Supplementing More Than 10,000 IU Of Vitamin D A Day Based On The Work Of Jeff Bowles

[Tarmander]

My random no evidence seat of my pants theory is that there are genetic mutations which prevent absorbing too much vitamin D from Sunlight, and these are mostly in white people. I imagine that in Northern climates, the vitamin D levels would be pretty constant, but sometimes an excess of sunlight in a year could pose a risk, and genetic mutations were adapted that provided robustness in those times. The opposite risk, of too little sunlight, would be accompanied by famine and other problems before too little vitamin D would become a real problem.

In our times, the people who are getting auto immune issues are these people, again, from my observation, mostly white people. There is some risk of too much vitamin D absorption, and these immune issues are in people who are equipped to handle too much D.

 

[lollipop]

After reading Bowles material on vitamin D, melatonin and longevity I asked Travis if he would share his thoughts on the subject. Here's his reply. Travis wrote:

"I think it can if used properly, yet too much would oppose the metabolic rate ≈ anti-aging scheme. Pro-melatonin ideas are often quite logical, at least superficially, and there are certainly no shortages of positive publications on melatonin. However, much of this seemingly-positive data on melatonin is counterintuitive: Most published melatonin science had been done using rats, a nocturnal species, and making extrapolations between them and humans in regards to pineal hormones must be make with caution if they should be made at all. Nocturnal species most active at night must respond to pineal hormones in a manner quite different to those diurnally active—at least in many ways.

Melatonin always appears to increase under darkness regardless of the species' circadian activity status. Yet some nocturnal species are very low excretors of melatonin, notably the owl and certain strains of rodents; some have a blunted response due to RORα receptor polymorphisms. Confusing the issue further is the fact that only some rodent species are low-excretors; some popular lab strains of mice had been bred according to the circadian cycle determined by the on/off switch of an artificial lamp. Upon each breeding cycle, the rodents had progressively assumed the the circadian whims of their keepers—litter through litter, little by little.

I am getting the impression the fully-nocturnal wild rats must produce melatonin membrane receptors either of lower activity or differential distribution. Cats appear to regulate their sleep–wake cycle more in response to oleamide than anything, ostensibly produced by eating antelopes and zebras. [Oleamide synthesis is a function of serum oleic acid × plasma ammonia concentration.]

Drawing assumptions based on epidemiological research can be confounded by vitamin D, a powerful hormone that also changes with latitude. Dr. John Cannell over-hypes vitamin D and cites many latitude-specific changes as evidence for its effect. Although melatonin certainly appears more powerful than vitamin D in general, even human latitudinal and interseasonal comparisons are still inter-confounded by each one. There are two hormones having concentrations that vary under UV light, and retinoids cis–trans isomerize under it's influence.

Most nearly everybody completely ignores methoxy-tryptophol, the 'other pineal hormone.' Long though as melatonin's little cousin, this long-ignored pineal hormone shouldn't be. Although it fails to activate melatonin membrane receptors, and thus cannot produce acute somnolence, it is equipotent on melatonin's hormonal nuclear receptors (i.e. RORα, RORβ, RORγ).

Melatonin is often said to 'stimulate the immune system,' yet in humans it puts neutrophils to sleep. The most extreme interspecial contradictions are noted between immunological studies of humans and rats: Since these two species are cumulatively responsible for most melatonin research on immunity, a marathon of superficial title & abstract-reading can quickly lead to the Cannell-type fallacy. The effect of melatonin on human immune cells is significant in in nanomolar concentrations, regulating both genetic expression through RORs and inhibiting defense enzymes directly. I feel the lower immunity observed during winter andversus latitude can more realistically be explained through 'more melatonin' than Cannell claim of 'lower vitamin D.'

Yet melatonin can be framed as 'anti-inflammatory' for this reason, and something can be said about that. I think some people could certainly benefit from a little melatonin at night, yet this greatly depends on the circumstance. Day/night cycles naturally modulate small-molecule redox immunity with repair, with imbalances enhancing infection risk in one direction and cancer risk in the other. I don't think that taking either vitamin D or melatonin is a particularly good idea, in general, although it is certain to help many people in some circumstances. [Even entire populations could perhaps 'benefit on average' depending on diet, stress, and latitude.] Although all B-vitamins are enzyme cofactors and thus tend always towards increased metabolic efficiency: pineal hormones, retinoids, and calciferols are circadian hormones that ought to be properly cycled. There lipid-solubility only potentiates their already high potency, and although some vitamins are safe in gram-sized doses these can be dangerous in the microgram range.

[*] Melatonin is amphiphilic, yet 5-methoxytryptophol is quite oil-soluble.
Melatonin does relax the brain facilitating cleansing: The interstices of the grey matter will relax at night—ostensibly effected by Na⁺/K⁺ redistribution—thereby allowing for the ingress of cerebrospinal fluid. This one melatonin effect certainly seems an important one, yet the amount of oral melatonin needed to achieve this—nighttime CSF concentration?—could probably be accomplished only by first inducing a nonphysiological plasma level. Melatonin works on immune cells in picomolar concentrations, and unnatural increases of that magnitude could have unanticipated effects—especially after considering the majority of immune & toxicity data had been obtained using melatonin-resistant nocturnals. Much safer for increasing brain melatonin at night may simply be the use of tinted eyeglasses in the evening, those excluding the blue spectral region:

Melatonin is far more potent than steroid hormones per molecule, with pharmacologists noting dissociation constants between 20 and 400 pM for the higher-affinity melatonin-1 receptor (MT₁). After converting into more intuitive mass units—equivalent to 86 to 172 pg/mL—this compares quite favorably with the human diurnal range:

Melatonin is sold in microgram-sized doses, yet those sold milligram-sized are more common. Not only would milligram-sized daily doses saturate all peripheral MT₁ receptors, these concentrations would be high enough to saturate them 27/7. Even when determining melatonin concentrations on the day after the last dose—after taking either 2.5 or 10 mg/d for months previous—the concentrations are an order of magnitude over the placebo group, in the nanogram per deciliter range:

'The melatonin groups had elevated daytime plasma melatonin levels relative to the placebo group by Holm-adjusted Mann-Whitney test. Residual daytime melatonin levels in the melatonin 10 mg group were highest (67.7 ± 281 ng/dL), followed by ML 2.5 mg (28.7 ± 67 ng/dL), and PLA (2.7 ± 4 ng/dL). Two subjects in the melatonin 10 group had midday melatonin levels greater than 600 ng/dL, and 1 subject in the melatonin 2.5 group had a level greater than 400 ng/dL. All subjects in the placebo group had melatonin levels that were normal midday values (<10 ng/dL).' ―Clifford

Since these levels are high enough to saturate both melatonin membrane receptors, MT₁ and MT₂, you could expect both cAMP and cGMP to be significantly reduced in all cells expressing both. Besides the two adenylate and guanylate cyclase-linked membrane receptors regulating the cell's metabolic rate, melatonin exerts genomic effects through three nuclear receptor transcription factors: RORα, RORβ, and RORγ. The expanded names of the class are 'retinoid orphan receptors,' being so-named before their endogenous ligand had been discovered. All immune cells express RORγt and bone cells, including osteoblasts and osteoclasts, express multiple forms including RORβ.

'To add to the confusion some authors have attempted to ascribe nomenclature to the receptors, such as ML-1 and ML-2. ML-1 has been used to encompass those receptors of high affinity (Kd = 20–400 pM) and selectivity for melatonin, whereas ML-2 refers to a [relatively] low affinity site...' ―Morgan

Retinoid orphan receptor β and γ are also clock genes. The expression of clock genes in the cell oscillates in a circadian manner, by definition, in cycles that can be entrained by only one of two things: Light, or melatonin. Since RORβ and RORγ are nuclear melatonin receptors, and also transcription factors, it would be natural to assume that they are responsible for melatonin-induced entrainment. The manner in which light does this is more esoteric: In some species, the photosensitive cryptochrome has been shown to quickly induce dNA transcription in response to light. Humans do have a cryptochrome homologue in the nucleus, yet the mainstream view is that it works only in the retinal. However! RORβ is also found in the pineal and suprachiasmic nucleus, notable on account of its expression being nearly exclusive to these two brain regions (and bone). Despite its rarity in fully-differentiated cells, retinoid orphan receptor β is expressed in all stem cells. This naturally leads to the thought that light and melatonin could direct the differentiation of stem cells

On account of the far-reaching implications surrounding clock gene desynchronization and bone turnover, long-term dosing in the milligram range might appear reckless. However, doses in microgram range could leave nuclear RORs largely unaffected: The two membrane receptors have quite substantial affinities for melatonin, with the former shown to prevent ACTH signalling in the adrenals. For RORs to become activated, it may be logical to then assume both high-affinity membrane receptors would initially need to become saturated, thereby allowing transmembrane permeation and nuclear activation. Nuclear receptor activation may require prior membrane saturation, which iscalculable.

Szymanska, Anna. "Diurnal profile of melatonin concentrations in patients with major depression: relationship to the clinical manifestation and antidepressant treatment." Neuroendocrinology Letters (2001)

Brainard, George. "Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor." Journal of Neuroscience (2001)

Morgan, Peter. "Melatonin receptors: localization, molecular pharmacology and physiological significance."Neurochemistry international (1994)

Singer, Clifford. "A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease." Sleep(2003)

Asher, Gad. "SIRT1 regulates circadian clock gene expression through PER2 deacetylation." Cell (2008)

Xie, Lulu. "Sleep drives metabolite clearance from the adult brain." Science (2013)"

I hope others find this information as helpful as I did!

@GAF some interesting thoughts on melatonin. Not sure if you saw this

 

[tankasnowgod]

It's unfortunate, I would like to read more posts from you in the future but you're implying here that you'll be ingesting a normal amount of calcium wih doses of vitamin D that start to enter the pharmacological territory.

Optimal Vitamin D Status: A Critical Analysis on the Basis of Evidence-Based Medicine | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic

It was posted elsewhere how 10000 IU/d elevated some people's blood levels of 25(OH)D to 80-something ng/ml.

Your concerns are noted, as are your sources. This study, especially, doesn't really say much about what doses of Vitamin D would induce toxicity, however. It's always at a high dose of some sort, and at a blood level somewhere over 100 ng/ml..... but there is a lot of territory that is far over that. From what I've gathered, those toxicity effects usually don't take place until the 400 ng/ml level, or with really high dose IU amounts, like accidental doses of millions of units, the once yearly doses of 200,000-300,000IU (which seems like it could come with it's own set of problems), or long term chronic doses in the 100,000 IU range with no monitoring or adjusting of does.

By the time magnesium has a chance to act, calcium has already turned you into a statue, an inverted marble centaur.

Ha! Unlikely. But being converted into a marble centaur would be a cool way to go.

Coimbra also acknowledged that K2 in his protocol was optional because it's ineffective for the range that they're working with (he probably used mostly MK-7, though).

This seems like the biggest oversight in the protocol. Even if you can't adequate K2, some would at least help toxicity effects, I would suspect.

 

[Cirion]

I would caution having around 50,000 IU or more. Having 50,000 IU every day resulted in something like 120 vitamin D levels after having a test done. As long as you get sunlight as much as you can I don't see any reason to have more than 10,000 a day.

 

[tankasnowgod]

I would caution having around 50,000 IU or more. Having 50,000 IU every day resulted in something like 120 vitamin D levels after having a test done. As long as you get sunlight as much as you can I don't see any reason to have more than 10,000 a day.

I agree. In the toxicity study I posted initially, they had the range up to 60,000 IU. Personally, I see these doses as more of a short term loading dose (in this case, short term being several months).

When you were at 120 (ng/ml I assume), did you notice anything, positive or negative?

 

[dbh25]

Taking 10,000 IU / day resulted in a level of 55 ng/ml.
(I weigh 80kg)

 

[GAF]

@GAF some interesting thoughts on melatonin. Not sure if you saw this

No I had not seen this. THANKS for finding it for me. ALL my questions are now answered and I know exactly what to do regarding melatonin.

 

[Cirion]

Honestly I did not notice a marked difference either positive or negative from vitamin D at that level, which leads me to believe that unless you have a deficiency, or a disease, it won't do a whole lot for you at that level of intake.

That said, Vitamin D seems to be an interesting thing to me. What I mean by that, I feel like there is a difference between vitamin D from sunlight and that from supplementation. I think the body is smart, and I couldn't begin to tell you the biological differences and biochemical reactions that occur when you get sunlight VS. when you just supplement vitamin D, but I think supplementation can never replace actual sunlight. I suspect sunlight does more than just give you vitamin D, and probably the vitamin D you get from sunlight has better utility in some way also. I don't get a noticeable "High" from supplementing vitamin D like I do going for a nice walk outside or something. This is why a current big goal of mine is to move to a beach.

 

[Cirion]

Taking 10,000 IU / day resulted in a level of 55 ng/ml.
(I weigh 80kg)

If 10,000 IU results in 55 ng/mL and 50,000 IU resulted in 120 ng/mL for me, then we can make an assumption that upwards of 30,000 IU (somewhere in between) probably results in something like 80 ng/mL (roughly, without bringing a calculator to the mix), which is just under the suggested max of 100 ng/mL, so maybe we could use 20-30,000 IU as the functional max recommendation.

Of course, this makes a lot of assumptions, like sunlight exposure. Do you work an office job also?

 

[lollipop]

No I had not seen this. THANKS for finding it for me. ALL my questions are now answered and I know exactly what to do regarding melatonin.

Woot! You are welcome - got to look after my fellow Dallas area Peat friend

 

[Braveheart]

@GAF some interesting thoughts on melatonin. Not sure if you saw this

Ok, I give up, where?......Ok I get it...

 

[lollipop]

Ok, I give up, where?

@bzmazu - @Blossom ’s post above - maybe on bottom of the first page of this thread. It is a long post about melatonin by Travis after Blossom asked him about it.

 

[tankasnowgod]

If 10,000 IU results in 55 ng/mL and 50,000 IU resulted in 120 ng/mL for me, then we can make an assumption that upwards of 30,000 IU (somewhere in between) probably results in something like 80 ng/mL (roughly, without bringing a calculator to the mix), which is just under the suggested max of 100 ng/mL, so maybe we could use 20-30,000 IU as the functional max recommendation.

Of course, this makes a lot of assumptions, like sunlight exposure. Do you work an office job also?

I do work in an office, although I do get some sun usually as well. I think weight brings something into the equation, and if D can result in quicker fat loss, there may be something to saturating fat stores with D as well. I'm using 25,000 IU right now, which is right in the functional max you suggested.

I am testing this out for some longer term health issues, mostly skin and minor, and also to see how it goes in regards to weight. When I was having pretty easy weight loss in my paleo days, I was taking quite a bit of D, and was reminded of that in the Bowles book, and also from the "D to A" ratio discussion that's going on in the Grant Generaux thread.

 

[Cirion]

Yeah it's hard to say for sure where the peak of the "U" in the curve in terms of benefits lie. How would one go about actually quantifying that point?

I will say I think it's probably difficult to get to truly "Toxic" levels and probably about the only way that will happen is if you supplement an obscenely high dose and/or have a job where you get a TON of sunlight like a lifeguard on a beach.

 

[sunraiser]

Just to add my personal experience as a possible word of caution.

I took 10k iu per day for a couple of months without k2. I was probably very deficient in vit k due to roaccutane use in the past, but I believed vit D would be the path towards magnesium tolerance.

Vitamin D used to occasionally feel good when I was dairy free. After increasing my calcium and vitamin A intake it makes me feel bad in general.

K2 mk7 makes me mega insulin resistant (even in small doses) ie sleeping or feeling severe exhaustion after meals. It also gives me mega magnesium cravings which for me are via white fish and mackerel, and to a lesser extent greens and dark chocolate. I can only tolerate smaller amounts of magnesium at the moment but I appear to need supra physiological amounts of mag while restoring my k2.

I think there's too much intracellular calcium while at the same time being bodily calcium deficient as a whole - I still crave dairy most days. I'm slowly dosing k2 mk7 (really really don't believe in mk4 being healthy from experience) and exercising when I feel like it. Exercising when feeling energy is the quickest way to feeling normal for me.

In effect, I appear to have caused some pretty mad issues from highish dose vitamin D. I'm not sure I would recommended anyone do the protocol you're trying but everyone doesn't have my history and physiology.

Remember if you need to mega dose something to feel effect your body is probably restricting uptake for a reason (or you're eating no fat).

 

[sunraiser]

I'm no longer allowed to edit. When I say "supra physiological amounts of mag" that's painting an inaccurate image. It just means i can't meet the demand with food and need an extra 200 to 400 mg despite eating 300 to 400mg from foods.

 

[dbh25]

Do you work an office job also?

Yes, and I ski in the winter.
I was as low as 10ng/ml before supplementing. The doctor recommended a Vit. D level in the 50s.

 

[baccheion]

If 10,000 IU results in 55 ng/mL and 50,000 IU resulted in 120 ng/mL for me, then we can make an assumption that upwards of 30,000 IU (somewhere in between) probably results in something like 80 ng/mL (roughly, without bringing a calculator to the mix), which is just under the suggested max of 100 ng/mL, so maybe we could use 20-30,000 IU as the functional max recommendation.

Of course, this makes a lot of assumptions, like sunlight exposure. Do you work an office job also?

55 ng/mL from 10,000 IU suggests you don't absorb vitamin D as well or didn't take for at least 6 months before checking serum.

I do work in an office, although I do get some sun usually as well. I think weight brings something into the equation, and if D can result in quicker fat loss, there may be something to saturating fat stores with D as well. I'm using 25,000 IU right now, which is right in the functional max you suggested.

I am testing this out for some longer term health issues, mostly skin and minor, and also to see how it goes in regards to weight. When I was having pretty easy weight loss in my paleo days, I was taking quite a bit of D, and was reminded of that in the Bowles book, and also from the "D to A" ratio discussion that's going on in the Grant Generaux thread.

It's more about getting serum vitamin D and PTH in range than the raw amount of vitamin D supplemented. Some doctors use 30,000 IU as a dose because it almost always puts serum between 80 and 120 ng/mL.

 

[tankasnowgod]

It's more about getting serum vitamin D and PTH in range than the raw amount of vitamin D supplemented. Some doctors use 30,000 IU as a dose because it almost always puts serum between 80 and 120 ng/mL.

You seem to know Bowles work quite well, and also look to have experimented with it. Have you noticed any benefits?

 

[baccheion]

You seem to know Bowles work quite well, and also look to have experimented with it. Have you noticed any benefits?

I mentioned my experience earlier in the thread.