Suggested, partial, initial, draft of a future FLCCC Vitamin D Supplementation Protocol

Robin Whittle rw@firstpr.com.au  2024-10-10   (#2024-10-17 update to my notes near the end, on 5000 IU vitamin D3 a day precipitating heart arrhythmias.)

Daylesford, Victoria, Australia  +61 3 5348 4794


For Dr Marik and Dr Dalgleish (printed) and all other FLCCC doctors and team members.  This is also written for Prof. Sunil Wimalawansa in New Jersey and Bill Grant PhD in San Francisco who I hope will want to work on a Vitamin D3 Supplementation Protocol along the lines of what have written.

This is a private web page which is not linked to from any site.   In addition to reading the printed version, please use your browser at:

https://5nn.info/private/dp/ 

to read this page https://5nn.info/private/dp/1-protocol/ so you can follow the reference links to the References section, which contains links to the cited articles.

I will, but have not yet, write some notes on how vitamin D3 supplementation is referred to in the current FLCCC protocols:

https://5nn.info/private/dp/3-notes/

There are some problems with the current material, including a misleading diagram in the Cancer Monograph, this monograph not addressing the problem of hypercalcemia in malignancy, and the Sepsis protocol, where calcifediol or loading dose vitamin D3 is most urgently needed, not mentioning vitamin D at all.


Notes in purple:

I propose that all the other FLCCC protocols, guidance documents and the Cancer Monograph be rewritten to refer the reader directly to this proposed Vitamin D3 Supplementation Protocol regarding long-supplementation and emergency 25(OH)D repletion with calcifediol or a loading dose of vitamin D3. 

These other protocols may elaborate on the core material below - especially the Cancer Monograph, concerning the potential problems of hypercalcemia in certain types of cancer.

Since the Cancer Monograph is intended to be a standalone document, it may be best to include this Vitamin D protocol, the summary, or a specially adapted version of these in the Cancer Monograph itself, or as an appendix.


If you send me an example Word file from which one of the Protocol PDFs were made, I can get all this text into that format, with the right paragraph styles - and you can work on it from there.   I would leave the references in their current form, since you will need to get them into your own Zotero or Mendeley databases to produce the final document.

Ideally, all the references in FLCCC protocols would include clickable links.  Without such links, as they are now, very few people will have the time or patience to actually read the references, such as by copying and pasting some text into Google Scholar.

This is all written freshly - not copied from my sites https://vitamindstopscovid.info or https://nutritionmatters.substack.com.

There's no need to credit me, since I have no academic qualifications or research experience.  I intend that the final document be improved and approved by Sunil, Bill and perhaps other long-time vitamin D researchers, who should be credited.

Ideally the FLCCC would not need to write anything like this.   You should be able cite an existing Consensus Statement on everything which follows, which had been published in a peer reviewed journal, and which was written and/or signed by a dozen or so of the most experienced vitamin D researchers/clinicians. 

However, it would be easier to herd cats than to organize these busy people to work on such an article together.  Until such an article is written, an FLCCC Protocol along the following lines will help hundreds of thousands of clinicians and researchers, and so millions of people.


Introduction

Since humans left African and other equatorial regions for higher latitudes, with darker winters and shallower sun rays even in mid-summer, inadequate circulating 25-hydroxyvitamin D has diminished the health of an increasing proportion of the world's population.

Today, most people can only attain the 50 ng/mL (125 nmol/L) level of circulating 25-hydroxyvitamin D which their immune systems need to function properly by taking supplemental vitamin D3 in quantities - which while small - are typically 8 or more times the very small quantities recommended by governments and many doctors today.

This Protocol provides:
Compared to many aspects of biology and medicine, the function and interactions of the three "vitamin D" compounds and their related enzymes and receptor are not complex.  Unfortunately, very few clinicians, immunologists and even researchers understand the crucial role 25-hydroxyvitamin D to calcitriol (1,25-dihydroxyvitamin D) intracrine and paracrine signaling play in many types of immune cells, and in cells of other types which are unrelated to immunity or calcium-phosphate-bone metabolism.

This biology is relatively easy to understand.  We are trying to bring forward the day when professionals in medicine and other related fields all clearly understand this biology, and so the need for most people, of all ages, to supplement vitamin D3 properly.  This will constitute a revolution in human health at least as significant as those which have resulted from sanitation, antibiotics, anesthesia and medical imaging.

Perhaps the greatest challenge in raising awareness of the importance of proper vitamin D3 supplementation is overcoming the objection, which Prof. Sunil Wimalawansa has frequently encountered in nearly three decades of research and advocacy: "How could it be true?  Its too simple."   In other words: "Isn't this just another over-hyped nutritional supplement?".

How indeed could a simple nutritional supplement, available at every supermarket and pharmacy, be the key to (very approximately) halving the burden of human ill-health, as veteran vitamin D researcher Bill Grant estimates?

One reason is that multinational pharmaceutical companies have many billions of dollars in annual profits to lose if everyone's immune systems ran properly from 50 ng/mL (125 nmol/L) circulating 25-hydroxyvitamin.  Of all the nutritional deficiencies, this is the most important and also the easiest to prevent.  (Boron, omega 3 fatty acids, magnesium and especially potassium need to be taken either every day and/or involve much greater quantities than vitamin D3 supplementation requires.)

Pharma grade vitamin D3 is made in only a handful of competitive factories worldwide, none of them owned by multinational pharmaceutical companies.  The mainstream pharmaceutical industry has long waged a campaign of dismissal, distraction and denial against proper vitamin D3 supplementation.  See Bill Grant's 2018 article Vitamin D acceptance delayed by Big Pharma following the Disinformation Playbook http://orthomolecular.org/resources/omns/v14n22.shtml. Other reasons include:

The need for 50 ng/mL or more 25-hydroxyvitamin D

A section below discusses and cites some of growing body of research which shows that the ability of the immune system to properly tackle cancer and infections caused by bacteria, fungi, yeast and viruses depends on it being supplied with 25-hydroxyvitamin D from the bloodstream, at a level (concentration) of at least 50 ng/mL (125 nmol/L).  It is reasonable to assume that this level, at least, is also needed for the immune system to be able to properly tackle multicellular parasites, and to reduce the risk of excessive inflammatory (indiscriminate cell destroying) immune responses to other types of infection, and in auto-immune responses to the body's own healthy cells.

This Protocol is a step towards ensuring that all people have at least this level of 25-hydroxyvitamin D, which is necessary for good health.  Since this level is central to all that follows, here we briefly describe the research by doctors at Massachusetts General Hospital which most clearly measures this need for 50 ng/mL circulating 25 hydroxyvitamin D. (#Quraishi-2014)

Over 9 years, the doctors performed Roux-en-Y gastric bypass operations for weight loss on 770 severely obese patients.  They recorded their patients' circulating 25-hydroxyvitamin D level before the operation and analyzed how this was associated with the risks of both hospital acquired and surgical site infections after the operation.  The results were striking, and should have become widely discussed and known to medical professionals, immunologists and public health officials all around the world:




The patients whose pre-operative 25-hydroxyvitamin D was 50 ng/mL or more would surely have attained this by substantial vitamin D3 supplementation.  These patients had a very low, ca. 2.5%, risk of both types of infection.  

The risk for other patients rose significantly, and then drastically, the further below 50 ng/mL their 25-hydroxyvitamin D level was before the operation.  25-hydroxyvitamin D levels are fairly stable week-to-week, and so are a good measure of the level during the operation and in recovery.  Here we observe a highly clinically significant increase in infection, due to increasing degrees of immune system failure, the further the 25-hydroxyvitamin D level was below 50 ng/mL.

Of all the research to date, this is the most direct, clear and easy-to-understand measure of immune system dysfunction, regarding responses to the primarily bacterial pathogens which cause these types of infection, as a function of circulating 25-hydroxyvitamin D level.

The red curves are direct from the journal article's graphs.  The dotted area at the lower left approximately depicts the distribution of 25-hydroxyvitamin D levels among the general population, in most or perhaps all countries, for people who are not supplementing vitamin D3 in quantities similar to those recommended by this Protocol. Some people follow government vitamin D3 supplementation recommendations, but these are for average daily amounts which are too small to generally attain 50 ng/mL circulating 25-hydroxyvitamin D or more. The primary aim of this protocol is to have everyone, of all ages, in all countries, attain levels above 50 ng/mL, and generally no more than 100 ng/mL.


Vitamin D3 supplemental intake quantities

Vitamin D3 is superior to Vitamin D2

Vitamin D3 calciferous, which is produced in the skin by the action of UV-B light on 7-dehydrocholesterol is the natural form of vitamin D.  Vitamin D2 ergocalciferol has a somewhat different molecular structure and is typically made by irradiating a compound derived from yeast.  Vitamin D2 is inferior in all respects to vitamin D3, as are its first and second hydroxylated versions 25-hydroxyvitamin D2 and 1,25-dihydroxyvitamin D2 to the natural D3 hydroxylates.  (#Houghton-2006, #Jones-2014, #Nasim-2019, #Durrant-2022.)

Here we discuss vitamin D3 and its first and second hydroxylates, but for brevity omit the '3': 25-hydroxyvitamin D calcifediol (also known as calcidiol) and 1,25-dihydroxyvitamin D calcitriol.

Vitamin D2 should only be used if D3 is not available.  Most supplemental vitamin D3 is manufactured by irradiating 7-dehydrocholesterol, which is derived from wool fat. (#Hirsch-2010)  For those seeking a vegan source of vitamin D, vitamin D3 extracted from algae is more effective than vitamin D2.

Food and ultraviolet B light

Food - including that which is fortified with vitamin D3 or the more stable vitamin D2 ergocalciferol - can provide only a small fraction of the vitamin D2/3 needed to maintain a healthy level of circulating (in the bloodstream) 25-hydroxyvitamin D.  This is made, primarily in the liver, by hydroxylating vitamin D3 cholecalciferol at the 25th carbon.  The level (concentration) of 25-hydroxyvitamin D is measured in "vitamin D" blood tests.

Ultraviolet B skin radiation can produce sufficient vitamin D3 to maintain 50 ng/mL (125 nmol/L) or more circulating 25-hydroxyvitamin D.  However, this UV-B always damages DNA and so raises the risk of cancer, so UV-B skin exposure is not a sustainable way to attain healthy 25-hydroxyvitamin D levels in the long-term.  Furthermore, pigmented skin greatly reduces the production of vitamin D3.  Clothing, housing and vehicular transport all greatly reduce the amount of skin exposure to the UV-B component of sunshine, for good reason. Most people, worldwide, live in locations where solar UV-B flux is too low for substantial amounts of cutaneous vitamin D3 production, in white skin, except in the middle of cloud-free mid-summer days.

So neither a "balanced diet" nor any practical, sustainable and safe level of exposing the skin to sunshine or artificial UV-B light can provide more than a fraction of the vitamin D3 we need to be healthy.

Many people think that any sunshine at all will enable their skin to produce significant amounts of vitamin D3, depending on its angle of incidence at the skin and on the area of skin which is exposed.  However, this is only possible with high elevation sunlight.  Generally, if the Sun is closer than 45° from the horizon, the longer path through the ozone layer and lower atmosphere significantly attenuates the ca. 293 nanometer UV-B light which best generates vitamin D3.  This light is at the far high-frequency end of the Sun's spectrum, and of what wavelengths can reach ground level through the atmosphere.

People with brown or black skin cannot rely on sun exposure to generate the full amount of vitamin D they need to be healthy, unless perhaps they spend most of their days outdoors, within 20° of so of the equator, with most of their body exposed and with no seasonal interruption from the monsoon.

Mihauchi and Nakajima provide a detailed treatise on vitamin D3 production in the skin upon exposure to ultraviolet B light.  (#Miyauchi-2016)  They advise that in order to maximize production, in any one day, no further benefit is achieved by exposing the skin to more than 1/3 of whatever amount of UV-B would be required to turn it somewhat red. They advise that UV-B light, such as from sunlight, can produce the amount of vitamin D3 needed for good health with relative safety.  However, the amount they assume is needed for adults is only 15 micrograms (600 IU) per day, which is about 1/8th of what we recommend for 70 kg body weight.  They estimate that 10 micrograms can be produced by a UV-B exposure of 1/3 of what would redden the skin, over a 600 square cm area of skin.  This is about 25 cm, or 10 inches, square.   Since average weight adults need about 50 times this, every day, to be healthy, it follows from their estimates that this would require the daily exposure of 3 square meters (32 square feet) of skin, which is impossible

If supplements were not available, it would be healthy to get at least some of the vitamin D3 we need via UV-B skin exposure, including by using special UV-B lamps with which eye protection must be used.  Fortunately, supplemental vitamin D is readily available, and involves no expenditure of time, or reliance on weather, location or the use of special lamps.

Sunil and Bill, do you recall an article which reported on lifeguards, at beaches or pools in Hawaii, or perhaps California, who spent a lot of time in the sun but only attained mean 25(OH)D levels in the mid-40 ng/mL range?   I think people greatly overestimate their ability to get sufficient vitamin D from being outdoors, even in summer.

Conventional recommendations and units

Government supplemental vitamin D3 guidelines are intended only to attain the 20 ng/mL (50 nmol/L, 1 part in 50,000,000 by mass) level of circulating 25-hydroxyvitamin D which the kidneys need to play their role, with the parathyroid gland and osteocytes, in regulating calcium-phosphate-bone metabolism.  These very small recommended vitamin D3 supplemental intake quantities, for adults, such as 15 to 20 mcg (the medical abbreviation for microgram) a day, on average, probably achieve this goal in many adults, but will not do so for many who are suffering from obesity. 

Vitamin D3 daily supplemental quantities are commonly expressed in units of:
Government guidelines, which are followed by most doctors worldwide, specify supposedly adequate amounts of vitamin D3 per day as fixed amounts for whole groups of people, stratified by age, with little or no account for body weight. (#Kimball-2020).


IUs are a serious impediment to proper vitamin D3 supplementation, since the numbers are so large.

"mcg" is far from ideal too.   Recently, a woman died in hospital after being given 100 milligrams of IV morphine rather than 100 micrograms: https://www.abc.net.au/news/2024-10-09/sheila-thurlow-morphine...

Recommended Daily Allowance (RDA)

The RDA is the amount of a nutrient to be ingested, per day, so that 97.5% of the target population have enough of this nutrient, or whatever the body converts it to, in order to be healthy.  In the United States and Canada - and more broadly in many countries - the most influential determination of an RDA for vitamin D3 was made in 2011 by the IOM (Institute of Medicine) (#IOM-2011).  For adults this is 15 micrograms = 600 IU per day, on average.

RDAs are intended to be directly used as guidelines for supplementation, after considering how much of the nutrient is typically consumed in food.

This Protocol cites numerous research articles which establish, beyond doubt, that for 70 kg 154 lb body weight, without obesity, it is necessary to gain (via food, supplements or cutaneous production), about 125 micrograms (5000 IU) vitamin D3 a day, on average, in order to attain at least the 50 ng/mL (125 nmol/L = 1 part in 20,000,000 by mass) level of circulating 25-hydroxyvitamin D which the immune system needs to function properly.

This is an 8 times the IOM's RDA.   Even if the IOM's 20 ng/mL (50 nmol/L) 25-hydroxyvitamin D target level is assumed to be valid, the IOM's RDA is far too low, due to faulty statistical calculations, as was pointed out in detailed critiques.  (#Veugelers-2014, #Heaney-2015)  However, the IOM's vitamin D3 recommendations have never been revised. They form the basis of many governments' official recommendations to this day.

There are numerous problems with RDAs, especially in the case of vitamin D3:
  1. For any given target population, the RDA is set almost entirely by how much vitamin D3 per day is required for the people in the 97.5% body weight percentile of the population to attain the desired 25-hydroxyvitamin D level.  (Individual variation in absorption and hydroxylation efficiency is the other factor.)

    In practical terms, this can be estimated only very approximately due to the difficulties in sampling individuals to participate in a clinical trial, lasting six months or more, with different intake quantities, since it takes this long for 25-hydroxyvitamin D levels to stabilize.  The expense of such trials for individual countries is prohibitive.

  2. Mens' body weight, on average, exceeds that of women's.

  3. For any given country or ethnicity, individual body weights vary widely for any class of person, such as "1 - 18 years" or "18 to 70 years", which are two of the classifications found in government vitamin D3 supplemental intake recommendations. (#Kimball-2020).  

  4. Average body weights vary widely between countries / ethnicities.  Extremes of the distribution are represented by Bangladesh and Tonga, with M / F mean body weights 55.2 / 49.8 kg in Bangladesh and 98.6 / 95.5 kg in Tonga.  (#WHO-2010, #WHO-2012)

  5. For any given amount of vitamin D3 supplemental intake, as a ratio of body weight, the level of 25-hydroxyvitamin D which is attained in the long term is lower in those suffering from obesity, for at least two reasons: Lower rates of hydroxylation, primarily in the liver; and Increased sequestration of 25-hydroxyvitamin D and/or vitamin D3 in the excess adipose tissue.  (#Roizen-2019, #Elkhwanky-2020, #Zhu-2021)

Obesity and ratios of body weight

Since good health can only be attained with 50 ng/mL (125 nmol/L) or more circulating 25-hydroxyvitamin D and since this can, with rare exception, only be safely and practically achieved by ingesting an appropriate average daily quantity of supplemental vitamin D3, for our entire population to attain good health it is necessary for most individuals to supplement a well chosen quantity of vitamin D3, on average per day.

Even in wealthy nations, it would be impractical and a waste of precious resources to ensure proper 25-hydroxyvitamin D levels through iterations of changes to supplemental vitamin D3 intake quantities, under the guidance of healthcare professionals, with typically multiple 25-hydroxyvitamin D blood tests.

Such medical attention and the requisite test facilities are not available in developing countries.

It is both necessary, and broadly sufficient, to choose the supplemental vitamin D3 intake quantity as a ratio of body weight, with higher ratios for those suffering from obesity.

Fortunately, a wide range of intake quantities, for any individual is broadly healthy.   Many medical professionals today are not aware that at least 50 ng/mL (125 nmol/L) circulating 25-hydroxyvitamin D is required for full immune system function.  Furthermore, the lower, average, levels of whole populations and an overly alarmist, poorly informed, understanding of toxicity mechanisms leads many medical professionals to regard levels which are in fact perfectly healthy - such as 50 to 100 ng/mL (125 to 250 nmol/L) - as dangerously high.  A section below reviews the toxicity concerns which arise with higher 25-hydroxyvitamin A levels than this, which generally begin above 150 ng/mL.

Self regulation of 25-hydroxyvitamin D level

Some nutrients, such as iron, are difficult to substantially supplement because humans have no proper mechanism for lowering the accumulated level.  The body is tolerant of a large range of vitamin D3 supplemental intake quantities in part because there is a broad, self-limiting, system by which higher circulating 25-hydroxyvitamin D levels lead to greater activity of a 24-hydroxylase enzyme.  This irreversibly hydroxylates vitamin D3, calcitriol and most importantly, circulating 25-hydroxyvitamin D, on the 24 carbon, which renders the molecule inactive and destined for breakdown.

Sunil and Bill, can you suggest one or two good references for this self-limiting process?  It is generally regarded as being controlled by calcitriol levels.  This might be true in lab experiments, but increased circulating 25(OH)D levels only marginally boost circulating calcitriol levels.  Where are these enzymes located?  I recall reading that the activity of these enzymes was significantly - largely? - controlled directly by circulating 25(OH)D levels, which makes sense, since this is what needs to be controlled.  I guess this happens simply because 25(OH)D has a small, but significant, affinity for VDR, and that VDR activation somehow controls the activity of the enzyme wherever it matters most for reducing circulating levels.  There's no need to explain it in such detail here, but it would be great to have one or two pertinent references.

The effect of this self-regulating mechanism can be seen in the curved lines of a graph which plots long-term circulating 25-hydroxyvitamin D levels against daily average vitamin D3 intake quantities, for underweight, normal weight, overweight and obese adult subjects, in Ekwaru et al.'s The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers.  (#Ekwaru-2014)




I will make an updated, simpler, version of this graph.  The original Fig 3 is poorly labeled and only shows the 25(OH)D level in nmol/L and the intake quantities in IUs.  I will make the green area extend from 50 ng/mL to the top of the graph.


Vitamin D3 supplemental intake quantities as three ranges of ratio of body weight

The term "dose" is used in medical interventions.  Here we are discussing long-term nutrition, so we use "supplemental intake quantity".

The introductory material above is sufficient to support an appreciation of the need for vitamin D3 supplemental intake quantity recommendations which are generally applicable to all people in the absence of medical advise to the contrary, as ratios of  body weight, with higher ratios for those suffering from obesity.

Sections below cite research which establishes the need for at least 50 ng/mL (125 nmol/L) circulating 25-hydroxyvitamin D and a tutorial explanation of the 25-hydroxyvitamin D to calcitriol intracrine and paracrine signaling systems which many types of immune cell rely upon, and which to the best of our knowledge can only operate properly with at least this level of circulating 25-hydroxyvitamin D.

These recommendations are Prof Sunil Wimalawansa's simplification and revision of his earlier work - the first such recommendations in the peer-reviewed literature - which were incorporated into some FLCCC Protocols in 2022. (#Wimalawansa-2022)

Each recommendation is a range of ratios, by which a body weight can be multiplied to give lower and upper amounts of vitamin D3, on average, per day, to supplement.  The exact amount to supplement is not critical.  It is more important to choose an amount which can be conveniently supplemented, such as by a single 1.25 milligram 50,000 IU capsule once a week, or once every ten days.

The half-life of circulating 25-hydroxyvitamin D is long enough at 50 ng/mL that larger quantities every week to ten days will not lead to significant variations in level.   Gaps of longer than this between vitamin D3 intakes should be avoided.

The ranges of ratios do not overlap.  This does not mean that an individual who at one point in time is overweight, and later becomes obese - even though the increase in body weight is only marginal, such as 10% - should suddenly switch from the first set of ratios to the second.  If there is uncertainty about whether an individual would be properly diagnosed as overweight, or obese, please use a range of ratios between the two sets described below, such as 80 to 100 IUs per kilogram body weight per day.

These recommendations have not been tested in a randomized controlled trial (RCT).  To do so would be a massive project which ideally will be undertaken in the years to come.

The base range of ratios, for people with underweight, normal and overweight body morphologies is derived from long-term observations of Iranian doctors working in Dubai.  (#Afshar-2020)   In ten years of advising over 500 of their opthalmology patients, of all body morphologies, to supplement 70 to 100 IU vitamin D3 per kg body weight, per day, their observations included:

This outcome - all 500+ patients within +/- 38% of 65 ng/mL is a much narrower and healthier distribution than would resulted from all these adults, with their differing body weights and obesity states, taking any single, exactly defined, quantity of vitamin D3 per day, on average.

In this distribution of circulating 25-hydroxyvitamin D levels, those with the lowest levels would have been those who were suffering from obesity.  A pure body weight ratio is fine for people who have the same general proportion ingested vitamin D3 converted to circulating 25-hydroxyvitamin D.  For most people who are not suffering from obesity, this proportion is, very approximately, 1/4.  However, the proportion is lower for those suffering from obesity.

For everyone's level to be safely over 50 ng/mL, without raising the level of those at the higher end of the distribution, it suffices to choose a greater ratio of body weight for those suffering from obesity, to compensate for their less efficient conversion of vitamin D3 to 25-hydroxyvitamin D.

The two other ranges of ratios presented below, for those suffering from obesity I and II and for those suffering from obesity III, are the result of Professor Wimalawansa's judgments according to clinical experience, great familiarity with the research in general, and in particular the observations and suggestions found in (#Ekwaru-2014) and in the 2011 Endocrine Society Clinical Practice Guidelines, which aimed to attain at least 30 ng/mL (75 nmol/L) circulating 25-hydroxyvitamin D.  (#Holick-2011)


Sufficient vitamin D3 from breast feeding or UV cutaneous production

There is no need for substantially breast-fed infants to be given supplemental vitamin D3 as long as their moms have good 25-hydroxyvitamin D levels: 50 ng/mL (125 nmol/L) or more.

People with light or moderately pigmented skin who in recent months have received sufficient UV-B skin exposure to tan significant areas of their body need less supplemental vitamin D3, and some may need none in order to attain at least the desired 50 ng/mL level of circulating 25-hydroxyvitamin D.  Few people can do this all year round.  While outdoor living and sun exposure in general have many health benefits, people who generate sufficient vitamin D3 in their skin, for extended periods of time, to attain this desired level, would probably improve their health by protecting their skin from ultraviolet light to a greater extent, and taking some fraction of the supplemental vitamin D3 quantities recommended in the following subsections.


Adverse reactions and potential toxicity

By the standards of the IOM and those adopted by most government regulatory agencies, which ignore the role of 25-hydroxyvitamin D in the immune system, 50 ng/mL is a relatively high level and 100 ng/mL is very high indeed.  However, in the only research which measured 25-hydroxyvitamin D in people assumed to be living like our African ancestors, the mean level of traditionally living East African Maasai herders and Hadzabe hunter gatherers, mean age 34, was 46 ng/mL (115 nmol/L).  (#Luxwolda-2012)

Conventional vitamin D toxicity - 25-hydroxyvitamin D levels above 150 ng/mL (375 nmol/L) which for some people may cause hypercalcemia (excessive calcium ion levels in the bloodstream) and/or loss of calcium in the bone - will not occur when the recommendations below are followed.

We regard 100 ng/mL (250 nmol/L) as the high end of the normal, healthy range, but there is no need for alarm if the level exceeds this modestly.  From the 2011 Endocrine Society Guidelines:

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 of 100 ng/ml provides a safety margin in reducing risk of hypercalcemia.

The clinicians and researchers who wrote these guidelines, and who have been proven to be wiser than those who wrote the IOM guidelines, were not concerned about 150 ng/mL circulating 25-hydroxyvitamin D.  They applied a large, arbitrary, 33% safety margin to arrive at 100 ng/mL  So there is no need to apply further margins and so become concerned with levels such as, for instance, 90 ng/mL or 100 ng/mL, or even, in the great majority of cases, 140 ng/mL.

While this excessive 25-hydroxyvitamin D level tends to raise circulating calcitriol levels, when disregulation of calcium ion levels, leading to hypercalcemia occurs, this is not necessarily due to the somewhat elevated calcitriol level.  Hypervitaminosis D (excessive, for that individual, circulating 25-hydroxyvitamin D) causes hypercalcemia largely or entirely due to the larger number of 25-hydroxyvitamin D molecules binding to VDR (the "vitamin D" - really the calcitriol - receptor) molecules, to which they have a small, but  in these circumstances significant, affinity.  (#Tebben-2015) 

Hypercalcemia can also occur without excessive 25-hydroxyvitamin D levels, such as due to genetic variations, an isomer of 25-hydroxyvitamin D which has higher affinity for VDR and malfunction of the 24-hydroxylase enzyme which degrades calcitriol and the other two compounds.  (#Tebben-2015)  Conventional treatments for these conditions for patients whose 25-hydroxyvitamin D levels are typically well below 50 ng/mL may not be appropriate for those with levels between 50 and 100 ng/mL, which are the limits of the levels likely to be attained by following the recommendations below.  Suspected or confirmed hypercalcemia should be regarded as contraindicating vitamin D3 supplementation unless there well informed medical advice that it is safe to do so.

Insight into the long-term safety of substantial vitamin D3 supplementation, in some cases with greater amounts than recommended below, can be found in McCullough et al. 2019, who reviewed long-term vitamin D3 supplementation of adult patients in a psychiatric hospital with 125 or 250 micrograms (5000 or 10,000 IUs) of vitamin D3 a day.  (#McCullough-2019)  Since 2011:

. . . we have admitted over 4700 patients, the vast majority of whom agreed to supplementation with either 5000 or 10,000 IU/day.  Due to disease concerns, a few agreed to larger amounts, ranging from 20,000 to 50,000 IUs/day.  There have been no cases of vitamin D3 induced hypercalcemia or any adverse events attributable to vitamin D3 supplementation in any patient.  Three patients with psoriasis showed marked clinical improvement in their skin using 20,000 to 50,000 IUs/day.

The mean 25-hydroxyvitamin D level of patients not supplementing vitamin D3, and of the baseline levels of those who did, was 27 ng/mL (68 nmol/L).  The researchers report no sign of hypercalcemia in the patients who supplemented vitamin D3:

Analysis of 418 inpatients on D3 long enough to develop 25(OH)D blood levels > 74.4 ng/mL showed a mean 25(OH)D level of 118.9 ng/mL, with a range from 74.4 to 384.8 ng/mL.  The average serum calcium level in these 2 groups was 9.5 (no D3) vs. 9.6 (D3), with ranges of 8.4 to 10.7 (no D3) vs. 8.6 to 10.7 mg/dl (D3), after excluding patients with other causes of hypercalcemia.

The great majority of the population, of all ages, who adopt vitamin D3 supplementation to attain at least 50 ng/mL (125 nmol/L circulating 25-hydroxyvitamin D will derive profound health benefits with respect to their prior condition of much lower levels, which had reduced, including to the point of crippling, their immune system's ability to respond to cancer cells and bacterial, fungal, viral and multicellular parasitic pathogens.  

However, among large numbers of people adopting this generally very healthy supplementation arrangement, there may be a few who suffer adverse reactions which have not yet been adequately observed and reported in the peer-reviewed literature.  If any adverse reaction to vitamin D3 supplementation is suspected, the supplements should be stopped immediately and medical advice sought.  See #Appendix-1 for notes on some indications that vitamin D3 supplementation may, for some individuals precipitate heart arrhythmias, despite such supplementation, in the general population, reducing the incidence of a major form of such arrhythmias: atrial fibrillation.

One class of conditions in which vitamin D3 supplementation is conventionally considered undesirable is granulomatous disorders such as sarcoidosis.  The immune system fails to regulate itself properly (likely due, in part, to inadequate circulating 25-hydroxyvitamin D) and multiple types of immune cell cluster together in a disordered, self-destructive, excessively inflammatory, response.  It as if the immune cells are fighting among themselves, for no good purpose.  Macrophages, in a spurious and undesirable activation of their intracrine/paracrine signaling systems, continually hydroxylate 25-hydroxyvitamin D to calcitriol.  This can occur to such a degree, in the whole body, that the calcitriol which diffuses from these cells significantly raises the very low level of circulating, hormonal, calcitriol, above the level which the kidneys, on their own, would maintain in order to achieve optimal calcium levels.  The result is potentially harmful or life-threatening hypercalcemia.  However, Kamphius et al. report that sarcoidosis patients do better with supplemental vitamin D3 and calcium.  (#Kamphius-2014)

The Cancer Monograph currently does not mention hypercalcemia of malignancy.  This is a serious omission since this is apparently a problem in up to 20% of cancers, and may conventionally regarded as a reason not to raise 25-hydroxyvitamin D levels, especially as high as this Protocol intends.

Hopefully Dr Dalgleish can advise on this.

A second class of such conditions is a subset of cancers in which large numbers of tumor-adjacent macrophages continually hydroxylate 25-hydroxyvitamin D to calcitriol.  This can lead to hypercalcemia secondary to elevated circulating (hormonal) calcitriol levels.  This sustained activity would surely deplete 25-hydroxyvitamin D in the vicinity of the tumor, which would reduce the immune system's ability to eliminate the aberrant cells.  These cancers include some types of lymphoma.  (#Hewison-2009)

Long-term 50 ng/mL or more circulating 25-hydroxyvitamin D will reduce the risk of cancers developing and spreading.  While this and emergency 25-hydroxyvitamin D repletion to this or higher levels will generally greatly strengthen immune responses to malignant cells, FLCCC protocols do not currently include recommendations on how best to tackle hypercalcemia of malignancy. 

Several types of cancer involve risk of hypercalcemia.  Those with suspected or diagnosed cancer should seek specialist medical attention, especially concerning the risk of hypercalcemia and to what extent this would contraindicate vitamin D3 supplementation.  (#Sternlicht-2015, #Tebben-2015) 

Authoritative guidance in Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline includes a variety of treatments.  (#Fuleihan-2023)  The authors do not specifically advise against cessation of vitamin D3 supplementation.  However, most of their patients would have supplemented little or no vitamin D3.  They state:

To avoid hypocalcemia in adults with HCM who receive antiresorptive therapy, vitamin D levels should be monitored and managed in accordance with Endocrine Society vitamin D guidelines.

However, these guidelines are intended to attain ca. 20 to 30 ng/mL (50 to 75 nmol/L) circulating 25-hydroxyvitamin D, while the recommendations below will attain two to three times this.
  

6 months or so for 25-hydroxyvitamin D levels to stabilize

Sunil and Bill: Is this a reasonable description?  To what extent is 25(OH)D stored in the liver?  The livers of at least some other vertebrates contain significant amounts of vitamin D3 and/or 25(OH)D.

Ingested vitamin D3 is hydroxylated, primarily in the liver, over a period of a week or so, to circulating 25-hydroxyvitamin D.  The level of circulating 25-hydroxyvitamin D takes months to to stabilize close to its long-term value, in part due to this level being coupled to 25-hydroxyvitamin D absorbed in adipose and other tissues, and which is to some extent later available to diffuse back into circulation.

This is clearly visible in time-series graphs of adults taking 125 and 250 micrograms (5000 and 10,000 IU) vitamin D3 a day in an Ohio psychiatric hospital.  (#McCullough-2019)





Higher initial supplemental intake to boost 25-hydroxyvitamin D level more rapidly

Anyone who has not been supplementing vitamin D properly, as described below, or has been doing so for a month or two, and is facing a clinical emergency, such as:
should consult the next section on using calcifediol or a loading dose of vitamin D3 to boost 25-hydroxyvitamin D levels as rapidly as possible.

Pregnancy arguably presents an urgent need for attaining at least 50 ng/mL circulating 25-hydroxyvitamin D, for reasons discussed in a later section.  Since the fetus' brain is building itself, and to reduce the risk of perinatal complications, at all stages of pregnancy, the impetus for 25-hydroxyvitamin D repletion is at its highest, since the mother is at risk and the entire life of the future child hangs in the balance.

Women of childbearing age are the group who most need to be supplementing vitamin D3 properly.  Since most of them don't, the chance of pregnancy and any stage in pregnancy and afterwards is a really good time to boost their 25-hydroxyvitamin D.  The graphs above show the slow rise of circulating 25-hydroxyvitamin D over months which results from proper vitamin D3 supplementation, but this is too slow at any stage of pregnancy considering what is at stake.

Here we suggest how this might be done, for adults, including pregnant women.  Similar principles apply to infants and children.

The first step is to estimate the likely 25-hydroxyvitamin D of the person, since 25-hydroxyvitamin D blood tests typically take days to generate results, and may not be available.  If the person is known, or reasonably assumed, to have been supplementing little or no vitamin D3 in recent months, and has not, in that time, had extensive UV-B exposure of ideally white skin, then they can be assumed to have 25-hydroxyvitamin D levels no higher than 20 ng/mL (50 nmol/L).

The elderly and people with brown or black skin can be assumed to have lower levels still, often down to 10 ng/mL (25 nmol/L).  Even in Israel, due to sun-avoidant clothing and lifestyle restrictions, approximately 23% of Arab women had 10 ng/mL or less 25-hydroxyvitamin D.  6% of these Arab women had 5 ng/mL or less, which is disastrously low.  (#Israel-2020) 

In the UK, 95% of people of Pakistani ethnicity were found to have 20 ng/mL or less 25-hydroxyvitamin D, averaging over all seasons.  65% had 10 ng/mL or less and 26% had 6 ng/mL (15 nmol/L) or less.  (#Darling-2020)

The following graph, prepared from UK Biobank data, depicts the proportions of different ethnicities whose circulating 25-hydroxyvitamin D levels are below 30, 20 and 10 ng/mL, with seasonal variation.  (#Sutherland-2020 Table 2, the '%' signs are spurious.)




People who are known, or reasonably assumed, to have 25-hydroxyvitamin D levels of 15 ng/mL (37.5 nmol/L) or less  can accelerate the rate at which their levels rise to much safer values, such as 40 ng/mL 125 nmol/L by, for instance:
These approaches bring 8, 12 and 14 weeks, respectively worth of vitamin D3 forward, into shorter periods. 

Those with 25-hydroxyvitamin D levels likely to be in the 15 to 30 ng/mL (37.5 to 75 nmol/L) range may wish to accellerate the rise in their levels as shown above, but for 4, 2 and 1 week respectively.


For underweight, normal weight and overweight people

Subject to the above-mentioned exclusions (medical advise to the contrary, any apparent adverse reactions, conditions which may cause hypercalcemia and infants substantially breast-fed by 25-hydroxyvitamin D replete mothers), we recommend that all people, of all ages, except those suffering from obesity, supplement vitamin D3 with daily average quantities within the following ranges of ratios of body weight.

70 to 90 IU per kilogram

32 to 41 IU per pound

1.8 to 2.3 micrograms per kilogram

0.8 to 1.0 micrograms per pound



I have elaborate graphs at:

https://vitamindstopscovid.info/00-evi/Vit-D-intakes-main-1400x1400.png

https://vitamindstopscovid.info/00-evi/Vit-D-intakes-obesity-1400x1400.png

but these are too fussy for an FLCCC Protocol.  Visual graphs for nutrient quantities are imprecise, especially for the small body weights of infants and children.

For particular body weights in kilograms, the following table shows the pounds equivalent and the recommended range of average daily vitamin D intake quantities in IUs and micrograms.


Kilograms
 Pounds
 IUs/day
 Micrograms/day
5
 11
 350 - 450
 9 - 11
10
 22
 700 - 900
 18 - 23
15
 33
 1050 - 1350
 26 - 34
20
 44
 1400 - 1800
 35 - 45
30
 66
 2100 - 2700
 53 - 68
40
 88
 2800 - 3600
 70 - 90
50
 110
 3500 - 4500
 88 - 113
60
 132
 4200 - 5400
 105 - 135
70
 154
 4900 - 6300
 123 - 158
80
 176
 5600 - 7200
 140 - 180
90
 198
 6300 - 8100
 158 - 203
100
 220
 7000 - 9000
 175 - 225


It is more important to find a convenient, easy to remember arrangement for supplementation than to choose an average daily intake of vitamin D3 which fits exactly within the recommended range.  A single daily capsule or tablet, in addition to the small amount of vitamin D3 found in a daily multivitamin capsule may be a good choice.

For instance, for 70 kg (154 lb) the recommended range of quantities is 4900 to 6300 IUs per day, on average.  5000 IU (125 micrograms) a day is a perfectly good choice, which can be attained with a daily 5000 IU capsule. 

In countries such as Australia, where the largest capacity vitamin D capsule or tablet which can be sold without prescription is 1000 IU (25 micrograms), it would be expensive, inconvenient and involve ingesting potentially excessive carrier oil to consume five of these a day. 

This is especially so in another example - 105 kg (231 lb) with obesity 1, as mentioned in the next section, for which a range between 10,500 and 13,650 IUs per day is recommended.

Sunil and Bill: Can you suggest one or a few K2 references?

Should we add a section on vitamin K2, since it is widely available in combination capsules with vitamin D3, and is a highly regarded supplement?   There are many commenters on Internet forums who will chime in about the need or at least desirability of vit K2 supplementation as soon as anyone mentions vitamin D3 alone.

Better choices may involve a daily capsule with 100 micrograms or more of vitamin K2 (which is generally beneficial for the immune system and help retain calcium in the bone and reduce the risk of hypercalcemia) and a small amount of vitamin D3, such as 1000 IU, with the difference being made up with 50,000 IU capsules every 5, 7 or 10 days.   In practice, 5000, 10,000 and 50,000 IU vitamin D3 capsules are available worldwide, including in Australia, via eBay and Amazon, including from eBay sellers in Australia who may not be aware of the regulations.

For instance the 105 kg person could take one of the many types of 5000 IU (125 microgram) vitamin D capsule which also contain vitamin K2, each day and take a 50,000 IU capsule once every ten days.  With 200 IU vitamin D3 in a daily multivitamin capsule, this would be 10,200 IU a day, on average.  With a weekly 50,000 IU capsule, this would be 12,343 IUs a day, on average.

Infants and young children should be given vitamin D3 drops.

We recommend choosing a well established brand of supplement, ideally made in a developed country, since there are a plethora of supplement brands with no substantial history available via online sellers, with low prices and a higher risk of not meeting proper quality standards.

For children, adolescents and adults suffering from obesity I and II

These two stages of obesity are most simply defined as BMI in the range 30 to 39.

100 to 130 IU per kilogram

46 to 59 IU per pound

2.5 to 3.3 micrograms per kilogram

1.1 to 1.5 micrograms per pound


Body Mass Index is calculated by dividing the body weight, in kilograms by the square of the height, in meters.   Alternatively, the weight in pounds can be multiplied by 703 and then divided by the square of the height in inches.  For example, with 227 pounds and 71 inches, BMI = (227 * 703) / (71 * 71) = 31.7.




The BMI formula is most applicable to average height Caucasian adults.  It overestimates obesity for tall adults and those with well developed musculature and underestimates it for short adults.  

Obesity in childhood and early adolescence is best determined by clinical diagnosis.  Obesity in Asian adults may be better determined by clinicians than by the BMI formula.


Kilograms
 Pounds
 IUs/day
 Micrograms/day
40
 88
 4000 - 5200
 100 - 130
50
 110
 5000 - 6500
 125 - 163
60
 132
 6000 - 7800
 150 - 195
70
 154
 7000 - 9100
 175 - 228
80
 176
 8000 - 10,400
 200 - 260
90
 198
 9000 - 11,700
 225 - 293
100
 220
 10,000 - 13,000
 250 - 325
120
 264
 12,000 - 15,600
 300 - 390
140
 309
 14,000 - 18,200
 350 - 455


For adolescents and adults suffering from obesity III

This is a serious, in-part inflammatory, metabolic disorder which requires concerted medical attention.  A BMI of 40 or more indicates obesity III, but please see the notes above on the superiority of clinical examination in making this diagnosis.

The recommended vitamin D3 supplemental intake quantity for those suffering from obesity III is expressed in four ways:

140 to 180 IU per kilogram

64 to 82 IU per pound

3.5 to 4.5 micrograms per kilogram

1.6 to 2.0 micrograms per pound


Kilograms
 Pounds
 IUs/day
 Micrograms/day
80
 176
 11,200 - 14,400
 280 - 360
100
 220
 14,000 - 18,000
 350 - 450
120
 264
 16,800 - 21,600
 420 - 540
150
 331
 21,000 - 27,000
 525 - 675
190
 419
 26,600 - 34,200
 665 - 855
240
 529
 33,600 - 43,200
 840 - 1080







This is where I am up to.

Below are some rough  headings to give an idea of the sections I am yet to complete.

Following those are the references and Appendix 1.


Rapid boosting of 25-hydroxyvitamin D to 50 ng/mL or more in clinical emergencies


Single oral dose of 0.014 mg calcifediol per kg body weight


(This is exactly as Prof. Wimalawansa recommends and has been incorporated into some FLCCC protocols.)

Sources of calcifediol

(There are Spanish capsules with 0.266 mg.  Otherwise, it is hard to obtain in substantial quantities.   There are small 0.01 mg tablets available without prescription in the USA.  100 of these provide 1 mg.   This can be inconvenient. However, they can be made into a drinkable, only slowly settling, slurry by adding a little xanthan gum and mixing quickly with a small amount of cold water.   See, broadly: https://vitamindstopscovid.info/04-calcifediol/.)


Research supporting this calcifediol protocol

(The Faes Farma patent graph.  Also, there was a similar graph published in a journal, but very rarely cited, which showed the rapid rise in 25(OH)D from oral calcifediol.   I recall this was in ca. 1976!  Imagine how many tens or hundreds of millions of lives would have been saved since then if this discovery was linked to the immune system and made very widely known.

Castillo et al.   Some mention of the other Spanish research trials, which did not have proper control groups and which took place later, after many people in the area had started taking calcifediol at home.)


Loading dose of vitamin D3


(I will find a simpler way of specifying the amount to use. 

There is some research to cite on its effectiveness in the ICU in general, and with COVID-19.)





Tutorial on the three vitamin D compounds and on intracrine and paracrine signaling


(This will be a much more streamlined version of material at: https://vitamindstopscovid.info/02-intracrine/ and https://vitamindstopscovid.info/00-evi/#02-compounds.)



Vitamin D3 cholecalciferol








25-hydroxyvitamin D, calcifediol, 25(OH)D









1,25-dihydroxyvitamin D calcitriol





Intracrine signaling

(Sometimes, incorrectly, referred to as "autocrine" signaling, as I did initially, and did Chauss et al.)





Paracrine signaling


(The intracellularly produced calcitriol, made only in response to that cell detecting a particular condition, diffuses to nearby cells, presumably of different types, at a local level significantly higher than the very low ~~0.07 ng/mL hormonal background level, and affects the behavior of those other cells.)



The dependence on the immune system and other systems, such as those concerning neurodevelopment and neuroprotection, on higher levels of 25-hydroxyvitamin D than are commonplace today


(There's a vast amount of research which we can cite here, including especially concerning COVID-19.  The trick will be to select the best and present it in a constructive way, better than the usual long laundry list of vitamin D this, vitamin D that, citations in research articles.

The 2008 Grassroots campaign for recognizing 40 to 60 ng/mL, recently revived to tackle the terrible, recent, Endocrine Society Guidelines.

https://www.grassrootshealth.net/scientists-call-daction-public-health-2024/


Many researchers and clinicians are endorsing this.  Sunil has a chart there which would be good to include in this FLCCC Vitamin D3 Supplementation Protocol:





Grassroots Health have some great charts showing disease severity vs. 25(OH)D, one of which is below.




There are various graphs of COVID-19 severity and 25(OH)D level I can adapt, including:





It would be best if I made a new diagram with 25(OH)D level on the horizontal axis, to match other diagrams.

The above diagram has a histogram I made from the raw Luxwolda et al. 2014 on Maasai and Hadzabe 25(OH)D levels.  I have never seen this data as a histogram.

The above diagram contains a copy of the histograms from Israel et al., which are most instructive:




I can redo all these graphics to better suit the FLCCC Protocol.   See more diagrams of potential interest at:

https://vitamindstopscovid.info/00-evi/


By the time the reader gets to this section, they will have a very clear idea of the mechanisms which underly this, which are all to do with 25(OH)D >>> calcitriol intracrine and paracrine signaling, and which have nothing to do with endocrinology, hormonal signaling, or the level of circulating calcitriol.)







Inflammation, helminths and the Coimbra high 25-hydroxyvitamin D protocol


(Excessive, self-destructive, indiscriminate cell destroying inflammatory immune responses cause a vast array of auto-immune disorders, as well as being the central problem in sepsis.   The evolutionary reasons for this are understood by helminth researchers, but vitamin D researchers and clinicians seem to know little about it. 

I think the helminth researchers and those who introduce helminths infections to suppress auto-immune disorders never think about vitamin D!

I think this FLCCC protocol should recognize the importance of these mechanisms and suggest that the Coimbra and similar protocols be considered.  However, the FLCCC currently lacks the expertise and experience to suggest exactly how to do it.

This is a fascinating and important field.   I don't know of any researchers or clinicians who discuss all this material together, but they are clearly linked, since both helminthic therapy and the Coimbra protocol successful suppress much the same set of disorders, by completely different mechanisms, and these disorders are conventionally regarded as incurable, or at least only suppressible by a dangerous mix of drugs which suppress not just inflammatory immune responses but most or all other immune responses.

I propose a much streamlined account of the research covered here:

https://vitamindstopscovid.info/06-adv/

Here is a brief account of these topics I wrote in a Substack comment recently.)

Helminthic therapy - introducing a helminth (intestinal worm) infestation - https:// helminthictherapywiki.org, without any attention to typically very low 25-hydroxyvitamin D levels, suppresses much the same set of diseases as the Coimbra and similar protocols which raise 25-hydroxyvitamin D levels typically well above 100 ng/mL (250 nmol/L), without helminth infections.  

See all the material at:  https:// vitamindstopscovid.info/06-adv/  Helminthic therapy plus 50 ng/mL (125 nmol/L) 25-hydroxyvitamin D would surely be better than just introducing helminths to people with typically very low (compared to this level) 25-hydroxyvitamin D.

In 2022 I counted the testimonials at this German site run by doctors who use the Coimbra protocol: https:// www.coimbraprotocol.com/testimonials-1:

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, and one each for Spongiotic dermatitis, Fibromyalgia, Alopecia, Schleroderma, Sjogren's syndrome, Psoriatic arthritis, Idiopathic thrombocytopenic purpura, Type 1 diabetes  (https:// www.coimbraprotocol.com/single-post/2018/08/01/valerio- marinaro-type-1-diabetes), Autoimmune polyneuropathy, Ichtyosis and Crohn's disease.

The Coimbra protocol involves vitamin D3 supplementation, with a low calcium, high water, diet (and probably vitamin K2 and attention to other nutrients) in order to attain much higher than natural 25-hydroxyvitamin D levels, such as well above 100 ng/mL (250 nmol/L).  This is done with medical monitoring of parathyroid hormone and calcium levels: https:// www.mdpi.com/2072-6643/14/8/1575 and https:// www.tandfonline.com/doi/full/10.4161/derm.24808.

In addition, the Batcheller Protocol https:// vitamindstopscovid.info/06-adv/#pb, http:// www.clusterheadaches.com, which is essentially the same as the Coimbra Protocol, successfully suppresses both cluster headaches and migraines in thousands of people.   This was developed not by a doctor, or conventional researcher, but by a retired U.S. Navy fighter pilot with a chemistry degree.

Both low 25-hydroxyvitamin D and absence of helminths greatly increase the proclivity to the indiscriminate cell destroying immune responses which are primarily evolved to tackle multicellular parasites, including helminths.   Ordinary adaptive immune responses (antibodies and macrophages) evolved to deal with cancer cells, bacteria, yeast, fungi and viruses.  However, they work on individual cells and viruses and are ineffective against multicellular parasites which have thick layers or protective cells.

Indiscriminate cell-destroying immune responses have evolved to tackle such parasites.  For instance eosinophils - the suicide bombers of the immune system - arrive on the scene, disintegrate and release the contents of the vacuoles which contain enzymes which destroy DNA, RNA and proteins.  Other type of immune cells, such as Th1 regulatory lymphocytes, control the activities of these cell-destroying immune cells, which kill host and parasite cells indiscriminately, by emitting cytokines (short-distance immune system signaling molecules) which up- or down-regulate the activities of eosinophils and the like.

"Inflammation" has a general meaning of recruiting immune responses, but also a particular meaning of unhealthy, self-destructive, indiscriminate cell-destroying immune responses - from which you and many other people suffer (along with our dewormed and often low-25-hydroxyvitamin D companion animals).

Helminths long ago (in mammalian or perhaps earlier vertebrate evolution) evolved to exude one or more compounds which down-modulate these inflammatory immune responses which target them.   The response of the hosts - our ancestors going back well before the evolution of humans and probably primates in general - was to evolve stronger indiscriminate cell-destroying immune responses, in the expectation that these would be down-modulated by ubiquitous helminth infections.   Now we are all de-wormed, in general, humans have excessively strong, self-destructive, inflammatory, indiscriminate cell destroying immune responses.  There is a great deal of individual genetic variation in this, so those with persistent inflammatory problems have probably inherited genetic patterns which predispose them to this.

To make matters much worse, most people have only a fraction of the 50 ng/mL 125 nmol/L of the circulating 25-hydroxyvitamin D their immune systems need to function properly.  This is needed for individual immune cells (of many types) intracrine and paracrine signaling systems, which communicate within each cell, and to nearby cells, respectively, information the cells need in order to respond to their changing circumstances.  

As far as I know, there are tutorial introductions to 25-hydroxyvitamin D >>> calcitriol (1,25-dihydroxyvitamin D) intracrine and paracrine signaling systems in the peer-reviewed literature.    Most doctors and immunologists have never heard of these, yet they are crucial to the ability of the immune system to work properly - and in most people today, they cannot work properly due to low 25-hydroxyvitamin D levels.   I wrote an introduction at the start of:  https:// vitamindstopscovid.info/00-evi/, based on a more detailed one at: https:// vitamindstopscovid.info/02-intracrine/.

Proper operation of this intracrine signaling system is required for to enable Th1 regulatory lymphocytes to transition from their pro-inflammatory startup program to their anti-inflammatory shutdown program when they detect the conditions to do so (a high level of a complement protein).  See Chauss et al. 2021 https:// www.nature.com/articles/s41590-021-01080-3  summarized at https:// vitamindstopscovid.info/00-evi/#chauss regarding Th1 regulatory lymphocytes from the lungs of hospitalized COVID-19 patients failing to transition from their pro-inflammatory start-up program to their anti-inflammatory shutdown program, despite detecting the condition to do so.  This failure of the Th1 cell's 25(OH)D based intracrine signaling system was due primarily or wholly to inadequate supplies of 25(OH)D.










References


#Quraishi-2014
Association Between Preoperative 25-Hydroxyvitamin D Level and Hospital-Acquired Infections Following Roux-en-Y Gastric Bypass Surgery
Sadeq A. Quraishi, MD, MHA; Edward A. Bittner, MD, PhD; Livnat Blum, BA; Mathew M. Hutter, MD, MPH; Carlos A. Camargo Jr, MD, DrPH
JAMA Surg. 2014;149(2):112-118  (Actually published on 2013-11-23)
jamanetwork.com/journals/jamasurgery/fullarticle/1782085
jamanetwork.com/journals/jamasurgery/articlepdf/1782085/soi130062.pdf
These are four of the numerous articles concerning the D2 compounds being inferior to the D3 compounds.
#Houghton-2006

The case against ergocalciferol (vitamin D2) as a vitamin supplement
Lisa A Houghton and Reinhold Vieth
American Journal of Clinical Nutrition 2006;84:694–7
doi.org/10.1093/ajcn/84.4.694


#Jones-2014
25(OH)D2 Half-Life Is Shorter Than 25(OH)D3 Half-Life and Is Influenced by DBP Concentration and Genotype
K. S. Jones et al.
Journal of Clinical Endocrinology & Metabolism 2014-09-01
doi.org/10.1210/jc.2014-1714


#Nasim-2019
Efficacy of Vitamin D3 versus Vitamin D2 in deficient and insufficient patients: An open-label, randomized controlled trial
Bina Nasim, Hana Al Sughaiyer, Samia Abdul Rahman, Rubina B. Inamdar, Razan Chakaki and Suha Abuhatab
Ibnosina Journal of Medicine and Biomedical Sciences 2019; 11(02): 57-61
doi.org/10.4103/ijmbs.ijmbs_8_19
This article reports that D3 calcitriol  affects more and somewhat different genes than D2 calcitriol.
#Durant-2022
Vitamins D2 and D3 Have Overlapping But Different Effects on the Human Immune System Revealed Through Analysis of the Blood Transcriptome
Louise R Durrant et al.
Frontiers of Immunology 2022-02-24
doi.org/10.3389/fimmu.2022.790444



#Hirsch-2010
Industrial Aspects of Vitamin D
Arnold L. Hirsch
Chapter in Vitamin D (Third Edition) 2010
sci-hub.se/10.1016/B978-0-12-381978-9.10006-X


#Miyauchi-2016

Determining an Effective UV Radiation Exposure Time for Vitamin D Synthesis in the Skin Without Risk to Health: Simplified Estimations from UV Observations
Masaatsu Miyauchi and Hideaki Nakajima
Photochemistry and Photobiology  2016-10-18
onlinelibrary.wiley.com/doi/10.1111/php.12651



#Kimball-2020
Official recommendations for vitamin D through the life stages in developed countries
Kimball, S. M., & Holick, M. F.
European Journal of Clinical Nutrition. 2020-08-20
doi:10.1038/s41430-020-00706-3
www.nature.com/articles/s41430-020-00706-3 (Paywalled.)
sci-hub.se/10.1038/s41430-020-00706-3



#IOM-2011
Dietary Reference Intakes for Calcium and Vitamin D
Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium
Editors: A Catharine Ross, Christine L Taylor, Ann L Yaktine, and Heather B Del Valle.
National Academies Press 2011
www.ncbi.nlm.nih.gov/books/NBK56070/



#Veugelers-2014
A Statistical Error in the Estimation of the Recommended Dietary Allowance for Vitamin D
Paul J. Veugelers and John Paul Ekwaru
Nutrients 2014-10-20
www.mdpi.com/2072-6643/6/10/4472



#Heaney-2015

Letter to Veugelers, P.J. and Ekwaru, J.P., A Statistical Error in the Estimation of the Recommended Dietary Allowance for Vitamin D
Robert Heaney, Cedric Garland, Carole Baggerly, Christine French and Edward Gorham
Nutrients 2015-03-10
www.mdpi.com/2072-6643/7/3/1688



#WHO-2010
Non-Communicable Disease Risk Factor Survey Bangladesh 2010
W.H.O. 2010
iris.who.int/handle/10665/279484



#WHO-2012

Kingdom of Tonga NCD Risk Factors STEPS REPORT
W.H.O. 2012
cdn.who.int/media/docs/default-source/searo/bangladesh/bangladesh-ncd-risk-factor-survey-2018.pdf



#Roizen-2019

Obesity Decreases Hepatic 25-Hydroxylase Activity Causing Low Serum 25-Hydroxyvitamin D
Jeffrey D Roizen et al.
Journal of Bone and Mineral Research 2019-02-21
asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3686



#Elkhwanky-2020

Obesity Represses CYP2R1, the Vitamin D 25-Hydroxylase, in the Liver and Extrahepatic Tissues
Mahmoud-Sobhy Elkhwanky et al.
Journal of Bone and Mineral Research Plus 2020-07-20
asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbm4.10397



#Zhu-2021

High Fat Diet and High Cholesterol Diet Reduce Hepatic Vitamin D-25-Hydroxylase Expression and Serum 25-Hydroxyvitamin D3 Level through Elevating Circulating Cholesterol, Glucose, and Insulin Levels
Tengfei Zhu et al.
Molecular Nutrition and Food Research 2021-08-27
onlinelibrary.wiley.com/doi/full/10.1002/mnfr.202100220



#Ekwaru-2014

The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers
John Paul Ekwaru, Jennifer D. Zwicker, Michael F. Holick, Edward Giovannucci and Paul J. Veugelers.
PLoS One 2014-11-05
journals.plos.org/plosone/article?id=10.1371/journal.pone.0111265



#Wimalawansa-2022
Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections - Sepsis and COVID-19
Sunil J. Wimalawansa 
Nutrients 2022-07-21
www.mdpi.com/2072-6643/14/14/2997



#Afshar-2020

Suggested role of Vitamin D supplementation in COVID-19 severity
The authors are directors at Iranian Hospital Dubai, Dubai, UAE:
Parviz Afshar, Hospital Director, Mohammad Ghaffaripour, ICU Director and Hamid Sajjadi, Neuro-Ophthalmology Director.
Journal of Contemporary Medical Sciences Vol 6 No 4 (2020): July-August 2020  2020-08-26
www.jocms.org/index.php/jcms/article/view/822



#Holick-2011

Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline
Michael F. Holick, Neil C. Binkley, Heike A. Bischoff-Ferrari, Catherine M. Gordon, David A. Hanley, Robert P. Heaney, M. Hassan Murad, Connie M. Weaver
The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 7, 2011-07-01
doi.org/10.1210/jc.2011-0385


#Luxwolda-2012
Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/L (46 ng/mL)
Martine F Luxwolda, Remko S Kuipers, Ido P Kema, D A Janneke Dijck-Brouwer and Frits A J Muskiet
British Journal of Nutrition 2012-01-23
doi.org/10.1017/S0007114511007161



#Tebben-2015
Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment
Peter J. Tebben, Ravinder J. Singh, and Rajiv Kumar
Endocrine Reviews 2016-09-02
doi.org/10.1210/er.2016-1070



#McCullough-2019
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, Jeffrey Amend
Journal of Steroid Biochemistry and Molecular Biology V189, May 2019
www.sciencedirect.com/science/article/abs/pii/S0960076018306228 (Paywalled.)
sci-hub.se/10.1016/j.jsbmb.2018.12.010



#Kamphius-2014
Calcium and Vitamin D in Sarcoidosis: Is Supplementation Safe?
Lieke S Kamphuis, Femke Bonte-Mineur, Jan A van Laar, P Martin van Hagen, Paul L van Daele
Journal of Bone and Mineral Research 2014-04-18
doi.org/10.1002/jbmr.2262  (Paywalled.)
sci-hub.se/10.1002/jbmr.2262



#Hewison-2009
Vitamin D-Mediated Hypercalcemia in Lymphoma: Evidence for Hormone Production by  Tumor-Adjacent Macrophages
Martin Hewison, Vitaly Kantorovich, Harley R Liker, Andre J Van Herle, Pejman Cohan, Daniel Zehnder and John S Adams
Journal of Bone and Mineral Research 2009-12-02
doi.org/10.1359/jbmr.2003.18.3.579



#Sternlicht-2015
Hypercalcemia of malignancy and new treatment options
Hillel Sternlicht and Ilya G Glezerman
Therapeutics and Clinical Risk Management 2015-10-23
doi.org/10.2147/TCRM.S83681



#Fuleihan-2023

Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline
Ghada El-Hajj Fuleihan et al, for the Endocrine Society
The Journal of Clinical Endocrinology & Metabolism, Volume 108, Issue 3, March 2023
https://doi.org/10.1210/clinem/dgac621



#Israel-2020

The link between vitamin D deficiency and Covid-19 in a large population
Ariel Israel et al.
medRxiv preprint, not peer reviewed, 2020-09-07
www.medrxiv.org/content/10.1101/2020.09.04.20188268v1



#Darling-2020

Very high prevalence of 25-hydroxyvitamin D deficiency in 6433 UK South Asian adults: analysis of the UK Biobank Cohort
Andrea L. Darling, David J. Blackbourn, Kourosh R. Ahmadi and Susan A. Lanham-New.
British Journal of Nutrition 2020-07-22
doi.org/10.1017/S0007114520002779



#Sutherland-2020

Differences and determinants of vitamin D deficiency among UK biobank participants: A cross-ethnic and socioeconomic study
Joshua P. Sutherland, Ang Zhou, Matthew J. Leach and Elina Hypponen
Clinical Nutrition 2020-11-17
doi.org/10.1016/j.clnu.2020.11.019




#W








Appendix 1 - Rare adverse reactions

I regard these first two reports of heart aryhtymias in response to healthy vitamin D3 supplementation as most likely genuine, though the third observational article lacks detail, is at odds with a meta-analysis and can't necessarily disentangle reverse causation such as those with general ill-health being motivated to supplement higher amounts of vitamin D3.

The first report of heart palpitations I knew of was from a friend, in her 60s, who found, by experimentation, that her vitamin D3 supplementation (I don't recall the amount, but it was less than 5000 IU/day) seemed to be causing her heart palpitations.  I can't attest to her general health, which is not perfect.  I think she drank caffeinated tea / coffee.  I have no idea what else she was supplementing.

The second report was from another friend, in his 60s, who I have known for decades.  He did not use caffeine, and he found that with at least two forms of vitamin D3, ca. 5000 IU a day, that he developed a pattern of a racing heart, at least at some times in the day or evening.  He did not supplement calcium and I recall that he did supplement magnesium and fish oil.  He went off vitamin D3 and on again, and perhaps a third time, and I recall that he tried a different type of capsule.  He found consistently, in the second or third rounds of resuming vitamin D3 supplementation that the symptoms reappeared within a day or so. 

#2024-10-17 update:
In the printed version, I wrote:

I have no idea what mechanisms might explain this, but the Deva Boone MD report below is probably pertinent.
Today I spoke with my friend again.  He told me that after the events of early 2023,reported above, he was having heart arrhythmias even without supplemental vitamin D3.  He was subsequently diagnosed with supraventricular tachycardia (SVT), though I am not sure which of the 8 types the Mayo Clinic lists:   www.mayoclinic.org/.../supraventricular-tachycardia/...

He now takes a blood pressure drug and a second drug to combat the SVT itself.  I guess he is not supplementing vitamin D3, and his symptoms have fluctuated, becoming worse in the last week or so.

A Google Scholar search for "supraventricular tachycardia"  "Vitamin D" turned up lots of articles on SVT being associated with, and so presumably in part caused by, low 25-hydroxyvitamin D and/or hypocalcemia.  The only potentially interesting article I found reference to which might concern higher 25(OH)D levels precipitating SVT was a 2015 article "Two cases of cardiac sarcoidosis in pregnant women with supraventricular arrhythmia" http://www.cvja.co.za/...50.html

The only mention of vitamin D in this article is that one of the women was given unspecified amounts of supplemental vitamin D and calcium after giving birth, with this continuing to 10 months later with her symptoms reducing.  There was no other mention of calcium, so the suspected sarcoidosis may not have caused hypercalcemia.

Cardiac sarcoidosis can be a very serious matter, including resulting in sudden death.   Generally, I would expect high 25(OH)D to protect against the development of sarcoidosis or any other granulomatous disorder, and for this higher, healthier, level to reduce the the immune system dysfunction which causes or at least facilitates sarcoidosis.

There are plenty of articles concerning "supraventricular tachycardia" sarcoidosis.   IF the tachycardia was caused or worsened by hypercalcemia, and IF already already developed sarcoidosis resulted in higher calcium levels when vitamin D3 is supplemented at ca. 5000 IU/day rates, THEN we might have an explanation for high 25(OH)D - or at least higher than before vitamin D3 supplementation - precipitating heart arrhythmias, due to more 25(OH)D being available for conversion to pathologically circulating calcitriol.

This extensive review article:
A Review of Arrhythmias in Endocrinology
Nanik Ram, Muhammad Salik
Bangladesh Journal of Endocrinology and Metabolism 2023-09-23
https://doi.org/10.4103/bjem.bjem_17_23

makes it clear that hypercalcemia raises the risk of heart arrhythmias.

So, perhaps vitamin D3 supplementation with already incident sarcoidosis (perhaps anywhere in the body, not specifically the heart) could, in principle,  increase the risk of heart arrhythmias due to the greater supply of 25(OH)D to the granulomatous lesions enabling them to produce even more calcitriol.  This would be despite this higher 25(OH)D being generally healthy, likely to reduce the risk of development of sarcoidisis, and in some or many cases, actually contributing to the suppression of the sarcoidosis.

If so, it does not necessarily follow that all vitamin D3 supplementation as suggested above be done only under medical supervision, even if we ignore the argument below about the rare serious risk being justified by the very substantial, very high probability, significant improvement in health such supplementation brings.

For instance, if vitamin D3 supplementation exacerbates a serious condition to the point of producing obvious symptoms, then as long as those symptoms do not cause lasting harm, this is arguably a good result, since the obvious symptoms will generally result in the person seeking medical treatment earlier than if their symptoms developed more gradually.

I have been meaning to ask the NISH list vitamin D researchers about this, but have not yet done so.

This section ends with an argument for robust vitamin D3 supplementation of the whole population, without medical monitoring, as described above, despite this probably leading to a small number of potentially serious adverse reactions.  To insist on blood tests and medical monitoring would continue to condemn the great majority of the population of all countries to weak and sometime debilitating immune dysfunction for their entire lives.

The same logic applies in everyday activities:  We routinely undertake on-average healthy activities such as walking or running in urban areas for exercise, or driving to medical appointments, despite the small, but non-zero risk we will be injured or killed in a traffic accident.

It is important to be open to indications of adverse reactions to vitamin D3 supplementation which have not yet been properly recognized by researchers or documented in the peer-reviewed literature.  Extensive long-term research such as that in the psychiatric hospital mentioned above (#McCullough-2019), may not detect subtle and relatively rare adverse reactions.

Here is an example of how such reactions may fly under the mainstream medical radar, while being mentioned in apparently substantial non-peer-reviewed web pages and the like.
Contrary to this conference presentation, a meta-analysis: The relationship between vitamin D and risk of atrial fibrillation: a dose-response analysis of observational studies, Xiao Liu et al. Nutrition Journal 2019-11-14 doi.org/10.1186/s12937-019-0485-8, reports that higher 25-hydroxyvitamin D levels were associated with decreased risk of atrial fibrillation.

Generally healthy supplemental vitamin D3 quantities, such as those recommended above, reduce the risk of atrial fibrillation, which is a common and potentially serious form of heart arrhythmia, in the general population.  However, perhaps, in some individuals, similarly and generally healthy vitamin D3 supplemental quantities increase the risk, or the risk of some other form of heart arrhythmias.

One response to cases such as this would be to insist that everyone who supplements vitamin D in quantities sufficient to attain at least the 50 ng/mL circulating vitamin D3 do so with regular 25(OH)D, PTH and calcium blood tests and medical monitoring.  However, this is rarely possible in rich developed countries even for adults of working age.  To insist on such expensive protection against rare individuals who would suffer hypercalcemia would deny the vast majority of the population, of all ages, in all countries, the ability to have a fully functioning immune system.

The patient described above suffered serious and potentially deadly symptoms which were directly obvious without the need for medical examination or tests.  This led to medical intervention, and resolved completely with lower but still healthy 25(OH)D levels.  By supplementing vitamin D3 substantially, she presumably avoided developing osteoporosis at an early age.  Assuming she continues to take smaller amounts of vitamin D3, since her early thirties and for the rest of her life she was, and will remain, at much lower risk of numerous diseases, not least cancer and dementia, than she would have been without any supplementary vitamin D3.

People with poorly functioning immune systems - or crippled immune systems for those with 25(OH)D levels below 10 ng/mL (25 ng/mL) - as are 43 to 65% of UK 45 to 69 year olds of Bangladeshi, Indian and Pakistani ethnicity (#Darling-2020) - are not just a threat to their own wellbeing, but are a greater risk to the health of others through harboring infectious diseases and antibiotic resistant bacteria and through poorer health when driving.  Women of childbearing age with such low levels are at much greater risk of pre-eclampsia, preterm birth, still birth and of their surviving children suffering profound neurological deficits.