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. 

Bipolar Depression: Histadelia Vitamins II

Nutrients commonly used for histadelic bipolars include:
SAMe, methionine, vitamin B6, magnesium and TMG, as per individual requirements. See:  the sample histadelia page from Natural Healing for Bipolar Disorder (as per my previous post).

Further histadelia nutrients can include:

Calcium — often depleted. Calcium decreases histamine and supports release of antidepressant neurotransmitters.
Inositol — may reduce anxiety, promote sleep. Critical to signalling. Counterbalances choline and supports folate, vitamin B6, vitamin B12, betaine and methionine.  Too much may promote anxiety or panic in some bipolars, but not usually histadelics.
Methyl  B12 — Needed to turn homocysteine to methionine. Especially critical if oxidative stress is prevalent.
Omega 3 — supports methylation.
Niacinamide — modest amounts, introduced gradually, with attention to reactions. If voices occur,  B3 tends to be crucial. Anxiety may also signal greater need.
Zinc — Counters overstimulation. Supports homocysteine metabolism to cysteine or methionine.

Antioxidant support. With undermethylation, oxidative stress increases, and further compromises methylation pathways and depletes neurotransmitter precursors. Consider the following antioxidants:
Glutathione — of prime importantce. Needed to support formation of methyl B12.
Selenium and E — works with glutathione.
Vitamin C — decreases histamine; moderates stimulation; antidepressant.
Vitamin A — helps counter the seasonal allergies.
Vitamin D — supports calcium absorption and helps counter depression. 
Acetyl-L-carnitine — a great mitochondrial antioxidant; need may be suggested by low mental energy. However, may overstimulated.
Other antioxidants, as relevant.

Other nutrients, sometimes indicated 
Serotonin support (e.g, St Johnswort, tryptophan, 5HTP) — modest intake may help balance mood, especially if depleted.
Kava — calms limbic activation, but overstimulating for some.
Tyrosine — may  temporarily help counter the depression, especially if depleted, at least until methylation increases.
Copper — supports dopamine and norepinephrine formation, decreases histamine. In histadelics, metal metabolism disorders tends toward overactivity, decreasing copper. If so, small doses,  in some cases, may become useful (but not if it worsens oxidative stress).

Diet

Plentiful quality animal proteins (preferably fish from mercury-free waters; organic meats, free-range poultry) provide methionine. A good whole foods diet is recommended, with lots of complex carbohydrates and vegetables (though intake of greens, in some cases where folate is too high, needs to be moderated), healthy fats, and some fresh fruit. Minimize/avoid immunoreactive foods. Dairy provides calcium, which the histadelic needs, but is commonly an allergen (if so, consider goat milk products and a possible need for more zinc). Avoid sugar, white flour, fried and hydrogenated fat.

Restrictions 
Folic acid, is typically excessive relative to methylation status, so often must be significantly restricted.
Choline (which counterbalances norepinephrine) may worsen histadelic depression, so may need to be limited. DMAE, especially, tends to be detrimental,
GABA often is less than helpful during low-catecholamine histadelic depression.

This material reflects approaches developed by Doctors: Walsh, Hoffer, Pfeiffer, Jaffe, Kruesi, Bibus, and others.  See Natural Healing for Bipolar Disorder for further info, including contraindications and references

Reminder: These are general summaries presented to educate the public and are not treatment recommendations. Treatment depends on the individual's unique biochemistry and response pattern. Attention to contraindications is essential.  If you need treatment for histadelia, bipolar, or any other medical condition, please consult a knowledgeable physician.

Bipolar Depression: Histadelia Nutrients

Additional histadelia nutrients next post. Stay tuned.
Meanwhile, for a more complete overview, see my site and my book Natural Healing for Bipolar Disorder.