Low Toxin Diet Grant Genereux's Theory Of Vitamin A Toxicity

[Travis]

I was brave yesterday and ate 2 oz of beef liver!!!

Did you have fava beans and Chianti with that?

No skin peeling.

Not today? But what about that lampshade quota?

I see now that you enjoy the look of . . . frightened emoticons.

 

[sunraiser]

250g chicken liver plus 32k retinol palmitate yesterday as an experiment.

Still here, added benefit of a ton of folate, selenium and b2. It also tasted amazing with some redwine vinegar, garlic and red onions plus a bit of paprika!

Today, liver is not remotely appealing. Comparing cravings for heavily dopaminergic activities or substances with non stimulant foods is not a useful comparison, imo.

Toxicity just equals a lack of cofactors. Vitamin A is challenging as both vitamin D and K are metabolised using magnesium, and if for any reason you're unable to increase or keep intracellular magnesium levels then excess retinol will be stored, perhaps with symptoms of toxicity as it'll use up your vitamin D stores which can't be replenished until you figure out your magnesium woes.

**I'm not advocating retinol supplements it was purely an experiment.

 

[Travis]

Fletcher, B. L. "Measurement of fluorescent lipid peroxidation products in biological systems and tissues." Analytical biochemistry (1973)

'An effective way to remove retinol fluorescence is to expose the chloroform-rich extract to high-intensity ultraviolet light for 30 sec. Photocatalytic oxidation of retinol in chloroform is very rapid. Spectra taken of extracts treated by exposure to ultraviolet light (Pen-Ray quartz lamp, Ultraviolet Products, Inc., San Gabriel, Calif. show loss of the retinol component while the fluorescent product of peroxidation damage remains, as shown in Fig. IB. All conjugated polyene systems like retinol and phytoflene should be similarly photo-oxidized by this procedure.' ―Fletcher​

The fluorescent spectra of retinol is dominated by absorption peaks stemming from its conjugated polyene tail and trimethylcyclohexenyl ring. As such, it would be little effected by conversion into retinoic acid. As you can see from above, the term 'oxidized' is freely used unmodified by chemists to indicate the lipid oxidation of retinol. Retinoic acid would be a minor nonenzymatic oxidation product based on statistical probability alone, and even more so after considering retinol's ω-end would likely be found buried near the center of milk's 10–15 micron liposomes due to solubility considerations.

 

[InChristAlone]

Did you have fava beans and Chianti with that?

Not today? But what about that lampshade quota?

I see now that you enjoy the look of . . . frightened emoticons.

Omg Hannibal is disturbing.

 

[Travis]

I tracked down a similar image to the one in the video I posted previously because I think it's a good visualization of what Grant has said about Retinoic Acid causing "head to toe destruction of the human body." That's no exaggeration.

View attachment 10143

Source: Accutane (isotretinoin) - How it Works, Side Effects, and Reviews

Some may still ask: What does this have to do with Vitamin A?

Well, Accutane is isotretinoin. And isotretinoin is an isomer of retinoic acid (it is an "isomer" because it has the same molecular formula [C20 H28 O2] but in slightly different "arrangement" — the important point for the layman to understand is that they are virtually equivalent in function in the human body).

So basically: isotretinoin (Accutane) ≈ retinoic acid.

And Vitamin A can and does convert to retinoic acid in the human body (especially under certain conditions).

As Grant says in his book:

"Where and when does this conversion take place in the body? It’s well documented in Retinoic Acid: Structure, Mechanisms and Roles in Disease (Microbiology Research Advances: Cell Biology Research Progress), both at the cellular and molecular levels. It's also documented in this 2006 report The acute and chronic toxic effects vitamin A.

From these two sources, it’s clear to see that the body will convert excess vitamin A (retinol) to retinoic acid. It’s going to happen and it happens normally. It will happen in the intestine and at the cellular level in any other tissues. Here is the key fact to remember:

Retinol is metabolized to retinoic acid in normal cells."

- p. 125, ETFOH​

This is why a key feature of Grant's theory is to explain a general association between excess Vitamin A consumption and taking Accutane — the key difference being a matter of degree.

Just for general illustration purposes, you could think of taking Accutane as being similar to consuming a huge amount of VA. Or, by consuming an excessive amount of VA chronically, it may have a similar effect to taking a small amount of Accutane.

But the key point for the theory is to understand the mechanism. Because this gives a mechanistic explanation as to why there could be such a thing as "subclinical" hypervitaminosis A from seemingly normal diet/lifestyles.

Accutane™ is synonymous with 13-cis-retinoic acid and becomes trans-retinoic acid on the skin after photoisomerization. Because 13-cis-retinoic acid is not a ligand for any known retinoid receptor, I had imagined that photoisomerization could account for skin-specific effects. I had done a search a few month's ago and had found this to be proven:

Tsukada, Miki. "13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors." Journal of investigative dermatology (2000)

Accutane™, a.k.a. isotretinoin and 13-cis-retinoic acid, can sneak past enzymes in the body towards the skin where it becomes cis–trans photoisomerized. As a relatively-inactive retinoid, it would largely bypass nuclear receptors that'd provide feedback inhibition—and greater toxicity—if trans-retinoic acid were used instead. Like a Trojan Horse it enters keratinocytes, yet instead of waiting for darkness to reveal the subterfuge it waits for direct sunlight. After becoming photoisomerized into the all-trans conformation—in keratinocytes—it increases skin turnover just as reliably as topical all trans-retinoic acid.

This mechanism of action is solid yet is not freely advertised. It would be 'rather uncomfortable' for Hoffman and La Roche if their patients knew that oral Accutane™ was tantamount to simply putting retinoic acid on the skin, albeit a far more dangerous and expensive way to do so. Most cis–trans activation ought to occur in light-exposed areas, meaning that certain areas of the brain could be effected. The eyes, optic nerve, suprachiasmic nucleus, and pineal gland are all theoretically-expected to receive photons under some paradigms of visual photoconduction:

Denman, Susan. "Abnormal night vision and altered dark adaptometry in patients treated with isotretinoin for acne." Journal of the American Academy of Dermatology (1986)

'Among fifty patients in an open prospective study of musculoskeletal changes associated with isotretinoin (1 mg/ kg/day), three patients spontaneously complained of decreased night vision and/or excessive glare problems, especially while driving. In two patients this occurred shortly after beginning a second four-month course of the drug, while the third patient developed symptoms 10 weeks into his first course of treatment.' ―Denman​

Park, Young. "Isotretinoin-induced Angle Closure and Myopic Shift." Journal of glaucoma (2017)

'Blepharoconjunctivitis, keratoconjunctivitis sicca, contact lens intolerance, transient blurring of vision, and acute transient refractive changes are well-known ocular adverse effects of isotretinoin use.' ―Park​

Wong, Adrian. "Isotretinoin-induced encephalopathy." Journal of Dermatological Treatment (2010)

'A 16-year-old male developed persistent headache 3 weeks after starting isotretinoin treatment at a dose of 80 mg per day (he weighed 60 kg) for severe cystic acne. His symptoms worsened within weeks and he developed nausea and visual hallucinations. At work he started complaining of difficulty using the computer – saying his ‘brain was not connected’, and he had word-finding difficulty. Ten weeks after starting isotretinoin he was admitted to hospital with persistent headache, word-finding difficulty, agitation, confusion, poor short-term memory and small myoclonic jerks of the hands.' ―Wong​

 

[franko]

250g chicken liver plus 32k retinol palmitate yesterday as an experiment.

Still here, added benefit of a ton of folate, selenium and b2. It also tasted amazing with some redwine vinegar, garlic and red onions plus a bit of paprika!

Today, liver is not remotely appealing. Comparing cravings for heavily dopaminergic activities or substances with non stimulant foods is not a useful comparison, imo.

Toxicity just equals a lack of cofactors. Vitamin A is challenging as both vitamin D and K are metabolised using magnesium, and if for any reason you're unable to increase or keep intracellular magnesium levels then excess retinol will be stored, perhaps with symptoms of toxicity as it'll use up your vitamin D stores which can't be replenished until you figure out your magnesium woes.

**I'm not advocating retinol supplements it was purely an experiment.

I have to say this is a foolish experiment, IMO.

If you have no history of autoimmune / inflammatory symptoms — e.g. irritable bowel, constipation, eczema / rashes, arthritis, asthma, etc — than you are not likely to get any kind of immediate "flare-up" symptoms. If you don't have any inflammatory symptoms, you are probably not one of those people who have reached or exceeded their body's retinol storage capacity (yet) — so you can probably take large doses and not feel a thing (yet).

I don't know why you would want to try mega-dosing VA as an experiment. What do you stand to gain? Is it just for pure curiosity? If so, I think the low VA diet is a much safer experiment to try. Most people have plenty of stored VA so that even if it was a "necessary nutrient" your body wouldn't be deplete for quite some time. (Grant has said that the research says you lose 0.5% of your VA stores per day on average, so it could take 200 days to deplete, but he has doubts about that — it could be much longer.)

 

[Mito]

If you have no history of autoimmune / inflammatory symptoms — e.g. irritable bowel, constipation, eczema / rashes, arthritis, asthma, etc — than you are not likely to get any kind of immediate "flare-up" symptoms. If you don't have any inflammatory symptoms, you are probably not one of those people who have reached or exceeded their body's retinol storage capacity (yet) — so you can probably take large doses and not feel a thing (yet).

Why do some young children have these problems since they likely haven’t been alive long enough to exceed their bodies retinol storage capacity?

 

[InChristAlone]

It seems everytime Franko posts I am just dumbfounded. IBS, constipation, rashes, eczema are not only caused by VA toxicity. I had horrible cramping bowel movements about once a month for much of my life , I had never used accutane or multivitamins I didn't drink milk or eat liver, but after quitting caffeine almost 2 yrs ago I have only had like one episode at the end of winter. I also started using ascorbic acid, but I haven't had it in a couple weeks and still no return of the cramping. The eczema patch on my eye lid is gone, with no return after higher VA days. I still have yet to solve my itchy bum but I still think that's fungal related. Not to mention we bring up anecdotes that people have solved their child's eczema with cod liver oil, of all the VA sources that one gets the most bad rap on a Ray peat group. This theory is just not adding up.

 

[Travis]

It seems everytime Franko posts I am just dumbfounded. IBS, constipation, rashes, eczema are not only caused by VA toxicity. I had horrible cramping bowel movements about once a month for much of my life , I had never used accutane or multivitamins I didn't drink milk or eat liver, but after quitting caffeine almost 2 yrs ago I have only had like one episode at the end of winter. I also started using ascorbic acid, but I haven't had it in a couple weeks and still no return of the cramping. The eczema patch on my eye lid is gone, with no return after higher VA days. I still have yet to solve my itchy bum but I still think that's fungal related. Not to mention we bring up anecdotes that people have solved their child's eczema with cod liver oil, of all the VA sources that one gets the most bad rap on a Ray peat group. This theory is just not adding up.

Retinoic acid activates at least two nuclear receptors, ROR and RXR, that can also dimerize with the vitamin D receptor (VDR) and many more. Retinoic acid also antagonizes the melatonin nuclear receptor RORβ in nanomolar concentrations, and if I recall correctly it also prevents transcription/melatonin binding of RORγ. Retinoid orphan receptor γ is found in circulating immune cells and RORβ in found in the bone. It seems plausible that retinoic acid would have a very broad spectrum of effects on account of the manifold nuclear receptors it either activates or represses.

 

[raypeatclips]

I have to say this is a foolish experiment, IMO.

If you have no history of autoimmune / inflammatory symptoms — e.g. irritable bowel, constipation, eczema / rashes, arthritis, asthma, etc — than you are not likely to get any kind of immediate "flare-up" symptoms. If you don't have any inflammatory symptoms, you are probably not one of those people who have reached or exceeded their body's retinol storage capacity (yet) — so you can probably take large doses and not feel a thing (yet).

I don't know why you would want to try mega-dosing VA as an experiment. What do you stand to gain? Is it just for pure curiosity? If so, I think the low VA diet is a much safer experiment to try. Most people have plenty of stored VA so that even if it was a "necessary nutrient" your body wouldn't be deplete for quite some time. (Grant has said that the research says you lose 0.5% of your VA stores per day on average, so it could take 200 days to deplete, but he has doubts about that — it could be much longer.)

Most of the things you mentioned are also related to vitamin D deficiencies.

Retinoic acid activates at least two nuclear receptors, ROR and RXR, that can also dimerize with the vitamin D receptor (VDR) and many more. Retinoic acid also antagonizes the melatonin nuclear receptor RORβ in nanomolar concentrations, and if I recall correctly it also prevents transcription/melatonin binding of RORγ. Retinoid orphan receptor γ is found in circulating immune cells and RORβ in found in the bone. It seems plausible that retinoic acid would have a very broad spectrum of effects on account of the manifold nuclear receptors it either activates or represses.

Do you not think the amounts of vitamin A discussed by Grant etc are ridiculous though? For example I struggle to think that 100 IU vitamin A could cause people massive issues, unless something else is at play, for example severe vitamin D deficiencies. I could see excessive amounts having problems though I get that bit

 

[franko]

Accutane™ is synonymous with 13-cis-retinoic acid and becomes trans-retinoic acid on the skin after photoisomerization. Because 13-cis-retinoic acid is not a ligand for any known retinoid receptor, I had imagined that photoisomerization could account for skin-specific effects. I had done a search a few month's ago and had found this to be proven:

Tsukada, Miki. "13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors." Journal of investigative dermatology (2000)

Accutane™, a.k.a. isotretinoin and 13-cis-retinoic acid, can sneak past enzymes in the body towards the skin where it becomes cis–trans photoisomerized. As a relatively-inactive retinoid, it would largely bypass nuclear receptors that'd provide feedback inhibition—and greater toxicity—if trans-retinoic acid were used instead. Like a Trojan Horse it enters keratinocytes, yet instead of waiting for darkness to reveal the subterfuge it waits for direct sunlight. After becoming photoisomerized into the all-trans conformation—in keratinocytes—it increases skin turnover just as reliably as topical all trans-retinoic acid.

This mechanism of action is solid yet is not freely advertised. It would be 'rather uncomfortable' for Hoffman and La Roche if their patients knew that oral Accutane™ was tantamount to simply putting retinoic acid on the skin, albeit a far more dangerous and expensive way to do so. Most cis–trans activation ought to occur in light-exposed areas, meaning that certain areas of the brain could be effected. The eyes, optic nerve, suprachiasmic nucleus, and pineal gland are all theoretically-expected to receive photons under some paradigms of visual photoconduction:

Denman, Susan. "Abnormal night vision and altered dark adaptometry in patients treated with isotretinoin for acne." Journal of the American Academy of Dermatology (1986)

'Among fifty patients in an open prospective study of musculoskeletal changes associated with isotretinoin (1 mg/ kg/day), three patients spontaneously complained of decreased night vision and/or excessive glare problems, especially while driving. In two patients this occurred shortly after beginning a second four-month course of the drug, while the third patient developed symptoms 10 weeks into his first course of treatment.' ―Denman​

Park, Young. "Isotretinoin-induced Angle Closure and Myopic Shift." Journal of glaucoma (2017)

'Blepharoconjunctivitis, keratoconjunctivitis sicca, contact lens intolerance, transient blurring of vision, and acute transient refractive changes are well-known ocular adverse effects of isotretinoin use.' ―Park​

Wong, Adrian. "Isotretinoin-induced encephalopathy." Journal of Dermatological Treatment (2010)

'A 16-year-old male developed persistent headache 3 weeks after starting isotretinoin treatment at a dose of 80 mg per day (he weighed 60 kg) for severe cystic acne. His symptoms worsened within weeks and he developed nausea and visual hallucinations. At work he started complaining of difficulty using the computer – saying his ‘brain was not connected’, and he had word-finding difficulty. Ten weeks after starting isotretinoin he was admitted to hospital with persistent headache, word-finding difficulty, agitation, confusion, poor short-term memory and small myoclonic jerks of the hands.' ―Wong​

Very interesting case studies. I'll be taking a closer look at them in time, but for now I'd say it's especially interesting to ponder the ones which show eye problems and night blindness from isotretinoin as those are classic symptoms purported to be caused by Vitamin A deficiency.

Grant also quoted (p 108 of PFP) some other research that confirms these as side effects of isotretinoin:

"Effects on vision and central nervous system. In addition to the xerophthalmia commonly experienced, and meibomian gland atrophy and corneal opacities reported with isotretinoin use, photophobia and decreased dark adaptation/night blindness can also occur. The loss of the dark adaptation maybe permanent."

Source: Retinoids and Carotenoids in Dermatology Anders Vahlquist, Madeleine Duvic
CRC Press, Jun 20, 2007 – Medical
See page 116​

This gets at the paradox that Grant highlights: the illogical explanation that both too little and too much VA could result in the exact same symptoms (e.g. night blindness and xerophthalmia).

Some will say: But there are many cases where too much and too little both cause problems!

Okay, but where does too much and too little cause the exact same problems?

For example, too much water and too little water both cause problems, but not the exact same problems — in fact, they cause the opposite problem — and the treatment will be the opposite — which is would you'd logically expect.

Imagine if eating too much and eating too little both caused people to become emaciated. That would be odd, wouldn't it? What we expect to see is that eating too much makes you obese and starvation makes you emaciated.

We logically expect opposite actions to yield opposite results. So when opposite actions (deficiency and excess) yield the same result — that's illogical, and we should examine that closely because there is likely a major error somewhere.

Grant's simple explanation: it's not a paradox — there was simply a mistake, a blunder, a human error which lead to a false conclusion.

It was never a deficiency in VA that caused these problems, it was always excess retinoic acid — which you can get by direct RA intake or by the natural conversion of VA to RA via chronic excess VA intake.

The documented side effects of isotretinoin and tretinoin establish that RA directly causes these symptoms, so to explain this "paradox" all we need to demonstrate is that in every study where a "VA deficiency" was purported to cause "deficiency" symptoms, there was a plausible source of excess VA or RA in the diet and/or a lack of protection from it.

 

[InChristAlone]

I developed contact lens intolerance when I got pregnant. I wore them for yrs prior. The only thing I started doing differently at that time was eating more salads. The eye dr said hormone changes can cause it.

 

[sunraiser]

I have to say this is a foolish experiment, IMO.

If you have no history of autoimmune / inflammatory symptoms — e.g. irritable bowel, constipation, eczema / rashes, arthritis, asthma, etc — than you are not likely to get any kind of immediate "flare-up" symptoms. If you don't have any inflammatory symptoms, you are probably not one of those people who have reached or exceeded their body's retinol storage capacity (yet) — so you can probably take large doses and not feel a thing (yet).

I don't know why you would want to try mega-dosing VA as an experiment. What do you stand to gain? Is it just for pure curiosity? If so, I think the low VA diet is a much safer experiment to try. Most people have plenty of stored VA so that even if it was a "necessary nutrient" your body wouldn't be deplete for quite some time. (Grant has said that the research says you lose 0.5% of your VA stores per day on average, so it could take 200 days to deplete, but he has doubts about that — it could be much longer.)

I didn't do it based on curiosity, I was craving liver and the sun hasn't been feeling good recently so I tried a higher vitamin A day to see how it impacted me.

I'm a prime candidate for so called toxicity as I took roaccutane for 6 months.

Incidentally, the experiment didn't help with sun feeling good, but I felt generally better. That's most likely the selenium though - it's so easy to be deficient!

 

[dbh25]

It seems everytime Franko posts I am just dumbfounded.

Me too.

About a month in, I gave myself a "cheat day" and ate a whole Little Caesar's cheese pizza which has 2729 IUs of VA

Btw, eating liver is essentially equivalent to taking a VA supplement.

Compared to the many videos of dogs excitedly eating raw meat and bone, there are very few videos on youtube of dogs eating raw liver, and in the few that do exist I have yet to see a dog excited to eat offer of raw liver.

And with Jordan Peterson it was his severe reaction to apple cider ("knocked him out" for a month)

He suspects it was sulfites in the cider

 

[franko]

Why do some young children have these problems since they likely haven’t been alive long enough to exceed their bodies retinol storage capacity?

Grant discusses this in chapter 9 of ETFOH, among other places.

The short answer is: Children have significantly less storage capacity than fully grown adults simply due to the their smaller size — i.e. being smaller in general means having smaller liver volume.

So it follows that it takes less intake and less time to reach their storage capacity.

Source: p. 97 of ETFOH

Also, Grant's theory has a simple explanation for how children can "outgrow" their eczema. By growing physically larger, they are increasing their VA storage capacity via liver volume and fat tissue, etc. and thus have greater protection from the toxin that causes it.

Btw, this also destroys any kind of "genetically inevitable" theory for autoimmune diseases that follow this age-related incidence pattern — your genetics don't change in your teens and then change back in your 50s.

Meanwhile in mainstream medicine:

"The cause of dermatitis is unknown but is presumed to be a combination of genetic and environmental factors."​

Wow, so helpful.

 

[franko]

It seems everytime Franko posts I am just dumbfounded [...] This theory is just not adding up.

This is probably because you haven't read the books.

I'm just posting snippets and summaries. You're not going to get the whole picture unless you read the books yourself.

If you don't want to read the books, that's fine. But you keep trying to debunk it anyway by posting your anecdotes. How do you expect to be able to debunk a theory without first reading and understanding the theory?

 

[Mito]

Grant discusses this in chapter 9 of ETFOH, among other places.

The short answer is: Children have significantly less storage capacity than fully grown adults simply due to the their smaller size — i.e. being smaller in general means having smaller liver volume.

So it follows that it takes less intake and less time to reach their storage capacity.

View attachment 10159
Source: p. 97 of ETFOH

Also, Grant's theory has a simple explanation for how children can "outgrow" their eczema. By growing physically larger, they are increasing their VA storage capacity via liver volume and fat tissue, etc. and thus have greater protection from the toxin that causes it.

Btw, this also destroys any kind of "genetically inevitable" theory for autoimmune diseases that follow this age-related incidence pattern — your genetics don't change in your teens and then change back in your 50s.

Meanwhile in mainstream medicine:

"The cause of dermatitis is unknown but is presumed to be a combination of genetic and environmental factors."​

Wow, so helpful.

I guess that explaination makes sense if you’ve seen a child “out grow” an autoimmune condition. I doubt that is the case for most children with an autoimmune disease.

 

[franko]

I guess that explaination makes sense if you’ve seen a child “out grow” an autoimmune condition. I doubt that is the case for most children with an autoimmune disease.

The theory doesn't say that all autoimmune diseases fit that pattern. It's just saying that for the ones that fit that age-related incidence pattern of appearing in childhood and then being "outgrown", this is a plausible explanation.

The classic examples of autoimmune conditions which can be "outgrown" are eczema and asthma. Do a search on "children outgrowing eczema / asthma" and you'll see many reports and references to children outgrowing those conditions.

 

[franko]

Grant has just posted a 4 year update on his blog to report on his progress after 4 years on his Vitamin A elimination diet.

The Four Year Update

Lots of interesting stuff including results of an eye exam, and blood lipid (cholesterol) tests, a kidney check up, and the announcement of an upcoming new book on breast cancer.

You ought to just go read the whole thing but here's one snippet:

"I finally got around to getting a comprehensive eye exam done. The results were all good. No glaucoma, no macular degeneration. The vision tests, both near and far, were a clear pass. The pressure test was fine. No need for reading glasses, and no need for driving glasses. I do still have a trace remnant of a cataract in the left eye. So, overall, my eye health and vision are excellent and of course, vastly improved compared to four years ago. But, the kicker was, as I was finishing up with the exam, the eye doc sat back in his chair, looked a little perplexed, and said: “I don’t understand how you could have gotten to be this age (58) and still have such good eye health and vision”. That was a completely unprompted remark, and I did not say a word about my peculiar diet. [...]

Anyways, the claim that vitamin A is needed to maintain human vision is now officially debunked, at least as far as I am concerned. My night vision remains very good too. [...]

Oh, I know there will be the skeptics and the naysayers who’ll claim that I’ve just not waited long enough for the great vitamin A deficiency to swoop down and take me out. No worries, I plan on maintaining my zero vitamin A diet at least for another five years, and I’ll let them know the moment that it catches up to me."
​

 

[Mito]

Grant has just posted a 4 year update on his blog to report on his progress after 4 years on his Vitamin A elimination diet.

The Four Year Update

​

I didn’t know a function of platelets was to repair damaged blood vessels. It would be interesting to see his hormone levels.