This originally went out on my email newsletter, but by popular demand I’m sharing it here. Many people asked me to post it so they could share it, so here it is.
If you’re not on my newsletter yet, you can sign up here.
I just got done doing a TON of research into riboflavin. I recorded a podcast on it with Alex Leaf of Examine.Com, where I focused on the basic science and Alex focused on the outcomes of supplementation studies. You can find that here.
One of the fascinating things we stumbled on is the possibility that the famous MTHFR polymorphisms — variations in the gene that uses riboflavin to make the methyl group of methylfolate — only decrease MTHFR activity because most people in whom the activity has been measured have mediocre riboflavin status.
Alex found some key studies supporting this and blogged about them here.
Here are the key findings:
- Using experiments in bacteria, where the part of the MTHFR enzyme that binds riboflavin is similar to humans and other animals, the reason that the polymorphisms decrease enzyme activity is because they make the enzyme bind to riboflavin more weakly. At low riboflavin concentrations, the enzyme has poorer activity. However, at high enough riboflavin concentrations, enzymatic activity is restored to normal.
- In humans who have the MTHFR C667T polymorphism, all of the elevated homocysteine is concentrated among people who have poor riboflavin status.
- 1.6 milligrams of riboflavin per day decreases homocysteine, and this decrease is highly concentrated among people with the C677T MTHFR polymorphisms who also have poor riboflavin status. In them, 1.6 milligrams of riboflavin decreases homocysteine a whopping 40%!
And how many people have poor riboflavin status? It’s generally assumed that riboflavin deficiency is rare in the developed world. Only 10% of Americans consume less than the RDA and clinical deficiency is rarely reported. But rarely does anyone study whether people have biochemical evidence of poor riboflavin status. A recent study in the UK found that a whopping 75% of boys, 87% of girls, and 41% of adults had blood markers of poor riboflavin status.
Because the best source of riboflavin is liver, and we don’t eat liver any more. Because the next best sources of riboflavin are heart, kidney, and almonds. We don’t eat heart or kidney and few people make large amounts of almonds a daily staple. The next best sources are red meat, cheese, eggs, salmon, mushrooms, seaweed, sesame, wheat germ, and wheat bran. But you have to eat lots of these foods to get enough riboflavin and most people don’t. They are either demonized (red meat, cheese, and in some circles eggs) or they are used once or twice a week at most (salmon) or as minor portions of dishes (everything else in the list, if they are used at all). And while some people do load up on red meat and cheese, often the rest of their diet is rather terrible because they are not health-conscious.
Another reason might be that poor magnesium status and any kind of problem with energy metabolism — like hypothyroidism, adrenal stress, or insulin resistance — hurts riboflavin retention. So we have worse food selection riding on top of poor metabolic health and poor magnesium status. Less riboflavin is coming in, and more is going out. We’re left with a double-whammy on our riboflavin status.
If suboptimal riboflavin status is truly widespread, and if that is the reason why the C667T and the A1298C polymorphisms lower MTHFR activity, it suggests that riboflavin should really be central to our thinking of how to deal with methylation issues.
But it also helps explain something else: why almost everyone has at least one of these genetic variations. Only about 10-15% of the population doesn’t have either one! In fact, they are combined in such a way that there is almost an even spread across the population. There are six possible combinations of the different MTHFR alleles, producing a continuous gradation of MTHFR activity from 100% of full activity in the best case to 25% of full activity in the worst. Roughly 15% or so of people fall into each one of the six combinations, leading to an even spread of MTHFR activity across the population.
This distribution is compatible with a tradeoff, as if both low methylfolate and high methylfolate levels had equal advantages and disadvantages. That’s conceivable.
But if these variations in enzyme activity are just a result of having crappy riboflavin status, then another explanation emerges: from an evolutionary perspective, these variations proliferated because they just didn’t matter. Our ancestors had better riboflavin status than we did. They ate more riboflavin. They ate more magnesium and peed out less of it. They held on to their riboflavin better because they had better magnesium status and better metabolic health. They could get away with MTHFRs that didn’t bind riboflavin as tightly because they had so much riboflavin around.
So, what do we do about this?
First, I have revised my MTHFR protocol. My MTHFR protocol is laid out on my Start Here for Methylation page. While that page has always mentioned riboflavin, until now it had given riboflavin a back-seat consideration. I have now moved riboflavin to the driver’s seat. The first point in the MTHFR protocol is to aim for 3 milligrams of riboflavin per day.
Here’s how I suggest doing that:
On one or two days a week, eat four ounces of liver, ideally from beef, bison, or lamb. On the other days, consume one “liver equivalent,” mixed and matched from the following foods. These foods supply 1/2 of a liver equivalent: kidney, heart, and almonds. These foods provide 1/6 of a liver equivalent: red meat, cheese, eggs, salmon, mushrooms, seaweed, sesame, wheat germ, and wheat bran. On days that you cannot meet the food requirement for a liver equivalent, take a low-dose riboflavin supplement or B complex providing 3-5 milligrams of riboflavin. For example, you could use a half a dropper of this liquid riboflavin supplement.
It’s important to note that endurance exercise, weight loss, high-fat diets, and sunlight exposure all increase your riboflavin requirement substantially. If two or more of these apply to you and you have low MTHFR activity, your riboflavin requirement could be closer to 5 milligrams per day.
It’s also important to note that we don’t know yet just how close to maximal the extra riboflavin can get your MTHFR working. It might be the case that enough riboflavin completely normalizes the MTHFR enzyme.
Since we don’t know for sure, my recommendation isn’t to get extra riboflavin and then forget everything else. Rather, I recommend getting enough riboflavin first and foremost, and then still engaging the rest of the protocol by increasing choline, getting enough folate and protein, and considering supplementation with creatine and either collagen or glycine on an as-needed basis.
Think how different this is than trying to make up for low MTHFR activity by taking extra methylfolate. One methylfolate molecule goes into your body, stays inside your cells for 200 days, and every day has 18,000 methyl groups added to it using MTHFR. If you have a 75% decrease in that, you’re losing 13,500 of those recycling events. You can’t take 13,500 times the normal dose of methylfolate. I have no idea what it would do but I know it’s not safe. Methylfolate is one of the primary normal food forms of folate, and I think it’s great. You need to get enough folate, so getting normal, reasonable doses of methylfolate into your diet makes complete sense. But adding more to make up for low MTHFR activity is ludicrous.
Doubling your riboflavin intake from 1.5 mg to 3 mg may normalize MTHFR activity, or get close. You help the enzyme work right, and then those 13,500 lost recycling events are suddenly recovered.
Taking riboflavin to support the enzyme is high-impact. Loading up on methylfolate is not.
This is why it’s really important to understand the biochemistry and to delve into the biochemical literature.
In addition to revising my MTHFR protocol on the Start Here for Methylation page, I have updated it in Testing Nutritional Status: The Ultimate Cheat Sheet as well.
By the way, I just released version 1.2 of the Cheat Sheet yesterday. The niacin and riboflavin sections have been completely overhauled, and it is now available in four formats instead of three: in addition to the traditional PDF, Kindle book, and iBook, I now have it as a Printer-Friendly PDF, where the hyperlinks are replaced by page number references, so you can flip through it as easily as you can click through the digital versions.
If you’ve already purchased the cheat sheet, you should have an email in your inbox giving you version 1.2 as a free update. If you don’t have it yet, you can get it here and you can use the code NEWSLETTER at checkout to get $5 off.
The third thing I’ve done is I’ve added the riboflavin podcast to the podcast series on managing nutritional status.
In the next few months, Alex and I are going to produce a podcast on each nutrient. I’m going to intensively research all the basic science, the food, the markers of nutritional status, and the dietary requirements, and Alex is going to research supplementation outcomes. These are often clocking in at over 3 hours, so they will often be released in two parts. For example, this Friday part 1 of our niacin podcast will come out and part 2 will come out two weeks from Friday. If you want to get notifications when each new episode comes out, you can sign up for notifications here.
As we research each nutrient, I expect we will stumble on more discoveries like this. So after each podcast, I’ll be revising that nutrient’s section in the cheat sheet and releasing the next version as a free update.
If I stumble upon any more amazing discoveries like this one, I’ll be sure to let you know with an email! So, if you’re not on my email list, you can sign up here.