MTHFR Protocol – Personalization by Chris

Masterjohn
Step 1 is to calculate your choline requirement.
The logic here is as follows:

 MTHFR is an enzyme, which is a type of protein that can help us convert one thing to another within our
bodies. MTHFR helps us form methylfolate from unmethylated folate. Methylfolate is then able to pass on its methyl
group to vitamin B12, which then passes it on to homocysteine, forming methionine. Methionine is then activated,
allowing it to methylated hundreds of other things.
 We have another way to do this: we have a different set of enzymes that will convert choline to another
compound known as betaine, also known as trimethylglycine (TMG), and use the TMG to convert homocysteine to
methionine. This makes choline or TMG an alternative to folate and B12.
 We would expect, then, that someone with low MTHFR status would have an increased need for choline.
 Studies have shown this to be true. One study, for example, found that women with poor methylfolate
production required 930 milligrams per day (mg/d) of choline rather than the standard recommendation for women of
425 mg/d.

The MTHFR protocol I sent you by default calls for 1000 mg/d of TMG. This is a little higher than the 930 used in the
study I just cited, which allows for a more general recommendation independent of sex and body size, and is easy to
reconcile with the fact that most TMG supplements are 500 mg per capsule. So, this would be two capsules per day. It
uses TMG rather than choline because TMG is what we use most directly for methylation.

However, you can personalize this dose using my free choline calculator if you have a 23andMe or Ancestry genetic
test. All you have to do is upload your raw data file into the calculator and within a minute or so it will give you a
recommended choline intake. This is based on a calculation from several genes that impact methylfolate levels,
including but not limited to MTHFR.

I recommend using the "file>print" and "save as PDF" functions to save both pages of the results, both under "Just
Gimme What Works" and "Advanced Stuff" and saving it somewhere. We will return to the results later to further
personalize your protocol.

If you don't have a genetic file, don't worry. A default intake of 1000 mg/d TMG is an excellent starting place, and you
can always tweak your dose later based on what you feel is providing you with the most benefit.

In step 1 of personalizing your MTHFR protocol, we used my free genetic choline calculator to calculate how much
choline you should get.

The question now is what form of choline should you use? Should you get it from food, or do you need a supplement?
Should you use TMG instead of choline, as in the default protocol, or should you supplement with something else?

The Three Most Important Forms of Choline

Before we dive in, here are the three most important forms, all of which occur in foods, and all of which are also sold as
supplements:

 Betaine or trimethylglycine (TMG) is the best form to support methylation. Technically it isn't a form of

choline, but rather a substance that we make from choline in order to use in the methylation process.
 Phosphatidylcholine is the best form of choline to support liver and gall bladder health and to support fat
digestion.
 Alpha-glycerophosphocholine (alpha-GPC) is the best form of choline to boost levels of acetylcholine.
Acetylcholine is a substance that supports cognitive performance under sustained, focused attention; learning and
memory; relaxation (it is used in the "rest and digest" parasympathetic nervous system, the opposite of the "fight or
flight" response), and muscular power.
There are many other forms of choline that you can find in supplements, but none of them have highly specific benefits
like these three compounds do. More to the point, most other forms of choline can be turned into another substance
known as TMAO by our gut bacteria. Some researchers believe TMAO contributes to heart disease. I'm not at all
convinced of that, for reasons I described here and here, but why take the risk for no specific benefit?

How to Decide Which Form to Use

When deciding between the three above, there are two things to consider:

 Your genetics, if you have a genetic analysis available.

 Your signs, symptoms, and response to different foods and supplements.

Your PEMT Gene

If you were able to run a genetic file through my free choline calculator in step 1, take a look at the results for the
PEMT gene on the "Advanced Stuff" page. This gene is responsible for the synthesis of phosphatidylcholine.

If your results were white with a green -/-, then it probably isn't very important how much of your choline comes from
phosphatidylcholine. If your results were yellow +/-, then you should get at least 25% of your choline as
phosphatidylcholine. If your results were red +/+, you should get at least 50% of your choline as phosphatidylcholine.

If you don't have a genetic file, don't sweat it. You can still use the next part.

Your Signs and Symptoms

Regardless of your genetics, consider your signs and symptoms:

 If you have fatty liver disease, elevated liver enzymes, any issues with your gall bladder, or trouble digesting
fat, emphasize phosphatidylcholine.
 If you feel like your brain doesn't perform well when you need to focus for long periods of time, like you're
always in a fight-or-flight mode, or like your muscles are weak, emphasize alpha-GPC.
 If you feel like none of these apply to you and methylation is your one big issue, emphasize TMG.

Important Dosing Issues

If you're using supplements, it is important to note that the dose on the supplement may not always line up perfectly
with how you are calculating your choline requirement:

 When using TMG, you don't need to make any calculation. 1000 mg TMG counts as 1000 mg choline.
 Alpha-GPC is only 40% choline. When using it to meet the choline requirement, multiply the labeled dose by
0.4, or multiply the choline requirement you are trying to meet by 2.5. In other words, if you need 1000 mg of choline,
taking 1200 mg alpha-GPC only provides 1200*0.4=480 mg of choline. Alternatively, you could say that if you need
1000 mg of choline, you need to take 1000*2.5=2500 mg of alpha-GPC to get it.
Please note that the standard dose of alpha-GPC used to benefit the brain (for example, in this study) is 1200 mg, taken
partly with breakfast and partly with lunch, while the dose shown to improve muscular power (in this study) was a
single dose of 600 mg taken before a workout. So your dose of alpha-GPC should be somewhere between 600-1200
mg/d if you use it, and then you should get the remainder of your choline requirement from one of the other sources. By
the way, the reason it's taken with breakfast and lunch but not dinner is that acetylcholine-boosting has the potential to
mess with sleep.
 Phosphatidylcholine is only 13% choline. When using it to meet the choline requirement, multiply the labeled
dose by 0.13, or multiply the choline requirement you are trying to meet by 7.7. For example, if you are using a
supplement that says it provides 100 mg of phosphatidylcholine per capsule and you take ten capsules to yield 1000 mg
of phosphatidylcholine, this provides you with 130 mg of choline. Put another way, if you are trying to get 1000 mg of
choline, you need to get 7,700 mg of phosphatidylcholine. Now, you may be thinking, "that's a lot of capsules." I agree!
I would never bother with capsules of phosphatidylcholine. I think the easiest way to supplement is to use lecithin,
where a tablespoon of granules provides about the amount of phosphatidylcholine in one egg yolk (around 135 mg) and
it can be blended into sauces or smoothies. But phosphatidylcholine is the main form of choline found in food, so eating
egg yolks and liver is actually the easiest way to get it.

Finally, many people who are taking betaine HCl to increase their stomach acidity and improve their digestion ask me
whether it contributes to their TMG. The answer is yes: betaine HCl is 76% betaine, so just multiply the amount of
betaine HCl you are using by 0.76 to see how much betaine it gives you. Remember, betaine and TMG are the same
thing.

Getting Choline and TMG From Foods

If you want to focus on food rather than supplements, in addition to the food recommendations listed in the MTHFR
protocol, check out my choline database. It allows you to search for specific foods, search within categories, or do a
blank search to rank all foods by total choline, or by any specific form of choline. You can even rank foods by TMG or
count the choline as "total egg yolk equivalents."

Quick Story and Further Reading

Here's a quick story.

Way back when I was in graduate school (I got my PhD in 2012 and you can read more about my academic
credentials here), my advisor was invited to write a review on green tea and non-alcoholic fatty liver disease for the
journal Nutrition Reviews. He essentially passed this task on to me, and I became the first author of the review, which is
published here.

When I research something, I research it to death. I just get obsessive until I completely understand the issue.

There were many nearly sleepless nights while I was writing that review. I remember one time I had a section due at 8
AM. I was up till about 7:45 AM working on it in the grad student office, then brought it upstairs to my advisor's office,
then went home to take a nap.

Anyway, many of those early-morning after-midnight hours were spent researching the role of choline in fatty liver
disease, which took me even as far back as research published in the 1700s! All of this became just a single
paragraph in the review!

So where did the rest of it go? It became this series of blog posts:

 Does Your Liver Look Like an Eskimo's Dinner? Fatty Liver Is a Silent Epidemic
 The Sweet Truth About Liver and Egg Yolks — Choline Matters More to Fatty Liver Than Sugar, Alcohol,
and Fat
 Does Choline Deficiency Contribute to Fatty Liver in Humans?
 Meeting the Choline Requirement — Eggs, Organs, and the Wheat Paradox

If you are interested in fatty liver disease, these posts are still a great read!

Allright, now that we are done with personalizing your choline intake, let's move on to personalize the dose and form of
folate you use tomorrow.

Today is time for step 3 in personalizing your MTHFR

protocol: which form and dose of Folate (B9) should you use?
As a default, it is best to pick a methylfolate supplement that has roughly 400 micrograms of dietary folate equivalents
(mcg DFE) per capsule. This lower dose (compared to, say, 1000 mcg DFE) will allow you to take it twice a day rather
than taking it all at once.
This is important because the goal is not simply to get a certain amount of methylfolate into the system. The goal is
actually to keep a slow drip of methylfolate into your system that lasts most of the day, so there is always some around.
The reason this is important is that methylfolate helps prevent you from losing glycine, and glycine helps stabilize the
methylation system, preventing swings back and forth in mood, mental state, and energy.

So, if you take a low dose at the end of breakfast and another low dose at the end of dinner, that will help spread the
dose out across the day to create the slow steady drip that you want.

Methylfolate is the same as 5-MTHF, L-5-MTHF, or L-5-methyltetrahydrofolate.

There are two cases where I think it makes sense to use something other than a 400 mcg DFE per capsule methylfolate:

 On a complete blood count (CBC) ordered by your doctor, your mean corpuscular volume (MCV) is
consistently elevated and it does not respond well to 800 mcg DFE/d methylfolate. In that case folinic acid would be a
better choice. Keep the dose the same. Folinic acid is better here because it is closer to the form of folate used for DNA
synthesis, and when that unmethylated form of folate is missing, blood cells can't divide as readily, they become larger,
and the larger size is reflected in the elevated MCV.

 If methylfolate makes you angry or depressed, or causes other symptoms you associate with
“overmethylation,” you may benefit from starting with a very small amount of methylfolate, adjusting to it over the
course of one to four weeks, and then slowly building up. The best way to do this is with Holistic Health liquid 5-
MTHF, where you can start with one drop providing 72 mcg, and work up by one additional drop every one to four
weeks. When taking multiple drops per day, spread the drops out as evenly across the day as possible.

o If even one drop causes problems, you can dilute it down to 7.2 mcg per drop by mixing one drop
with ten drops of olive oil or another edible oil you use. If doing this, work under as little light as possible (or best,
under a red light), don’t take longer than needed, and don’t mix it more than is needed to make it homogeneous. Make
this in small batches, and store the diluted liquid away from light and preferably in the refrigerator until used up.

Now that we've personalized the form and dose of both choline and folate, it's time to personalize the glycine portion of
the MTHFR protocol.

The Importance of Glycine to MTHFR

Here's the importance of glycine for MTHFR in a nutshell:

 Glycine is your endogenous buffer of methyl groups. When the supply of methyl groups is high -- for example,
after you just ate a methionine-rich steak -- you will get rid of the extra methyl groups by methylating glycine. You
never methylate glycine because you have too much glycine. Rather, you methylate glycine because you have too many
methyl groups.
 If you only methylate glycine a little bit, glycine can hold on to the methyl groups and save them for later. For
example, five hours after you ate the steak, when you are done digesting it and have no more incoming methionine until
your next meal. Glycine can then release the methyl groups it had stored when the supply of steak was still rich.
However, if you methylate glycine too much, you will pee out the methylated glycine and lose it forever.
 Losing glycine is double trouble. The first problem is that if your glycine levels run too low, you become
vulnerable to swinging back and forth between undermethylation and overmethylation. This is because you can't buffer
the supply of methyl groups: you can't remove them when there are too many, and therefore you can't hold on to them
for when there aren't enough. The second problem is that glycine does lots of other important things and now low
glycine levels will hurt those other things too.
 Glycine is a major component of collagen, so it is needed for healthy bones and skin. Glycine supports the
liver's detoxification processes, helps us digest fats, and stabilizes our blood sugar. Finally glycine acts as a
neurotransmitter, where it plays a role in calmness and sleep.
 When our methyl supply is low, we do not want to methylate glycine. In those cases, we use methylfolate as
the off-switch for the glycine buffer system. If our MTHFR activity is low and we don't have enough methylfolate, that
off-switch will be dysfunctional. We will methylate glycine whether we need to or not. This will cause us both to lose
methyl groups when we need them, and to lose more glycine in the urine than we should.

While the most important thing to do is try to stop the loss of glycine by keeping methylfolate levels adequate, there's
no guarantee that we will put a stop to the loss of glycine.
Glycine: What Our Grandparents Were
Eating
More to the point, even people whose MTHFR works perfectly fine are likely to need more glycine.This is because we
have changed our collective eating habits as a society to move away from nose-to-tail and toward skinless, boneless
chicken breast. Nose-to-tail diets balance the methionine-rich muscle meats with the glycine-rich bones, cartilage,
tendons, and skin. Skinless, boneless chicken breast provides an excess of methionine-rich muscle meats without any of
the glycine-rich parts to balance it.

The glycine part of the MTHFR protocol is emphasized because poor MTHFR activity causes glycine loss. But even if
we get methylfolate levels to where they should be, the amounts of glycine found in the protocol would benefit most
people anyway and are basically similar to what we would get if we were eating nose-to-tail like our grandparents and
their grandparents did.

Personalizing the Glycine Part of the Protocol

There are two questions we will tackle when personalizing the glycine part of the protocol:

1. What form of glycine should you use? Gelatin? Collagen? Bone broth? Glycine powder?
2. When should you think about changing the dose from the default used in the protocol?

Which Form of Glycine

The default recommendation in the protocol is that you can choose whichever source of glycine you prefer.

Your preference in this case could come down to taste, texture, or functionality. Glycine powder is sweet, and you
might like it as a sugar substitute in your coffee. Gelatin can be mixed into home-made gummy deserts. Collagen mixes
with water best if you want to down it quickly or mix it into a smoothie.

However, there are some good health-related reasons to choose certain forms over others:

 Gelatin (plus 48 milligrams of vitamin C) is what has been used prior to exercise to improve collagen
synthesis in the joints. Gelatin is nothing other than collagen that has been unwound from its spiral shape using heat.
When gelatin, collagen, or hydrolyzed collagen are digested, they are broken down into building blocks that are more
easily made into collagen than the pure amino acids. Presumably, this is the advantage of gelatin for the joints, and
presumably, collagen and hydrolyzed collagen have the same advantage.
 Some hydrolyzed collagen supplements are broken down enzymatically, and others are broken down with
heat. I have had some consulting clients that get digestive distress from heat-processed collagen supplements but do fine
with enzymatically processed ones. Examples include Thrive Market and Vital Proteins. If you get digestive distress
from certain collagen or gelatin supplements, you may want to go with an enzymatically processed hydrolyzed collagen
product.

 Glycine powder is what has been used to improve blood sugar and sleep, and with high doses,
even schizophrenia.

 Gelatin and collagen contain hydroxyproline, which can raise oxalate levels. Glycine powder does not have
this substance. Vitamin B6 probably helps prevent this, but if you suffer from kidney stones or have high levels of
oxalate in your blood and urine, glycine powder is probably the best form to use.

From this we could say the following:

 Use gelatin, collagen, or hydrolyzed collagen before exercise with about 50 milligrams of vitamin C or food
providing the equivalent of that when trying to benefit joint health.
 Use enzymatically processed collagen such as Thrive Market or Vital Proteins if you otherwise have
digestive trouble from gelatin or collagen.
 Use glycine powder to improve blood sugar or to gain benefits associated with glycine's function as a
neurotransmitter, such as sleep, or stabilizing mood or mental state; or, use glycine powder if you are at a high risk of
kidney stones or have elevated oxalate levels.

Otherwise, it doesn't really matter, and just go with what you like better.

What Dose of Glycine?

The dose of glycine to improve sleep was 3 grams, although one of my consulting clients reported sleeping better only
when she raised the dose to 6 grams.

The dose used to improve blood sugar ranged from 3.6 to 5.4 grams with a single meal, and another study showed that 5
grams per day improved inflammation in people with diabetes.

The study using gelatin with vitamin C before exercise to improve collagen synthesis in the joints found that 15 grams
of gelatin was effective but 5 grams was not. 15 grams of gelatin provides about 5 grams of glycine.

The studies showing glycine has an antipsychotic effect in schizophrenic patients generally use about 60 grams per day
of glycine. The one I linked to above started with 14 grams per day divided into 3 doses, then it increased the dose by
14 grams per day every other day until reaching 56 grams per day.

Thus, it appears that the minimally useful dose of glycine is 3-5 grams, which is the equivalent of 9-15 grams of gelatin
or collagen.

If glycine or the equivalent gelatin or collagen were used at three meals a day, before sleep, and before a workout, this
would add up to 15-25 grams of glycine. Given the studies in schizophrenia, up to 60 grams per day appears to be safe.

I would say, then, that the therapeutic range outside of schizophrenia seems to be between 3 and 25 grams per day,
though generally no more than 6 grams at a time.

It is notable that our ancestors ate nose-to-tail and didn't throw out collagen-rich parts of an animal. Animal protein is
usually 25-30% protein, so our ancestors likely consumed roughly a quarter of their protein as collagen. If they
consumed 50-100 grams of muscle protein per day, they would consume 12.5-25 grams of collagen per day, yielding
about 4-8 grams of glycine beyond what is found in the meat, roughly equivalent to two "therapeutic" doses of glycine
per day as described above.

One sign you might need to increase your dose of glycine beyond what is in the protocol or what you've arrived at from
reading the information I just gave you: if you find that you swing back and forth between different moods, mental
states, or energy levels in response to methylated B vitamins, this may be a sign you need more glycine. I would try
adding 3 grams per day and stay on the new dose for a week before adding another 3 grams per day, and continue that
to see if increasing it over time helps.

Does Timing Matter? With a Meal or

Without?
If we follow the research studies I linked to above, we can say the following:

 When used for joint health, 15 grams of gelatin or collagen and something providing about 50 mg of vitamin C
should be taken 1 hour before exercise. This is because the exercise helps pump the amino acids into the joints.
 When taken for sleep, glycine at least 15 minutes but no more than one hour before bed.
 When taken for blood sugar, glycine should be taken with a meal, with the effect being most relevant to your
blood sugar in the hours after that particular meal.

One other note: although studies on blood sugar show that taking glycine while fasting does not cause hypoglycemia,
one of my consulting clients has reported getting hypoglycemia from it. Thus, while I believe this is rare, it appears
some people do get low blood sugar from taking glycine, and they might do best ensuring that glycine is always taken at
the end of a meal that contains some healthy carbs.

Other than these concerns, the timing shouldn't matter much. For example, if you find glycine to be calming or to help
you focus, but it doesn't ever impact your blood sugar, then there is no particular reason not to just take some when you
feel you need it.

That's it for glycine! Tomorrow we tackle riboflavin.

We are now on to step 5 of personalizing the MTHFR

protocol: the Riboflavin (B2) recommendation.
The logic of including riboflavin, also known as vitamin B2, is this:

 Riboflavin is a cofactor for MTHFR. It is physically part of the MTHFR enzyme and plays a direct role in
forming the methyl group of methylfolate.
 The C677T variation of MTHFR binds to riboflavin less strongly than the normal version of MTHFR. This
suggests that the C677T variant may only produce low MTHFR because of the poor riboflavin binding, and that if we
get extra riboflavin to compensate, we might "fix" the MTHFR.
 People with low MTHFR activity only have elevated homocysteine (a sign of poor MTHFR activity) if they
also have poor riboflavin status.
 Supplementation with 1.6 milligrams per day of riboflavin lowers homocysteine in people with the MTHFR
C77T variation, but not in people with the normal version of MTHFR.

All this together suggests that enough riboflavin can fix a poorly working MTHFR, even when the underlying reason is
genetic.

While the dose used to lower homocysteine in the study I linked to above was only 1.6 milligrams, we have to keep in
mind that the average person is already eating 2.6 milligrams per day, suggesting the total dose needed to lower
homocysteine in low-MTHFR folks could be over 4 milligrams.

The protocol assumes you already have some other reasons to need more riboflavin, so rounds this up to 5 milligrams
per day.

But what are the reasons you might need a higher riboflavin intake? That's where the personalization comes in.

Here are some things we know increase your need for riboflavin:

 Dieting and exercise both increase the need for riboflavin, and when weight loss diets are combined with doing
a half hour of cardio five or more times a week, they increase the requirement by 27%. Note that if dieting, you are
eating less food, and therefore eating less riboflavin when you actually need more.
 Infants with jaundice are treated with phototherapy, but since light destroys riboflavin, this can
cause riboflavin deficiency. Although no one has directly studied the issue, it's almost certainly the case that spending a
lot of time in the sun, using phototherapy for eczema or psoriasis, or using tanning beds increases your need for
riboflavin.
 Burning fat requires 89% more riboflavin than burning carbohydrate, so it's likely that eating a high-fat diet
increases your need for riboflavin.

This is largely an educated guess, but I would suggest that if none of the above apply to you, even with MTHFR you
might get away with 3 milligrams per day, while you should add an additional 0.3-0.5 milligrams per day for each of the
bullet points that apply. This would place the personalized riboflavin intake for low-MTHFR folks between 3 and 5
milligrams depending on how many of these other issues apply.

So you might need a bit less than the protocol suggests, but the 5 milligrams should be plenty for almost everyone.

But when would you need to get more?

The main reason is if you suffer from migraines. 200-400 mg/d are used to treat migraines without any known adverse
effects, and doses under 200 milligrams do not seem to be very effective.
In these cases, the high dose is probably helping fix something broken inside the mitochondria, the so-called "power
house of the cell."

Far less common than migraines, there are rare genetic disorders in riboflavin metabolism that are treated with 10
milligrams per kilogram bodyweight per day, which would be 700 milligrams per day for the average adult, and up to
1500 milligrams per day have been used for children with extreme cases.

Surprisingly, some genetic disorders have turned out to be treatable with high-dose riboflavin even when the disorders
themselves have nothing to do with riboflavin metabolism. This is because riboflavin helps proteins fold into three-
dimensional shapes correctly, and enough riboflavin can reverse some genetic disorders where the problem is that
certain proteins fold up the wrong way.

While I can't back this up with an air-tight case, it's my suspicion that there could be many strange, unresolved health
problems that respond to high-dose riboflavin like migraines do. So, if you have such a problem, it's a shot in the dark,
but that might be a reason to try high-dose riboflavin.

Is there any danger? While studies using high-dose riboflavin suggest it is overwhelmingly safe, I did have one person
who once asked me if it can cause headaches, since it seemed to cause her headaches. It's  possible that riboflavin could
cause some adverse effects by stealing away other B vitamins that it cooperates with from other important roles. So,
given the possibility of imbalances, I don't think we should resort to high-dose riboflavin unless we have a good reason.
Still, it's a very safe thing to try when there is a good reason.

So far we have personalized every essential component of the MTHFR protocol except the creatine.

The reason that creatine is included is as follows:

 About 40% of your methylation is used to synthesize creatine.
 When supplementing with creatine, we can expect creatine concentrations of our muscles and many other
tissues to increase for about eight weeks, and after everything settles down to a new equilibrium, we should be
synthesizing a lot less creatine because we are getting it as a supplement. That would suggest creatine supplementation
could eliminate the need for roughly 40% of our methylation. This would help us conserve methylfolate.
 In support of this, we have a case study where someone who was homozygous for MTHFR C677T cut his
homocysteine down from 33 to 17 after a month of creatine supplementation. Similarly, creatine decreased
homocysteine from 12 to 9 in a group of athletes, Even in some studies where creatine doesn't lower homocysteine, it
still reduces the demand for methylation, which is the reason it is included in this protocol.

Creatine personalization basically comes down to these options:

 You can exclude creatine if you consume 2-3 pounds of meat per day. However, as the protocol states, doing
this can raise your need for glycine even further. When eating a diet very rich in meat like this, match each 100 grams
of protein you eat with an additional 3 grams of glycine over and above what the protocol calls for.
 There's a very high chance you will gain some weight in the form of better water retention in your muscles,
which makes them stronger. If you don't like this, you can choose to exclude creatine from the protocol. This may make
it a little harder to conserve methylfolate and might require increasing the doses of TMG/choline or folate, or spreading
out folate into more frequent smaller doses, but it won't stop the protocol from being effective.
 If you experience adverse effects from the creatine, such as bloating or insomnia, these will probably resolve
themselves if you lower the dose to something that doesn't cause much discomfort and keep using it for a month or two.
However, you can always choose to exclude something if it bothers you, and you should always listen to your body and
hold the signals it gives you as more important than anything you read from me or anyone else. When lowering the
dose, you can calculate 2% of your bodyweight in kilograms, divide that by 1000 (which is the same as converting
kilograms to grams), and use that as your minimum daily dose. To calculate this, you first need your weight in
kilograms. If you usually measure your weight in kilograms, you already have this. If you usually measure it in pounds,
divide your weight in pounds by 2.2. Once you have the kilogram weight, multiply it by 0.02. Although your answer is
technically in kilograms, use this as the grams of creatine in your minimal daily dose (which is the same as dividing it
by 1000). For example, if you are 154 pounds, you are 70 kilograms, and 70*0.02 is 1.4. Your minimal daily dose
would be 1.4 grams. You can also experiment with even lower doses, but you are unlikely to reap the full benefits
without reaching the minimal daily dose as just calculated.

Congratulations! Now that we have personalized creatine, we've personalized each and every essential component of the
MTHFR protocol!
Does that mean we're done?

Well, we've reached a milestone.

But we're not done.

Why?

Two reasons:

 We've based everything so far on the status of your MTHFR gene. We not only have about 30,000 other genes,
but genes just tell us what our predispositions are, not what is actually happening within our bodies. As famously said
by Judith Stern, Distinguished Professor of Nutrition and Internal Medicine at the University of California,
Davis, "genetics loads the gun but the environment pulls the trigger." This interaction between roughly 30,000 genes
and uncountable triggers in our diet, our lifestyle, and our many other interactions with our environment produces the
biochemical events that actually happen within our bodies, so we need to cover ways to test  what is actually
happening within our bodies.
 Context is everything. There are over 30 essential nutrients we need to be optimally healthy, and our system
is only as good as the weakest link in the chain. If any one nutrient is deficient, present in excess, or imbalanced with
other nutrients, neither MTHFR nor any of the other thousands of enzymes that support our life and health will function
optimally.

Tomorrow, I will cover the ultimate personalization: using lab tests to understand what is actually happening within our
bodies.

So far we have personalized all the essential elements of the MTHFR protocol.

This is a major milestone.

And yet, it's just the beginning.

As I mentioned in yesterday's email:

 Genes like MTHFR just load the gun; our diet, lifestyle, and all of our other interactions with our environment
pull the trigger (a paraphrase of Judith Stern).
 Context is everything. We are only as good as the weakest link in our chain. Any deficiencies, toxicities, or
imbalances of the more than 30 essential nutrients will limit the function of one or more of our roughly 30,000 genes.
As a result, neither our MTHFR nor our body as a whole will be able to support our maximal health, well being, and
performance.

How Common Are Nutrient Deficiencies?

And just how likely is it that our nutrition needs some adjustment?

When scientists ask people in the United States what they eat, a whopping 93% fail to consume enough of at least one
vitamin or mineral.

Scientists have also studied the number of Americans who have evidence of serious nutrient deficiencies showing up in
their blood tests. When they do this, 31% of Americans have at least one deficiency and over 6% have multiple
deficiencies.

Unfortunately, when looking at people who represent the entire population at large, we only have blood tests for 8
nutrients, and there are more than 30 that we need. Since these blood tests look for serious deficiencies, and since most
of the nutrients haven’t been measured, it’s likely that far more than 30% of Americans have a health problem that
could be solved by fixing a nutrient deficiency.

In other words, the problem is at least as bad as the data make it sound.

So:
 The blood tests show us that at least 30% of us have at least one serious nutrient deficiency.
 The dietary surveys show us that most of us could do a much better job getting our nutrients in.

Our Unique Needs Change Over Time

When I first sent you the MTHFR protocol, I listed two of the most important insights of my career:

1) your needs are not mine, and mine are not yours; we are each unique.

2) my needs are not what they were ten years ago and yours are not what they will be in ten years;  our needs change
over time.

One of the examples I gave in my story that I shared with you in the two emails that followed was how organ meats and
red meat were instrumental in my recovery from veganism, yet contributed to my iron overload once I reached my late
20s, until I started giving blood. I never would have figured out how my needs changed over time if I hadn't figured out
the right blood tests to run. Had I known my genetic predisposition to iron overload in the first place and never done
any lab testing, I might have even prevented myself from ever recovering from my vegan diet. The reality is
I needed the iron-rich animal foods at one point in my life, and at another point my needs changed, and I needed
to limit them unless I took other measures to manage my iron overload.

Iron can be particularly hard to understand without proper testing, because many of the signs and symptoms of iron
overload are the same as those of iron deficiency!

For example, both iron overload and iron deficiency can cause fatigue, dizziness, depression, and hair falling out.

Both of them can mess with the thyroid: iron overload, because it causes oxidative stress that damages the thyroid
gland; iron deficiency, because iron is a cofactor for the enzyme that uses iodine to make thyroid hormone.

There are other symptoms unique to each condition that can help tease them apart. For example, joint pain, high
cholesterol, and menstrual problems are more likely to occur with iron overload, and pale skin is more likely to occur in
deficiency. But some of these take a long time to manifest and none of them are very specific. Very rarely would any
doctor think you have an iron problem because your cholesterol is high. If they are hard to tell apart, then it can actually
be dangerous to try treating either one, because you have a 50/50 chance of making the problem worse.

The solution? Testing!

Yet testing for iron issues is often inadequate. If your doctor runs a yearly complete blood count with an annual
physical, you will get markers of iron-deficiency anemia. You may even get your ferritin checked. Far less common is
the far more useful marker, transferrin saturation, measured. And when it is, the lab range used is so wide (20-50%) that
it becomes hard to see a problem until it's bad. Once you understand that optimal transferrin saturation is 30-40%, you
can identify iron problems before they get bad.

In my case, finding my transferrin saturation at 55% was the key finding that led to the completely game-changing
realization that I needed to start donating blood.

Iron and Methylation: An Example of a Hard-

to-Detect Problem
And how does this all play into methylation?

One of my consulting clients had a very stubborn case of see-sawing between undermethylation and overmethylation.
Glycine helped, but he remained so sensitive to methylfolate supplements that he wound up getting a compounding
pharmacy to make him a low-dose time-release methylfolate with only 25 micrograms per tablet!

All of this began to change once we realized he had a hard-to-detect iron deficiency. His functional medicine
practitioner gave him a few iron infusions and suddenly his methylation started balancing out.
Why would that be the case?

As I mentioned in the glycine email, glycine is our endogenous methyl buffer. When we have too many methyl groups,
glycine soaks them up. As long as we don't overburden the glycine buffer system, glycine will be able to release them
later when we don't have enough. The enzymes that free up these methyl groups from glycine are iron-dependent.

So, without iron, glycine will soak up the methyl groups when there are too many, but it won't be able to release them
when there aren't enough!

And if glycine doesn't release them, then eventually all the glycine will get methylated, and if you don't replace it,
glycine will stop soaking up the extra methyl groups too.

Why was my client's case hard to detect?

Because his doctors put too much emphasis on the fact that his ferritin was running high. Ferritin is not a specific
marker of iron status. It increases in inflammation to stop iron from feeding infectious bacteria that might be present,
and it increases during oxidative stress because unhinged iron running around freely can make oxidative stress much
worse.

My client had oxidative stress and inflammation that explained the high ferritin, and it was his low transferrin saturation
that gave it away.

Self-treating an issue like this without a doctor is dangerous. In some cases a person could have an actual systemic
infection and an iron infusion could make it dramatically worse. My client's doctors were present and involved the
whole way through.

But, I was able to help break through their fixation on the ferritin as a marker of iron status, and this was because of my
expertise in nutritional sciences, the basic science of how vitamins and minerals work within the body.

Doctors Aren't Well Trained in Nutrition

While it is critically important to see a physician for your annual check-up and while you should never contradict
medical advice to act on anything I have to offer in my educational services, it is also the case that  doctors are not well-
trained in nutrition.

Medical schools are not required to teach anything about nutrition. The average medical student receives only 19 total
hours of training in nutrition over the course of four years, with little or no additional training once their schooling is
done. In fact, 95% of doctors say it is their responsibility to counsel patients on nutrition, yet a whopping 90% also say
that they didn’t receive enough training to do so properly.

While doctors do sometimes refer patients to dietitians, this happens rather rarely. For example, in the United States,
only ten people out of a thousand see a dietitian within a hospital, and only three people out of a thousand see a dietitian
at a doctor’s office.

Unfortunately, doctors are often the gateway to getting lab tests. In most of the US, direct-to-consumer services such
as directlabs.com can get around that.

However, no one actually has the expertise to interpret nutritional lab tests! Doctors receive very little training in
nutrition, consumers who want to order testing direct have no such training at all, and dietitians advise people what to
eat but ordering lab tests is considered outside their scope of practice.

That means that, while cooperating with your doctor is important, when it comes to nutrition, you need to take
managing your nutritional status into your own hands and you need to learn the ropes for interpreting nutritional lab
tests.
My Background: Research Into Nutritional
Biomarkers
I earned my PhD in Nutritional Sciences from the University of Connecticut at Storrs in 2012. I went on to do my
postdoctoral research at University of Illinois at Urbana-Champaign until 2014, and from then until 2017 I served as
Assistant Professor of Health and Nutrition Sciences at Brooklyn College in Brooklyn, NY.

One of the things my doctoral lab studied was, what makes a good biomarker? That is, what can we measure in
someone that will help us predict whether there is a nutritional problem that we can solve? If we try a solution, what can
we measure to know whether it's working?

What Makes a Good Marker of Nutritional

Status?
Oftentimes I hear health professionals expressing opinions like "everything should be measured in tissues, not in
blood." Technically blood is a tissue, but the reason this is wrong is because it actually has nothing to do with the basic
principles of what makes a good biomarker.

Good biomarkers of nutrient status are tested in depletion-repletion studies. For example, elegant studies have isolated
college students in dorm rooms for weeks on end and measured all kinds of things in their blood while they went on a
zinc-deficient diet, and then later went on a zinc-sufficient diet. Their symptoms were monitored, and the blood markers
were tested to see which of them could predict who would get symptoms when. We know from these studies
that plasma zinc is the best marker of zinc status, and we know exactly where the cutoffs for symptom development lie,
and where we need to be to have no risk of deficiency. These studies validated plasma zinc as a marker of zinc
nutritional status.

In this case the nutrient is measured in the blood, not in other tissues.

Yet the plasma concentration of a nutrient in other cases is not very useful. For example, plasma B6 is much more
reflective of your recent intake, whereas your urinary loss of certain breakdown products of the amino acid tryptophan
is actually the best set of markers of your B6 status.

In other cases, we really need to look at multiple markers. For example, serum folate mainly reflects your production of
methylfolate using MTHFR, while red blood cell folate reflects your total folate stores. By measuring both, we can see
whether your issue is you need more dietary folate, or instead that we need to better support or compensate for poor
MTHFR function.

Sometimes getting the wrong measurement can make people much worse. For example, I once was contacted on social
media by someone who had only been measuring red blood cell magnesium. They kept supplementing more, and it
would never budge from the low range. They were supplementing with 2000 milligrams of magnesium per day and
trying to figure out why their heart rate was becoming abnormally slow!

This approach is quite dangerous. If you don't measure serum magnesium and you only measure red blood cell
magnesium, you will have no idea whether RBC magnesium is low because you aren't consuming enough magnesium,
or because magnesium isn't getting into the cells. If magnesium isn't getting into the cells, it could be because you don't
have enough insulin, you aren't sensitive enough to insulin, or because you don't eat enough salt or have enough B6. But
if it doesn't get into the cells, where does it wind up? A lot of it winds up in your serum, and if you keep increasing the
dose without ever checking the serum level, the serum level could easily get high enough to start messing with your
heart rate.

Another problem I see is the desire to find quick ways to test everything at once. While this is certainly a desirable goal,
many people have started using a test where the lab takes out your white blood cells and tests how fast they grow with
and without the addition of nutrients. While there's no problem with wanting to test everything at once, the problem is
that techniques like this have never been validated in depletion-repletion studies, so we really have no idea what they
actually mean.
The Need for a Resource
Because of my expertise in nutritional biomarkers, in 2017 I started a podcast series on managing nutritional status. I
searched the literature far and wide for everything important to understanding what a nutrient does in the body, how we
know if we are deficient, toxic, and imbalanced, and how to measure and manage our status.

This included collecting the best, science-backed, validated biomarkers of nutritional status for each of the vitamins,
minerals, and essential fatty acids.

I was inundated with requests to make something simple people could buy that collected all the essential information
into one place.

While this started with the idea of a "cheat sheet" that would tabulate the best markers and ranges for each nutrient on a
single page, I realized while putting it together that interpreting the data properly required consideration of the diet and
supplements, as well as the signs and symptoms. While the best markers might fit on a page, a comprehensive guide to
using them had to be a lot longer than that.

So I call what I produced The Ultimate Cheat Sheet.

Context is everything.

There are over 30 essential nutrients we need to be optimally healthy, and our system is only as good as the weakest
link in the chain. If any one nutrient is deficient, present in excess, or imbalanced with other nutrients, neither MTHFR
nor any of the other thousands of enzymes that support our life and health will function optimally.

So let's open up this unexpectedly expansive universe of nutrients that contribute to methylation.

First, let's take a step back and define methylation.

A Brief Introduction to Methylation

All life on earth is made of carbon. Being made of carbon makes something organic. That's what the word "organic"
means in that high school class most of us were afraid of, organic chemistry.

Most molecules within our bodies are hydrocarbons. This means that they are a string of carbons attached to one
another, where each carbon in the string has the ability to bind to two or three other atoms, and most of those other
atoms are hydrogen.

The simplest way you can add a carbon atom to one of these molecules is to add a methyl group. A methyl group is a
single carbon with three hydrogen atoms attached. Since this is the simplest way you can add a single carbon atom to a
molecule, methylation is also known in biochemistry as one-carbon metabolism.

The role of MTHFR in all of this is to add a methyl group to the B vitamin folate (also known as vitamin B9) to
produce methylfolate. Methylfolate then passes the methyl group to vitamin B12, which passes it on
to homocysteine. This converts homocysteine to methionine.

This is why if you have low MTHFR activity, or you are deficient in folate or B12, your homocysteine will rise. High
homocysteine increases your risk of cardiovascular disease.

But the role of MTHFR is not just to lower homocysteine. It is also to make sure you have enough methionine to
support methylation. To do this, methionine gets activated using ATP, the basic unit of energy produced by our
mitochondria, the so-called "powerhouse of the cell," yielding SAMe. SAMe, which you can find as a supplement
online or in a supplement store or health food store, is the universal methyl donor for hundreds of different methylation
reactions.

Sometimes methylation is used to make something. For example, over 40% of methylation is used to make creatine,
which prevents depression, makes your muscles strong, supports digestion and healthy skin, powers your eyesight, and
powers sperm to swim up the vaginal canal. About 45% is used to make phosphatidylcholine, a form of choline that
lines your cell membranes, prevents fatty liver disease, maintains the health of your liver and gall bladder, and helps
you digest fat.

Other times methylation is used to regulate something. For example, methylation regulates dopamine in a way that
makes you less mentally rigid and more mentally flexible. This makes you less likely to ruminate on depressing or
anxiety-producing thoughts, and more able to fluidly move between mental states, which can prevent abrupt changes in
your mood.

Methylation is also used to regulate gene expression, usually to turn them down or turn them off when they shouldn't be
expressed.

Yet other times methylation is used to get rid of things. For example, we use it to detoxify a lot of nasty things, and we
use it to get rid of excess histamine. Too much histamine can cause acid reflux, allergy-like symptoms, anxiety, or
panic.

There are hundreds of different things like this that methylation does. So, at a bird's eye view, methylation is a process
that uses a variety of nutrients, especially B vitamins, to support our mental and physical health.

The Many Nutrients That Support Methylation

Biological complexity is like an onion.

You think you see it. But when you peel back a layer, you find another layer underneath. You peel that away, and
there's yet another layer. And another. And another.

We can do this with methylation to see all of the different nutrients involved.

MTHFR
Let's start with MTHFR.

We already covered how it's using folate and B12 to move methyl groups to homocysteine.

To make the methyl group on methylfolate, MTHFR also requires magnesium, vitamin B2, or riboflavin, as well as
vitamin B3, or niacin.

MTHFR doesn't actually transfer a methyl group to folate. Instead, it finishes making a methyl group on folate by
adding a hydrogen to it. Getting that hydrogen there in the first place
requires thiamin, calcium, magnesium, and glucose. Glucose is a sugar that we get from breaking down starch or
natural sugars in our diet, or that we can make mainly from protein.

But that's just the last hydrogen of the methyl group. We said above that a methyl group is one carbon and three
hydrogen. Where do the carbon and the other two hydrogens come from?

The carbon comes either from the amino acids serine or glycine, or comes from extra methyl groups from a previous
meal that glycine had been holding on to. Collectively, getting the carbon from these different sources requires vitamin
B6, zinc, lipoic acid, and iron, as well as three nutrients we have already mentioned: magnesium, niacin, and
riboflavin.

Getting the other two hydrogens of the methyl group requires potassium, as well as nutrients we've mentioned before:
niacin and magnesium. If you run low in magnesium, a different mineral, manganese, can step in to help.

So, just to get that methyl group on methylfolate so we can pass it on to B12 and then homocysteine already requires a
list of fourteen different nutrients!

These are folate, B12, magnesium, riboflavin, niacin, thiamin, calcium, glucose, vitamin B6, zinc, lipoic acid, iron,
potassium, and manganese.
Using Choline/Betaine as an Alternative
The MTHFR protocol includes choline or betaine (also known as trimethylglycine) to get around low MTHFR activity
by using these to support the methylation of homocysteine instead of folate, B12, and MTHFR.

This alone adds choline and betaine to our list of nutrients.

Yet, there's more.

The enzymes that help us use choline and betaine in this way depend on the familiar niacin, riboflavin, potassium, and
zinc, as well as two more nutrients we can add to our list: sulfur and coenzyme Q10.

Activating Methionine
In order to use methionine for methylation, we first need to activate it by converting it to SAMe.

This requires the familiar magnesium and potassium, but it also requires ATP.

And what is required to produce ATP?

Quite a long list of nutrients! In addition to ones we have mentioned, such as thiamin, riboflavin, niacin, B6, lipoic acid,
iron, sulfur, glucose, potassium, and coenzyme Q10, and to a lesser extent folate and B12, we also have critical roles for
vitamin B5, also known as pantothenic acid, vitamin B7, also known as biotin, and copper.

Additionally, our ATP production is very strongly regulated by thyroid hormone, and in order to make thyroid hormone
we need iodine.

So we can add B5, B7, copper, and iodine to our list.

Buffering Extra Methyl Groups

Glycine is in the MTHFR protocol because glycine is what we use to buffer extra methyl groups, and since methylfolate
is the off-switch for the glycine buffer system, low MTHFR activity can lead to overusing that system, which can
deplete glycine.

The buffer system adds another nutrient to our list: vitamin A is needed to produce the buffer system. If we don't have
enough vitamin A, we will be subject to symptoms of overmethylation.

Once those extra methyl groups are buffered, reusing them later requires folate, riboflavin, niacin, iron, vitamin B6,
lipoic acid, and magnesium. If we are missing any of these, we can become vulnerable to symptoms of
undermethylation.

Missing anything involved in the buffer system can make us vulnerable to swinging back and forth between
undermethylation and overmethylation like a seesaw.

Breaking Down Homocysteine

When we eat a meal that has a lot of methionine, such as a steak, we will wind up with too many methyl groups.
Glycine will buffer them, but this will leave us with homocysteine. Since we have too many methyl groups, we don't
want to recycle homocysteine to methionine. We want to get rid of it.

This isn't just taking out the trash. Homocysteine is broken down into building blocks that can be used to make
glutathione, taurine, and sulfate. Glutathione is the master antioxidant of the cell, a key detoxifier, and helps keep
mucous fluid in our airways and keep our bronchioles dilated, which prevents asthma. Taurine plays an essential role in
vision and has a calming effect in our brains, helping reduce anxiety and helping us get good sleep. Sulfate is used in
detoxification, and is used to regulate the action of many different hormones.

Breaking down homocysteine always requires iron and vitamin B6, and sometimes also requires folate and zinc.

Breaking it down, though, will generate stuff that really does need some cleaning up, especially sulfite and ammonia.

Sulfite is downright toxic. It can cause histamine release, leading to hives and other symptoms of allergic reactions. It
can increase our sensitivity to glutamate, which can make us overstimulated or hurt our ability to calm down and sleep.
It can cause deficiencies of thiamin and vitamin B6, and it probably plays a role in the morning sickness of pregnancy.

In order to turn sulfite, which is toxic, into sulfate, which is very useful, we need the mineral molybdenum.

While ammonia is necessary, too much of it can make our breath smell bad and cause fatigue.

There are various ways of getting rid of ammonia, and collectively, they require ATP, pantothenic
acid, sodium and chloride (as in sodium chloride, or table salt), potassium, magnesium, and manganese.

So we can add molybdenum and salt to our list.

Oxidative Stress
Oxidative stress is the wear and tear on our tissues as we age, which accelerates during disease, inflammation, or
exposure to heavy metals and toxins.

The master antioxidant of the cell is glutathione.

Since we need to break down homocysteine to make glutathione, oxidative stress will cause us to break down
homocysteine regardless of whether we have enough.

So, while everything I wrote above about "breaking down homocysteine" happens when we have too many methyl
groups, it also happens when we have oxidative stress, regardless of methyl groups.

That means that if we only have just enough methyl groups, or worse, we don't have enough, oxidative stress will steal
them away by breaking down homocysteine instead of allowing its recycling to methionine.

That means that in order to support methylation, we need antioxidant protection.

And how do we get that?

This relies on a network of different nutrients: vitamin E, vitamin C, selenium, and a number of nutrients we have
already covered: manganese, zinc, copper, iron, and magnesium. Antioxidant protection is also dependent on energy,
and that energy is transferred using niacin, riboflavin, thiamin, calcium, magnesium, glucose, and ATP.

What a Long List!

Just covering the basics, we already have a list 27 nutrients long!

Here's where we are so far: folate, B12, magnesium, riboflavin, niacin, thiamin, calcium, glucose, vitamin B6, zinc,
lipoic acid, iron, potassium, manganese, sulfur, coenzyme Q10, pantothenic acid, biotin, copper, iodine, vitamin A,
molybdenum, chloride, sodium, vitamin E, vitamin C, and selenium.

At this point, there aren't that many nutrients left!

But we will see that as we peel back the next layer of the onion, we will find more nutrients. For example, vitamin
D helps us make the enzyme that uses methylation to regulate dopamine and favor mental flexibility.
How many nutrients we see is limited only by how many layers of the onion we peel back.

This symphony of nutrient complexity is why I was making such a pitch for Testing Nutritional Status: The Ultimate
Cheat Sheet earlier. We are only as good as our weakest link, and context is everything. As we peel back the layers of
complexity, we realize the context includes everything. All the essential nutrients feed into an optimally working
methylation system.

I'm sure this seems a little overwhelming.

But I will break it down for you, and make it as useful as I possibly can. Over the coming weeks, I'll take off only a bite
we can chew each day, looking at one nutrient at a time. We will cover not just how it supports methylation, but what
else it is good for, how much we need, how to get it from food, which supplements to use and when, how to know if we
are getting enough, and what to do about it if we are getting too little or too much.

In my "The Other 25 Nutrients That Support Methylation" email, we saw how virtually every nutrient known is needed
to support healthy methylation.

In order to bring that high-level discussion down to earth, it's time to start breaking this down into bite-size chunks and
start making it simple and practical.

Since MTHFR operates in the context of some 30,000 other genes, and since methylation operates in the context of
many other complex systems, we should look at each nutrient holistically. We can't just look at what it does for
methylation. We need to look at what it does more broadly.

This isn't just for the sake of appreciating the nutrient. It has a very practical purpose: if we understand what else
vitamin A, for example, does for us besides support methylation, then we can have clues that will tell us if we are
getting too little or too much vitamin A. This will, in turn, help us understand whether a problem that seems driven by
methylation could actually be helped by better managing our vitamin A status.

For example, you might experience sensitivity to methylfolate supplements. This could be related to a problem with the
glycine buffer system. This could be a result of vitamin A deficiency, but how would you know? If you understand that,
for example, dry eyes are a tell-tale sign of vitamin A deficiency, and you happen to have a problem with dry eyes,
suddenly you can connect the dots in a way you would never have been able to do without understanding the broad
importance of vitamin A.

How Vitamin A Supports Methylation

The principal way vitamin A supports methylation is to signal our cells to produce the machinery of the glycine buffer
system.

This machinery is what allows glycine to soak up extra methyl groups when we have too much, and release them later
when we don't have enough. For example, if we eat a steak, there is a lot of methionine that comes in. It gives us more
SAMe than we need. Glycine takes the methyl groups and holds on to them. A few hours later, we no longer have
enough methyl groups because we have used the ones that came from the steak and we haven't eaten again yet. Glycine
releases them.

If we don't have vitamin A, we won't make the machinery that operates this buffer system. This will make us vulnerable
to overmethylation symptoms soon after eating and undermethylation symptoms when we are fasting.

Symptoms of overmethylation include distractibility, difficulty focusing, impulsivity, substance abuse, difficulty
breaking free from psychological conditioning, difficulty falling asleep or poor quality sleep, and faster aging skin.

Signs and symptoms of undermethylation include the following: fatty liver disease, neural tube birth defects, elevated
homocysteine and associated cardiovascular risk, fatigue, poor exercise capacity, histamine intolerance, difficulty
ignoring negative thoughts and thought patterns, depression, anxiety, obsessive compulsive disorder, histamine
intolerance, inability to adequately eliminate arsenic, inability to properly utilize selenium or excrete excess selenium.
Severe deficiencies in methylation could contribute to deficiencies of zinc, copper, and perhaps other positively charged
minerals.
Either of these extremes might contribute to cancer, and there are actually a number of other ways that vitamin A
protects against cancer.

If you've been using the Cheat Sheet, you will find all these symptoms collected under "Signs and Symptoms of
Imbalances" in the "B Vitamins Involved in Methylation" section.

But there is so much more to say about vitamin A!

Lots More to Say About Vitamin A

Do your eyes ever feel dry?

Or do you have trouble seeing at night?

Maybe your eyes are fine, but you get colds a lot. 🤒

Or your sleep is really messed up... like your body just doesn't know when it's time to sleep or time to wake up. Your
mind racing at night, and your eyelids drooping in the day.

Or maybe your skin gets crusty underneath your hair, or you get little bumps that look like goosebumps or acne but they
never go away.

How Vitamin A Makes Our Eyes Moist, Our

Skin Smooth, and Our Immune System Strong
All of these problems can be caused by too little vitamin A. Why? First of all, vitamin A lubricates your eyes. But
vitamin A isn't "wet." It doesn't moisten everything in sight. Instead, it's what your tissues use to develop properly. It's
how they "know" what they're supposed to do. It's a tool our cells use to know they are creating the right things and
putting them all in the right places.

They use it like we use mirrors. The mirror doesn't make your lips red, but try putting lipstick on without one and you
might look a little silly. 😬

Your eyes use vitamin A to become moist, but your skin uses it to become soft and smooth.

Then inside your throat, on the way down to your lungs, there are little "hairs" that catch all the junk and little microbes
you breath in and help you cough it all out. Vitamin A helps make those hairs! As if that weren't enough, vitamin A
helps your immune system become strong, making antibodies and virus-busting proteins. These help fend off any nasty
critters that made it past your moist eyes, your smooth skin, and your killer cough response.

And that is exactly how your cells "decide" to make the glycine buffer system, using vitamin A like a mirror to help it
know what it needs to make more of.

In technical jargon, cells making these "decisions" is called gene expression.

But... oh man... let's go back to the eye for a minute.

No, I mean, this is some crazy stuff going on in the eye. 👀

How Vitamin A Promotes Healthy Vision and

Healthy Sleep
Vitamin A is what your eyes use to sense light. When the light enters your eye, it hits a molecule of vitamin A, and that
triggers a reaction that sends an impulse to your brain. Your brain takes thousands of these impulses in any given instant
and integrates them together to make your sense of vision.

If you are deficient in vitamin A, you don't go blind... at least not at first.

Why?

Because you have two different types of cells in your eyes: rods help you see shadows in the dark, cones help you see
colors in the day. Vitamin A is equally important to both of them, but when you're running low, your body starts setting
priorities. Back before artificial lighting, there wasn't much to do at night. Chat by the fire, then hit the sack. Being able
to see at night wasn't that big of a deal. It was time to sleep. The day was time for hunting. Gathering. Making tools. So
we sacrifice our night vision when we become deficient in vitamin A. This helps make sure we have enough vitamin A
to see during the day.

And you know what ELSE light does in our eyes? Besides help us SEE??? 👀

It tells our brains that it's day time. Have you noticed the "blue-blocking" bandwagon so many people are hopping onto
lately? Like "Nightshift" on iPhone, "Night Mode" on Android, Flux on the computer, or those funky amber-colored
glasses the geeky guys (like me!) wear? These block the blue light from our light bulbs and digital screens. That blue
light tells our brains that it's day time. Just like vitamin A transmits light signals to the brain to help us see, it's vitamin
A transmitting these signals that it's daytime. So if you feel awake at night or tired during the day, one possibility is that
vitamin A is missing... The light hits your eyes, but the vitamin A isn't there to transmit the signal to your brain.

Your brain knowing when it's daytime and when it's nighttime is called your circadian rhythm. This is why the Cheat
Sheet  lists "disrupted circadian rhythm and an inability to use light therapy to entrain a healthy circadian rhythm" as a
symptom of vitamin A deficiency.

Other Amazing Things Vitamin A Does

Vitamin A does some other amazing things:

 It protects against kidney stones.

 It protects against "autoimmune" diseases. These are diseases where the body attacks itself,
like type 1 diabetes.
 It protects against asthma and allergies.
 And it protects against food intolerances like celiac disease (a condition where gluten, a
protein in wheat and several other grains, wreaks havoc on the intestines).
 It helps make hormones like testosterone and estrogen.
 In fact, without vitamin A, boys won't go through puberty!

Vitamin A in Foods
So how do we get enough vitamin A?

There are two forms of vitamin A: the form in plant foods, and the one in animal foods. The plant form is actually a
collection of compounds. One of them is beta-carotene. The others are similar to it and called "carotenoids."

These are named after carrots. 🐰

Oops that's a rabbit.

Let's try this again.

These are named after carrots. 🥕

The animal form of vitamin A is called retinol. This is named after the retina, the part of the eye where most of the
vitamin A is found.

We don't need the plant form (carotenoids) in our bodies. We do need the animal form (retinol). But! We can convert
the plant form into the animal form. In other words, we can convert carotenoids to retinol. There's actually over SIX
HUNDRED (!!!) different carotenoids, and not all of them act as vitamin A. For example, lutein and zeaxanthin, found
in spinach and eggs, might help protect us from going blind when we get old. This is because they protect against a
disease called age-related macular degeneration. But they don't act as vitamin A. Some people think the lycopene in
tomatoes protects against prostate cancer or cardiovascular disease (it's controversial!). But lycopene doesn't act as
vitamin A. Only about 10% of carotenoids act as vitamin A, and these are called "provitamin A carotenoids." The PRO
in "provitamin A" refers to the fact that they can be converted into the active form of vitamin A, retinol.

Carotenoids are colorful! They can be red, orange, or yellow. So, you know your plant foods have vitamin A potential if
they are red, orange, or yellow. But get this... GREEN foods have potential vitamin A too! Why? Because the green is
chlorophyll, which plants use to obtain energy from the sun. The carotenoids act as the chlorophyll's assistants, so you
can always be sure that when you see green, those other colors are lurking beneath the surface.

For example, have you noticed the colors the leaves turn in the fall? Those shades of red, orange, and yellow are
carotenoids. As the chlorophyll degrades, it reveals the other colors that had been present all along. So, to get vitamin A
from plants, we eat red, orange, yellow, and green vegetables.

When we eat vitamin A, guess where we hold on to it? Our livers! And just like we store vitamin A in our livers, so do
fish, cows, chickens, and all the other animals. So, the best source of animal-form vitamin A is liver. Cod liver oil can
be used as a supplement because it's simply the oil squeezed out of the livers of fish. Most other animal foods are not a
good source of vitamin A, with two exceptions: eggs and milk. Why? These are the two foods meant to nourish young
animals, who need lots of vitamin A to grow correctly. In fact, an egg has a rather marvelous task to fulfill: it has to fit
enough nourishment to last the chick 21 days until it hatches and eats its first worm. It has to pack a LOT of nutrition.
And milk is meant to nourish the growing calf. Both of these have vitamin A... but nowhere near as much as liver.

Now, you might think we could get vitamin A from plant foods and animal foods equally well. But here's the thing: We
need the animal form, retinol. We don't need the plant form, carotenoids. So when we get vitamin A from plant foods,
everything comes down to how good we are at converting the carotenoids to retinol.

Getting Vitamin A From Plant Foods Is Hard!

And there are SO MANY things that get in the way:

❌fiber

❌parasites

❌toxic metals like mercury and lead

❌damaging molecules produced during metabolic problems like diabetes

❌iron deficiency

❌zinc deficiency

❌protein deficiency

❌hypothyroidism

The worst of these is GENETICS. About half the population has their ability to get vitamin A from plant foods cut at
least in half. And half of those people -- a quarter of the total population -- has it cut by 75%. Layer on any of the ❌'s
listed above and the picture just gets more and more bleak.

So colorful vegetables MIGHT be a good source of vitamin A for you, but ARE they? ‍♂️
Things That Boost Our Vitamin A
Ok, enough of the stuff that makes getting vitamin A *harder.*

Here are things that help!

 Vitamin A mixes with fats and oils better than it mixes in water. That means eating it with
fat helps us absorb it.
 The best fats to use are animal fats and traditional oils like palm oil and olive oil. If you
want to look up a specific oil, look up the type of fat it has and use oils that are low in
polyunsaturated fat.
 Cooking or pureeing vegetables helps us get more vitamin A from them.
 Vitamin E helps us get more vitamin A from plant foods.

Here's what I recommend as the best way to get vitamin A:

 Eat 4 ounces of liver once a week, or eat a half ounce every day.
 If you tolerate eggs, eat up to three whole eggs a day.
 If you tolerate milk, consume up to three servings of full-fat dairy per day.
 Eat 3 or 4 cups of red, orange, yellow, and green vegetables a day.
 Don't go out of your way to eat a high-fat diet, but don't avoid fat either.
 To super-charge your vitamin A, use grass-fed butter and red palm oil for your added fats.

Red palm oil is a great plant source of vitamin A. It happens to be super-rich in carotenoids *and* vitamin E *and* all
the right fats. And it's even better than pureed vegetables. Because it is an oil, the carotenoids are already perfectly
dissolved and you don't need to do much digesting to extract them.

Vegans, Low-Fat Dieters, and Children

Now, some people will need to change things up!

First, LOW-FAT. If you avoid adding fats and oils to your food, emphasize lean cuts of protein, and avoid egg yolks or
full-fat milk products, you qualify as "low-fat."

👉Triple your animal-form vitamin A by eating 12 ounces of liver a week.

Second, VEGAN. If you don't eat *any* animal products, you're a vegan.

👉Use red palm oil liberally as often as you can stand it.

👉Supplement if you have symptoms of deficiency.

And then there's CHILDREN. The best thing to do for children is cut these down based on the amount of food they eat.
For example, if they eat half as much as you, feed them half as many of these foods. If they eat twice as much as you,
feed them twice as many of these foods. If you want to put numbers on it, cut these serving sizes in half, then multiply
that by every 1000 Calories in your child's diet. Do the same thing for the supplement doses I'll discuss below.

Vitamin A Supplements
If you can't meet the food recommendations (or just refuse to eat liver and palm oil!), you should consider
supplementing. When supplementing, we need to start counting. Vitamin A is measured in "international units" or IU.

🥄Cod liver oil providing 3000 IU per day from a brand that doesn't use synthetic vitamins is the most natural source.
💊 You can also just take a vitamin A supplement. Take 3,000 IU a day, or 10,000 IU twice a week. If you take more,
you should work with a knowledgeable health care practitioner and make sure all your other nutrients are adequate to
avoid imbalances.

Vitamin A Toxicity
Vitamin A has a dark side. Yes, it can be toxic! 😬

☣️It can hurt your bones, especially when you don't have enough vitamin D.

☣️In the first 8 weeks of pregnancy, too much might cause birth defects.

Taking way too much for way too long a time can cause these problems:

☣️Fatigue

☣️Hair loss

☣️Upset stomach, nausea, and vomiting

☣️Dry, peeling, or itchy skin

☣️Cracked lips

☣️Headache

The best way to avoid these problems is to avoid taking too much, and to keep the rest of your diet balanced. Here are
some rules to follow to make sure you don't experience any problems from too much vitamin A:

✅ Keep retinol to no more than 3,000 IU per day or 10,000 IU twice a week unless you have deficiency symptoms that
only go away at higher doses.

✅ If you supplement with more, include supplements of vitamins D, E, and K. I'll give you dosing recommendations
when we get to those lessons!

✅ Work with a knowledgeable health care practitioner if using high doses, especially if you have any symptoms of
toxicity.

Testing for Vitamin A

If you have a copy of Testing Nutritional Status: The Ultimate Cheat Sheet, definitely check out the vitamin A section,
which has two blood markers for testing deficiency and eight for testing toxicity.

A Quick Note on Genetics

A quick note on genetics: the majority of my consulting clients get their BCO1 genes tested, which shows us genetic
variation in the ability to get vitamin A from plant foods. In my experience, almost everyone has at least one of the
variations that we know of, and this rarely seems to be the main driver of whether they have vitamin A deficiency
symptoms. After reviewing a great many of my clients' BCO1 genetics, I am of the opinion that these genes, while they
matter, rarely make or break whether someone should be getting any given amount of vitamin A from plant or animal
foods.

So, I'm of the opinion that everyone should attempt to get at least the basic requirement from retinol, whether that is
from animal foods or a supplement, and that vegans should emphasize red palm oil or supplements, and should be
especially proactive about testing their blood levels.
Wrapping Up
So, in the background of using the MTHFR protocol, you should make sure you're getting enough vitamin A using the
principles outlined above. If you have any of the symptoms we discussed, you might need more vitamin A. If
you also are vulnerable to swings back and forth between undermethylation and overmethylation, or if you are very
sensitive to methylated B vitamin supplements, then fixing your vitamin A status might be an important way to help
stabilize your methylation.

Allright, that's it for vitamin A!

Tomorrow we move on to thiamin, or vitamin B1!

Understanding all the nutrients that impact methylation is a marathon, not a sprint!

We were out of the gate with vitamin A and now we are committed to the first lap, counting up the B vitamins starting
with vitamin B1.

Vitamin B1 is also called thiamin.

How Thiamin (Vitamin B1) Supports Methylation

Thiamin is absolutely 100% critical to the function of MTHFR.

Although thiamin isn't used directly by MTHFR — in fact, the role of thiamin is very indirect — it is still the case that
every single time MTHFR completes the methyl group of methylfolate, it does it using material taken directly from
other processes that require thiamin.

MTHFR doesn't actually make the whole methyl group of methylfolate. It merely finishes making the methyl group that
another enzyme, MTHFD1, had started. Remember, virtually every molecule in every living organism is made mostly
of carbon and hydrogen, and a methyl group is a carbon with three hydrogen attached. By the time MTHFR sees folate,
it already has a carbon and two hydrogen attached. MTHFR needs to add a hydrogen. And in order for that hydrogen to
stick to the methyl group, it needs to add some "glue." That "glue" is an electron, the most basic negatively charged
particle we find within any atom.

So, the job of MTHFR is to finish making the methyl group of methylfolate by adding the last hydrogen to it, and it
adds it using the "glue" of an electron.

Where does the hydrogen and electron come from?

Ultimately, it comes from glucose. The hydrogen and electron is ripped off of glucose, passed on to niacin (vitamin B3)
and then niacin passes them to the riboflavin (vitamin B2) tucked away inside the MTHFR enzyme, and the riboflavin
does the work of adding them to folate.

In order to get them from glucose to niacin in the first place requires a lot of complex maneuvering that involves a
bunch of different enzymes and one of them is transketolase. This is the enzyme that requires thiamin.

Without thiamin, transketolase will not work. Without transketolase, the hydrogen and electron will never move from
glucose to niacin. Niacin will never be able to pass it to the riboflavin tucked away in the MTHFR enzyme. So MTHFR
itself will not be able to work.

There is a second way thiamin helps with methylation: it protects against oxidative stress. That's because the very
same enzyme, transketolase, allows those same hydrogens and electrons to be passed on through niacin and then
riboflavin, and then, instead of giving them to MTHFR, gives them to a different enzyme, glutathione reductase, which
recycles glutathione, the master antioxidant of the cell.

As I discussed in the "25 Other Nutrients That Support Methylation" email, oxidative stress makes you break down
homocysteine instead of recycling it to methionine. Oxidative stress can thus sap your methionine levels, which can
tank your SAMe levels, and wreck your methylation. Thiamin, by allowing glutathione recycling, protects against this.
If you have a copy of the Cheat Sheet, you will see that the transketolase activity of your blood cells is one of eight
different markers that can be used to know whether you are deficient in thiamin. Everything I just described above is
why transketolase activity is such an important thing to measure.

Finally, there is a third way thiamin supports methylation: many other enzymes besides transketolase use thiamin,
and they include enzymes needed to break down any food for energy, making thiamin absolutely essential for
making ATP. ATP is needed to activate methionine to SAMe, so without thiamin, it will be harder to convert
methionine (which we already have less of due to poor MTHFR activity and oxidative stress) to SAMe.

That's methylation, but there is so much more to say about thiamin!

The Carb-Burner
I call thiamin the carb-burner.

It's the first of eight B vitamins that we will cover (the first of nine if you count choline!). And it's the first of seven B
vitamins whose overwhelming role is to help you extract energy from the food you eat and put it toward good use. I call
it the carb-burner because it's the B vitamin that specializes in burning carbs.

Carbs, or carbohydrates, are the type of energy you get from sweet or starchy foods, like fruit, potatoes, beans, and
grains. 🍇🥔🍛

... or candy 🍭 😳

... or soda and other sugary drinks 🥤😬

Don't get me wrong. You need thiamin to burn any kind of energy, including protein and fat. And you need all the other
energy B's to burn carbs.

But here's the thing:

 You need TWICE as much thiamin to burn carbs as you need to burn fat.
 No other B vitamin has such a special role in burning carbs.

Thiamin and Glucose Intolerance

Eating carbs won't deplete your thiamin. But not getting enough thiamin *will* prevent you from burning carbs. What
would happen if you eat carbs that you can't burn? The carbs will build up in your blood. Specifically, glucose, a type of
sugar, is the main carbohydrate in our blood. If there is too much in our blood after we eat, we call it "glucose
intolerance." Let glucose intolerance go on long enough, and we wind up with diabetes. 😬

Thiamin deficiency isn't the only factor in diabetes, but it's probably one of them. There aren't many studies testing
whether thiamin helps prevent our blood glucose from rising too much after we eat, but there are some, and they are
promising.

A lot of people feel better on low-carbohydrate diets. Are they deficient in thiamin? ‍♂️

Let's come back to that when we talk about how we become deficient.

If modest deficiencies of thiamin make us bad carb-burners, what do really bad deficiencies do?

Severe Thiamin Deficiency

Ok, severe deficiencies of thiamin:
  They make your hands and feet tingle, or become weak, numb, or painful.
 They cause the muscles around your eyes to become weak, paralyzed, or disordered. This
can cause twitching or drooping.
 They can cause your heart rate to go up, or cause other heart trouble.
 They can make it harder to control your own body movements.
 They can make you feel weak.
 They can make you feel confused.
 They can make you feel apathetic.
 They can give you amnesia, and cause you to make up, distort, or misinterpret your own
memories.

When severe thiamin deficiency only affects your hands, feet, and heart, it's called "beriberi." When it affects eye
muscles or your control over the bigger movements you make in your day-to-day life, it's called "Wernicke's
encephalopathy." When it affects your mind, it's called "Korsakoff's psychosis."

In the absolute worst cases, severe, untreated thiamin deficiency leads to seizures, paralysis, and death. This is sad,
because severe thiamin deficiency is often diagnosed *after* someone dies and they perform an autopsy. This is
because many older medical textbooks insist on using the combination of eye problems, loss of control over body
movements, and confusion for diagnosis. But a thiamin-deficient patient often just shows up feeling apathetic and
moving more slowly, before things get rapidly worse... and become fatal.

Thiamin Deficiency Starves the Nervous

System of Glucose
Notice how much these all center around your brain and nerves.

This is because your nervous system, far more than any other system in your body, requires glucose -- the major
carbohydrate -- to function. Every day, your brain consumes 120 grams of glucose, the amount found in 3-4 large
potatoes. This glucose doesn't just provide energy. It's also needed to make many of your neurotransmitters, the
chemicals that your brain cells use to communicate with each other. These neurotransmitters are also what your nerves
use to control your muscles.

You may have heard of the ketogenic diet. It's a low-carbohydrate, high-fat diet. When you spend a while on this diet,
your nervous system readjusts how it uses its energy, and it starts consuming 75% less glucose than it usually does. And
what are ketogenic diets most effective for? Epilepsy! That's what they were first invented for. So they help the brain.
Many people report feeling calmer or sleeping better on them. More effects on the brain. Some people report brain fog
that improves on a ketogenic diet. More effects on the brain.

Thiamin deficiency is overwhelmingly a problem of being a bad carb-burner, and having the nervous system starve as a
result.

Are ketogenic diets just treating thiamin deficiency? Probably not "just." But thiamin may often be an important part of
the picture.

Other Cool Things Thiamin Does

By the way, thiamin does some other cool things besides help us burn carbs:

 It helps protect us from oxidative stress. This is the wear and tear on our tissues that happens
as we age. It gets worse with metabolic diseases like diabetes, or exposure to toxins like
alcohol and cigarette smoke.
 It helps us recycle other vitamins, like vitamin K and, as in the case of MTHFR, folate.
 We need it for detoxification.
  We use it to synthesize a lot of different things. For example, fats, cholesterol, and the
building blocks of our DNA.

Getting Thiamin From Food

So how do we get thiamin from food?

The most certain way to do it is to eat three servings of anything from this list per day:

 2 heaping teaspoons of nutritional yeast

 3-4 ounces of legumes (lentils, peas, beans) measured before cooking
 3-4 ounces of whole grains, measured before cooking

Enriched flour also has thiamin added to it, as a public health measure to prevent deficiency.

The thiamin content of meat is a confusing topic. Older databases say that red meat animals (beef, lamb, bison) have the
most thiamin. They say pork is a mediocre source, and that poultry have very little. The newest databases say that pork
is an awesome source, while red meat animals and poultry have very little.

I think I have an idea why there might be conflicting information about the thiamin content of animal products, and I'll
explain it in just a bit. But for now, let's say meat is a "maybe."

You know what's a definite no?

FAT! That's right, fat has no thiamin to speak of. And this is the great irony. Although ketogenic diets spare thiamin
better than any other diet, if they aren't designed carefully they can give you a thiamin deficiency. Even though you
need twice as much thiamin to burn carbs as you need to burn fat, you still need thiamin to burn fat.

If your keto diet has several servings of meat per day, it has enough "maybe" food that it *might* keep you out of
deficiency. But a heaping tablespoon of nutritional yeast, a thiamin supplement, or a multivitamin could go a long way
if you aren't going to eat legumes or whole grains.

If you eat paleo, if you can tally these foods up to a total of 2 pounds measured before cooking, you can get plenty of
thiamin:

Okra, Jerusalem artichoke; garlic; dandelion greens; acorn squash, and butternut squash; asparagus, kale, or Brussels
sprouts; bamboo shoots; maitake, shiitake, oyster, or white mushrooms; taro root or leaves; white potatoes, sweet
potatoes, and yams; beet greens; nori or spirulina; wasabi; mustard; thyme; caraway seeds; savory; nutmeg; anise;
mace; marjoram; tarragon; curry.

And carnivore? Just go with pork and hope for the best? Or nutritional yeast.

In other words, yeast, legumes, and whole grains are our sure-fire tickets to Thiamin Land. If we don't eat them we rely
on huge volumes of other foods, or supplements.

So how much sense does it make that low-carb or keto helps some people by sparing the need for thiamin, if these diets
themselves are often low enough in thiamin to cause deficiency? 🤔

Well, to get a handle on this, we need to turn our attention to thiamin antagonists.

Thiamin Antagonists From Foods and Microbes

Here are a list of foods and microbes that contain things that actually hurt thiamin status:
❌ Raw fish and shellfish

❌ Ferns

❌ The larvae of the African silkworm anaphe venata, a traditional food in many African countries

❌ Various bacteria found in human feces (there are no tests for them! 😔)

❌ Several known fungi

❌ At least one amoeba that sometimes pollutes drinking water

❌ Sulfite

The antagonists in fish and shellfish are destroyed by heat. Their content in these foods varies widely for reasons that
are largely unknown.

Sulfite is used as a food additive (🍷!), is produced by gut bacteria that make your farts smell like rotten eggs, and is
produced in our own body when we eat a diet high in animal protein and low in liver and legumes.

The human gut is a black box. We know from research done decades ago that humans carry bacteria that destroy
thiamin. We just have no way to test for them right now.

But this story gets even crazier. 😬

Thiamin Antagonists In the Environment

Thiamin deficiency is being caused by something in the ENVIRONMENT. Thiamin deficiency bad enough to cause
seizures and paralysis has been found in wild fish, birds, and reptiles from the US, Canada, Iceland, Sweden, and the
UK. Outbreaks come in waves and affect the wildlife in large numbers. We DON'T KNOW what's causing it.

So could you wind up sparing thiamin by going low-carb, even if you cut out some of your best sources of thiamin in
doing so?

Yes!

Or, at least, maybe!

As confusing as it is, this could make sense if we are suffering from exposure to unknown amounts of environmental
thiamin antagonists.

Could this explain why older databases show different distributions of thiamin among meat products than newer
databases do? Red meat animals like cows, buffalo, and sheep have a giant bacterial mega-factory called the rumen. A
healthy rumen may provide these animals with lots of thiamin. An unhealthy rumen (from grain-feeding?) may provide
them with lots of thiamin antagonists. We don't currently know if the mysterious cause of thiamin deficiency in wildlife
also affects farm animals, but it might.

Other Causes of Thiamin Deficiency

There are a few causes of thiamin deficiency that we do understand well:

❌ Gastrointestinal diseases hurt thiamin absorption.

❌ Persistent vomiting causes us to lose thiamin in the vomit.

❌ Liver diseases hurt thiamin storage.

❌ Alcohol abuse hurts its absorption, its storage in the liver, and its activation for use with our enzymes.

❌ HIV/AIDS patients, anorexics, and hunger strikers are at high risk.

Are Thiamin Supplements Safe?

Now, for some good news! Finally! Thiamin has no known toxicity! Zero! Zilch! This means that it's very safe to play
around with thiamin supplements even if we don't know for a fact we have a deficiency and don't know for sure if they'd
help.

There are a few different types. Thiamin hydrochloride or thiamin HCl is the cheapest and most common. Benfotiamine
is more expensive. It's thought to be better at getting into the nervous system, but it's superiority over the cheap stuff
hasn't been clearly demonstrated. The same is true of thiamin tetrahydrofurfuryl disulfide or TTFD. Thiamine
pyrophosphate (TPP) is the activated form. In theory, it could be more effective for people who have energy problems
(thyroid, low adrenals, diabetes). We know alcohol hurts our ability to activate thiamin, so maybe environmental
antagonists do too. But none of this has been clearly studied. Worse, TPP is probably not absorbed intact.

Testing Thiamin Status

If you're using the Cheat Sheet, you will find eight markers of thiamin status. One is the active form in whole blood, one
is the transketolase enzyme we discussed above, and the others are "functional" markers that show you whether the
thiamin-dependent enzymes are actually working. These include amino acids and various products of energy
metabolism in the blood and urine. The functional markers can be very important if you're dealing with an
environmental exposure to antagonists that we can only speculate about. For example, from my consulting work I know
that people who have indoor mold exposure and neurological problems from it generally have disrupted functional
markers of thiamin status, but there is no research to say for sure whether the antagonists are destroying the thiamin,
hurting its activation, or disrupting its interaction with those enzymes. So blood levels of thiamin might not always
reflect disruption of the functional markers, but the functional markers may still tell you that you need to try
supplementing with thiamin, possibly at high doses.

Wrapping Up
So let's wrap this up with some take-home points. Make sure to follow these as a background to using the MTHFR
protocol. Look for symptoms that might indicate you need more thiamin. If you experience them while also
experiencing symptoms of undermethylation, this would be a clue that fixing your thiamin status will be an important
way to fix your methylation. Here are the tips:

 Get thiamin from nutritional yeast, legumes, or whole grains if you tolerate these well.
 Get it from huge volumes of the vegetables and spices I listed, if not.
 Fixing your gut might help, but we don't know exactly how.
 When all else fails, a carefully designed low-carbohydrate diet or thiamin supplements may
help.
 When supplementing, using 100 milligrams multiple times a day is safe!
 We only get 1-2 milligrams from food, so expensive forms that provide, say, 10 milligrams
may be perfectly effective.
 Try the cheap stuff first if you're concerned with money. Try the others to see if you get
better results.
 You don't need to eat fat, or even food at all to absorb it.
 Still, you will retain and activate more if you take it with food and spread the dose across
your meals.
 If you have signs of deficiency, or respond well to supplements, see if there are sources of
antagonists you could clean up, like raw fish and shellfish, ferns, sulfites, or gut problems.

That concludes thiamin.

See you tomorrow for riboflavin!

Our marathon is running on, and today we are covering riboflavin. Riboflavin is also known as vitamin B2.

How Riboflavin Supports Methylation

Riboflavin is included in the MTHFR protocol first and foremost because it is physically part of the MTHFR enzyme
and is what MTHFR uses to carry out its work. In fact, we know that in the C677T variation of MTHFR, the reason the
enzyme is less effective is because it doesn't bind riboflavin as tightly. We also know that riboflavin supplementation
can fix this, at least in part, if not entirely.

Riboflavin supports methylation in five other ways:

 We need it to use choline for methylation. The MTHFR protocol uses choline or TMG to
get around a poorly functioning MTHFR because TMG can be used as
an alternative. Unless you are supplementing with TMG, your body is most likely using
choline for this. To use choline, we first have to convert it to TMG. That conversion requires
riboflavin.
 We need it to release methyl groups from glycine. When we eat a meal rich in
methionine, such as a steak, we have too many methyl groups. Glycine comes in and stores
them for later. When its been hours since our last meal, we have no new incoming methyl
groups, so we start releasing them from glycine. Releasing them requires two different
enzymes and both of them require riboflavin.
 We need it to break glycine down as an extra source of methyl groups. When glycine
hasn't stored enough methyl groups to release between meals, we need to make new ones.
To do that, we need to get carbon from somewhere, and one way we can get it is to break
down glycine into pieces and take one of its carbons. Doing that requires riboflavin.
 Riboflavin is needed to make ATP. Riboflavin is central to breaking down food for
energy, and that energy is used to make ATP. ATP is needed to activate methionine to
SAMe, and SAMe is what we use directly for methylation.
 Riboflavin protects against oxidative stress. Oxidative stress causes us to break down
homocysteine instead of recycling it to methionine. This can sap our methionine levels,
which would tank our SAMe levels. Less SAMe means less methylation. Riboflavin is
needed to recycle glutathione, the master antioxidant of the cell. By boosting glutathione
status, riboflavin protects us from oxidative stress. This preserves homocysteine for
recycling to methionine, allowing it to be converted to SAMe to support methylation.

Riboflavin achieves this last point by supporting the enzyme glutathione reductase. If you are using the Cheat Sheet,
you will find "EGR" in the comprehensive screening. This is the glutathione reductase activity of your red blood cells,
which is used as a marker of riboflavin status for the reasons I just described.

That's riboflavin in methylation, but there's so much more to say about this vitamin!

So Much More to Say About Riboflavin

I call it the FAT-BURNER.

Why?

Because burning fat requires almost twice as much riboflavin as burning carbs. You use riboflavin to burn anything for
energy, and you need all the other energy Bs to burn fat. But none of the other Bs stand out as so clearly related to fat-
burning as riboflavin. This doesn't mean that extra riboflavin will help you lose weight. But it *does* mean that when
you lose weight you need more riboflavin.

In fact:

 Losing weight increases your need for riboflavin by 60% during the active weight loss.
 Doing 20-50 minutes of cardio six days a week increases your need for riboflavin by 60%.
 Doing BOTH of these together more than DOUBLES your riboflavin requirement!

And what's nuts is that when you're losing weight you're eating less food. So your riboflavin intake goes down, but your
riboflavin requirement goes up! 😬

As we will see, though, you don't need to be losing weight to run low in riboflavin. In fact, recent estimates suggest that
almost half of adults and over 75% of children run short on it.

Amazing Things Riboflavin Does

Why is this a problem?

Because riboflavin does lots of other amazing things besides burn fat:

 It helps you absorb and utilize iron, which prevents anemia.

 As I mentioned above, it prevents oxidative stress. This is the wear and tear on our tissues
that occurs with age. It contributes to a lot of diseases, and a lot of diseases make it happen
more. So does exposure to toxins like cigarette smoke and alcohol.
 It keeps the eyes healthy by preventing cataracts.
 It prevents preeclampsia. This is a dangerous condition in pregnancy involving high blood
pressure and swelling. About 5% of women with preeclampsia wind up with eclampsia,
which causes seizures, hemorrhage, and in the worst cases death.
 It helps keep blood pressure under control.
 It helps you feel energetic and feel good when you exercise.
 In people who suffer from migraines, high doses of riboflavin make the migraines shorter
and make them happen less often.

Riboflavin Deficiency
When riboflavin deficiency gets REALLY bad, things really start going haywire, especially in your skin:

 The outer edges of your lips get red and crusty.

 The corners of your mouth crack or fissure.
 Your tongue and all throughout the inside of your mouth gets red, bloody, and swollen.
 The skin gets red, scaly, itchy, greasy, and painful. It's often infected with candida, a nasty
fungus. It's worst at the outer edges of the nostrils, the smile lines, ears, eyelids, and genitals.
 Your hands and feet can get unusually sensitive to touch, heat, or pain.

How Much Riboflavin Do We Need?

One way to look at how much riboflavin we need is to look at the RDA. The RDA is the recommended dietary
allowance, the official recommendations for how much we need in a day. The RDA is 1.3 milligrams per day (mg/d) for
men and 1.1 for women. Women require some extra during pregnancy and lactation, and children are adjusted down for
bodyweight.
However, our true needs are probably closer to 2-5 mg/d. For children, I would divide the dose in two and multiply it by
every 1000 Calories they eat. As we already covered, dieting and cardio will double the requirement by 60% each.
High-fat diets increase the requirement by 20-40% depending on how much fat you eat. Exposure to sunlight and
tanning beds increases your needs, but no one knows exactly by how much.

So we might think of 2 mg/d as the bottom of a good intake, but as we pile on things like weight loss, cardio, high-fat
diets, MTHFR, sunlight exposure, and tanning beds, we move toward needing 5 mg/d.

Getting Riboflavin From Food

Food sources come in five tiers.

 Tier 1 gives you 2-5 mg for every 3-4 ounces (oz). These are foods where one serving a day
keeps the deficiency away. Tier 1 contains liver. Chicken liver is at the bottom of the tier
and pasture-raised lamb liver imported from New Zealand is at the top. But it's just liver in
this tier. It's lonely at the top. 😢 But someone's gotta be there. 👑
 Tier 2 provides 1-2 mg for every 3-4 oz. These are foods where two servings a day keep the
deficiency away. Kidney, heart, and almonds are in this tier.
 Tier 3 provides 0.4-0.5 mg for every 3-4 oz. These are foods where four to five servings a
day keep the deficiency away. Red meat, cheese, eggs, salmon, mushrooms, seaweed,
sesame, wheat germ and bran are all in this tier.
 Tier 4 provides 0.2-0.4 mg for every 3-4 oz. These are foods where five to ten servings a
day are needed. This tier includes most other meats not mentioned in tier 3, and it includes
milk.
 Tier 5 is all the foods that are safe to bulk up on *if* they don't come at the expense of top-
tier foods. These have little bits of riboflavin (0.1-0.3 mg) that are meaningful in high
volumes, but eating them doesn't really help you out unless it's displacing sugar and fat. This
tier includes whole grains, nuts, seeds, and vegetables (including beans and other starches).

Enriched flours tend to fall into tier 3 or 4.

A lot of people think nutritional yeast is a good source of riboflavin. It isn't naturally, but many products are enriched
with riboflavin, just like refined flours are.

The foods that contain ZERO riboflavin are sugar and fat. These hurt your riboflavin status by displacing foods that
have riboflavin.

Let's talk about three dietary patterns!

VEGANS

Vegans have fewer superfoods available. They have almonds in tier 2; mushrooms, seaweed, sesame, and wheat
germ/bran in tier 3, but nothing in tier 1. They need to emphasize the vegan tier 2/3 foods, to avoid sugar and fat more
strictly, and to bulk up on tier 5 foods.

HIGH-FAT

Burning fat requires more riboflavin, yet fat doesn't have any riboflavin! Since fat takes up room in the diet and
displaces foods that contain riboflavin, it's a double-whammy against riboflavin status. The solution? Double-down on
the riboflavin superfoods in tiers 1 and 2. Bulk up on the tier 3 foods.

For vegans, the problem is they don't have access to the top foods. But if they avoid sugar and fat, they can bulk up on
the tier 4 foods. For high-fat, the problem is they don't have room to bulk up on the tier 4 foods. But they *do* have
access to all the superfoods. So, leverage your strengths to make up for your weaknesses. 💪

MINDLESSLY ALL-NATURAL
Doing things the natural way is great, but when you take control of your own nutrition, you take responsibility to learn
proper planning. Refined flour is fortified with B2 by edict of the public health authorities. Cut it out and start eating
more fat, and your riboflavin status will tank unless you start emphasizing the superfoods.

Other Causes of Deficiency

Riboflavin deficiency isn't all about diet. Here are some other causes of deficiency:

❌ Low stomach acid hurts protein digestion, which is needed to release riboflavin from the proteins in food.

❌ Exposure of YOU to sunlight or tanning beds destroys riboflavin inside of you.

❌ Exposure of your FOOD to light kills riboflavin. For example, putting milk in sunlight for two hours destroys half
the riboflavin.

❌ Alcohol hurts your ability to absorb and use riboflavin. Alcoholics often have low intake too.

❌ Low thyroid or adrenal hormones hurt your ability to activate riboflavin and cause you to lose more in your pee.

❌ Poor magnesium status acts just like low thyroid and adrenal hormones.

❌ Intestinal inflammation hurts your ability to absorb riboflavin.

❌ Bad gut bugs may make riboflavin antagonists.

❌ Diabetes, stress, trauma, and kidney dialysis (a treatment for people with poor kidney function) cause you to lose
riboflavin in your pee.

❌ As noted earlier, weight loss, cardio, MTFHR genes, and high-fat diets increase your needs.

❌ Diabetes, heart disease, and cancer often provoke or exacerbate a riboflavin deficiency.

❌ Anorexics are at high risk because of low intake.

Riboflavin Supplements
Good news! Like thiamin, riboflavin has no known toxicity! 😀

There are two supplements on the market. Free riboflavin, plain old' normal cheapo riboflavin, is the first form.
Riboflavin 5'-phosphate is the other form. It's often called FMN or "activated" or "coenzymated" riboflavin. There is
NO EVIDENCE that the second form is EVER better than the first! Why? Because you cannot absorb it until you
convert it into the cheap stuff. And if you have intestinal damage, you might not be able to convert it to the cheap stuff,
and it might actually be *less effective.*

Although riboflavin is not a "fat-soluble vitamin," it mixes quite a bit with both water and fat. So it's *a little* like
vitamin A. It's better absorbed with a meal, and the meal should have some fat. The natural fats in your foods are fine --
no need for gobs and gobs of added fat. Although you can absorb a lot of riboflavin at once, you will always hold on to
the riboflavin and put it to use better if you spread the doses evenly across your meals. So if you take a supplement, the
ideal thing is to take it at each meal.

Most people would benefit from a low-dose supplement of 2-5 mg/d on days where they can't meet the requirement
from food. You can find liquid supplements that offer these doses, or you can find them in some B complexes and
multivitamins.

I don't recommend using high doses unless you have a good reason to. However, there is no evidence that doing so is
unsafe. 100 mg per meal would be an example. These are the doses effective against migraines! A number of rare
genetic disorders are treatable with high-dose riboflavin. 10 mg per kilogram bodyweight for children, and up to 1500
mg/d in one case. Right now these are all genetic defects in riboflavin absorption or use. But there is a fascinating
possibility that high-dose riboflavin can correct other genetic disorders that have nothing to do with riboflavin. Again, I
don't recommend using high-dose riboflavin with no specific purpose, but trying it for strange, unexplained health
problems just to see if they do anything is a reasonable idea.

Riboflavin supplements will turn your pee neon yellow. 😳This isn't bad. It's riboflavin leaving your body when you
couldn't activate it and start using it right away. It doesn't mean your dose was too high. It doesn't mean you're wasting
riboflavin. You might need the high dose to ram it into your metabolism by force. 👊

Wrapping Up
So let's wrap up! Riboflavin is already part of the MTHFR protocol, so these tips should be used mainly to see if you
have any signs or symptoms of deficiency and need to adjust your dietary approach to getting riboflavin from food, or
need to adjust the dose of your supplement. Here are the take-home points:

✅ Ideally, eat a half ounce to an ounce of liver every day, or 3-8 oz per week; eat a few foods from tier 2 or 3 every
day, and minimize sugar.

✅ Vegans avoid sugar *and* fat, and emphasize the tier 2 and 3 foods available to them.

✅ High-fat diets, cardio, weight loss, tanning, and low-MTHFR genes require doubling or tripling down on the
superfoods.

✅ Various disease states, alcoholism, anorexia, and thyroid and adrenal problems are all red flags.

✅ When foods won't cut it, supplement. Free riboflavin is best, taken with meals and spread out evenly across those
meals.

✅ Low doses of 2-5 mg/d are best for most people, but some people require high doses, especially for migraines
(common) and genetic disorders (rare).

Ok, we're done with riboflavin! 😁

I'll see you tomorrow for niacin.

Our marathon continues, and today we cover vitamin B3, also known as niacin.

I called thiamin the carb-burner and riboflavin the fat-burner. But get this… I don't have a nickname for niacin.

What I can tell you, though, is it's essential above all to a healthy mind, a healthy gut, and healthy skin.

First, though, let's look at how it supports methylation.

How Niacin Supports Methylation

Like riboflavin, niacin directly supports MTHFR.

Unlike riboflavin, however, niacin is not part of the MTHFR enzyme. In order to understand its role, we have to
remember that a methyl group is a carbon atom with three hydrogens attached, and that MTHFR does not make a new
methyl group to put on methylfolate. Instead, it finishes making the methyl group that another enzyme, MTHFD1
had started making. MTHFR finishes by adding the third and final hydrogen. To make the hydrogen stick, it uses an
electron as the "glue." An electron is the smallest unit of negative charge we can find in any atom.

Where do the hydrogen and electron come from?

Glucose. Glucose is a carbohydrate. It is the main form of sugar in our blood, as well as what we get when we break
down starches and sugars in our diet.
In order to get the hydrogen and electron from glucose over to the MTHFR enzyme, niacin carries it. It passes it on to
the riboflavin tucked away in the MTHFR enzyme, and then riboflavin does the rest of the work.

Niacin also supports methylation in five other ways:

 It helps us use choline for methylation. Like riboflavin, niacin also helps us convert
choline to TMG so we can use it for methylation.
 It helps us break down glycine to make new methyl groups. When we eat a meal rich in
methionine, like a steak, we have an excess of methyl groups and glycine stores some of
them for later. After a few hours, we no longer have new methyl groups coming in, and need
to use the ones that glycine had saved. Riboflavin is needed to release them, but niacin is
not. However, if glycine hasn't stored enough methyl groups to get us through to the next
meal, we need to break glycine into pieces and take some of its carbons to make new methyl
groups. Like riboflavin, niacin is needed for that.
 It helps us prepare carbons to become methyl groups using MTHFR. In between meals,
there are numerous ways to get carbons to form methyl groups. No matter how we get them,
three different enzymes (one of them is MTHFD1) use niacin between two and five times to
modify the carbon in preparation for MTHFR's final action, where it uses niacin again to
finish the methyl group.
 Niacin is needed to make ATP. Niacin is absolutely ubiquitous throughout all of energy
metabolism. Like riboflavin, we need niacin to make ATP. We need ATP to activate
methionine to SAMe. And SAMe is the universal methyl donor.
 Niacin protects us against oxidative stress. Like riboflavin, we need niacin to recycle
glutathione, the master antioxidant of the cell. This protects us from oxidative stress, which
stops us from breaking down homocysteine and allows us to recycle it to methionine so it
can continue to be used for methylation.

I've mentioned MTHFD1 here a few times. If you calculated your choline requirement in "Step 1" using my free choline
calculator, your MTHFD1 genetics made up part of your "methylfolate score."

That's how niacin supports methylation. Niacin also interacts in methylation in another important way.

Why Niacin Shouldn't Be Used to Soak Up

Extra Methyl Groups
Many people advocate using niacin as a methyl buffer to suppress symptoms of overmethylation.

I consider this a very bad idea.

Don't get me wrong. It works.

But niacin doesn't act as a buffer of methyl groups like glycine does. It doesn't soak up the extra to save for later when
we don't have enough.

Rather, excess niacin is detoxified using methylation, which stops it from hurting various cellular processes and helps us
pee it out.

This isn't always a bad thing. As long as we are getting enough niacin, there will be some cells in our body that, in any
given moment, see some particular molecules of niacin as "extra" and will methylate them to get rid of them. Anyone
who isn't clinically deficient in niacin will have some methylated niacin found in their urine.

On the other side of the spectrum, however, high enough doses of niacin can cause liver failure. How? By depleting
methyl groups!
Most doses of niacin that most people take, even when very high, are not going to do serious damage. But if you
are trying to deplete methyl groups with niacin on purpose, you're basically playing chicken with its main mechanism of
causing liver failure. This strikes me as playing with fire.

By contrast, glycine is an authentic methyl buffer.

Let's compare them:

 Glycine only gets methylated when we have too many methyl groups. As long as we don't

overwhelm the glycine buffer system, glycine will save them to release later when we don't
have enough. Glycine allows us to always stay in that "just right" Goldilocks area where we
have the supply of methyl groups that we need.
 Niacin gets methylated whenever we have too much niacin, and this happens regardless  of
whether we have too many, too little, or just the right number of methyl groups. Niacin
doesn't save methyl groups for later. Methylated niacin just winds up in the urine.

Using high-dose niacin to try to counteract an episode of overmethylation is using niacin as a drug to try to push the
methyl balance in one certain direction. Getting enough glycine is giving our body what it needs to self-regulate the
number of methyl groups to keep them always just right.

One of my consulting clients was very vulnerable to see-sawing back and forth between under- and overmethylation.
Before he became my client, he spent several years counteracting episodes of overmethylation with high-dose niacin.
This worked, but often just swung him back into episodes of undermethylation and never put an end to the see-sawing
effect. After he became my client, we first added glycine and creatine into his regimen. This led to the first major leg of
progress. Then, using the rather sophisticated approach in the Cheat Sheet, we identified an iron deficiency. Since iron
is needed to harvest stored methyl groups from glycine, this ended up being the final resolution to the see-sawing. High-
dose niacin had never been more than a short-term fix. Addressing the glycine buffer system actually solved the
problem.

That's methylation. But there is so much more to say about niacin!

Why Niacin Is Important

Niacin is the most foundational and universal B vitamin in all of energy metabolism. There are no tricks to pull to
reduce your need for it:

 Breaking something down? You need niacin.

 Building something up? You need niacin.
 Detoxing? It requires energy. You need niacin.
 Recycling other nutrients, like vitamin K and folate? It requires energy. You need niacin.
 Defending against oxidative stress? It requires energy. You need niacin.

But what's cray cray about niacin is that it does some super important stuff that has nothing to do with its role in energy
metabolism:

✅ It helps you use your neurotransmitters, those little chemicals that allow your brain cells to communicate with one
another, and allow your nerves to control your muscles and to sense your environment.

✅ It repairs your DNA whenever it gets damaged.

✅ It lengthens your telomeres. These are little caps on the ends of your chromosomes, the bundles of DNA that house
all of your genes. This helps them keep your cells dividing and staying strong as you age, allowing you to live longer.

What's nuts about niacin is that these last three roles actually *consume* niacin. In energy metabolism, niacin is just
shuttling energy around. But in these roles, niacin gets used up. That's why, molecule for molecule, we require 38
TIMES as much niacin per day as riboflavin!
Although niacin is important everywhere for everything, it's especially important to the brain, gut, and skin.

Why?

 In the brain, it's consumed during every single release of neurotransmitters.

 In the gut, your intestines get wildly assaulted by all the nasty stuff in the food you eat that
winds up in your... 💩 The cells get replaced every two or three days. That requires LOTS of
energy and repair.
 Every ray of 🌞 that strikes your skin damages your DNA. Your skin is in DNA repair mode
nonstop. Gotta git dat niacin, gotta git dat ni-ni all the time-time.

Rea-D-D-D-y to learn about niacin deficiency?

(You'll get that spelling joke in a just a sec. Trust.)

Niacin Deficiency
Let's consider severe niacin deficiency first. It will help us think clearly about what moderate deficits might look like.

Severe niacin deficiency is called pellagra. Optimists say it's the three D's: dementia, dermatitis, and diarrhea.
Pessimists add the fourth D: death.

The "dementia" actually starts out as depression. When it gets bad, it turns into suicidal or aggressive behavior, and
eventually to hallucinations and schizophrenia-like psychosis. Some cases of depression might be pellagra. There's no
way to know except to look for a niacin deficiency, try to fix it if you find it, and see if the depression goes away. Same
with schizophrenia. The tell-tale sign it's a true niacin deficiency is that high-quality food or niacin supplements make it
go away in minutes. We've tried treating regular schizophrenia with niacin, and it doesn't work. Strangely, though,
there's a connection. Most people get a "flushing" reaction to high-dose niacin that we'll talk about in just a bit.
Schizophrenics and their close relatives tend not to flush. Perhaps run-of-the-mill schizophrenia involves some kind of
disturbance in niacin metabolism?

The next D, dermatitis, starts with red skin. As it gets bad, the skin starts scaling and gets much darker. The tell-tale
sign it's niacin deficiency is it only occurs when you go out in the sun. This is because the sun causes DNA damage and
there's not enough niacin to repair it.

The diarrhea is just that -- diarrhea. You can't replace the cells that absorb your nutrients, so you stop absorbing
nutrients. You develop other deficiencies, and all the stuff you don't absorb gets flushed out the other end.

So what might we expect from more modest deficiencies?

 One possibility is just very weak versions of pellagra -- depression that responds to niacin,
gut problems that respond to niacin, or skin problems that get worse in the sun.
 Accelerated aging in any form. Especially of the skin. And especially as a result of sun
exposure.
 Fatigue or exercise intolerance, because of its role in energy metabolism.
 People with poor niacin status are more likely to have an inflamed esophagus.
 They're also more likely to develop cancer of the esophagus, skin cancer, and leukemia.
Failure to repair DNA correctly may be the culprit.

How to Get Niacin From Food

Look, we're not done talking about how nuts niacin is.

There are three ways to get niacin:

✅ We can actually MAKE niacin from protein! (nuts, right?)

✅ The niacin in grains, seeds, and coffee is bound up, and these foods need to be processed in special ways to release
it.

✅ Niacin is freely available in animal foods, yeast, and pulses (lentils, peas, and beans).

Protein
Making niacin from protein ain't easy.

 Making it from protein requires iron, riboflavin, and vitamin B6. Deficient in these? You're
out of luck. In men, the ability to convert protein to niacin might just be a way of getting rid
of excess protein. The body doesn't have a way of engaging the pathway more when you
need more niacin. In women, estrogen increases the conversion of protein to niacin.

Is this a way to support the huge energy needs of making a baby? Or to supply the baby with niacin? I don't know, but it
means that you make more niacin when you're ovulating, about to start menstruating, taking birth control, pregnant, and
young. You make less after menopause.

The RDA, the official recommendations for how much niacin we need, says that women need less than men. But they
ASSUMED this because women weigh less and eat less than men. Even the studies they had in 1998, when they made
the RDA, showed that women needed more. And the role of estrogen suggests women have specific needs for niacin
during times when estrogen runs high. Women may be better than men at making niacin from protein. So women on
high-protein diets who have plenty of iron, riboflavin, and vitamin B6 in their diet might need less preformed niacin
than men. But women on low-protein diets or who have deficiencies in those nutrients (SO MANY WOMEN!) likely
need more food niacin than men.

And neither men nor women make more niacin from protein specifically because they eat less niacin from food. So
there's never a guarantee you'll get enough from protein.

Coffee, Grains, and Seeds

Please don't tell me you like weak, light roast, decaf coffee. 😔

Coffee is a great source of niacin, but:

💪 Roasting frees the niacin. Compared to light roast, dark roast doubles it and Italian heavy roast triples it.

💪 The stronger your coffee, the more niacin in a cup. The weaker your coffee, the less.

😳 Decaf cuts the niacin in half.

85-90% of niacin in whole grains is bound up, and 40% of the niacin in seeds is bound.

✅ Traditional rising of a yeast bread frees 25% of the niacin.

✅ Sprouting for 3 days frees 20% of the niacin.

✅ 8-hour sourdough fermentation frees 80% of the niacin.

✅ Baking with 3.5 grams of baking soda per 100 grams of flour frees all of the niacin.

So:

 Don't trust nutritional databases for coffee, grains, or seeds.

  Make strong, dark or heavy roast, fully caffeinated coffee.
 Use a combination of 3-day sprouting and 8-hour sourdough fermentation for grains, or bake
them with a hefty dose of baking soda.

I recommend eating enough protein AND covering your needs for preformed niacin from food, leaving enough wiggle
room to cover increased needs during pregnancy and lactation.

For protein, eat between 0.5 and 1.0 grams of protein per pound of bodyweight per day. Double this if you weigh
yourself in kilograms. Consider more if you're an athlete.

The Five Tiers

For food niacin, we can break it down into five tiers. In all cases, a "serving" is 3-4 ounces unless otherwise stated.

Tier 1 gives you enough niacin for a day in one serving. This includes fresh yellowfin or shipjack tuna, anchovies, liver
(beef, lamb, pork), and unfortified nutritional yeast in the amount of 3 heaping tablespoons.

Tier 2 gives you enough niacin for a day in two servings. This includes peanuts and peanut butter; liver (veal, chicken,
turkey); most fresh meat products from typical farm animals and game if they are lean cuts; certain fish (canned or fresh
bluefin tuna, salmon, mackerel, yellowfin, halibut, American shad, sturgeon, cod, mahimahi, and bluefish); certain
seeds (hemp, chia, sunflower).

Tier 3 gives you enough niacin for a day in 3-5 servings. This includes most but not all other finfish (but not shellfish);
sesame seeds and tahini, pumpkin and squash seeds, pine nuts, almonds, chestnuts, flax seeds, peas, cuts of meat that
are not muscle or liver (e.g. tongue) or are fatty cuts of muscle, many mushrooms (white, portabella, shiitake, oyster,
crimini). Tier 3 also includes coffee *if* it's Italian "heavy" roast (that's darker than dark roast!) brewed with 10 grams
of coffee per cup.

Tier 4 are foods that you can feel free to bulk up on without *hurting* your niacin status, but they aren't doing you any
big niacin favors. This includes most beans, most crustaceans, processed meats, white and sweet potatoes, tomatoes,
kale, cabbage, and whole grains processed to fully free their niacin. If you brew it at 10 grams per cup and keep it fully
caffeinated, dark roast coffee occupies the top of tier 4, while light roast occupies the bottom of tier 4.

Decaf? Weak coffee? Fuggedaboutit.

Tier 5 is foods that you can *only* bulk up on if you meet your requirements from the first three tiers first. This
includes virtually all other foods not mentioned above except sugar, fat, and enriched flour.

Enriched flour has niacin added and tends to occupy tiers 2 or 3.

Sugar and fat don't have niacin. The more sugar and fat you eat, the more you detract from your niacin status and the
more you need to focus on niacin superfoods.

For children, adjust the doses based on food intake. If they eat half as much as you, feed them half as many niacin-rich
foods. If they eat twice as much, feed them twice as many. To put numbers on it, divide all the doses in the lesson by 2,
then multiply them by every 1000 Calories your child eats.

Making It Simple
Are you feeling the need to simplify? 😬 I am! 😁

Across this series so far, we see that:

✅ Liver is a great source of vitamin A, riboflavin, and niacin, but not thiamin.

✅ Unfortified nutritional yeast is a great source of thiamin and niacin, but not riboflavin or vitamin A.
So...

✅ A half ounce to an ounce of liver per day and 3 heaping tablespoons of unfortified nutritional yeast would take care
of ALL your needs for these four nutrients without worrying about anything else, and without relying on any unnatural,
synthetic vitamins.

Comforting, right?

Other Causes of Deficiency

Deficiency isn't just about diet. Here are a few other things that cause deficiency:

❌ Hartnup's disease, a rare genetic disorder.

❌ Serotonin-producing tumors.

❌ Digestive disorders such as Crohn's and megaduodenum.

❌ Certain drugs used to treat cancer, autoimmune disorders, tuberculosis, and Parkinson's.

❌ Alcohol abuse.

❌ HIV/AIDs

A few other things are likely to increase niacin needs:

❌ Bodybuilding directs protein into muscle-building instead of niacin synthesis.

❌ Stress does something similar by directing protein into synthesis of serotonin, your stress-coping chemical.

❌ Anything that lowers energy production, like thyroid and adrenal problems, are likely to hurt niacin status.

❌ Anything that causes cellular damage, ranging from simple sunlight exposure to injury, disease, and aging, depletes
niacin in repair processes.

Remember how sunlight and tanning destroyed riboflavin? It also makes *you* destroy your niacin to repair your DNA.

And aging? We all age! Since we all age, and aging depletes niacin, many people in the anti-aging community are
enamored with niacin supplements.

Niacin Supplements
Niacin supplements have a lot of promise... But they also have a dark side.

This dark side goes well beyond the famous flushing reaction (redness, heat, itching) to high-dose niacin used to
manage cholesterol. Unlike thiamin and riboflavin, niacin can be toxic. In fact, enough niacin can cause liver failure in
humans and can kill lab mice.

What causes liver failure? As I mentioned toward the beginning of this email, we detoxify niacin using methylation.
High doses of any form of niacin will put a tax on the methylation system. Moderately high doses could make you feel
weak or throw you off mentally and emotionally, while high enough doses can damage your liver.

With that said, there are ways to manage these problems. So let's talk about each form of niacin supplement and how to
use it safely.

NICOTINIC ACID
This is often just called "niacin." It's used at high doses to lower cholesterol levels. It seems to reduce the risk of heart
disease, but for every 7 people it saves from heart disease it gives 3 people diabetes.

Using this form in this way has NOTHING to do with using niacin as a nutrient. It works as a drug that alters how you
handle fats and carbohydrates. The best way to avoid diabetes (apart from not taking it) is *probably* to avoid snacking
on carbs in the 3-6 hours after each dose of niacin you take. This is also the form that causes flushing (redness, heat, and
itching). Taking 325 mg aspirin 20-30 minutes prior can fix the flushing. Taking glycine at half the dose of the niacin
*might* help.

SLOW-RELEASE AND INOSITOL HEXANICOTINATE

These are forms of nicotinic acid that reduce the flushing, but increase the risk of liver toxicity at high doses. Although
small doses of inositol hexanicotinate in multivitamins and B complexes are probably perfectly safe, I'd rather avoid
them.

EXTENDED-RELEASE OR WAX-MATRIX

Niaspan (prescription) or Enduracin (over-the-counter) are examples. These are forms of nicotinic acid that reduce the
flushing but aren't as toxic to the liver at high doses when compared to the slow-release. If you insist on using niacin to
manage cholesterol, you'll stop flushing so much if you just stick to your guns and keep taking it. But if you can't stand
the heat, the best path out of the kitchen is to take the extended-release form. Still, I'm not a fan of using niacin to
manage cholesterol.

NIACINAMIDE/NICOTINAMIDE

As a standalone supplement, this form is sort of pointless. It doesn't cause flushing in most people and it has a lower
toxicity profile than the forms we discussed above. But it also doesn't do anything to manage cholesterol levels.
Nevertheless, it's fine as a way to make up for low intake from food.

NICOTINAMIDE RIBOSIDE (NR)

This is the best form to use for anti-aging, but it's expensive. It's superior to all other forms at nourishing your niacin
status, and it doesn't cause flushing or mess with your cholesterol. Reasonable doses to experiment with range from 75
to 2000 mg/d.

Warning:

 The anti-aging benefits make sense and there are great studies in mice.
 There are lot of positive stories from people taking this stuff.
 But no one has shown this supplement to do anything great in humans with a properly
designed study... yet.

NICOTINAMIDE MONONUCLEOTIDE (NMN)

This is probably digested into nicotinamide riboside before you absorb it. So it probably works just like NR.

Making Niacin Safe

Here are some safety suggestions for using ANY form of niacin:

✅ Don't use high-dose niacin supplements for any purpose if you have a history of liver disease, or if you have
diabetes, active peptic ulcers, gout, cardiac arrhythmia, irritable bowel disease, migraines, or alcoholism. If you
*insist,* discuss it with your doctor.

✅ Always take it with food, and spread the dose evenly across each meal.

✅ Let your doctor know if you are taking more than 750 mg/d nicotinic acid ("niacin") or 3000 mg/d of niacinamide,
NR, or NMN. Don't take these doses without a good reason to do so.
✅ Pair nicotinic acid ("niacin") or niacinamide with an equal amount of trimethylglycine (TMG). Pair NR or NMN
with half the dose of TMG. This protects against liver toxicity.

✅ Pair nicotinic acid ("niacin") with half the dose of glycine. For example, for 1000 mg nicotinic acid, include 500 mg
of glycine. You could also use gelatin or collagen if you multiply the dose of glycine by 3. For example, for 1000 mg
nicotinic acid, include 1.5 grams of gelatin or collagen. Don't worry about glycine for the other forms of niacin.

When looking for multivitamins and B complexes, my preference would be to avoid nicotinic acid and inositol
hexanicotinate. I would prefer nicotinamide riboside, but it's patented and isn't included in multivitamins or B
complexes right now. Short of NR, niacinamide (nicotinamide) would be my preference.

Wrapping Up
Allright! Let's wrap up. These tips should form the background against which you implement the MTHFR protocol. If
you have signs or symptoms discussed in this email, you may need to improve the niacin content of your diet or take a
niacin supplement. If you also have symptoms of undermethylation, or if you are see-sawing back and forth trying to
manage overmethylation with niacin supplements, then fixing your approach to niacin may be part of what you need to
fix your methylation. Here are the take-home points:

✅ We need to get enough niacin to have healthy methylation. But don't use high-dose niacin supplements to try to
suppress symptoms of overmethylation.

✅ Niacin is especially important to your mind, gut, and skin.

✅ Stress and injury as innocent as simple sunlight or as serious as dangerous diseases all increase niacin needs.

✅ 3 tbsp of unfortified nutritional yeast and 0.5-1 ounce of liver give you all your vitamin A, thiamin, riboflavin, and
niacin.

✅ If you don't use the superfoods, select your foods carefully based on the 5-tier distribution.

✅ If you use niacin to lower cholesterol, avoid snacking on carbs 3-6 hours post-dose and pair it with glycine and
TMG.

✅ If you use niacin for anti-aging, use NR and pair it with TMG.

✅ If you use multivitamins or B complexes, look for niacinamide/nicotinamide.

How Pantothenic Acid (B5) Supports Methylation

Pantothenic acid is not directly used by MTHFR the way niacin and riboflavin are, but it still supports methylation in
several ways:

 It is absolutely fundamental to breaking down food for energy and using the energy to
make ATP. ATP is needed to activate methionine to SAMe so it can be used for
methylation.
 ATP is also required to make glutathione, the master antioxidant of the cell. That
means pantothenic acid helps protect us from oxidative stress. This helps prevent us
from breaking down homocysteine unnecessarily, which makes it available to recycle
to methionine so that it can be used for methylation.
 When we do have to break down homocysteine, some of it generates ammonia.
Ammonia can make our breath smell bad and make us feel fatigued. Pantothenic acid
helps us clear away the ammonia.

As with the other B vitamins, there's so much else that pantothenic acid does!
So Much to Say About Pantothenic Acid
Have you ever felt down in the dumps? Weighed down with fatigue? Or, just lost all your enthusiasm?

Maybe it's pantothenic acid deficiency?

Most nutrition scientists would say... probably not. Or... No, definitely not. No one gets pantothenic acid deficiency.

But here's the thing. If thiamin was the carb-burner, riboflavin was the fat-burner, and niacin was the left-out B vitamin
with no nickname, pantothenic acid is...

The MYSTERY Vitamin.

Now, don't get me wrong. We know a LOT about what pantothenic acid does in the body. We know how it works.
What we don't know that much about is how much we need, or what might have to go wrong to make us deficient.

Everything we know about pantothenic acid deficiency came from highly controlled experiments. To make people
severely deficient they had to do both of these two things to them at the same time:

❌ Feed them an artificial diet that had ZERO pantothenic acid.

❌ Give them a toxin that interfered with the normal function of pantothenic acid.

Still, there's a LOT we can learn from this experiment. You ready?

Pantothenic Acid Deficiency

Eating a diet with zero B5 made people complain about fatigue, and made them seem like they had no energy or
enthusiasm. No toxin was needed to make this happen.

But the anti-B5 toxin did a lot more:

 The people started acting childish and arguing with each other all the time.
 Sometimes they'd spend all day in bed.
 Their hands and feet would go numb. They'd stamp their feet and shake their hands all the
time, trying to make them feel normal.
 They couldn't stand on their tippy toes, and some of them started walking funny.
 They got insomnia.
 Their pulse would start beating real fast from doing the tiniest bit of work.
 They got cramps, felt nauseated, farted more... and sometimes they threw up. 🤢

What B5 Does For Us

Notice how B5 deficiency has its own set of problems, yet it overlaps with the other Bs in so many ways.

For example, the funny feelings in the hands and feet happen in thiamin and riboflavin deficiency, and the mood and gut
is impacted in niacin deficiency.

The similarities reflect how closely related the B vitamins are.

When we break down food for energy, we break the food molecules into pieces and extract the energy that had been
used to hold the molecules together.

Pantothenic acid is what helps break apart the pieces.

Thiamin, niacin, and riboflavin extract the energy.

They're all components of the same system.

Other Cool Things B5 Does

But pantothenic acid does more. He takes those little pieces of food molecules and starts building things with them.

And he starts sticking them onto things, rearranging things in the cell, putting this thing here, that thing there... until
everything is just right.

He does the heavy lifting... but he's the part-time interior designer and decorator too.

While pantothenic acid is adding his magic touch ✨

... a bunch of cool stuff happens:

✅ Serotonin, the stress-coping hormone, gets converted to melatonin, the hormone that makes you sleep at night. 😴

✅ Hemoglobin gets made. This is what carries oxygen to your muscles and helps you feel energized.

✅ As I mentioned at the beginning, ammonia gets cleaned up. When you eat protein, the stuff in meat and beans that
builds your muscles, you generate a little ammonia. If you don't get rid of it, you smell funny and feel really tired.

B5 makes LOTS of other things. For example, it helps make the mucus that moistens your eyes, ears, nose, mouth,
genitals, and internal organs.

And there's a few things we think it MIGHT do: help prevent acne, reduce pain in rheumatoid arthritis, lower
cholesterol, help wounds heal faster, and maybe, maybe just maybe, keep our hair from going gray.

The Great Pantothenate Mystery

So what's the mystery then?

Here's how the standard story goes.

Pantothenic acid is so easy to get from food that you can't become deficient if you eat natural foods. You can't even
become deficient by eating junk food. The only way to get deficient is to be in a laboratory experiment designed to give
you a deficiency. In fact, pantothenic acid takes its name from the Greek word "pantos," which means "everywhere" or
"everything." Pantothenic acid is EVERYWHERE. It's in EVERYTHING. Therefore, you will never become deficient.

As a result of this idea, we have way less research into how much we need to be healthy. The Food and Nutrition Board
of the Institute of Medicine is the committee that makes the RDAs. The RDA is how much people should eat of a
particular nutrient, on average, to make sure that most people aren't at risk of getting too little. Sometimes there's not
enough evidence to make an RDA. Instead, the committee makes an "adequate intake" or "AI." An AI basically means
"people are already eating this much and nothing seems to be wrong with them, so it's probably OK." And that's exactly
what we have for pantothenic acid.

Is it really true that none of us will ever run deficient? There are some good arguments against that idea:

 The study that produced fatigue and loss of enthusiasm on a zero-B5 diet only lasted 9
weeks. Things could have gotten a lot worse if it went on longer.
 Alcohol actually acts like an anti-B5 toxin, and lots of us drink alcohol.
 Because there's so little research, we hardly know anything about what increases our needs
for B5.
  Fatigue, grumpy mood, gut problems, cramps, and insomnia are pretty common. In fact,
tingling in the hands and feet isn't even that rare.

All of these things could have plenty of other causes, but how will we ever know if B5 is part of the picture if we just
assume that it isn't?

The official recommendation is 5 milligrams per day (mg/d) for most adults, 6 mg/d for pregnant women, and 7 mg/d
for lactating women. I recommend shooting for 10-12 mg/d. I also recommend increasing your B5-rich foods or trying
B5 supplements if you have anything that seems like it could be a B5 deficiency problem.

We're about to start looking at foods. One thing to keep in mind as we do: A lot of B5 gets destroyed by heat,
processing, and storage. So it's VERY important never to use values for raw foods in a nutritional database unless the
food is fresh (not canned or frozen) and you're eating it raw. Everything I'm about to show you uses data for cooked
foods, except a few cases where the food is usually eaten raw. I point it out whenever that's the case.

All right, ready to look at foods?

B5 in Foods
We can separate the foods into five tiers. Unless otherwise stated, a serving is 100 grams, or 3.5 ounces.

TIER 1 gives you 10 mg in one serving.

There's one natural food in this tier...

... and it's not liver. 😯

That one food is 2 heaping teaspoons of unfortified nutritional yeast (used raw).

TIER 2 gives you 10 mg in two servings.

It includes the livers of chicken, beef, lamb and veal.

And, roasted sunflower seeds.

TIER 3 gives you 10 mg in three servings.

 beef pancreas or kidney

 gjetost cheese
 black and red caviar
 kidney from lamb imported from New Zealand
 pork liver (and most products made from it)
 shiitake mushrooms or canned grape leaves

Many cuts of muscle meat belong in tier 3, but many belong in tier 4.

TIER 4 gives the AI (5 mg) in five servings.

 Eggs
 Duck, goose, or emu
 Fresh salmon or trout
 Raw avocado or canned chilli
 Peanuts, peanut butter, and cashews
 White or portabella mushrooms
 Pate
  Giblets or heart from chicken or turkey
 Beef thymus or heart
 Pork kidney or brain
 Lamb brain

TIER 5 are foods where you would meet the AI of 5 mg if you ate four pounds of them collectively.

Tier 5 includes cuts of fresh meat that aren't in higher tiers, whole grains, most natural dairy products besides butter,
most seafood that isn’t canned, most beans that aren’t canned, raw coconut, most nuts and seeds, most processed meats,
and most spices.

Watch Out for These If You Don't Want to Be

Deficient!
Refining flour removes half the B5, and B5 is *not* added to enriched flours.

Sugar, fat, refined flour, and many canned, heavily cooked, or heavily processed foods have little to no pantothenic
acid. The more of these foods you include, the more important it is to eat from the top tiers.

There are a few things we should suspect raise the need for pantothenic acid:

❌ Burning fat requires about 20% more pantothenic acid than burning carbs. This is a small effect compared to
riboflavin, but a high-fat diet may modestly increase our needs.

❌ Alcohol inhibits the activation of B5 and prevents us from using it properly.

❌ In the third trimester of pregnancy, the mother starts sending large amounts of pantothenic acid to the fetus at her
own expense.

❌ A lactating mother puts almost 2 mg/d into her milk.

❌ Gut bacteria might play a role in making pantothenic acid for us, stealing it from us, or making antagonists.

❌ There is a collection of very rare genetic defects in the ability to activate B5.

❌ Pantothenic acid is harder to extract from food than other B vitamins. A healthy person may only extract half the B5
from food, and someone with poor digestion might get even less.

✅ However, the major forms in food cannot be obtained from any supplements on the market! They are a lot easier to
convert into the active forms that we need in our bodies. We *know* the forms in food are superior for these folks. And
they MIGHT be for the rest of us!

B5 Supplements
Pantothenic acid supplements come in a few different forms.

PANTOTHENATE

This comes as sodium pantothenate or calcium pantothenate. It's one of the forms you get from natural foods. It works
perfectly fine as a means of fulfilling your basic needs. It's probably what's in your multivitamin or B complex.

Nutritional doses of pantothenate are in the range of 5-15 mg. Our needs are very poorly studied, though, and 100 mg/d
seems to be used well by the body rather than going to waste.
1 gram per day has been used to reduce pain in rheumatoid arthritis, and doses between 2 and 10 grams per day have
been used for acne.

PANTETHINE

This exact molecule isn't found naturally in food to any meaningful extent, but it breaks down into natural forms within
your intestines, and it *might* be made by some of the bacteria in our gut.

It does supply you with pantothenic acid to help meet your requirement, and it may actually be better at doing that than
pantothenate.

It is mainly used, though, for lowering cholesterol.

At 300 mg taken three times a day, it has special drug-like effects not shared by ordinary pantothenic acid that lower
cholesterol levels. It's definitely effective at doing that, but hasn't been studied for its ability to reduce heart disease.

DEXPANTHENOL

This is a topical form designed to be stable in creams and lozenges. It's used to speed up wound healing. The creams go
on injured skin and the lozenges are for injured tissue within the mouth or throat. Once they dissolve, the dexpanthenol
converts to pantothenic acid. Several studies suggest it works.

While there are more questions than answers with pantothenic acid, the good news is there is no known toxicity.

At 900 mg/d of pantethine, barely more than 1% of people get heartburn, itchiness, or diarrhea.

Occasionally someone develops irritation or eczema from using the topical creams.

In theory, high doses of pantothenate might hurt the absorption of biotin, or vitamin B7, a nutrient we'll cover two
lessons from now.

I don't recommend taking doses higher than 100 mg unless you have a good reason to do so. And when doing so, it's
wise to make sure you're getting plenty of all the other B vitamins.

Wrapping Up
Let's wrap up! These tips should form part of the background against which you implement the MTHFR protocol. If
you have signs of deficiency, you may need more B5. If you also have signs of undermethylation, then fixing your B5
might help you fix your methylation. Here are the take-home points:

✅ Pantothenic acid deficiency is most likely to cause fatigue and tiredness.

✅ It may also cause poor mood, insomnia, gut problems, cramps, and numbness or tingling in the hands and feet.

✅ Acne, high cholesterol, and poor wound healing might be helped by B5.

✅ Shoot for 10 mg/d. A little nutritional yeast and liver give you way more than that.

✅ If you have any signs of deficiency, it's harmless to try extra B5 to see if it helps.

✅ High doses and topical creams are safe, but use them only with a good reason to do so and make sure you've got
plenty of other Bs.

How Vitamin B6 Supports Methylation

Vitamin B6 is often included in supplements designed to reduce levels of homocysteine. These supplements aim to
lower homocysteine because too much of this compound contributes to heart attacks and strokes. Vitamin B6 helps us
break down homocysteine when we have too many methyl groups and don't need to recycle it for use in methylation
(such as after a protein-rich meal), or when we are experiencing oxidative stress and need to break it down to make
glutathione. When we break down homocysteine, some of it is turned into ammonia, which can make us smell funny
and make us feel very tired. Vitamin B6 helps us clear away the ammonia.

Vitamin B6 also supports methylation in several other ways:

 One of the ways we can get carbons to make new methyl groups in between meals is to take
them from serine, an amino acid. This requires vitamin B6.
 Another way we can get carbons to make new methyl groups is to break down glycine into
pieces. This also requires vitamin B6.
 When we are fasting, or when we are eating a low-carb diet, we will need to release stored
glucose or make new glucose from protein. Vitamin B6 is needed for both of these
processes. Glucose is needed to provide the hydrogen and its electron "glue" that MTHFR
uses to finish making the methyl group of methylfolate.
 Vitamin B6 helps us burn food for energy, especially protein. This helps us make ATP,
which is needed to convert methionine to SAMe so it can be used for methylation.

That's methylation, but there's so much else to say about vitamin B6!

So Much More to Say About Vitamin B6

To review our B vitamins so far:

 Thiamin was the carb-burner.

 Riboflavin was the fat-burner.
 Niacin was the nicknameless foundation of all energy metabolism and repair.
 Pantothenic acid was the mystery vitamin.

What is B6?

Vitamin B6 is...

The MAGICIAN. ✨

 He changes protein, the stuff in meat and beans that makes your muscles grow, into carbs,
the stuff in rice and potatoes!
 He changes protein into neurotransmitters, the little molecules that your brain cells use to
talk to one another, and that your nerves use to sense your environment and to control your
movements.
 He makes protein DISAPPEAR.
 He makes glucose, the main carbohydrate you use for energy, APPEAR seemingly out of
nowhere!

Ok, analogies are fun, but let's get more technical.

What Vitamin B6 Does For Us

Protein is present in all foods, but especially rich in lean meats. Fatty cuts of meat, eggs, and most dairy products
besides butter are also rich in protein. Among plant foods, pulses like lentils, peas, and beans have the most. Protein is
made of building blocks called amino acids.
Vitamin B6 does lots of things with these amino acids.

✅ It converts the amino acids into neurotransmitters.

✅ When you have too much of one amino acid and not enough of another, it converts the one you have to the one you
need.

✅ It converts the amino acids into glucose whenever you don't have enough.

✅ Most things you do with protein generate some ammonia. If you don't get rid of this, you'll smell funny and feel like
crap. B6 helps you convert the ammonia into urea, which isn't toxic and has no color or odor at all. That stuff, you just
pee out. Basically, it makes protein disappear! ✨

B6 even does things that are unrelated to protein.

✅ You store carbohydrate in your muscles for use during high-intensity exercise, and in your liver to sustain your blood
sugar in between meals. B6 helps release the stored carbohydrate so you can use it.

✅ It helps you make hemoglobin, which you use to carry oxygen in your blood. This prevents anemia and helps you
feel energized.

✅ Homocysteine is a little chemical that tries to do good, but sometimes gets into trouble, especially when you eat a lot
of animal protein. High levels might contribute to heart disease. When there's too much hanging around, B6 helps get
rid of it.

✅ Histamine is famous for causing allergies. Believe it or not, lots of FOODS have histamine, and B6 helps you get rid
of it.

✅ Oxalate is a chemical that contributes to kidney stones. Some veggies are very high in oxalates, and B6 won't do
anything about those. But many people nowadays are consuming lots of bone broth, or collagen supplements. Those can
generate oxalate and B6 DOES help prevent that from happening.

Vitamin B6 Deficiency
So what does B6 deficiency look like?

You might become more irritable, depressed, confused, or anxious, or develop insomnia. This is from your
neurotransmitters getting messed up. You can develop skin problems that look a lot like riboflavin deficiency (review
the B2 email if you need to!). B6 helps regulate the immune system by putting its energy into the right uses. In
deficiency, you get sick more often. Yet you're more likely to have chronic inflammation, like arthritis. Basically, your
immune system gets confused. Deficiency causes anemia, because you can't make hemoglobin. Your homocysteine will
run high, but mainly after you eat, so a fasting blood test will probably miss it. Your blood sugar might drop, making
you feel irritable, shaky, or fatigued between meals. This is unlikely, though, because your body does its best to
conserve B6 for blood sugar regulation even when you're running low on it. Low B6 levels might also contribute to
kidney stones, cognitive decline in old age, and the morning sickness of pregnancy.

Vitamin B6 in Foods
B6 comes in two forms in foods:

🥩 Animal foods have pyridoxal.

🌱 Plant foods have pyridoxine.

Similar to vitamin A, it's the animal form that we need. We can convert the plant form into the animal form within our
liver, but it requires riboflavin and a healthy liver. Additionally, most plants have a lot of their B6 bound to sugars that
make it hard to absorb. We can get, at best, only half the B6 from these sugar-bound forms. At worst, we might not get
any. As a result, you should NEVER trust the values for B6 in a nutritional database when looking at plant foods.

Cooking presents another important issue. Cooking makes B6 bind to the protein in the food. This doesn't just destroy
the B6. It actually turns it into a B6 antagonist! Now the magician himself is victim to the dark magic of the oven.
Overall, you can expect cooked animal food to have 25-30% less B6 activity than the raw version, and 40% less for
plant foods. It depends how much you cook them though.

The RDA for B6 is 1.3 mg/d for most adults. Over the age of 50, it goes up to 1.7 mg/d for men and 1.5 mg/d for
women. In pregnancy, it goes up to 1.9 mg/d, and in lactation it goes up to 2 mg/d. Let's use 2 mg as our benchmark
when we look at foods, and go with the 5-tier approach we've been using. Unless otherwise noted, a serving is 100 g
measured before cooking. These are all natural, unfortified foods.

TIER 1 gives you 2 mg in one serving.

1.25 heaping teaspoons of unfortified nutritional yeast (used raw).

TIER 2 gives you 2 mg in three servings.

Liver (beef, turkey, veal, lamb), emu, fresh tuna, salmon, chicken and turkey breast, top round and eye of round beef
steak, Canadian goose, rice bran.

Pistachio nuts MIGHT belong here but I don't know how much of their B6 is sugar-bound.

TIER 3 gives you 2 mg in five servings.

It includes chicken liver, and many cuts of fresh meat, poultry, and fish not in tier 2, though many of these go in tier 4,
and there is little rhyme or reason to it.

Chestnuts, sesame seeds, sunflower seeds, and ginkgo nuts MIGHT belong here, but I don't know how much of their B6
is sugar-bound.

TIER 4 gives you 2 mg if you eat two pounds of these foods collectively.

Many fresh cuts of meat, poultry and fish, many processed meat products, some cheese (American, feta, soft goat),
whelk, and octopus. Beef heart.

Hazelnuts, walnuts, corn, peanuts and peanut butter, white rice, and bananas.

These foods MIGHT belong in tier 4, but I don't know their sugar-bound content: Hemp seeds, buckwheat, brown rice,
quinoa, teff, cashews, barley, mung beans, macadamia nuts, potatoes.

Most beans that have been measured have high sugar-bound content, so these probably aren't good sources, but if their
sugar-bound content were low, they'd be in tier 4: lentils, lima, chickpeas, lupins, several beans (yellow, white, French,
kidney, yardlong).

TIER 5 provides 2 mg if you eat four pounds collectively (the average person eats four pounds of food a day, total).

Many cuts of fresh meat, poultry, and fish go here. There is little rhyme or reason to which ones go in tiers 3, 4, or 5.
Eggs go here. Crab goes here, but most shellfish not already listed don't make the cut. Many nuts not already listed go
here, but almonds don't make the cut. Some cheeses (brie, gjetost, soft goat), coconut, most soy products. Mungo beans
MIGHT go here, but I don't know how much B6 is sugar-bound in them.

FOODS THAT DON'T MAKE THE CUT

Here are foods that don't even make it into tier 5: fat, canned fish, almonds, collagenous tissues like feet and bones;
most non-liver organ meats; most cheeses, many beans, fried foods, and heavily processed foods.
Simplifying the Food Sources
Obviously we need to simplify this.

Since many good foods don't even make the cut, and since different cuts of meat are so wildly variable, it makes sense
to do the simple thing: if you don't supplement, throw 1.25 teaspoons of unfortified nutritional yeast into one of your
meals. After all, every B vitamin except riboflavin has so far been a reason to get at least that much.

Other Reasons for Deficiency

There are a number of things that could make us deficient besides just poor food choices:

❌ Riboflavin deficiency prevents us from getting B6 from plant foods.

❌ Variations in genetics and gut flora may also make it harder to get B6 from plant foods.

❌ Estrogen from oral contraceptives, pregnancy, or the peaks at ovulation and just before menstruation raise B6 needs.

❌ Sulfite destroys vitamin B6. Sulfite can come from food additives (🍷!). It also rises during pregnancy or when we
consume a diet high in animal protein and low in legumes. Bad bacteria in the gut can make sulfites too.

❌ Inflammation raises our needs for B6.

❌ High-protein diets raise our needs for B6.

❌ Nonsteroidal anti-inflammatory drugs (NSAIDs) and drugs used to treat tuberculosis and Parkinson's raise needs for
B6.

❌ There are rare genetic disorders that require extremely high doses of vitamin B6 to correct.

A Note on Estrogen
One of my consulting clients had very high estrogen levels and suffered from insomnia. Estrogen makes us convert the
amino acid tryptophan into niacin (see the previous email on vitamin B3 for more on this!). When we don't have enough
B6, tryptophan only gets partly converted to niacin and gets turned into some chemicals that can cause us to feel
overstimulated and can cause insomnia. Using the testing for vitamin B6 status outlined in the Cheat Sheet, we were
able to identify these exact chemicals in her urine. This made it clear that the estrogen was increasing her need for
vitamin B6 beyond what she could get from food. She started taking vitamin B6, and boom! Better sleep than she'd had
in many months.

Testing for Vitamin B6 Status

Testing for vitamin B6 status is not as straightforward as you would think. You can get your blood levels checked at
LabCorp or Quest, but these don't tell you whether enough vitamin B6 is getting into your cells and doing its job. In
fact, some people have poor transport of B6 into their cells, and their blood levels run high even though they need more.
And if you've been taking B6 supplements, the blood levels are mostly worthless. The best tests are actually three
chemicals that appear in your urine on a urinary organic acids test. These are all outlined in Testing Nutritional Status:
The Ultimate Cheat Sheet, my comprehensive system for managing nutritional status.

Vitamin B6 Toxicity
Given all this, maybe it's time for a supplement!
But wait!

Unlike B1, B2, and B5, B6 pairs up with B3 in being toxic at high doses. 😬

Signs of B6 toxicity are numbness to touch or temperature, tingling, burning or pain in the hands, feet, arms, or legs,
and loss of full control over body movements. To avoid toxicity, start with low doses around 10 mg/d. Work up slowly
to a maximum of 100 mg/d. Only go higher than this with the guidance of a health care practitioner.

The good news is B6 toxicity symptoms usually go away as soon as you stop supplementing. 😁

Vitamin B6 Supplements
So let's take a look at the supplements available. There are two main forms.

PYRIDOXINE HCL

This is the form found in plants. While it is the most studied and it clearly works, I don't favor using it because its
efficacy will depend on your genetics, liver health, and riboflavin status.

PYRIDOXAL 5'-PHOSPHATE (P5P)

This is the form found in animal products. I recommend always using this simply because you don't need to worry about
your genetics, riboflavin status, or liver health in the way you do with pyridoxine.

I recommend trying supplements whenever you have symptoms that might be related, and when a food-first approach
just doesn't seem to work. High estrogen levels or inflammation are two common reasons to need supplements. There
may be other reasons that none of us yet understand. Just work up slowly from a low dose toward 100 mg/d and see if it
helps.

Wrapping Up
Let's wrap up! These tips should form part of the background against which you implement the MTHFR protocol. If
you have signs of B6 deficiency, you may need more vitamin B6. If you also have high homocysteine or signs of
undermethylation that are especially strong in the fasting state, fixing your B6 status may be an important way to help
fix your methylation. Here are the take-home points:

✅ Insomnia, problems with mood or mental health, and anemia are the biggest clues of needing more B6.

✅ High estrogen, high-protein, inflammation, certain drugs, and sulfites are the biggest reasons to need more.

✅ A little nutritional yeast every day is the best insurance against deficiency.

✅ Pyridoxal 5'-phosphate (P5P) is the best supplement. Use it when food doesn't seem to work, and move slowly from
10 to 100 mg/d as needed.

How Biotin (B7) Supports Methylation

Biotin is critical to our ability to break down food for energy. That makes it critical for making ATP, and we need ATP
to activate methionine to SAMe so we can use it for methylation.

Energy is also needed to protect against oxidative stress, because ATP is needed to make glutathione, the master
antioxidant of the cell. Since oxidative stress leads us to break down homocysteine, biotin's antioxidant protection can
preserve homocysteine so that it can be recycled to methionine and used for methylation.
When we do break down homocysteine, some of it will generate ammonia. Ammonia can make us smell bad and feel
tired. Although biotin is not absolutely necessary to clear ammonia, it helps us use the carbs in our diet to mop up
ammonia more effectively.

As with the other Bs, there is so much more to say about biotin!

So Much More to Say About Biotin

Itch itch itch.

Itchy itch itch itch itch itch.

Biotin deficiency, like many of the other B vitamin deficiencies, can really mess up your skin. In this case, the areas
affected tend to be the eyes, nose, mouth, and the perineum, which is the area between the anus and genitals. The skin in
these areas gets scaly and red, and may be oily. As was the case with riboflavin, the rash is usually infected with
candida. You may even get conjunctivitis. Your hair, including your eyebrows and eyelashes, can start falling out.

You may get depressed, feel lethargic, and get some tingling, numbness, or a sense of something crawling on your skin.

It can get worse.

When it gets really bad, it causes you to lose control over your body movements, hallucinate, and sometimes even have
seizures. In infants, it causes "floppy baby syndrome" from low muscle tone, plus fatigue and slower than normal
development.

What Biotin Does for Us

Biotin protects against all of this by serving as the MASTER BUILDER. Biotin builds things up. In fact, even when
biotin helps break things down, it's by building them up:

🔥 Biotin builds the fire in which all our food is burned for energy.

🔥 Several amino acids (the building blocks of protein) require additions made by biotin in order to enter that fire.

And then there are times when biotin builds things up to actually build bigger things that will hang around. Specifically,
biotin is needed to synthesize fatty acids, which are the oily components of the fat in our diet and the major components
of the membranes that envelop our cells and all of their inner compartments.

Biotin doesn't just make new fatty acids. It also takes smaller fatty acids and makes them bigger. Eventually in this
series we will cover the essential fatty acids. For now, let's just say that animal foods contain the ones we need, while
plant oils contain smaller version of them. Biotin helps us convert the smaller ones in plant oils into the bigger ones we
get from animal foods.

Overall, biotin's roles are simple -- only five enzymes require it. For some other B's, there are hundreds! The skin
problems are probably from a deficiency of the essential fatty acids needed to make the skin barrier. The neurological
problems are from a lack of the fire needed to burn food to fuel the brain's enormous energy requirement.

There's just one more piece to the puzzle.

Remember how we said pantothenic acid breaks apart food molecules into little pieces, while niacin and riboflavin
extract the energy? The reason a few amino acids require biotin to enter the fire is that their pieces are stuck to
pantothenic acid until biotin makes the additions needed to pry them off. When biotin deficiency gets really bad, it's
probably the case that B5 gets "functionally deficient." It's there, but its hands are tied. It watches our metabolism start
falling apart and it just can't do anything because it's busy juggling all these pieces of amino acids that never make it
into the fire. So some of the parallels with B5 deficiency like depression, fatigue, numbness, and tingling might result
from this functional B5 deficiency, in addition to the general failure of the metabolic flame.

And the red, scaly, oily skin that it shares in common with B2 and B6 may be related to their common roles in deriving
essential fatty acids from plant oils. B6 and biotin help us get those fatty acids directly. B2 helps us harvest B6 from
plant foods.

See how much we get from TEAMWORK?! 😃

Getting Biotin From Food

Just as there are fewer things to say about what biotin does in the body than other B's, looking at where we get it from
food is simple too. The best sources, by far and away, are liver and egg yolks.

Meanwhile, egg WHITES have a substance that binds biotin and prevents its absorption. Therefore, consuming egg
whites without the yolks creates the greatest risk of biotin deficiency. In fact, before we knew what biotin was, we
called its deficiency "egg white injury." The fact that "egg white injury" could be cured by eating liver led to the
eventual discovery of biotin!

Thankfully, cooking egg whites helps destroy their biotin-binding substance. However, it depends how you cook the
egg:

 Poaching does very little, leaving behind 71% of the anti-biotin activity.
 Frying is better, but it still leaves behind 33% of the anti-biotin activity.
 Boiling for four minutes destroys most of it, leaving behind 5-10%. Boiling for six minutes
destroys nearly all of it.

Thankfully, egg yolks are incredibly rich in biotin. If you consume a raw egg, the yolk will give you enough biotin to
mop up all of the biotin-binding substance, and then half of the biotin will be available to you. If you consume a fried
egg, almost 80% of the biotin gets absorbed. A boiled egg? All cash in the bank. 💸😁

The real problem is if you throw out the yolks. Then, the biotin-binding of the egg white will mop up the *precious
little* biotin in the rest of your diet. Only liver can save you from "egg white injury" then. Still, if you boil the egg
whites till they're as firm as they would be in a boiled egg, you should be safe.

With that said, if you don't eat egg yolks or liver you're really missing out on biotin. The USDA database doesn't even
have data on biotin! But the scientific literature has a few papers. Meat, fish, peanuts, sunflower seeds, almonds,
walnuts, pecans, canned mushrooms, broccoli, and avocado have decent amounts.

But how much do these foods contain?

 100 grams of whole eggs has 21.4 micrograms (mcg).

 Beef liver has double this. Chicken liver has 9 times this.
 Meats are variable, but have only about 20% as much.
 Peanuts are close to eggs at 81% as much.
 Sunflower seeds have only 36%.
 Almonds have 20%.
 Walnuts have 12%
 Pecans and canned mushrooms have 10%.
 Broccoli and avocado have 4%.

Nuts and seeds seem the best choices for vegans, with fruits and vegetables providing teeny bits that can be significant
with large volumes.

How Much Do We Need?

As with B5, when the Food and Nutrition Board of the Institute of Medicine met in 1998 to set an RDA for biotin, they
didn't have enough evidence. They set an "adequate intake" or "AI" (an "everyone else is doing it and they seem OK")
of 30 mcg/d for all adults, adding nothing for pregnancy and increasing to just 35 mcg/d for nursing women.

You can get this from 3 whole eggs, 2.5 ounces of beef liver, or just over half an ounce of chicken liver. It would
require 6 ounces of peanuts, 13 ounces of sunflower seeds, 1.5 pounds of almonds, or 2.5 pounds of walnuts. Nuts are
great, but they contain substances you shouldn't overdo, so I don't recommend eating pounds of them.

For omnivores, these are the best biotin rules:

✅ Eat liver once or twice a week.

✅ On the days you don't eat liver, eat three eggs.

✅ Or, if you spread your liver out to an average of 4-8 ounces per week, eat two eggs most days and three on one or
two days a week.

For vegans:

✅ Focus on nuts, seeds, fruits, and vegetables.

✅ If you like peanuts, eat 'em!

✅ Look out for signs of deficiency, and take a supplement if you notice any.

Gut flora *might* provide biotin, but the jury is still out.

Pregnancy!
But there's one big, big, big issue we still need to discuss: PREGNANCY. The blood that nourishes the fetus during
pregnancy has 3 to 17 times more biotin than the mother's blood. The milk of a nursing mother has 10-100 times more
biotin than her blood. A mother's body expends enormous energy supplying biotin to her baby at her own expense.

One-third of mothers spontaneously become biotin-deficient during pregnancy. This is based on blood and urine tests
showing the deficiency. Not all of them develop symptoms. But, when lab animals develop the same degree of
deficiency, the risk of birth defects increases dramatically. So it's SUPER important for pregnant women to get enough
biotin. Pregnant women, to be on the safe side, should limit liver to 4 ounces per week. So, it's either eggs or
supplements.

Other Causes of Deficiency

There are a few other causes of deficiency:

❌ Chronic alcoholism

❌ Gastrointestinal diseases

❌ Dialysis, a treatment for poor kidney function

❌ Several rare genetic disorders

❌ High-protein diets raise the need for biotin. If you're supplementing with protein or eating more protein than usual
because you're trying to meet fitness goals, it is best to get one microgram of biotin for every gram of protein in your
diet.
Biotin Supplements
Once again, talking about biotin supplements is SIMPLE! Biotin supplements are just plain ol' biotin. They are usually
at least 5-10 milligrams, which is 500-1000 eggs worth. Some genetic disorders are treated with 200 mg/d orally or 20
mg intravenously. The absorption is 100% and there is no known toxicity. So, if you notice anything that might seem
like symptoms of deficiency, it's totally harmless to try supplements at high doses.

In fact, there's some evidence that high-dose supplements can help restore a lost sense of taste.

The only downside is that biotin shares a transporter with B5 and lipoic acid. So if you are taking biotin supplements, it
is best to take them separately from supplements of these other two nutrients and away from your best food sources of
those nutrients.

Biotin and Lab Testing

As with vitamin B6, blood levels of biotin are not the best measure of biotin status. Roughly a third of people with
biotin deficiency will be missed if relying on these tests. The best marker is a breakdown product of the amino acid
leucine that can be found in your urine. Details about testing biotin status can be found in Testing Nutritional Status:
The Ultimate Cheat Sheet.

As covered in the Cheat Sheet, taking biotin supplements can cause false readings on some lab tests. If you're getting a
test, avoid biotin supplements for four days prior just to be safe.

Wrapping Up
These tips should form part of the background against which you implement the MTHFR protocol. If any signs,
symptoms, or dietary patterns described here resonate with you, then you might need more biotin. If you also have
symptoms of undermethylation, fixing your biotin status may be an important part of fixing your methylation. Here are
the take-home points:

✅ Red, scaly, skin on the face and genitals, depression, tiredness, and various neurological problems can indicate
deficiency.

✅ Pregnancy, dialysis, digestive disorders, and alcoholism are red flags for deficiency.

✅ Egg whites are dangerous if they aren't boiled, but including the yolks makes them fine.

✅ 3 eggs a day or one serving of liver for omnivores.

✅ Nuts, seeds, fruits, and vegetables for vegans, but look out for deficiency and consider a supplement.

✅ If you are on a high-protein diet for fitness goals or taking protein supplements, get one microgram of biotin for
every gram of protein.

✅ Supplements are totally safe at high doses, just stop them four days before lab tests and don't take them close to
supplements of B5 or lipoic acid or your most important food sources of those nutrients.

Folate, occasionally called "vitamin B9," is one of the first things people think of when they think of nutrients related to
MTHFR and methylation. After all, the whole point of the MTHFR enzyme is to help us use folate to support
methylation. The protocol itself, as well as my earlier email, "Step 3: Folate Form and Dose" already covered the
essentials of folate and methylation.

Therefore, this email focuses on what else we can say about folate. Understanding folate's other roles will help us better
understand if we might need to change our dietary folate intake, tweak our folate supplements, or otherwise change
something we are doing that could impact what folate is doing in our bodies.
Folate Beyond Methylation
Folate prevents anemia, which keeps us feeling energized and keeps our brain in tip-top shape. B12 helps with this, but
it's by boosting the specific form of folate used to prevent anemia. Choline or betaine may play a *minor* role by taking
over for folate in the methylation system so that folate can focus on preventing anemia.

Folate Deficiency
When we talk about "folate deficiency" in its classical sense we mean anemia. Specifically, "macrocytic, megaloblastic"
anemia, where you have fewer red blood cells than you should, and where they are bigger than they should be. When
it's bad, this can make you feel tired, weak, and cause you to get short of breath when you exert yourself. It can make
you pale, or cause your heart to skip beats or beat irregularly.

More commonly, we look for moderate deficits of folate that elevate homocysteine. Unlike B6 deficiency, which
mainly elevates homocysteine after you eat, folate deficiency elevates it when you are fasting, so you're more likely to
catch it on a blood test.

Folate is needed to prevent neural tube defects. These are a devastating category of birth defects that include spina
bifida and anencephaly. Spina bifida leads to life-long paralysis. Anencephaly causes babies to die within hours or days
of being born. 😢

How Much Folate Do We Need?

How much folate we need is *very* difficult to answer. Why?

At least 26 other nutrients all support folate's role in the methylation process, or, like choline and betaine, help spare it
by supporting methylation independently.

With that said, let's use the RDA as a target, to get a handle on what we need to eat to hit the target from food. Folate is
measured in "micrograms of dietary folate equivalents" (mcg DFE), where different forms are counted differently
because they are more or less absorbable or usable than others. The RDA is 400 for most adults, 600 for pregnancy, 500
for lactation, and adjusted downward by bodyweight for children. For children, I personally recommend adjusting by
energy intake. In other words, if they eat twice as much as you they should get double the folate; if they eat half as
much as you, half the folate; or, make sure they get 200 mcg DFE for each 1000 Calories.

How to Get Folate From Food

Folate is most abundant in what I call "the three L's." Liver, legumes, and leafy greens. Actually for greens, it's the
"green" part that matters, not the leafy part. Look for dark green colors. In general, you want three servings per day
from this group, where a serving is 100 g. Liver should only be eaten once or twice a week, so legumes and greens are
the jackpot.

Some of these foods are so rich that you can cut the requirement down to TWO servings instead of three:

✅ Any kind of liver.

✅ Chickpeas, or any of these beans: kidney, lima, soy, mung, black, and pinto.

✅ Leeks, spinach, and broccoli.

If you are preparing for pregnancy, pregnant, or lactating, however, you need to increase these foods by one serving.

Folate is stable in liver during cooking, but in plant foods some is destroyed by heat and some is lost in the cooking
water. If you cook all your plant foods, you should add an extra serving per day, and if you discard the water, you
should add another extra serving. Folate is also stable in frozen liver but not frozen vegetables. Count frozen veggies as
ZERO. So, buy veggies as fresh as possible and use them within 3-5 days of buying them. Given the heat sensitivity,
you should also avoid canned legumes. Finally, folate is lost during the rinsing of veggies. It's the cut surfaces that lose
folate, so always rinse before you cut or dice, not after.

There might be a silver lining. Four-day sprouted legumes have 4-6 times more folate than raw legumes. Since chickens
raised on pasture eat grass, a leafy green, their eggs may be several times higher in folate than conventional eggs.
Unfortunately, we don't have enough data for me to be highly confident in the numbers. But, it seems that one or two
pasture-raised eggs per day or half a serving of sprouted legumes MIGHT be able to give us enough folate. Since the
data are so scant, I recommend trying to hit the 2-3 serving mark and using pasture-raised eggs and sprouted legumes
for an extra boost.

Synthetic Folic Acid

In addition to the natural food sources listed above, supplements and fortified foods such as enriched flour contain folic
acid. Folic acid doesn't occur naturally in foods, but we readily convert it into the natural forms, so we can all use it as if
it came from food.

With that said, folic acid isn't a perfect angel. 😇

We have an enzyme, DHFR, that recycles folate when we use it to prevent anemia. This enzyme converts folic acid into
a type of folate that is indistinguishable from food folate. Some people have genetic variations in this enzyme that
makes them slower at incorporating folic acid. They have folic acid floating around in their blood.

Folic acid has some good things about it:

😇 It's cheaper and more shelf-stable.

😇 It's 70% more absorbable than food folate.

😇 It cures folate-deficiency anemia.

😇 It prevents 70% of neural tube defects.

And it has some bad things about it:

👿 It may be less effective in people with low DHFR activity.

👿 There might be harmful effects of folic acid swimming around in the blood that hasn't been converted to folate.

So folic acid isn't the ideal form of folate. 👿

But it isn't all bad either. 😈

Dietary Patterns
So let's look at a few dietary patterns.

MINDLESSLY ALL-NATURAL

This person cuts out white bread, loaded with folic acid, and starts eating frozen veggies, which have little to none. The
veggies may be "better" than the bread, but the folic acid in the bread was supporting methylation and preventing
anemia, and now it's gone.

MEAT AND POTATOES

While liver is rich in folate, muscle meat is not. Potatoes provide some folate, but not enough.
CARNIVORE

2-4 pounds of meat per day may provide enough creatine to cut the folate requirement in half. But carnivores should
play it safe and consume pastured eggs and liver, to get folate and choline.

KETO, LOW-CARB, & PALEO

These approaches are unlikely to include legumes, but if they place special emphasis on fresh, properly prepared, low-
carb, high-folate greens they can get enough.

Genetic Variations in Folate Metabolism

Numerous genes can impact folate requirements. My free choline calculator, which I first told you about in "Step 1:
Calculate Your Choline Requirement," will tell you your status for the major ones if you upload a 23andMe or Ancestry
raw data file.

Other Causes of Folate Deficiency

There are a few other things that can hurt your folate status:

❌ Alcohol and cigarette smoking appear to hurt folate absorption and utilization.

❌ Digestive disorders can cause poor folate absorption.

❌ Cancers may steal folate from you, using it to fuel their own growth but making you deficient.

❌ Some drugs antagonize folate. Methotrexate is used to treat cancer, rheumatoid arthritis, and psoriasis and does so
specifically by antagonizing folate. Various other drugs antagonize folate as well.

❌ Sunlight and tanning hurt folate status.

❌ There are rare genetic defects in folate absorption.

Is Folate Toxic?
Although folate has no known toxicity, the Food and Nutrition Board of the Institute of Medicine set the upper limit for
supplemental folate at 1 mg/d. This was based on rare hypersensitivity reactions and on cases where supplemental folate
seemed to *cause* patients with vitamin B12 deficiency to start developing neurological problems. I recommend
keeping supplemental folate under 1 mg DFE unless you have a strong reason to use higher doses. Most of the time that
higher doses are being used, they aren't needed.

Folate Supplements
Folate supplements come in several forms.

FOLIC ACID

This is cheaper, but may not be used as well by people with low DHFR activity, which there are no easy tests for. It is
not found naturally in food.

FOLINIC ACID

This is one of the forms of folate found in food. It is a little better at supporting anemia prevention than methylfolate,
but the difference is small.
METHYL-FOLATE

This is one of the forms of folate found in food. It's a little better at supporting methylation than folinic acid. In people
with very low MTHFR activity, this form might be especially potent at supporting methylation and conserving glycine.

I recommend consuming 400 mcg DFE of methylfolate on days where you don't think you can hit your folate
requirement from food. Taking it with a meal once a day is fine. However, if you are dealing with very low MTHFR
activity, I recommend using 400-800 mcg DFE and spacing it out evenly across meals.

Folate from both food and supplements can make it harder to detect B12 deficiency, something we'll talk about
tomorrow.

Some people report negative mental and emotional reactions to methylfolate. I recommend starting with very small
doses spread evenly across meals (such as 7.2-72 mcg DFE per dose) and increasing that by the same increment after
each full week with no side effects, first adding additional doses of the same amount spaced 4-6 hours apart, and then
by increasing those doses. You can use Holistic Health liquid methylfolate for this, and dilute it in oil (with only enough
mixing as necessary and low light in the room, storing it away from light once you are done) with one drop of the
supplement per ten drops of oil to reduce the dose to 7.2 mcg.

Wrapping Up
To wrap up:

✅ Folate prevents anemia and birth defects, and by supporting methylation supports mental, emotional, and physical
health.

✅ 2-3 servings of liver, legumes, or leafy greens.

✅ One more for pregnancy, lactation, or for always cooking plant foods, and another for always throwing out the water.

✅ Don't wash veggies after cutting and don't trust frozen veggies or canned beans.

✅ Cutting out enriched flour can hurt folate status.

✅ Sunlight, tanning smoking, alcohol, digestive disorders, various drugs, cancer, and rare genetic disorders hurt folate
status.

✅ Low DHFR activity makes it harder to use folic acid, but there's no good tests for it.

✅ Use my choline calculator to get your methylation genetics if you haven't already.

Allright, that's it for folate! I'll see tomorrow for B12. 🙂

B12 mostly overlaps with folate, but has one role outside of methylation, which is in energy metabolism. Supporting
energy metabolism makes B12 indirectly responsible supporting the antioxidant system so that homocysteine can be
recycled to methionine instead of broken down, and more directly responsible for providing the ATP that is needed to
activate methionine to SAMe so it can be used for methylation.

At this point let's briefly review some of the benefits of supporting methylation:

✅ Preventing a "sticky brain" that ruminates on negative thoughts and emotions.

✅ Keeping histamine levels low and preventing too many allergies or allergy-like symptoms from creeping up.

✅ Boosting choline to protect against fatty liver, and to support the digestion of fat, strong muscles, and sustained,
focused attention.

✅ Making creatine to support big, strong muscles, healthy digestion, and a positive mood.
B12 overlaps even further with folate. There was one thing folate did outside of its role in methylation: prevent
macrocytic, megaloblastic anemia (too few red blood cells that are all bigger than they should be). B12 is needed for
that too!

B12's One Role Outside of Methylation

But there's one super big crazy stupid lotsa luvly califragilistic totally expialidocious thing that B12 does that has
nothing to do with folate, choline, methylation, or any of this nonsense.

Remember when we said that biotin is needed to make some additions to the breakdown products of certain amino acids
in order to pry them off from pantothenic acid and throw them into the burning, fiery, furnace? 🔥

There are two events where this happens, and in one of them biotin simply prepares these breakdown products for B12,
and it is B12 that binds them and casts them into the burning, fiery furnace. 🔥

And if B12 does not bind them, and cast them into the burning, fiery furnace 🔥

... then, as with biotin deficiency, the pieces get stuck to pantothenic acid, causing a secondary deficiency.

This loss of B5 function is probably responsible for many of the parallels in the neurological dysfunction caused by
each of the three vitamin deficiencies. And yet they will each manifest differently, because they each have their own
unique roles.

B12 and Irreversible Nervous System

Degeneration
B12 deficiency appears to be uniquely dangerous among any of the B vitamin deficiencies because it can cause
IRREVERSIBLE nervous system degeneration. This uniqueness probably results from the combination of functional
B5 deficiency, the toxicity of amino acid breakdown products that cannot be thrown in the fire, and a failure of the
methylation system.

Many of its features are mental:

 Memory loss
 Changes in personality or mood
 In severe cases, delirium or psychosis

Outside the brain, changes generally begin at the feet and work their way up.

They can include:

 Incorrect sense of position

 Tingling, numbness, or the feeling of something crawling on your skin
 Loss of full control over your movements
 Being unable to relax your muscles
 Walking strangely

B12 deficiency can cause a few other things:

 Optic neuritis, which can cause pain and temporary loss of vision in your eyes
 Visual disturbances
 Dizziness or faintness upon standing from sudden changes in blood pressure
 Exercise intolerance from your heart not adjusting properly to accommodate your exertion
B12 and Folate Interactions
B12 deficiency causes the same macrocytic, megaloblastic anemia that folate deficiency causes. This is because the
methylation system gets backed up and folate gets trapped in that system. As a result, it is unable to leave the
methylation system and fulfill its anemia-preventing roles.

Folate, in turn, has the ability to mess with B12 in two ways:

 First, a high folate intake, from foods or supplements, can mask a B12 deficiency. That's
because it's a lot easier for your doctor to see objective evidence of anemia than it is to
notice changes in your nervous system. Since folate prevents the anemia but not the nervous
system degeneration, it can eliminate the only early objective sign of deficiency.
 Second, folate supplementation at doses of 1 milligram per day or more might actually
*cause* the onset of nervous system degeneration in people with B12 deficiency. It's unclear
why this would happen, but it may be that the folate directs B12 into the methylation system
where they act as partners, and takes it out of its role in amino acid metabolism, where it
partners with biotin.

Vitamin B12 in Vegan Foods

Avoiding B12 deficiency means eating right and taking care of your digestive system. Digestive disorders can hurt the
absorption of any nutrient, but B12 is the one case where the overwhelmingly most probable reason for deficiency is
poor absorption rather than poor intake.

With that said, foods are still very important, so let's talk about them first. Vitamin B12 is found almost exclusively in
animal products. The exceptions appear to be a very specific subsets of mushrooms and algae. For mushrooms: black
trumpet, chanterelle, and shiitake. For algae: green or purple laver (nori). Nutritional yeast does not contain B12 unless
fortified, and any other vegan foods claimed to have B12 do not, unless fortified. The vegan sources of B12 also contain
B12 antagonists. Recent studies have shown that they DO support B12 status in vegans. Still, I would caution against
ASSUMING they will support B12 status in vegans without either testing or supplementing, simply because the foods
do contain antagonists and the issue is so poorly researched.

Vitamin B12, Meal Timing, and Meal

Frequency
There's one other principle we need to discuss before diving into specific foods. You can only absorb one day's worth of
B12 at a meal. This is very important because many foods like liver, oysters, and clams have many days worth of B12
in one serving. You can't eat these foods every once in a while in large amounts and "stock up" on the B12.

One thing you CAN do is stock up by eating a day's worth at each meal. We can actually store about 30 years worth of
B12 in our bodies. How do you get a stash like that? Eat a day's worth at every meal, and each year you've got two more
years' worth in the bank. 15 years of this, and your stash is topped off.

Another thing you can do is stock up on B12 regularly during part of the year and take part of the year off. For example,
if you eat a day's worth of B12 at every meal for two-thirds of the year, you can spend four months as a vegan without
the special B12 foods or any supplements and STILL come out at the end of the year with an extra year's worth in your
stash. If you're feeling more like the grasshopper than the ant, you could just eat a day's worth at each meal for four
months. Go zero-B12 for 8 months, and you break even.

What you CAN'T do is eat clams once a month or liver once a week and expect these to supply your whole B12
requirement just because it averages out on paper.

Vitamin B12 in Specific Foods

Here are a few ways to eat a day's worth of B12 in one sitting:

✅ 8 grams of liver

✅ 8 grams of clams or oysters

✅ 8 grams of nori (laver)

Here are a few ways to eat 1/3 of a day's worth at one sitting (so you have to do these three times a day just to break
even!):

✅ 100 grams of meat, poultry or fish

✅ 8 ounces of milk or 100 grams of cheese

✅ 100 grams of black trumpet, chanterelle, or shiitake mushrooms

Unfortunately, eggs are not a good source of B12, and what they have is not absorbable. This means that lacto-ovo
vegetarians that don't eat the vegan foods above rely exclusively on milk products to get their B12. And even many
omnivores may be in trouble. If you don't eat liver, oysters, or clams, you have to eat at least 12 ounces of meat, poultry,
fish, or dairy just to break even. You have to eat a lot more to build up long-term stores.

Pernicious Anemia, Gastritis, Vegetarianism,

and Veganism
But the MAIN reasons people become deficient are not dietary. The main reason for B12 deficiency in the general
population is poor absorption.

❌ Pernicious anemia occurs in 0.1% of the general population and 2% of the elderly. This is an autoimmune condition
where the body attacks its own cells, specifically destroying the stomach cells that produce the machinery needed to
absorb B12.

The second reason is far more common.

❌ Half of us have a bacterium known as H. pylori in our stomachs. It starts causing inflammation, known as gastritis,
in childhood. Even if it doesn't ever cause symptoms, it gets worse each year, and it hurts B12 absorption. By the time
you hit age 65, it has a 20-30% chance of making you deficient. As a result, 10-15% of the elderly have B12 deficiency,
mostly from this.

Still, a much smaller proportion of the elderly are deficient than vegetarians or vegans. Putting age aside, over 70% of
all vegetarians and over 90% of all vegans have evidence in their bloodwork of early B12 deficiency. Because most
people are not vegetarian or vegan, most people who are B12-deficient are not vegetarian or vegan. But becoming a
vegetarian or vegan dramatically increases the risk of B12 deficiency.

Notice, too, the value of stocking up. If you spent your early years collecting a 30-year stash, the gastritis or pernicious
anemia could hit you at age 65 and you could make it to age 95 without bad problems. But most of us don't eat liver,
oysters, or clams, and we're just slipping by.

Other Causes of B12 Deficiency

A few other things can hurt your B12 status:

❌ Other digestive disorders that hurt nutrient absorption more generally.

❌ Stomach surgery that damages the parts needed for B12 absorption.
❌ Alcoholism, AIDS, and antacids hurt absorption.

❌ Rare defects in the absorption or utilization of B12.

Vitamin B12 Supplements

B12 supplements exist in various forms, including injection. Even when someone has pernicious anemia, they will
generally absorb a small percentage of a megadose. And there is no evidence of toxicity at high doses. High-dose oral
B12 supplements at doses of 2000 mcg per day are usually effective at treating pernicious anemia without the need for
injections.

Here are the major forms of B12 supplements.

HYDROXYCOBALAMIN

This is a major form of B12 in all natural foods. It is the "neutral" B12, not yet tagged to participate in any specific
system. I recommend it as the default form of B12.

METHYLCOBALAMIN

This is a major form in milk. It may be slightly better to use for someone with specific problems related to methylation.
On the other hand, some people with methylation problems are hypersensitive to the supply of methylated vitamins and
might experience mental or emotional side effects from this form.

ADENOSYL-COBALAMIN

This is a major form found in meat. It's the form that partners with biotin to throw amino acids into the burning, fiery
furnace. Unfortunately, it appears that we might need to break off the adenosyl part before getting it to where it needs to
go, so this form might not have any specific benefits.

CYANOCOBALAMIN

This form is not found in natural foods. Ordinarily, we use B12 to detoxify cyanide that we are exposed to from
cigarette smoke and certain vegetables. We make cyanocobalamin and pee it out. Although this form is adequate to cure
a deficiency, it is lost in the urine at a greater rate than other forms and is less effective at improving B12 status. It's
advantage is that it's cheap.

Testing Vitamin B12 Status

I believe anyone who eats a vegetarian diet and anyone over the age of 65 should be proactive about testing vitamin
B12 status, and it is best if everyone gets their vitamin B12 status checked at least once. The normal range is generally
too broad and should start at 400 pmol/L. Still, B12 levels in some cases do not tell you that the B12 is necessarily
getting into your cells and doing it's job. I provide a more complete procedure for testing B12 levels from multiple
angles in Testing Nutritional Status: The Ultimate Cheat Sheet.

Wrapping up
These tips should form part of the background against which you implement the MTHFR protocol. If you have signs of
undermethylation, macrocytic anemia, or B12-deficiency nervous system degeneration, you may need more B12.

Here are the take-home points:

✅ B12 has all the benefits of folate in methylation and the prevention of anemia AND it prevents irreversible nervous
system degeneration.

✅ High intakes of folate can mask B12 deficiency and possibly even provoke its neurological problems.
✅ Liver, clams, oysters, and nori allow you to get a day's worth into a meal, which can slowly build a 30-year storage
supply.

✅ Meat, milk, cheese, chanterelle, black trumpet, and shiitake mushrooms allow you to break even when you eat a lot.

✅ Eggs aren't a good source.

✅ Vegetarians and vegans are high-risk and should be proactive about testing or supplementing.

✅ Elderly are at high risk due to poor absorption.

✅ High-dose supplements are safe and usually effective even in cases of poor absorption.

✅ Hydroxycobalamin is the preferred default supplement, and methylcobalamin can be used to tinker with the
methylation system.

Ah! Ok, B12 is the eighth B vitamin. So choline is basically the ninth B vitamin.

In fact, in 1998 when the Food and Nutrition Board of the Institute of Medicine set the RDA's (and, when they didn't
have enough evidence, the AI's) for the B vitamins, they called them "The B Vitamins and Choline."

Choline and Methylation

Choline's role in methylation is accounted for in the MTHFR protocol by the use of trimethylglycine (TMG) by default,
and step 2 of the followup suggested reasons to use phosphatidylcholine or alpha-GPC instead.

Its role in methylation means it is important to all these things we reviewed yesterday:

✅ Clearing homocysteine, which might protect against heart disease and cancer.

✅ Minimizing histamine, which... 🤧

✅ Preventing "sticky brain" syndrome.

✅ Making creatine to support 💪, healthy digestion, smooth skin, and a happy mind.

Choline does ALL THOSE THINGS.

Interactions With B12 and Folate

There's a very important difference between how choline interacts with B12 and folate and how B12 and folate interact
with each other. Folate and B12 are partners in methylation and one will not work without the other. Choline is Team B.
Choline works IN PLACE OF folate and B12.

This means that:

 The more folate and B12 you get, to a certain point, the less choline you need.
 The more choline you get, to a certain point, the less folate and B12 you need.

But that is NOT true for folate and B12's interaction with each other. In fact, in the last two lesson we saw that:

 Folate supplementation may actually spark neurological degeneration in B12 deficiency.

So, if you want to use Team A (folate/B12), you need both players. If you need to take one off the field, don't use half
of Team A; use Team B (choline).
Choline and MTHFR
This is why low MTHFR activity increases your need for choline. One of the players on Team A is injured, so you pull
in Team B. In the average person, Team A and Team B make a 50/50 contribution to methylation. Still, there are parts
of your body where only Team A gets called in. So you can't rely totally on choline. Also, folate prevents anemia.
Choline can't do anything for that at all, except help indirectly by relieving folate of some of its methylation duties. And
B12 prevents irreversible nervous system degeneration. Again, choline does nothing for this, except relieve B12 of
some of its methylation duties.

Fatty Liver, Fat Digestion, Strength, Brain

Power, Rest and Digest
You can't just rely on folate and B12 either. Choline does two incredible things that folate and B12 don't:

 All of our cells, and all of their internal parts, are enclosed in a fatty membrane. A major
component of these membranes is phosphatidylcholine, which is made from choline. This
membrane also encloses the vehicles we use to move fat out of our livers. If we don't have
enough, we develop fatty liver disease, which increases our risk of diabetes and heart
disease. Sometimes the liver can get so damaged that we wind up in the hospital needing
emergency treatment. Phosphatidylcholine also helps us digest fat!
 Choline is used to make the neurotransmitter acetylcholine. You use this to contract your
muscles, which makes you strong. You also use it for your "rest and digest" mode, which
keeps you out of the "fight or flight" mode. Inside your brain, you use it to sustain focused
attention, to learn, and to form memories. You also use it to get REM sleep, which is a type
of sleep that supports creativity and mental health.

Can folate and B12 help? A little bit. By relieving choline of some of its methylation duties, they can let choline focus
more on liver health, fat digestion, strength, and brain power. In fact, if you don't eat enough choline, you can even use
folate and B12 to MAKE some. But this is 3 times less efficient than eating choline, so you don't want to do this when
you don't have to.

The best way to think about this is:

✅ Any deficiency in Team A (folate/B12) makes all the problems of a Team B (choline) deficiency worse.

✅ Any deficiency in Team B makes a deficiency in Team A worse.

✅ But Team A by itself can't make a Team B deficiency disappear, nor can Team B do that for Team A.

So, let's make sure we get enough choline!

How Much Choline Do We Need?

As with B5 and biotin, the Food and Nutrition Board set an AI instead of an RDA, because less evidence was available.
The AI is 550 mililgrams per day (mg/d) for men. For women, it's 425 mg/d, but increases to 450 in pregnancy, and in
lactation in becomes equal to the one for men. As usual, the AI for children is adjusted downward by bodyweight. As
usual, I recommend adjusting it on energy intake instead: 275 mg for every 1000 Calories. I will make the case later in
the lesson that women should shoot for the men's target, but let's just assume that for now.

Of course, if you calculated your choline intake using my free choline calculator, you have an even better target
designed for you according to your genetics.
Choline in Foods
As with biotin, the best sources of choline are liver and egg yolks. Since eggs are so much more popular than liver, let's
talk about the choline requirement in terms of "egg yolk equivalents." The AI for men is equal to a little over 4.2 large
eggs, including the yolk.

The following foods are equivalent to ONE egg yolk, meaning you need to mix and match four a day:

✅ Liver, measured before cooking: 1.5 ounces beef or veal; 2.0 ounces turkey; 2.5 ounces chicken.

✅ Nuts and seeds, measured dried or roasted: 200 grams of flaxseed, pistachios, pumpkin, squash, or cashews; 250
grams of pine, sunflower, or almonds; 300 grams of hazelnuts or macadamia; 400 of walnuts; 450 of Brazil nuts; 500 of
sesame.

✅ Meat and fish: 9-12 ounces, measured before cooking. Salmon clocks in at only 6 ounces though!

✅ Vegetables, spices, and dairy products: 1-2 POUNDS of these foods, measured raw. (This is 2-4 cups of milk.)

✅ 100-200 grams of beans, measured before cooking.

✅ Grains are highly variable. Measured dry, amaranth and buckwheat require half a pound; barley malt, whole wheat,
oat, and kamut, require a pound; whole corn requires 1.3 pounds and teff requires over 2 pounds.

If you eat a whole-foods diet, you are likely to get at least one egg's worth of choline from your non-egg foods. For
example, let's say you eat 12 ounces of ground beef, 3.5 ounces of lentils, both measured before cooking, and the rest of
your diet is vegetables and whole grains. You'd have an egg's worth from the beef and an egg's worth from the lentils.
This is two out of the 4.2 eggs you need. The vegetables and whole grains probably provide at least an extra half an
egg's worth. This can give you that funny little 0.2 remainder and a tiny bit of wiggle room.

What's left? You need to eat two eggs.

Betaine in Foods
Now, there's another little molecule called betaine. When we use choline for methylation, we actually turn it into
betaine first, and there's some betaine in foods. When in supplements, betaine is called trimethylglycine (TMG) and it's
the default form used in the MTHFR protocol. Eating betaine can help relieve choline of its methylation duties, but you
can't directly turn it into phosphatidylcholine or acetylcholine. So, for general health I think it is best to use betaine for
up to half of your choline intake. In the MTHFR protocol it is used as the only supplement by default, but you shouldn't
use that supplement to replace all the choline in your foods. In other words, make sure to get at least half of the AI for
choline from food choline (about two eggs' worth of choline) even if you are supplementing with TMG.

Here are the best food sources of betaine:

✅ 100 grams of raw beets or 50 grams of canned beets supplies one egg's worth as betaine.

✅ 100 grams of frozen spinach (it hasn't been measured fresh) provides one egg's worth as betaine.

✅ Wheat germ is special here. 70 grams of it provides 2 egg's worth of betaine AND one egg's worth of choline.

Vegans, Autoimmune Paleo, Egg Allergies, and

Low-Cholesterol Diets
So, let's take a look at some dietary patterns
VEGAN

Vegans won't eat the eggs or the liver. If they tolerate grains, the simplest thing to do is consume 145 grams of wheat
germ, which provides 2 egg's worth of choline and over 4 egg's worth of betaine. They can diversify by replacing some
of this with nuts, seeds, and beans.

AUTOIMMUNE PALEO

The Paleo Autoimmune Protocol ("AIP") eliminates eggs, nuts, and seeds, on top of the existing paleo restrictions on
beans and grains. The best thing to do is eat beets and spinach for 2 egg's worth of betaine, 10 ounces of beef liver per
week (providing 1 "egg" per day), and 12 ounces of meat or fish per day (providing the fourth "egg").

EGG ALLERGIES

People with egg allergies have it easier than the AIP! They have the liver AND the wheat germ option, as well as the
less potent but still useful options of beans, nuts, and seeds.

LOW CHOLESTEROL

Low-cholesterol diets restrict eggs and liver. The vegan options apply here, though meat and fish will provide some
choline.

Men and Women, and Genetics

The AI for choline is based on a study showing that 500 milligrams per day (mg/d) protected men against signs of liver
injury. Although the official numbers adjust it downward for women based on average bodyweight, there is no evidence
that women need less. In fact, estrogen, the main female hormone, causes women to make more choline. This suggests
that, if anything, they need more in their bodies.

Young women are every bit as vulnerable to fatty liver disease on low-choline diets as men are. But when estrogen
levels tank after menopause, women become TWICE as vulnerable.

The gene responsible for the ability to make choline is called PEMT. It uses the methylation system, with the help of
folate and B12, to make phosphatidylcholine, the specific form of choline needed to support liver health and fat
digestion. Some people have low PEMT activity, just because of genetics. They don't need more choline. They are just
more likely to hurt their liver and pummel their fat digestion on a low-choline diet.

Now, low MTHFR activity, on the other hand, increases your need for choline by at least 60% and might DOUBLE it.
This is because Team B (choline) needs to take over for Team A (folate/B12) when one of their players (folate) is
injured. People with the biggest hits against their MTHFR activity may need 7 to 9 eggs worth of choline per day. That's
why TMG plays such a prominent role in the MTHFR protocol.

Choline Toxicity and TMAO

Are there any risks to too much choline?

Choline at doses of 7-10 grams per day has caused low blood pressure, a fishy body odor, sweating, and salivation. The
maximum amount discussed in this email, up to 9 egg's worth a day for people with low MTHFR activity, is only 1.2
grams, far beneath this level.

Nevertheless, some people are concerned about lower amounts. There are little microbes in your gut that will turn some
choline into a compound called TMA, that your liver then turns into TMAO. The TMA causes fishy body odor, and
some people believe TMAO contributes to heart disease. The jury is out on whether TMAO does, in fact, contribute to
heart disease.

Regardless of whether it does, choline that your gut bugs turn into TMA is choline you couldn't put to good use. So we
don't want that conversion happening, one way or another.
The best ways to avoid TMAO production are:

✅ Get your choline as phosphatidylcholine, the main form found in food, rather than choline salts such as choline
bitartrate.

✅ Spread it out evenly across your meals.

Choline Supplements
Here are the main supplements.

ALPHA-GPC

This form of choline generates acetylcholine ten times more effectively than the other forms. This is the best form if
you are using it for brain power, rest and digest mode, or muscular strength. Use it at 300 mg 3-4 times a day, and
multiply the dose by 46% to see how much choline you are getting from it.

PHOSPHATIDYL-CHOLINE

This is the main form of choline found in food. It is especially good at supporting liver health and fat digestion, but it is
readily used for methylation as well. Beware of the label: only 13% of phosphatidylcholine is choline.

LECITHIN

This is a more practical way to get phosphatidylcholine, the main food form. You can add it to sauces, dressings, or
smoothies. One tablespoon provides an egg's worth of choline.

TRIMETHYLGLYCINE (TMG)

This is another word for betaine, not a form of choline. This is the form that directly supports methylation.

Capsules usually come in 500 mg. Count this as two egg's worth.

OTHER FORMS

Other forms include choline bitartrate and CDP-choline. I don't recommend these because they generate 3-4 times more
TMAO than phosphatidylcholine and have no special benefits.

Testing Choline Status

Choline levels in the blood aren't a terrific marker of choline status, but when combined with other measurements they
can be very insightful. The Genova Methylation Panel is particularly useful for seeing how well you are converting
choline to betaine and to what degree you are relying on it for methylation. Testing Nutritional Status: The Ultimate
Cheat Sheet has a 2-page guide to interpreting the Genova Methylation Panel.

Wrapping Up
Choline is already a component of the MTHFR protocol and steps 1 and 2 in the email followup covered calculating
your choline intake and choosing a specific form to supplement with. Use these take-home points to help fine-tune your
diet and supplements according to your choline needs:

✅ Choline supports all the methylation functions of folate and B12, and helps them focus on other tasks like preventing
anemia and supporting the nervous system.

✅ Choline itself protects against fatty liver, and supports fat digestion, muscle strength, and brain power.
✅ Eggs, liver, and wheat germ are the best choline sources; meat, fish, nuts, seeds, and beans follow.

✅ Alpha-GPC is the best supplement for brain health, calming, and muscle strength.

✅ Trimethylglycine (TMG) is the best supplement for methylation.

✅ Phosphatidylcholine is the best supplement for liver health and fat digestion. It should also be the default for
replacing food because it is the main form found in food.

✅ Limit to 1200 mg/d and spread the doses out evenly across meals.

Allright, we're done with choline, and with that, the first leg of our marathon is done. Having covered A and all the Bs,
our next stop is vitamin C!

How Vitamin C Supports Methylation

Vitamin C isn't usually thought of as related to methylation, but it is.

Vitamin C is critical as an antioxidant. Without enough vitamin C, we will have oxidative stress that will pull and tug at
homocysteine, sucking it all out of the methylation cycle to be used to synthesize glutathione, the master antioxidant.
When we do this, we lose the ability to use MTHFR to recycle homocysteine to methionine and then activate the
methionine to SAMe to use for methylation.

How would you know when this is happening?

It's not always obvious. It could make your homocysteine low. But imagine you also had problems recycling
homocysteine to methionine due to deficient folate, B12, or choline, or to genetic issues such as MTHFR. Those things
would tend to raise homocysteine. But if you have those issues raising your homocysteine and oxidative
stress lowering your homocysteine, your homocysteine levels might look totally normal.

And that might give you confidence that you are managing your methylation properly. Yet, it would be wrong. If you
have trouble recycling homocysteine to methionine and you break too much of it down to counter oxidative stress, then
your methionine levels are actually taking a double-hit. Your homocysteine might look great but your methylation
might be terrible.

Case in point. One of my consulting clients recently came to me suffering from terrible headaches that were interfering
with his work productivity. Based on his response to foods, he seemed clearly intolerant to histamine, and also seemed
to have high histamine levels all the time. Based on his genetics, it seemed methylation strategies were the most
sensible thing to work on. Yet they didn't seem to work. So we had his doctors run a Genova Methylation Panel. Lo and
behold, this showed that he's actually using folate, B12, and choline quite effectively, but oxidative stress was causing
all his homocysteine to be broken down to make glutathione. Yet his glutathione status was relatively poor.

Why?

Oxidative stress was depleting his glutathione, making him break down homocysteine to make more. The oxidative
stress was severe enough that his glutathione status was still relatively poor, but his homocysteine was being taxed hard.
This made less available for methylation, which raised his histamine levels, which caused his headaches. Although the
problem was impacting methylation, the solution was dealing with oxidative stress. Only after we shifted our focus
toward antioxidant support did he start suffering from fewer and fewer headaches.

All that said, vitamin C is involved in so much more than antioxidant support and methylation!

The Many Other Roles of Vitamin C

.
If some days you feel like a capybara, it's because we actually have one really important thing in common. While
virtually all animals can make their own vitamin C, humans and capybaras cannot. Others that can't include non-human
primates (like monkeys, baboons, chimpanzees, and gorillas), guinea pigs, locusts, Indian fruit bats, trout, salmon,
bulbuls, and swallows.

Since we cannot make it ourselves, we humans are one of a few select species that have to eat foods with vitamin C.

Why Vitamin C is Famous

Vitamin C is pretty famous. When most people think of vitamin C, they think of taking it for colds. 🤧

If they're sophisticated, they think of it as an antioxidant, which means that it protects our tissues from wear and tear as
we age and accumulate stress.

Vitamin C and Scurvy

In the textbooks, it's famous for preventing scurvy. Scurvy is a disease that causes bleeding in the gums and other areas
inside the mouth, bruises that appear out of nowhere, and hairs that take on the shape of a corkscrew. These are the
things you see. Beneath the surface, scurvy causes bleeding in your internal organs that can, in the most severe cases,
cause death. Vitamin C is also known as ascorbic acid, which means "the acid that prevents scurvy."

The reason for the bleeding and funny-shaped hairs in scurvy is that without vitamin C we make very weak collagen.
Collagen is a major protein in our skin, joints, bones, and the membranes that enclose all of our organs. We don't use
vitamin C to make collagen. We make it to strengthen collagen. So in scurvy, we have plenty of collagen. But man, that
collagen is WEAK. It can't hold back the blood, and it can't create proper structure for our hairs.

In scurvy, vitamin C is very deficient, so it makes the difference between weak and strong collagen. What your body
really wishes it could do is make it stronger. When you don't have scurvy, though, your collagen is pretty strong. Your
body isn't concerned with making it stronger. Instead, your body wants to make new collagen when old collagen gets
damaged. Your body will only do that if it can make the new collagen just as strong as the old collagen. If you leave
behind old collagen, you get wrinkles, joints that hurt, and bones that break more easily. Getting enough vitamin C will
help us keep our skin, joints, and bones renewed and fresh.

Vitamin C as an Antioxidant
Vitamin C doesn't just help us replace damaged collagen. It helps PREVENT damage in the first place. That's its role as
an "antioxidant." We are exposed to damaging molecules called "oxidants" all of the time, and they get worse when we
are sick, have a chronic disease like diabetes, smoke cigarettes or drink alcohol, or are around a lot of pollutants. These
oxidants cause little bits of damage as they go through our system. This causes wear and tear on our tissues over time.
Vitamin C neutralizes the oxidants, which protects against this wear and tear!

Vitamin C and Immune Function

Its roles in strengthening collagen and serving as an antioxidant are both important to its ability to help prevent colds.
Strong collagen provides a physical barrier against bad bugs that would come in and invade us.

But when they do...

You know all that stuff you have in your bathroom cabinet to sanitize things? Hydrogen peroxide? Bleach? We make
ALL OF IT inside our cells to kills those little buggers that make us sick. Hydrogen peroxide and bleach are both
examples of oxidants. They'll kill the bad guys, but they'll kill us too if we don't have protection. So, our immune
system uses vitamin C to protect itself while it's directing all the oxidants at the invaders. It's sort of like those guys in
HAZMAT suits cleaning up toxic waste. Vitamin C is the HAZMAT suit.

Vitamin C does some other amazing things.

Peeing Too Much, Gray Hair, Brain Power, Sex
Drive, and More
It makes a bunch of neurotransmitters:

✅ One of them stops you from peeing, especially at night when you're sleeping.

✅ A second one stops you from eating too much, increases your sex drive, and stops your hair from going gray.

✅ A few of them boost your thyroid, adrenal, and sex hormones. Together, these keep your brain power at full blast,
keep you lean and energized, and increase your confidence and sex drive.

✅ Finally, we use vitamin C to make oxytocin, the so-called "love hormone." We release this in response to intimacy of
any kind, from petting a dog to nursing an infant, and we release the most during orgasmic sex with someone we love.

Adrenal Hormones, Coloring the Skin, Eyes,

and Hair
We use vitamin C to make noradrenaline and adrenaline, also known as norepinephrine and epinephrine. Our adrenal
glands make these in response to stress during the "fight-or-flight" response. Inside the brain, norepinephrine makes us
feel awake during daytime. It also helps us creatively explore opportunities and commit our efforts to our best options.

We also use vitamin C to make melanin, the main pigment that colors our skin, eyes, and hair. Vitamin C plays a dual
role in keeping our hair from going gray: in the brain, it makes signals that our hair SHOULD be our birth color; then in
our hair follicles, we use vitamin C to actually make the color.

Vitamin C also plays many interacting roles in making us high-powered revved up sex machines. It makes the signals in
the brain that activate our adrenals, and then it also makes the adrenal hormones. It makes the oxytocin that produces
the affectionate response to getting close, and it also makes the signals to make sex hormones like estrogen and
testosterone. Vitamin C makes the brain signal that tells our thyroid gland to make thyroid hormone, and that's what
keeps the whole system running at top speed.

Vitamin C Interactions with B Vitamins, Iron,

and Copper
Vitamin C can't do all this alone.

When it acts as an antioxidant, it uses energy taken from thiamin, riboflavin, and niacin. In many of its other roles, it
directly partners with iron or copper. And one other thing it does is get rid of histamine, that thing that makes us 🤧. It's
especially important to clearing the histamine in the food we eat. To do that, it partners with copper and vitamin B6. So
it's important to get enough vitamin C, but also to realize that it can only do its job right when everything else is in
place.

How Much Vitamin C Do We Need?

So how much do we need?

The Food and Nutrition Board of the Institute of Medicine set the RDA for vitamin C in the year 2000. They based it on
the amount of vitamin C that would maximize antioxidant protection and immune function without much vitamin C
spilling into the urine. This amount was 75 milligrams per day (mg/d).
The research was in men, so they adjusted it downward by average bodyweight to make it 60 mg/d for women,
increasing to 85 during pregnancy and 100 during lactation. Women do, in fact, appear to need a little less than men to
achieve the same amount in their blood. For children, it is also adjusted downward by bodyweight.

One problem with the RDA is that they didn't choose the number that maximized antioxidant support or immune
function. Their data indicated that 100 mg/d gives you most of the benefit, while 150 mg helps you eek out a little bit
more. They picked a lower number that would prevent loss in the urine. But who cares about a little urinary loss if it
leads to better health?

The risk of cardiovascular diseases and some cancers is lowest at a vitamin C intake of around 90 mg/d. Maximal
benefit to immune function and antioxidant protection is about 100-150 mg/d. The maximum levels in your blood you
can achieve are by getting 400 mg per day split between two or more doses that are no larger than 200 mg at a time. The
blood levels associated with maximal protection against cardiovascular disease and cancer range in different studies
between those associated with 100 mg/d and those associated with 400 mg/d.

My suggestion would be that adult men should seek 100-150 mg/d from food, and that women and children should
adjust this amount based on calorie intake: 50-75 mg for every 1000 Calories. For extra benefit, intakes as high as 400
mg per day could be used if spread out across the day.

Vitamin C, Storage, and Cooking

Vitamin C is extremely stable in dry foods and powders, but degrades in the presence of moisture and heat. Vegetables
lose 15% of their C when stir-fried, 30% when baked or boiled, and 50% if you boil them and throw out the water. The
best way to protect vitamin C during cooking is to add a source of acidity, such as vinegar. Non-citrus fruits lose 20% of
their C when baked or broiled, and 30% when sauteed. Citrus fruits are probably more stable because of their acidity.
Meats don't contain very much vitamin C, but their losses are similar to vegetables.

Vitamin C in Foods: The Five Tiers

The foods I discuss below are raw. If you cook them, eat 40-50% more. Where you can, add a dash of vinegar and
consume any cooking water. We START with plants.

TIER 1 provides over 150 mg in one 100-gram serving.

Acerola cherry, coriander, thyme, green chilli peppers, sweet yellow or green peppers, guavas, currants.

TIER 2 provides 90-150 mg per serving.

Kale, broccoli, kiwifruit, the peels of lemons and oranges, sweet red peppers, jalapeno peppers, red chilli peppers,
parsley, Tahitian taro, mustard spinach, drumstick pods, and pokeberry shoots.

TIER 3 provides 50-100 mg, guaranteeing the RDA for lactating women in 2 servings.

Oranges, strawberries, pineapple, papayas, lemons, peas, cabbage, Green cauliflower, Brussels sprouts, banana pepper,
red or cayenne pepper, mustard greens, persimmons, kohlrabi, pummelo, turnip greens, balsam pear, taro leaves,
drumstick leaves, marjoram, saffron, dill weed, chives, longans, and litchis.

TIER 4, 30-50 mg, guaranteeing the women's RDA in 2 servings.

Cantaloupe, clementines, grapefruit, mangos, passion fruit, kumquat, asparagus, beet greens, cauliflower, Chinese
cabbage, Broccoli raab, collards, dandelion greens, Swiss chard, zucchini, sprouted kidney beans, bay leaf, lotus root,
watercress, wasabi, nori (laver), lambsquarters, mulberries, elderberries, broadbeans, cowpeas, sage, peppermint, garlic,
tree fern.

TIER 5, 15-30 mg, guarantees the men's RDA in 5 servings.

Potatoes, plantains, butternut squash, cassava, arugula, okra, radish, spinach, turnips, purslane, rutabagas, jicama, rowal,
quinces, durian, raspberries, gooseberries, blackberries, limes, and breadfruit.

Many beans: lima, navy, yardlong, winged, snap, mung, and soy.

Many spices go in tier 5: caraway, fennel, anise, mace, cardamom, dill, white pepper seed, coriander, and basil.

Foods With Smaller Amounts

Most other fresh plant foods provide some amount of vitamin C that will, if consumed in large amounts, be meaningful.
If you follow the official recommendations to eat 5-9 servings of fruits and vegetables a day, you will probably hit the
RDA without thinking about it.

Vitamin C in Animal Foods

You might think it would be hard to get vitamin C on a carnivore diet, but there's quite a bit in organ meats. Here's the
carnivore version of the breakdown. There's no tier 1 or 2. BUT...

CARNIVORE TIER 3 provides 50-100 mg, guaranteeing the RDA for lactating women in 2 servings.

Adrenal glands.

CARNIVORE TIER 4, 30-50 mg, guaranteeing the women's RDA in 2 servings.

Beef or veal thymus or lung.

CARNIVORE TIER 5, 15-30 mg, guaranteeing the men's RDA in 5 servings.

Fish roe, most liver, lamb or veal brain, lamb or pork pancreas, lamb spleen.

Limitations to Using Animal Foods

Liver should generally be limited to two servings per week. Adrenal glands contain hormones that are unsafe in large
amounts. And most people won't eat enough of these foods to hit the RDA.

Many shellfish also provide 5-10 mg/serving, and fresh meat or fish generally provides 1-3 mg. Consumed in large
amounts, these foods may prevent scurvy or at least prolong its development. On a zero-vitamin C diet, scurvy could
start developing within 30 days. Perhaps on a carnivore diet rich in shellfish and fresh, quality meats, it would take
years. The natives of the Arctic, where plant foods were very limited, knew about scurvy and deliberately used adrenal
glands to prevent it. This suggests that, over the length of many years, fresh meat is not sufficient to prevent scurvy and
organ meats play a central role in preventing it when plant foods are scarce.

Vitamin C and Dietary Patterns

The dietary patterns that affect vitamin C status are very simple:

 Fresh fruits and vegetables, especially raw, are the best sources.
 Organ meats and non-grain starches are good sources.
 Meat, fish, and especially shellfish, provide some, but not enough for optimal health.
 Fat, sugar, grains, and refined and processed foods hurt vitamin C status by displacing C-
rich foods.
Other Things That Hurt Vitamin C Status
Some other things can hurt our vitamin C status:

❌ Smoking raises needs by 35 mg/d.

❌ People with frequent colds may benefit from 250 mg/d, especially if they engage in intense and high-volume
exercise.

❓ Some people claim that needs for C are less on a low-carb diet; others that they are higher; neither claim has strong
evidence.

Is Vitamin C Toxic?
Vitamin C is not toxic at any dose. However, high doses can cause diarrhea. Usually this is 4-10 grams, but it varies
from person to person.

Additionally, doses greater than 1000 mg/d can generate a compound known as oxalate, which causes kidney stones.
People with a history of kidney stones should be careful with vitamin C supplements. Vitamin C can be harmful to
people with hemochromatosis, a condition of iron overload. It can also be harmful to people with glucose 6-phosphate
dehydrogenase deficiency, a genetic defect that affects 8 percent of the world's population.

Some people believe high doses could also impair the ability to get fit in response to exercise, but this is controversial.

For most people, supplementing with vitamin C at doses just below what causes diarrhea is perfectly safe.

However, I recommend only using vitamin C supplements if you can't get 150 mg/d from food, or if you find that
higher doses are helping reverse signs of deficiency (like increased colds, for example).

Vitamin C Supplements
There are at least a dozen forms of vitamin C on the market, but there is currently no clear evidence that any of them
provide meaningful differences from plain old ascorbic acid.

 The flavanoids in "whole food" preparations may have health value, but they don't alter the
value of the ascorbic acid.
 Ascorbic acid is acidic, whereas mineral ascorbates (such as sodium ascorbate) are not.
Some people may find one or the other better on their digestive system, but there is no
evidence either one is better in general. When using a mineral ascorbate, you need to be
aware that you are also supplementing with the mineral (for example, sodium ascorbate
provides sodium).
 There is no evidence that Ester-C, ascorbyl palmitate, or liposomal vitamin C differ from
ascorbic acid either.

You may find that one or another supplement agrees with your gut best. And some people swear that liposomal vitamin
C prevents them from getting sick the best. The available scientific evidence suggests that, in general, it doesn't matter.

Wrapping Up
These tips should form part of the background against which you implement the MTHFR protocol. If you have any
signs or symptoms of vitamin C deficiency, you may need more vitamin C. If you also have signs of
undermethylation, especially if your homocysteine is normal or low, fixing your vitamin C status may be needed to help
fix your methylation. Here are the take-home points:
✅ Vitamin C supports methylation by acting as an antioxidant, which prevents homocysteine from being sucked out of
the methylation cycle.

✅ Vitamin C deficiency causes scurvy, which involves unexplained bruising and bleeding inside the mouth.

✅ Beyond scurvy, we need vitamin C for strong bones, robust immunity, resistance to illness and toxic stress, brain
power, sex drive, love and affection, energy, healthy skin, and gray-resistant hair.

✅ A diet rich in fresh fruits and vegetables, especially raw, provides the most.

✅ Organ meats and non-grain starches provide decent amounts.

✅ Fresh meat and fish, especially shellfish, provide a little but not enough.

✅ If you can't hit 100-150 mg/d with food, you should supplement.

✅ Athletes may need more to minimize colds. If you feel that higher doses improve your health, they are harmless to
most people

✅ 200-1000 mg are reasonable doses. For most people, any dose that doesn't cause diarrhea is safe.

✅ People with a history of kidney stones, hemochromatosis, or glucose 6-phosphate dehydrogenase deficiency should
be careful with vitamin C supplements.

They are so closely related we need to cover them together to make any sense out of them. To make the next few emails
a manageable length, we will introduce the nutrients today and cover foods and supplements in the next two emails.

How Vitamin D, Calcium, and Phosphorus

Support Methylation
Phosphorus is a critical part of ATP, which we use to activate methionine to SAMe for use in methylation. ATP is also
needed to support the production of methylfolate, and is needed for the synthesis of glutathione, the master antioxidant,
which protects homocysteine from being taken out of the methylation pathway. ATP is also needed to activate most of
the B vitamins, which themselves play many critical roles in methylation, as we've already discussed.

Calcium is needed to help remove hydrogens, electrons, and energy from glucose so that MTHFR can use them to finish
making the methyl group of methylfolate. Alternatively, once taken from glucose these things can be used to recycle
glutathione, the master antioxidant.

Vitamin D is needed to absorb calcium and phosphorus, and makes all this possible.

Vitamin D also helps us make various enzymes that use methyl groups. For example, it helps us make an enzyme
known as COMT, which uses methylation to make our mind more flexible so that we are less likely to get stuck in a rut
or to ruminate on negative thoughts and emotions.

With that said, these fellas do so much more.

Opening Up the Giant World of Vitamin D,

Calcium, and Phosphorus
Calcium and phosphorus are best friends. 👬💛

Vitamin D is their chaperone. 👵

But they are all introverts. Although they love the things they do together, they each need their alone time.

Bones, Teeth, Heart Disease, and Kidney

Stones
Calcium and phosphorus will stick together like birds of a feather whenever they run into one another. When this
happens in your bones and teeth, it's GRRRR-EAT! That's because calcium and phosphorus are the major minerals of
your bones, and are a huge part of what makes them strong. When it happens in your kidneys or blood vessels, though,
it's not so great. That can cause kidney stones or heart disease.

Vitamin D helps us extract these minerals from food. Once they're in the body, vitamin D helps put them where they
belong and keep them out of where they don't belong. Calcium mostly belongs in the bones and teeth. These are the
"hard tissues." Everything else should only have a tiny bit of calcium, and what it has should be calcium that's getting
its "introvert time" in, doing things on its own. All these other tissues are the "soft tissues." If calcium and phosphorus
come together inside them, it will make them hard like bone. This is a bad thing, and we call it "soft tissue
calcification."

This can happen in more than your kidneys and blood vessels. It can happen in your joints, your bladder, or virtually
anywhere.

In fact, in children, this can stop them from growing! Kids get taller when the cartilage inside their bones helps the
bones get longer. Cartilage is a "soft tissue" even though it is inside the bone. When it calcifies, the bone stops growing
and the kid stops getting taller. So "soft tissue calcification" can stop kids from growing.

When vitamin D helps you absorb calcium and phosphorus from your food, it acts without the help of other vitamins.
When it directs those minerals into your bones and teeth and away from your soft tissues, it partners up with vitamins A
and K.

Balancing Calcium and Phosphorus

It's important to balance calcium and phosphorus. Inside your gut, calcium and phosphorus will pair up with one
another and get so wrapped up in playing together that they forget to ever enter the body. You know where they wind
up?

Vitamin D, the chaperone, works by keeping them separated. She shuttles calcium into the body. Then phosphorus gets
jealous and follows closely behind.

But vitamin D can only watch over so many kids at a time. If you have way too much calcium and too little phosphorus,
then vitamin D shuttles some of the calcium atoms into the body but there are so many left over they all pair up with
phosphorus and play in the poo. 💩 If you have way too much phosphorus and too little calcium, phosphorus becomes a
"bad influence" on calcium. It overwhelms the chaperoning influence of vitamin D and convinces calcium to go on a
wild ride looking for the light at the end of the tunnel. 💩 So much phosphorus is left over that plenty enters the body on
its own, but without enough calcium being absorbed.

Once inside the body, they still need to be balanced. Too much of either mineral can overwhelm the ability of vitamins
D, A, and K to put them in the right places. This worsens the risk of heart disease or kidney stones. Whichever one is
too high will bring the other into the soft tissues to cause trouble together, leaving too little behind to fulfill its
"introverted" functions.

The "Introverted" Functions of the Trio

Vitamin D, calcium, and phosphorus, all do some unique things on their own.
Remember what we said about vitamin A?

"It's a tool our cells use to know they are creating the right things and putting them all in the right places. They use it
like we use mirrors. The mirror doesn't make your lips red, but try putting lipstick on without one and you might look a
little silly. 😬"

This same principle is true of vitamin D. In this case, our cells are using it to make decisions about things like:

✅ How much calcium and phosphorus should I absorb from my food?

✅ How much should I put in the bone, and how much should I put in other places?

And lots more decisions. Vitamin D helps with lots of things:

✅ It partners with vitamin A to boost our immune system and keep us from getting sick.

✅ It partners with vitamin A to help prevent asthma and allergies.

✅ It protects against psoriasis, a skin condition.

✅ It might partner with vitamin A to help prevent type 1 diabetes.

✅ It might help reduce blood pressure.

✅ In some people, it helps with insomnia.

✅ It helps boost testosterone in men, and helps decrease male hormones in women when they are too high.

✅ There seems to be a "Goldilocks amount," not too high, not too low, that protects against heart disease.

✅ It reduces the risk of certain cancers in the gut and in the male and female reproductive organs.

Calcium and phosphorus each have their own unique roles as well. Both of them act as "on/off switches" for a large
number of things that happen in our bodies.

We use calcium as the on-switch for all of these processes:

✅ The release of all neurotransmitters, allowing your brain cells to communicate with one another, and allowing your
nerves to control your muscles and sense your environment.

✅ Clotting the blood when we get injured, which prevents us from bleeding to death.

✅ Contracting our muscles.

Notice that calcium plays a dual role in muscle contraction. Let's say your brain decides you're going to raise your hand.
In your nerve, you used calcium as the switch that released the neurotransmitters. Then those neurotransmitters told
your hand to raise. Then, inside the muscles of your arm, you released calcium to make the muscles contract and to
make the hand go up.

The importance of calcium for the nerves and muscles gives one additional job to vitamin D. Since the blood is what
nourishes the nerves and muscles, it's critically important that the amount of calcium in the blood never drops too low.
Vitamin D, as the chaperone, makes sure that never happens. So vitamin D tries to put calcium in the bone, but if it has
to, it will break down bone just to keep enough calcium in the blood.

Now, phosphorus, too, has its own unique roles.

Phosphorus is so fundamental to the life of our cells that it's found practically everywhere:
✅ Our cells, and all of their internal compartments, are enclosed in an oily membrane. These membranes are more than
ten percent phosphorus.

✅ The information for everything we make inside our body is contained within our genes, which are made of DNA.
DNA is almost 30% phosphorus.

✅ Most of the B vitamins involved in energy metabolism get activated using phosphorus. In fact, when we eat food, we
transfer almost all of the energy into phosphorus-containing compounds before we use it.

Remember how we said burning fat requires a little more pantothenic acid than burning carbs? That's partly because
when we bring fats into cells, we keep them there by attaching them to pantothenic acid. When we burn carbs, by
contrast, we bring them into our cells and then keep them there by attaching them to phosphorus!

In addition to all of these structural roles, phosphorus acts as an on/off switch that controls an enormous number of
processes.

For example, when we are fasting, our cells use phosphorus to turn on a whole slew of things we do best when we are
running low on energy. Then after we eat, we use phosphorus to switch those things off and to switch on a whole
different set of things we do best when we're well-fed.

Phosphorus is Distributed in Foods More

Widely Than Calcium
We need large amounts of calcium and phosphorus for structural purposes, but only tiny amounts for our on/off
switches. Calcium only plays a structural role in the bones and teeth. Phosphorus plays structural roles
EVERYWHERE. As a result, bone contains 99% of our calcium, but only 85% of our phosphorus.

One of the things we will notice when we look at foods is that there is a little bit of calcium in most foods, but only a
handful of foods contain a lot of calcium. That makes it fairly easy to become deficient if your diet isn't planned
correctly. By contrast, because phosphorus is so central to the structure of so many things, there's a lot of it in almost
any food, and it's very hard to become deficient.

Severe Deficiencies: Rickets, Osteomalacia,

and Tetany
Now that we have a handle on all three nutrients, let's take a look at deficiencies and excesses.

Severe deficiencies of vitamin D, calcium, and phosphorus can all cause rickets in children, which is known as
osteomalacia in adults. This happens when you don't have enough mineral to make the proper bone structure. Vitamin
D's role is to help you absorb the minerals from your food. Rickets and osteomalacia involve painful and fragile bones,
weakness, and skeletal deformities such as thickened wrists and ankles, a compressed spine, and bow-shaped legs. The
deformities are especially prominent in children.

Another severe deficiency is tetany. This is due to a low amount of calcium in your blood. This leads to low amounts of
calcium in your muscles and nerves. Since you use calcium to control neurotransmitter release and muscle contraction,
this leads to dysfunctional control of your nerves and muscles. Muscle twitches, tremors, and spasms are early signs,
and as it gets worse it can lead to confusion, seizures, coma, and death.

Since tetany is specifically a result of low calcium, and not low phosphorus, deficiencies of calcium or vitamin D can
cause it, but deficiencies of phosphorus cannot.

Osteopenia and Osteoporosis

Too little calcium or vitamin D, at more moderate levels of deficiency, contribute to osteopenia and osteoporosis. These
are both conditions where there is too little mineral in the bone. Both osteopenia and osteoporosis make you more likely
to fracture a bone. Osteopenia is a more moderate form of the disease; osteoporosis is more severe.

Rickets and osteomalacia result from mineral deficiencies so severe that you cannot form proper bone structure. In
osteopenia and osteoporosis, the overall bone structure is fine, and the deformities don't exist. You just have less
mineral in the bones because you are using the minerals to keep their levels in the blood normal.

Calcium and Vitamin D Make Bones Stronger,

Phosphorus Makes Them Weaker
At first glance, it may seem like deficiencies of all three nutrients would contribute to these diseases. After all, bone
mineral is made of calcium and phosphorus, and vitamin D is needed to absorb them.

Outside of severe deficiency, calcium and phosphorus actually have opposite effects on bone. This is because of two
important principles:

 Because calcium and phosphorus play together so much, our bodies very carefully regulate
their balance in the blood.
 Although they are both needed for strong bones, bone holds more calcium than phosphorus.

As a result:

 When there is extra calcium in the blood and not enough phosphorus, we push the extra
calcium INTO bone.
 When there is extra phosphorus in the blood and not enough calcium, we take calcium OUT
of the bone.

Outside of severe deficiency, then, calcium makes bones stronger while phosphorus makes them weaker.

Since vitamin D helps you absorb both minerals, it might be confusing why vitamin D makes bones stronger. This is
because vitamin D only directly impacts calcium absorption. Remember, phosphorus just gets jealous and follows
calcium along for the ride. So vitamin D only helps enough phosphorus come in to follow calcium right into the bone. It
never makes "too much" come in that would draw calcium out of the bone.

Excess of All Three Cause Soft Tissue

Calcification
On the flip side, excesses of all three nutrients can cause soft tissue calcification, contributing to problems like kidney
stones and heart disease. In the case of vitamin D, it's because cells get confused when there's too much around.

Let's bring back that mirror analogy.

"It's a tool our cells use to know they are creating the right things and putting them all in the right places. They use it
like we use mirrors. The mirror doesn't make your lips red, but try putting lipstick on without one and you might look a
little silly. 😬"

Well, have you ever tried to put on lipstick when you were surrounded by a dozen mirrors? Trust me, you'd be
confused.

One of vitamin D's normal roles is to keep blood levels of calcium from dropping too much. But toxic levels of vitamin
D cause confusion and make the calcium levels run too high. Another role of vitamin D is to partner with vitamins A
and K to protect the soft tissues from calcification. When vitamin D is supplied in great excess of its partners, that
system can also gets dysfunctional. Since vitamin D will move calcium from bone to blood when needed, the
"confusion" of vitamin D toxicity will actually rob the bones of calcium, putting it everywhere it doesn't belong.

In the case of the minerals, too much of either one will cause the system to overflow. Vitamin A, D, and K, the
protectors of the soft tissues, get overwhelmed.

Toxicities of Calcium and Vitamin D Have

Opposite Effects on Bone
Toxic doses of calcium and phosphorus do the same thing to bone that moderate excesses do:

 Calcium increases the amount of mineral stored in bone.

 Phosphorus decreases the amount of mineral stored in bone.

In both cases the soft tissues calcify, but calcium makes bones heavily mineralized and brittle, while phosphorus makes
them porous and weak.

Healthy Levels of Calcium Protect Against

Kidney Stones
One more thing. Although toxic levels of calcium can cause kidney stones, within healthy dietary ranges, calcium
actually protects against kidney stones in two ways:

 Kidney stones are often made from calcium oxalate. Oxalate is a compound found in many
vegetables and also produced in small amounts within the body. Calcium binds oxalate in
the digestive tract and prevents its absorption. This way, oxalate will not get into the body,
where it would bind to calcium to form kidney stones.
 Second, eating calcium provides calcium to the blood, making it less likely you will need to
take calcium out of your bones to keep the blood levels high enough. When you take
calcium out of your bones, it comes out as little chunks that are far more likely to cause
kidney stones than the fully dissolved calcium you absorb from food.

Wrapping It Up
To recap:

✅ Vitamin D helps us make enzymes that use methylation, such as COMT, which uses methylation to make us more
mentally flexible. It also helps us absorb calcium and phosphorus. Phosphorus is needed to support methylation and
antioxidant defense as part of ATP, while calcium does the same by helping us use energy and components from
glucose.

✅ Deficiencies of all three lead to low bone mineral content.

✅ Outside of deficiency, calcium and vitamin D make bones stronger while phosphorus makes them weaker.

✅ Calcium protects against kidney stones within healthy dietary ranges.

✅ Toxicities of all three nutrients cause soft tissue calcification.

✅ Toxicities of vitamin D or phosphorus cause low bone mineral content, while calcium toxicity causes bone mineral
content to get too high.
Tomorrow and the next day we will dig into diet and lifestyle more to better understand how we can use these principles
to support the optimization of the MTHFR protocol.

This is part two of our series on Vitamin D, calcium, and phosphorus. Today we cover sources of vitamin D, and
tomorrow we do the same for calcium and phosphorus.

Let's recap from last email:

✅ Vitamin D helps us make enzymes that use methylation, such as COMT, which uses methylation to make us more
mentally flexible. It also helps us absorb calcium and phosphorus. Phosphorus is needed to support methylation and
antioxidant defense as part of ATP, while calcium does the same by helping us use energy and components from
glucose.

✅ Deficiencies of Vitamin D, calcium, and phosphorus all cause rickets and osteomalacia.

✅ Deficiencies of vitamin D and calcium, but not phosphorus, cause tetany.

✅ Outside of deficiency, calcium and vitamin D make bones stronger while phosphorus makes them weaker.

✅ As a result of their effects on bone strength, calcium and vitamin D protect against osteopenia and osteoporosis,
while phosphorus worsens these diseases.

✅ Toxicities of calcium cause bones to gather too much mineral and become brittle, while toxicities of vitamin D and
phosphorus cause them to become porous and weak.

✅ Toxicities of all three nutrients cause soft tissue calcification, which can stop children from growing prematurely or
contribute to heart disease and kidney stones.

So, it's very important to get each nutrient within it's own sweet spot, and it's also important to get them in the proper
balance.

Vitamin D From Sunshine

Before we get to food, we first need to talk about sunlight!

Remember how sunlight destroyed riboflavin and to a lesser degree folate, and caused us to use up niacin to repair
damage to our DNA? In quite the plot twist, it turns out that sunlight actually CREATES vitamin D when it strikes our
skin. More precisely, it converts precursors in our skin into vitamin D.

Yeah. It's crazy.

Sunlight hurts your status of several B vitamins but helps you get vitamin D, so it makes sense to shoot for the dose of
sunlight that gives you the vitamin D you need but goes no further. In fact, sunlight will only help you make vitamin D
up to a certain point anyway. After you cross the line, more sunlight does nothing to give you more D.

It's not always obvious exactly where the line lies, but it always lies before the point where your skin starts changing
color. If you get a little red, or you get a tan, you've passed the point where you stopped making more D. If you get
burned, you went WAY past that point. As a rule of thumb, it's good to know your response to the sun and stay beneath
this point. You are free to cross the line into tanning if you like the aesthetics. Just keep in mind that you aren't getting
any extra vitamin D from it, you are sapping your B vitamins, and you might be raising the risk of skin cancer.

How long it takes you to max out your vitamin D creation depends on your skin color. If you have very fair skin, always
burn, and never tan, you reach that point in ten minutes. If you have dark black skin, never burn, and always tan, it will
take you two hours to reach that point. Everyone else lies in the middle. If you have some ability to tan or burn, and
would classify your skin as fair, medium, olive, or brown, you lie somewhere on the scale between ten minutes and two
hours.
With modern indoor lifestyles, it may be harder for people with dark skin to get enough vitamin D. You only get
vitamin D when you go outside, and working near a window will never work. Most of us are outdoors for ten minutes a
day, but few of us are outdoors for two hours a day.

Still, we need to understand the issue a lot better. Although people of all other races have, on average, lower vitamin D
levels than light-skinned people with European ancestry, the light-skinned Europeans appear to require higher levels
than everyone else, genetically. It may be the case that none of us need to reach the point where we max out our vitamin
D creation in order to get enough. So, we should get plenty of sunlight, but we shouldn't assume we need to max out the
D we get from it.

Naked and Lying Down

How much vitamin D you make isn't just about time. All clothing except see-through blouses, and any sunscreen with
an SPF of 8 or higher, will stop the creation of vitamin D in the areas of skin they are covering. And when you are
standing up, the sun is hitting the top of your head, which is usually covered in hair. When you're lying down to
sunbathe, by contrast, the sun is hitting most of your body on the half that's exposed.

So we can imagine a spectrum of vitamin D creation where we make the least when we are fully clothed and standing
up, and make the most when we are naked and lying down... all assuming there's no sunscreen involved.

The best thing to do if you go sunbathing is go without sunscreen at first, and then before you have a chance to get the
slightest pink, put the sunscreen on. Sunbathing can be especially helpful if you have dark skin. Imagine two people
expose their hands and face for 12 minutes. One has very fair skin and one has dark black skin. The fair-skinned person
would get 10 times more vitamin D. The person with darker skin could get just as much as the person with fair skin if
they spend those 12 minutes sunbathing with at least their arms and legs exposed. And they'd get way more in a bathing
suit. The same thing is true of medium skin tones. You may have olive skin, and it might take you 30-60 minutes to max
out your D creation, but you may only have ten minutes of outdoor time a day. Sunbathe!

But, the plot thickens yet again. 😯

Noon on a Summer Day

If you live close to the equator, you can get vitamin D from the sun pretty much any time of the day, any time of the
year. As you get farther away from the equator, it gets more complicated. During the summer, you get vitamin D at any
time of day, but during the spring and fall, you only get it within a couple hours of noon. Far from the equator, we may
get little if any vitamin D from the sun during winter.

Even when the sun is happy to provide us with vitamin D, there are other things that get in the way:

❌ Clouds

❌ Tall buildings

❌ Pollution

❌ As we move toward old age, we make less from the sun

Balancing the Noon and Morning Sunshine

Although the most reliable time to get vitamin D from the sun is close to noon, getting sunshine in the morning helps us
get good sleep. Remember from lesson 1? The light hits vitamin A inside our eyes, which transmits the signal to our
brain that it is day time. This helps our brains recognize night time better when it comes.

So the best habits to develop around sunshine are:

✅ Get a half hour of sunshine in the morning, making sure your eyes are exposed and not worrying about your skin.
✅ Use your lunch break to get at least ten minutes of sunshine within a couple hours of noon. The darker your skin, the
more time you should spend outside on lunch break, and if you can't leverage more time, expose more skin.

✅ If it's summer, or you live near the equator, you can combine the first two to get all your sun in the morning.

Vitamin D in Foods: How Much Do We Need?

We also get vitamin D from food!

Like vitamin A, vitamin D is measured in "international units" or IU. The RDA is 600 IU for almost everyone. It goes
up to 800 IU for people over 70 and goes down to 400 IU for infants. People over 70 require more because they make
less from the sun and they absorb less from food.

Vitamin D requirements are highly controversial, so I think the best thing to shoot for is what we would expect to get
from sun if we lived a traditional lifestyle at the equator. This is, after all, where we come from as a species. This is
about 3,000 IU. This should cover the increased needs of pregnant and breastfeeding moms as well as people over the
age of 70.

All of these numbers apply to the combination of sun exposure, food, and supplements. Sun exposure is the wild
card. 🃏We just never know exactly what we are getting from the sun.

I recommend approaching this as follows:

✅ Try to work vitamin D-rich foods into your diet regardless of sun exposure, because these foods are rich in other
nutrients you need anyway.

✅ The further you fall from optimal sun exposure, the closer to 3,000 IU you should shoot for foods and supplements.

In the winter, you may not be getting much vitamin D from the sun regardless of how much time you spend outside,
depending on where you live. So you may want to shoot for 3,000 IU from foods and supplements during the winter
regardless of your sun exposure. You may not need to, though, since we can store extra D we get during the summer
and use it as reserves during the winter. Still, there is little harm in shooting for that target, and there may be some
payoff if you suffer from any of the vitamin D-related ✅'s we discussed last time, like asthma, allergies, autoimmunity,
blood pressure, psoriasis, or hormone problems.

Vitamin D is Found in the Fat

Vitamin D, like vitamin A, mixes better in fat than in water. It is the second "fat-soluble" vitamin we are looking at. So,
it's found in the fatty portions of our foods, such as the yolk of an egg or the butterfat of milk. Even in a food that is low
in fat, such as a mushroom, if you squeezed oil out of it, the vitamin D would come out in the oil.

That also means we will absorb more of it if we eat it with fat. It's best to consume vitamin D-rich foods or vitamin D
supplements at our biggest meal if our meals don't vary much in their fat content, or at our highest-fat meal if they do.

D2 vs D3
Vitamin D comes in two forms: most animals have D3, the form we make in the sun; mushrooms have D2; some fish
have a mix. Whether it matters if we get D2 or D3 is controversial. Some people believe D3 is superior to D2, some
believe it doesn't matter. No one makes the argument that D2 is better. So, it's better to shoot for foods with D3, but how
important it is to do so is a gray area.

Vitamin D in Foods: The Three Tiers

All right, let's break down the specific foods!
All servings are 100 grams or 3.5 ounces measured raw unless otherwise stated.

TIER 1 provides 1000 IU per serving.

2 tbsp of natural, unfortified cod liver oil (check the label to be sure).

Some fish (carp, Greenland halibut).

4-5 egg yolks from chickens raised in the outdoor sunshine.

Some mushrooms that have been exposed to ultraviolet light (brown, Italian, crimini, portabella, maitake).

TIER 2 provides 500-1000 IU per serving.

Tier 2 has certain fish: eel, most salmon (except those in tier 3), mackerel, trout, chinook, swordfish, sturgeon, and
catfish.

TIER 3 provides 100-500 IU per serving.

3 egg yolks from conventionally raised chickens. Queso fresco cheese.

Pork lard and the fat of veal, turkey, and chicken. Butterfat from cows raised in the outdoor sunshine.

Some mushrooms (chanterelle, morel)

Lots of fish: some salmon (wild coho, farmed Atlantic, canned chum), non-Greenland halibut, whitefish, fish roe and
caviar, pompano, Spanish mackerel, tuna, sea bass, sardines, shad, Atlantic herring, Pacific rockfish, tilapia, perch,
flatfish, herring, sole, flounder, and pike.

Fortified Foods, Blood, and Other Foods

Many foods are fortified with vitamin D: margarines (tier 2); and dairy products, baby foods, and cereals (tier 3).

Foods with less than 100 IU have very little value, because you are likely getting much more than this from sunshine. If
you're not, you have problems that 100 IU isn't going to solve. So there's no tier 4.

We should note here that the livers of land animals are not rich in vitamin D. This is because land animals store their
vitamin D in their blood. In fact, many traditional diets contained blood, and one cup of animal blood from an animal
raised in the outdoor sunshine would provide 4000 IU of vitamin D!

Potential Downsides of Vitamin D-Rich Foods

Most of the foods rich in vitamin D either contain the somewhat questionable vitamin D2 (mushrooms) or very large
amounts of omega-3 fatty acids (fatty fish and cod liver oil). As we will discuss later when we cover essential fatty
acids, omega-3 fatty acids are very vulnerable to damage inside your body, which can increase the wear and tear on
your tissues. I recommend limiting cod liver oil to 1 teaspoon a day and fatty fish to 2 servings a week.

Vitamin D Supplements
Supplements can be added to your food and sunshine to bring your total up to 3,000 IU. Any D3 supplement will work.

If you supplement with more than that, work with a health care practitioner to make sure your blood levels are in the
right ranges and your other fat-soluble vitamins are in the proper balance. We will revisit the topic of balancing them
after we get a chance to cover the other two fat-soluble vitamins, E and K.
Some people may need much higher doses of vitamin D. However, keep in mind the interactions with calcium and
phosphorus:

✅ Outside of deficiency and toxicity, vitamin D and calcium need to be balanced with phosphorus.

✅ The more calcium you get, the less vitamin D you need.

✅ The more phosphorus you get, the more calcium or vitamin D you need.

Vitamin D Testing
Vitamin D testing has been very controversial for at least the last 15 years, and remains as controversial as ever. The
labs used to say 12 ng/mL was the cutoff for "normal" vitamin D levels. Then they changed it to 30 or 32 ng/ml. Then
the Institute of Medicine said it should actually be 20 ng/mL, but no one listened to them. Meanwhile, the whole time
many scientists were arguing the normal range should be above 50 or 60 ng/mL!

I actually have a very different take on this issue. I never look at vitamin D status without also looking at parathyroid
hormone (PTH), which tells you what your body's own perception of your vitamin D status is, and calcitriol, or
1,25(OH)2D, the active hormone form of vitamin D, which can tell you whether your vitamin D status is low because
you need more vitamin D, or if it's low because you actually need more calcium. Other markers can also be helpful if
you need to understand whether your calcium and phosphorus might be out of balance.

If you are using the Cheat Sheet, see the "Vitamin D, Calcium, and Phosphorus" section under "The Fat-Soluble
Vitamins and Related Minerals" where my complete testing algorithm can be found.

So, that brings us to tomorrow's email on calcium and phosphorus. By the time we finish that email, we'll have a very
good grasp of how to balance these three intimately connected nutrients, and we will recap what we've learned across
this little series.

Today is the last of our three emails on vitamin D, calcium, and phosphorus. We are covering calcium and phosphorus
in foods and supplements.

First, let's review some key principles:

✅ Vitamin D helps us make enzymes that use methylation, such as COMT, which uses methylation to make us more
mentally flexible. It also helps us absorb calcium and phosphorus. Phosphorus is needed to support methylation and
antioxidant defense as part of ATP, while calcium does the same by helping us use energy and components from
glucose.

✅ Outside of deficiency and toxicity, where most of us are, vitamin D and calcium are on one team and phosphorus is
on the other.

✅ Getting enough calcium reduces the amount of vitamin D we need. Getting too much phosphorus raises the amount
of calcium we need, which then raises the amount of D we need.

So, we're looking for the right balance of the three nutrients. But we also need to make sure we're getting enough of
each nutrient on its own, and not so much that we overwhelm our ability to use it properly.

So, let's look at what we need for calcium first.

How Much Calcium Do We Need?

The RDA is 1000 milligrams per day (mg/d) for most people over the age of 3. It increases to 1300 for children aged 9-
18 to account for increased growth, and to 1200 for women over the age of 50 and men over the age of 70. The RDA is
200 mg/d during the first six months of life, 260 during the next six, and 700 mg between the ages of 1-3.
While not without controversy, the calcium RDAs are among the best supported by large amounts of evidence. Many
people object that the only way to get the RDA is to drink milk, and many human societies have thrived without using
milk. But there are many other sources of calcium. In the Arctic, for example, where there are no cows and plant foods
are limited, the natives ate dried, pulverized fish bones. In Africa, a group of hunter-gatherers known as the Hadza
consume large amounts of baobab. This is a plant with more calcium than milk, is considered a "food group," and
makes up over 20 percent of their diet. Similarly, the Native Americans of the Northern Plains ate stinging nettles,
which is much higher in calcium than milk. Each culture found prized sources of calcium-rich foods and made them
critical parts of their traditional diets. Ours is dairy, and if we leave dairy behind we need to find another.

Calcium Absorption From Different Foods

Most foods have some calcium in them, and many besides milk have a lot. 🙂

But then... there is absorption. 😔

We absorb calcium from food much better when we get enough vitamin D. Nevertheless, for a given amount of vitamin
D, the absorbability of calcium differs greatly among different foods:

 A little over 30% of the calcium in milk is absorbed. Edible bones have not been tested but
they are probably similar.
 40-60% of the calcium in most cruciferous vegetables is absorbed. These are foods like
broccoli, kale, and bok choy.
 20-25% of the calcium in legumes is absorbed.
 Rhubarb (9%) and spinach (5%) have very poor absorbability.

Unfortunately, there are a tremendous number of foods where we don't know for sure how absorbable the calcium is.
Let's start by looking at foods where it's been directly measured, then make some guesses about the rest of the foods we
eat.

Meeting the Calcium Requirement With Food

To meet the RDA, children up to 3 years old need the equivalent of two 8-ounce glasses of milk. Most adults need three
glasses, while children and adolescents 9-18, women over 50, and men over 70 need four glasses. This would provide
everyone with calcium within 100 milligrams of the target, which would be filled in by the other foods they consume.

For foods where the absorption has been directly measured in humans, these are each the equivalent of one 8-ounce
glass of milk (or the same amount of yogurt or kefir). The veggies are measured after cooking:

 40 grams of (g) cheddar cheese

 90 g napa cabbage
 100 g Chinese mustard greens
 190 g bok choy
 270 g kale
 290 g Chinese spinach
 320 g broccoli
 430 g white beans
 700 g pinto beans
 790 g rhubarb
 1.4 kilograms of (kg) spinach
 1.6 kg sweet potatoes
 1.7 kg red beans

Of the plant foods, the most practical to use is Chinese mustard greens. 100 g is a little over two-thirds of a cup. It
would require just over 2 cups, measured after cooking, to yield the equivalent of 3 cups of milk. Close behind is napa
cabbage. 90 g is three-quarters of a cup. Just under 2.3 cups yields the equivalent of 3-milks-a-day. 190 g boy choy is a
little over one cup. 3.4 cups of it will meet the target.

Going further down the list starts to become impractical. For example, it would take over 6 cups of kale or broccoli to
meet the target.

One of the most common traditional sources of calcium in dairy-free cultures has been bones. You can gnaw the ends
off the small bones in a roast chicken. You can eat the bones in canned sardines or canned salmon. As mentioned
before, the natives of the Arctic would dry and pulverize fish bones to get their calcium. Although no one has directly
measured how much calcium humans absorb from edible bones, we have good reason to think that it is similar to milk.
First, most calcium is present in bone bound to phosphate. The absorption of calcium phosphate has been tested in
humans, and it's about 25%, a little less than the 32% we absorb from milk. Second, in lab animals, the proteins found
in bone increase the absorption of the calcium. So we humans probably absorb the calcium from bone at least as well as
we do from milk. We can obtain our three-milks-a-day target from bone, then, by consuming just over two-thirds of a
teaspoon of powdered bone. If you eat canned fish, count each 30% of the daily value for calcium as one glass of milk.

Putting this all together, your best bet is to mix and match three of any of the following foods each day:

✅One cup of milk, yogurt, or kefir.

✅One serving of canned fish providing 30% of the daily value of calcium.

✅One cup of Chinese mustard greens, napa cabbage, or bok choy.

So far we have been limiting our scope to the foods where the absorption has been directly measured.

We can broaden our scope by making some reasonable guesses about how much we absorb from other foods. The most
important inhibitor of calcium absorption in plants is oxalate. This is the same oxalate that we talked about causing
kidney stones in part 1. Let's assume that most low-oxalate vegetables have similar calcium absorbability. Let's also
assume that most nuts, seeds, and beans have similar absorbability as the beans that have been measured.

The following foods should be equivalent to one cup of milk:

 100 g sesame seeds, hull included

 150 g chia seeds
 180 g flax seeds
 200 g typical tahini
 270 g almonds
 290 g Brazil nuts

These options, while helpful, are quite impractical to rely on because of the amount of calories they supply. Calories
(Cal) are units of energy, and too many will make you fat! 😬Plus you can only fit so many in your tummy at a time. A
cup of full-fat milk has 146 Cal and low-fat milk has even less. 150 g chia seeds has 729 Cal and 200 g of tahini has
1190 Cal!

This brings us back to our original conclusions: mix-and-match dairy, bones, or the top three greens (Chinese mustard,
napa cabbage, or bok choy) to get your calcium. If you have space for the calories, you can replace one of those with
some of the nuts and seeds. If you have space for the volume, you can replace one of those with some of the other
vegetables.

Calcium in Mineral Water

Before we talk supplements, let's talk about one thing that's not really a food or a supplement: mineral water. The
minerals in mineral water are fully dissolved, and are likely very well absorbed. For example, Gerolsteiner and
Ferrarelle have more than a cup of milk's worth of calcium per liter. Perrier, Uliveto, San Pellegrino, and Lete have a
little under half that.
Calcium Supplements: Safety Concerns
Calcium supplements are a mostly safe and effective way to bring your intake up to the target.

There are a few special concerns, however:

 In supplemental form, calcium might enter your system too quickly and promote soft tissue
calcification.
 Calcium supplements sometimes cause "calcium-alkali syndrome."

This syndrome can make you unusually thirsty and pee too much. It can make your heart beat more slowly, skip a beat,
or flutter. It may make you confused, weak, or depressed.

Typically the person who develops this syndrome fits these criteria:

 She is a woman who is elderly, pregnant, or bulimic.

 She is also taking antacids, nonsteroidal anti-inflammatory drugs (NSAIDs, such as aspirin
or Advil) or medications to manage blood pressure and swelling.
 Her calcium supplement is calcium carbonate, oxide, or hydroxide.

We can avoid the risk of soft tissue calcification and calcium-alkali syndrome by sticking to some easy rules:

✅ Use calcium supplements to help you meet the RDA when you cannot do so with food alone. Don't use supplements
to exceed the RDA.

✅ They will hit your system more slowly, like food, if you mix them into your food. If you don't want to mix it, take it
at the end of your meal.

✅ Always spread your calcium evenly across 3-4 meals.

✅ Don't use carbonate, oxide, or hydroxide.

✅ If you fit the other criteria for calcium-alkali syndrome, keep your total intake under 1000 mg/d and discuss your
supplement with your doctor.

Calcium Supplements: Which Forms Are

Best?
There are an incredible number of forms that calcium supplements come in, so rather than discuss every single one in
detail, we'll cover them in groups.

BONE MEAL / MCHC / MCHA

This form is a traditional food, like the pulverized fish bones the natives of the Arctic used. Bone can be contaminated
with lead, so look for manufacturers that test and disclose the contaminants. This is a good default for most people. It
contains many proteins and traces of non-calcium non-phosphorus minerals that support bone health. Bone meal might
be poorly absorbed in those with low stomach acid, and it is too high in phosphorus for people who need to avoid it. It is
rich in collagen, which supports healthy hair, skin, and nails. Most people could use more of it. However, people who
develop calcium oxalate kidney stones may benefit from avoiding collagen. MCHC and MCHA are other names for
bone meal.

CALCIUM PHOSPHATE
Examples include tricalcium phosphate and dicalcium phosphate dihydrate. These are similar to the calcium in bone
meal, but without the protein and extra minerals. They are less nourishing as a result, and they still can't be used by
people who need to avoid phosphorus, but they would be better than bone meal for people who need to avoid collagen.

CALCIUM CITRATE, MALATE, LACTATE, GLUCONATE, GLUBIONATE, SULFATE, &

GLYCEROPHOSPHATE

All of these forms are highly absorbable, and all of them except glycerophosphate are good for people who need to
avoid phosphorus. Calcium citrate is better studied and more popular than the others, giving it a good safety record. The
citrate is helpful for kidney stone prevention.

CALCIUM CARBONATE, HYDROXIDE, AND OXIDE

These are popular because they are cheap, especially calcium carbonate. They lack phosphorus and collagen, which can
be advantageous for some people, but they account for most reports of calcium-alkali syndrome, suggesting they are
less safe than other forms.

OYSTER SHELL, EGG SHELL, CORAL CALCIUM, DOLOMITE

These are all mostly calcium carbonate. Since they are natural, they have the advantage of proteins (except dolomite)
and other minerals, and the disadvantage of possible contaminants. Since they contain calcium carbonate, they may
carry the same risk of calcium-alkali syndrome.

The bottom line:

✅ Use a bone meal if you have no need to avoid collagen or phosphorus. Choose a product where the contaminants are
measured and disclosed.

✅ Use calcium citrate if you need to avoid collagen or phosphorus, especially if you are at high risk of kidney stones.

How Much Phosphorus Do We Need?

Phosphorus is a simpler discussion. Most people actually get too much. In part one, we pointed out how only 1% of our
calcium but a full 15% of our phosphorus is found outside of our bones. This much wider distribution of phosphorus
means it's found in far more foods, is much easier to obtain, and far less likely to run deficient.

The RDA for phosphorus for all adults is 700 mg/d. For children older than one and for adolescents, the RDA is
adjusted according to their needs for growth and age-related differences in how well they absorb phosphorus from food.
It is 460 mg/d for children 1-3, 500 mg/d for children 4-8, and 1250 mg/d for adolescents 9-18. For infants, there wasn't
enough evidence for an RDA, so they set an "everyone-is-doing-it-so-it-must-be-ok," also known as an "adequate intake
(AI)," of 100 mg/d for the first six months of life and 275 mg/d for the next six months. This is based on what infants
were consuming in milk and baby food.

It's Hard to Become Deficient in Phosphorus

When consuming natural foods, it is nearly impossible to become deficient in phosphorus. For simplicity, let's consider
the adult target of 700 mg/d.

These are what you'd get if you ate 2,000 Calories (typical for an average daily intake) of a single food group all on its
own:

 Dairy: 2,600 mg.

 Eggs: 2,100 mg.
 Meat, poultry, or fish: 1700 mg.
 Legumes, nuts, or seeds: 1600 mg.
 Veggies 1100 mg.
  Grains: 1050 mg.
 Fruits: 608 mg.

What do Fruitarians, Refined Flour-Heads,

and Keto-Carnivores Have in Common?
Ok, so strict fruitarians might be at risk. But the least of a fruitarian's problems will be phosphorus. In fact, their
phosphorus intake would be amazing compared to their calcium intake.

A more dangerous dietary pattern would be the fat-bomber. 2000 Calories of fat only provides about 150 mg of
phosphorus.

Keto dieters can get plenty from animal products and low-carb veggies. Carnivores can get plenty from meat. The
potential problem would be with keto carnivores. The phosphorus requirement could be met with 550 Calories of dairy,
670 Calories of eggs, or 850 Calories of meat, poultry, or fish. But just animal fat wouldn't cut it.

In theory, someone could develop a moderate phosphorus deficiency from relying exclusively on refined flour. 2000
Calories of white flour only provides 593 mg of phosphorus. As with fruitarianism, though, the phosphorus actually
looks really good on that diet compared to many other nutrients, including calcium. As we will see soon, though, most
white flour products are full of hidden phosphorus.

Starvation, Refeeding, and Hungry Bones

There is one way to become deficient in phosphorus: don't eat. Starvation and eating disorders can lead to extended
periods of time with little or no phosphorus consumed, and breakdown of lean mass that allows stored phosphorus to be
lost in the urine. Rapid refeeding, especially with poor-quality food, causes phosphorus to get sucked up into the
muscles, which causes blood levels to drop to dangerous levels. This is called "refeeding syndrome" and it can also
affect magnesium and potassium. The best way to keep phosphorus levels up is to eat lots of meat and eggs.

Something similar happens after medical correction of a disorder causing bone loss. Phosphorus, calcium, and
magnesium all get swept up into bones, and the blood levels drop. This is called "hungry bone syndrome" and dairy
products are the best remedy.

Meat and eggs are the best match for refeeding syndrome because the phosphorus is going into the muscles where it
doesn't need calcium, and meat and eggs provide phosphorus without calcium. Dairy is the best match for hungry bone
syndrome, because the phosphorus is going into the bones where it does need calcium, and dairy provides both
minerals.

Hidden Phosphorus Additives in Processed

Foods
Overwhelmingly, most of us are likely to get too much phosphorus, not too little. The average intake in the United
States is almost twice the RDA. Nearly 500 mg/d come from unlabeled food additives!

Phosphorus is added in large amounts to cola, anything with baking powder, and processed, parmesan, or American
cheese.

Phosphorus is usually added to the following products:

 anything with baker's yeast

 cocoa powder
 non-perishable fruit juice
 vegetable spreads for bread
  cold cuts, hot dogs, and sausages

Phosphorus is sometimes added to these:

 frozen meat
 canned seafood
 many cheeses
 yoghurt
 chocolate
 beer
 instant coffee

These additives are very often unlabeled. Worse, studies suggest that ONLY these hidden additives hurt bone health.
Meat seems neutral and dairy beneficial.

So the end result:

✅ We can get enough phosphorus by eating a mix of natural whole foods.

✅ We can avoid too much phosphorus by avoiding processed foods.

✅ There's no need for supplements. Just meat and eggs for refeeding syndrome, and dairy for hungry bone syndrome.

Wrapping It All Up
All right, let's wrap up our three-part series on vitamin D, calcium, and phosphorus. Use these principles as part of
the background against which you implement the MTHFR protocol. If you have signs of deficiencies or imbalances
discussed here, you might need more D and calcium or to work on your calcium/phosphorus balance. If you also have
signs of undermethylation, then addressing these three nutrients might be needed to fix your methylation. Here are the
take-home points:

✅ Vitamin D helps us make enzymes that use methylation, such as COMT, which uses methylation to make us more
mentally flexible. It also helps us absorb calcium and phosphorus. Phosphorus is needed to support methylation and
antioxidant defense as part of ATP, while calcium does the same by helping us use energy and components from
glucose.

✅ Deficiencies of vitamin D, calcium, or phosphorus contribute to rickets and osteomalacia.

✅ Deficiencies of calcium or vitamin D contribute to tetany.

✅ Toxicities of all three cause soft tissue calcification.

✅ Toxicities of vitamin D or phosphorus cause weak, porous bones; calcium toxicity causes hard, brittle bones.

✅ Most of us lie in the middle where calcium and vitamin D are on one team and phosphorus is on the other.

✅ In this middle area, calcium and vitamin D protect against osteopenia and osteoporosis; phosphorus makes these
diseases worse.

✅ We also want "team calcium and vitamin D" for blood pressure, asthma, allergies, colds and flu, autoimmunity,
insomnia, hormones, heart disease, and cancer.

✅ Our best sources of vitamin D are sunshine, pastured egg yolks, cod liver oil, certain fish, or certain mushrooms (the
mushrooms contain D2, possibly less effective than D3).

✅ Sunshine is best mid-day, and this matters most outside of the summer and far from the equator.
✅ The darker your skin, the more time you need in the sun, or the more you should focus on exposing more skin and
lying down.

✅ The best sources of calcium are dairy, bones, napa cabbage, Chinese mustard greens, bok choy, and high-calcium
mineral water. Mix and match two for young kids, three for most adults, or four for women over 50, men over 70, or
adolescents.

✅ Try to meet your targets with food first, and use supplements to fill the gaps. Bone meal from a lead-tested product is
the best by default. Calcium citrate is best for those who need to avoid phosphorus or collagen, or who are at high-risk
of kidney stones.

✅ Phosphorus deficiency is mainly a risk of mostly fat diets, starvation, anorexia, or eating disorders.

✅ Keto carnivore is at the greatest risk of deficiency but can avoid it with enough dairy, eggs, or meat. Regular keto
can use veggies too.

✅ Phosphorus levels drop in refeeding syndrome or hungry bone syndrome. Meat and eggs are great for refeeding and
dairy is great for hungry bone.

✅ We can avoid getting too much phosphorus by avoiding processed foods.

✅ Remember that vitamin D requirements go down when you get enough calcium and go up when you get too much
phosphorus. Before concluding you need more D than recommended in these emails, check your calcium/phosphorus
balance.

That's all for today!

See you tomorrow for vitamin E!