Myths of Methyl B12 and Methylfolate Benefits: Part 2

Debunking The Myths

Author: Dr. Stephen Chaney


Now that I have shared the saga of how the methylfolate and methyl B12 stories progressed from a kernel of truth to myths and eventually to outright lies, let me systematically debunk the myths of the mehtyl B12 and methylfolate benefits.


Debunking The Myths of Methylfolate Benefits


Methylfolate Benefits Myth: Methylfolate is natural. It comes from whole food. Folic acid is synthetic.

Fact: I covered this earlier. Methylfolate is chemically synthesized from folic acid. It is physically impossible to extract enough from whole foods.


Methylfolate Benefits Myth: Methylfolate is better utilized by the body than folic acid.

Fact: This claim is based on levels of methylfolate in the blood after taking supplements providing equivalent amounts of methylfolate and folic acid. However, methylfolate has no biological activity in our blood. The measurement that matters is total folate levels (methylfolate plus other folates) in our cells. If you take equivalent amounts of folic acid and methylfolate, you end up with identical folate levels in your cells (B.J. Venn et al, The Journal of Nutrition, 132: 3333-3335, 2002 ). In short, there is no difference in our ability to utilize methylfolate and folic acid.


Methylfolate Benefits Myth: If you have a mutation in the MTHFR gene, folic acid isn’t effective.

Fact: MTHFR slightly increases the need for folic acid (from 400 ug to between 600 and 800 ug), but multiple studies show that folic acid supplementation is effective in people with MTHFR mutations. For example, homocysteine levels are easily measured and are a reliable indicator of methylfolate status. One study has shown that folic acid and methylfolate were equally effective at lowering plasma homocysteine in people who were MTHFR C677T homozygotes (I.P. Fohr et al, American Journal of Clinical Nutrition, 75: 275-282, 2002 ). That study also showed that folic acid was more effective than methylfolate at lowering homocysteine in people who were C677T heterozygotes and in people with normal MTHFR activity. Another study showed folic acid was just as effective as a diet providing equivalent quantities of folate from foods at lowering homocysteine levels in people with various MTHFR mutations (P.A. Ashfield-Watt et al, American Journal of Clinical Nutrition, 76: 180-186, 2002 ).

At present, lowering of homocysteine levels is the only indicator of methylfolate status for which methylfolate and folic acid have been directly compared. However, there are other studies suggesting that folic acid is likely to be effective for people with MTHFR defects.

For example, folic acid has been shown in multiple studies to be effective in preventing neural tube defects (L.M.De-Regil et al, Cochrane Database Systematic Reviews 2010 Oct 6;(10):CD007950. PMID: 20927767 ), which are highly associated with the C677T MTHFR gene defect. Three studies have shown that supplementation with folic acid, B12, and B6 slowed cognitive decline in older people with elevated homocysteine levels (J.Durga et al, The Lancet, 369: 208-216, 2007 ; A.D.Smith et al, PLoS ONE 5(9): e12244. doi:10.1371/journal.pone.0012244, 2010 ; G.Douaud et al, Proceedings of the National Academies of Sciences, 110: 9523-9528, 2013 ). In contrast, the one study that substituted methylfolate for folic acid showed no effect (J.A. McMahon et al, New England Journal of Medicine, 354: 2764-2769, 2006 ).


Methylfolate Benefits Myth: Folic acid causes cancer.

Fact: The studies suggesting that folic acid supplementation might increase the risk of cancer were all “outliers.”  By that I mean they contradicted many other studies showing no increased risk. Scientists are accustomed to this. We know that studies sometimes come up with conflicting results. In some cases, we can point to an error in experimental design or statistical analysis as the cause of the aberrant results. In other cases, we never methylfolate benefitsknow the reason for the differences, so we go with the weight of experimental evidence (what the majority of studies show). The weight of evidence clearly supports the safety of folic acid.

However, that is not enough. If there is the slightest possibility that something causes cancer, we investigate it further. Consequently, the scientific community followed up with larger studies. Those studies showed either reduced cancer risk or no difference in cancer risk with folic acid supplementation. None of the studies found any evidence that folic acid increased cancer risk. I have covered this in detail for folic acid and colon cancer risk in a previous issue of “Health Tips From The Professor.”

There have also been a couple of small studies suggesting that folic acid might increase the risk of prostate and breast cancer. Although these were small, individual studies, they have been widely hyped by the methylfolate advocates. Once again, the definitive study has been done (S.E. Vollset et al, The Lancet, 381: 1029-1036, 2013 ).

It was a meta-analysis of every placebo controlled study prior to 2010 that analyzed the effect of folic acid supplementation on cancer risk, a total of 13 studies involving over 50,000 subjects. The results were clear cut. Folic acid supplementation caused no increase in overall cancer risk, and no increase in the risk of colon cancer, prostate cancer, breast cancer, or any other individual cancer. Moreover, the average dose of folic acid in those studies was 2 mg/day, which is 5 times the RDA.

Of course, the bloggers and the companies selling methylfolate supplements ignore the definitive studies showing folic acid does not increase cancer risk. The myths and the lies continue.


Methylfolate Benefits Myth: Folic acid supplementation during pregnancy increases autism risk.

Fact: This myth is based on a recent study presented at an international meeting. There are two important things you should know about this myth.

#1: This study has not yet gone through the peer review process necessary for publication. We do not know if it is a valid study.

#2: The authors of this study are desperately trying to correct the misleading information that is being circulated on the internet about their study. They say their study does not apply to women taking a prenatal supplement containing folic acid during pregnancy. In fact, several studies  show that supplementation with 400 ug of folic acid during pregnancy decreases autism risk.

The authors emphasize that the increase in autism risk in their study was only seen in women with 4 times the recommended levels of folate in their blood at delivery. In other words, it only applies to women taking mega-doses of folic acid during pregnancy. Taking mega-doses of any vitamin during pregnancy is a bad idea.

Unfortunately, the best efforts of the authors have not deterred irresponsible bloggers and journalists from spreading the myth that folic acid supplementation during pregnancy may cause autism. That is incredibly bad advice because it may discourage some expectant mothers from taking prenatal vitamins with folic acid. Multiple studies have shown folic acid supplementation during pregnancy reduces the risk of birth defects.


Methylfolate Benefits Myth: Folic acid can mask a B12 deficiency.

Fact: True, but irrelevant if you use a supplement with folic acid and B12 in balance.

For more details and references, watch my “Truth About Methyl Folate” video in the Video Resources section of Health Tips From The Professor.


Debunking The Myths of The Methyl B12 Benefits

Along with the methylfolate myths have come the methyl B12 myths. Some supplement manufacturers are now claiming that methyl B12 (methylcobalamin) is more natural and more effective than the cyanocobalamin that has been used in supplements for the past 70 years. The arguments are essentially the same as for methylfolate, so let me briefly debunk the methyl B12 claims as well.


methylfolate benefits and methyl b 12Methyl B12 Benefits Myth: Methyl B12 (methylcobalamin) is more natural than cyanocobalamin. We get the methyl B12 in our supplements from foods.

Fact: As with methylfolate, it would be impossible to extract enough methylcobalamin from foods. In fact, most of the methylcobalamin in supplements is chemically synthesized from either cyanocobalamin or hydroxycobalamin. It can never be more natural than it’s starting ingredients. A small amount of methylcobalamin is made from genetically modified bacteria.


Methyl B12 Benefits Myth: Cyanocobalamin is toxic.

Fact: You get much more cyanide from common foods such as almonds, lima beans, any fruit with a pit such as peaches, and even some fruits with seeds, such as apples. For example, a single almond contains 200 times more cyanide than a supplement providing the RDA of cyanocobalamin.


Methyl B12 Benefits Myth: Because methylcobalamin is one of the active forms of B12 inside cells (adenosylcobalamin is the other), it is better utilized by cells than cyanocobalamin.

Fact: Cyanocobalamin and methylcobalamin are equally well absorbed by the intestine and equally well transported to our cells. At the cell membrane, the cyano and methyl groups are stripped off and cobalamin (B12) binds to a transport protein called transcobalamin II. Once inside the cell either a methyl group or adenosyl group is added back to cobalamin. In short, methylcobalamin offers no advantage over cyanocobalamin because its methyl group is removed before it enters our cells. Once the methyl and cyano groups have been removed, the cell has no way of knowing whether B12 started out in the methyl or cyano form.


Methyl B12 Benefits Myth: Methylcobalamin is better utilized than cyanocobalamin for people with methylation defects.

Fact: A methylation defect would affect methylation of cobalamin once it is released from transcobalamin II inside the cell. Because the methyl and cyano groups are removed before cobalamin binds to transcobalamin II, methylcobalamin offers no advantage over cyanocobalamin.


What Does This Mean For You?

MTHFR mutations only result in partial loss of activity. Most individuals with MTHFR defects remain symptom free with the RDA, or slightly above the RDA, of folic acid. However, there may be some individuals with a MTHFR defect and additional gene defects in metabolic pathways involving methylation who might benefit from methylfolate. This is due to a phenomenon that geneticists call penetrance and would likely represent a small subset of the population with MTHFR defects. The claims that everyone would benefit from methylfolate instead of folic acid are false. They are contradicted by human metabolism and published clinical studies.

The claims that everyone would benefit from methylcobalamin (methyl B12) instead of cyanocobalamin is even more outrageous. Anyone who takes the time to research how B12 enters our cells would realize that the claim is biochemically impossible.

In short, folic acid has been used for over 80 years and cyanocobalamin for 70 years. There are hundreds of clinical studies showing they are safe and effective, even in most individuals with a MTHFR deficiency. I can’t tell you whether the companies selling methylfolate and methyl B12 are ignorant of basic metabolism and the published studies refuting their claims or whether they are purposely trying to deceive the public—but neither is a good thing.


The Bottom Line


Last week I shared the story about how the myths about methylfolate and methyl B12 arose and how they eventually became lies. This week I debunked the myths of methyl B12 and methylfolate benefits.


These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.


Methylfolate and Methyl B12 – Myths or Lies? Part 1

How Did The Myths Arise?

Author: Dr. Stephen Chaney


methylated b liesHow did methylfolate become the center of a myth? 

How are the lies of the food supplement industry created? Some of them start innocently enough. They are often based on a kernel of truth which is misinterpreted by some well-meaning medical doctors. It’s not their fault. We teach future doctors what I call “metabolism light” in medical school. There simply isn’t room in the medical curriculum to teach all the details and nuances of human metabolism. We also try to teach them the basics of how to interpret the scientific literature. However, it takes years of experience to get really good at picking out the strengths and weaknesses of clinical studies.

The doctors form their hypothesis and test it on a few patients. If it works, they publish a paper. At that point their idea is picked up by the “sensationalist” bloggers. These are the bloggers who like to focus on the sensational. They delight in writing about “new findings” that go against what the medical profession has been telling you for years. The bloggers don’t stop there. They usually expand the claims. They ‘cherry pick” the scientific literature by quoting only studies that support their viewpoint, and ignoring studies that refute it. In short, they put together a very compelling story. Soon the story is picked up by other bloggers who embellish it further. After it appears in enough sites, people start believing it. A myth is born.

Then supplement companies get in the act. They sense there is money to be made. They manufacture supplements to provide nutrients supported by the myths. They embellish the mythology even more and put together a compelling story to market their products. This is where the mythology becomes deception. Companies have the responsibility to design their products based on the best science. They have an obligation to tell the truth about their products. They know, or should know, that all their claims are not true. When they make claims they know cannot be true, they are lying to you.

The saga of the methylated B vitamins is a perfect example of how observations based on a kernel of truth became myths and eventually became downright lies. Let me share that story with you.


The Kernel Of Truth About Methylfolate


methylated b folic acidLet’s start with the “kernel of truth” that launched the whole methylfolate saga. It started with a doctor who was having a very difficult time finding a solution for a patient with some significant health issues. The doctor ordered a genetic test and discovered the patient had a deficiency in the methylene tetrahydrofolate reductase (MTHFR) gene. The doctor remembered the reaction catalyzed by MTHFR, and a light bulb went off. “Eureka”, he said. His patient must be unable to make N5-methyltetrahydrofolate (commonly referred to as methyl folate), and methylfolate is required for some very important methylation reactions in the cell.

He gave his patient methylfolate, and the patient’s symptoms got better. The doctor leapt to the conclusion that other patients with MTHFR deficiency needed methyl folate as well. Many of those patients responded to methylfolate as well. He didn’t bother to check whether they responded equally well to folic acid. He just assumed methylfolate was the magic elixir. He wrote a paper on his clinical observations, and the methylfolate story was launched. It all seemed so logical. However, the story was not nearly as straight forward as the doctor and the people publicizing his findings assumed. Let me walk you through some “Metabolism 101”. Don’t worry. There won’t be a quiz.


Why The Original Assumptions About Methylfolate Were Misleading


MTHFR mutants only have a partial loss of activity.

  • Individuals with 2 copies of a mutation from A to C at position 1298 of the MTHFR gene(A1298C homozygotes) comprise about 5% of the US population. They have 60% enzyme activity and appear to be normal in clinical studies.
  • Individuals with 2 copies of a mutation from C to T at position 677 of the MTHFR gene (C677T homozygotes) have 30% enzyme activity. They comprise about 10% of the US population. C677T homozygotes often have elevated homocysteine levels. The homozygous C677T mutation is associated with depression, anxiety, and mood swings in some people, but not in others (I will come back to the significance of that qualifying statement later).
  • C677T heterozygotes (one mutant gene) have 65% activity and are normal.

We Don’t Need 100% MTHFR Activity

space shuttleOur human body is wonderfully designed. For many of our most essential metabolic reactions we have built in redundancy. We don’t require 100% activity of key enzymes. This helps protect us from bad effects of mutations as they arise.

The best analogy I can think of is the US space program. Most space vehicles had built in redundancy so that if one system failed, the mission could go on. For example, you may remember the Hubble space telescope. It was launched with four gyroscopes to keep the telescope pointed in the right direction. After a few years, one gyroscope gave out. That was not a problem because there were three left. A few years latter the second gyroscope gave out. Again, there was no problem because there were still two gyroscopes left. It was only after the third gyroscope gave out that Hubble became a bit “wonky”, and a space shuttle was sent up to replace the gyroscopes. It is the same with MTHFR. Only when you get down to around 30% activity, does it become a bit wonky”. (That’s about as non-technical as I get.)

Not Everyone With MTHFR Deficiency Experiences Symptoms

This is due to a phenomenon my geneticist friends refer to as penetrance. Simply put, that means that not everyone with the same mutation experiences the same severity of symptoms. That is because the severity of a mutation is influenced by diet, lifestyle, and genetic background. Let me start with genetic background. In terms of MTHFR mutants you can think of genetic background as being mutations in a related methylation pathway. People who have a mutation in both MTHFR and a gene in a related pathway will experience more severe symptoms and are more likely to require methyl folate. Once you understand penetrance, you realize that individuals requiring methyl folate may represent only a small subset of people with MTHFR mutations.

Penetrance is a concept that most proponents of the methylfolate hypothesis completely ignore. The most severe MTHFR mutation (C677T homozygote) increases the probability that individuals will exhibit symptoms, but some individuals with that mutation are completely normal. Now that you understand the concepts of redundancy and penetrance, you can understand why that is.


When Did The Kernel of Truth About Methylfolate Become A Myth?


methylated b mythsUp to this point the hype around methylfolate could be chalked up to an honest misunderstanding. The doctors who published the original papers may not have known that MTHFR mutations only resulted in a partial reduction in enzyme activity. They probably didn’t know the concepts of redundancy (our cells don’t need 100% enzyme activity) or penetrance (the same mutation may cause severe symptoms in some patients and have no effect in others). It seemed logical to assume that everyone with a MTHFR mutation might do better with methyl folate supplementation. That was incorrect, but it was an honest mistake.

However, the message was picked up by the bloggers who specialize in sensational stories, especially stories that contradict what experts have been telling you for years. They picked up the methyl folate story and distorted it beyond recognition. They knew that “natural” is a buzz word, so they told you that methylfolate was natural and folic acid is synthetic (I exposed that lie earlier). They told you that methylfolate was better utilized than folic acid. They told you that methylfolate was more effective than folic acid. They told you folic acid was toxic. It was going to increase your risk of heart disease and cancer. Suddenly, it was no longer about people with MTHFR deficiency. You were being told that everyone should avoid folic acid and use methylfolate instead.

methylated b folicOn the surface, these pronouncements should not have passed the “If it sounds too good to be true…” test, or in this case, the “If it sounds too bad to be true…” test. You were being asked the believe that folic acid, which has been in use for over 80 years and is backed by hundreds of studies showing it is safe and effective, was neither safe nor effective. You were asked to believe that the government was poisoning you by fortifying foods with folic acid.

However, to make their blogs sound more convincing, they listed clinical studies supporting their stories. The problem is they “cherry picked” the studies that supported their story and ignored the rest. Their bias was particularly outrageous when it came to the “story” that folic acid increases cancer risks. They ignored 10 or 20 studies showing no cancer risk and reported one suggesting it might increase risk. I call that deceptive.

Unfortunately, the myths created by the bloggers have been repeated often enough that many people now believe they are true. I will debunk their myths next week, but first let me touch on how their deceptions became downright lies.


When Did The Myths About Methylfolate and Methyl B12 Become Lies?


If you are writing a blog, you are covered by “freedom of speech.” You can say whatever you want. It doesn’t have to be true. However, if you are a supplement manufacturer, you are held to a higher standard. Ignorance is no longer an excuse. You can no longer cherry pick the “facts” you like and ignore the rest. You are ethically obligated to research all the available literature and be guided by the best scientific evidence.

Reputable companies have been guided by the scientific evidence and have not jumped on the methylfolate bandwagon. They know folic acid is both safe and effective in a wide variety of clinical situations. They also know that, while methylfolate may be just as effective as folic acid, its potential is largely unproven at this point. It has not been tested in many clinical situations.

Less reputable companies, however, sensed money to be made by capitalizing on the buzz around methylfolate. They repeated the myths of the bloggers to claim that their products were superior to others on the market. They call it marketing. I call it lying. They have an obligation to fact check their claims, and only make claims that are true.

It gets worse. Since lots of people already believed they needed methylfolate, why not extend the claim to one of the methylated B vitamins, methyl B12? That would boost sales even more. The claims for methyl B12 were even more outrageous than for methylfolate. There wasn’t even a “kernel of truth” like MTHFR deficiency to serve as a foundation. The claim was the methyl B12 was needed because of some sort of ambiguous “methylation deficiency”. The lies had become whoppers.

Next week I will debunk the methylfolate and methyl B12 myths. Stay tuned.


The Bottom Line


This week I have shared the story about how the myths about methylfolate and methyl B12 arose and how they eventually became lies. Next week I will debunk the myths.


These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.

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