A Silent Epidemic with Serious Consequences—What You Need to Know about B12 Deficiency

Benjamin, First I will post the entire decision tree based on observational analysis of some thousands of people over 10 years, the specific parts dealing with “detox”, “detox” when starting methylation programs, “detox” from adding any number of vitamins and supplements to an existing program, “detox” from NAC, “detox” from glutathione and porecursor sets, and “detox” from whey. Then I will describe how it came about and answer your specific questions.

TRANSLATION OF POPULAR DESCRIPTIVE TERMS TO PRACTICAL CORRECTIONS WITH DECISION TREE – beta
version 1.2 – 05/28/12

During “methylation” treatments for FMS, CFS, ME, MS. Cures or long term remissions can occur if the clues are understood and followed. Also suggestive of possible ways to detect impending MS, ALS and Parkinson’s 10-20 years before diagnosis and hopefully prevent.
There are several popular nutritional treatments and variations for FMS, ME, CFIDS, CFS and several other syndrome names. There is at least one study being conducted for use in MS of exactly the same nutrients because people are having success on them. Many of the same nutritional supplements may be taken in the various programs and by people in general just trying to be healthy.

Under the banner of “partial methylation block” theory there are a number of programs that center on several forms of cobalamin and of folate with additional vitamins, minerals and supplements. The number and completeness of those other items determine if it is the “full methylation protocol” or “simplified methylation protocol” (SMP). Under the banner of “Functional Deficiency Diseases” which include “active b12 deficiencies (4 deficiencies)” and “induced or paradoxical folate deficiency” there is the “Active b12 and folate protocol” (ABP).

Whatever names these diseases are called they deal with a universe of symptoms that include up to 400 symptoms and signs, depending upon granularity (ie “peripheral neuropathy” encompasses dozens of possible symptoms and signs). They are in several main categories. They might be grouped as endothelial, epithelial, immune, neurological, blood, and other tissues. Or they might be classified as Skin, GI, lung, heart, veins, arteries, neurological –brain, neurological – cord, neurological – peripheral, neurological – other, neuro-psyc, blood, mood, personality etc.

WHEN TREATED
All of these are flags indicating healing is occurring. Minimizing nervous system response reduces or stops healing, especially of the nervous system. Minimizing ATP response prevents normalization of biochemistry.
1 – Low potassium, almost everybody when healing starts. – often called “detox”
2 – Low folate symptoms even with small doses of Metafolin – often called “detox”
3 – Nervous system activation, everything is perceived as more intense – often called “detox”
4 – ATP activation, everything is more energetic and intense – often called “detox”

Whatever distinctions are made, a key characteristic is that symptoms, once well developed, of these syndromes will include multiple tissue types, multiple systems. To the casual observer they appear to be not connected. After all what do blood abnormalities, eczema, irritable bowel syndrome, daily nausea and vomiting, severe fatigue, muscle atrophy, asthma, hypersensitive nervous system responses, muscle pains, MCS, mood and personality changes, widespread body pain, peripheral neuropathy, poly neuropathies, burning bladder, poor immune response, FMS, CFS, autoimmune response, raspy voice, unable to focus eyes, faded vision, multi sensory hallucinations and many others have in common? They all share a common set of nutritional deficiency causes. Some will argue that these are not “absolute deficiencies” but rather “functional deficiencies”. For treatment purposes that doesn’t matter unless one is trying to restrict access to treatment (insurance won’t cover)

The more severely affected a person is the harder hitting the vitamins are when started. There are several initial responses that may occur. In the popular terminology most of them are lumped together under the term “DETOX” reaction or response. These responses may start in minutes to days depending up many circumstances.

The supplements being considered here are methylcobalamin, adenosylcobalamin, hydroxycobalamin, cyanocobalamin, folic acid, folinic acid, Metafolin-methylfolate, SAM-e, L-carnitine, glutathione, NAC (N-acetyl cysteine), Cerefolin-NAC, Whey, Metanx, Deplin.
More rarely Vitamins D – A – C, magnesium, zinc, p5p

Glutathione, NAC, Cerefolin-NAC, whey are all glutathione or glutathione precursors. The NAC typically overpowers the Cerefolin completely.
Metafolin, methylfolate, Deplin are all methylfolate
Metanx is Metafolin, methylb12 and P5P
B12 forms, in order of effectiveness and likelihood of causing the responses listed here are methylcbl, adenosylcbl, hydroxycbl, cyanocbl

Typically several of these symptoms will appear suddenly with more appearing and worsening over time if corrections are not made. While these groups of symptoms are called “detox” by some alternative practitioners and many people otherwise knowledgeable about vitamins and supplements, depending upon what theories they are operating under, use this term. Typically they are working on a “toxin” theory of CFS/FMS/ME/MCS etc and that these vitamins and supplements mobilize the toxins which then cause all sorts of symptoms in the groups listed. As the “translations” are made it is clear that actual “detox” if it exists, has nothing to do with these symptoms and they can be dangerous to ignore. If it is “detox” in an actual sense, then it is in what is left after these other things are accounted for and/or corrected, perhaps 5-10% of the total initial number. Also, co-morbidities often show up in this way..

Group 1 – Hypokalemia onset. Symptoms may appear with serum potassium as high as 4.3. May become dangerous if ignored. Considered “rare” with cyanocobalamin it is very common with methylb12 and adensosylb12 and less so with hydroxycobalamin..
IBS – Steady constipation , Nausea, Vomiting, Paralyzed Ileum, Hard knots of muscle, Sudden muscle spasms when relaxed, Sudden muscle spasms when stretching , Sudden muscle spasms when kneeling, Sudden muscle spasms when reaching , Sudden muscle spasms when turning upper body to side, Tightening of muscles, neck muscles, Muscle weakness, Abnormal heart rhythms (dysrhythmias), Increased pulse rate, Increased blood pressure, Emotional changes and/or instability, dermal or sub-dermal Itching, and if not treated potentially paralysis and death.

Group 2a – Both
IBS – Diarrhea alternating with constipation, IBS – Normal alternating with constipation

Group 2b – Either or both
Headache, Increased malaise, Fatigue

Group 3 – Induced and/or Paradoxical Folate deficiency or insufficiency
IBS – Steady diarrhea, IBS – Diarrhea alternating with normal, Stomach ache, Uneasy digestive tract, increased hypersensitive responses , Skin rashes, Increased acne, Skin peeling around fingernails, Skin cracking and peeling at fingertips, Angular Cheilitis, Canker sores, Coated tongue, Runny nose, Increased allergies, Increased Multiple Chemical Sensitivities, Increased asthma, Generalized inflammation in body, Increased Inflammation pain in muscles, Increased Inflammation pain in joints, Achy muscles, Flu like symptoms, Depression, Less sociable, Impaired planning and logic, Brain fog, Low energy, Light headedness, Sluggishness, Forgetfulness, Confusion, Difficulty walking, Behavioral disorders, Dementia, Reduced sense of taste, Increase irritability, Loss of reflexes, Fevers, Old symptoms returning, Heart palpitations, Bleeding easily.

Group 4
Itchy bumps generally on scalp or face that develops to acne like lesions in a few days from start.

Group 3 symptoms, induced paradoxical folate deficiency or insufficiency are corrected quickly with titrated doses of Metafolin, methylb12 and adenosylb12. If glutathione (precursors) are the cause then larger doses of Metafolin, 7.5-15mg,or maybe more are needed. Different tissues are affected at different levels of methylfolate, it comes or goes in stages. Very strong dose proportionate characteristics are present. Serum folate levels may be high or even very high despite Metafolin responsive deficiency/insufficiency symptoms.
Group 1 symptoms respond readily to potassium. The symptoms and response to potassium may occur at a serum level of 4.3 or less.

IF taking Glutathione, NAC, Cerefolin-NAC, whey, all glutathione or glutathione precursors
AND often sudden onset of several group 3 symptoms (“Detox”) maybe in a sequence, ie pain and inflammation the first day, cheilitis occurs on day 2-3 and IBS on day 5-6, plus any group 2 symptoms. Symptoms increase for weeks or months and can vary from mild to extreme.
THEN Induced Paradoxical Folate Deficiency onset. B12 deficiencies follow in a week for methylb12 deficiency symptoms and several weeks for adenosylb12 deficiency symptoms. None of the other supplements can overcome the effects of glutathione or NAC.
ELSE – all other conditions
IF injecting b12
AND itchy bumps and acne type lesions appear mostly on scalp and face but not exclusive
THEN B12 was hydroxycbl OR photolytically deteriorated methylcbl OR cyanocbl, Lesions can be reversed in days with methylcbl injections not exposed to light at all.

IF starting or adding methylb12, adenposylb12 or hydroxycbl, AND OR Metafolin (perhaps 80%)
AND the approximately 3rd day or later onset of symptoms (“Detox”) from Group 1 and/or group2
THEN this can be the onset of Hypokalemia triggered by sudden widespread healing onset. This usually occurs as soon as methylation therapy starts widespread healing process by allowing DNA replications with methylb12 and methylfolate.

IF adding adenosylcobalamin AND OR L-carnitine fumarate AND OR SAM-e to program (perhaps 50%)
AND the approximately 3rd day or later onset of symptoms (“Detox”) from Group 1 and/or group2
THEN this can be the onset of Hypokalemia triggered by sudden healing and /or muscle growth. This usually occurs when the person has experienced muscle shrinkage perhaps from decades of inactivity, as soon as these supplements step up mitochondria functioning.

IF adding or increasing any of Vitamins D, A, E, or C, magnesium, zinc (perhaps 10%)
AND on the approximately 3rd day or later onset of symptoms (“Detox”) from Group 1 and/or group2
THEN this can be the onset of Paradoxical Folate Deficiency (or Insufficiency). Folinic acid is the primary form found in vegetable source. In some unknown percentage of people who appear unable to convert folinic acid adequately to methylfolate the accumulating unconverted folinic acid can actually block the methylfolate.

IF starting or increasing folic acid
AND usually takes a number of days to accumulate to a level leading to onset of symptoms (“Detox”) from Group 3 and/or group2
THEN this can be the onset of Paradoxical Folate Deficiency (or Insufficiency). Folic acid is the most oxidized form of folate that anybody can use. In some unknown percentage of people who appear unable to convert folic acid adequately to methylfolate the accumulating unconverted folic acid can actually block the methylfolate.

IF starting or increasing folinic acid
AND usually takes a number of days to accumulate to a level leading to onset of symptoms (“Detox”) from Group 3 and/or group2
THEN this can be the onset of Paradoxical Folate Deficiency (or Insufficiency). Folinic acid is a less oxidized form of folate than folic acid.. In some unknown percentage of people who appear unable to convert folinic acid adequately to methylfolate the accumulating unconverted folinic acid can actually block the methylfolate.

IF an increase in dietary vegetable folate, “green drinks”, a garden feast
AND usually takes a number of days to accumulate to a level leading to onset of symptoms (“Detox”) from Group 3 and/or group2
THEN this can be the onset of Paradoxical Folate Deficiency (or Insufficiency). Folinic acid is the primary form found in vegetable source. In some unknown percentage of people who appear unable to convert folinic acid adequately to methylfolate the accumulating unconverted folinic acid can actually block the methylfolate.

IF starting or increasing folic acid AND OR starting or increasing folinic acid AND OR an increase in dietary vegetable folate
AND the approximately 3rd day or later onset of symptoms (“Detox”) from Group 1 and/or group2
AND usually takes a number of days to accumulate to a level leading to onset of symptoms (“Detox”) from Group 3 and/or group2
THEN this can be the onset of Paradoxical Folate Insufficiency AND this can be the onset of Hypokalemia triggered by sudden healing

IF starting or Methylfolate – Metafolin starting low and titrating
AND the approximately 3rd day or later onset of symptoms (“Detox”) from Group 1 and/or group2
AND OR usually takes a number of days to accumulate to a level leading to onset of symptoms (“Detox”) from Group 3 and/or group2
THEN this can be the onset of Paradoxical Folate Insufficiency, a “donut hole” deficiency. The effects of folate deficiency/insufficiency comes in layers. Several tissue groups can be healing at the same time as other tissue groups are deteriorating. IBS and angular cheilitis can be worsening at the same time as muscles are healing or growing. There is a dose of Metafolin that can start more tissue formation than the same dose can sustain causing a Paradoxical Folate Insufficiency at the same time. In some people at least as they increase Metafolin the need for potassium increases approximately proportionately. The donut hole can be closed with total daily doses of Metafolin of about 15mg for many people.

TWENTY FIRST CENTURY MYSTERY SYNDROME

In the early 1940s a Nobel prize was awarded for folic acid. As we know now, folic acid is totally ineffective for 20% of the population due to genetic polymorphisms. Another 30% have very limited effectiveness from folic acid with only partial conversion to methylfolate. Even the 50% with the best conversion has limited amounts converted, an amount insufficient to maintain health for many people. Then, even worse, for some percentage of these people the inactive unconverted folic acid actually blocks methylfolate taken as a supplement from being effective. Again, illumination of this process is aided by the ready availability of Metafolin. So what do you call these people with a folate deficiency because they can’t utilize folic acid or in some cases, folinic acid, the vegetable folate form? Because it is genetic these folks are ill for a lifetime with this paradoxical folate deficiency. At some point they can and do get ill. You say “Paradoxical folate deficiency? What’s that, you never heard of it? Excuse me, you might know it better under the more familiar names of FMS or CFS or maybe MS. Since “folate deficiency” is a known item that has been dealt with by folic acid how can that be? Once again it is, mystery disease time, because the lack of 100% effectiveness of folic acid had been forgotten.

Since the middle of the last century there has been an explosion of neurological and other disorders including fibromyalgia syndrome, Chronic fatigue syndrome, M.E., Parkinson’s disease, MS, ALS, Alzheimer’s, Autism, SupraNuclearPalsy. The mystery syndrome includes many other potentially named diseases and syndromes. What ties these together? Results of research studies. The specific studies were those that compared cerebral spinal fluid cobalamin levels to blood serum cobalamin levels. Some of them also measured and compared CSF MMA and Hcy to serum HCy and uMMA. In 1948 the Nobel Prize was awarded for a lab mistake, the mis-identification of cyanocobalamin as “B12” instead of the real B12s, methylcobalamin and adenosylcobalamin.

For all of the named conditions low CSF cobalamin level was found to be independent of blood serum cobalamin level. Further, for those measuring it, CSF HCY was independent of blood serum HCY and CSF MMA was independent from urine MMA.

Research on cyanocobalamin and hydroxycobalamin since the 1950s have given the impression that “b12 deficiency” is one thing. Since the late 90s the ready availability of methylcobalamin and adenosylcobalamin have allowed anybody interested to demonstrate and experience the differences between cyanocbl/hydroxycbl and the two active b12s, methylb12 and adenosylb12. As the official “b12” is cyanocbl the deficiencies are defined in terms of cyanocbl. On an internationally based list of b12 deficiency symptoms expanded for maximum detail added to by what methylcobalamin and adenosylcobalamin directly affect in humans, the problem becomes readily apparent; cyanocbl has no effectiveness in 1/3 of subjects in just about every study ever done considering only symptoms known to be affected by cyanocbl. Further 2/3 of the total symptoms affected by the two active cobalamins are completely unaffected by cyanocbl and hydroxycbl. Then somehow, physicians and researchers have forgotten about all these symptoms unaffected by cyanocbl/hydroxcbl. They have become “mystery syndromes”.

A careful observation of the effectiveness of adenosylcobalamin and methylcobalamin makes it very clear, in combination with the CSF cobalamin level studies that there are 4 distinct b12 deficiency syndromes; CNS-adenosylcobalamin, CNS-methylcobalamin, body-adenosylcobalamin and body-methylcobalamin. In addition there are 4 forms of methylfolate deficiency; folic acid blocked methylfolate paradoxical folate deficiency, folinic acid blocked methylfolate paradoxical folate deficiency (vegetable food source folate included), Methylfolate triggered symptomatic methylfolate partial insufficiency and glutathione/NAC triggered paradoxical folate deficiency.

These syndromes, FMS and CFS, respond promptly to methylcobalamin, adenosylcobalamin and methylfolate. For those with anxiety the methylcobalamin and adenosylcobalamin must be titrated very slowly starting at perhaps 50mcg of sublingual b12 (literally a crumb) of each form on alternating days working up very slowly, below “alarm” level, until full equilibrium is established when no further increase in dose makes a difference. For those without anxiety a 1000mcg sublingual dose is an effective starting point. With the two 5 star effective brands, Jarrow Formulas and Enzymatic Therapy methylcobalamin, maintaining the tablet under the upper lip for 45-120 minutes causes absorption, tested in comparison with injections, in the 15-25% range typically (10-33% extremes). Source Naturals Dibencozide (adenosylcobalamin) 10mg has no folic acid in it and is acceptable in both absorption and effectiveness. About 80% of people starting these active b12 forms with methylfolate will demonstrate the start of healing with epithelial tissue healing and dropping/low potassium symptoms within about 3-4 days. Additional potassium may be needed from 400mg to 2000mg or more daily. I take 1200mg of potassium from potassium chloride as 600mg with each meal and 300-400mg as potassium gluconate tablets twice a day. If a person wakes to middle of the night spasms 500mg of potassium from potassium gluconate with a large glass of water will relieve them within 30 minutes generally. Lasix and other diuretics need to be taken into consideration. Paradoxical folate deficiency can alternate with low potassium. Edema is sometimes related to paradoxical folate deficiency and as the water is excreted the potassium may drop rapidly.

glutathione and NAC triggered paradoxical folate deficiency
Glutathione and NAC, both cause the same “detox” reaction with the group 3 symptoms. Hypothetically the glutathione combines with the methylcobalamin and adenosylcobalamin forming glutathionylcobalamin which then shows up in the urine in profusion in the next few hours. Without the active b12s in the cells the methylfolate is flushed from the cells (“methyl trap”) causing rapid onset of folate deficiency symptoms regardless of serum folate levels or dose of Metafolin. People who claim relief of symptoms from glutathione are reporting an effect. Those people who have anxiety as a symptom respond to both neurological methylcobalamin and methylfolate response and to ATP startup response with adenosylcobalamin as “unbearable” and greatly increasing their anxiety. The glutathione almost immediately relieves and stops methylcobalamin and methylfolate effects and rapidly decreasing adenosylcobalamin ATP effect. Those who have had pronounced healing from methylcobalamin, adenosylcobalamin and methylfolate undergo immediate progressive return of deficiency symptoms, and large body wide increases in pain and inflammation . In six weeks continued usage of the glutathione can cause neurological damage with a noticeable increase in Sub-acute Combined Degeneration damage. Glutathione/NAC “relieves” neurological pain and discomfort by damaging the nerves to the point of numbness by combining with and removing essentially all active circulating mb12 and adb12 from the body starting in minutes..

Strategy for overcoming paradoxical folate deficiency/insufficiency from vegetable food source folate
A number of people have found the following method effective, with variations, at overcoming life-long paradoxical folate deficiency/insufficiency from vegetable food source folate.
Wakeup – 2400mcg Metafolin on empty stomach
First meal – 4000mcg Metafolin with meal
Mid-afternoon – 2400mcg Metafolin on empty stomach
Dinner – 4000mcg Metafolin with meal
Bedtime – 2400mcg Metafolin on empty stomach
And NO FOLIC ACID, NO FOLINIC ACID and modest high folate vegetable consumption. Vegetarians will have a problem. So the b-complex must be without any form of folate except methylfolate or Metafolin. Further, no glutathione, no NAC, no whey