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. The process mostly refers to the “activation” of folate, and it involves passing the methyl group from one compound to another to drive various chemical reactions. This process is one of the liver’s six main pathways for detoxification. But it’s also critically important for the production of many neurotransmitters associated with mood. Here’s how it works.

Methyl Donors and Neurotransmitter Activation

If you google the methylation cycle you’ll mostly get very complex biochemical pathways, parts of which aren’t relevant to this discussion. This picture depicts the parts that matter (albeit without the smooth arrows you’ll find elsewhere, because if my program has that capability, I don’t know about it. Sorry). 🙂 Let me break it down in words.

Folic acid (the entry point here, in green) is what’s in most multivitamins (though not the good ones, because if you have a defect in the MTHFR enzyme, you end up with a buildup of homocysteine and not enough SAMe. This is bad because homocysteine is inflammatory to the cardiovascular and neurological systems. High levels also correlate with too little BH4 and SAMe, which means low neurotransmitter levels… as I’m hopefully about to explain.)

Folic acid turns into folinic acid (which you can also buy if you want to skip to this step), which turns into 5-MTHF, the active form of folate. If you skip straight to this step by taking a 5-MTHF supplement, 5-MTHF then gets recycled into folinic acid, which then produces BH4 (called tetrahydrobiopterin.)

BH4 in turn is a cofactor (like fuel for the enzyme) to take the two main amino acids, tyrosine and tryptophan, and turn them into the happy neurotransmitters we’re most familiar with, which is everything in blue: dopamine, norepinephrine and epinephrine (aka “adrenaline”), serotonin, and melatonin.

The steps converting norepinephrine to epinephrine, as well as serotonin to melatonin, also require SAMe, which we made in the original cycle.

Why We Care

As we know from the medications associated with depression, mood is largely mediated by the neurotransmitters in the above image: serotonin, dopamine, norepinephrine, and epinephrine.

An inefficient methylation cycle means inadequate levels of these neurotransmitters, which can in turn lead to depression. This is a good reason to be aware of the state of your methylation cycle, particularly if you struggle with depression. You can determine this 1) by looking at your MTHFR enzyme status (if you have mutations, it’s not as efficient as it should be), and 2) by looking at your homocysteine levels. You want them around 6 (ignore the reference range). If it’s too high, that tells you that your methylation cycle is less efficient than it should be.