Histadelia and Methylation. Part V-a: TransSulfuration Pathway

Homocysteine

Despite the notorious dangers of excess homocysteine,* normal levels are necessary to body chemistry, particularly the methylation cycle and the transsulfuration pathway. Homocysteine lies at the intersection of the two, serving as a precursor to methionine (which forms SAM), and also as the antecedent to cysteine, taurine, glutathione and sulfate.
* Chronically elevated homocysteine is infamous for its association with heart disease and may also play a role in memory impairment. It degrades collagen and elastin and damages the lining of blood and lymphatic vessels, via oxidative stress, inflammation, fibrin deposits, etc.  Similarly, it compromises the blood brain barrier.

The Transsulfuration Pathway (under the Methionine cycle (4) on the bottom right of this diagram)

During the methylation cycle, insufficient glutathione at the homocysteine-to-methionine step prevents methyl from linking to B12, and thereby impedes methionine formation.
Homocysteine  is instead diverted down the transsulfuration pathway to form glutathione.
This pathway transforms homocysteine into sulfur antioxidants and detox agents. And typically removes half the homocysteine from the methylation cycle.  But when it goes wrong, it produces toxic sulfur compounds. 
Here is an introduction to the chemistry:

Essentially:

 Homocysteine with the help of:
        vitamin B6 (as P5P), vitamin B3 (as NAD),

         magnesium, serine, selenium, molybdenum and oxygen

                       produces cysteine, glutathione, taurine and sulfate.
 Or, lacking required nutrients or energy, or with sulfur accumulation or dietary sulfur overload:
      Homocysteine forms cystine (instead of cysteine), excessive ammonia,  hydrogen sulfide and other toxic sulfur compounds.

Specifically (enzymes are in parenthesis):
1 Homocysteine  + B6  (as P5P*) + Mg   (via CBS)  yields Cysteine (+ AKG** + Ammonia).
2 Cysteine + serine + selenium + glutamate   yields  Glutathione.
3 Cysteine  + vitamin B3  (as NAD)   yields  Taurine.
4a Sulfite (from cysteine or food)  + molybdenum + B6 (P5P) + oxygen  (via SUOX***)   yields  Sulfate.
4b Without these nutrients, Sulfite produces toxic sulfur compounds.

* B6 metabolism to P5P is supported by AKG, B6, and magnesium. If there is difficulty forming P5P, it is often supplemented directly. 
** AKG (alpha-ketoglutaric acid) is a Kreb's energy cycle component. AKG also helps remove ammonia, and form P5P.

*** SUOX also influences the creation of glutathione.

Importance of Glutathione, Cysteine and Taurine

Glutathione is the body's premiere counter to oxidative stress, and is critical in encouraging homocysteine metabolism to methionine and SAM.
Cysteine is the precursor of glutathione, taurine and sulfate.

Taurine is a major inhibitory neurotransmitter, which often seems to stabilize both mood and neural activity (and also is critical in heart, eye, liver, and gall bladder function).

Next post: Sulfates, sulfites, and sulfur and phenol sensitivity.
For information on effects of histadelia on bipolar symptoms, see my book, Natural Healing for Bipolar Disorder.

Histadelia and Methylation. Part IVB: SAM to HCY

1. In giving up its methyl to proteins and DNA, SAM becomes SAH.

2. SAH then releases adenosine and re-forms homocysteine. 
See diagram here.

SAH accumulation when adenosine is over-elevated
This latter reaction (2), however, is suppressed if adenosine and homocysteine are already excessive. Moreover, the reaction itself is reversible.

When SAH accumulates, it suppresses methylation (by inactivating methyltransferases).

This situation is usually due to severe oxidative stress, interfering with both methylation and glutathione availability.*

* Note: And is common in autistics. A study by Dr. S. Jill James, for instance, finds methionine, SAM and glutathione low, but excessive SAH, adenosine, homocysteine and oxidized glutathione. Sulfur antioxidants, including glutathione are excessively low, but excreted in the urine. Severe oxidative stress (compounded by metal metabolism dysfunction) interferes with methionine formation via methyl B12, thus compromising methylation. Further discussion of autism chemistry here.

Histadelic bipolar treatment (Walsh) 

(In presence of severe oxidative stress, creating SAH and perhaps some HCY accumulation.)

1 Supply glutathione to create homocysteine from SAH, and to attach methyl to B12 so it will convert HCY to methionine. Or, methyl-B12 may need to be provided directly.

2 Address any factors worsening oxidative stress, such as metal metabolism dysfunction.


On the other hand, if the cycle proceeds normally, we get:
SAM methylation reactions  --via methyl transferase--   yield SAH
SAH  --via  SAH hydrolase--- yields adenosine + homocysteine

At homocysteine we come to diverging paths

1 Homocysteine may continue within the methylation cycle.
2 However, when more glutathione is needed to support the methyl B12/ methionine synthase step, which turns homocysteine into methionine,
homocysteine is diverted down the transsulfuration pathyway to create more glutathione.

See Dr. Deth's discussion of this choice point here:
 

Our next post, will explain more about the Trans-Sulfuration Pathway, which, when functioning well, creates critical sulfur antioxidants, and ultimately transforms or eliminates problematic sulfur compounds and other toxins.

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 info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder
 

Histadelia and Methylation. Part IV. What SAM does.

S-Adenosyl methionine (SAM) and Genetic Expression

1 By methylating DNA, regulates, usually suppressing, genetic expression, the process by which our genes cause RNA or specific proteins to be formed.
On the other hand, acetylation --by acetyl CoA, bolstered by folic acid-- typically promotes genetic expression.
So from moment to moment, the balance of SAM to folic acid at the chromatin strands, determines whether the chemical blue print encoded in the DNA will be used to form a new biomolecule, or will be suppressed.

2 Protects, repairs and stabilizes DNA.

Influence of SAM on dopamine, norepinephrine and serotonin activity

1 Functions as a natural reuptake inhibitor* for dopamine, norepinephrine and serotonin, increasing availability/activity of these neurotransmitters in the synapse.
Walsh explains that SAM inhibits reuptake epigenetically, by methylating (turning off) the neural membrane DNA which creates transporter proteins. If undermethylated, these transporters would remove neurotransmitters from the synapse, returning them to previous (pre-synaptic) neurons. Methylation by SAM, on the other hand, suppresses transporter creation, leading to an accumulation of dopamine, norepinephrine and serotonin in the synapse, thereby increasing neurotransmitter activity. (For more, see Nutrient Power by Dr. Walsh)

2 Influences tetrahydrobiopterin (BH4) synthesis of serotonin and dopamine: via methyl folate, which regulates BH4 production (click to enlarge).


3 Is used to recycle/inactivate norepinephrine, dopamine, epinephrine and serotonin.
  — With magnesium, forms COMT, which removes epinephrines and dopamine from the synapse. 
  — Regulates stress by metabolizing norepinephrine and epinephrine (adrenalin):  Methylates norepinephrine into epinephrine which, via COMT, is broken down into metanephrine.
  — With B5, metabolizes serotonin into melatonin (the hormone which triggers sleep).


SAM provides methyl to form proteins and lipids critical to mental function
1 Including melatonin, phosphatidyl choline, myelin, epinephrine, carnitine, Co-Q10, and creatine. 
2 Also helps form  cholesterol, steroids, calmodulin (which modulates calcium use) and polyamines (from histamine). Inactivates estrogen by (forming a methyl estrogen).

SAM is important in immune function (which repercusses on mental function)

1  In turning off DNA replication, helps defend against viruses which use our DNA to replicate. 
2 Important to cell-mediated (non-antibody) immune function.
3 Helps flag and remove toxins.
4  Helps regulate the formation of sulphur molecules, such as cysteine, glutathione, sulphate, and taurine. These are major antioxidant and detox agents.

See next post, The Transsulfuration Cycle.

Review the methylation diagram here

These diagrams provide a wider picture of cycle interactions (scroll down)

For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder

Histadelia and methylation. Part IIC: A Note on the Betaine Pathway

Betaine is trimethyl glycine. It is particular rich in beets and quinoa, and also found in spinach, broccoli and grains. The betaine-to-methionine pathway looks like this:

choline --via NAD (from B3) + choline-dehydrogenase + aldehyde-dehydrogenase-- yields betaine* 
* That is: trimethylethanolamine  --via NAD... -- goes to trimethylglycine

homocysteine + betaine   --via zinc + betaine-homocysteine-S-methyltransferase--  yields methionine + dimethyl glycine


Methionine proceeds, as in my previous post, to form SAM:
methionine   --via magnesium (or cobalt) + potassium + methionine adenosyl transferase--  yields SAM

See: diagram of the betaine pathway (enlarge)

Use of the folate vs. the betaine pathway

The betaine pathway is often not very efficient, especially when the folate/B12 to methionine pathway (previous posts) is being reasonably well-utilized

However, in people who drink alcohol regularly and in some others, the methyl-folate pathway may be too compromised to be effective, even with nutrient support. 
So you would then get homocysteine elevation, even when methyl is added to the system (e.g., with supplements of methyl B12, methionine and/or SAM).  The added methyl cannot help convert enough homocysteine back to SAM.
This situation is not common in histadelia, but can occur.

Therapeutic approaches (Walsh)

To restore methylation and better protect the heart:
1 Recycle HCY through the betaine pathway, above (and keep folate low to encourage this path).
2 Vitamin B6 and serine to convert homocysteine to sulfur antioxidants (coming up, post after next).
3 Address oxidative stress.

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 info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder

In the next post we will talk about what SAM does.

Histadelia and Methylation. Part III: Forming SAM.

In the next step, methionine is transformed into SAM, the most important methylator in the human body:

  Methionine  --via ATP + magnesium + MAT*--  yields SAM

Problems forming SAM in the brain** (assuming methionine is sufficient):
1 A genetic enzyme disorder. 
2 Scarcity of magnesium.
3 Conceivably, insufficient brain ATP.*** 

Therapeutic Considerations (Walsh)
Give SAMe, perhaps magnesium.
 Methionine and TMG are of little benefit.

Caution: Some psychiatrists warn against giving SAMe to bipolars, even for bipolar depression.

Walsh, on the other hand, states that when you are dealing with histadelics with subnormal production  of SAMe, supplementation is helpful, rather than a problem, as long as introduced gradually, to the level appropriate for the individual. Then, once improvement is established (within a month or so), most patients are tapered off while introducing methionine (which is cheaper).

* The enzyme, methionine adenosyltransferase
** These occur in a small number of histadelics.
***ATP provides energy to our cells. It is formed via glycolysis (carbohydrate to pyruvate metabolism), acetyl-CoA creation, and the mitochondrial Krebbs cycle and electron transport chain. Some of the nutrients involved in this process: vitamins B3 (NADH), B2 (R5P), B5, B6 (P5P), B12, B1, C; biotin, CoQ10, carnitine, alpha lipoic acid, malic acid, magnesium, chromium, sufficient oxygen and antioxidants, and thyroid-support nutrients, as relevant.

To review where we are in the methylation cycle click here.

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 info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder
In the next post we will talk about what SAM does.

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. 

Bipolar: Natural Healing vs. Biochemistry

To readers not into biochemistry.

We are going to go more deeply into biochemistry in the next few posts to answer questions people have brought up on mechanisms underlying the histadelia treatments.

However, rest assured, we will get back to a more direct exploration of nutritional therapies shortly.

Meanwhile, for info on bipolar nutrients, see my book, Natural Healing for Bipolar Disorder.

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

Histadelia and Methylation. Part I. Basics.

We are going to examine the methylation cycle step by step over the next several weeks, focusing on the implications for histadelia (a biotype common in bipolars, and characterized by undermethylation, folate accumulation, and high histamine -- see posts Dec 3, 2010 to Jan 27, 2011, and Nov 9, 29. )

Our purpose: to address some of those questions people tend to have about histadelia, e.g., How can folic acid supplements be harmful?  What is the connection to oxidative stress? or to sulfur sensitivity? Why is methyl B12 so important? And what does methylation do anyway? etc.

Part I: Methylation Cycle Basics 
HCY   ---via methyl-B12---   Methionine   ---via ATP---   SAMe

1 Homocysteine via methyl B12 turns into methionine.
2 Methionine via ATP and Magnesium becomes SAMe.
3 SAMe methylates body molecules and DNA.
As it loses methyl, SAMe becomes SAH, which  again forms homocysteine.
4 Homocysteine continues to cycle or, via vitamin B6, is metabolized into various sulfur molecules.

Diagram of the methylation cycle

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

Causes of High Histamine and Some Effects

An interesting description of histadelia causes and effects at Roo's Clues: http://roosclues.blogspot.com/2010/03/overview-of-high-histamine-also-called.html

Aside from under-methylation [a critical factor, determining how well histamine can be eliminated], Roo lists the following
conditions which can increase histamine:
  Adrenal fatigue.
  Damage to mast cells, e.g., by mercury.
  Chronic and excess exposure to allergens.
  Auto-immune conditions and chronic inflammation.
  Gut flora imbalances. Yeast overgrowth (especially with sensitivity to the body's own yeast).
  Deficient amylase, diamine oxidase or certain other enzymes 

The site also notes that high histamine can increase blood brain barrier permeability, heightening vulnerability to toxic injury, and facilitating viral infection of the brain.

For more information on histadelia, see my book, Natural Healing for Bipolar Disorder.

Insomnia Chemistry II: Low Melatonin in the Histadelic

Chemistry underlying histadelic insomnia
Due to the poor methylation, histadelics* rarely have enough SAMe (or serotonin) to create sufficient melatonin.**
Which would explain the chronic and often severe insomnia in histadelia, contribute to the general stimulation, and may, in somes cases, help trigger mania (despite the prevailing depression).
Ideally, such nutrients as magnesium and melatonin*** (and perhaps kava, inositol, B1, B3, B5, B6, C, zinc, etc.) will permit enough sleep, and reduce stimulation enough, so that methylation therapies can proceed, eventually enabling the body to create sufficient melatonin on its own.


Cautions about the degree of methylation support during histadelic mania 
As discussed in the previous post, SAMe is contraindicated for most bipolars, as it can trigger mania, and worsen cycling. Dr. Walsh, however, finds that for bipolars whose methylation activity is chronically low (histadelics), SAMe is often important in bringing methylation up to a more normal level. And that this more normal status of methylation function will generally go towards resolving the prevailing histadelic depression, rather than triggering mania. That is, as long as started conservatively enough, and gradually increased to relevant levels for the individual. 

However, with histadelic mania, further caution is imperative. For example, you don't want SAMe (or too much of other methylators)  increasing or overactivating promanic neurotransmitters.
So the histadelic regimen may be modified some, until symptoms permit stronger support toward a reasonable level of methylation.


Note: The sedative and stimulant actions of SAMe
Odd isn't it, that SAMe, a major antidepressant, is also critical in creating melatonin and sleep. (May be one of the reasons so many depressions are accompanied by insomnia.) 


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 insomnia, mania, bipolar, or any other medical condition, please consult a knowledgeable physician. 


* Note: We have switched our discussion to histadelia, which entails a very different chemistry than that of histapenics (discussed in recent posts). For more on histadelia, see entries from Dec 3 to Jan 27, 2011.

** The hormone responsible for initiation and maintenance of sleep. As per my previous post, methylation must occur to turn serotonin into melatonin:
       1. Methionine is created using  B1, B6, zinc, folate, methyl-B12, glutathione, + protein
       2. SAMe is created  from the methionine + magnesium
       3. B5 is used to acetylate serotonin; SAMe then methylates N-acetyl-serotonin into N-acetyl-5-methoxytryptamine, otherwise known as melatonin.

*** If indicated, melatonin supplements, themselves, will bring more methyl into the system.

Insomnia chemistry: Producing melatonin from vitamins, minerals, and aminos.

Our bodies should be creating serotonin in the morning to keep us happy, converting it to melatonin at night, so we can sleep. 
With serotonin/melatonin related insomnia, anxiety or depression, one might want to analyze what part of the cycle is not working, and then consider supportive vitamins, etc. targeting that particular step. Some of the nutrients involved:

To create tryptophan you use:
     vitamins B1 and B6, zinc, and protein
         (with enough stomach hydrochloric acid (HCl), zinc, B1, B6 to break down the protein).
     Complex carbs help foster tryptophan uptake into the brain.

To turn tryptophan into 5HTP:
     folic acid, B3 (niacin), calcium, iron
 
To turn 5HTP into  serotonin:
     vitamins C and B6, zinc, magnesium
     Serotonin production is fostered by sunlight, exercise and kindness

To turn serotonin into melatonin:
       1. Create methionine* using  B1, B6, zinc, folate, methyl-B12, glutathione, and protein (+ HCl)
       2. Create SAMe from the methionine + magnesium
       3. SAMe* + B5 + serotonin are then used to create melatonin.

* Warnings: Many bipolars get manic on SAMe, even on methionine, especially if already overmethylated, (histapenic).  Some authors suggest SAMe is always contraindicated for bipolars.

Note: Excess copper will block vitamins B1, C, folate, zinc and magnesium.
 
For the diagram of tryptophan to melatonin biochemistry which inspired this post, see:
http://www.understand-andcure-anxietyattacks-panicattacks-depression.com/5-htp-Melatonin.html

Influence of exercise, light, protein...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077351/

Continued in the following post.

Histapenia in bipolars: Vitamins

The focus in histapenia treatment  is reducing brain overmethylation, increasing folate and histamine, and addressing high copper and metal metabolism problems, if present.

Treatment must reflect individual biochemical requirements.

Doctors Pfeiffer, Hoffer, Walsh and other orthomolecular physicians have, over tens of thousands of histapenic patients, have found these vitamins almost always beneficial, roughly grouped around the following symptoms:

Voices and other psychotic symptoms.

Vitamin B3 — Critical to brain circulation and metabolism, histamine production, metal metabolism, copper elimination. Antioxidant. May create a flush.
Vitamin C — Counters overstimulation, voices, and paranoia. Promotes copper excretion, protects brain tissue from oxidation.
Vitamin B6 — May be even more important than B3 for psychosis in children. Helps form GABA, glutathione, CoQ10. Antioxidant. Supports B12 absorption, zinc metabolism. May decrease available methyl.
Zinc — Inhibits absorption and promotes copper excretion. Facilitates histamine storage. Antioxidant. Helps maintain GABA levels.

Paranoia:

Vitamin C, Zinc (above)

Stress, overstimulation, hypomania, mania:

Vitamins B3, C, B6, Zinc, Magnesium. Plus:
B complex — Supports neural function; helps prevent deficits due to high doses of specific B vitamins.
Pantothenic acid (B5) — Supports adrenals. Helps keep copper low.
Manganese — Lowers dopamine. Supports metal metabolism and copper elimination. Makes choline available to form acetylcholine.
Choline or DMAE — Counters dopamine  and norepinephrine.
GABA — Counterbalances norepinephrine. But may interact with meds.
Valerian — Only if needed. Check for drug interactions.

Depression: 
Vitamins B3, C, B6, B5, omega 3,  L-carnitine.
Folic acid and B12 — Counterbalance and trap methyl.   Helps produce histamine (via BH4).

High copper and poor metabolism of divalent metals:

Zinc, C, B6, B3. manganese.
Molybdenum — Important to copper metabolism. Especially suggested by pronounced allergies and high urinary sulfite.
NAC — Critical in decreasing copper. Introduced slowly, and only after at least three months of zinc, etc. Can cause severe symptoms if given too early. For a discussion on decreasing copper see: Copper Tox Doc.

Neural support
B complex, zinc, magnesium. 

Vitamin C and E, selenium, other antioxidants — Helps protect against peroxidation due to overstimulation and to elevated copper.
Omega 3 — Supports neural receptor function.  

Chronic lack of physical energy,  but not indicated if voices or overstimulation worsen:
 L-carnitine — Brings fuel (fats) to the mitochondria (cellular energy factories) and protects mitochondria from oxidative stress.
Iron — only if deficient.

Other

Isoleucine — Helps retain B3. While usually not needed, Hoffer finds it rapidly effective in some acute low-B3, high-leucine patients.

Diet — Fresh whole foods (organic, if possible), omega 3 fish, abundant folic acid-rich vegetables. Avoid allergens, fried or hydrogenated fat, sugar, alcohol, refined carbs.
Intake of meat depends on individual reactions and chemistry.*

* Meat is rich in B3, B6, B12, zinc and carnitine, and benefits hypoglycemia. However, as Walsh points out, meat can markedly increase methionine and methylation.

Cautions

Methionine and SAMe increase methylation.
Copper worsens voices, paranoia, overstimulation and hypomania.
SSRI’s, and St Johnswort may produce adverse reactions.


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

Symptoms in Histapenic Bipolars

History

The histamine imbalance biotypes were initially introduced by Dr. Pfeiffer, who found extremes in blood histamine in many of his schizophrenic patients, with improvement occurring as nutrients brought histamine toward normal (as indicated by biochemical tests).
Dr. Walsh later suggested that the primary imbalance in low histamine (histapenic) patients was actually brain overmethylation accompanied by insufficient folate. Blood histamine is still the best test for this condition.

Symptoms of histapenia in bipolars
Common symptoms in histapenic bipolars can include anxiety, panic, hyperactivity, racing thoughts, hypomania or mania, and general overstimulation. And, especially with low niacin and zinc, and high copper: paranoia, and psychotic mania. Manic or hypomanic periods may be more prevalent than in other biotypes, though depression also occurs.

Descriptions of both mental and physical symptoms of histapenia can be viewed online in the sample pages from my schizophrenic book (though note, these pages focus more on schizophrenic manifestations of histapenia)  on the boragebooks.com website at:

http://boragebooks.com/schizophrenia_3_histapenia.html
http://boragebooks.com/schizophrenia_4_histapenia.html

For further details see my book, Natural Healing for Bipolar Disorder.



Reminder: This information is presented for educational purposes only, and is not intended for diagnostic or treatment purposes. If you need treatment for mania, bipolar, or any other medical condition, please consult a knowledgeable physician.

Bipolar Mania and Histapenia

Approximately 25% of bipolars are histapenic (indicated by low blood histamine). Bipolars with this biotype are often overstimulated, prone to psychosis, and generally tend to spend more time in mania or hypomania than other biotypes. Here is Dr, Walsh, with a short overview of histapenia:

Dr. William J Walsh,  introducing histapenia

(biochemically, brain overmethylation with low folate)
Video produced by http://www.biobalance.org.au/

http://youtube.com/watch?v=IFBTQzBCr9s

Warning: This video ends with a comment about patients being able to reduce meds. Remember that the support of a knowledgeable physician, along with a cautious (and almost always, gradual) approach is imperative when decreasing or changing medication.  See my previous post: http://naturalhealingforbipolardisorder.blogspot.com/2010/04/nutrient-approaches-for-bipolar-and.html

For more information on histapenia, see my book, Natural Healing for Bipolar Disorder. 

Mania Vitamins: Attention to Potency of Therapy

Thoughts on mania

Our brains feed on stimulation. New experiences, and ideas, and learning in general, are exciting.
But with mania, excitement comes without the counterbalance. So one cannot distinguish whether one idea is more relevant than another. And information can come so fast, that it cannot be integrated with past knowledge. Eventually, neurotransmitter pathways can be so overloaded that neurons do not have time to recover between messages.
Essentially, excitatory messaging and/or second-messaging predominate, excluding inhibitory activity needed to maintain useful function.

A severe enough mania can elude an arsenal of potent meds (even the more powerful herbs).
And even when you are able to suppress the mania, research is beginning to suggest that by attacking aggressively (perhaps, especially with substances not intrinsic to brain biochemistry) you may have set the stage for bipolar deterioration longterm.

Acute manias and vitamins
On the other hand, orthomolecular physicians are finding that nutrient therapies which nourish inhibitory mechanisms and normalize excitatory systems tend to work increasingly well with time, while usually proceeding gradually enough* to sidestep the above mania escalation and chronic repercussions.

See my posts here on inhibitory aminos, from June 21 to Aug 24, 2010, and also the outline of Mania and Stabilization info at the top of the Borage Books Nutrient Summary page.

* Nonetheless, in some cases, e.g., with violence or heart problems, a more rapid improvement may be necessary. See previous post on IV therapies.

Addressing root causes
Aside from resolving acute episodes,  ferreting out and addressing root causes (e.g., methylation imbalances, hormonal issues, pyroluria, problems with metal metabolism, etc.) is particularly important to long-term mood stability. See Ongoing Mood Stability, Biotypes, Toxicity, and Health at the bottom of the Borage Books Nutrient Summary page.

For further details, including contraindications, see my book, Natural Healing for Bipolar Disorder.

Reminder: This information is presented for educational purposes only, and should not be construed as treatment recommendations. Treatments should be fine-tuned to individual biochemical requirements. Also note: sudden changes in medications can be disastrous. See:
http://naturalhealingforbipolardisorder.blogspot.com/2010/04/nutrient-approaches-for-bipolar-and.html
If you have concerns about meds, or if you need treatment for mania, bipolar, or any other medical condition, please consult a knowledgeable physician.

Radiation Protection Vitamins and Other Natural Approaches

See my new blog: http://radiationprotectionvitamins.blogspot.com/

Bipolar Vitamins and Mood Stability

In general vitamins work gradually. The right nutrients, tailored to unique individual needs, will steadily promote and build brain health (and support body health as well), because, along with oxygen, nutrients are the main constituents of brain biochemistry.

 

Most of the time, for bipolars, the gradual improvement that vitamins provide is ideal, as the alternative, rapid change, tends to increase cycling and ultimately destabilize mood. After all, in the abstract sense, we probably all intuit that the cure for bipolar disorder is moderation.  

Even so, rapid change is sometimes needed during life-threatening mood states. This is the point at which people are usually taken to the hospital. Wouldn't it be great if the hospital had IV orthomolecular treatment available (i.e., intravenous nutrients as per unique need)? So a person could stabilize while supporting brain function and vitality?

For some of the work now being done with IV vitamins, see:
Dr. Joan Larson's site

For a general overview of  the nutrients now being studied for bipolar, see:
http://boragebooks.com/bipolar_treatments.html

or, to learn more, check out my book, Natural Healing for Bipolar Disorder

Videos: Histadelia: Depression, OCD, SAMe and Serotonin

Some great histadelia (neurotransmitter undermethylation) videos by Dr. William J. Walsh, a pioneering researcher of the effects of brain methylation imbalances on mental symptoms:

Dr. Walsh explains symptoms  of undermethylation (histadelia) including OCD (obsessive compulsive disorder) and depression, the relevance of SAMe and serotonin and other vitamin therapies, and the prevalence of histadelia in people of high accomplishment and drive (athletes, scientists, CEOs). http://www.youtube.com/watch?v=VZ7ZakljZu8



Dr Walsh on histamine tests, brain methylation, histapenia and histadelia symptoms and vitamins, and epigenetics: http://www.youtube.com/watch?v=7CRTL0-kDmI


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

Bipolar Vitamins: Histadelia and Folic Acid

Folic acid is a critical vitamin for both mood and neurological health in general.

So why should histadelics restrict it?

1 They are already overloaded in folic acid.
2 Histadelics do not readily turn folic acid into methyl folate, which is needed to support  neurotransmitter methylation. Instead folic acid accumulates, worsening histadelic depression.


So the focus of therapy becomes: restrict folate, and support brain methylation (see previous posts).

Note: We are talking here only of histadelics, that is, people with undermethylation of brain neurotransmitters, and already elevated folate. For almost everyone else with mood problems, folic acid tends to be essential.

For more information, see my book, Natural Healing for Bipolar Disorder.

Reminder: This information is presented for educational purposes only, and should not be construed as treatment recommendations. If you need treatment for histadelia, bipolar, 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.

Bipolar depression: Histadelia treatment

Again, histadelia can look like bipolar, bipolar depression, psychotic depression, obsessive compulsive, schizoaffective, dual diagnosis, or (especially if also pyroluric) conduct disorders.

For an overview of symptoms and therapeutic nutrients, see these concise descriptions of the biotypes by Dr. William Walsh. Histadelia is first:
http://alternativementalhealth.com/articles/commoncauses.htm

For histadelia subgroups and more details on the approach of Dr. Walsh,
see this page from Natural Healing for Bipolar Disorder.

Note: Histadelics do better if isolation and loneliness can be reduced, and if they can be effectively supported in continuing to take vitamins and avoid addictions.

For more info, see boragebooks.com

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 and Histadelia Symptoms

Histadelia signs and symptoms can be generally broken down as follows:

Effects on the mind: Chronic profound depression, suicidality, episodes of blank mind, obsessions, compulsions (e.g., gambling, shopping, pulling out hair), delusions and phobias. Strong will, perfectionism, perhaps hypomania.

May have been diagnosed with: Psychotic depression, bipolar, unipolar, mixed state, schizoaffective, dual diagnosis, OCD, delusional or oppositional defiant disorder.

High metabolism effects: Elevated body temperature, insomnia, lean body, good appetite, severe inner tension.
Elevated body fluids: Mucous, saliva, semen, digestive fluids, sweat.

Prone to: Seasonal allergies,  frequent colds, asthma, osteoporosis, arthritis, headaches, body pain, automimmune disorders, addictions. 

Lab: High blood histamine remains the clearest indication. 

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



. 

Bipolar Depression: Histadelia, Serotonin and Norepinephrine

Histadelia is the most common biotype in bipolars. It is characterized by undermethylation of brain neurotransmitters, including key antidepressant neurotransmitters such as serotonin, norepinephrine and dopamine. This causes chronic severe suicidal depression.

In the last post, I directed you to:

The Mood Cure Questionaire by Julia Ross

and the rest of her site. And to:

Dr. Priscilla Slagle's free ebook (The Way Up From Down):

which also talks about the use of amino acid precursors (e.g. tyrosine and tryptophan) for depression.

However, for histadelics, the major focus is not so much on supplying the precursors for serotonin, norepinephrine or dopamine, but on whether these neurotransmitters are being methylated. Intake of tyrosine, tryptophan, etc., may be helpful to some extent, but the key therapeutic target, and generally the most stabilizing treatment for the histadelic bipolar, is on getting these neurotransmitters working properly.

That is, by supporting neurotransmitter methylation with specific nutrients, while avoiding others which are counterproductive for the histadelic (such as folic acid).

 I will talk about signs and symptoms, as well as lab tests, in the next post.

For more info til then, you can always see my book: Natural Healing for Bipolar Disorder.

Depression Nutrients: The difference between Unipolar and Bipolar Therapies

To begin with, let's look at nutrient approaches used for unipolar depression (especially amino acid therapies). Check out:

The Mood Cure Questionaire by Julia Ross

While there, you may want to explore the entire site.

Dr. Priscilla Slagle's free ebook (The Way Up From Down):

And the "Recommendation Summary" half way down the page.

The problem is, many treatments (either pharmaceutical or nutritional) developed for unipolar depression can destabilize bipolars.

This is because bipolars can be particularly sensitive to changes in brain stimulation. In general, the more extreme the antidepressant treatment, and the more quickly it works, the greater the likelihood of triggering mania,  more rapid or frequent cycling, and general worsening of the illness over the long term.

So  —

(1) Bipolar antidepressant nutrients should be as gentle and gradual as possible, while still addressing symptoms sufficiently. For instance, one might want to consider tyrosine instead of phenylalanine, tryptophan instead of 5HTP, green tea instead of coffee,  etc., And the lowest doses that do the job. Generally: good food, relevant vitamins, exercise, creativity, friendship, and moderation rather than overstimulation.

(2) Even though trying to elevate mood, concurrent therapies that support stability are critical!

More later. 

For more information, see my book, Natural Healing for Bipolar Disorder.

Nutritional Approaches for Bipolar Disorder: Overview

Now that we're faced with autumn I'm going to focus more on mood-elevating vitamins/nutrients.
To start,  you may want to review my overview of investigational targets:
Natural Healing for Bipolar Disorder: Nutritional Approaches on the Borage Books website.

For fuller descriptions, as well as lab tests, contraindications, studies, etc.,
See my book, Natural Healing for Bipolar Disorder.
You can buy it here.

Great Natural Health Conferences

After cloistering myself for almost seven years (writing and researching Natural Healing for Bipolar Disorder), and so looking with a fresh eye, I have been struck by how absolutely stunning natural health conferences can be.

This year, I made my way  to
The Society for Orthomolecular Health Medicine's Scientific Meeting at the end of February.

The International Society for Orthomolecular Medicine's Annual International Conference: Orthomolecular Medicine Today  in late April.
The Cancer Control Society's Annual Cancer Convention on Labor Day Weekend.  

Each one was a veritable festival of life, intelligence, striving, and hope.

Kudos to the organizers, who have, for decades now, brought together health professionals, researchers, writers, recovered patients, and people looking to learn, to interweave a tapestry of current developments and possibilities in the field of natural medicine.

So readers, mark your calendars for next year.

Bipolar Aminos: Taurine or GABA?

Taurine and/or GABA?

Both are held to support mood and neurological stability, relaxation and sleep, and generally reduce neurotransmitter overstimulation in many individuals. So how does one choose?

Taurine: some of the physical considerations

1 Heart issues (common in bipolar mania) or eye problems may be additional indications of need for taurine. (Note: Taurine is concentrated in the heart and eye (as well as the brain)).
2 Taurine may be especially needed if the diet is high in fats or if having problems handling fats due to insufficient bile.

What to watch out for:

1 Taurine in some cases, counterintuitively, contributes to agitation, irritability, and mania, perhaps related to a need for more zinc (as in histapenia, pyroluria, and metal metabolism dysfunction).
2 High doses of taurine (and magnesium, and very high doses of vitamin C) may contribute to diarrhea.
3 Taurine may be less than useful in some persons with significant low blood pressure or hypoglycemia.

With such problems, and especially if chronic pain is involved, GABA may be a better choice.

On the other hand, for many bipolars, a particular pattern of GABA, taurine, and glycine (or magnesium glycinate) over the day (one example might be: one amino AM, a different one at lunch, all three PM) may optimize benefit. The physician and patient can work together, over time, to fine tune amino acid choices and dosage.

See posts from June 21 to August 24 for more on inhibitory aminos. And, for fuller coverage, including studies, see my book, Natural Healing for Bipolar Disorder.

Mania Nutrients: Taurine

Taurine, like GABA, is an amino acid and a major inhibitory neurotransmitter. It generally regulates electrical and chemical communication between neurons, depressing the firing of brain cells, and reducing brain stimulation. 

Some bipolars seem to do better with GABA, others with taurine, or a combo of both. Dr. Joan Larson, PhD, finds taurine (500 mg, 3x/day) can stabilize mood as effectively as pharmacological lithium. 

Mechanisms that may help counter mania
1 Taurine concentrates and acts in electrically excitable tissues, stabilizing membrane excitability, and exhibiting anticonvulsant properties.  (Thus, Dr Walsh suggests it may be most relevant for bipolars with neurological symptoms.)
See: Seizural/bipolar connections and inhibitory aminos
2 Acts in brain regions which modulate mood (hippocampus (critical to memory), the pineal (light/dark response), and the olfactory lobe.
3 Inhibits stimulating, and activates inhibiting, neurotransmitters. (Suppresses release of dopamine, norepinephrine, glutamate, and aspartate (stimulating transmitters). On the inhibitory side, increases acetylcholine, and may increase hippocampal histamine (which counterbalances dopamine).
4 Regulates electrolytes, influencing membrane stability, receptor activity, second messenger signalling, electrical communication along the axon, and chemical communication between cells.
5 Modulates creation and activity of cAMP (which helps initiate the second messenger cascade).

6 Moderates hormonal activity. Decreases thyroid and adrenal overactivity. Supports normal thyroid function. Reduces blood sugar, enhances use and storage.
7 Antioxidant. Helps regulate copper and iron. Supports immune function and helps prevent chemical sensitivity.
8 Needed in fat absorption, metabolism, elimination. (Fats are critical to neural signalling, and the formation of hormones which affect mood.)

You can find a good introduction to taurine in the second half of Dr. Priscilla Slagle's Jan 15, 2000 Newsletter.  
Also see, Birdsall, TC, Therapeutic applications of taurine. Altern Med Rev. 3(2):128-36; April 1998.
 
For references, and further discussion of bipolar issues, see Natural Healing for Bipolar Disorder.

Reminder: Treatment must be tailored to each individual's unique biochemical requirements, including contraindications. If you need treatment for bipolar disorder, or any other medical condition, consult a knowledgeable physician. In some cases, this will be an orthomolecular or other nutritionally-oriented physician.

Words of Support

Thought I'd pass along these words of support

from Marcia Purse: From Blue Zebra: About Me, About You  (Wed, Aug 11, 2010)

Along with this Video of Famous Bipolars

Bipolar nutrients: GABA may also stimulate

 GABA may also stimulate -- which is one of the reasons we cannot always assume it will be antimanic for everyone.
http://cellscience.com/reviews1/GABA_excitation_the_bipolar_neurotransmitter.html

See previous few posts for more on GABA.
For a wider context see Natural Healing for Bipolar Disorder