If you have been researching topics related to nootropic supplements or cognitive health, you may have heard about a process known as “methylation.” This process is an essential factor that affects many different mental and physical factors.
We think it’s certainly worth understanding the basics of methylation if you are interested in holistic nootropic supplements.
Methylation is the process of adding methyl groups to DNA in a way that modifies gene expression. It is a mechanism for transmitting information through DNA replication and cell division.1Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role Adv Nutr. 2012
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Methylation and Epigenetics
Methylation affects a cell’s epigenetic expression. Epigenetics is the study of heritable changes in gene expression that do not result from changes in the primary DNA sequence. Meaning, those that result from environmental or lifestyle factors.2Fazzari MJ, Greally JM. Introduction to epigenomics and epigenome-wide analysis Methods Mol Biol. 2010
So, according to epigenetic researchers, what you eat, how you sleep, where you live, who you interact with, and other factors can affect how your genes express themselves. These changes can even be passed down to offspring.
Methylation can either turn up or down the expression of a gene. While more methylation may seem like a good thing, too much (hypermethylation) of the wrong genes and not enough (hypomethylation) of the right genes can be harmful.
Methylation changes, both global and gene-specific, have been observed to be associated with diseases, particularly in cancer.3Tost J. DNA methylation: an introduction to the biology and the disease-associated changes of a promising biomarker Methods Mol Biol. 2009
The methylation process can have a profound effect on mental health and mood. According to some surveys, more than 60% of anxiety, depression, and psychosis patients exhibit serious methylation imbalance.4William J. Walsh. EVALUATION & TREATMENT OF OVER- AND UNDER-METHYLATION IN THE PSYCHIATRIC POPULATIONWalsh Research Institute, 2015
Undermethylation vs. Overmethylation
Having too much or too little methylation can both be detrimental to physical and mental health but in distinct ways.
Undermethylation can contribute to several conditions such as autism spectrum disorder, antisocial personality disorder, schizoaffective disorder, anorexia, and depression.
People who are deficient in methylation may exhibit some of the following signs:
- Seasonal inhalant allergies
- Highly competitive
- Difficulty with authority
- High inner tension
- OCD tendencies
- Overcontrolling tendencies
- High libido
- Good response to SSRI medication
In contrast, overmethylation may be a factor in panic/anxiety disorders, paranoid schizophrenia, ADHD, behavior disorders, and depression.
Symptoms of overmethylation include:
- High anxiety/panic tendency
- Hyperactivity/nervousness
- Sleep disorder
- Absence of seasonal allergies
- Food/chemical sensitivities
- Dry eyes and mouth
- Highly empathetic
- Non-competitive in sports and academics
- Adverse reactions to SSRIs
Methylation And Diet
DNA methylation can be affected by dietary levels of methyl donor components such as folic acid or homocysteine. These levels can be dependent on dietary intake, and can also be altered through supplementation
Dietary supplementation of folic acid during pregnancy has been shown to increase DNA methylation and alter methylation-dependent phenotypes in offspring.5Waterland RA, Jirtle RL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases Nutrition. 2004
How Methylation Affects Mood
Childhood adversity can cause epigenetic alterations in several genes that are tied to mood and emotion. One study found that men who had suffered difficulties in early childhood are far more likely to exhibit changes in methylation that are consistent with causing depression and anxiety.6Labonté B, et al. Genome-wide epigenetic regulation by early-life trauma Arch Gen Psychiatry. 2012
Depression
DNA methylation may be a causal factor in developing Major Depressive Disorder.7Lopez JP, Mamdani F, Labonte B, Beaulieu MM, Yang JP, Berlim MT, Ernst C, Turecki G. Epigenetic regulation of BDNF expression according to antidepressant response Mol Psychiatry. 2013
Changes in methylation are linked to low levels of folate, otherwise known as folic acid, or vitamin B9. This can be a major factor in mood and depression.8Krista S. Crider, et al. Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role Adv Nutr. 2012
Patients with depression consistently have lower levels of serum and red blood cell folate than normal or nondepressed patients. Decreased folate levels are associated with lower response rates to standard antidepressants.9Papakostas GI, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression J Clin Psychiatry. 2004
Luckily, recent studies show that folate supplements increase medication response in depressed patients, and decrease overall depressive symptoms.10Morris DW, Trivedi MH, Rush AJ. Folate and unipolar depression J Altern Complement Med. 200811Jacob RA, et al. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women J Nutr. 199812Morris MS, et al. Depression and folate status in the US Population Psychother Psychosom. 2003
Another study found an association between high homocysteine levels and depression. Homocysteine is a naturally occurring amino acid that your body creates as part of the methylation process.13Enko D, et al. Association between increased plasma levels of homocysteine and depression observed in individuals with primary lactose malabsorption PLoS One. 2018
S-adenosylmethionine (SAM) is another byproduct of methylation that may be linked to mood disorders. SAM levels were significantly lower in severely depressed patients than in a control group according to one study.
Administering SAM caused a significant rise in concentrations in the cerebrospinal fluid of patients, indicating that it crosses the blood-brain barrier. These observations indicate that SAM may have an antidepressant effect.14Bottiglieri T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine J Neurol Neurosurg Psychiatry. 1990
Alzheimer’s And Memory Impairment
Although the evidence is still preliminary, there is a reason to think that methylation may be a factor in Alzheimer’s Disease.
One trial found that SAM levels were low in a group of patients with Alzheimer’s dementia, suggesting a possible disturbance of methylation in such patients.15Bottiglieri T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine J Neurol Neurosurg Psychiatry. 1990
Stress Response
Methylation may play a role in the function of what’s known as the “HPA axis,” which regulates stress in the body.
The HPA axis refers to the hypothalamus, pituitary, and adrenal glands. Their interaction plays a vital role in stress response.
When the HPA axis undergoes increased stress, this may alter methylation patterns in genes that control the brain’s communication with the adrenal glands. This action could ultimately cause an increase in stress-related hormones in the body.16Elliott E, et al. Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice Nat Neurosci. 2010
So, by modifying DNA methylation, stress can alter gene expression. This action could have a long-lasting effect on the body, potentially resulting in pathology. This effect may be particularly strong if the stress occurs in early childhood.17Elena M. Vidrascu, Alexander C. Bashore, Timothy D. Howard & Justin B. Moore. Effects of early- and mid-life stress on DNA methylation of genes associated with subclinical cardiovascular disease and cognitive impairment: a systematic review BMC Medical Genetics. 2019
Cognitive Enhancement
Low levels of folate and increased levels of homocysteine can be signs of methylation issues that may cause cognitive problems. Research shows that folate depletion can decrease DNA methylation and increase homocysteine levels.18Jacob RA, et al. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women J Nutr. 1998
In one animal study, researchers gave rats homocysteine, which lowered hippocampal brain-derived neurotrophic factor (BDNF). BDNF promotes neuroplasticity and overall brain function. These mice showed impaired memory and cognition, indicating how methylation may play a role in these processes.
However, folic acid seemed to reverse these negative effects in this study.19Matté C, et al. Acute homocysteine administration impairs memory consolidation on inhibitory avoidance task and decreases hippocampal brain-derived neurotrophic factor immunocontent: prevention by folic acid treatment Neuroscience. 2009
Low vitamin B12 levels are a major determinant of elevated homocysteine levels. This may also play a role in properly regulating methylation.20Robertson J, Iemolo F, Stabler SP, Allen RH, Spence JD. Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products CMAJ. 2005
How Methylation Works
At its core, the process of methylation involves the addition of methyl groups to the cytosine and adenine base pairs of DNA. It is a critical biological process that depends on the availability of methyl groups and the function of methyl donors and acceptors.21Biswas S, Rao CM. Epigenetics in cancer: Fundamentals and Beyond Pharmacol Ther. 2017
Adding and removing methyl groups to DNA can cause significant epigenetic changes in the organism. This could affect many different bodily systems.
Micronutrients such as folate, choline, betaine, vitamin B12, and other B vitamins contribute to DNA methylation by acting as methyl donors and co-factors.22Zeisel S. Choline, Other Methyl-Donors and Epigenetics Nutrients. 2017
Methyl Donors
SAM
S-adenosylmethionine (SAM) is a major methyl donor in the cell. It is involved in numerous cellular reactions, including DNA methylation, synthesizing phosphatidylcholine, and regulating neurotransmitters. SAM comes from the compound methionine, which is supplied either by the diet or generated from homocysteine.
SAM also enhances the conversion of homocysteine into cysteine. Cysteine is the precursor of glutathione and taurine – 2 of the body’s biggest antioxidants.23Rima Obeid. The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway Nutrients. 2013
Folate
Folate (vitamin B9) is a member of the B-vitamin group. It is required for many critical cell processes. Green leafy vegetables are rich sources of folate, but it is also available as a supplement. The recommended daily intake of folate in adults is about 400 mcg/day.
Folate deficiency causes several metabolic changes in the cell, raising homocysteine levels and lowering SAM levels, which can lead to undermethylation.24Duthie SJ, et al. Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cellsNutr Cancer. 2000
Folate deficiency also causes anemia and depression and increases the risk of pregnancy complications and birth defects.25Rima Obeid. The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway Nutrients. 2013
B12
Low levels of B12, along with low levels of folate, can lead to high levels of homocysteine, which correlates with the categories of coronary artery diseases.26Ma Y, et al. Serum high concentrations of homocysteine and low levels of folic acid and vitamin B12 are significantly correlated with the categories of coronary artery diseases BMC Cardiovasc Disord. 2017
Choline
Choline can indirectly support homocysteine methylation. One study showed that choline supplementation lowered plasma levels of total homocysteine, indicating that it was methylating properly.27Wallace JM, et al. Choline supplementation and measures of choline and betaine status: a randomised, controlled trial in postmenopausal women Br J Nutr. 2012
Red meat, poultry, milk, egg, and fish are rich sources of choline.28Cho E, et al. Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study Am J Clin Nutr. 2006
In contrast, mice deficient in choline have high homocysteine and low phosphatidylcholine levels, which may present a problem for methylation.29Jacobs RL, et al. Physiological regulation of phospholipid methylation alters plasma homocysteine in mice J Biol Chem. 2005
Choline deficiency may also reduce liver SAM (a primary methyl donor) by 60%.30Zeisel SH, et al. Effect of choline deficiency on S-adenosylmethionine and methionine concentrations in rat liver Biochem J. 1989
Betaine
Betaine is a methyl donor in the BHMT (betaine homocysteine methyltransferase) pathway. It is important to the methylation process because it converts homocysteine to methionine, which is important for the production of SAM.
The BHMT pathway is particularly active in the liver and the kidney, which are the main organs that store large amounts of betaine.
Betaine supplementation was able to prevent and reverse fatty liver, lower serum ALT (a sign of liver damage), and improve insulin resistance in mice. Betaine was also able to improve insulin signaling.31Kathirvel E, et al. Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine Am J Physiol Gastrointest Liver Physiol. 2010
Wheat bran, wheat germ, spinach, and beets are all rich sources of betaine in the human diet.
Women tend to have lower plasma concentrations of betaine and choline than men. Younger subjects also showed lower betaine concentrations than older subjects.32Holm PI, et al. Betaine and folate status as cooperative determinants of plasma homocysteine in humans Arterioscler Thromb Vasc Biol. 2005
Genes
Methylation transmits epigenetic information by adding methyl groups to DNA. There are a few genes that have a particular influence on methylation.
MTHFR
The MTHFR gene encodes for an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. This is an incredibly important process that affects many different aspects of health and mental function.
There are specific genetic variants in the MTHFR gene that can affect how it carries out this process.
The C677T variant of this gene can result in higher levels of homocysteine and lower levels of folate and other critical vitamins. This can result in lower levels of methylation, which could result in numerous health effects.33Zhang T, et al. Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature PLoS One. 2013
COM-T
COM-T is the gene that encodes for the catechol-O-methyltransferase (COMT) protein. COMT is responsible for breaking down and removing catecholamine neurotransmitters such as dopamine, serotonin, and norepinephrine in the brain.
It does this by methylating the neurotransmitter and deactivating it. It is a critical aspect of normalizing levels of these transmitters in the brain.
- 1Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role Adv Nutr. 2012
- 2Fazzari MJ, Greally JM. Introduction to epigenomics and epigenome-wide analysis Methods Mol Biol. 2010
- 3Tost J. DNA methylation: an introduction to the biology and the disease-associated changes of a promising biomarker Methods Mol Biol. 2009
- 4William J. Walsh. EVALUATION & TREATMENT OF OVER- AND UNDER-METHYLATION IN THE PSYCHIATRIC POPULATIONWalsh Research Institute, 2015
- 5Waterland RA, Jirtle RL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases Nutrition. 2004
- 6Labonté B, et al. Genome-wide epigenetic regulation by early-life trauma Arch Gen Psychiatry. 2012
- 7Lopez JP, Mamdani F, Labonte B, Beaulieu MM, Yang JP, Berlim MT, Ernst C, Turecki G. Epigenetic regulation of BDNF expression according to antidepressant response Mol Psychiatry. 2013
- 8Krista S. Crider, et al. Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role Adv Nutr. 2012
- 9Papakostas GI, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression J Clin Psychiatry. 2004
- 10Morris DW, Trivedi MH, Rush AJ. Folate and unipolar depression J Altern Complement Med. 2008
- 11Jacob RA, et al. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women J Nutr. 1998
- 12Morris MS, et al. Depression and folate status in the US Population Psychother Psychosom. 2003
- 13
- 14Bottiglieri T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine J Neurol Neurosurg Psychiatry. 1990
- 15Bottiglieri T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine J Neurol Neurosurg Psychiatry. 1990
- 16Elliott E, et al. Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice Nat Neurosci. 2010
- 17Elena M. Vidrascu, Alexander C. Bashore, Timothy D. Howard & Justin B. Moore. Effects of early- and mid-life stress on DNA methylation of genes associated with subclinical cardiovascular disease and cognitive impairment: a systematic review BMC Medical Genetics. 2019
- 18Jacob RA, et al. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women J Nutr. 1998
- 19
- 20Robertson J, Iemolo F, Stabler SP, Allen RH, Spence JD. Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products CMAJ. 2005
- 21Biswas S, Rao CM. Epigenetics in cancer: Fundamentals and Beyond Pharmacol Ther. 2017
- 22Zeisel S. Choline, Other Methyl-Donors and Epigenetics Nutrients. 2017
- 23Rima Obeid. The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway Nutrients. 2013
- 24
- 25Rima Obeid. The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway Nutrients. 2013
- 26Ma Y, et al. Serum high concentrations of homocysteine and low levels of folic acid and vitamin B12 are significantly correlated with the categories of coronary artery diseases BMC Cardiovasc Disord. 2017
- 27Wallace JM, et al. Choline supplementation and measures of choline and betaine status: a randomised, controlled trial in postmenopausal women Br J Nutr. 2012
- 28
- 29Jacobs RL, et al. Physiological regulation of phospholipid methylation alters plasma homocysteine in mice J Biol Chem. 2005
- 30Zeisel SH, et al. Effect of choline deficiency on S-adenosylmethionine and methionine concentrations in rat liver Biochem J. 1989
- 31Kathirvel E, et al. Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine Am J Physiol Gastrointest Liver Physiol. 2010
- 32Holm PI, et al. Betaine and folate status as cooperative determinants of plasma homocysteine in humans Arterioscler Thromb Vasc Biol. 2005
- 33Zhang T, et al. Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature PLoS One. 2013
