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I was giving a lecture to a group of psychiatric fellows recently, and I got to my slide on folate. I get excited about this topic, and so I rambled on about the one-carbon cycle, and SAMe, methylcobalamin, and the MTHFR mutation. As I looked away from my slides, I could see the vacant stares from the near-audience and knew I had lost them. If highly educated and trained physicians don't know about this, it may be safe to assume that the average woman with mental illness may not either. This article will serve as a boarding call for anyone not on the methylation-train.
Here's the deal: there are a number of processes in the body that, when compromised, broken, or otherwise dysfunctional can manifest as fatigue, worry, insomnia, low mood, poor concentration and attention, agitation, a trip to your psychiatrist, and a stop off at the pharmacy.
What if you could manage this particular problem without a psychiatrist? When I consider symptoms of psychiatric illness, I think gut, hormones, mitochondria, and methylation. These arenas are so intimately inter-connected, that it rarely makes sense to look at one without the other, and it never makes sense (to me, anymore) to think about invented neurochemical imbalances before addressing these bedrock issues.
When you eat folate, or B9, in foods like spinach, or you take a multivitamin or eat flour "enriched" with the much-lauded folic acid, your body has to convert that into a usable form. This process requires an enzyme called MTHFR (5,10-methylenetetrahydrofolate reductase) to convert folic acid and food folate into 5-methylenetetrahydrofolate. Here's what this form of folate does:
- Donates a methyl group to homocysteine to ultimately make SAMe – the brain's major methyl donor which is responsible for the formation of phospholipids, glutathione, myelin, coenzyme q10, carnitine, and creatine. Vital stuff.
- Synthesizes BH4 or biopterin, a major cofactor for neurotransmitter synthesis.
- Synthesizes DNA and tRNA.
- Recycles the inflammatory amino acid, homocysteine.
- Builds red and white blood cells, and platelets.
Methyl-folate is pretty busy. It doesn't work alone; however. Vitamins B2, B6, and B12 as well as cofactors like magnesium all help support the functioning of this pivotal cycle in the body.
Maybe She's Born With It
MTHFR is just one example of a gene for which we can test for decently studied variants at a local lab. There are two common variants to this gene wherein replacements of single nucleotides results in lesser functioning. These variants are inherited.
C677T – one bad copy means your enzyme is functioning at 70% and two means you're down to 30%. This mutation has been associated with cardiovascular and psychiatric pathology and its impact is often assessed through screening of homocysteine.
A1298C – this variant has been less well studied but is estimated to confer 70% functioning when both copies are mutated. This mutation has been implicated in the production of neurotransmitters (because of its involvement in making biopterin, and important cofactor), and breakdown of ammonia.
Predicated on associations of low folate to depression incidence and treatment resistance, this review discusses the evidence-based association between MTHFR C677T and depression, schizophrenia, and bipolar, but only included one study on 1298.
Estimates of prevalence for these variants range by ethnicity from 2-20%, but in my practice, over 5 years of testing for this gene, only 3 patients have been mutation-free.
Given the prevalence of thyroid dysfunction in women, it is worth noting that active thyroid hormone is needed to support MTHFR function, so women with hypothyroidism may bring an additional handicap to this process. Thyroxine regulates conversion of riboflavin, a necessary co-factor for the FAD, an MTHFR-stabilizing enzyme.
Alcohol and yeast overgrowth also produce acetylaldehyde which functionally interferes with a related enzyme MTR, which allows activated folate to enter this one-carbon cycle.
Brain access to activated folate may be dramatically improved by non-synthetic forms as demonstrated in this case report of reversal of paraplegia with folinic acid. Even cow dairy can cause increase in folate receptor antibodies which functionally interfere with cerebral access to folate.
There are also a number of medications that interfere with folate metabolism including metformin, oral contraceptives, and lamotrigine. Antacids can alter the stomach conditions needed for B12, a vital cofactor for the one-carbon cycle.
In this way, we begin to paint a picture in which available nutrients, genetic variants, and interfering factors may all result in different symptom states.
The Good News
Through the wonder of epigenetics, we have recovered power over our genes and learned ways to influence more optimal expression. Methyl-folate (or 5MTHF) is a form of this critical B vitamin that can be taken, over the counter, in an effort to bypass any gene mutations. Different forms of activated B12 (hydroxy, methyl, and adenosylcobalamin) are typically essential players in treatment with methylfolate, as well.