concerning vitamin D and autoimmune diseases


00 Quick intro and some articles of interest

The articles linked to from the  ../05-mds/ page are broadly sufficient to understand everyone's need for circulating 25-hydroxyvitamin D levels of 50ng/ml 125nmol/L or more, in order that the immune system can work properly.  This is normally best achieved with supplemental vitamin D3, though in emergencies, a single, small, oral dose of calcifediol repletes these levels in about 4 hours.  Calcifediol is the name most commonly used for 25-hydroxyvitamin D as a pharmaceutical: .

These discussions apply directly to humans - and generally to companion and agricultural non-human animals, who - without proper supplementation - may not be getting the D3 they need to be healthy.

This page concerns:
I can't write about all this yet, since I need to carefully read the articles first!


01 Higher than normal D3 intakes to suppress autoimmune overly-inflammatory conditions:


The Coimbra Protocol

This was developed by Dr Cicero Coimbra in Brazil to suppress MS (Multiple Sclerosis) and potentially other autoimmune diseases.   I know two people who have used this approach to successfully suppress extremely debilitating rheumatoid arthritis.

Here are two key articles on the Coimbra protocol:

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

(These notes added 2023-06-23.)

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 was 14.9 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 guessed  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.

I later found confirmation of this important mechanism:

Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment
Peter J. Tebben, Ravinder J. Singh, and Rajiv Kumar
Endocrine Reviews 2016-09-02

The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D.

(They discuss this 5,5 trans isomer - a different shape of the same molecule - in the article. They researched it in rats.  To what extent this is important in humans was unknown.  See here for the article in which they report this, and articles which cite it.)

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.

This article from the Calgary Vitamin D Study:

Adverse Effects of High‐Dose Vitamin D Supplementation on Volumetric Bone Density Are Greater in Females than Males
Lauren A Burt, Emma O Billington, Marianne S Rose, Richard Kremer, David A Hanley, Steven K Boyd
Journal of Bone and Mineral Research 2020-08-10 (Paywalled.)

reports that while bone mineral density falls with age, that post-menopausal women who took 4000 IU vitamin D3 a year for 3 years, and those who took supposedly 10,000 IU a day for three years (but the content diminished, so they had less in the later part of the trial, and their 25-hydroxyvitamin D levels were only somewhat above those of the 4000 IU/day subjects after 3 years) had a greater rate of bone mineral density decline than those women who took 0.01 mg 400 IU a day.

The researchers were not expecting this.  These were the results of a very careful trial, with precise X-rays of exactly the same part of the bones, with the same X-ray machine.  Bone strength was computed from the detailed structure of the bone, and this showed no such decline in the higher vitamin D3 intake subjects with respect to that of the women taking 400 IU a day.  No such discrepancies were found in men of the same 55 to 70 age group. 

(I have studied this in some detail but not yet written up what I found.  There has been some discussion of this research - and there are citing articles.   I would like to follow this up more, but it takes days and weeks to thoroughly research material like this - and I am an electronic technician and computer programmer, not someone who is earns their living for such work.)

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, both of 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 is what activates the vitamin D receptors in the same, or in nearby, cells and so changes their behaviour. 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.

This second article summarises the work of a German medical practice with nearly 319 patients over several years:

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

There is no mention of helminths. They regard the proclivity to auto-immune diseases as resulting from genetic variations in a number of vitamin D related genes.  This is not incompatible with the notion of lack of helminths exposing a long-evolved overly inflammatory response.  Still, the fact that helminth infection reduces or resolves some or all of the conditions they treat surely should be part of their theoretical framework, since helminths' influence on the body is totally different to the high vitamin D3 and related treatments they use.

It is not at all clear to me that these doctors understand the importance of circulating 25(OH)D to intracrine (AKA somewhat incorrectly, autocrine) and paracrine signaling.  Instead they focus, rather diffusely, I think, on 1,25-dihydroxyvitamin D somehow "regulating" immune responses. They even refer to this as a "hormone" which is a mistake, except for the very low level of circulating 1,25-dihydroxyvitamin D maintained by the kidneys to regulate calcium-phosphate-bone metabolism. .

Although they have some measurements of patients' 25(OH)D levels, they do not require these.  Nor do they measure circulating 1,25-dihydroxyvitamin D levels - which is fine, since these levels are normally not raised by increased 25-hydroxyvitamin D levels above, very approximately, 20 ng/mL.

Average vitamin D3 intakes were 1.32 mg 52,955 IU a day for patients suffering from MS (multiple sclerosis) and 0.742 mg 29,683 IU a day for patients suffering from rheumatoid arthritis, psoriatic arthritis, connective tissue diseases, plaque psoriasis, inflammatory bowel diseases and autoimmune inflammation of the thyroid gland.

Their protocol includes magnesium and vitamin A and K2 supplementation, drinking 2.5 litres of water a day, quite a long list of prohibited foods and special attention to reduce calcium intake to less than 500 mg / day.

This is a carefully medically managed process with, apparently, generally good results and no significant safety problems.

I know of no doctors in or even near Australia who work with the Coimbra protocol or something like it.  I wonder whether these German doctors work via video-link consultations with patients in Australia.  I know two people here who are suffering from Crohn's disease - and another in Ireland.

I think this is a most interesting article on a hugely important protocol which has helped many people.  However, I am concerned that doctors and researchers are like ships passing each other in the night, unseen by each other, regarding the actual way the immune system uses 25(OH)D and the effects of helminths.

(This added  on 2023-06-23.)

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

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.

This 806 ng/mL a much higher level than any I recall reading about.  The Endocrine Society 2011 recommendations include these statements, including an arbitrarily derived 100 ng/mL threshold - but there is no account for bodyweight or obesity:

Although it is not known what the safe upper value for 25(OH)D is for avoiding hypercalcemia, most studies in children and adults have suggested that the blood levels need to be above 150 ng/ml before there is any concern. Therefore, an upper limit UL of 100 ng/ml provides a safety margin in reducing risk of hypercalcemia.

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 .

(I am yet to identify, read and analyse the best research on kidney stones and vitamin D.)

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 they 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.

(New material added 2023-06-23.)

There are links to 113 pages (August 2022), each a testimony with photographs of a person who benefited from the Coimbra protocol.

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, which is run by some of the doctors who co-wrote Amon et al. above, has 58 testimonials:

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.

(This subsection added 2023-06-23.)

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

Crohn's disease

Lyme disease

Parkinson's disease  *



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

multiple sclerosis 

neurodegenerative disease


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 Parkinson's disease 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.  As described below, our immune system evolved to cope with helminthic compounds which downregulated the inflammatory, indiscriminate cell-destroying, immune responses which tackle these parasites.  So, in general, our inflammatory responses are stronger than what would be most healthy for us, in the absence of those down-modulatory compounds.  Most people in developed countries are not infested with 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.


Patrick McCullough and colleagues in Ohio

Dr McCullough takes 1.25mg 50,000IU D3 a day to suppress psoriasis.  He and his colleagues research healthy D3 intakes for most people, and the much higher intakes which (with suitable medical supervision) suppress a variety of auto-immune diseases.

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 (Paywalled.)

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


Pete Batcheller - cluster headaches and migraine

The above two MDs are world leaders in clinical research regarding higher than normal D3 intakes to suppress MS, rheumatoid arthritis, psoriasis etc. - all of which are well known to be caused by excessive inflammation.

Pete Batcheller (Washington State, USA) is another such pioneer, though he has no medical qualifications.  He has a chemistry degree and is a retired US Navy fighter pilot and commander.  His research and outreach was prompted by his own debilitating cluster headaches.   He used oxygen as an abortant (to stop the CH attack within minutes or tens of minutes) and after some years noticed that he had little trouble with CHs in summer - the time of peak vitamin D, since he spent a great deal of summer outdoors. 

By experimentation, very extensive reading of prior research literature, and work with now thousands of sufferers, Pete Batcheller has developed a detailed, reliable, protocol which greatly reduces and for some people eliminates the occurrence of these frightening, exceedingly painful, cluster headaches.

He has helped over 5000 cluster headache and migraine sufferers (personal conversation, 2021-08-22) suppress their symptoms with a protocol which resembles that of Dr Coimbra - with whom he has corresponded.   

The link between excessive inflammation and his own cluster headaches was made clear in after he cleared the windscreen of his pickup truck of a layer of pollen which had settled there.  His D3, boron and other nutrients protocol had kept the CHs in abeyance for years, but they returned with a vengeance within hours of this gross pollen insult to his immune system.   Illness can reduce circulating 25-hydroxyvitamin D levels and so cause CHs to occur again - so extra D3 and/or first generation antihistamines (which cross the blood-brain barrier) can be used to counter this.

Pete Batcheller's success in largely suppressing these awful conditions, with the help of people who he communicates with via his website, shows that there are significant human health problems which are not yet solved by MDs and professional researchers, but which are amenable solution to imaginative, highly motivated people who lack medical qualifications.   His website is:

His Protocol is available as a PDF (Download the CH Preventative Treatment Protocol . . .) at:

Suggested Preventative Treatment Protocol for Neurologists, Pain Specialists, and Primary Care Physicians using the Anti-Inflammatory Regimen to Treat Patients with Cluster Headache
Pete Batcheller, CDR USN (Ret.) January 15, 2017

This guidance for primary care physicians and neurologists has been used successfully and without adverse outcomes by over 5000 cluster headache (and migraine) sufferers in the past 4 years.    It includes suggested testing frequency for 25-hydroxyvitamin D levels, and for total calcium and parathyroid hormone levels, the latter two which should be monitored every 6 or 12 months to ensure they remain within their reference ranges.

Although directed at the needs of cluster headache sufferers, and to the similar needs of those suffering from migraine, I think this document is an excellent reference for people who are suffering from other systemic hyper-inflammatory disorders, including all those mentioned in the title of this page.

It is not an RCT or a peer-reviewed journal article.  It is the product of years of research and working with hundreds of people by the time it was written.  The subsequent thousands of successful interventions (according to self-reported survey responses) and the absence of reports of problems - to the researcher / sufferer who is unusually well connected with thousands of sufferers - indicate that this Protocol contains valuable guidance.

The mean 25OHD of CH sufferers before commencing the protocol was 22.8ng/ml.  Typical daily D3 intakes were of the order of 0.25mg 10,000IU - along with omega 3 fatty acids, particular forms of vitamin K2, boron, zinc, magnesium and B vitamins as well as other vitamins and minerals.

The optimum pain-free 25-hydroxyvitamin D serum concentration was 83.4ng/mL = 208.5nmol/L.
A handful of CHers under physician’s supervision, have reported sustained
serum 25(OH)D concentrations above 100 ng/mL, (250 nmol/L) some as high as 198 ng/mL.  They also reported total calcium serum concentrations were within normal reference ranges and PTH concentrations at the low end of the reporting range with no other symptoms other than a cessation of their CH.  

Please also see this page:

which mentions the protocols of Dr Somerville, Dr Gominac and Dr Bredsen, along with those of Dr Coimbra and Mr Batcheller.

Mechanisms by which higher than normal D3 intakes might help suppress auto-immune hyper-inflammatory diseases:

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


02 Helminths downmodulate inflammatory responses

Please also see:

As best we know, our ancestors, going back tens of millions of years, were ubiquitously infected with helminths (intestinal worms) which evolved to exude compounds which down-modulate the inflammatory immune responses which mammals evolved to destroy multicellular parasites.  Antibodies and macrophages (adaptive responses) and the innate responses which work well against viruses, bacteria and fungi are no use against multicellular parasites. 

Inflammatory immune responses involve large-scale, indiscriminate, destruction of multiple cells - ideally those of the parasite but also, unavoidably, our own.   There are several mechanisms, but one example is regulatory lymphocytes secreting pro-inflammatory cytokines (immune system signaling molecules)  into the area where the parasite is located, which attracts eosinophils [WP] to the site.  Eosinophils are the suicide bombers of the immune system.  Once activated (by appropriate cytokines) the eosinophil disintegrates, releasing a variety of compounds from its vacuoles.  These destroy proteins, DNA, RNA and disrupt cells in other ways, such as with reactive oxygen species.  They also release cytokines which affect the behaviour of other immune cells.  

Inflammatory responses can also play a role in fighting some viral infections.  See McGregor et al. 2020 for Th1 regulatory lymphocytes responding to SARS-CoV-2 infection in the lungs by emitting a pro-inflammatory mix of two-cytokines in their startup program (a lot of a pro-inflammatory cytokine and a little of an anti-inflammatory cytokine).   After some time (hours, I guess) the Th1 lymphocyte detects changes in other parts of the immune system in its vicinity (a high level of a complement protein [WP]) which causes it to switch to an anti-inflammatory shutdown program, by producing a little of the pro-inflammatory cytokine and more of the anti-inflammatory cytokine.  This is presumably a healthy response to this infection.   However, if the TH1 lymphocyte does not have enough 25-hydroxyvitamin D, then it cannot make this transition, and remains stuck indefinitely in its pro-inflammatory program. 

McGregor et al. observed this failure to transition to the anti-inflammatory shutdown program in Th1 cells from the lungs of severe COVID-19 patients.  It is reasonable to assume that the lack of 25-hydroxyvitamin D caused these Th1 cells to produce the (pro-inflammatory) cytokine storm which causes widespread destruction of endothelial cells, especially in the lungs, leading to hypoxia and tissue damage which cause microembolisms and larger clots in the lungs, brain, heart and all other organs: harmful and possibly deadly severe COVID-19.

It is also reasonable to assume similar processes are at work in other acute hyper-inflammatory immune dysregulation disorders which are to a large extent caused by inadequate levels of 25-hydroxyvitamin D: sepsis (GS), Kawasaki disease (Stagi et al. 2015), Multisystem Inflammatory Syndrome (Fekatea et al. 2020) and pre-eclampsia [GS] .

However, for most people in many or most countries since  (very approximately) the early 20th century, an additional problem drives excessive inflammatory responses: due to not having helminth infections, our inflammatory immune responses are far stronger than what would be healthy, because the genetic instructions which create the immune system evolved over tens of millions of years in which the base level responses had to be stronger than whatever strength is most healthy, to compensate for the weakening effects of the immunomodulatory compounds (we assume there are more than one) exuded by likely several species of helminths.

The combination of nearly ubiquitous lack of helminths (leading to overly strong inflammatory responses, differing from one individual to the next according to genetic variation) AND the very widespread lack of sufficient (such as 50ng/ml) 25-hydroxyvitamin D, is the setting which gives rise to vast amounts of auto-immune disorders AND to the acute hyper-inflammatory dysregulated immune responses which drive sepsis, severe COVID-19 etc.

As we see from the previous section, for some or many people who experience auto-immune problems with common (lower than 50ng/ml) 25-hydroxyvitamin D levels, and with 50ng/ml, it is frequently possible to suppress the pathologically hyper-inflammatory immune responses which cause their conditions by higher than normal (well above 50ng/ml) 25-hydroxyvitamin D levels.  As far as I know, there is no detailed research on the mechanisms which cause this.

In this context, I was not surprised to find this important new research:

Effect of co-infection with intestinal parasites on COVID-19 severity: A prospective observational cohort study
Dawit Wolday et al.
EClinicalMedicine  2021-09-01

Ethiopian COVID-19 patients with active helminth infections were found to have a 77% lower chance of severe COVID-19 compared to those without such infections.  (p < 0.0001)

11 of the 257 patients without helminth infections died.  None of the 284 patients with helminth infections died.  (p = 0.009).

These two highly significant results are strong arguments for the causality being from helminth infections to protection from hyper-inflammatory immune responses.  However, two other mechanisms come to mind, which I guess are of limited or no significance:
  1. it is possible that a secondary cause might be people with poorer sanitation and so living conditions (who are more prone to helminth infections) may spend more time outdoors and so have higher 25-hydroxyvitamin D levels.  Unfortunately these levels were not measured.

  2. Assuming there is significant variation in the strength of the immune response (in the absence of helminths) between individuals, as is surely the case, then perhaps those with the stronger inflammatory immune responses are less likely to be infected with helminths - and these same people are  more likely to develop severe COVID-19 because of that stronger inflammatory response.

The researchers attribute their observations to the patients having a "different, more activated" immune response as a result of helminth infection.  However, there's no reason to believe that helminth infections lead to better immune responses. For this to occur, they would either have to produce anti-viral compounds which the human immune system had not evolved, or somehow stimulate a greater antiviral response than the human immune system would generate on its own.  These mechanisms can't be ruled out, but a more likely explanation for most or all of the observed differences in outcome is as just mentioned, especially in the context of the research by Miri Blank and colleagues mentioned below.

Helminth infections cannot reasonably be introduced to fight severe COVID-19, because they would take too long to develop.  However, these observations are most informative when trying to understand all the factors which affect COVID-19 disease progression.

Ideally, I think, we would have one or more of the immunomodulatory compounds exuded by helminths (at least one is currently known) available as pharmaceutical treatments to suppress autoimmune disorders AND sepsis, severe COVID-19 etc.

This little known field is fascinating and potentially as important for the health of humans and our companion and agricultural animals as vitamin D.

As best I can tell, the helminth researchers and vitamin D researchers have little or no contact or knowledge of each other's work.   They  should compare notes more!

Here is one of the research articles concerning a helminthic compound which down-modulates inflammatory immune responses.  Ideally I would have time to research this field more thoroughly.  This page is an early work in progress. 

Helminths-based bi-functional molecule, tuftsin-phosphorylcholine (TPC), ameliorates an established murine arthritis
Miri Blank, Tomer Bashi, Jordan Lachnish, Dana Ben-Ami-Shor, Ora Shovman, Mati Fridkin, Miriam Eisenstein, Alexander Volkov, Iris Barshack and Yehuda Shoenfeld.
PLoS One 2018-08-08

Some people find relief from autoimmune disorders by the introduction of helminths: .  This is a highly significant research article:

Trichuris suis therapy in Crohn’s disease
R W Summers, D E Elliott, J F Urban Jr, R Thompson and J V Weinstock  Gut 2005

871 Google Scholar citations.

An older Crohn's disease article.  I want to find some more recent ones too. See the articles which cite this one:

Therapeutic Effect of Vitamin D Supplementation in a Pilot Study of Crohn's Patients
Linlin Yang; Veronika Weaver; Jill, Smith; Sandra, Bingaman; Terry, Hartman and Margherita Cantorna
Clinical and Translational Gastroenterology 2013-01-13

176 Google Scholar citations.

Here are two other articles concerning helminths and COVID-19:

Helminth coinfection and COVID-19: An alternate hypothesis
Russell Hays, Doris Pierce, Paul Giacomin, Alex Loukas, Peter Bourke and Robyn McDermott.
PLOS Neglected Tropical Diseases 2020-08-17

26 Google Scholar citations.

Old friends meet a new foe: A potential role for immune-priming parasites in mitigating COVID-19 morbidity and mortality
Tara J Cepon-Robins, Theresa E Gildner
Evolution, Medicine & Public Health  20201-10-20

9 Google Scholar citations.

There are other articles of interest in these citation lists.


03 Connections between Rheumatoid Arthritis (RA), psoriasis and potentially other conditions - and some cell-biology hypotheses of contributing causes

Regarding RA, please also see my earlier material on boron: .

Perhaps there is a way of connecting tenuous knowledge of:
These are all deep and developing fields.  I expect my rabbit-hole alarm to go off frequently.  Hopefully I will find something interesting without being lost interminably in the warrens.

Citrullination [WP] involves an enzyme modifying an arginine amino acid when it is part of a protein.  An NH ketamine group is replaced with an O ketone group, both doubly bonded to the molecule.  This changes the arginine into citrulline, which is not a protein building amino acid.  The behaviour of the whole protein changes in several ways, and this can trigger the production of antibodies and then those antibodies attaching to said proteins, triggering a cell-destroying (inflammatory) response.

The articles below also concern some aspects of the HLA-DR [WP]  which may be involved in both RA and worse outcomes in COVID-19.  (I am yet to read these articles, except the last: Martin et al. 2021.)

How citrullination invaded rheumatoid arthritis research
Walther J van Venrooij & Ger JM Pruijn
Arthritis Research & Therapy 2014-01-29

Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis
Christina Gerstner, Anatoly Dubnovitsky, Charlotta Sandin, Genadiy Kozhukh, Hannes Uchtenhagen, Eddie A. James, Johan Rönnelid, Anders Jimmy Ytterberg, Jennifer Pieper, Evan Reed, Karolina Tandre, Mary Rieck, Roman A. Zubarev, Lars Rönnblom, Tatyana Sandalova, Jane H. Buckner, Adnane Achour and Vivianne Malmström
Frontiers in Immunology 2016-11-14

Progression on Citrullination of Proteins in Gastrointestinal Cancers
Shuzheng Song and Yingyan Yu
Frontiers in Oncology 2019-01-23

The influence of HLA genotype on the severity of COVID-19 infection
David J. Langton, Stephen C. Bourke, Benedicte A. Lie, Gabrielle Reiff, Shonali Natu, Rebecca Darlay, John Burn and Carlos Echevarria
HLA Immune Response Genetics 2021-04-19

Association between psoriasis and rheumatoid arthritis in a nationally representative population in the United States
Amylee Martin, Akshitha Thatiparthi, Jeffrey Liu, Jashin J. Wu.
Journal of the American Academy of Dermatology  Letter 2021-07-15 (Paywalled.)

(Dr Wu has kindly sent me a copy of this article.)

A carefully conducted survey found that 8.1% of people with psoriasis reported a history of RA, while such a history was reported by only 4.0% of people without  psoriasis.  The OR for these findings varied from 2.82 for subjects aged 20 to 49 and 1.64 for subjects aged 50 and above.  The authors write:

This association may be attributed to a similar pathophysiology, with
tumor necrosis factor-alpha and interleukin 17 implicated in both the disorders.  Interestingly, tumor necrosis factor-alpha inhibitors have been reported to paradoxically induce and/or worsen psoriasis, most commonly, in individuals with RA or Crohn disease.


Recently discovered - or at least little known to MDs - but potentially significant vitamin D compounds

Add a hydroxyl group to the 20th carbon in D3 and . . .

20S-Hydroxyvitamin D3, a Secosteroid Produced in Humans, Is Anti-Inflammatory and Inhibits Murine Autoimmune Arthritis
Arnold E. Postlethwaite, Robert C. Tuckey, Tae-Kang Kim, Wei Li, Syamal K. Bhattacharya, Linda K. Myers, David D. Brand, and Andrzej T. Slominski
Frontiers in Immunology 2021-06-30

Sulphated 25-hydroxyvitamin D is prevalent in the circulation:

The serum vitamin D metabolome: What we know and what is still to discover
Robert C. Tuckey, Chloe Y.S. Cheng, Andrzej T.Slominski
Journal of Steroid Biochemistry and Molecular Biology  2018-09-04 (Paywalled.)
60 Google citations.


05 Regulation of circulating 25-hydroxyvitamin D levels by enzymes which degrade it, at rates approximately proportional to its concentration, forming a negative feedback system which makes it harder to raise higher levels than lower levels

I have a general idea that this works, but would like to know a lot more about the mechanisms and to what extent they are affected by and affect D3 levels - and more broadly conversion of D3 to 25OHD in cells outside the liver.

See the above-mentioned article: The serum vitamin D metabolome . . . .


06 Review articles concerning vitamin D and autoimmune diseases

Here are some which review this field.  I start with a widely cited article from early 2017 and then look at several subsequent articles which cite it.

At present this is just a listing of the articles.  When I have time I will write some notes on them.

Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential
Wendy Dankers, Edgar M. Colin1, Jan Piet van Hamburg and Erik Lubberts
Frontiers in Immunology 2017-01-20

(Only partially read so far, but it seems there is no recognition of autocrine signaling - it is as if the only thing which matters to immune cells is the level of circulating and so hormonal 1,25-dihydroxyvitamin D.  This is incorrect:  Some of the trials used very small amounts of D3 and some used calcitriol - which does not raise 25-hydroxyvitamin D levels at al.)

In 2021-10 this had 291 Google citations including the following articles which I chose to discuss below:

Vitamin D and juvenile systemic lupus erythematosus: Lights, shadows and still unresolved issues
Stefano Stagi and Donato Rigante
Autoimmunity Reviews 2017-11-13

Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions
Roger Bouillon, Claudio Marcocci, Geert Carmeliet, Daniel Bikle, John H White, Bess Dawson-Hughes, Paul Lips, Craig F Munns, Marise Lazaretti-Castro, Andrea Giustina and John Bilezikian
Endocrine Reviews 2018-10-12

Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance
Dayong Wu, Erin D. Lewis, Munyong Pae and Simin Nikbin Meydani
Frontiers in Immunology 2019-01-15

Micronutrients in autoimmune diseases: possible therapeutic benefits of zinc and vitamin D
Inga Wessels and Lothar Rink
The Journal of Nutrtional Biochemistry 2019-09-09

Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti-Inflammatory
Emma L Bishop, Aiten Ismailova, Sarah Dimeloe, Martin Hewison and John H White
Journal of Bone and Mineral Research PLUS 2020-08-22

© 2021 Robin Whittle   Daylesford, Victoria, Australia