Methylation involves taking a group of one carbon and three hydrogens (-CH3) from one biochemical compound and tacking it on to another. This changes the identity of both compounds.

Why Methylation Matters

The process is necessary for synthesis of the primary neurotransmitters, including serotonin, melatonin, and the catecholamines: dopamine, norepinephrine, and epinephrine—which makes it important for the stress response too (since those latter two are also known as adrenaline).

Methylation is also necessary for gene expression, DNA replication and DNA repair mechanisms. Since folate is critical for methylation, this is one main reason why methotrexate is a common chemotherapeutic agent, as it blocks folate production. Additionally, adequate DNA methylation is necessary for protection against autoimmunity as well. Of course, DNA replication is also of critical importance in pregnancy, which is why folate is such an important nutrient in prenatal vitamins.

Because oxidative stress plays an important role in DNA damage in the first place, and particularly in mitochondrial DNA damage, methylation indirectly supports mitochondrial function as well.

Methylation is also one of the liver’s six main pathways for detoxification, which also generates glutathione, the body’s master antioxidant.

Histamine is eliminated via methylation.

Methylation is also the method used for detoxification and elimination of sex hormones, though this isn’t part of the methyl generation process; the COMT enzyme responsible for this merely transfers already created methyls from one compound to another.

How Methylation Goes Awry

Because methyl groups are primarily created in a cycle whose central enzyme is created by the MTHFR gene, mutations in this gene, or the ancillary genes (particularly MTRR), may lead to under or overmethylation.

Even if there are no homozygous genetic mutations that account for methylation defects, sometimes a pathway can just get overloaded due to overuse. High stress might deplete catecholamines, for example, leading to increased methyl demand.

Or, histamine intolerance secondary to gut inflammation, or Mast Cell Activation Disorder might lead to excess histamine levels that need to be eliminated, leading to increased methyl demand.

Excessive toxins requiring methylation for elimination might increase methyl demand.

Increased DNA damage (which might occur due to any number of toxic exposures, but EMF toxicity comes to mind) or increased oxidative stress generally may lead to increased methyl demand.

Undermethylation: Signs and Symptoms

Because the causes for undermethylation are much more broad than just genetic mutations (though they include this too), undermethylation is more common than overmethylation. If you take a look at the above list of jobs that methylation performs, it might not be hard to predict the signs and symptoms. One might expect:

Low levels of neurotransmitters: serotonin, melatonin, dopamine, norepinephrine, and epinephrine. This would likely lead to depression, low catecholamine anxiety, OCD tendencies, and insomnia.
Poor stress tolerance and a constant state of “fight or flight”. Fatigue may certainly go along with this, too.
Histamine intolerance. High levels of histamine might be the cause (see above) and might be the effect, but once histamine levels are high, undermethylators will have a harder time getting rid of it. Since histamine gets stored in basophils, often high basophils correspond to this. Symptoms of histamine intolerance, or high levels of histamine, also include insomnia, as well as arrhythmia or palpitations, rashes and hives, headaches and migraines, vertigo, flushing, nasal congestion, swelling, and abdominal cramping. Often those with this issue also have GI distress, which is usually an indication that the problem started with gut inflammation.
High homocysteine. Homocysteine is a breakdown product of the methylation cycle, but it should be reincorporated, rather than accumulate. High levels (over 7 on labs) are inflammatory to the cardiovascular and neurological systems, and can lead to low stomach acid production.
High folic acid. Folic acid is the version of folate that needs activation to enter the methylation cycle, to turn into first folinic acid and then 5-MTHF. Poor methylators won’t utilize folic acid properly, and it will just accumulate.

Undermethylation Nutritional Support

All of the vitamin and mineral cofactors necessary for the methylation cycle would likely be needed in greater amounts to compensate for the under-functioning (or overworked) enzyme. These include:

The major methyl donors and cofactors:

Vitamin B12
Folate
Vitamin B6: a cofactor in the methylation cycle and also a main cofactor in neurotransmitter production
Choline
Methionine: this is the main methyl donor of the cycle, becoming SAMe
Magnesium
Copper

Nutrients that might indirectly get depleted include:

zinc, particularly in cases of DNA damage or oxidative stress
Vitamin B2, also critical for ATP production in the mitochondria
Vitamin B3, also critical for ATP production in the mitochondria, and DNA repair
Glutathione. Since glutathione is produced via methylation, undermethylation can lead to low levels (which in turn will lead to increased oxidative stress and toxicity)—or, alternatively, low levels can lead to undermethylation.

In many cases I can get away with just Methyl Balance, 1 cap daily, to support undermethylation. More resistant cases might require additional supplementation as well.

Overmethylation: Signs and Symptoms

Those with more methyl groups than they can use are more likely to have a “speed-up” genetic mutation at MTHFR and/or MTRR.

Expected symptoms, as listed above, might include:

Excessively high levels of neurotransmitters. Very high dopamine can lead to severe anxiety with panic, ADHD, restlessness, and behavioral issues. High levels of serotonin can also lead to lower motivation.
Low histamine on labs.
Low homocysteine on labs.

Overmethylation Nutritional Support

Folic acid might be a good idea for those suffering from overmethylation, rather than the activated versions that will speed up the methylation cycle.
Lithium has been shown to have a beneficial effect.

The Upshot

Traditional labs do offer MTHFR testing, but it does not indicate (nor do most other genetic testing methods) whether the mutation is “speed-up” or “slow down.” You can infer this by symptoms, but also by testing homocysteine, histamine, folic acid, and neurotransmitter levels.

Methylation Defects