Government vitamin D3 supplementation recommendations are about 1/8th of what is needed for immune system health
Mainstream medicine's most disastrous mistake
A primary goal of this Nutrition Matters Substack is to work towards an understanding of why most physicians, immunologists etc. (those whose COVID-19 advice governments are largely bound to follow) know so little about vitamin D and so keen to suppress discussion of the now numerous, inexpensive and often non-prescription early treatments for COVID-19: c19early.com . Your comments will be a vital part of this project.
Our understanding of the three vitamin D compounds:
D3 cholecalciferol. [Wikipedia]
25-hydroxyvitamin D calcifediol (AKA calcidiol). [WP]
1-25-dihydroxyvitamin D calcitriol. [WP]
began in the early 20th century and has progressed enormously since the discovery of the latter two in the early 1970s by Micheal Holick - then a graduate student and now professor and medical doctor. [Google Scholar] Since the 1980s, all MDs have known how the liver coverts D3 to circulating 25-hydroxyvitamin D (by adding a hydrogen-oxygen group to the 25th carbon atom) and how the kidneys hydroxylate some of this again (adding an OH group to the 1st carbon) to create a tightly regulated, very low, level of circulating, hormonal (long distance signaling via the bloodstream) 1,25-hydroxyvitamin D which regulates calcium-bone metabolism.
Only in the late 2000s were the roles of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the immune system discovered, primarily by Martin Hewison [GS] and colleagues, who researched vitamin D based autocrine (inside each cell, AKA intracrine) and paracrine (to nearby cells) signaling. These signaling systems are crucial to the ability of individual immune cells to respond to their changing circumstances.
When particular conditions are detected, which are different for each type of immune cell, the vitamin D based autocrine signaling process is activated to hydroxylate 25-hydroxyvitamin D - which has already diffused inside the cell from the bloodstream - to 1,25-hydroxyvitamin D, which promptly binds to Vitamin D Receptor (VDR) molecules there. (The vitamin D receptor is more correctly known as the calcitriol receptor [WP], since it is only activated to a very small degree by the other two compounds.) These bound complexes migrate to the nucleus [WP] where they up-regulate and down-regulate the transcription [WP] of dozens of genes, in ways which are specific to each cell-type. This alters the proteins produced by the ribosomes [WP] in the cytoplasm [WP] of the cell and so alters the cell’s behavior. Here is a diagram from my page which attempts to describe vitamin D based autocrine and paracrine signaling: vitamindstopscovid.info/02-autocrine/.
I made this page since I could not find any peer-reviewed article or website which explained these signaling systems in an accessible manner.
McGregor et al. 2020 greatly extended our knowledge of vitamin D based autocrine signaling by elucidating the molecular biology of how Th1 regulatory lymphocytes normally transition from their pro-inflammatory startup program, in response to a high level of a complement [WP] protein, to their anti-inflammatory shutdown program. These researchers show that the Th1 lymphocytes they isolated from the lungs of hospitalised COVID-19 patients did not make this transition, and so remained pro-inflammatory, due solely to a lack of 25-hydroxyvitamin D. I think this research is Nobel Prize material and should be known to every physician and immunologist.
Vitamin D based autocrine or paracrine signaling is used in numerous types of cell, including most or all types of immune cell. So far, the molecular and cell-biology details have been researched in only in a handful of immune cell types, but it can be reliably inferred that an unknown but large number of cells types, including some which are unrelated to the immune system, use these signaling systems. This is reasonable to assume from the large number of genes which are regulated by the activated VDR complex and which are known to be activated in cell types which are unrelated to calcium-bone metabolism.
Most MDs and some vitamin D researchers have not heard of vitamin D based autocrine / paracrine signaling - which are not related to or affected by the one hormonal function of the three compounds: a very low level of circulating 1,25-dihydroxyvitamin D (calcitriol) to regulate calcium-bone metabolism. They do however broadly recognise that the vitamin D compounds are important for at least some types of immune cell.
Lacking proper understanding, these researchers and MDs sometimes assume that immune cells work better with higher levels of hormonal 1,25-hydroxyvitamin D (calcitriol). This lead at least one group of researchers prescribe oral calcitriol to treat sepsis - a grossly dysregulated hyper-inflammatory attack which damages organs and kills about 11 million people a year. This tragic death toll could be largely prevented by immediate boosting of 25-hydroxyvitamin D above 50ng/ml. The 11 million per annum estimate was before COVID-19, in which people usually die from much the same hyper-inflammatory immune attack as sepsis.
For instance, Leaf et al. 2014 found that oral calcitriol did not help sepsis patients. In 2021 he and one of his colleagues still thought that “circulating levels of 1,25-dihydroxyvitamin D, the active form of vitamin D” were important to the immune system, because they argued for these to be measured when treating COVID-19 patients with vitamin D.
The same lack of understanding about the immune system’s total reliance on good 25-hydroxyvitamin D levels is presumably behind the Front Line COVID-19 Critical Care Alliance’s adoption of calcitriol (since September 2021) in their I-MASK+ early treatment and MATH+ hospital treatment protocols. (I wrote to them about this and so did at least one long-time vitamin D researcher I know.) This may upset calcium-bone metabolism and does nothing to raise 25-hydroxyvitamin D levels, which is what most people’s immune systems desperately need. Ordinary healthy daily D3 intakes such as 0.125mg 5000IU takes months to raise 25-hydroxyvitamin D levels over 50ng/ml. The following graph is adapted from McCullough et al. 2019.
Since almost all COVID-19 patients have less than half the 25-hydroxyvitamin D their immune system needs, the best approach to attaining 50ng/ml and higher levels is a single oral dose of 0.014mg per kilogram bodyweight of calcifediol (25-hydroxyvitamin D), which goes straight into circulation. This is 1mg for 55 to 85kg bodyweight. Sunil Wimalawansa, retired Professor of Medicine in New Jersey, has the details. Life-saving, healthy, 25-hydroxyvitamin D levels will be reached within 4 hours. Calcifediol is available without prescription, with online ordering in the USA and Australia, with the Australian site shipping up to 1.8mg to any other country: vitamindstopscovid.info/04-calcifediol/ . This page cites Castillo et al. 2020 in which about half this amount of calcifediol, for hospitalised COVID-19 patients, reduced ICU admissions from 50% to 2% and deaths from 8% to zero.
If calcifediol is not available, a single loading (bolus) dose of D3, such as 10mg 400,000IU should be used. This relies on the liver to hydroxylate the D3 into circulating 25-hydroxyvitamin D over several days.
Physicians are busy and rely on immunologists for advice regarding the immune system. Immunologists are busy too - their field is second only in complexity to neuroscience. It seems very few immunologists understand vitamin D based autocrine and paracrine signaling - or know much about vitamin D at all. Two recent, highly regarded, immunology textbooks (Janeway's 9th 2017 and Abbas 10th 2021) cover a tremendous range of complexities in their 1500 total pages. However, there is no mention of vitamin D in their indexes.
Humanity depends entirely physicians and so immunologists getting things right. However, the great majority of them do not understand the immune system’s complete reliance on 50ng/ml or more circulating 25-hydroxyvitamin D.
If they did know this, and if they had been able to convince most people to supplement D3 properly to attain such levels, there would be no COVID-19 pandemic, since severe disease would be rare, average disease severity and duration would be a fraction of the current averages, and so average viral shedding would be very much reduced - greatly reducing transmission. Even with the delta variant, no vaccinations, no early treatments and no lockdowns, social distancing or masks, this would reduce R0 to well below 1.0 in most settings. Aged care homes, hospitals, prisons and within homes might be exceptions, but overall the pandemic spread of the virus in most parts of most countries would not occur. Providing early treatments, for all newly infected people - such as melatonin, quercetin and/or ivermectin - would further reduce shedding, transmission, suffering, harm and death and so end pandemic transmission in all locations.
It is debatable whether MDs, collectively, could have convinced most people to take the D3 they need, though it is only a gram every 22 years (for 70kg bw), with an ex-factory cost of USD$2.50 a gram. Pharmaceutical grade D3 is made in only a handful of highly specialised factories, none of them owned by the multinational pharmaceutical companies - who would loose tens or hundreds of billions of dollars of sales due to the reduction in numerous health problems which would result from most peopl having 50ng/ml or more 25-hydroxyvitamin D.
However, now that most people in some nations have been convinced to accept novel mRNA and adenovirus vector COVID-19 vaccines - with their invasive nature and non-trivial risks - it is easier to imagine most people being happy to take D3 every day or week or so, for more robust protection against this and numerous other diseases.
This problem of most physicians and immunologists being unaware of the need for at least 50ng/ml 25-hydroxyvitamin D is decades-old. Initially it was due to lack of research. However, physicians do not easily change their thinking (often for good reasons) and most have never heard of, or taken notice of, the efforts of physicians and researchers (some are both) since 2008 to establish 40 to 60ng/ml (100 to 150ng/L) 25-hydroxyvitamin D as the proper standard of vitamin D sufficiency: the Grassroots Health Call to D*Action: www.grassrootshealth.net/project/our-scientists/.
This was fully justified by Quraishi et al. 2014 who found rapidly escalating risks of post-operative infection, due to weakened innate and adaptive immune responses to primarily bacterial pathogens, in proportion to how much below 50ng/ml each patient’s pre-operative 25-hydroxyvitamin D levels were. See the Quraishi et al. graph near the start of my first article:
To this day, government vitamin D supplemental intake recommendations and those of many physicians are based on the outdated and faulty 2011 report from the Institute of Medicine (IOM), with 20 or 30ng/ml (50 or 75nmol/L) 25-hydroxyvitamin D being widely regarded as the proper measure of sufficiency. The IOM chose 20ng/ml, which is probably sufficient for most peoples’ kidneys to maintain a very low level of circulating, hormonal, 1,25-dihydroxyvitamin D to regulate calcium-bone metabolism. However, the IOM rejected advice from physicians and researchers to adopt a higher level to meet the needs of the immune system. Furthermore, the IOM completely fluffed their vitamin D3 RDA (Recommended Daily Allowance) calculation for this 20ng/ml 25-hydroxyvitamin D level - which was the most important part of their 1133 page report.
D3 is hydroxylated in the liver to become the circulating 25-hydroxyvitamin D the kidneys and immune cells need. This level is measured in vitamin D blood tests. Neither D3 nor 25-hydroxyvitamin D acts as hormones: vitamindstopscovid.info/02-autocrine/#02-nothorm . D3 supplies the liver, which supplies 25-hydroxyvitamin D to be used by the kidneys and by cells all over the body. There is very little D3 in food or multivitamins. D3 can be made in the skin when exposed to UV-B light, but this is not available to most people except in the middle of cloud-free summer days - and raises the risks of skin cancer. The only practical way most people can achieve proper (50ng/ml or more) 25-hydroxyvitamin D levels all year round is to supplement D3. For 70kg (154lb) bodyweight, on average, 0.125mg 5000IU D3 a day will get most people’s levels up to or above 50ng/ml after several months.
The RDA is the quantity of a nutrient which a population of adults must consume in order that 97.5% of them will attain blood levels above a specified healthy level. This is a blunt, simplistic, way of specifying nutritional intakes due to the wide range of bodyweights amongst “adults”, but it is still widely used as the basis of vitamin D3 supplementation guidelines.
The IOM worked from several studies, each concerning multiple individuals with varying D3 intakes and 25-hydroxyvitamin D levels. To calculate the RDA, at least for that particular group of individuals - which is supposedly representative of all “adults” - it is necessary to analyse the variance (statistics of the distribution of individual values) of the results from each of these individuals. Instead, the IOM did their calculation from variance of the averages of the individuals in each of the several studies - and so drastically underestimated the RDA.
At this point, anyone familiar with statistics will be perplexed and alarmed. This is good practice for the coming months and years as we all come to realise that the COVID-19 pandemic, and numerous other acute and chronic health conditions, would have been very much less of a problem if most physicians and immunologists had properly understood vitamin D and the immune system. The most pertinent research articles which support this understanding are cited at: vitamindstopscovid.info/05-mds/ .
It is difficult for most MDs and most members of the public to imagine that mainstream medicine - tens of millions of doctors, nurses and researchers worldwide - could have been so wrong as to not understand this relatively simple aspect of human biology. But that is exactly what has happened, despite these people working so hard and frequently achieving miraculous preventive and therapeutic outcomes.
The IOM calculated that the RDA for vitamin D3 to attain at least 20ng/ml 25-hydroxyvitamin D (one part in 50,000,000 by mass) was 0.015mg 600IU. This is the basis of many MD’s and most or all governments’ recommendation for daily D3 supplemental intake quantities. In 2015, Robert Heaney and colleagues, performed a proper analysis and concluded that the real RDA is approximately 0.175mg 7000IU / day: www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4377874/ . Robert P Heaney (1927 - 2016) was a remarkable doctor and researcher: asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbmr.2981 .
It makes little sense to have a recommended daily allowance for “adults”, since there are such wide variations in bodyweight between adults within any one country or ethnicity, with wide variations in average bodyweights between these peoples [WP].
The best way to calculate the proper D3 supplemental intake is to aim for a proper level, such as 50ng/ml, make it a ratio of bodyweight and recommend a higher ratio for those suffering from obesity, since their excessive fat cells absorb, and to not return to circulation, a higher than usual proportion of circulating 25-hydroxyvitamin D.
There is a Grassroots Health D3 calculator: www.grassrootshealth.net/project/dcalculator/ which aims for 40 to 60ng/ml. However, it does not provide a higher ratio for those suffering from obesity, and its daily quantity is clipped at 0.25mg 10,000IU, which is surely inadequate for people with high bodyweights. I tabulated the calculator’s results at: vitamindstopscovid.info/01-supp/b-grh/ .
In 2020, Iranian doctors working in Dubai published an article with broadly similar D3 supplementation recommendations as a ratio of bodyweight: Afshar et al. 2020. My summary and appreciation for this article is at: aminotheory.com/cv19/#2020-Afshar . Over ten years, 500+ patients followed this bodyweight ratio based recommendation. Before supplementation, 95% percent of them had 25-hydroxyvitamin D levels below 35ng/ml. All attained levels between 40ng/ml and 90ng/ml. There was no toxicity, which is not surprising since there are self-limiting enzymes which degrade 25-hydroxyvitamin D progressively according to its level. 150ng/ml can only be attained after weeks or months of D3 supplemetation in much higher quantities.
100ng/ml is regarded as the high end of normal, and toxicity affects some people only with levels above 150ng/ml: Endocrine Society, 2011: www.endocrine.org/clinical-practice-guidelines/vitamin-d-deficiency. “most studies in children and adults have suggested that the blood levels need to be above 150 ng/ml before there is any concern.”.
Nonetheless, many people with - autoimmune problems such as psoriasis, rheumatoid arthritis, cluster headaches and migraine - find that higher then normal D3 intakes, and so 25-hydroxyvitamin D levels (with regular calcium and parathyroid hormone tests to ensure all is well, such as according to the Coimbra Protocol) suppress their symptoms without the need for anti-inflammatory drugs, which also suppress innate and adaptive immune responses: vitamindstopscovid.info/06-adv/ .
Since I could not find any ratio-based D3 supplemental intake guidelines which accounted for obesity, and since obesity involves such high risks of harm and death with COVID-19 aminotheory.com/cv19/obesity/ , I derived my own ratio-based recommendations for underweight to overweight people, and for those suffering from obesity: vitamindstopscovid.info/01-supp/#ratios . This is based on the Ekwaru et al., 2014 The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers. The self-limiting 25-hydroxyvitamin D degradation processes are evident in the roll-off in levels for higher D3 intakes, as seen in the following graph adapted from this article:
My recommendations come with various caveats, starting with a note that they are the work of an electronic technician and computer programmer. Ideally something along these lines would be published by physicians and qualified researchers.
The critical importance of raising 25-hydroxyvitamin D levels to suppress COVID-19 severity, viral shedding and so transmission and total harm is obvious from the graph at the end of my first substack article, which you can see, with references, at: aminotheory.com/cv19/#vc . Without supplementation, most people have only a small fraction of the 50ng/ml they need (adapted from Weisharr et al. 2013):
This is especially a problem for people who are of advanced age, with dark skin, sun-avoidant lifestyles and clothing, who suffer from obesity and/or who live far from the equator. These people have suffered the worst outcomes from COVID-19 - largely due to their low 25-hydroxyvitamin D levels.
If you enjoy reading beyond the abstracts of research article and can tell the difference between a ribosome [WP] and a mitochondrion [WP] at 1000 nanometres, perhaps you would like to join the Nutrition for Immune System Health (NISH) email discussion list: NISH.groups.io .