Methylation issues

Nutrition_green

Methyl groups are essential components of our diet. They are found in foods rich in folate, B12, B6, betaine, choline and methione, for example in fish, meat, eggs, beets and green leafy vegetables such as spinach. They consist of a carbon and 3 hydrogen atoms and contribute to a process called methylation. Methylation is involved in almost every biochemical reaction in our body and is contributes to detoxification, immune function and DNA expression, mood balancing and energy production

  • It occurs billions of times every second in our cells
  • Methylation is necessary for the replication of our DNAKikuchi, A. and Arita, K. (2025) ‘A comprehensive review of structural insights into DNA methylation maintenance’, Genes & Genetic Systems
  • Methylation helps turn one neurotransmitter into another (for example noradrenalin turns into adrenaline by having a “methyl” group added)Khalil, B., Rosani, A. and Warrington, S.J. (2024) ‘Physiology, Catecholamines’, in StatPearls

Methylation and mental health

Methylation is a key factor in the epigenetic processes that regulate key neurotransmitters essential for mental health:

  • Impaired methylation can result in a lack of the components needed to generate neurotransmitters like serotonin
  • It can also lead to problems converting serotonin to melatonin
  • The enzyme that converts norepinephrine to epinephrine is dependent on methylation for activationKhalil, B., Rosani, A. and Warrington, S.J. (2024) ‘Physiology, Catecholamines’, in StatPearls
  • Imbalances in the methylation pathway can also affect the neurotransmitter dopamine
    • Methylation supports dopamine receptor activity by keeping phospholipids in the cell membrane fluid
    • This allows the receptor to be able to move freely within the membrane making it more efficient in ‘catching’ free dopamineSharma, A., Kramer, M.L., Wick, P.F., Liu, D., Chari, S., Shim, S., Tan, W., Ouellette, D., Nagata, M., DuRand, C.J., Kotb, M. and Deth, R.C. (1999) ‘D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia’, Molecular Psychiatry, 4(3), pp. 235–246.
  • The methyl/folate ratio has a powerful impact on the gene expression of re-uptake transport proteins
  • More than 60% of anxiety, depression and psychosis patients exhibit a serious methylation imbalance Walsh, W. (2014). Methylation, Epigenetics and Mental Health. [online] Naperville, IL: Walsh Research Institute, p. 13. Available at: http://www.walshinstitute.org/uploads/1/7/9/9/17997321/methylation_epigenetics_and_mental_health_by_william_walsh_phd.pdf [accessed 19 Sep. 2026].

There are two types of methylation disorders which can adversely affect mental health:

  • UNDER Methylation, also called histadelia
  • OVER Methylation, also called histapenia

Undermethylation refers to a depressed methyl/folate ratio and low catecholamine level (dopamine, adrenaline, and noradrenaline). People who undermethylate may not produce enough key neurotransmitters for mental health, which may lead to depression and other mental health symptoms.

Whole blood histamine levels are tested when determining cause of depression and other mood disorders. Elevated histamine depletes methyl compounds and the resulting undermethylation leads to depression and a host of other mental health issues.

This imbalance is associated with:

  • Depression, especially seasonal depression (SAD)
  • OCD
  • High libido
  • Low levels of serotonin
  • Seasonal allergies
  • Elevated body temperature
  • Very strong willed, oppositional to authority
  • Calm demeanour, but high inner tension
  • OCD tendencies, controlling behaviour
  • Good response to selective serotonin reuptake inhibitors (SSRIs)

Walsh, W. (2014). Methylation, Epigenetics and Mental Health. [online] Naperville, IL: Walsh Research Institute, p. 13. Available at: http://www.walshinstitute.org/uploads/1/7/9/9/17997321/methylation_epigenetics_and_mental_health_by_william_walsh_phd.pdf [accessed 19 Sep. 2026].

Sufferers of undermethylation may be depressed due to low levels in calcium, magnesium, methionine, and vitamin B-6 with excessive levels of folic acid.

Overmethylation (too many added methyl groups) results in excessive levels of the neurotransmitters dopamine, norepinephrine and serotonin. Characteristics may include:

Sufferers of over-methylation have a tendency to be very depressed in folates (a form of folic acid), niacin and Vitamin B-12 and overloaded in copper and methionine (a sulfur-containing amino acid) and supplements of these nutrients must be strictly avoided Walsh, W. (2014). Methylation, Epigenetics and Mental Health. [online] Naperville, IL: Walsh Research Institute, p. 13. Available at: http://www.walshinstitute.org/uploads/1/7/9/9/17997321/methylation_epigenetics_and_mental_health_by_william_walsh_phd.pdf [accessed 19 Sep. 2026].

Functional testing for methylation

  • Homocysteine Test
    • Homocysteine is synthesized from methionine by removal of a methyl group
  • B12 and MMA Test
    • Methylmalonic Acid (MMA) requires B12 as a co-enzyme, MMA levels are a good indicator of B12 status
  • Methylation Profile
    • Evaluates the plasma levels of methionine, cysteine, SAM, SAH, homocysteine and cystathionine and the “methylation index” (ration of SAM to SAH)