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The role of methylation in supplementation

by Dr Nina Bailey BSc (Hons), MSc, PhD, RNutr

Our bodies are constantly working to produce energy, clear toxins, make and support brain chemicals, and keep our hearts healthy. The key system that helps keep these critical biological processes running smoothly is called one-carbon metabolism. It includes three important pathways: the methylation cycle, the folate cycle, and the transsulfuration pathway - a detoxification pathway.

If any of these pathways become off balance, which can be caused by stress, poor diet, or even simply due to our genetic makeup, it can affect overall health. Notable physical and emotional symptoms can manifest as low energy, brain fog, and mood swings, some of which are linked to difficulty in detoxing.

 

Each part of the system relies on key nutrients, including folate and vitamin B12. By supporting the smooth running of this system through diet and supplements, we can influence how we feel and function.

The role of methylation

Methylation occurs in every cell, working like a biological ‘on/off switch’ to control gene activity, brain chemicals, and detoxification. This important and complex process relies on an adequate supply of tiny carbon units called ‘methyl groups’, which attach themselves to important molecules like DNA, proteins, and neurotransmitters. This process of methylation keeps everything functioning smoothly; however, it requires a steady supply of methyl nutrients from food and supplements to run efficiently. If the body uses up methyl groups too quickly or if the supply is inadequate, it can affect everything from mood to energy production. This has the potential to lead to more serious health concerns. (1)

The four main steps of the methylation cycle:
1.    The body turns methionine (an amino acid derived from protein) into a helper molecule called SAMe
2.    SAMe gives away tiny chemical parts called methyl groups, which help many body processes. When SAMe donates a methyl group, it turns into SAH 
3.    SAH is then changed into another substance called homocysteine
4.    Homocysteine is recycled back to methionine using nutrients including folate (as methylfolate, or 5-MTHF for short), vitamin B12 (as methylcobalamin) and riboflavin (as riboflavin 5’-phosphate)

 

The ‘detox’ pathway helps the body manage excess homocysteine (an amino acid that can be harmful if it builds up). This process needs vitamin B6 (as pyridoxal 5’-phosphate) to work properly.

B12 and folate genetics explained – why methylated forms matter

Not all B-vitamins are created equal, especially when it comes to how your body uses them. The active form of vitamin B12, methylcobalamin, directly serves as a methyl donor. While cyanocobalamin is the form that is commonly found in supplements and fortified foods, it is not only synthetic and inactive, but it also includes a cyanide molecule that must first be detoxified by the liver before it can be converted to active B12 forms. Unfortunately, people with metabolic issues (such as poor kidney or liver health) may have issues converting cyanocobalamin efficiently.  

 

Folate, in contrast, is an umbrella term that refers to all forms of vitamin B9. This includes food folate, active methylfolate form, and folic acid (the synthetic form used in supplements and fortified foods). Before the body can use folic acid, it must be converted in the liver to methylfolate. This conversion depends on an enzyme called methylenetetrahydrofolate reductase (MTHFR).t

Certain changes in the MTHFR gene, known as Single Nucleotide Polymorphisms (SNPs), can reduce the activity of the MTHFR enzyme. This negatively affects how the body processes folate and breaks down homocysteine, which, when elevated, is linked to heart and brain health issues. 
 

To put this into context, over half of Europeans carry an SNP affecting how they convert folic acid and food folate into active methylfolate. This is especially significant for folic acid, as the reduced conversion can lead to a build-up of unmetabolised folic acid (UMFA), a form the body cannot use and one that may be associated with potential health risks. (2)

By choosing the active forms, methylcobalamin and methylfolate, it is possible to bypass this blocked pathway and to ensure optimal support for methylation. Moreover, while SNPs affecting the production of methylfolate are generally well recognised, there are multiple SNPs affecting other related pathways, and having one or more of these SNPs in combination can lead to a range of potential effects on health. 

 

For those who wish to gain more information on how SNPs may affect them, Lifecode Gx® is an example of a UK-based company that offers comprehensive, practitioner-led genetic testing.

Why methylation matters for your health

1.    Epigenetics
Methylation plays a vital role in controlling which genes are turned on or off, a process known as epigenetics. Not all genes should be active all the time, and the methylation of a gene has a switch-off effect, thereby ‘silencing’ it. It is this ‘silencing’ mechanism that helps protect against disease.(3)
 

2.    Detoxification
Methylation supports the liver in breaking down and removing harmful substances, including environmental toxins and byproducts produced during normal metabolic activity. Methylation is also required for the production of glutathione, a powerful antioxidant derived from homocysteine. Glutathione helps the liver detoxify harmful substances by making them easier to remove. Efficient methylation, therefore, keeps the detox system running smoothly, reducing the risk of toxic build-up that can lead to fatigue and inflammation.(4)
 

3.    Energy
Around 70% of methyl groups go towards the creation of fats that are crucial building blocks for healthy cell membranes, as well as creatine, a substance that is essential for energy in muscles and the brain. If your body doesn’t have enough methyl donors, it can slow down production of these important compounds, leading to fatigue and weakened cell membranes.(1)
 

4.    Liver health
The liver is rich in mitochondria, the tiny powerhouses within cells that generate energy. The fats that are created by methylation are not only a major component of mitochondrial membranes, but are also needed to make other specialised forms of fats (called lipoproteins) that play a role in the healthy transport of triglycerides and cholesterol away from the liver to other parts of the body. Triglycerides transported by lipoproteins provide energy to muscles and other tissues, while cholesterol is needed for functions such as making bile for fat digestion and producing vital hormones. When methylation is impaired, it negatively affects the health of our mitochondria, leading to low energy, but also leads to the storage of unhealthy levels of triglycerides by the liver, a major contributor to fatty liver disease.(5)
 

5.    Mental and cognitive health
Methylation is essential for mental and cognitive health because it supports the production of neurotransmitters, such as serotonin and dopamine. Unsurprisingly, disruptions in methylation have been linked to mood disorders, including depression and anxiety, as well as developmental conditions like ADHD.(6, 7)
 

6.    Heart and brain health
Under normal conditions, methylation helps convert homocysteine back into methionine or towards glutathione production; when these pathways are disrupted, homocysteine levels can rise. Elevated homocysteine is a well-established risk factor for heart disease, stroke, cognitive decline, and neurodegenerative disorders. (8) Maintaining healthy methylation is, therefore, vital for keeping homocysteine in check and supporting optimal cardiovascular and neurological function.
 

7.    Immune and inflammatory health 
Healthy methylation ensures the proper expression of immune-related genes while silencing genes that promote chronic inflammation and supporting a balanced and effective immune response. Methylation, therefore, plays a key role in regulating immune function and controlling inflammation.(9)

Choosing the right methylated supplements

An optimal supply of methyl donors is essential for supporting all three branches of one-carbon metabolism, and a well-balanced diet rich in whole, unprocessed foods provides the key nutrients needed (see table ‘Common methyl donors/methyl supporters’). 

However, multiple factors can influence how the body absorbs, converts, utilises or stores methyl-supporting nutrients; supplementation in combination with a methyl-supporting diet offers a way to overcome potential barriers and provide consistent support. Choosing an appropriate product to support the folate, methyl and detox pathways will depend on the level of support required. 

For everyday support

Pure & Essential Multivitamin & Minerals - Provides 21 key vitamins and minerals, including our full methylated B-Complex and is ideal for those individuals seeking medium intensity support.  ‘For Women’ provides iron in the gentle bisglycinate form and is ideal for women of menstruating age. ‘For Men’ is an iron-free formula with added lycopene. 

For intensive support

Super B-Complex - As our advanced formula is designed to offer comprehensive support for homocysteine recycling, Super B-Complex is ideal for those seeking energy, mood, and cardiovascular benefits. Alongside high-dose methylfolate and methylcobalamin, Super B-Complex also provides the methyl support nutrients riboflavin 5’-phosphate and pyridoxal 5’-phosphate

For children

Be Kind Kids Multivitamin Gummies - provides 11 vitamins and minerals, including methylfolate and methylcobalamin at appropriate doses for younger children. 

during pregnancy

Be Kind Prenatal Vitamins – Methylation demands are elevated during pregnancy, and folate requirements increase significantly to support this. This 23-nutrient multi offers comprehensive support for mums-to-be, including boosted methylfolate and additional choline.

Whether you require intensive methyl support or simply want to optimise your health, our range of methylated vitamins offers a perfect solution:

Highly bioavailable forms: active, methylated B-vitamins and cofactors to bypass conversion barriers

All-day nutrient coverage: B-vitamins are water-soluble and quickly excreted; using split dosing and sustained-release forms helps maintain steady blood levels throughout the day

Multiple health benefits, including: energy, mood, detox, and cardiovascular health

Ideal for genetic variants: ideal for those with MTHFR or other methylation-related SNPs

Vegan & clean-label formulas: no hidden nasties!

REFERENCES

1. Bellini et al., Exercise Prescription for Postprandial Glycemic Management. Nutrients. 2024 Apr 14;16(8):1170. https://pmc.ncbi.nlm.nih.gov/articles/PMC8912639/
2. Surwit et al., Stress management improves long-term glycemic control in type 2 diabetes. Diabetes Care. 2002 Jan;25(1):30-4.  https://pubmed.ncbi.nlm.nih.gov/11772897/

3. Petrangolini G et al., Development of an Innovative Berberine Food-Grade Formulation with an Ameliorated Absorption: In Vitro Evidence Confirmed by Healthy Human Volunteers Pharmacokinetic Study. Evid Based Complement Alternat Med. 2021 Nov 27;2021:7563889. https://pubmed.ncbi.nlm.nih.gov/34904017/

4. Dong et al., Berberine in the Treatment of Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis Evid Based Complement Alternat Med 2012 Oct 15;2012:591654. https://pubmed.ncbi.nlm.nih.gov/23118793/

5. Rondanelli et al., Berberine Phospholipid Is an Effective Insulin Sensitizer and Improves Metabolic and Hormonal Disorders in Women with Polycystic Ovary Syndrome: A One-Group Pretest-Post-Test Explanatory Study. Nutrients. 2021 Oct 19;13(10):3665.  https://pubmed.ncbi.nlm.nih.gov/34684666/

6. Cesarone et al., Borderline hyperlipidemia preventive management with Berberine PL in asymptomatic prevention of early atherosclerosis. Minerva Gastroenterol (Torino). 2024 Mar;70(1):10-15. https://pubmed.ncbi.nlm.nih.gov/37856087/

7. Cesarone et al. Borderline hyperlipidemia preventive management with Berberine PL in asymptomatic prevention of early atherosclerosis. Minerva Gastroenterol (Torino). 2024 Mar;70(1):10-15.  https://pubmed.ncbi.nlm.nih.gov/37856087/

8. Mergenthaler et al., Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 2013 Oct;36(10):587-97. https://pmc.ncbi.nlm.nih.gov/articles/PMC3900881/

9. Suksomboon  et al., Systematic review and meta-analysis of the efficacy and safety of chromium supplementation in diabetes. J Clin Pharm Ther. 2014 Jun;39(3):292-306. https://pubmed.ncbi.nlm.nih.gov/24635480/

10. Tarrahi  et al., The effects of chromium supplementation on lipid profile in humans: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2021 Feb;164:105308. https://pubmed.ncbi.nlm.nih.gov/33197598/

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We are here to help

Our expert nutritionists and in-house medic are here to answer your questions and advise about supplementation, dosing and contraindications. Do you have a question about one of our products or have a specific health goal in mind?

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