Low Toxin Diet Let's Talk About Eggs, Why Do Some People Seem to Do Better On Them in the Low Toxin Groups?

[mosaic01]

Do you have a reference for this, I'd like to read it.

Dietary Reference Values for vitamin A

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies derived Dietary Reference Values for vitamin A. The Panel considered that a concentration of 20 µg retinol/g liver can be used as a target for establishing the Average Requirement (AR) for...

www.efsa.europa.eu

"At the FAO/WHO Expert consultation of 1998 (WHO/FAO, 2004), experts maintained the approach that had been proposed previously (FAO/WHO, 1988). The mean requirement was defined as the minimum daily intake of vitamin A required to prevent xerophthalmia in the absence of clinical or subclinical infection. A mean requirement of 4–5 μg/kg body weight per day was estimated from the depletion–repletion study by Sauberlich et al. (1974). Vitamin A mean requirements of 300 μg RE/day for men and 270 μg RE/day for women were proposed."

"Olson (1987) has proposed a minimum concentration of 20 μg retinol/g liver (0.07 μmol/g) (i.e. as free retinol and retinyl esters) as a criterion to define adequate vitamin A status, based on the following considerations: (1) no clinical signs of deficiency have been noted in individuals with this or a higher liver concentration; (2) at this concentration and above, the liver is capable of maintaining a steady- state plasma retinol concentration, as determined by the relative dose–response test in rats (Loerch et al., 1979) and humans (Amedee-Manesme et al., 1987); (3) biliary excretion of retinol increases significantly when liver stores rise significantly above this concentration in rats (Hicks et al., 1984)"

"Excretion of labelled retinol metabolites in bile of rats fed increasing amounts of retinol traced by [3H]-retinyl acetate was constant when hepatic retinol
concentrations were low (≤ 32 μg/g and increased rapidly (by eight-fold) as liver retinol concentration increased, up to a plateau at hepatic retinol concentration ≥ 140 μg/g (490 nmol/g) (Hicks et al., 1984). This increased biliary excretion may serve as a protective mechanism for reducing the risk of excess storage of vitamin A."

So, how much vA is needed to reach 20mcg/g liver levels?

"Ribaya-Mercado et al. (2004) investigated the relationship between dietary vitamin A intake and total body and liver retinol stores in a cross-sectional study in men and women aged 60–88 years in the rural Philippines. (...) the authors estimated a mean liver retinol concentration of 40 ± 17 μg/g in men and 40 ± 27 μg/g in women. The mean vitamin intake of the men and women with a liver concentration ≥ 20 μg retinol/g (0.07 μmol/g) (n = 53) was 135 ± 86 μg RAE/day (n = 27) and 134 ± 104 μg RAE/day (n = 26), respectively."

"The calculated mean liver vitamin A concentration of the Filipino elders (0.14 μmol/g liver) is also lower than values obtained by direct measurement of liver vitamin A in autopsies of subjects who were ≥ 60 y old at the time of death (values in μmol/g liver): 0.34 in Illinois (24), 0.44 in Canada (25), 0.57 in 5 US areas (Missouri, Iowa, Ohio, California, and Texas) (4), 0.57 in London (26), 0.93 in New Zealand (27), and 1.22 in Washington, DC (28)."

https://www.sciencedirect.com/science/article/pii/S0002916522038977

From all of the above info, I conclude that the amount of retinol that induces biliary excretion is very low, and probably around 300mcg. The biopsy studies show that most people have 10 times the 20mcg/g amount that is defined as "sufficient".

Everyone's needs are different. Someone who is active, builds muscle, gets a lot of sunlight, etc, can get away with more A.

Yes, there's of course individual variation, as always. But tendencies and patterns can still be observed. If you say one can get away with more, you imply it is toxic. The question is - at what point does this toxin magically turn into a vitamin?

The studies are clear, even a diet with only 100mcg of RAE does not induce any issues. So the only question is how much can you take before you start destroying your body. Intake above 200-300mcg seems to be toxic indeed and lead to the above mentioned results of liver biopsies showing overt toxicity in 1/3 or so of cases. The biopsy studies show that almost everyone has retinol amounts storted that induce this kind of biliary excretion.

 

[youngsinatra]

What do you think is the solution in that case?

TMG increases SAMe.

"In rats supplemented with an additional 0.5% betaine in their feed, it appears that SAMe production in the liver is increased two-fold relative to control; this is increased to five-fold if the rats were pretreated with ethanol (which normally impairs this pathway)[137] and injections of betaine have demonstrated dose-dependent increases in red blood cell concentrations of SAMe in rats.[138]"

Research Breakdown on Betaine - Examine

examine.com

Interesting, but those rats did not have mitochondrial problems, right?

I have seen a few methylation panels from people with CFS and seen a similar pattern like this:

Chris Masterjohn now thinks in a similar way.

How Energy Deficiency Hurts Methylation

I'm increasingly seeing this pattern in my consulting practice.

chrismasterjohnphd.substack.com

 

[mosaic01]

I have seen a few methylation panels from people with CFS and seen a similar pattern like this:

What do you think is the best strategy to address these issues?

 

[orangebear]

@orangebear has reported that he does better on eggs, I believe he said that his digestion improves with them, and I am not sure what else. Hopefully he can fill us in on how he felt before eggs, and how he felt afterwards and what they improved. And also hopefully @orangebear can bring us up to speed on why he thinks these improvements happened and what are the reported great thing about eggs.

I think I'll have to go back a couple years to explain what changed with eggs. I developed digestive issues in 2017: IBS, SIBO, GERD, etc. The doctors weren't very helpful so I started experimenting with keto on and off, and easier to digest carbs when I wasn't doing keto, such as rice. I also went gluten free around that time because gluten would often make me dump the contents of my digestive tract after eating any significant amount (a bit of soy sauce with sushi was OK but a slice of bread was too much, for example). I never solved my digestive issues but I was more or less able to keep them under control with a gluten free diet and cannabis. Then in mid-2020, I developed a weird dizziness, anxiety, insomnia, neurological issues, and brain fog. So I tried to figure out what was going on and how to fix it. I tried a bunch of different things and nothing seemed to work until I came across Morley Robbins' "Root Cause Protocol". I got a reduction of my symptoms following the protocol but about half a year later they came back, almost as strong as before, along with a sharp increase in my muscle stiffness and arthritis pain, which I've had since my early twenties. I then pivoted towards Ray Peat principles and the pattern repeated, but in a slightly lesser fashion: at first feeling better, and then having my insomnia, anxiety, brain fog, etc. return. So in May 2022, I came across the vA thread on this forum and decided to try it. I made the classic mistake of switching everything up immediately rather than gradually, and my experience was roughly like this: I initially felt relief, then a week later I would get bile dumps that would have me nauseous enough to nearly pass out, then after that things slowly got better, mostly. So, I had a significant improvement in the neurological issues, insomnia, and whatnot over the next few months, but they were rather slow after the initial rollercoaster. However, after about a year or so some of the joint pain, brain fog, and anxiety, among other old and new things started getting ever so slowly worse. Also, sticking to the extremely restrictive Grant/Garrett style low vA diet was getting rather difficult. I would often want foods that are not approved and have zero appetite when trying to eat approved foods. Even though low vA had been the most successful thing I'd tried since 2020, it seemed to plateau and even start regressing.

I came across the ideas of adding eggs back in and increasing the variety of food while trying to keep the vA intake somewhere between 50%–100% of the RDA on the Facebook group, along with explanations of why we might want eggs (choline), bread (betaine), skipjack tuna (small amounts of active B6 and other cofactors; supplementing B6 can be dangerous for reasons I won't go into here), etc. Since I started that approach, I've been able again reduce my anxiety, insomnia, brain fog, etc. In particular, here are some major differences I've noticed:

1. Bile dumps generally have become less painful in my gut and the symptoms have become less extreme; I still get bile dumps and they can still mess me up in various ways, but the symptoms are much more manageable. Theoretically, this has to do with phosphatidylcholine binding to some of the toxins in bile and making it less corrosive when it hits the gut. Also, theoretically, it has to do with choline being involved in cell membrane health and repair.
2. My constipation has improved. I never had constipation until about a year on low vA. Introducing eggs hasn't eliminated it, but it has improved it significantly. I don't know what the mechanism is—perhaps increased bile production due to choline; not sure—but others reported the same thing in the FB group so it was one of my reasons for trying it. It hasn't solved all my other digestive issues, which I still experience occasionally.
3. I was gluten sensitive for around 5 years. After doing low vA for about a year I would no longer dump the contents of my gut immediately after eating gluten, but it would give me severe joint pain. A month or so after introducing eggs (and then catching and getting over COVID) I tried eating a sandwich with sourdough and experienced no joint pain. Since then I've been making up for all the gluten I've missed over 5 years.
4. After adding eggs back in, my anxiety actually slightly increased, but after looking into it and talking to the people in the group, I came to the hypothesis that is had to do with my genetic predisposition to overmethylate. I am homozygous for the MTHFR A1298C mutation, which fails to put the brakes on methylation. I've heard niacin uses up methyl groups, which is why it's often recommended to take betaine with it, so I added niacinamide at the time (I still use both forms of niacin today) and it balanced things out.
5. I got some swelling in my hands and feet on RP foods and then more while doing low vA, but some of it has reduced since adding eggs, bread, and niacin.

Now, I'm not sure if I can attribute this all to eggs, or if some of it is more about generally increasing variety in my food, but this is generally the sequence of events and how I interpret them so far. Also, I did lose some weight while doing the stricter low vA diet even if I was feeling much worse towards the end of the first year on it than I do now, but I haven't lost any since I increased the variety of my food. I have been eating a bit more calories as well though since my appetite is better. It's hard to say exactly what's going on and I could certainly lose some of the fat I've gained with RCP and RP foods, but I just want to be transparent about both pros and cons to my current approach.

It is reported that the choline in the eggs drives "vitamin A" into the liver and locks it there, or I think that is how the argument goes? Is that how it makes a person feel better by slowing down the detox? Or, is it somehow helping the detox and maybe opening up bottlenecks?

That would be Dr. Smith's interpretation. People in the FB group have reported increased bile flow with eggs though (and perhaps that explains the relief of constipation) so I'm not sure that's an accurate explanation. If I understand correctly, choline helps to shuttle vA to the liver, and then it can be detoxed and excreted into the gut from there. If this it true, then it would generally be a good thing that choline transports vA to the liver, as the vA would then do less damage all over the body. I can see how it could put an extra burden on the liver if the liver is already over capacity on vA though. It might one of those things that you would want to do slowly as to not overwhelm the liver, but the overall idea seems to be a good one: 1) bring the crap out of peripheral tissues into the liver, 2) break it down, and 3) put it in the gut to leave with the poop. I don't know if that's exactly how it works but that's more or less how I imagine it.

Is the "vitamin A" content all that high in eggs and enough to worry about? Is there substances in eggs that we need to help the detox? Let's crack open this subject and see what we find.

The vA content of one egg is less than that of 1 tbsp butter (which Dr. Smith allows for). On the other hand, eggs do have significantly more lutein than butter. Too much lutein seems to give me insomnia. I can handle chicken eggs OK, but I'll get insomnia after eating salmon caviar, for example. So, there are good and bad compounds in eggs, and different people in different contexts will react differently to them.

 

[orangebear]

That brings another great question. If a person does not handle eggs, should they might supplement Phosphatidylcholine for the reported detox enhancing properties?

I've never gotten a clear answer to that question. I did take a supplement when I started eggs, but only did one every other day. Truth be told, I don't know whether the supplement did anything or not for me. I didn't take it for very long. At least no bad acute effects, I guess.

 

[orangebear]

I’ve been on again off again with eggs since early 2020 when covid was first unleashed on us. I started eating some again on work days for convenience and to avoid starving when I was working at the hospital. There weren’t many decent choices to say the least so that’s my excuse.
I’m currently off eggs and I think my problem with them personally is sulfur tbh but I’m homozygous for CBC c699t and apparently people with that SNP do better keeping sulfur low. Right now I’m experimenting with sunflower lecithin but it’s only been a couple days so it’s too soon for me to tell anything yet.

Yeah, sulfur can be an issue with eggs, including for myself. I'm still trying to figure out how to solve it but I'm currently working with the theory that you need active B6 (not from supplements; people are likely to have plenty in their bodies and adding more can cause problems; but there are deficiencies that need to be addressed and problems that can deactivate B6 and turn it into a toxic compound), B2, molybdenum, and perhaps B12, and folate to get sulfur metabolism back on track. Sorry, that's not a good explanation of it. Meri Arthur has some videos that go deep into the biochemistry on it but it's hard to wrap my brain around them. Basically, what I do right now is supplement a little B2, some molybdenum, and I occasionally have some skipjack tuna. It might be working but I need more time to figure it out. Basically, I think sulfur issues are an indicator of metabolic problems; when the metabolism is working correctly, we should be able to handle sulfur.

 

[orangebear]

High acetylcholine can inhibit dopamine/norepinephrine release iirc, leading to this depressed state.

I get a similar effect from taking too much thiamine, pantothenic acid or from eating night shades.

I wonder if that is dependent on the location of the acetylcholine. From what I've heard, the lack of it in the gut can cause constipation and an increase in acetylcholine in the gut could be one of the ways eggs relieve constipation, since it is used for muscle contraction.

 

[Blossom]

Yeah, sulfur can be an issue with eggs, including for myself. I'm still trying to figure out how to solve it but I'm currently working with the theory that you need active B6 (not from supplements; people are likely to have plenty in their bodies and adding more can cause problems; but there are deficiencies that need to be addressed and problems that can deactivate B6 and turn it into a toxic compound), B2, molybdenum, and perhaps B12, and folate to get sulfur metabolism back on track. Sorry, that's not a good explanation of it. Meri Arthur has some videos that go deep into the biochemistry on it but it's hard to wrap my brain around them. Basically, what I do right now is supplement a little B2, some molybdenum, and I occasionally have some skipjack tuna. It might be working but I need more time to figure it out. Basically, I think sulfur issues are an indicator of metabolic problems; when the metabolism is working correctly, we should be able to handle sulfur.

Thanks @orangebear, that’s the second time I’ve run across the name Meri Arthur recently so I definitely need to check out her information. I’ve increased my molybdenum recently and added B2 both of which seem helpful. Methylation is something I admittedly still need to understand more. I currently react poorly to methylated supplements. Peat didn’t think much of methylation so I never really looked into it in depth. Masterjohn’s choline calculator says I need the equivalent of 7! egg yolks per day fwiw. I’ve also read that in menopause women benefit from more choline so there’s that to consider as well. I’m just going to keep experimenting, stay curious and open minded and continue learning. :)

 

[orangebear]

Thanks @orangebear, that’s the second time I’ve run across the name Meri Arthur recently so I definitely need to check out her information. I’ve increased my molybdenum recently and added B2 both of which seem helpful. Methylation is something I admittedly still need to understand more. I currently react poorly to methylated supplements. Peat didn’t think much of methylation so I never really looked into it in depth. Masterjohn’s choline calculator says I need the equivalent of 7! egg yolks per day fwiw. I’ve also read that in menopause women benefit from more choline so there’s that to consider as well. I’m just going to keep experimenting, stay curious and open minded and continue learning. :)

One interesting thing I found is that not all molybdenum supplements seem to work for me. Liquid ammonium molybdate seemed to have no effect but Mo-Zyme seems to work. I also don't react well to methylated B vitamins, probably because of my genetic predisposition to overmethylate.

 

[charlie]

I never did that well with eggs,

Did you ever do raw egg yolks only?

I do supplement with a little creatine while on Niacin and felt better when ate 2 eggs

Good to know, thank you.

I think the best way to test whether eggs are needed is to take 1-2 raw egg yolks on an empty stomach without other food, and that may be sufficient to do every 1-2 weeks to help the liver.

Just started my egg-pirement of two raw eggs in the morning upon waking.

Not Betaine HCL by the way - betaine is usually called trimethylglycine (TMG).

Andrew thinks betaine and choline are super important for this process and thinks these two should be focused on first.

So Charlie, my TestoShakes are far from poisoning people to say the least.

I am not convinced of that statement.

I think I'll have to go back a couple years to explain what changed with eggs. I developed digestive issues in 2017: IBS, SIBO, GERD, etc. The doctors weren't very helpful so I started experimenting with keto on and off, and easier to digest carbs when I wasn't doing keto, such as rice. I also went gluten free around that time because gluten would often make me dump the contents of my digestive tract after eating any significant amount (a bit of soy sauce with sushi was OK but a slice of bread was too much, for example). I never solved my digestive issues but I was more or less able to keep them under control with a gluten free diet and cannabis. Then in mid-2020, I developed a weird dizziness, anxiety, insomnia, neurological issues, and brain fog. So I tried to figure out what was going on and how to fix it. I tried a bunch of different things and nothing seemed to work until I came across Morley Robbins' "Root Cause Protocol". I got a reduction of my symptoms following the protocol but about half a year later they came back, almost as strong as before, along with a sharp increase in my muscle stiffness and arthritis pain, which I've had since my early twenties. I then pivoted towards Ray Peat principles and the pattern repeated, but in a slightly lesser fashion: at first feeling better, and then having my insomnia, anxiety, brain fog, etc. return. So in May 2022, I came across the vA thread on this forum and decided to try it. I made the classic mistake of switching everything up immediately rather than gradually, and my experience was roughly like this: I initially felt relief, then a week later I would get bile dumps that would have me nauseous enough to nearly pass out, then after that things slowly got better, mostly. So, I had a significant improvement in the neurological issues, insomnia, and whatnot over the next few months, but they were rather slow after the initial rollercoaster. However, after about a year or so some of the joint pain, brain fog, and anxiety, among other old and new things started getting ever so slowly worse. Also, sticking to the extremely restrictive Grant/Garrett style low vA diet was getting rather difficult. I would often want foods that are not approved and have zero appetite when trying to eat approved foods. Even though low vA had been the most successful thing I'd tried since 2020, it seemed to plateau and even start regressing.

I came across the ideas of adding eggs back in and increasing the variety of food while trying to keep the vA intake somewhere between 50%–100% of the RDA on the Facebook group, along with explanations of why we might want eggs (choline), bread (betaine), skipjack tuna (small amounts of active B6 and other cofactors; supplementing B6 can be dangerous for reasons I won't go into here), etc. Since I started that approach, I've been able again reduce my anxiety, insomnia, brain fog, etc. In particular, here are some major differences I've noticed:

1. Bile dumps generally have become less painful in my gut and the symptoms have become less extreme; I still get bile dumps and they can still mess me up in various ways, but the symptoms are much more manageable. Theoretically, this has to do with phosphatidylcholine binding to some of the toxins in bile and making it less corrosive when it hits the gut. Also, theoretically, it has to do with choline being involved in cell membrane health and repair.
2. My constipation has improved. I never had constipation until about a year on low vA. Introducing eggs hasn't eliminated it, but it has improved it significantly. I don't know what the mechanism is—perhaps increased bile production due to choline; not sure—but others reported the same thing in the FB group so it was one of my reasons for trying it. It hasn't solved all my other digestive issues, which I still experience occasionally.
3. I was gluten sensitive for around 5 years. After doing low vA for about a year I would no longer dump the contents of my gut immediately after eating gluten, but it would give me severe joint pain. A month or so after introducing eggs (and then catching and getting over COVID) I tried eating a sandwich with sourdough and experienced no joint pain. Since then I've been making up for all the gluten I've missed over 5 years.
4. After adding eggs back in, my anxiety actually slightly increased, but after looking into it and talking to the people in the group, I came to the hypothesis that is had to do with my genetic predisposition to overmethylate. I am homozygous for the MTHFR A1298C mutation, which fails to put the brakes on methylation. I've heard niacin uses up methyl groups, which is why it's often recommended to take betaine with it, so I added niacinamide at the time (I still use both forms of niacin today) and it balanced things out.
5. I got some swelling in my hands and feet on RP foods and then more while doing low vA, but some of it has reduced since adding eggs, bread, and niacin.

Now, I'm not sure if I can attribute this all to eggs, or if some of it is more about generally increasing variety in my food, but this is generally the sequence of events and how I interpret them so far. Also, I did lose some weight while doing the stricter low vA diet even if I was feeling much worse towards the end of the first year on it than I do now, but I haven't lost any since I increased the variety of my food. I have been eating a bit more calories as well though since my appetite is better. It's hard to say exactly what's going on and I could certainly lose some of the fat I've gained with RCP and RP foods, but I just want to be transparent about both pros and cons to my current approach.

That would be Dr. Smith's interpretation. People in the FB group have reported increased bile flow with eggs though (and perhaps that explains the relief of constipation) so I'm not sure that's an accurate explanation. If I understand correctly, choline helps to shuttle vA to the liver, and then it can be detoxed and excreted into the gut from there. If this it true, then it would generally be a good thing that choline transports vA to the liver, as the vA would then do less damage all over the body. I can see how it could put an extra burden on the liver if the liver is already over capacity on vA though. It might one of those things that you would want to do slowly as to not overwhelm the liver, but the overall idea seems to be a good one: 1) bring the crap out of peripheral tissues into the liver, 2) break it down, and 3) put it in the gut to leave with the poop. I don't know if that's exactly how it works but that's more or less how I imagine it.

The vA content of one egg is less than that of 1 tbsp butter (which Dr. Smith allows for). On the other hand, eggs do have significantly more lutein than butter. Too much lutein seems to give me insomnia. I can handle chicken eggs OK, but I'll get insomnia after eating salmon caviar, for example. So, there are good and bad compounds in eggs, and different people in different contexts will react differently to them.

@orangebear thank you for sharing!

 

[mosaic01]

Andrew thinks betaine and choline are super important for this process and thinks these two should be focused on first.

So here's some things that are usually referenced when talking about methylation:

- TMG/Betaine
- Choline
- Creatine
- Glycine
- B9 (Folate)
- B2
- B12

90% of methylation is busy with producing creatine and phosphatidylcholine, so naturally ingesting more creatine and choline (beef has both), will reduce the methylation burden of the entire body. Beef also has lots of methionine.

Glycine is used to protect against overmethylation, as it mops up excessive methyl groups.

TMG is the primary source of methyl groups in the diet, next to methionine and choline - it's methylated glycine. TMG will help the body with producing creatine and choline.

The b-vitamins are needed in certain steps of the methylation process, especially folate.

---

I have read a lot of stuff Andrew posted on ggenereux.info, with his extreme focus on choline-rich foods.

From all what I have read from him - I can't take him serious at all. He started with his egg obsession, telling people that it's important to eat several of them every day, up to 8 or something, and at one point he even said with massive amounts of choline you can eat as much vA as you like.

Recently he said on that forum that he advises people to start slow on TMG, only 500mg, and otherwise it "can cause headaches". I know several people who have taken TMG, it's a very safe substance. It's pretty much not something that causes any issues usually. The only problem can be when people are glycine deficient, as then the excess methyl groups are unopposed.

I think he interacts with people who are extremely sick and react to literally everything, and so he is lead into the wrong conclusions and concepts.

For example, when it comes to choline. A diet with wheat, beef, beans, cauliflower, bananas, potatoes, etc., will provide already 400-800mg choline plus lots of betaine, depending on calory intake. That's pretty much all that's needed. No need to "replete choline" over a many months process.

The people at risk for choline deficiency are those who eat the typical SAD diet without nutrient dense whole foods, and then only get something like 100-200mcg choline on the background of fructose, PUFA, alcohol, etc..

For example the following diet has 700mg choline plus 100mg+ betaine. Certainly nothing that causes choline deficiency. It's way above the usual recommendations.

 

[Blossom]

This might be of interest to some. It’s just another perspective to consider for people who seem to have higher choline needs/requirements. I ignored the vA portion since I’m recovering from toxicity and have the labs to prove it. :)
From Reddit r/MTHFR

“MTHFR: A Supplement Stack Approach

This post describes a plan for implementing a nutrient/supplement stack to address MTHFR.

The plan is in phases and incrementally ramps up over time, as it is quite common for people to have sensitivities to changes in their methylation status.

This plan is also a layered approach: each phase adds in a layer of nutrients/supplements. So, we are building an 'MTHFR stack'.

The view I am following for MTHFR is largely derived from that recommended by [Chris Masterjohn](https://chrismasterjohnphd.substack.com/p/mthfr-protocol), but with some differences, and the phases are my design. The result is therefore internet advice from a non-professional, it is general advice and not specific to any individual, and should be treated accordingly.



# AIMS

1. Due to the reductions in methylfolate production, the folate/B12-dependent remethylation pathway is impaired. Therefore, support the choline-dependent remethylation pathway.
2. Optimize the impaired folate/B12-dependent remethylation pathway to make best use of its remaining functionality.
3. Reduce demand on the methylation cycle.



# GENERAL

* Unless you have a specific reason to take them, avoid B complexes. They tend to be high doses and often cause more issues, rather than help. It also makes it impossible to adjust individual nutrient levels.
* Avoid the synthetic vitamins folic acid and cyanocobalamin.
* A food diary app like [Cronometer](https://cronometer.com/) can be very useful for tracking your average nutrient intakes, or looking up specific foods to see nutrient content.
* Time per phase: A few people may be able to do everything all at once (assuming B12 levels are ok); other people who are more sensitive to methylation changes may require 1-2 weeks or longer per phase, ramping up doses incrementally during that phase.
* Just be aware that the more things you do at once, the harder it can be to diagnose which component may be causing you issues, if any occur.
* People with COMT V158M 'Met/Met' (aka '+/+' or 'AA') tend to be more sensitive.
* People with existing mental health issues can be more sensitive.



# ABOUT MTHFR

* 'MTHFR' is short for 'methylene tetrahydrofolate reductase'.
* MTHFR is the final enzymatic step in the conversion of food folate, folic acid, or folinic acid to methylfolate. If the methylation cycle were thought of as a gear that is turned by a crank handle, then methylfolate is the hand that turns the crank handle - with poor methylfolate status, the methylation cycle performs poorly.
* The cofactor is B2.
* P39P
* P39P alternate name: rs2066470
* [74-95%](https://www.ncbi.nlm.nih.gov/snp/rs2066470#frequency_tab) of people have the Green (-/-) variant.
* I am unaware of evidence that this SNP is impactful.
* C677T and A1298C
* C677T alternate names: 677C-T, 677C>T, C665T, 665C>T, Ala222Val, rs1801133, C667T
* A1298C alternate names: 1298A-C, 1298A>C, 1286A>C, GLU429ALA, rs1801131, E429A
* These two SNPs can appear in different permutations of variants, which affect the performance of MTHFR.
* Per the [table on Genesight](https://genesight.com/white-papers/what-is-the-clinical-significance-of-the-mthfr-a1298c-polymorphism/), the resulting percent of performance for the various combinations are:

|Genotypes|677CC (-/-) \[GG\]|677CT (-/+) \[AG\]|677TT (+/+) \[AA\]|
|:-|:-|:-|:-|
|1298AA (-/-) \[TT\]|100%|51-73%|22-32%|
|1298AC (-/+) \[GT\]|69-92%|36-60%|n/a|
|1298CC (+/+) \[GG\]|52-60%|n/a|n/a|

* **NOTE**: MTHFR is only the last step in the folate conversion cycle. There can be SNPs in preceding enzymes such as MTHFD1 or SLC19A1 which may also degrade performance of the folate cycle. The Stratagene report mentioned at top of post will analyze these SNPs. Also, Chris Masterjohn's free [Choline Calculator](https://chrismasterjohnphd.substack.com/p/how-much-choline-should-i-eat-the) will analyze MTHFD1 and SLC19A1 from your 23andme or Ancestry data.



# PROTOCOL SUMMARY / TLDR

* This summary does not include all notes and details - see each phase for more detailed information.
* When adding the supplements specified in each phase, *start with low doses* and increment up slowly over days (or weeks) to the recommended levels.
* This is a lifetime plan, not a quick fix. Expect incremental improvement over several weeks or months.


|PHASE|PURPOSE|SUPPLEMENT(S)|NOTES|
|:-|:-|:-|:-|
|1|Resolve B12 deficiency (if present)|Sublingual Hydroxocobalamin or Adenosylcobalamin|If not B12 deficient, skip to Phase 2. Otherwise, supplement as needed to resolve deficiency or per doctor's direction.|
|2|Improve MTHFR function|Vitamin B2, 10-100mg/day|If your only MTHFR variant is A1298C, B2 may or may not improve MTHFR function.|
|3|Support the Methyl Buffer System. Reduces risk of overmethylation side effects.|Glycine, 3-10g/day and vitamin A (retinol form), 50-100% of RDA|Collagen or magnesium glycinate may be substituted for glycine. See Phase 3 details.|
|4|Decrease methylation burden|Creatine (monohydrate or HCL), 3-5g/day|Micronized creatine mixes better in liquids. While this phase is beneficial, it is optional.|
|5a|Determine total choline needs|n/a|Upload your genetic datafile to the [Choline Calculator](https://chrismasterjohnphd.substack.com/p/how-much-choline-should-i-eat-the) to determine dietary choline need. This will be given in units of 'number of eggs' worth of choline. If you do not have a genetic datafile to upload, use a choline need of '8 eggs' as your daily goal.|
|5b|Support alternate methylation pathway|1/2 of the total # of eggs worth of choline|See Phase 5 detail for choline equivalents. TMG may be used instead of choline for this portion (use 150mg of TMG per egg equivalent).|
|5c|Support phosphatidylcholine production; decrease methylation burden|1/2 of the total # of eggs worth of choline|Do NOT substitute TMG for this choline portion. See Phase 5 detail for choline equivalents.|
|6|Increase folate intake, as needed|Folate from food; methylfolate or folinic acid|WARNING - See Phase 6 details: starting with too high of a dose of methylfolate can cause side effects!! Start low, go slow.|
|Maintenance|Fine-tuning|\-as needed-|Adjust supplements and dosages as needed over time, to compensate for improvements in methylation and to make your routine more sustainable.|



# PHASE 1 - B12

* We start with B12 because if we get MTHFR working better, there needs to be adequate B12 actually utilize the methylfolate that MTHFR produces.
* B12 is necessary to utilize the methylfolate (either produced by MTHFR or supplemented) to convert homocysteine back to methionine using the methionine synthase (MTR) enzyme. Inadequate B12 can cause a "[folate trap](https://www.firstclassmed.com/articles/2017/folate-trap)", where methylfolate cannot be used by MTR and so it accumulates; homocysteine levels rise due to the lack of conversion back to methionine, and tetrahydrofolate is not recycled back into the folate cycle, causing reduced activity of other important functions of the folate cycle.
* IF YOU ARE B12-SUFFICIENT:
* If you are B12-sufficient and obtain adequate B12 from dietary sources, then there is no need to supplement B12. Go to Phase 2.
* IF YOU ARE B12-DEFICIENT:
* If you suspect or know that your are B12-deficient, then supplement sublingual adenosylcobalamin or hydroxocobalamin for at least 1-2 weeks, or until your doctor tells you are no longer B12-deficient, before proceeding to Phase 2, and continue supplementing until your levels are toward middle to higher-end of normal range, or as your doctor prescribes.
* Methylcobalamin can be used instead, but many people initially can be sensitive to the excess methyl groups provided by methylcobalamin, at least until Phase 3 has been implemented. So adenosylcobalamin or hydroxocobalamin are simply less problematic at this initial phase.
* NOTE: There is an interesting [case report](https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.12966) where hydroxocobalamin, which is a natural inactive form of B12, was functionally ineffective in the patient. Replacing the hydroxocobalamin with methylcobalamin resolved the patient's B12-related symptoms.



# PHASE 2 - B2 (Riboflavin)

* If you have a C677T yellow (heterozygous), or red (homozygous) variant, or both C677T yellow (heterozygous) and A1298C yellow (heterozygous) variants:
* Research dosages were 1.6mg/day.
* Typical supplement doses are 10-100mg/day (either riboflavin or riboflavin 5-phosphate).
* Video: [How to get enough riboflavin from food](https://youtu.be/E5wR_iCWVyk).
* The C677T yellow (heterozygous) or red (homozygous) variant reduces riboflavin binding affinity. Higher levels of B2 will improve the binding success.
* If you only have a yellow or red variant in A1298C, it is not clear if added B2 will help or not. It is up to you if you want to add in supplemental B2 in hopes it *may* help.
* NOTE: Hypothyroidism can reduce conversion of riboflavin to the active forms FAD and FMN.
* [Abstract](https://pubmed.ncbi.nlm.nih.gov/3809170/), [paper](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015041/).
* Reference: [Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism - PubMed
* Video: [
(https://youtu.be/Fp6u82coOYE)]View: https://youtu.be/Fp6u82coOYE](https://youtu.be/Fp6u82coOYE)

* Riboflavin has [no defined Tolerable Upper Limit](https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/#h16), due to lack of toxicity.



# PHASE 3 - Methyl-Buffering System

* The body has a built-in system to store excess methyl groups and retrieve them when needed. This requires iron, glycine, and vitamin A:
* IRON: If you are iron-deficient, resolve that deficiency.
* VITAMIN A: Eat retinol-rich foods and/or supplement retinol-based vitamin A to at least reach [RDA/day](https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/#h2). Conversion of beta-carotene from plant sources to retinol vitamin A varies greatly between individuals and so is unreliable. I use cod liver oil (see my supplement list below).
* GLYCINE: Supplement 3-10g of glycine/day, in one or more of the following ways:
* **Plain glycine powder or capsule**s. If you are sensitive, ramp up dose over a week or so. (I use 3-5g/day in my coffee, as glycine powder is sweet-tasting.) Do not use TMG as a glycine source, as it is a methyl donor, and we are trying to prepare our body ahead of time for methyl donors.
* **Collagen powder** (e.g., Great Lakes collagen peptides). For some, this allows achieving the desired glycine levels while avoid an excitatory effect. Check the glycine amount in the ingredients label. NOTE: If collagen powder causes depressive mood, this [may be due to an absence of tryptophan](https://www.everywomanover29.com/blog/collagen-gelatin-lower-serotonin-increase-anxiety-depression/) in standard collagen powder. Consider switching to a collagen powder with added tryptophan or add tryptophan seprately.
* **Magnesium glycinate**. If you have a reason for supplementing magnesium, this may be an option. 300mg of elemental magnesium from magnesium glycinate [contains almost 2 grams of glycine](https://chrismasterjohnphd.com/blog/balancing-methionine-and-glycine-in-foods-the-database/).
* **Bone broth**. This can be another source of glycine, but the glycine content is variable, and [may be insufficient](https://pubmed.ncbi.nlm.nih.gov/29893587/). Further, bone broth tends to be high in histamines, which you may want to avoid if you have slow MAO-A.
* NOTE: Glycine is an inhibitory neurotransmitter and is usually calming. But for some people, glycine acts as a stimulant.
* Chris Masterjohn has a [video](https://youtu.be/1uEDpHT0zWI) where he discusses glycine and GABA causing these kinds of paradoxical reactions due to a lack of carbs needed to create glutamate to offset the inhibitory effects of glycine or GABA, and in this second [video](https://youtu.be/7ugZ5X7M2uE) Chris discusses the role of electrolytes as related to glycine/GABA.
* If interested, [here is a detailed post](https://www.reddit.com/r/MTHFR/comments/169595o/overundermethylator_or_deficient_methyl_buffering) on the methyl-buffering system.



# PHASE 4 - Reduce creatine demand on methylation

* Creatine production uses up [40](https://pubmed.ncbi.nlm.nih.gov/21387089/)\-[45](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754151/)% of methylation output (i.e., SAM).
* Supplement \~3-5g/day of creatine monohydrate or creatine hydrochloride (HCL).
* 'Micronized' powder products are finer and not gritty. I stir it into my coffee.
* If symptoms of overmethylation occur, start low and ramp up dose incrementally over a week or so.
* NOTE: If creatine causes insomnia, please see [this post by Chris Masterjohn](https://chrismasterjohnphd.substack.com/p/why-would-creatine-cause-insomnia), recommending lower methionine (i.e., lower protein), keeping folate status high, and supplementing glycine.



# PHASE 5 - Support alternate methylation pathway and reduce phosphatidylcholine demand on methylation

* *CHOLINE IS THE KEY INGREDIENT TO MAKE THIS PROTOCOL WORK. WITHOUT ADDED CHOLINE, YOU CANNOT COMPENSATE FOR THE FOLATE PATHWAY (e.g., MTHFR) LIMITATIONS.*
* Phosphatidylcholine production uses up another 40-45% of methylation output (i.e., SAM).
* Phosphatidylcholine can be produced from choline.
* The alternate pathway (BHMT) through the methionine cycle unburdens demand on MTHFR.
* This path depends on B3, B6, zinc and TMG (aka betaine anhydrous).
* TMG can be created from choline.
* Maintain healthy normal B3, B6, and zinc status.
* Eat choline rich foods and/or supplement choline to achieve 1000 - 1200mg of choline/day. E.g., 8 eggs/day is \~1000mg of choline.
* For a more customized review of your specific choline requirements, Chris Masterjohn has a free [Choline Calculator](https://chrismasterjohnphd.substack.com/p/how-much-choline-should-i-eat-the) where you can upload your 23andme/Ancestry/SelfDecode data and it will analyze relevant SNPs and tell you your choline need, in units of number of eggs.
* Chris Masterjohn has a [Choline Database](https://chrismasterjohnphd.com/tools/2019/04/17/the-choline-database) of choline content of foods. Some are listed below:
* Eggs - a large egg has 136mg of choline; almost all of this is in the yolk.
* Meat/fish - 9-12oz of meat or fish is equivalent to one egg worth of choline.
* Lecithin - 1 tbsp of lecithin is equivalent to one egg worth of choline.
* TMG (aka betaine anhydrous) - this is a suitable substitute for only up to half of the need for choline, as [the conversion from choline to TMG is irreversible](https://www.sciencedirect.com/science/article/pii/S0022316622158554#s0015), and thus phosphatidylcholine cannot be made from TMG. \~150mg of TMG is equivalent to one egg worth of choline.
* Do not confuse 'betaine anhydrous' with 'betaine HCL': betaine HCL is not usable for this purpose.
* 1/2 tsp of TMG powder is \~1500mg of TMG.
* TMG has little to no taste, so it is easy to add to liquids or food.
* TMG is a methyl donor. People with slow COMT or who are sensitive to changes in methylation should consider starting with small doses (e.g., 1/8 tsp or less) of TMG powder and slowly increment the dose over time.
* CDP Choline (aka Citicoline) - 18.5% choline content; thus 735mg of CDP Choline is equivalent to one egg worth of choline.
* Phosphatidylcholine - 15% choline content; thus 906mg of phosphatidylcholine is equivalent to one egg worth of choline.
* Alpha-GPC - 40% choline content; thus 340mg of Alpha-GPC is equivalent to one egg worth of choline.
* Choline Bitartrate - 40% choline content; thus 340mg of choline bitartrate is equivalent to one egg worth of choline. This form of choline reportedly is [less efficiently absorbed](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893749/) than choline in egg yolks. Consider taking a combination of choline bitartrate and inositol, as the inositol may prevent depression that some people have experienced with choline bitartrate. In fact, choline bitartrate and inositol are often combined together as a product.
* NOTE: A small percentage of people may experience depression from supplementing choline. So monitor your mood for any indication of this.
* Consider adding inositol as this may prevent depression due to choline supplementation.
* Some alternatives to supplementing choline would be sticking with food-based choline only, or trying alternative choline supplement forms, such as CDP choline, choline bitartrate, lecithin, phosphatidylcholine, or Alpha-GPC.



# PHASE 6 - Folate intake

* It is important to keep in mind that we are not trying to 'fix' MTHFR by taking folate.
* Why do we need folate?
* To supply folate for methylfolate production for the remethylation of homocysteine. Although the methylfolate production by MTHFR is diminished, it is not zero.
* To supply folate for methylfolate production to turn off the methyl buffer system. There are several control signals between the folate cycle and the methionine cycle to maintain proper methylation levels. This is one of those control signals.
* The folate cycle is involved in DNA repair and replication.
* The folate cycle participates in the biopterin cycle.
* The folate cycle performs the interconversion of serine and glycine.
* When to supplement folate?
* You are folate-deficient (per blood test).
* You were recently folate-deficient, and are still repleting your folate stores. This repletion may take several months, up to a year.
* Your diet is folate-deficient.
* You have folate absorption issues.
* Increase folate intake from food. This [NIH folate list](https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/#h3) may be helpful.
* Methylfolate supplements are a double-edged sword: while methylfolate is a readily usable natural form, it is a methyl donor and so may cause sudden changes in methylation which can result in side effects ranging from symptoms such as irritability, anxiety, headaches, fatigue to depression, depersonalization/derealization, and more. Yet, if side effects are minimized by careful dosing, that boost in methyl groups can create a sense of cognitive and mood improvement, at least in the initial weeks or months of the protocol.
* Methylfolate Dosing:
* Sublingual, or liquid drops, is the preferred supplement form. Sublinguals can easily be broken apart into 1/4 or 1/8 pieces to allow starting with small doses. For even smaller starting doses, liquid drops may be better.
* Typical sublingual methylfolate are 1000mcg. So, a 1/8 size piece (barely a crumb) is 125mcg.
* Sensitive people: Start with 125mcg once/day and see how it goes for several days. Increase next to twice per day. Increase next to 250mg twice per day, and so on.
* Very sensitive people: If even small amounts of methylfolate are causing issues and food folate is not enough, consider using the folinic acid form of folate. This is an unmethylated folate, also available as a sublingual. Follow the same incremental process above, starting at 125mcg.
* Very, very sensitive people: Use low-dosage liquid methylfolate and dissolve 1 drop in 10 equivalent drops of an oil (e.g., olive oil); this dilutes the folate drop by 10x. Then take just a drop of that diluted folate. Incrementally work your way up over time. See [this video segment](https://youtu.be/GT27aTx3A70?t=836).
* Less sensitive people: Start with 1/4 sublingual (250mcg) once/day at a meal and see how it goes for several days. Increase next to 250mcg twice per day at meals. Increase next to either 500mcg twice/day at meals or 250mcg 3 times/day at meals.
* Final dosage goal: This is highly individual. Some people may find that 500mcg (1/2 sublingual) per day suffices, some may find that 1000mcg or more is beneficial, and as noted earlier, some may find food folate alone sufficient. You need to monitor your own wellbeing and health to determine what is right for you.
* Folinic acid supplements are another natural usable folate form; however, folinic acid is not methylated, and still needs to be processed through MTHFR to become methylfolate. These factors make folinic acid much less likely to cause side effects compared to methylfolate.
* Folinic acid may not be advisable if you have significant slowdown of the MTHFS gene.
* Folinic acid dosing:
* Sublingual is the preferred supplement form. Sublinguals can easily be broken apart into 1/4 or 1/8 pieces to allow starting with small doses. For even smaller starting doses, liquid drops may be better.
* Typical sublingual folinic acid are 1000mcg. So, a 1/8 size piece (barely a crumb) is 125mcg.
* Sensitive people: Start with 125mcg once/day and see how it goes for several days. Increase next to twice per day. Increase next to 250mg twice per day, and so on.



# MAINTENANCE Phase - Ongoing Steps

* With all the preceding steps, we have now implemented our basic MTHFR 'stack':
* B2 (1.6-100mg/day), if C677T is involved.
* Glycine (3-10g/day)
* Vitamin A (as needed to reach RDA/day)
* Creatine (3-5g/day)
* Choline (1000-1500g/day, or as recommended by the [Choline Calculator](https://chrismasterjohnphd.substack.com/p/how-much-choline-should-i-eat-the))
* Half of the choline requirement may come from TMG.
* Folate source(s) (some combination of food, methylfolate, folinic acid)
* Monitor with blood tests as needed.
* Anecdote: 6-7 months after starting this protocol I rely almost entirely on food folate. I take methylfolate once/week, but I do not know if that is even necessary. Every person will have to gauge their own situation.
* B12
* Monitor with blood tests as needed, and supplement as needed, with hydroxocobalamin, adenosylcobalamin, or methylcobalamin forms of B12.
* Ongoing B12 supplementation is not needed if B12 levels are in the desired range and dietary B12 intake is adequate, unless you have specific reasons or doctor's direction to continue supplementing.
* NOTE: Methylcobalamin may still be problematic for some people who are very sensitive to excess methyl groups.
* Fine-tuning:
* You may find you need to adjust some of these components up or down over time, as your life changes or as your body adapts.
* Some people may want to experiment with additional methylation support, such as SAM (aka 'SAMe') to further optimize their health and mental state. Consider these as additional enhancements, rather than replacements for any of these stack components. Start with small doses and monitor.
* Pay attention to your body. You might find after a while that you have the urge to occasionally skip a day or more of some or all supplements. If this results in unchanged or even improved status, it may be a beneficial practice and/or a signal to revisit your supplement list and dosing regimen.



# Supplements Examples

* I provide this just as examples, not as endorsements. I have no financial interest:
* [Now Foods 100mg B2](https://www.amazon.com/Vitamin-100mg-Capsules-Riboflavin-Pack/dp/B002LIOHOE)
* [Now Foods Glycine Powder](https://www.amazon.com/dp/B0013OVZJW)
* [On Target Living Alaskan Cod Liver Oil](https://www.amazon.com/dp/B07JC7QZ69) (vitamin A)
* [Optimum Nutrition Micronized Creatine Monohydrate Powder](https://www.amazon.com/dp/B002DYIZEE)
* [Zazzee Extra Strength Citicoline CDP Choline](https://www.amazon.com/dp/B071KRRMTX)
* [EZ Melts Dissolvable Folate](https://www.amazon.com/EZ-Melts-L-5-Methylfolate-Sublingual-Vitamins/dp/B00VVQJNCI) or [Seeking Health L-5-MTHF Lozenge](https://www.amazon.com/gp/product/B00E0THMZS)
* [Seeking Health Folinic Acid](https://www.amazon.com/gp/product/B00UUEMZ4K)
* [Foods Alive Non-Fortified Nutritional Yeast](https://www.amazon.com/dp/B08BW8GC88) (general B vitamin support)
* [Best Naturals Betaine Anhydrous](https://www.amazon.com/Best-Naturals-Betaine-Anhydrous-Trimethylglycine/dp/B08NMSY353) (TMG Powder)

​

EDITS:

* 20231011 - Replace methylfolate timing advice 'take at mealtimes' with 'away from meals' based on interaction of methylfolate and the methyl buffer system. Reformat post with large text section headers. Add notes under glycine. Add comments in Phase1 & Maintenance about methylcobalamin. Add folate trap comments in Phase1. Other minor cleanup.
* 20231105 - Add 'About MTHFR' section.
* 20231122 - Add reference and video links for riboflavin.
* 20231128 - Add hypothyroid comments under B2 section.
* 20231202 - Change magnesium glycinate to a glycine source with reference. Add references for creatine production burden. Minor text changes.
* 20231205 - Update riboflavin doses to include the research 1.6mg dose. Update creatine dose from 5g to 3-5g.
* 20231209 - Add reference link for choline-to-TMG irreversibility.
* 20231218 - Major revision of the choline phase, based on Chris Masterjohn's [choline article](https://chrismasterjohnphd.substack.com/p/choline).
* 20231220 - Add note about collagen missing tryptophan. Add note about not confusing betaine anhydrous with betaine HCL.
* 20231222 - Add Summary/TLDR section.
* 20231230 - Rewrite folate phase to clarify that folate supplementation is conditional, not required.
* 20240115 - Add choline bitartrate as a choline option. Add link to Masterjohn article re creatine causing insomnia.
* 20240214 - Add suggestion to try adding inositol if choline supplementation causes depression.
* 20240025 - Add AIMS section. Add creatine HCL as an alternative form of creatine.

 

[Hidden49]

When I first went low Vit A and had bad Vit A toxicity I couldn't tolerate eggs at all, however now I can eat as many eggs as I want and I find them beneficial. I think the quality of the egg will be play a major role in whether you're able to tolerate them or not eg: were the chickens fed glyphosate sprayed feed and vitamin A supplements, are the yolks yellow or orange (yellow people are much more likely to tolerate but orange yolks people don't usually) farmers feed chickens marigold extract to manipulate the colour of the yolk to make it an rich orange colour. I have been on holiday and had issues with the eggs there and they were actually from a farmers market but the oragnic eggs I get from the supermarket here in the UK I have no issues.

 

[charlie]

however now I can eat as many eggs as I want and I find them beneficial

Do you mind sharing the benefits?

 

[Hidden49]

Do you mind sharing the benefits?

Nothing in particular, I just feel good from eating them and it makes a change from only eating chicken or beef for my protein the whole time. I still eat meat everyday pretty much but there are sometimes where I don't feel like meat and only feel like eating eggs instead. I do think eggs are a lighter food and easier on digestion than meat is. I also recall also eating eggs and then feeling amazing in the sun afterwards so I guess there is some nutrient in eggs linked to that. I also have noticed my face looks younger and healthier when I eat them.

 

[Parrot]

Thanks Blossom, that was very interesting...

This might be of interest to some. It’s just another perspective to consider for people who seem to have higher choline needs/requirements. I ignored the vA portion since I’m recovering from toxicity and have the labs to prove it. :)
From Reddit r/MTHFR

“MTHFR: A Supplement Stack Approach

This post describes a plan for implementing a nutrient/supplement stack to address MTHFR.

The plan is in phases and incrementally ramps up over time, as it is quite common for people to have sensitivities to changes in their methylation status.

This plan is also a layered approach: each phase adds in a layer of nutrients/supplements. So, we are building an 'MTHFR stack'.

The view I am following for MTHFR is largely derived from that recommended by [Chris Masterjohn](https://chrismasterjohnphd.substack.com/p/mthfr-protocol), but with some differences, and the phases are my design. The result is therefore internet advice from a non-professional, it is general advice and not specific to any individual, and should be treated accordingly.



# AIMS

1. Due to the reductions in methylfolate production, the folate/B12-dependent remethylation pathway is impaired. Therefore, support the choline-dependent remethylation pathway.
2. Optimize the impaired folate/B12-dependent remethylation pathway to make best use of its remaining functionality.
3. Reduce demand on the methylation cycle.



# GENERAL

* Unless you have a specific reason to take them, avoid B complexes. They tend to be high doses and often cause more issues, rather than help. It also makes it impossible to adjust individual nutrient levels.
* Avoid the synthetic vitamins folic acid and cyanocobalamin.
* A food diary app like [Cronometer](https://cronometer.com/) can be very useful for tracking your average nutrient intakes, or looking up specific foods to see nutrient content.
* Time per phase: A few people may be able to do everything all at once (assuming B12 levels are ok); other people who are more sensitive to methylation changes may require 1-2 weeks or longer per phase, ramping up doses incrementally during that phase.
* Just be aware that the more things you do at once, the harder it can be to diagnose which component may be causing you issues, if any occur.
* People with COMT V158M 'Met/Met' (aka '+/+' or 'AA') tend to be more sensitive.
* People with existing mental health issues can be more sensitive.



# ABOUT MTHFR

* 'MTHFR' is short for 'methylene tetrahydrofolate reductase'.
* MTHFR is the final enzymatic step in the conversion of food folate, folic acid, or folinic acid to methylfolate. If the methylation cycle were thought of as a gear that is turned by a crank handle, then methylfolate is the hand that turns the crank handle - with poor methylfolate status, the methylation cycle performs poorly.
* The cofactor is B2.
* P39P
* P39P alternate name: rs2066470
* [74-95%](https://www.ncbi.nlm.nih.gov/snp/rs2066470#frequency_tab) of people have the Green (-/-) variant.
* I am unaware of evidence that this SNP is impactful.
* C677T and A1298C
* C677T alternate names: 677C-T, 677C>T, C665T, 665C>T, Ala222Val, rs1801133, C667T
* A1298C alternate names: 1298A-C, 1298A>C, 1286A>C, GLU429ALA, rs1801131, E429A
* These two SNPs can appear in different permutations of variants, which affect the performance of MTHFR.
* Per the [table on Genesight](https://genesight.com/white-papers/what-is-the-clinical-significance-of-the-mthfr-a1298c-polymorphism/), the resulting percent of performance for the various combinations are:

|Genotypes|677CC (-/-) \[GG\]|677CT (-/+) \[AG\]|677TT (+/+) \[AA\]|
|:-|:-|:-|:-|
|1298AA (-/-) \[TT\]|100%|51-73%|22-32%|
|1298AC (-/+) \[GT\]|69-92%|36-60%|n/a|
|1298CC (+/+) \[GG\]|52-60%|n/a|n/a|

* **NOTE**: MTHFR is only the last step in the folate conversion cycle. There can be SNPs in preceding enzymes such as MTHFD1 or SLC19A1 which may also degrade performance of the folate cycle. The Stratagene report mentioned at top of post will analyze these SNPs. Also, Chris Masterjohn's free [Choline Calculator](https://chrismasterjohnphd.substack.com/p/how-much-choline-should-i-eat-the) will analyze MTHFD1 and SLC19A1 from your 23andme or Ancestry data.



# PROTOCOL SUMMARY / TLDR

* This summary does not include all notes and details - see each phase for more detailed information.
* When adding the supplements specified in each phase, *start with low doses* and increment up slowly over days (or weeks) to the recommended levels.
* This is a lifetime plan, not a quick fix. Expect incremental improvement over several weeks or months.


|PHASE|PURPOSE|SUPPLEMENT(S)|NOTES|
|:-|:-|:-|:-|
|1|Resolve B12 deficiency (if present)|Sublingual Hydroxocobalamin or Adenosylcobalamin|If not B12 deficient, skip to Phase 2. Otherwise, supplement as needed to resolve deficiency or per doctor's direction.|
|2|Improve MTHFR function|Vitamin B2, 10-100mg/day|If your only MTHFR variant is A1298C, B2 may or may not improve MTHFR function.|
|3|Support the Methyl Buffer System. Reduces risk of overmethylation side effects.|Glycine, 3-10g/day and vitamin A (retinol form), 50-100% of RDA|Collagen or magnesium glycinate may be substituted for glycine. See Phase 3 details.|
|4|Decrease methylation burden|Creatine (monohydrate or HCL), 3-5g/day|Micronized creatine mixes better in liquids. While this phase is beneficial, it is optional.|
|5a|Determine total choline needs|n/a|Upload your genetic datafile to the [Choline Calculator](https://chrismasterjohnphd.substack.com/p/how-much-choline-should-i-eat-the) to determine dietary choline need. This will be given in units of 'number of eggs' worth of choline. If you do not have a genetic datafile to upload, use a choline need of '8 eggs' as your daily goal.|
|5b|Support alternate methylation pathway|1/2 of the total # of eggs worth of choline|See Phase 5 detail for choline equivalents. TMG may be used instead of choline for this portion (use 150mg of TMG per egg equivalent).|
|5c|Support phosphatidylcholine production; decrease methylation burden|1/2 of the total # of eggs worth of choline|Do NOT substitute TMG for this choline portion. See Phase 5 detail for choline equivalents.|
|6|Increase folate intake, as needed|Folate from food; methylfolate or folinic acid|WARNING - See Phase 6 details: starting with too high of a dose of methylfolate can cause side effects!! Start low, go slow.|
|Maintenance|Fine-tuning|\-as needed-|Adjust supplements and dosages as needed over time, to compensate for improvements in methylation and to make your routine more sustainable.|



# PHASE 1 - B12

* We start with B12 because if we get MTHFR working better, there needs to be adequate B12 actually utilize the methylfolate that MTHFR produces.
* B12 is necessary to utilize the methylfolate (either produced by MTHFR or supplemented) to convert homocysteine back to methionine using the methionine synthase (MTR) enzyme. Inadequate B12 can cause a "[folate trap](https://www.firstclassmed.com/articles/2017/folate-trap)", where methylfolate cannot be used by MTR and so it accumulates; homocysteine levels rise due to the lack of conversion back to methionine, and tetrahydrofolate is not recycled back into the folate cycle, causing reduced activity of other important functions of the folate cycle.
* IF YOU ARE B12-SUFFICIENT:
* If you are B12-sufficient and obtain adequate B12 from dietary sources, then there is no need to supplement B12. Go to Phase 2.
* IF YOU ARE B12-DEFICIENT:
* If you suspect or know that your are B12-deficient, then supplement sublingual adenosylcobalamin or hydroxocobalamin for at least 1-2 weeks, or until your doctor tells you are no longer B12-deficient, before proceeding to Phase 2, and continue supplementing until your levels are toward middle to higher-end of normal range, or as your doctor prescribes.
* Methylcobalamin can be used instead, but many people initially can be sensitive to the excess methyl groups provided by methylcobalamin, at least until Phase 3 has been implemented. So adenosylcobalamin or hydroxocobalamin are simply less problematic at this initial phase.
* NOTE: There is an interesting [case report](https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.12966) where hydroxocobalamin, which is a natural inactive form of B12, was functionally ineffective in the patient. Replacing the hydroxocobalamin with methylcobalamin resolved the patient's B12-related symptoms.



# PHASE 2 - B2 (Riboflavin)

* If you have a C677T yellow (heterozygous), or red (homozygous) variant, or both C677T yellow (heterozygous) and A1298C yellow (heterozygous) variants:
* Research dosages were 1.6mg/day.
* Typical supplement doses are 10-100mg/day (either riboflavin or riboflavin 5-phosphate).
* Video: [How to get enough riboflavin from food](https://youtu.be/E5wR_iCWVyk).
* The C677T yellow (heterozygous) or red (homozygous) variant reduces riboflavin binding affinity. Higher levels of B2 will improve the binding success.
* If you only have a yellow or red variant in A1298C, it is not clear if added B2 will help or not. It is up to you if you want to add in supplemental B2 in hopes it *may* help.
* NOTE: Hypothyroidism can reduce conversion of riboflavin to the active forms FAD and FMN.
* [Abstract](https://pubmed.ncbi.nlm.nih.gov/3809170/), [paper](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015041/).
* Reference: [Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism - PubMed
* Video: [
(https://youtu.be/Fp6u82coOYE)]View: https://youtu.be/Fp6u82coOYE](https://youtu.be/Fp6u82coOYE)

* Riboflavin has [no defined Tolerable Upper Limit](https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/#h16), due to lack of toxicity.



# PHASE 3 - Methyl-Buffering System

* The body has a built-in system to store excess methyl groups and retrieve them when needed. This requires iron, glycine, and vitamin A:
* IRON: If you are iron-deficient, resolve that deficiency.
* VITAMIN A: Eat retinol-rich foods and/or supplement retinol-based vitamin A to at least reach [RDA/day](https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/#h2). Conversion of beta-carotene from plant sources to retinol vitamin A varies greatly between individuals and so is unreliable. I use cod liver oil (see my supplement list below).
* GLYCINE: Supplement 3-10g of glycine/day, in one or more of the following ways:
* **Plain glycine powder or capsule**s. If you are sensitive, ramp up dose over a week or so. (I use 3-5g/day in my coffee, as glycine powder is sweet-tasting.) Do not use TMG as a glycine source, as it is a methyl donor, and we are trying to prepare our body ahead of time for methyl donors.
* **Collagen powder** (e.g., Great Lakes collagen peptides). For some, this allows achieving the desired glycine levels while avoid an excitatory effect. Check the glycine amount in the ingredients label. NOTE: If collagen powder causes depressive mood, this [may be due to an absence of tryptophan](https://www.everywomanover29.com/blog/collagen-gelatin-lower-serotonin-increase-anxiety-depression/) in standard collagen powder. Consider switching to a collagen powder with added tryptophan or add tryptophan seprately.
* **Magnesium glycinate**. If you have a reason for supplementing magnesium, this may be an option. 300mg of elemental magnesium from magnesium glycinate [contains almost 2 grams of glycine](https://chrismasterjohnphd.com/blog/balancing-methionine-and-glycine-in-foods-the-database/).
* **Bone broth**. This can be another source of glycine, but the glycine content is variable, and [may be insufficient](https://pubmed.ncbi.nlm.nih.gov/29893587/). Further, bone broth tends to be high in histamines, which you may want to avoid if you have slow MAO-A.
* NOTE: Glycine is an inhibitory neurotransmitter and is usually calming. But for some people, glycine acts as a stimulant.
* Chris Masterjohn has a [video](https://youtu.be/1uEDpHT0zWI) where he discusses glycine and GABA causing these kinds of paradoxical reactions due to a lack of carbs needed to create glutamate to offset the inhibitory effects of glycine or GABA, and in this second [video](https://youtu.be/7ugZ5X7M2uE) Chris discusses the role of electrolytes as related to glycine/GABA.
* If interested, [here is a detailed post](https://www.reddit.com/r/MTHFR/comments/169595o/overundermethylator_or_deficient_methyl_buffering) on the methyl-buffering system.



# PHASE 4 - Reduce creatine demand on methylation

* Creatine production uses up [40](https://pubmed.ncbi.nlm.nih.gov/21387089/)\-[45](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754151/)% of methylation output (i.e., SAM).
* Supplement \~3-5g/day of creatine monohydrate or creatine hydrochloride (HCL).
* 'Micronized' powder products are finer and not gritty. I stir it into my coffee.
* If symptoms of overmethylation occur, start low and ramp up dose incrementally over a week or so.
* NOTE: If creatine causes insomnia, please see [this post by Chris Masterjohn](https://chrismasterjohnphd.substack.com/p/why-would-creatine-cause-insomnia), recommending lower methionine (i.e., lower protein), keeping folate status high, and supplementing glycine.



# PHASE 5 - Support alternate methylation pathway and reduce phosphatidylcholine demand on methylation

* *CHOLINE IS THE KEY INGREDIENT TO MAKE THIS PROTOCOL WORK. WITHOUT ADDED CHOLINE, YOU CANNOT COMPENSATE FOR THE FOLATE PATHWAY (e.g., MTHFR) LIMITATIONS.*
* Phosphatidylcholine production uses up another 40-45% of methylation output (i.e., SAM).
* Phosphatidylcholine can be produced from choline.
* The alternate pathway (BHMT) through the methionine cycle unburdens demand on MTHFR.
* This path depends on B3, B6, zinc and TMG (aka betaine anhydrous).
* TMG can be created from choline.
* Maintain healthy normal B3, B6, and zinc status.
* Eat choline rich foods and/or supplement choline to achieve 1000 - 1200mg of choline/day. E.g., 8 eggs/day is \~1000mg of choline.
* For a more customized review of your specific choline requirements, Chris Masterjohn has a free [Choline Calculator](https://chrismasterjohnphd.substack.com/p/how-much-choline-should-i-eat-the) where you can upload your 23andme/Ancestry/SelfDecode data and it will analyze relevant SNPs and tell you your choline need, in units of number of eggs.
* Chris Masterjohn has a [Choline Database](https://chrismasterjohnphd.com/tools/2019/04/17/the-choline-database) of choline content of foods. Some are listed below:
* Eggs - a large egg has 136mg of choline; almost all of this is in the yolk.
* Meat/fish - 9-12oz of meat or fish is equivalent to one egg worth of choline.
* Lecithin - 1 tbsp of lecithin is equivalent to one egg worth of choline.
* TMG (aka betaine anhydrous) - this is a suitable substitute for only up to half of the need for choline, as [the conversion from choline to TMG is irreversible](https://www.sciencedirect.com/science/article/pii/S0022316622158554#s0015), and thus phosphatidylcholine cannot be made from TMG. \~150mg of TMG is equivalent to one egg worth of choline.
* Do not confuse 'betaine anhydrous' with 'betaine HCL': betaine HCL is not usable for this purpose.
* 1/2 tsp of TMG powder is \~1500mg of TMG.
* TMG has little to no taste, so it is easy to add to liquids or food.
* TMG is a methyl donor. People with slow COMT or who are sensitive to changes in methylation should consider starting with small doses (e.g., 1/8 tsp or less) of TMG powder and slowly increment the dose over time.
* CDP Choline (aka Citicoline) - 18.5% choline content; thus 735mg of CDP Choline is equivalent to one egg worth of choline.
* Phosphatidylcholine - 15% choline content; thus 906mg of phosphatidylcholine is equivalent to one egg worth of choline.
* Alpha-GPC - 40% choline content; thus 340mg of Alpha-GPC is equivalent to one egg worth of choline.
* Choline Bitartrate - 40% choline content; thus 340mg of choline bitartrate is equivalent to one egg worth of choline. This form of choline reportedly is [less efficiently absorbed](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893749/) than choline in egg yolks. Consider taking a combination of choline bitartrate and inositol, as the inositol may prevent depression that some people have experienced with choline bitartrate. In fact, choline bitartrate and inositol are often combined together as a product.
* NOTE: A small percentage of people may experience depression from supplementing choline. So monitor your mood for any indication of this.
* Consider adding inositol as this may prevent depression due to choline supplementation.
* Some alternatives to supplementing choline would be sticking with food-based choline only, or trying alternative choline supplement forms, such as CDP choline, choline bitartrate, lecithin, phosphatidylcholine, or Alpha-GPC.



# PHASE 6 - Folate intake

* It is important to keep in mind that we are not trying to 'fix' MTHFR by taking folate.
* Why do we need folate?
* To supply folate for methylfolate production for the remethylation of homocysteine. Although the methylfolate production by MTHFR is diminished, it is not zero.
* To supply folate for methylfolate production to turn off the methyl buffer system. There are several control signals between the folate cycle and the methionine cycle to maintain proper methylation levels. This is one of those control signals.
* The folate cycle is involved in DNA repair and replication.
* The folate cycle participates in the biopterin cycle.
* The folate cycle performs the interconversion of serine and glycine.
* When to supplement folate?
* You are folate-deficient (per blood test).
* You were recently folate-deficient, and are still repleting your folate stores. This repletion may take several months, up to a year.
* Your diet is folate-deficient.
* You have folate absorption issues.
* Increase folate intake from food. This [NIH folate list](https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/#h3) may be helpful.
* Methylfolate supplements are a double-edged sword: while methylfolate is a readily usable natural form, it is a methyl donor and so may cause sudden changes in methylation which can result in side effects ranging from symptoms such as irritability, anxiety, headaches, fatigue to depression, depersonalization/derealization, and more. Yet, if side effects are minimized by careful dosing, that boost in methyl groups can create a sense of cognitive and mood improvement, at least in the initial weeks or months of the protocol.
* Methylfolate Dosing:
* Sublingual, or liquid drops, is the preferred supplement form. Sublinguals can easily be broken apart into 1/4 or 1/8 pieces to allow starting with small doses. For even smaller starting doses, liquid drops may be better.
* Typical sublingual methylfolate are 1000mcg. So, a 1/8 size piece (barely a crumb) is 125mcg.
* Sensitive people: Start with 125mcg once/day and see how it goes for several days. Increase next to twice per day. Increase next to 250mg twice per day, and so on.
* Very sensitive people: If even small amounts of methylfolate are causing issues and food folate is not enough, consider using the folinic acid form of folate. This is an unmethylated folate, also available as a sublingual. Follow the same incremental process above, starting at 125mcg.
* Very, very sensitive people: Use low-dosage liquid methylfolate and dissolve 1 drop in 10 equivalent drops of an oil (e.g., olive oil); this dilutes the folate drop by 10x. Then take just a drop of that diluted folate. Incrementally work your way up over time. See [this video segment](https://youtu.be/GT27aTx3A70?t=836).
* Less sensitive people: Start with 1/4 sublingual (250mcg) once/day at a meal and see how it goes for several days. Increase next to 250mcg twice per day at meals. Increase next to either 500mcg twice/day at meals or 250mcg 3 times/day at meals.
* Final dosage goal: This is highly individual. Some people may find that 500mcg (1/2 sublingual) per day suffices, some may find that 1000mcg or more is beneficial, and as noted earlier, some may find food folate alone sufficient. You need to monitor your own wellbeing and health to determine what is right for you.
* Folinic acid supplements are another natural usable folate form; however, folinic acid is not methylated, and still needs to be processed through MTHFR to become methylfolate. These factors make folinic acid much less likely to cause side effects compared to methylfolate.
* Folinic acid may not be advisable if you have significant slowdown of the MTHFS gene.
* Folinic acid dosing:
* Sublingual is the preferred supplement form. Sublinguals can easily be broken apart into 1/4 or 1/8 pieces to allow starting with small doses. For even smaller starting doses, liquid drops may be better.
* Typical sublingual folinic acid are 1000mcg. So, a 1/8 size piece (barely a crumb) is 125mcg.
* Sensitive people: Start with 125mcg once/day and see how it goes for several days. Increase next to twice per day. Increase next to 250mg twice per day, and so on.



# MAINTENANCE Phase - Ongoing Steps

* With all the preceding steps, we have now implemented our basic MTHFR 'stack':
* B2 (1.6-100mg/day), if C677T is involved.
* Glycine (3-10g/day)
* Vitamin A (as needed to reach RDA/day)
* Creatine (3-5g/day)
* Choline (1000-1500g/day, or as recommended by the [Choline Calculator](https://chrismasterjohnphd.substack.com/p/how-much-choline-should-i-eat-the))
* Half of the choline requirement may come from TMG.
* Folate source(s) (some combination of food, methylfolate, folinic acid)
* Monitor with blood tests as needed.
* Anecdote: 6-7 months after starting this protocol I rely almost entirely on food folate. I take methylfolate once/week, but I do not know if that is even necessary. Every person will have to gauge their own situation.
* B12
* Monitor with blood tests as needed, and supplement as needed, with hydroxocobalamin, adenosylcobalamin, or methylcobalamin forms of B12.
* Ongoing B12 supplementation is not needed if B12 levels are in the desired range and dietary B12 intake is adequate, unless you have specific reasons or doctor's direction to continue supplementing.
* NOTE: Methylcobalamin may still be problematic for some people who are very sensitive to excess methyl groups.
* Fine-tuning:
* You may find you need to adjust some of these components up or down over time, as your life changes or as your body adapts.
* Some people may want to experiment with additional methylation support, such as SAM (aka 'SAMe') to further optimize their health and mental state. Consider these as additional enhancements, rather than replacements for any of these stack components. Start with small doses and monitor.
* Pay attention to your body. You might find after a while that you have the urge to occasionally skip a day or more of some or all supplements. If this results in unchanged or even improved status, it may be a beneficial practice and/or a signal to revisit your supplement list and dosing regimen.



# Supplements Examples

* I provide this just as examples, not as endorsements. I have no financial interest:
* [Now Foods 100mg B2](https://www.amazon.com/Vitamin-100mg-Capsules-Riboflavin-Pack/dp/B002LIOHOE)
* [Now Foods Glycine Powder](https://www.amazon.com/dp/B0013OVZJW)
* [On Target Living Alaskan Cod Liver Oil](https://www.amazon.com/dp/B07JC7QZ69) (vitamin A)
* [Optimum Nutrition Micronized Creatine Monohydrate Powder](https://www.amazon.com/dp/B002DYIZEE)
* [Zazzee Extra Strength Citicoline CDP Choline](https://www.amazon.com/dp/B071KRRMTX)
* [EZ Melts Dissolvable Folate](https://www.amazon.com/EZ-Melts-L-5-Methylfolate-Sublingual-Vitamins/dp/B00VVQJNCI) or [Seeking Health L-5-MTHF Lozenge](https://www.amazon.com/gp/product/B00E0THMZS)
* [Seeking Health Folinic Acid](https://www.amazon.com/gp/product/B00UUEMZ4K)
* [Foods Alive Non-Fortified Nutritional Yeast](https://www.amazon.com/dp/B08BW8GC88) (general B vitamin support)
* [Best Naturals Betaine Anhydrous](https://www.amazon.com/Best-Naturals-Betaine-Anhydrous-Trimethylglycine/dp/B08NMSY353) (TMG Powder)

​

EDITS:

* 20231011 - Replace methylfolate timing advice 'take at mealtimes' with 'away from meals' based on interaction of methylfolate and the methyl buffer system. Reformat post with large text section headers. Add notes under glycine. Add comments in Phase1 & Maintenance about methylcobalamin. Add folate trap comments in Phase1. Other minor cleanup.
* 20231105 - Add 'About MTHFR' section.
* 20231122 - Add reference and video links for riboflavin.
* 20231128 - Add hypothyroid comments under B2 section.
* 20231202 - Change magnesium glycinate to a glycine source with reference. Add references for creatine production burden. Minor text changes.
* 20231205 - Update riboflavin doses to include the research 1.6mg dose. Update creatine dose from 5g to 3-5g.
* 20231209 - Add reference link for choline-to-TMG irreversibility.
* 20231218 - Major revision of the choline phase, based on Chris Masterjohn's [choline article](https://chrismasterjohnphd.substack.com/p/choline).
* 20231220 - Add note about collagen missing tryptophan. Add note about not confusing betaine anhydrous with betaine HCL.
* 20231222 - Add Summary/TLDR section.
* 20231230 - Rewrite folate phase to clarify that folate supplementation is conditional, not required.
* 20240115 - Add choline bitartrate as a choline option. Add link to Masterjohn article re creatine causing insomnia.
* 20240214 - Add suggestion to try adding inositol if choline supplementation causes depression.
* 20240025 - Add AIMS section. Add creatine HCL as an alternative form of creatine.

Thanks Blossom, that was very interesting...

 

[Highserotonin90]

@mosaic01 Can you clarify the conversion between units and mcg? what should I look at on cronometer? Does cooking a hard-boiled egg eliminate some of the retinol compared to eating it almost raw?