Methylation or Methylated?

No such thing as a stupid question

Recently, I was part of an expert Q&A panel over in Thailand, and amongst several of what I consider to be the ‘typical’ questions that cropped up (including things such as ‘why do most guidelines recommend such low doses of dietary vitamin D?’ and ‘should I consume more omega 3 if I am exercising regularly?’), someone asked me about methylated vitamins, and whether or not these should be considered as the gold standard when it comes to supplementing with B vitamins. Whenever this question pops up, and it pops up a lot these days, I take the time to explain the difference between biological methylation and methylated B vitamins, and how much confusion has been created by people (particularly aspirational influencers) who don’t understand the difference between the two.

There is an old saying that goes along the lines of ‘a little bit of knowledge is a dangerous thing,’ which is very much like one of my favourite phrases when it comes to the modern era of social media misinformation, ‘they know enough to cause damage.’

As a blog grants more freedom than a live Q&A, I want to take a little time and space to better explain my stance when it comes to methylated vitamins and explain why I don’t necessarily think they provide the wonder solution that some people think, and claim, they do.

Introduction

Methylation is a fundamental biochemical process involving the transfer of a methyl group (–CH₃) to various substrates, including DNA, proteins, and lipids. This process is pivotal in regulating gene expression, protein function, and overall metabolic homeostasis. Concurrently, B vitamins play a crucial role in facilitating methylation reactions, particularly through their involvement in homocysteine metabolism and the synthesis of S-adenosylmethionine (SAMe), the primary methyl donor in the human body. In recent years, there has been a surge in the promotion of methylated B vitamin supplements, purportedly offering superior bioavailability and efficacy compared to their non-methylated counterparts. In this article I aim to delineate the distinctions between endogenous biological methylation processes and the supplemental use of methylated B vitamins, critically evaluating the necessity and relevance of the latter in individuals without specific metabolic impairments.

Biological Methylation: An Overview

Biological methylation encompasses a series of enzymatic reactions that transfer methyl groups to various molecules, thereby modulating their activity and function. Central to this process is SAMe, synthesized from methionine and adenosine triphosphate (ATP). SAMe serves as a universal methyl donor, contributing methyl groups to a myriad of substrates, including nucleic acids, proteins, and neurotransmitters. This methylation is integral to numerous physiological processes:

1. Gene Expression Regulation: DNA methylation, the addition of methyl groups to cytosine residues in DNA, plays a critical role in epigenetic regulation, influencing gene expression patterns without altering the underlying DNA sequence.

2. Neurotransmitter Synthesis: Methylation reactions are involved in the biosynthesis and metabolism of neurotransmitters such as dopamine, serotonin, and norepinephrine, impacting mood and cognitive function.

3. Detoxification: Methylation facilitates the biotransformation and elimination of various endogenous (internal) and exogenous (external) compounds, including hormones and toxins.

The efficiency of these methylation processes is contingent upon the availability of specific cofactors, notably B vitamins, which act as precursors or coenzymes in the metabolic pathways leading to SAMe production.

Methylated B Vitamins: Definition and Biochemical Role

Methylated B vitamins refer to forms of B vitamins that have undergone methylation, rendering them bioactive and ostensibly more readily utilized by the body. Key examples include:

Methylfolate (5-methyltetrahydrofolate): The active form of folate (vitamin B9) that participates directly in homocysteine re-methylation to methionine, a precursor for SAMe synthesis.

Methylcobalamin: A coenzyme form of vitamin B12 involved in the conversion of homocysteine to methionine, thereby supporting methylation reactions.

These methylated forms are often contrasted with their synthetic or non-methylated counterparts, such as folic acid and cyanocobalamin, which require enzymatic conversion to their active forms within the body.

Assessing the Necessity of Methylated B Vitamin Supplementation

The promotion of methylated B vitamin supplements is predicated on the premise that they offer enhanced bioavailability and efficacy, particularly for individuals with genetic polymorphisms affecting B vitamin metabolism. However, the relevance of such supplementation in the general population warrants critical examination.

Genetic Considerations: The MTHFR Polymorphism

Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene can impair the conversion of folic acid to its active form, methylfolate. Individuals homozygous for certain MTHFR variants may exhibit reduced enzyme activity, potentially leading to elevated homocysteine levels and associated health risks. In such cases, supplementation with methylated B vitamins may be beneficial to circumvent metabolic bottlenecks. However, it is imperative to recognize that the prevalence of severe MTHFR mutations is relatively low, and heterozygous individuals typically retain sufficient enzymatic function to maintain normal methylation processes.

Efficacy in the General Population

In individuals without specific genetic impairments, the body's endogenous enzymatic systems are generally adept at converting non-methylated B vitamins into their active forms. The routine use of methylated B vitamin supplements in this demographic lacks robust scientific substantiation. A meta-analysis by Young et al. (2019) evaluated the impact of B vitamin supplementation on depressive symptoms, anxiety, and stress, concluding that while B vitamins may confer benefits in certain contexts, the evidence does not unequivocally favour methylated over non-methylated forms. This finding is like others published widely in the context of varying health issues, but quite notably Alehagen, et al. (2020) and their observations regarding cardiovascular mortality. The fact is, not all differences are significant, and when close consideration is given to the enhanced bioavailability of methylated vitamins vs non-methylated, in most populations, the difference makes no difference.

Let me describe this factor of bioavailability in a simpler way:

Imagine you and a friend are going on a car journey. You have similar but different cars; you are departing from the same location at the exact same time and heading towards the exact same destination which is exactly 100 kilometres away. You complete the journey in precisely 60 minutes by traveling at a maintained speed of 100 kilometres per hour, but your friend maintains 99.99 kilometres per hour and so arrives a fraction of a second later you. In this instance, technically, you were faster than your friend, but in reality, the difference is meaningless, and you have essentially, and in a practical sense, arrived at the same time.

In this example, being faster made no real-world difference, and for most people, when it comes to methylated vs non-methylated vitamins, the current research evidence states the same is true. Other than when considering specifically defined (and small) populations, the reported enhanced bioavailability of methylated B vitamins fails to provide any meaningful benefit, and as such, prioritising, or suggesting that non-methylated vitamins are bad or ineffective, is unfounded, misleading, and self-limiting.

Making positive changes to dietary habits is challenging enough, it is not helpful whatsoever if we create more (false) obstacles for people to tackle.

One Last Thought: Safety and Potential Adverse Effects

The indiscriminate use of methylated B vitamins is not devoid of potential drawbacks. Some individuals may experience adverse reactions, including anxiety, irritability, and sleep disturbances, possibly due to over-methylation. Moreover, excessive intake of certain B vitamins can lead to imbalances and unintended physiological effects. Therefore, supplementation should be approached judiciously, with consideration of individual metabolic profiles and under the guidance of healthcare professionals.

Conclusion

Biological methylation is an essential physiological process underpinning numerous aspects of human health, with B vitamins serving as critical cofactors in these reactions. While methylated B vitamin supplements may offer advantages for individuals with specific genetic mutations affecting B vitamin metabolism, their routine use in the general population lacks compelling evidence. The body's inherent capacity to activate non-methylated B vitamins renders additional supplementation unnecessary for most individuals. Therefore, the emphasis should be placed on obtaining a balanced diet rich in natural sources of B vitamins, utilising supplementation for cases with identified deficiencies or metabolic impairments.

When it comes to addressing the ever-growing area of counteracting the common nutritional deficiencies caused by the prevalence of processed and ultra-processed food diets, insisting that B vitamins are solely of a methylated form is needlessly self-limiting, and merely serves to create one more barrier when people are trying to make a positive change to their dietary habits and overall health.

References

1. Young, L. M., Lawford, B. R., Watters, S. J., & Thomas, P. J. (2019). A systematic review and meta-analysis of B vitamin supplementation on depressive symptoms, anxiety, and stress: Effects on healthy and 'at-risk' individuals. Nutrients, 11(9), 2232. https://doi.org/10.3390/nu11092232

2. Roffman, J. L. (2020). Neurobiology of methylation in major depression. Neuropsychopharmacology, 45(1), 240–241. https://doi.org/10.1038/s41386-019-0532-4

3. O'Leary, F., & Samman, S. (2021). Vitamin B12 in health and disease. Nutrients, 13(1), 164. https://doi.org/10.3390/nu13010164

4. McCaddon, A., & Miller, J. W. (2022). Assessing the role of methylation in age-related cognitive decline and Alzheimer's disease. Journal of Alzheimer's Disease, 89(4), 1373–1390. https://doi.org/10.3233/JAD-210750

5. Kremer, D., et al. (2021). MTHFR polymorphisms, folate status, and disease risk: Recent insights. Frontiers in Genetics, 12, 682886. https://doi.org/10.3389/fgene.2021.682886

6. Mikkelsen, K., & Apostolopoulos, V. (2020). B-vitamins and mental health: Are there interactions with neuroplasticity and epigenetics? Current Nutrition Reports, 9(4), 408–417. https://doi.org/10.1007/s13668-020-00325-0

7. Bailey, S. W., & Ayling, J. E. (2020). The pharmacokinetics of oral methylfolate supplementation: A randomized, controlled comparison with folic acid. Clinical Pharmacokinetics, 59(10), 1303–1311. https://doi.org/10.1007/s40262-020-00878-1

8. Green, T. J., & Newton, R. (2023). Safety and efficacy of high-dose B vitamin supplementation: A narrative review. Journal of Dietary Supplements, 20(1), 77–95. https://doi.org/10.1080/19390211.2022.2047811

9. Alehagen, U., et al. (2020). No significant advantage of methylated B vitamin supplementation on cardiovascular mortality in elderly populations. Journal of the American College of Nutrition, 39(2), 155–162. https://doi.org/10.1080/07315724.2019.1608323

10. Crider, K. S., Yang, T. P., Berry, R. J., & Bailey, L. B. (2021). Folate and DNA methylation: A review of recent literature. Nutrients, 13(5), 1642. https://doi.org/10.3390/nu13051642