Histadelia and Methylation. Part IIB. Oxidative stress, Glutathione and B12.

Even if methyl folate is available, that methyl cannot always be used to form methyl B12, as either glutathione or B12 may be unavailable.

Glutathione (GSH) acts to:

1 Increase B12 availability. Glutathione normally protects B12, which is highly reactive, from being diverted* by reacting with free radicals, toxins, immune or stress molecules, etc.
GSH also, as a critical antioxidant and detox agent, and metal metabolism activator, reduces the levels of such toxins.
* Suggested by elevated methylmalonic acid. 

2 Turn hydroxy B12 into glutathionyl-B12, an intermediate step toward methyl-B12 formation.
Thus, low glutathione decreases the transfers of methyl from methyl-folate (5MHTF) to B12, and so fosters methyl folate accumulation.

3 Stimulate methionine synthase to create methionine.
When glutathione levels are too low, the methylation cycle slows. Thus:
Homocysteine  --via methyl folate +  B12 +  low GSH--  will not yield much methionine
Instead, homocysteine will be be diverted down the transulfuration pathway, to create more glutathione. More on this in a future post.

4 Protect all cells from oxidative stress, including the mitochondria, which supply cellular energy (by creating ATP). 

Glutathione can be low* due to

1 Genetic problems in creating or recycling glutathione.
2 High demand, e.g., ongoing oxidative stress. Also, chemical or heavy metal toxicity, infections, vaccinations, chronic stress, injury or surgery.
* Suggested by decreased SAM and accumulation of SAH and oxidized glutathione, as well as other measures of oxidative stress.

Therapeutic Considerations (Walsh)

Glutathione to support B12 availability, to attach methyl to B12, and to stimulate methionine formation.
Plus, in some cases, methyl-B12 may need to be supplied directly.

Glutathione and other needed antioxidants. Elimination of factors worsening oxidative stress.

Attention to any metal metabolism dysfunction, toxicity, relevant health issues, other mental and physical stressors.

More on glutathione:
Dr. Mark Hyman's video.
Also, this youtube.  (A good presentation, but ignore the marketing.)

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician. 

For more info on histadelia and bipolar disorder, see my book, Natural Healing for Bipolar Disorder

Histadelia and Methylation. Part II: B12 and folate

Folic acid accumulation, methyl-B12, and histadelic bipolar disorder

Dr. Walsh, 2008:  "For most undermethylated persons, folate and B12 are critical to therapy. However, psychiatric patients with abnormal levels of norepinephrine, dopamine, or serotonin are an exception to this rule. They represent a special case, in which the methyl/folate ratio in the brain becomes the predominant concern."

We are focused here on our step #1 in the methylation cycle:
Homocysteine  --via methyl folate + methyl B12--  yields methionine
See: Diagram of the methylation cycle.


Here is what is supposed to happen:

1A
Folic acid  --methylene-tetrahydro-folate-reductase + SAM--  yields a methyl-folate (5-MTHF)
That is:
Folic acid is methylated by 5-MTHF-R to create 5-MTHF  (methylene-tetrahydro-folate), a methyl folate, the active form of folic acid.

1B
Homocysteine  --via methionine synthase + methyl B12*--  yields Methionine
That is:
Methyl is transferred from 5-MTHF  to B12, creating methyl-B12 (methyl-cobalamin).  
The enzyme, methionine synthase, transfers the methyl from methyl-B12 to homocysteine, converting it into methionine.

* Or via the betaine (trimethylglycine) pathway: HCY + TMG  yields  Methionine + DMG 

This pathway is enhanced when the b12/methionine path is suppresed, but is not very efficient in some people anyway.

Histadelics can have problems methylating folate due to:

1 Genetic MTHFR  dysfunction (relatively common in schizophrenia, bipolar and autism).

2 Insufficient methyl.

Why should histadelics limit folic acid?

— Histadelic generally already show excess accumulation of folic acid and deteriorate when given folate supplements.

— As Walsh has proposed, folic acid can increase synaptic reuptake, reducing serotonin and dopamine availability in the synapse, worsening the already severe depression of histadelia. (Specifically, folate modifies histones so as to generate acetylase enzymes, which promote expression of transporters, which remove serotonin and dopamine from the synapse, decreasing levels available to interact with receptors.) Increased synaptic reuptake turns out to be more critical to histadelic mood than the potentially supportive effect of folate on methylation. (See Walsh 2010: Depression)

— Other potential problems: difficulty joining methyl to the folic acid or transferring that methyl to B12. Or, folic acid may trap methyl molecules.

Therapeutic approaches  (Walsh)
External methyl sources are given to ramp up the methylation cycle:
   Methionine, SAMe, increased dietary methyl,  as relevant.
Supplemental methyl B12 (or betaine, if indicated) may be needed to insure that homocysteine is metabolized to methionine.
Again, supplemental folic acid is not recommended as it will just increase already high levels of folate.
Note: If  folic acid is not excessive, restriction is harmful to health and is not indicated.

Next post: Histadelia, B12 and glutathione

For more info on histadelia and bipolar disorder, see my book, Natural Healing for Bipolar Disorder

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment bipolar disorder, or any other medical condition, please consult a knowledgeable physician. 

Histadelia and Methylation. Part IB. What is Methylation?

Methyl is CH3, a carbon with three attached hydrogens.
Methylation, simply put, is the addition of methyl to a molecule.
An example: Serotonin is methylated to form melatonin.

The connection to histadelia

High histamine.  Methylation is needed to metabolize histamine. When insufficient, histamine accumulates. An inherited tendency to brain under-methylation seems to be a major cause of histadelia.
Low catecholamines and serotonin. Undermethylation of both the dopamine/norepinephrine cycle and the serotonin cycle often leads to low levels of these neurotransmitters.
Folic acid accumulation. Since folic acid is not being easily methylated into its more active form, it tends to accumulate.

What the methylation cycle does:
   1. Provides methyl to create phosphatidylcholine, melatonin, epinephrine, carnitine, Co-Q10, creatine, and other molecules critical to mental and physical functioning.
  2. Helps govern (usually silencing) gene expression (the process by which DNA manifests the directives encoded within it, by causing specific proteins or RNA to be produced).
  3. Helps regulate the formation of taurine, cysteine, glutathione and other sulfur molecules. 

Both the neurotransmitter under-methylation and the elevated histamine contribute to histadelic characteristics.

For more info, see my book, Natural Healing for Bipolar Disorder