Active B12 therapy and methylation FAQ

Phoenix-RisingAn Index to ‘B-12 the Hidden Story’

When I discovered methylation and B12 therapy, I became obsessed with understanding it (and my startup reaction). I read through the entire ‘Hidden Story‘ thread (maybe 80 hours worth) on Phoenix Rising (and watched all of the methylation videos I could get my hands on). It seemed to me that lots of valuable information was buried in the ‘Hidden Story’ and I wanted to make it accessible to people without the time on their hands (or clarity) to read 2,750+ posts.

So here, I’ve pulled out the discussion that might interest the greatest number of readers. This project got a boost when my wife asked me what methylation was and I could not give her a simple answer (even after being immersed in it for weeks). Unless otherwise noted the author of the answers below is Freddd whose active B12 protocol I’m following. There are other B12 protocols like Amy Yasko, Ben Lynch and the late Rich van Konynenburg’s and where possible I’ve tried to include information about the differences between them.

I’m partial to Freddd because of his remarkable personal crisis and careful experimentation – the true canary in the coal mine. You’ll note that I’ve incorporated a certain amount of repetitiveness in the questions – that’s because I needed motivation to push through startup symptoms and I found it reassuring to read the same answer written several times in different ways! A great big thanks to everyone participating in the discussion and of course especially Freddd, Rich (posthumously) and Cort Johnson for creating and maintaining Phoenix Rising.










What is methylation?

Eric: Methylation is a biochemical process that builds neurotransmitters like dopamine and serotonin, produces energy, processes hormones, builds immune cells, turns genes on and off, synthesizes DNA, produces the protective coating on your nerves and transforms toxins into safer substances. Chemically speaking, methylation describes the addition of a methyl group to a substrate (source material) thereby producing a new chemical. Sometimes instead of simply adding a methyl group, some other atom or group in the substrate is replaced.

Methylation happens in all the cells of your body distributing methyl (CH3) groups to as many as 50 or more other chemical processes in the body. That’s why you can’t be vibrantly healthy if methylation isn’t running smoothly in your body. That’s also why the symptom list associated with methylation disfunction is so long – it includes allergies, Chronic Fatigue Syndrome, Autism, PMS, erectile dysfunction, heart arrhythmia and palpitations, IBS, Crohn’s disease, depression, Seasonal Affect Disorder, MCS, Alzheimer’s, sleep disorders, dementia and countless others.

Methylation depends on a number of vitamins and cofactors which must be present for adequate functioning – those include folate and vitamin B12. Each of these is a potential weak link which may hobble your methylation cycle because of deficient diet, genetic mutation, toxic exposure, high stress, virus, infection or any combination of those. The toxic exposure factor is particularly interesting because most of us think we’re in the clear when we’re not.

You may never have thought about your exposure to toxic chemicals because you don’t work in a factory, but today, just about every manufactured item you touch leaves traces of industrial chemicals in your body. Every can of tuna, every plastic bag, Styrofoam cup, cleaning product and consumer product you touch is introducing chemicals into your blood that were unknown 200 years ago. You don’t even need to touch anything — just get in your new car and drive to OfficeMax to pick up some paper. The air you’ve breathed is full of petrochemicals and they make their way into your bloodstream. Or maybe you have mercury containing dental fillings. That’s all it takes.

There’s not a person alive today that doesn’t have heavy metal levels wildly exceeding those that would’ve been found 500 or 1,000 years ago in humans. That’s a problem because heavy metals like mercury probably have the ability to partially block the methylation cycle. Methylation is catalyzed by enzymes which are fragile and easily damaged by toxins like heavy metals (especially mercury). Here is a more understandable explanation of how Mercury may be related to vitamin B12 written by Christina Bolander-Gouaille:

The monovalent cobalt atom in methyl B12 is readily oxidized by various compounds – for instance nitrous oxide. This oxidation inactivates methioninsyntase (MS) which has then to be formed de novo. Mercury, as we know, does oxidize many compounds, logically also cobalt. lf this hypothesis (which is about to be verified), is confirmed, it means that mercury can block the methylation cycle and thus induce a functional B12-deficiency (folates are not altered). This in turn is one explanation of why symptoms of mercury overload and vitamin B12-deficiency may be identical!

There is also a second possible interaction between vitamin B12, and mercury. Mercury has indeed been shown to impair the Transport of vitamin B12 over the blood-brain barrier which results in a low CSF/serum concentration ratio of the vitamin. Low CSF levels of vitamin B12 (and high CSF-homocysteine levels) have been observed in fibromyalgia (chronic fatigue syndrome), MS and in dementia. High doses of vitamin B12, that overcome the block to some extent, has had sometimes stunning results in these conditions.

The good news is this: your methylation cycle can be easily fired up again regardless of the cause for its malfunction. Your body will begin responding (healing) within minutes to active B12 supplementation which bypasses the blocks caused by heavy metals, genetic errors (polymorphisms), stress, etc. The bad news for some is this: The length of time it takes for you to recover your health will depend on how long it took for you to lose it, and your symptoms may worsen at first during startup.

Still, active B12 therapy has a lot going for it – you can do it on your own without a doctor, the supplements are inexpensive, the risks are low and the results start to show quickly. If your situation is complicated by heavy metal toxicity, there is a solution for that also called Frequent Dose Chelation which shares some of the same characteristics – also possible without a doctor using inexpensive supplements and carries low risk.

What is B12 deficiency and what’s it got to do with methylation?

Eric: Because vitamin B12 plays a critical role in the methylation process which exists in every cell of the body and is responsible for distributing methyl groups to 50+ other chemical processes in the body, a B12 deficiency can cause a tremendous cascade of symptoms ranging from significant nuisances like allergies and headaches to life-altering conditions such as depression, sleep disorders, dementia, Autism, Chronic Fatigue, Crohn’s disease and Alzheimer’s.

It’s well-established that a deficiency in vitamin B12 is one of the hallmarks of a vast constellation of symptoms grouped together under the label Chronic Fatigue Syndrome (CFS). One of the key diagnostics for chronic fatigue is exercise intolerance. That means that if you don’t respond like a normal human to exercise by getting tired, sleeping well and waking refreshed, you probably have CFS and by extension a vitamin B 12 deficiency (and methylation block).

What do those of us cursed with exercise intolerance experience? We pay a terrible penalty for exercising; we become exhausted and may not move for several hours, we get thick brain fog and cognitive impairment, may feel flu-like, may feel anxious or jittery and have difficulty sleeping. The next day, we continue to feel knocked-out and generally function at a low level. That’s what we call ‘crashing’.

Chronic fatigue is the extreme case that probably helped researchers understand the impact of B12 deficiency and relationship with methylation cycle blocks. There are lots of other equally terrible symptoms of B12 deficiency, however, like Crohn’s disease and Alzheimer’s and then there are others that you may just consider a normal part of life like PMS or depression. Just as there are many ways for B12 deficiency to express itself, there are multiple causes for B12 deficiency.

B12 deficiency can develop from diet (vegetarians are at great risk), heavy metals or supplementation with cyanocobalamin, hydroxycobalamin, folic acid and maybe folinic acid, glutathione/precursors. When a person is sitting on the edge, it can be triggered by any stress that challenges your biology significantly – whether by illness, injury, toxins or even a vaccination. B12 deficiency can exist in the tissues independent of blood levels and also in the cerebrospinal fluid (CSF) independent of blood levels and tissue levels. There are two active forms of vitamin B12, of which, you may have a deficiency of either or both.

The two active forms of B12 are methylcobalamin (also known as methylb12, mb12, mecob, mecbl) and adenosylcobalamin (also known as adenosylb12, adb12, adob12, cobamamide and dibencozide). Chemically, methylcobalamin is a co-enzyme for methionine synthase (in the methylation cycle) whose purpose is to convert homocysteine to methionine. Adenosylcobalamin is a co-enzyme for methylmalonate CoA mutase which feed certain fuels into the Krebs cycle to help make ATP, a critical energy source in your body.

What are the 4 active deficiencies?

There are two active b12s and there are two deficiency symptoms subsets (syndromes) for each one. There is the general body level deficiency of methylb12 and one of adenosylb12. Then in some people there are central nervous system/cerebral spinal fluid deficiencies of mb12 and adb12. These have been detected in folks with CFS/FMS and Alzheimer’s as CSF cobalamin levels at 25% to 50% of that of control groups when a spinal fluid draw is tested.

As this is quite new, relatively speaking, and it takes 3-5 years for each generation of research to build on previously discovered things, there is NO DEFINITION of what constitutes “deficiency” and there is zero distinction between adb12 and mb12 deficiencies. There also are no mechanisms defined as to why some people have these depressed symptoms. Those may come before I die of old age or not. A therapy based on those definitions is probably at least 50 -100 years away. The Japanese are the only ones looking.

In the meantime I have devised a pragmatic way of testing for such deficiencies and am getting close to being able to define the symptoms subsets of each. If you look at the protocol for testing posted earlier in this thread, you will see a 50 mg single dose trial of each kind of active cobalamin. After a person has reached equilibrium in the body a 50mg single dose over a 2-3 hour period will have no effect, the same as in a person who never had any level of deficiency.

Some people, such as myself have a substantial effect from each kind of active b12, distinct and separate from each other. The hypothesis is that enough active b12 penetrates the CSF via diffusion when the gradient gets steep enough. The mb12 starts healing central problems such as neuropsych damage and sub-acute combined degeneration and the adb12 populates the neural mitochondria energizing the CNS, in a very pleasant way giving improved mood, more clarity of thought and so on. Between the two of them it appears to be the final assault on brain-fog. Just remember, neural healing induces changes, much quicker changes than the deterioration which occurred over 20 years or more.

What should healthy people do to prevent B-12 deficiencies? Eric: Avoid taking any supplements that contain inactive forms of B vitamins which not everyone is able to convert to the active forms. Avoid these:

  • HydroxyB12 also known as hydroxycobalamin
  • CyanoB12 also known as cyanocobalamin
  • Folic acid

Take a B complex that contains the active forms (the one I use is by pure encapsulations and it’s available on Amazon):

  • MethylB12 also known as mb12 or methylcobalamin
  • Folate also known as metafolin
  • AdenoslyB12 also known as adb12 or adenosylcobalamin or dibencozide

Before and during times of physical or psychological stress, surgery, toxic exposure, etc, give yourself some extra mb12 and adb12 using the Enzymatic Therapy and Source Naturals Dibencozide sublinguals. Note that if you experience a reaction when you do this, it means you have a deficiency. The Pure Encapsulations B complex doesn’t contain adb12, but that’s OK if you take it separately. Here’s one from Thorne that does contain both b12 forms.

What is the significance of cerebral spinal fluid (CSF)?

Since a substantially reduced CSF cobalamin level has been detected in both FMS/CFS and Alzheimer’s so far regardless of serum level, that is not addressed at all by small amounts of hydroxyb12 or mb12 or adb12 for that matter. The Japanese mb12 research with high doses does address that. Also, the high dose form of the active b12 protocol does address that. Whether that is a genetic concern I do have in common with most CFS/FMS patients or of some other causality is unanswered. And once again, there is a differential effect of adb12 and mb12 in some people at high CSF/CNS penetrating doses, once again presumed by diffusion. This can be easily demonstrated but only after a person has already become accommodated and equilibrium reached at body levels. There is a sudden threshold (indicated by Japanese research) effect when the dose gets high enough and it can happen with either adb12 or mb12 or both separately. The effects of the two active b12s are distinctly different. This does not appear to have anything at all to do with genetic lack of certain enzymes. Other research appears to indicate that there are two potentially different problems, a hindrance in absorption into the CSF and an overly rapid clearance of cobalamins. Some people may have both. This low CSF cobalamin level may turn out to be a smoking gun for CSF/FMS/Alzheimer’s.

What is the overdose potential with active B12’s?

To keep things in perspective, b12 including methylb12, adenosymb12 and hydroxyb12 have no known toxicity, 35,000,000 micrograms IV of hydroxyb12 was given FDA approval for treating cyanide poisoning. It is the most stable of the 3. Rich has pointed out that at some “huge” IV dose it was suspected of causing neurological effect by forming methylmercury in 2 persons with high mercury load. According to a model of it I built using various sources of data, the minimum dose of mb12 size for causing enough circulating methylmercury to trigger minimal neurological toxic damage was about 700mg IV, but that could be 7,000mg depending upon assumptions about what percentage of methylb12 losses it’s methyl group to mercury before it is vary rapidly excreted. Whatever ones assumptions it is a very large dose of methylb12 approximately 50-100 times larger or more of a possible and probable high dose of methylb12.

There are no known “overdose” symptoms. There are no known toxic symptoms except for cyanocobalamin which carries a cyanide group into the body with each molecule.

Some people have had extremely unpleasant startup symptoms of probably many varying causes and chose to stop because of that. Most people will experience startup symptoms, some a multitude of severe seeming sensations. It is said that some 600 processes may all be on hold waiting for the b12. It can be very intense when they all try to start up at once And some things hurt when they are healing. Various people have various hypothesis’ to explain what is happening and they evaluate what is going on in terms of their hypothesis and continue, cutback or quit depending upon their hypothetical considerations. Is it accurate to say no harm can come from trying out this protocol other than some discomfort?

In some hundreds of people who have started and continued this, the only DANGEROUS reactions I have heard of or experienced myself is hypokalemia (Potassium deficiency). Some people think that mobilized heavy metals might be a problem. Unfortunately we are lacking the kind of research that would really answer that question. There was a discussion of mercury and it’s mobilization by mb12. However, everything indicates that it would take huge single doses if IV mb12 to cause a toxic mercury reaction. Further the mb12 mobilization of the mercury allows it to be removed by the liver at a known rate which ought to clear it from the body over several years. Also, while mb12 has been researched for it’s neural protective properties with some substances, that question hasn’t been examined with mercury. There is no evidence at all that the kind of doses we are taking about here can cause a toxic amount of mercury to mobilize and the amounts needed to theoretically do so are 100x more. There is evidence that a lot of the damage mercury causes by remaining in the body is by disabling the usual trickle of mb12.

If there are other possibly dangerous situations they haven’t shown up yet. People with lots of reaction have hypothesized about lots of possible causes. Those that continue, have so far gotten through without trouble, with things normalizing over some months and continuing for more than a year. There is much fine tuning that can be done as things progress. As regards potassium, at least have it on hand. If you have a serum level test even better. Below 4.3 or so start 1 or 2 a day. Below 4 start 2-3 a day. Above that you can wait and see. If you suddenly get spasms while resting or any other sudden muscle peculiarity get some potassium into you. Too much potassium can be a problem also. My first experience with it was 3-4 days after starting mb12, again 3-4 days after starting adb12 and then again 3-4 days after starting methylfolate. If your MCV is above 100 also start 1 when you start the vitamins. I have talked to people who have had MCV at around 92 who have still had it so it may not be completely limited to blood healing but rapid healing in general.

Is it possible to just be adb12 deficient?

It is possible to be just adb12 deficient, but it is usually a blend to some extent. The mb12 affects melatonin production. Many find it advantageous to take all their mb12 in the morning, especially at first. That you have any effect at all indicates that you are mb12 deficient. Taking the mb12 does kind of shake things up. I’ve called it playing 52 pickup with symptoms. It directly affects the brain neurology, activating various sections and affecting neurotransmitters. It’s not unusual having both effects you have had as your brain starts to wake up. It is an aspect of startup. Generally speaking these two supplements with methylfolate will normalize sleeping. B12 deficiencies causes sleep disorders of many varieties. I would bet you will feel better rested too as restorative sleep is restored. One of the effects I had was that while I was deficient the difference between sleeping and waking was opening my eyes. After getting established with the mb12 I was awake during the day and got really tired at night for the first time in decades instead of being all dragged out all the time. Tomorrow just continue your titration taking 3/4 of a tablet. You might try it all at once or not, your choice. Just make each piece last 45 minutes or more if possible. Some found under the upper lip to be best for that and most effective. Right now you are bringing you body level up. Healing is just starting up. As your body level increases, healing increases as there is some proportionality. You need to determine whether you do better with a higher level for a shorter time or a somewhat lower level for a longer time. To heal my neurology I need a very high level constantly. The “wired and then crash” will generally smooth out. That pattern is often indicative of a lack of a cofactor which will be taken care of as things continue. Don’t worry about it, just enjoy the ride.

Who is Freddd?

Eric: In short, Freddd was ill from the time he was a small boy but experienced a severe disabling decline in 1987 which lasted for 16 years until he started supplementing with the active forms of vitamin B 12. This therapy brought about a full recovery over the course of seven years during which time he has helped thousands of others in online forums using his hard earned knowledge of B12 deficiency. Here are a few quotes from his posts: “In 1987 I had a complete CFS/FMS crash that lasted 16 years until I started active b12s. . . Physically rebuilding a wrecked body, helping others recover.” “I was quite totally disabled and waiting to die (as the song goes) when I started the mb12 . . . I couldn’t even manage to cook for the family as I had done for decades. I had some clumsy accidents with knives and didn’t use anything bigger than a paring knife at that point. I’m back to using my French Chef’s knife without accidents now.” “I was totally desperate 7 years ago. My life; everything that mattered, had been taken from me by some horrid undiagnosable disease. I ended up loosing my wife, the childhood years of my children, my business, by social relationships, my friends, my health, my retirement savings, etc to it. I could no longer see well enough to read many days, I had no balance, no energy, constant nausea, feet going numb, loosing motor control of my legs and feet, position sense, etc. If it had continued much longer I would have ended up in a wheelchair in a diaper, unable to read, unable to track a movie, unable to remember. I had congestive heart failure so it was unlikely to continue much longer.

I didn’t have any faith in any of the many practitioners that assured me they had a handle on my situation. Not one did. They all took my money for no results. It was most educational in what is wrong with our medical system. The only practitioner that delivered any results worth his charges was my chiropractor for an old back injury. The pain docs at least relieved my suffering a bit but made clear that they were not out to heal anything or figure out what the problems were.”

I was told for years that whatever ideas I had about “real b12″ compared to cyanocobalamin were wrong. Nothing else was available except liver and I tried 100 tablets of dessicated liver a day. It helped almost imperceptibly and only until I had an increase in pain (car wreck) or got sick. It didn’t improve my health but it did allow the lights to come on for a few weeks or months on several occasions over several years for the first time in my life. Knowing what I do now I should have moved that up to 400 tablets a day. It might have changed my life, given me the 20 years I lost. I puzzled over 100 practitioners, mostly MD’s but not all.”

Yes, I was my own test subject. I was an extreme one. One of the most difficult and troublesome you could find. I’ve been kicked out of more practices than anybody else I’ve come across because I refuse to keep doing the same things that never worked before in the hope of magic. I had more things wrong than any 3 typical people. Most people only have some subset of my problems. Some have additional things. A lot of things cross over, such as the brand and method of use of sublingual mb12 appears to apply to everybody. Being my own subject I could easily perform trials without getting anybody but my doctor to agree. Some people have more sensitivity to specific oils or brands of SAM-e or other things that didn’t affect me. I try to learn from those and include those as well. In presenting this protocol all I can really say is that based on the composite experience of many people doing these things in these ways appears to give the best odds of having beneficial results. I often question people closely, not because I doubt what reactions they had but because I want to know the exact circumstances and details of their reactions.”

What happened in Freddd’s life when he got well?

My health almost couldn’t be better. I will be glad to answer questions that I have missed during my absence and if you post and ask again with a link to your earlier full posts I will get to it quicker than in review of what has happened over the past few months. I am posting a look back on my last nearly 8 years to show you what the stakes are for which we are actually playing; life, health and wealth. These are the real consequences of what we are speaking. One thing I don’t mention below is that my eyes were unable to focus well enough to read books or screens much of the time up to May 21, 2003. My wife had read me THE HOBBIT and the entire Lord of the Rings trilogy because I was unable to read it myself. The saddest thing of all is the sheer hell I put her through with 17 years of physical, neurological, emotional and personality disabilities. Those 17 years cost me the years of my children growing up, my marriage, my business, building the solar house I had designed and almost everything I could do. While I have recovered pretty much, what was gone is gone and can’t be reclaimed. I am attempting to build a new business, to rebuild relationships with my children, and have a good relationship with a woman and find some friends, most of whom went their way with others as I could no longer participate, not even to play a few hands of bridge.

While I might say 95% recovery or so across the board with most symptoms 100% gone and some remaining, almost nothing unchanged what does that actually mean in indirect measures? I am rehabilitated. I can work up to and maintain whatever level of aerobic fitness I am willing to give the time to. I can walk 5 miles and do that each day. I can work in the garden with pick and shovel for hours at a time. I can go hiking. I would even consider going skiing again if I had the money and medical insurance as I cant afford to get injured. I’m not in a wheel chair. I’m not falling down. I can balance on one foot. I haven’t had an accident of incontinence in 8 years. I don’t have acid rising into my throat each night, I don’t vomit daily, I haven’t had a cold in 7 years. I haven’t been sick in 7 years except for H1N1 flu last year and it was mild. I haven’t had a pneumonia or two. I don’t have multiple chemical sensitivity any more. I don’t have daily chronic headaches, muscle spasms all over uncontrollably, no more IBS, CFS, FMS etc. I have a life again. Now for the quantifiable.

As my 8th anniversary my 5 star mb12 startup approaches I have reached the 7th anniversary of the beginning of large savings on my medical and pharmacy costs. My pharmacy costs went down about $1000/month of previous costs to that next year and stayed down. Over the next year or so my physician visits fell off more than 50% to the minimum needed to maintain my remaining prescriptions and my tests fell off about 90%. In the past 7 years I have saved approximately $100,000 which is the difference between being homeless and having a place to live. I feel decent at least instead of in continual misery.

Who and where are the people that have tried Freddd’s protocol?

Go read the wrong diagnosis forum which has been running for several years, 2 years with people doing an active b12 protocol. . You will find lot’s of people reporting doing much better and going on their way. Not everybody heals but then this isn’t a universal fix. People are sick with lots of other things too. It only works in situations where there is a nutritional deficiency of the type repairable by the given vitamins and supplements.

One of the things I discovered in myself was that almost everything people were calling “adverse reactions” with methylb12 were nothing of the sort. They were abrupt startup of healing on hundreds of things. I’m healed of most all the things people here are suffering from. You have to choose for yourself what to believe or at least allow as a hypothesis. The hypothesis I follow has lead to a lot of healing for a lot of people. Those who go by the adverse reaction hypothesis and stop the active b12s are still sick. That will be the case here in a year too. Those that continued the b12 despite the startup responses will be substantially better. That might not be true for every single person because there are always exceptions to everything. By and large the explosion of symptoms and changes that can occur with mb12 startup are affecting those symptoms that will heal given a little time. I don’t know of anybody whose startup responses didn’t fade with continued usage with the underlying problems improving. I gave mb12 and/or adb12 to over 1000 people face to face in the first few years after I tried it. Those with no potential b12 deficiency symptoms had no responses at all. Those with a ton of symptoms had 2 tons of start-up responses. Some people who had said “no symptoms” but had startup responses on further questioning said “I didn’t know you meant THOSE symptoms which the doc said didn’t matter”. The results were very clear-cut. About half the people had startup responses and all of them had symptoms. Those that truly had no symptoms had no responses at all, not even subtle ones. Those that said “Oh it didn’t do anything, just gave me more energy and an improved mood” always had a lack of energy and/or a down mood. Those with lots of energy didn’t have more. Those with a good mood didn’t have a change. Those with symptoms, but not of those on the list pointing at b12 deficiencies didn’t generally have any responses either.

Where do Freddd, Amy Yasko and Rich van Konynenburg agree and disagree?

Rich: I understand what your (Freddd) views are about the need to use methyl and adenosyl B12 rather than hydroxo B12, and also your views about the need to use higher dosages of the active B12s. These make particular sense to me for people whose cells are genomically not able to do the conversions, but I agree that this approach will also work for those whose cells can make the conversions, so in that sense, your protocol is a more general treatment than the “simplified treatment approach” that I have suggested for CFS.

As I think I’ve mentioned before, Amy Yasko bases the choice of whether to use hydroxocobalamin or methylcobalamin on the person’s individual genomics. In particular, she looks at polymorphisms in the COMT enzyme and the Vitamin D receptor. For people who have a greater need for methyl groups, based on whether these polymorphisms are present or not, she recommends methylcobalamin. In choosing the supplements from her overall treatment program for the “simplified treatment approach,” I chose hydroxocobalamin because of my concern about moving mercury into the brain, as I’ve mentioned. I think that inorganic mercury is more of an issue in CFS than in autistic children, with whom she primarily works.

I still haven’t gotten to studying your mathematical model involving mercury. Sorry about that. It may be true that with high enough dosages of methylcobalamin, mercury can actually be removed from the brain, as we have discussed earlier, but I don’t have clinical or experimental evidence to support this mechanism, so for now I feel that I have to remain cautious about the possibility that such an approach could move mercury into the brain from elsewhere in the body.

Freddd: The differences in a nutshell are a difference in philosophy and hypothetical considerations. Rich believes that hydroxyb12 (an inactive form) will correct some of the problems in 2/3 of the people trying it with depleted methylation, and it will, a methylation block he is calling it. I expect a combination of methylb12, adenosylb12, and methylfolate (all active forms required by the body) with necessary cofactors, to work more quickly to greater depth on more of the symptoms for more of the folks with those symptoms and on virtually all the symptoms for some of the folks.

He divides his approach into simplified and full depending upon the number of supplements used. I’ve divided it into essentials, basics (a&d etc) and critical cofactors. The active b12 full program is more complicated than Rich’s as a person has to do a lot of individual testing/trials to come up with the best doses and balance. However, the full program of Rich’s depends upon expensive lab tests. The active b12 program is based on modification by results. Except for the active b12s vs hydroxyb12 we are dealing with basically all the same nutrients with minor differences.

Is it possible to overdrive the methylation cycle with the active B12s whilst at the same time remaining B12 deficient?

My experience of energy production, coming up from a totally collapsed state is that after 16 years at rock bottom, any increase felt comparatively huge and wrong. With each change it felt like there was overshoot and then a new equilibrium was reached and everything normalized again and again. According to some researchers, there are at least 600 processes affected by the active b12s. The neurological effects are profound and can be very disturbing while happening. When feeling comes back from numb, first there is pain, then hypersensitivity and finally relatively normal feeling.

What are the symptoms of methylation dysfunction (under and over)?

Here is a collection of symptoms, signs and characteristics of overmethylators and undermethylators from several sources. A few specific items are footnoted. I found the specific interesting. The consensus as to which is what is a bit fuzzy. Some things like depression show up on both lists according to different people. Many of the symptoms on BOTH lists are active b12 and folate deficiency symptoms. As far as response to b12 and folates are concerned, I’m just including what the sources say, not what I think. The ONLY thing they are all (sources) in full agreement on is response to SAM-e.


High salivary flow
High tear flow
Never dry eyes
Good tolerance of cold
Poor tolerance of heat
Unexplained nausea
Frequent colds and flu
Highly motivated
Hard driving personality
Poor pain tolerance
Joint pain
Joint swelling
Joint stiffness
Excess perspiration
Addictive tendencies
bipolar disorder
Muscle pains
Abundant or excess saliva in mouth
Obsessive compulsive
Do worse on b12 and folates (4)
Shopping/gambling disorders
Oppositional –defiant
Seasonal depression
Inhalant allergies
Frequent headaches,
Vasomotor rhinitis
Allergic skin disorders
Excess stomach acid
High libido
Sparse body hair
Elevated absolute basophils
Extreme internal anxiety despite outwardly calm
Delusion thinking rather than hallucinations
Respond well to SAM-e, methionine, avoid folic acid (1)
Low serotonin
Low dopamine
Low norepinephrine
Prone to hives
High motivation


Elevated serotonin
Elevated dopamine
Elevated norepinephrine
High religiosity
High artistic/musical ability
Self injury
Auditory hallucinations
Absence of seasonal inhalant allergies
Frequent dry eyes
Multitude of chemical sensitivities
Multitude of food sensitivities
High anxiety evident to all
Low libido
Obsessions but not compulsions
Auditory hallucinations
Underachievement as child
Heavy body hair
Nervous legs
Respond well to b12 but avoid SAM-e, inositol, methionine TMG and DMG (1)
Treatment revolves around folic acid, niacin, B12, and a high protein diet. (2)
Panic attacks
Upper body pain Head pain
Low salivary
Low tears
High pain tolerance
Low motivation
“space cadet”
Learning disabilities
Intolerance to SSRI drugs
Low perspiration

If the body actually “exhausts” some small number of micrograms daily (some say as few as 2 mcg), why would we need to take large quantities of B12s?

Rich: A normal, healthy person who has a good inventory of B12 can go for a year or more without taking in more B12, before symptoms show up. It may not last as long in a person with ME/CFS, because glutathione is depleted and is not there to protect B12 from reactions with the toxins that have built up

Freddd: Most of an mb12 dose is excreted via the kidneys within 24 hours. These facts about b12 lead some to believe that more can’t be effective. I, and many others, have experienced the benefits of an excess over the amount exhausted daily. The effect is that the mb12 is instantly available for functioning anywhere in the body without waiting and that appears to happen only when there is enough to mb12 present to be able to diffuse to where it is needed, bypassing the standard distribution system. With the excess I have enough nerve function in my feet to be able to walk normally and not fall down, to sense the position of my feet and legs, to feel a stone in my shoe or a toenail digging into another toe or anything else. Without sufficient excess, my feet have increasing numbness within 3 days and it gets worse from there working up to my thighs and becoming incontinent. Eighteen months ago, before finding the effective dose, I was falling down, unable to sense where my feet were with large totally numb areas in my feet. Right now they hurt like hell, but believe me, that is far better than numb and I am not in a wheel chair. Right now, my feet are more functional than they have been since 1993. It takes 3 x 10mg injected daily to be this functional despite the damage. The actual healing goes slowly but appears to be progressing. I lost the last dead numb area a few months ago and it hasn’t been back. On Cycbl or Hycbl I would be in a wheelchair in diapers, unable to read, unable to type (loss of fine muscle control in my hands), loosing my memory and cognitive abilities. That was close to where I was at 7 years ago, getting very close to that wheelchair. More likely I would have been dead by 5 years ago. I was headed rapidly that direction when I tried the mb12 for the first time. I have no desire to go that far down that path again.

Yes, it gives me expensive urine. However, it is what the mb12 does for me while still in my body that matters, not that it is rapidly excreted. I was told the same expensive urine story when I started high dose vitamin C after 2 years of an incurable urinary infection. The “excess” vitamin C acidified my urine to the extent that the urinary infection subsided within days. In the short time I had it in my blood it also stopped cold my 6 streps a year and cut them down to less than 1 per year. It wasn’t until I started mb12 that the streps stopped completely along with the pneumonia every few years, colds that went to my lungs for months, asthma and seasonal allergies, chemical sensitivities, etc. So “replacement” amount certainly doesn’t indicate “effective amount”.

Rich: For what it’s worth, in my hypothesis for CFS (the Glutathione Depletion–Methylation Cycle Block Hypothesis) B12 is being “hijacked” by reactions with toxins.

It has been found (and published) that glutathione normally protects B12 at an intermediate stage in its metabolism inside the cells, before it is converted to the active forms methylcobalamin and adenosylcobalamin.

Lab testing has shown that glutathione is usually depleted in CFS. In an individual case, one can have this measured by the Health Diagnostics and Research Institute methylation pathways panel. I have seen the results of many reports of this panel from people who have CFS, and most are depleted in glutathione. There is, however, a subset of PWCs who do not have depleted glutathione. In those cases, I suspect that there are polymorphisms in the enzymes that use glutathione: the glutathione peroxidases and/or glutathione transferases. This could produce essentially the same effects as depleted glutathione.

Because glutathione is depleted, it is necessary for people with CFS to take very large dosages of B12 initially, until their glutathione levels are restored.

It is necessary to take both large dosages of B12 and at least RDA levels of one or both of the active folates (folinic acid or 5-methyl tetrahydrofolate, or preferably both) in order to lift the partial methylation cycle block, which will eventually raise glutathione automatically. I think this is the key feature of the methylation protocols, of which there are now several in use, including the one suggested by Freddd and the Simplified Treatment Approach that I extracted from the full Yasko protocol, with the help of a CFS patient. (I should note that Dr. Alan Vinitsky’s protocol uses folic acid instead of the active forms of folate, but he uses massive doses of it, rather than RDA levels. The other methylation-type protocols all use active forms of folate.)

Freddd and a few others on this forum have reported that boosting glutathione or its precursors set them back. I don’t understand this in the light of the GD-MCB hypothesis, though Freddd has reported that he has an inherited mutation in his B12 processing enzymes, and I think that could account for it in his case. Nevertheless, direct glutathione boosting is not part of the Simplified Treatment Approach. We have found by lab testing that when the methylation cycle is brought back up to normal operation, the glutathione level is automatically restored.

Could a severe allergic reaction cause a B12/Methylation issue?

I can only answer for myself and I am by no means an expert on anaphylaxis. In talking to thousands of people over the past 8 years what I have seen is that almost any type of stress on the body can tip some people over the edge into the b12 deficiency and methylation shutdown. We see physical injury is often the key in FMS. Half a dozen viral or bacterial infections have been associated with triggering the descent into CFS. I experienced both of those. I have also talked to people in which the stress appeared to be vaccine because it puts a sudden stress on the immune system, not because it is any specific vaccine.


Should I get injections?

Only mb12 injections will be more effective than sublingual mb12 and then not always due to many problems. Based on 7 years experience, I consider sublinguals to be more reliable than injections which are subject to easy breakdown and loss of effectiveness from light exposure at any point. If 15-20mg of sublinguals don’t produce all the effectiveness you need and you try the 50mg single dose and find substantial benefit, then injections of 7.5mg or larger of MB12 could help. It is better to start with the sublingual 5 star brands as an injection can be totally overwhelming and only some small percentage actually need them. There is a way to tell if you can benefit from injections of mb12 once you titrate up to a large enough level of on the sublinguals that it won’t flatten you. Even a 1000mcg sublingual putting 250mcg into serum if held under lip for 2 hours can floor a person. Also, the sublinguals are in general more reliable due to handling problems such as exposure to light of the injectable. The startup responses can be intense as hundreds of things start happening all at once. Also, other vitamins and minerals can be rapidly depleted in the startup phase, potassium dangerously so. Read the basics and the cautions and then lets discuss it further.

I felt amazing the day after my first shot and also the next day. Then it wore off, never to be repeated with the subsequent shots. Why?

In my experience the usual reason for a one time effect is that a person is out of necessary cofactor(s). For example, if you can’t convert folic acid adequately (half the population) then methylfolate might bring methylb12 back to life as it were. That you had a the reaction at all indicates deficiency. People who don’t have symptoms and are not deficient don’t have reactions to mb12. Another factor could be that you are actually deficient in adenmosylb12 and that you converted OK and that takes much longer to have a response again.

Mb12 is often the main limiting factor. As soon as that is [present the body goes to work repairing itself and promptly runs out of something else and comes to a grinding halt. Many people have demonstrated this over and over. In the earlier posts there is one called “Why B12 doesn’t work” or something like that. It gives all the usual reasons for b12 not working such as you have experienced. A methylb12 injection only lasts a few days before symptoms start returning. Read the ZONEs page that explains the different healing zones and how they relate to dosage types and amounts.

Is it possible that a subcutaneous injection of .15ml of 25mg/ml b12 every second day is not as effective as 2mg or even 1mg of jarrows sublingual?

Yes. For several possible reasons.

  1. Mb12 exposed to room light (not deep red safe-light) during preparation, drawing into syringe or injection.
  2. Original mb12 crystals are not as effective as other batches of mb12 crystals, hypothetically because of minor differences based on the bacteria used to brew it. Different forms are known to be produced but assumed to be the same.
  3. Because of short serum half-life the average serum level is higher with daily doses.


How were the symptom lists compiled?

The symptoms list is compiled from lists from multiple countries for starters for b12 and folate. When there are official health services I used those. I used the Merck manual and other diagnosis guides. The USA lists focus on those things that cyanocbl might help, the UK (health service list) list on Hydroxycbl helped symptoms, Australia, Canada, New Zealand, India and those in English from Japan. Each country’s idea of what should be on the list is different and no two of the lists are the same. MB12/adb12 work on all the symptoms any other form helps and then a lot more. Then there are things that various folks have that responded to mb12/adb12/metafolin. Then a single line like “peripheral neuropathy” was broken down to symptoms of peripheral neuropathy. The “muscle pain” was broken down to a dozen or so different muscle pains as experienced by me and others that is helped. Then there are often two or more forms of some things including the “sign” as the doctor might describe it and common language descriptions as people who experience might describe it. The purpose was to have people be able to find a suitable description that they experienced or were told by their doctor they have. The greater detail allows a progression to be described over time so for instance both early neuropathy symptoms and later stage symptoms are listed.

My fingernails are flaking and breaking, why?

Rich: Fingernails and hair are composed of the protein alpha keratin. The normal strength and rigidity of hair and nails is due to cross-linking between the long-chained protein molecules. This cross linking occurs by the formation of disulphide bonds between cysteine residues in adjacent protein molecules to effectively form cysteine.

When the sulfur metabolism is operating normally, about half of a person’s cysteine is made from methionine, because in most diets there is not enough cysteine to supply all of the body’s needs. When there is a partial methylation cycle block, however, the entire sulfur metabolism is disrupted, because the methylation cycle lies at the beginning of the sulfur metabolism. One result is that sulfur metabolites tend to drain down the transsulfuration pathway and into the sulfoxidation pathway, and then be excreted. This causes deficiencies throughout the sulfur metabolism, including in cysteine. So then when the alpha keratin is being made for hair and nails formation, there isn’t enough cysteine available. The result of this is that the usual formation of the protein and the cross-linking are disrupted, and the hair or nails are easily broken.

It is also interesting to note that the formation of protein has a higher priority in the body than does the formation of glutathione. This is built into what are called the Michaelis constants for the binding of the amino acids, including cysteine, in the processes of forming proteins and glutathione, respectively. This means that if the hair or nails are falling apart, it is likely that glutathione is also very depleted.

The way to restore cysteine, hair, nails, and glutathione, as well as lots of other things in CFS, is to lift the partial block in the methylation cycle, and that’s what the treatments we are dealing with here are all about.

So why does it get worse before it gets better when you do this treatment? Well, when you stimulate the methionine synthase enzyme by using B12 and folate, more of the homocysteine is converted to methionine, and less goes down the transsulfuration pathway to make cysteine and glutathione. So initially, you have less of these. However, over time the whole sulfur metabolism gets restored, and then the situation with the hair, nails, etc., improves. This can take considerable time, especially if a lot of toxins have accumulated during the time this partial block was in place and the detox system was dysfunctional, because detoxing requires a lot of sulfur. Freddd: I can’t tell you the biochemistry of it as Rich has done. I can tell you what things affected my hair and nails. Before starting on mb12 but on a complete set of vitamins, minerals and various supplements, I had thin, easily tearing nails. They did not flake that I ever noticed. The items that increased the thickness and toughness of my nails noticeably were methylb12, then again 9 months later adb12, then 6 months later SAM-e and then another 12 months later l-carnitine fumarate. My hair also became less brittle and dandruff went away 100%.

I get heart palpitations, what can I do about that?

…both forms of active B12s are important for the heart. What ended up stopping decades of palpitations [for me] in the end was, after everything else was in place and they were still happening, was b-complex twice a day. For the palpitations to come back all I have to do is to cut back on the B-Right to once a day and they are back in 2 days. Going back up to twice a day and they were gone in a day or two.

I have a LOT of neurological/psychological symptoms – terrible memory/cognitive problems, depression, personality changes eg severe rage/irritability, apathy…

Those are primarily methylb12 deficiency symptoms. They can get stirred up when starting mb12 but they do calm down with continued usage. Some of it occurs while healing is happening.

I have burning mouth, neuropathy, beef-red tongue, brain fog, and extreme fatigue.

The burning beef red tongue came and went along with the burning bladder and burning muscles, which took about 10 days to clear and the burning stomach took much longer to clear up. The brain fog took much longer and cleared in half a dozen specific steps; mb12, adb12, l-carnitine fumarate, Zinc, SA mg mb12 sublingual and 50mg sublingual adb12.

My wife has just been diagnosed with some small holes in her retina, and they are going to do some laser work on her tomorrow. Her vision is terrible. Is this a common symptom with the ME/CFS community?

Clearly there are a lot of visual problems with b12 deficiency as you can see from the symptoms list at the beginning of this thread. Age related macular degeneration is also a b12 deficiency characteristic that will be on the next version of the list.

So it is looking like your wife also has paradoxical folate deficiency. I have this from folic acid, folinic acid and vegetable food source folate. I happen to have what I think is a very nice organic garden. When I started eating a lot of greens a couple of months ago the folate deficiency symptoms started popping up again. I have to be careful how much how often I eat the greens and timing with respect to metafolin. She needs to learn to recognize the onset symptoms quickly so it doesn’t go all the way to a crash before she realizes it. Remember, lots of foods also have folic acid added so the problem isn’t going to go away. I’m glad to hear that she is doing better again.

Another person has written me that his retinal problems are improving with enough mb12 and Metafolin. Neurological healing takes sustained action for healing. Setbacks hit neurological damage harder and faster.


If I have many B-12 deficiency symptoms, should I do blood work first or start the protocol?

As damage increases daily if it is happening, if you have to wait it’s probably not worth it, since the tests in no way predict who will or will not have a response to the active b12s. Said response often happens so quickly and strongly that there is no doubt at all that there has been a response. If you have been taking b12 in any form including breakfast cereals, multivitamins, etc, you have probably absorbed enough that you are not “clinically” deficient. As people can be functionally deficient to well over the top end of measurement range, it can only tell you if 2 cars of the body train have tipped over, as it were, and it can’t tell you at all if you have a CNS/CSF cobalamin deficiency.

So if it doesn’t take food out of your pocket, you don’t have to wait and if you haven’t been supplementing then testing might be interesting to know, but it won’t stop anything. There is no answer these tests can give that should override symptoms. Before mb12, no supplement ever seemed to do anything [for me]. After mb12, almost all the supplements did things [for me].

Where’s the protocol and should I start with very low dosages and titrate up?

Eric: yes, here’s the protocol, and the titration guide but consider going much slower if you’ve been sick for a long time and/or have significant responsibilities and can’t afford any hiccups. Freddd: Definitely some people need to titrate. The standard AMA wisdom is that any perceivable effect from b12 is a placebo effect. It has no Known toxic limits. . . . Taking adb12 and all these things is like accelerating your car from the 5 mph it has been stuck at for 15 years to 70 mph on the interstate for the very first time above 5 mph. 70mph causes more stress on all the systems. Problems hiding for years or broken mechanisms that made no difference at 5 mph could make a big difference, like not advancing the spark. In a shakedown cruise one expects things to go wrong that still need repair or aren’t finished being repaired. We are taking these very broken down bodies and trying to patch them up. Some things probably get stressed in doing that because that part isn’t as repaired as a different one.

What’s changed since ‘B12 – The Hidden Story’ was posted in 2009?

Eric: Reading through 138 pages of posts and this update, this is my take-away on what’s new: Brands:



My skepticism prevents me from trying the protocol… what do you say to that? Fortunately no faith is required. You can perform your own test. In fact I’m tell you what criteria to use to include yourself in as a likely responder or not, and then it is up to you to do the work. First of all compare 100% of your symptoms to the list at the beginning of this thread I believe it is. If you can’t find it I’ll post the most recent revision. First list all of your symptoms by decade of life compared to that list of symptoms based on if present at any time during the decade. Use the list to help spark your memory. Then make a second list of all your symptoms that are not on the list of symptoms.

After you make the lists I’ll tell you what to look for. Then if those things indicate a likelihood of being response to active b12 a single dose of a combo of 5 star mb12 and adb12 (1 of each kind of tablet under lip for 45-120 minutes) and by 120 minutes, if you have ANY perceptible response the probability is approximately 100% that you will respond to the protocol. You see, cycbl or hycbl will have no noticeable response in that time period and usually no noticeable response at all. People without symptoms generally have no response at all as they have no symptoms to change. I have already run this kind of trial on about 1000 people in person and watched their responses after taking their histories. As you will have already had a response to adb12/mb12 before starting the protocol you know without a doubt that you are a responder. Of course there are those who MUST have a certain cofactors to respond, most especially Metafolin, but often that will increase response but it’s lack won’t prevent it 100%. Also there are those whose symptoms are such that they only respond over time. This kind of test gives an estimated 25% false negatives and 0% false positives. It won’t catch everybody who might respond given some time or cofactors, but it catches a large percentage of the worst afflicted.

I need to run 1,000 people again and this time not be so sick as to not track the data well. I need to work out what are the most significant symptoms and combinations. I might be able to narrow it down to the top 50 or so with a little work.

Me, I was totally desperate 7 years ago. My life; everything that mattered, had been taken from me by some horrid undiagnosable disease. I ended up loosing my wife, the childhood years of my children, my business, by social relationships, my friends, my health, my retirement savings, etc to it. I could no longer see well enough to read many days, I had no balance, no energy, constant nausea, feet going numb, loosing motor control of my legs and feet, position sense, etc. If it had continued much longer I would have ended up in a wheelchair in a diaper, unable to read, unable to track a movie, unable to remember. I had congestive heart failure so it was unlikely to continue much longer.

I didn’t have any faith in any of the many practitioners that assured me they had a handle on my situation. Not one did. They all took my money for no results. It was most educational in what is wrong with our medical system. The only practitioner that delivered any results worth his charges was my chiropractor for an old back injury. The pain docs at least relieved my suffering a bit but made clear that they were not out to heal anything or figure out what the problems were.

If you are suffering enough to be motivated to find something to treat your problems, go through the screening exercise and then the single challenge dose. Then do a longer trial only after you have already demonstrated it could work. No faith required but some effort is.

I am ready to start the B12 protocol. I’ve got a cart-full of supplements, what should I take first?

I would not suggest starting everything at once. It can be way to overwhelming and you don’t learn as much.

Ideally I would suggest starting a,d,e,b-complex, calcium, magnesium, omega3 oils, potassium and other basic items if inclined, like Lecithin, chromium, selenium multiminerals etc. The ALA can be started too at this time. But not the critical cofactors. This gives the body a chance to bring any of those deficiencies up to par. After a few days, I would add Country Life adb12. This separates out the mitochondria startup to a large extent. Then after a few days start adding in Jarrow mb12. Be sure to use the brands specified for predictable response of sublinguals as there is a substantial difference in effectiveness by brand. Also method of use is important. Hold under upper lip in front for 45 minutes or longer for maximum effectiveness.

After adding in the adb12, the mb12 and things have stabilized, add in the methylfolate. After that has stabilized add the l-carnitine fumarate. That can have a much larger effect than the adb12 on energy generation. Actually whichever of that pair is added second is usually the most energetic. If the carnitine/adb12 pair is very energetic you may find that the TMG and smooth that out and make it more comfortable.

After all this has stabilized add the SAM-e taking one tablet to begin with and letting that stabilize. Then add another to see if it makes any difference over the first one. Then finally, try the D-ribose. Or the D-ribose can be started after comfort is reached on the first SAM-e. They work on different pathways.

How do you avoid irritating your stomach with so many supplements? Other considerations? Starting all the basics, vitamins and minerals, is not difficult and rarely causes a reaction. The way to avoid stomach irritation with a large number of supplements is this, take them with a meal. Basically eat about 1/3 of the meal. Then take a few pills and a bite or two of food. Do this during the middle part of the meal and get all the vitamins in. Then eat the last third of the meal on top of the vitamins. The meal should have a mixture of protein, fats and carbs to aid absorption and prevent irritation. Taking a lot of supplements with only scrambled eggs for instance can cause nausea and vomiting. Add a piece of toast and fruit and no problem. Most of the supplements should be taken with food. Some should only be taken without food.

SAM-e, l-carnitine fumarate, TMG for instance should be taken 30 minutes or so before food or at least 2 hours after on an empty stomach. Methylfolate appears to be absorbed better without food but with food works ok. B-complex and methylfolate need to be taken twice a day because of short serum half-lifes for best effectiveness. I take a methylfolate with each dose of b12 without foods and at two meals. I can take fewer tablets with more doses with superior effectiveness as the serum half-life is only 3 hours. One other main caution. CoQ10 being taken at the same time as mb12/adb12/methylfolate is started can cause a significant increase in blood pressure. This goes away after some unknown number of months and CoQ10 can then be taken again. It appears to be a problem only in the early stages of healing. Iron, taken within some hours before will block both b12 and vitamin E. I don’t know about oral b12 but the sublingual pretty well gets around absorption problems.

Startup or detox symptoms?

I choose to continue the word “startup” because it denotes the timing so well. Also, the startup symptoms appear to be self-limiting. I have noticed that those who choose to user the word “startup” tend to have shorter less severe reaction periods than those who apply “detox” to the symptoms. Start-up symptoms may indeed include “detox” symptoms and as the toxins flush from the body or are chemically changed the problem leaves. Those who do a start and stop approach appear to have long drawn out problems repeating the same unplesant steps over and over again and not getting past them for long durations. There is a lot of fear wrapped up in the assumptions of “detox”. Fear and anxiety make any of these startup reactions worse.

In my experience with a lot of people those who continue to press on ahead, regardless of pace, get through it. Titration can work in that. But stopping and starting appears to be a strategy that doesn’t work because one becomes stuck in the very worst steps. It’s very obvious that “detox” is a convenient term for certain not understood reactions that have nothing to do with actual detox.

The major startup responses usually come from mb12. The first thing it does, in minutes to hours, is change how the nervous system works. It almost immediately starts restoring lost functionality. This is perceived as unpleasant mostly as all the many neurological (all aspects of neurological system, peripheral and central) symptoms, many of which people were unaware of as they crept up slowly over 20 years, become very apparant. Nerves that had become slowly pretty numb spring painfully back to life and muscles and things start reacting. At the same time cell division picks up as there is now enough mb12 for that to happen and all sorts of tissues start healing. My burning tongue, burning muscles and burning bladder stopped burning in the first 10 days.

While some people attribute these things to “detox” there is very little evidence that is at all common. There are a set of common startup responses that most people have some or all of. So either EVERYBODY with visible or occult b12 deficiencies of a certain severity has “detox” symptoms or almost nobody has them. Those that become concerned about startup responses and call them “detox” and stop the mb12 are just as sick a year later. Those that put up with the startup responses and continue titrating have about a 75% reduction of affected symptoms after 1 year, assuming they add all the needed cofactors. After a year I was quite ready to start rehabilitation which is an entirely different thing. A body inactive for 17 years can become quite debilitated. It took me a year to work up from being able to walk 600 feet to 5-6 miles. At first I increased the distance I walked each day by one house lot along the street. An increase of 100 feet per day for 50 days is a mile.

How long do start up effects last?

With the active b12s and folate, initial startup effects of whatever cause are usually more or less finished in 2-4 months though they may be more intense while occurring. . . As other cofactors are added in additional startup effects often occur, also of up to several months duration typically. Further, neuropsychiatric healing appears to take several months to start and to have a several month unpleasant period quite independent of what the body is doing.

Who Is likely to have a big reaction to active B12 supplements?

Methylb12 does indeed cause major startup symptoms in the severely deficient such as long term CFS/ME/FMS. It affects virtually every one of as many as 200-300 symptoms all at once and can certainly look like a worsening when in fact it leads to actual healing and recovery. The majority see significant results, the most significant being seen in those that have the most intense startup effects who are usually the sickest . . .

People without methylb12 deficiency symptoms have no reaction to mb12 at all. People without adenosylb12 deficiency symptoms have no reaction to adb12 at all. Some people have reactions to both. They are both absolutely essential to the proper functioning of the body, there are no substitutes or workarounds. Using inactive cobalamin pseudo vitamins such as hydroxyb12 and cyanob12 reduces reaction by severely reducing effectiveness limited to what the body can convert, which can range from zero to a couple of 10s of mcg per day.

And not everybody who can convert it, converts both forms. That appears to be how ME gets started, an inability to either convert dietary adb12 from meat into mb12 or a failure to transport it into the cerebral spinal fluid. It’s sad to see so much misunderstanding about these things.

When B12 therapy fails, what are the most common reasons?

1. They take an inactive b12, either cyanob12 or hydroxyb12. The research “validating” their use was primarily for reducing blood cell size in Pernicious Anemia, keeping the serum b12 level over 300pg/ml at the end of the period between injections. They make a statistically significant effect that can be seen in lab tests in a significant percentage of people compared to placebo. They do not heal most damage done by active b12 deficiencies and have little or no effect on the vast majority of symptoms. They may even block active b12 from receptor sites hindering the effects of real b12. They both cause a keyhole effect of having only a very limited amount (estimated at 10-30mcg/day) that can actually be bound and converted to active forms. They in no way increase the level of unbound active cobalamins which appear required for most healing. They do nothing beneficial in a substantial percentage of people (20-40%) while giving the illusion that the problem is being treated and if it doesn’t work, oh well, that’s the accepted therapy. There is no “dose proportionate” healing with these inactive b12s because it all has to go through this keyhole. Some people are totally incapable of converting these to active forms because they lack the enzyme

2. They take active b12 as an oral tablet reducing absorption to below 1%. A 1000mcg active b12 oral tablet might bind as much as 10-30mcg of b12. Again the b12 has to be squeezed through a keyhole that limits the amount and is subject to binding problems in the person whether genetic or acquired.

3. They take a sublingual tablet of active b12 and chew it or slurp it down quickly reducing absorption back to that same 1% and limited to binding capacity. With sublingual tablets absorption is proportionate to time in contact with tissues. I performed a series of absorption tests comparing sublingual absorption to injection via hypersensitive response and urine colorimetry.

4. Of the many brands of sublingual methylb12 only some are very effective. Some are completely ineffective and some have a little effect.

5. For injectable methylb12, if it is exposed to too much light (very little light actually is too much) it breaks down. Broken down methylb12 is hydroxyb12. It doesn’t work at healing brain/cord problems of those who have a presumed low CSF cobalamin level. That requires a flood of unbound methylb12 and adenosylb12 (2 separate deficiencies) that can enter by diffusion. Adenosylb12 from sublinguals can ride along with injected methylb12.

6.They don’t take BOTH active b12s.

7. They don’t take enough active b12s for the purpose. Active b12s have a dose proportionate activity. There is a threshold effect at high levels of dosage when the cerebral spinal fluid is penetrated for some people, especially with CFS/FMS/Alzheimer’s and sub-acute combined degeneration.

8. Lack of methylfolate – This is the number one lack after right b12s are in place.

9. Lack of other critical cofactors. Lack limits healing with most people to some degree, fully prevents effectiveness to a lesser extent.

10. Lack of basic cofactors. Lack limits healing in most people to some degree and fully prevents effectiveness to a lesser extent.

These represent the actual order, more or less I go though these items with people when they say “I’m taking b12, why don’t I get better?” Taking the wrong kind and/or wrong brand and/or wrong method turns out to be the BINGO factor in most people.

Is there a pattern where people on active B12 protocol seem not to notice or accept progress during startup?

Eric: in reading through this massive thread, I’ve noticed a remarkable pattern of which you can see some evidence in posts like these. “Quick update and a question. Wife hasn’t really seen any major improvement. Some of it may be hard to track and she has come off a lot of medicines. The improvement would have to be very noticeable before she would admit it. She seems to be sleeping through the night, despite coming off all her sleeping meds. Some of the startup symptoms seem to have subsided.”

The wife in question had a complete recovery and was out dancing after 50 days:

My wife has been on the b-12 protocol for about 50 days (We haven’t even re-ordered supplements yet). It was rough in the beginning. It was hard to tell what were normal symptoms or start up symptoms or reactions.

She just pushed through and the turnaround has been amazing. We went out Saturday night and partied from 6-Midnight. Not once did she get fatigued. Eyes wide open the entire night. I specifically watched her and paid close attention.

She gets up early and goes to work now. Before, it was a challenge to get out of bed. I could go on and on….” Here’s the 6 month update:

“I just wanted to let everyone know that she has been training for a sprint triathlon (5k run/500M swim/15 mile ride) for about 2 months. The race is in two weeks and she is more than prepared. For practice and on different days, she runs 8k, swims 1000M and bikes well over an hour.

Amazing turnaround from what felt like a death sentence only 6 months ago.”

Does it matter what brand I buy when shopping for cofactors?

On these cofactors some people have noted differences by brand but it doesn’t appear consistent like the mb12 differences. SAM-e is likely the one that will show the most brand difference. I use Nature Made. I have tried several brands and that worked the best for unknown reasons. Jarrow probably came in #2 with a just noticeable difference. The differences were not day and night as with the mb12. I suspect that it is a matter of slightly different forms or maybe just the difference in effectiveness of the enteric coating for my chemistry.

I use the the NOW or Jarrow TMG and find no difference and the Jarrow L-carnitine fumarate, available in several sizes making titration easy.

What is the 50 mg penetrative dose? The 50mg sublingual doses, equivalent to about 7.5-12.5mg injected, is sufficient to cause a CNS response AFTER the body has reached an equilibrium at which an increase causes no additional response. The CNS response is DIFFERENT for adb12 and for mb12. Both are far more subtle than body reactions and are only slightly noticeable generally, and then only if the person has a depressed CSF/CNS level despite a high body level. Some respond to adb12 or mb12 and some to each. As they are different the most information is gained by doing each separately. I can repeat the mb12 twice a day with a separate response each time, but not 3x per day as equilibrium is reached with that. I can repeat the adb12 once each month or two only or there is no response. Metafolin may be needed to have any response. If you are in a state of folate deficiency the dose of b12 will make no difference. Metafolin helps you retain more of the b12 for longer.

I start with 5 and add the other 5 over the first hour. The whole things takes about 3+ hours. The mb12 and adb12 can be done on successive days. I have performed that trial with Country life several times and I did once with Source Naturals immediately after switching, too soon to detect anything but a differential effect. I will repeat after a couple of months on the Source Naturals to see if the smaller doses are effective. Then a few days after the source Naturals 50mg I will do the Country Life to see if there is a differential effect. If there is, I will know that the Source Naturals isn’t as effective for some reason. Right now I don’t know if the Source Naturals will work or not. I know that the Country Life can work.

Could my dizziness be from sensitivity to the fillers or what they use to make the supplements – the Jarrow methyl b12 has some sort of fruit flavour in it…

A lot of people who have healed extensively with these supplements found dizziness to be a temporary effect while going through certain stages of neurological healing. When I was hit the first day of a 16 year crash, overwhelming dizziness was one of the symptoms. It faded a bit over the years and when I started healing flared up again for a while until it healed and went away never to return. People will often progress backwards though a whole series of symptoms as they heal. Methylb12 directly affects the neurology very quickly and causes a whole lot of symptom shakeup as the healing progresses. A person doesn’t want to get off the bus right in the middle of severe dizziness and stay there. Many people have experienced this while healing and found it to be temporary as long as they continued. Sunday: I have been on this protocol for coming up on 4 months now. For the first couple of weeks I felt good (one week even really good). Then I crashed for 2 months, exacerbation of all symptoms including dizziness, PEM, nausea, the lot. It was awful. I was discouraged. I thought it might never, ever end.

The thing is, when I came out of that LONG crash (probably partly helped by acupuncture), I took the first (very slow) 20-minute walk I had taken in half a year. I was able to do other things I haven’t been able to do, too.

Every time I up my dosage on this (I’m titrating very slowly) I crash again. But I keep noticing the reduction of symptoms (using Freddd’s list helps keep track). It doesn’t happen all at once; it doesn’t even have a linear progression. It’s a gradual, spiral effect. I’m willing to pay the price of the crashes because now I’m crashing to get better. Before I was crashing and felt as if I was just getting worse. Sunday: My own titration was slow; I’d read about the awful effects and wanted to go easy, because I was already feeling bad.

Working off of Freddd’s treatment plan (page 1 of this thread), I started with the “essentials” as a foundation, then started adding things from the “critical minimums” list one at a time. B-Right, then adb12 (seemed to have fewer dire effects, and one of my main problems was and is energy lack). I was going to divide the adb12 but the pills are so small I couldn’t physically do it. For me, that was OK, for others, not.

I added mb12 very slowly, since I’d read about its weird (and often none too pleasant) effects on this thread. I started with 1/3 of a 1,000mcg tablet (couldn’t cut it smaller). After the dust had settled, I went up to 2/3, then a whole tablet, then 1 1/3. After this I bumped up my dosage by 1mg until I reached 5mg. We’re talking months, here. My most recent bump-up has been pretty drastic, testing F’s theory that it’s the first small doses that cause the greatest commotion. Well, I have felt like serious crap (OK, occasionally amusing crap) for the last week, but it’s not as bad as I’ve known. And yes, a return of dizziness, orthostatic intolerance, PEM, brain-fog, neuropathies, the whole shebang. That’s what I mean by, it’s not a linear process. It seems you have to get worse to get better.

During the process of upping the mb12 I also started the methylfolate. On the suggestion of David and Velha, I recently doubled my dosage on that, a rough ride but I think essential. I will probably be tinkering with this and the “possibly critical cofactors” for some time. It might have been smart to add the methylfolate before the b12s, as its essential to their action.

The thing about using Freddd’s list of symptoms is that it can remind you that things are changing. For instance, in my 2-month crash all my symptoms were very bad, except my neuropathies. They’d always kicked up during crashes, but not this time. That told me something different was happening. Now my neuropathies are back, worst they’ve ever been as far as extent. I just have to trust that this is another level of healing. It’s a SLOW process for me. I committed myself to 6 months of it and then a reassessment. I’m sticking with that. I may not see 95% improvement on this, as Freddd did, but methylation feels crucial to me.

Lena: I went through the same thing though I did have a long honeymoon with the B12 the first time I tried them. I am on my fourth try. Started a very slow titration the beginning of Dec. 2009. The first 9 weeks never could get off the couch, also nausea every day. I upped my B-right to twice a day and had three better days than 4 worse days, the last 3 weeks nausea disappeared. The last 9 days I have felt better, the crushing fatigue has turned to tiredness. I can sit up for longer periods of time, can drive to the grocery store and do a few errands. Even played bridge for 2 hours and wasn’t exhausted. Can go out to dinner with husband without being totally miserable.

Right now my dosage is:

2 – B-right
1 – adb12
2 – mb12 5 mg
1 – folate

Why can’t I sleep when I take AdoCbl / Dibencozide?

A major clue appears to come from the results with the adb12. Adb12 is really limited. It does only one thing in the body. It occupies a place in the mitochondria and participates in the generation of ATP, the body’s energy “currency”.

Let’s consider what that might mean. Control of metabolism is a multifactorial thing. Let’s suppose that your mitochondria had a 1% occupancy rate by adb12. If a dose raises that to 5%, that is a huge increase percentage wise. Before, your body was saying produce ATP at 100% rate all the time and still never have enough. So the throttle is set for 100%. Suddenly you take adb12. Now 5% are occupied and that 100% throttle now produces 5x more energy. It interferes in sleep and other things. It takes a while for the body mechanisms to adjust back to having that much energy and adjust the throttle accordingly. Switching from anaerobic energy production that produces lactic acid which burns in the muscles to aerobic energy production produces 6x more energy from each reaction.

Coming back to normal is a huge shock to the system and takes a while to adjust. After the mitochondria are 100% charged up with adb12, and this is where much of the body’s working supply of b12 is, in the mitochondria, taking adb12 produces no noticeable effect at all. It appears that keeping it high so that it seems like “too much energy” is what it takes to make the body readjust it’s settings to take account of the new situation over time so that the body can readjust to the genuine “normal”. Having mitochondria producing energy in all mitochondria allows the body to exercise, restores ability to build up aerobic endurance and normal exercise tolerance and to build muscle from exercise and to repair muscles.

When the mitochondria have adb12 in the neurological tissue it also affects how our brains and nerves work. It appears to make differences much more noticeable and increases the strengths of emotions and moods. The balance between mb12 and adb12 and methylfolate, as well as b-complex and other factors appears to affect qualitative aspects of moods and emotions.

I’m struggling, should I step back and start the mb12 at a much lower dose and climb slower?

Try taking all the mb12 for the day before noon, even better by 10 am. That allows the melatonin to be generated in the evening. Serum half-life of b12 that freshly enters the blood is 20-50 minutes dropping to about 4 hours at 12 hours following dose. That means that if you succeed in getting 256 mcg into your blood by 10 AM, there is likely only a few mcg left by midnight. It doesn’t linger long. Only the b12 that is actually in place functioning is felt. As mb12 isn’t locked in place long-term like adb12 is, it keeps getting flushed out and needs daily renewal. Please ask some questions if you don’t understand. Playing yoyo with the doses won’t do what you expect. Your body will adjust more rapidly with a higher dose and not spend most of it retracing the same ground every day. I’ve been through this and walked some hundreds through this. Good luck.

This morning I put the adb12 Country Life under my upper lip for over 45 minutes. No real reaction except a little shaky in my legs. When I compare this to the reaction I had taking B-right for the first time the adb12 was more subtle. Is that normal?

Adb12 lev els off very quickly because the adb12 parks in the mitochondria and stays there a long time. Once all the parking spaces are filled, there is no more change and everything related to adb12 gets steady as long as other cofactors are in place. Mb12 is the main circulating form and is used in every cell that is reproducing in every part of the body. It affects literally everything. Mb12 startup is much more ragged and it requires far more cofactors. It also drains from the body very quickly. A steady-state is reached rapidly at a given level of dose. At too low a dose, there is never enough and so the body never levels out, always playing yoyo. At a higher dose, mb12 is there at 100% of needed places as needed and everything smooths out as all sorts of processes don’t start and stop and start and stop, every day.

Is stopping and starting ok?

Stopping for a few days doesn’t mean starting all over fortunately. The ad b12 that is in place in the mitochondria will all still be in place. The mb12 that has gone into the tissues will still be there. Only the current serum levels will be down. However, you couldn’t possibly reach such a highly depleted state without going months or more without. A person in a state of saturated equilibrium with b12 who can’t feel any size dose in any way, will regain the ability to feel a dose, but only slightly, after 3 days. Those of us who require our bodies to be in a state of saturated equilibrium for health will start to have a slight loss of energy and other deficiency symptoms barely begin after 3 days without. So don’t worry, it’s not a start-over and a single dose will put it back.

I started the Jarrow methyl b12 5000mcg. I put 1/8 tablet under my upper lip – anti-climatic. After about 30 minutes jittery, some dizziness and my left calf very achy.

Don’t be concerned about the size of the reaction. If you had taken a 5mg all at once it would have been bigger. The titration is for comfort. ANY reaction at all indicates that the b12 is doing something. Big immediate reactions indicate that a person has a lot of the functional type things that can correct very quickly. One thing I noticed here was a lot of people appeared to have the expectation of no perceivable difference and were getting upset with startup effects. They do indicate that b12 is going to work. More at one time causes more tissue penetration for a shorter time and hence more startup effects. The important thing is getting that b12 to a saturated equilibrium level to be sure it is available everywhere it is needed. For many people startup effects diminish quickly.

I’ve started back on the methyl b12 recently, after introducing the adb12, just 1/4 of a tablet but have tried to increase to 1/4 (3 times a day) and starting to feel much the same, ‘brain damage’ and dementia like symptoms, not being able to read or think properly, severe brain fog – I’m very worried!

These are all b12 deficiency symptoms of various stages of deficiency and healing. They happen much faster while healing and coming back to normal.

Can Mb12 kick-start methylation too much?

The methylb12 has only a tiny fraction “methyl” which is CH3. That is a total of only 18 out of more than 1335 total molecular weight. Compared to methylfolate or SAM-e or other methylators, Mb12 is very weak and has very little methyl to contribute. Much of the detox mb12 does is combining the cobalamin portion with the toxin and making it harmless and transporting it out of the body. Most of the effect of mb12 is to the nervous system actually functioning better and being more aware of what is happening. Mostly 95% is excreted unchanged within a few hours.

The mb12 reduces inflammation pretty quickly as it restores the ability of the body to make new cells. This shows up with decreasing inflammation, often in less than 10 days. At 1/4 of a 1mg tablet you are absorbing about 15% (in 45 minutes of 250mcg, a total of perhaps 35-40 mcg, which has very little to do with methylation but a whole lot to do with functioning. Even at that pace a lot of empty sites for the mb12 will be occupied pretty soon. Startup can be ragged is all. Don’t let it scare you and it too shall pass and you will be feeling better. You might find that after the 1/4 tablet you can add several more 1/8ths during the day without things changing too much which can speed up that initial “charge-up” period without making it more intense.

Since starting the b12 and 5 methyl folate I’ve started having some dizziness. I’m wondering what supplement I am missing that might be causing this. Could it be low potassium. I’m not taking a potassium supplement. I don’t think this is a potassium situation as that usually manifests in the muscles but I don’t know that for sure. I suspect that as mb12 and adb12 does directly affect the neurology in many ways that changes are occurring. Others have experienced some dizziness during healing and it normally has resolved. I don’t know of any that haven’t. Too much [potassium] is really bad . . . and too little can be fatal. That is really really bad. For people trying to start methylation and succeeding, their potassium will drop and become symptomatic. Titrating for effectiveness [possibly as high as 2,000 mg] and watching for returning symptoms of deficiency for extra doses is required for safety and comfort and effectiveness.

“Normal” levels of potassium do not mean asymptomatic. Various labs call 4.0 down to 3.5 the low limit. I have middle of the night screaming spasms at 4.2 as do others. Too much needs to be watched out for. However, probability of LOW potassium with mb12/Metafolin is near 100%. The probability of actually dangerously high potassium is a minute fraction of that, perhaps 1:100,000 or less, while cell formation is going on without taking huge huge doses. I don’t try to take enough to never have low potassium responses. I just try to keep the episodes down to once a week and adjust my dose to achieve that.

Since starting the ab12 and mb12 twelve days ago, I’ve had markedly more energy and some headache/faceache symptoms almost each time I take or increase the dose of mb12. For the last three days, though, I’ve felt very tired, and I don’t know why that would be. I’m having to lie down more than usual. I don’t have muscle weakness, soreness or cramping – just muscular & general fatigue. Any ideas?

The number one candidate is potassium. A single 500mg dose (nowhere near any possibility of fatality) will tell you in 30 minutes. Number two probability is Metafolin deficiency, then b-complex, magnesium, zinc, SAM-e, TMG, L-carnitine fumarate etc.

A side note on B1, that is one of those b-vits I take additional of. It is vital. If a person is taking b-complex twice a day it reduces the probability that B1 is the limiting factor.

I also take Pantethine, p-5-p and Biotin. The Pantethine makes me feel sick but only when in folate deficiency. Combinations are critical.

I’ve never lasted longer than three days because of immediate noticeable (and unpleasant) increase in muscle cramping/tightness/pain

I get muscle cramping/tightness/pain 3 days after starting mb12, adb12, Metafolin and a few other things. It is relieved in 30 minutes with 500mg of potassium and can be generally prevented by some amount of daily potassium which for me is about 1200mg a day plus occasional additional doses. 99mg isn’t likely to stop it.

I do well on the adenosyl and methyl B12 – nothing but feeling better after a week of start-up symptoms. But the folate makes me sick, sick, sick. I added in 1/2 tab on Saturday, and had a day of extreme fatigue, feeling fluey.

It’s fascinating where the startup reactions are in this whole business. In what I have experienced and observed in many people is that the reaction happens with the factors that are the most limiting ones, the ones the person is most deficient in. The methylfolate is absolutely essential to the proper functioning of both b12s. For instance, the reaction could very well be caused by your immune system starting to work better. Folate is kind of a medium serum half-life component. It takes perhaps 5 to 10 days to reach equilibrium on any one dose. Like the active b12s, the reaction to dose is not linear. The first 200mcg can make all the difference between zero functioning and functioning and may very well make more difference than the next 600mcg combined. As all the processes that it influences have to start up if your body is to function normally, the choice comes down to how fast one goes through the startup process. The startup process at the initialization of using these vitamins is a result of many stalled processes getting started, sort of like a new driver letting out the clutch for the first time. It can be a bumpy ride.

Folate makes me sick – any idea what the reaction is due to – kicking off methylation? With 1/2 tablet?!

Methylation may be involved, but there are hundreds of other things it could be too, and maybe 20 or 30 of them at the same time. And methylation is involved in some of them as in cell reproduction. It has to happen for your body to heal. It’s a good thing, not a terrible thing. As mb12 also provides a methyl source it likely is a functional item as a cofactor doing exactly what it is supposed to do for the body to function. This appears more to me a cell formation type of reaction which could leave you depleted of serum potassium within a few days. That’s why potassium is on the list for initial startup items, to prevent the temporary hypokalemia that can easily happen during the startup period for any of a number of supplements. I would be inclined to titrate it. If you leave it out all together, then the things that have started up will shut down and you have to go through that startup all over again; like losing the same 5 pounds 10 times instead of losing 50 pounds. If you were to continue with 1/4 tablet a few days and let the startup at that level take it’s course, it likely will be different each day. You can choose to interpret it as something causing great distress or as indicating that your body was very deficient of it. Getting hundreds of shut down reactions going again isn’t pleasant and yet there is no way to restore the body without that happening. My experience with myself, my family and hundreds of others like you and myself is that all these things pass, usually pretty quickly, with continued usage.

In my experience the things that kick up fastest when starting these supplements are also the things that correct and heal the fastest. These are functional things that can start correcting just by putting gas in the tank, as it were. The actual healing is one of the things that can get started immediately but takes longer to complete.

Should folate be started BEFORE or AFTER the active B12s?

The explanation is based on the pragmatic results with the internal processes hypothesized afterwards rather than an explanation based on theory and hypothesis in advance of the results. So rather than “what should happen” it’s based on what did happen, over and over.

First, to be clear, the interaction and interdependency between methylfolate, methylb12 and adb12 are extreme. Their deficiency symptoms overlap extensively and are just about impossible to separate. In some functions they provide alternate biochemical pathways. The availability of Metafolin (methylfolate) has made for a reliable folate supplement with distinctive results not available with folic acid.

One of the functions of methylfolate is that it increases absorption and retention in the body of both adb12 and mb12. If a person is severely deficient it makes both b12s “hit harder and quicker” with a smaller dose. In effect it makes titrating more difficult. This has been demonstrated over and over. By leaving the methylfolate to being started after both b12s it also allows one to see if folic acid has been sufficient or not. It spreads out the startup symptoms. It allows one to see the unique effects of methylfolate and to identify the pivot point symptoms unique to folate.

If one is going for maximum startup effect to see if they have any deficiency reactions to b12 then methylfolate should be taken first. If one would prefer to slow down and moderate the startup symptoms then it should be taken after the two active b12s have been established. This is purely experientially based. If one doesn’t have a lot of startup symptoms from the active b12s it might be started within a week.

Methylfolate is a major methylator for the body and priming the pump with it as it were appears to cause gang-buster startup b12 symptoms. Because it was not available I wasn’t able to start it until well after both active b12s and SAM-e and had only very minor startup symptoms with it. I started dreaming again for the first time in decades the very first night after taking it and my angular chelitis started healing immediately and was completely gone for the first time in my life in 10 days. I was injecting mb12 by that time, more than a year into it, and methylfolate allowed twice as much b12 to be injected before showing up in the urine. For some people the need for folate is so severe that they have almost no startup at all from the b12 but a lot when they start the methylfolate. It’s severe lack can cause b12 to be totally ineffective.

How much metafolin per day should I work up to?

…for most people most of the time 800mcg is entirely satisfactory. I did well on that until the glutathione precursor trial. I’m on more but plan to start decreasing in another 2 weeks.

On the L-carnitine fumarate 125mg is quite possibly a good amount to start with. It can be very energetic in reaction. It works with the adb12. Of course you may not have a shortage there and then it will do nothing. For me at least 500mg once a day 30 minutes before food is as good as it gets.

Don’t forget that exercise is an important part of recovery. Start increasing as soon as exercise tolerance develops. Start low and slow and increase slowly. Recovery can take longer than healing.

I am a physical wreck – should I take glutathione?

The mb12 and methyfolate generates glutathione, but not in a quantity so as to disable themselves, the active b12s and folate. My suggestion is to allow the active b12s and folate to normalize the body for several months, during which an awful lot of healing can occur and re-evaluate then. This evaluation is in the midst of all sorts of things being broken down. The tests confirm what you already knew; that things are broken. The epithelial and endothelial tissue damages can be caused by the b12 and folate deficiencies themselves. That’s what those deficiencies do is damage all those tissues. Give them some time. Right now you have started taking action but not gone long enough for that action to show up. Making more changes may be swinging at phantoms that are already changing and may interfere.

B12 deficiency directly damages the muscles, GI lining, veins, heart and arteries lining, skin, mitochondria, neurology, blood, bladder, and all other tissues in the body.

I was steadily increasing my adb12 dosage and then suddenly felt sick nauseous and dizzy, what went wrong?

I think it’s more important to get a good balance of things going than a lot of one thing like Adb12. A single tablet of Adb12 and of Mb12 plus b-complex and all the basics and so on gives the body a chance to heal many things. The higher doses can wait until you see what doesn’t work at lower ones. Balance is important. The balance between adb12 and mb12 plays a substantial but not easily discernible or well documented or explored role.

The exact balance a person needs is not easily arrived at so we try for an approximate balance. Most people find between 1 adb12 per day and 1 per week perfectly suitable when they are taking the mb12, methylfolate and such. Ad b12 doesn’t drain from the body as quickly as mb12. Higher doses may be effective in some circumstances but that has to be tried after a balance all the way around is reached or you don’t know what you are seeing.

Added SAM-e yesterday, 125mg. Effects so far, nausea, increased appetite, drowsiness. I’m guessing I don’t need this co-factor?

I wouldn’t bet on that. If it did nothing at all at 1/3 the typical dose I would suggest 400mg, a typical dose to see the effects. It’s supposed to be effective for detoxing the liver and it augments the effectiveness of mb12 and methylfolate. When one of these things does something noticeable it is usually worth noticing. Clearly it is doing something. So continue until no effect then step it up a notch. The drowsiness and increased appetite are usually good signs. Nausea can often be a neurological change or some liver detox etc. You are on a minimal dose.

Do you have to go through the bad to get to the other side?

I’m not sure. Some of the effect you were having may be an artifact of which you started first and the ratio between them. I was well established on the mb12 before starting. The mb12 is protective of the neurology in a way that adb12 is not. It is unique in this and more of the other kinds don’t produce that effect. I had to go though all sorts of effects as different processes came back to functioning at an uneven rate.

By 3 weeks a lot of symptoms were very much improved. The only thing that worsened after 3 weeks was neurology. Moods and such, irritability, personality changes and such got really ragged for a couple of months about 1 month into it. That happened 3 more times each time I added an important cofactor that caused more neurological healing. Nerves coming back to function produce all sorts of painful and irritating effects before they start working properly.

Is there any particular reason to choose adding l-carnitine fumarate before SAM-e, or to do it the other way around?

There is nothing I can really point to. In the end a lot of people need both and some need neither. In the end you may not be able to tell the difference between them in their actions. They both can increase energy, improve mood, improve tissue healing, improve neurological functioning but for entirely different reasons through different functioning. They both help active b12s to function better.

I have been taking mb12 sub-lingual for 1 month and felt some boost from it early on but now when I take it I get dizzy / light headed for several hours. Is this normal?

The effects you are having appear to be caused by your neurology actually starting to heal. There is no way your neurology can heal WITHOUT noticeable effects. This may continue for several months and might increase and change with methylfolate instead of folic acid and adding adb12 might modify it as well. TMG may also moderate it the effect some. MB12 has the unique characteristic of promoting neurological healing.

This can affect everything neurological and neuropsychiatric including moods, personality, sensations and the like. Sensory hallucinations that are present with deficiency can clear within hours sometimes depending upon how severe the underlying damage is. The “dizzy and lightheaded” is a generally a good sign with taking mb12. It’s on the road to healing based on the experience of many.

For the last two months I’ve been taking sublingual B12 5mg from Jarrow. The first three weeks of taking this I did not notice anything, however for the last five weeks I’ve noticed dizziness when taking the B12 and shortly after, why?

That dizziness is certainly “normal” in the sense that it happens almost universally to people taking the mb12 effectively. As it happens to virtually everybody with any degree of neurological damage and malfunctioning I doubt sincerely that it has anything at all to do with “detox” unless the detox is allowing healing to take place. You are not used to your nervous system having the mb12 it needs for better functioning. It is something that appears to happen as the neurology is starting to be affected and goes away after a while. Methylfolate and other cofactors may will aid the healing and may or may not intensify various other startup symptoms. The SAM-e and methylfolate are both potentially key players in this. I would suggest the methylfolate first and b-complex is critical, calcium/magnesium, C, E, A, D, omega3 oils are critical for nervous system healing. The SAM-e should wait until after the basics are on board including adenosylb12 (Country Life Dibencozide).

Establishing a new balance of nutrients is important. Everybody that heals goes through things like this. This is a common signpost on the road to healing. I have been through that and a whole lot more. If I hadn’t continued and let any of 100 startup and neurological symptoms changes scare me off I would be in a wheelchair with a diaper or dead now. I have walked this path. It is the way through this stuff, whatever the temporary cause. When you have to go through 1000 changes to heal, 999 of them are just different ways to feel wrong. They pass and change to something else as progress is made.

Sunday: My two cents’ worth on the dizziness thing: I’m a little over 3 months into this protocol. For the first few weeks it was like a honeymoon, but then the proverbial excrement hit the fan. Every time I up my dosage of methylfolate or mb12 I have dizziness and/or orthostatic intolerance. The first time (after the “honeymoon”) lasted for two months, with a lot of other symptoms, and was no picnic. I recently re-upped my methylfolate and today just upped my mb12, and am worse in the dizziness/orthostatic intolerance department.

So why do I keep this up? Because, after each round, every time I stabilize, I am measurably better. For me, progress is agonizingly slow. But I notice things such as: I don’t have brain fog all the time. When I do have it, it’s much lighter and doesn’t last as long. My neuropathies are getting better. My energy level is still low, but at least I have some sometimes; I didn’t used to.

The pattern that seems to be – may be – emerging for me is that whatever gets worse gets better – that is, if upping dosage on or adding a supplement increases a symptom, when I finally come out the other side, when I stabilize, that symptom has usually gotten better. I will say, as Freddd has pointed out, that the first couple months or more seemed to be just random symptoms firing off everywhere.

I do think it makes sense to check for metals toxicity, as that would probably change the way you do this protocol, or possibly change whether you do this protocol. But I would also point out that methylation is what allows us to detox (at least that’s my understanding). Freddd makes no secret of the fact that this protocol produces scary nasty awful effects, but I can understand why it still comes as a surprise, because I find this aspect very disheartening to deal with.

I think it’s important to sort out our fears from the facts: check to see if you have heavy metals poisoning, there are relatively cheap tests for this. If you don’t, consider the fact that these reactions may feel wrong because they send us back into the pit of hell, and that is scary.

This protocol reminds me of Dante’s Inferno. When Dante is being guided out of hell by Virgil, they have to crawl over the Devil, who is stuck in this big sort of drain-hole in the bottom, the entryway from hell to limbo (that’s back when there was limbo). At one point, they make a sharp turn, and Dante cries out that they are headed straight back to hell, Virgil is misleading him. Virgil says, in this dimension, directions get confused; while they are heading in what feels like the wrong direction, he knows it is the right one, because he has made the journey before.

I’m lightheaded/dizzy, should I take Dibencozide in addition to MeCbl? What’s the best timing for taking AdoCbl?

The adb12 may or may not make a difference. It is critical typically where there is severe fatigue and brainfog, lack of exercise tolerance, muscles that don’t repair from exercise damage and don’t grow. On the other hand methylfolate can aid absorption and utilization of both kinds. Both on the same day is fine. Even both at the same time seems to work well.

For me the methylfolate was an incremental improvement in a number of areas but not earthshaking. Others may find it quite intense. I find I do best taking the adb12 6 at a time once a week 2 hours after an injection of mb12. It appears that I need to get it into the CSF, and that makes a neurological difference. This amount of and timing of adb12 appears to be a major area of fine tuning and varies perhaps more than anything else which was evident early on. My daughter finds she has to take it every day, but one daily does it all for her.

I want to order TMG from iHerb but I don’t know which one. Which one should I use and what dose I should start with?

I’ve used both NOW foods and Jarrow with identical results. Order the smallest one. If you cut them they swell up with moisture rapidly becoming a mess. So if you cut them, put them in capsules immediately and store in container with desiccant. With sensitivity I would shoot for 125mg or less.

I had more energy the other day and today as well. The problem though, is I’m waking up like 5 hours after I go to sleep, and can’t fall back to sleep…

A study on sleep and mb12 I read a few years back said that less but more restful sleep was often a result of mb12. That is certainly a common experience. I would advise not to get upset about the hours but rather judge it based on how you feel. It affects melatonin production and can take some time to get regularized. MY experience of the first 3 months excluding the time switched to a zero star brand was that it was like 20 steps forward on energy each day and 19 steps fallback by the next morning. Each day though I had an increase in base energy and that is what my body adapted to with a little lag.

Do people tend to get worse before experiencing positive benefits? Do you start out with small amounts and increase?

My lifelong depression started lifting after about 15 minutes after that first mb12 went under my tongue (by the Rolling Stones?). After 1 hour I had enough energy to walk up a flight of stairs normally for the first time in 16 years. However, all my symptoms were perceived far more intensely in exquisite detail. However, as that was also accompanied by the start of brainfog lifting and seemed connected, it wasn’t “bad”. Some aspects were unpleasant. Remember though, many of the things are just changes in perception, an increase of intensity becasue the nerves are suddenly working better, well enough to perceive all the damage. The things that exploded into awareness most were also the first things to heal.

I started with a 1mg sublingual which delivers about 150-250mcg to serum in 45-120 minutes. Over the next 4 months I titrated up to 20-25mg sublingual/day (delivering about 4-5mg to serum) taken in divided doses throughout the day. After 3-4 months of startup it fell off in 1 week as I just took more and more mb12 saturating the system.

The more I took the less effect each tablet had until they ceased to be any reaction at all and everything stabilized. From that point on symptoms got progressively better and milder. After 9-12 months I was able to discontinue or reduce most of my medications. The neurological pain was 99% gone. My allergies and asthma was gone. The burning bladder was gone. The IBS was reduced and as soon as I got rid of milk went away completely.

Before the mb12 I was sensitive to everything and milk was no different. After mb12 it was the only thing remaining. The constant nausea and vomiting was gone. The waking up at night with acid shooting up my throat was entirely gone. I had exercise tolerance back. My muscles started growing with exercise. It took a few more cofactors to finish the job but looking at my muscles now you would never know that they were mere shadows of themselves 7 years ago.

I’ve been producing swamp-smelling urine since I began Freddd’s protocol. Is it the result of some sort of detox, or just one of the supplements itself that causes it?

I can tell you what started for me. It lasted for about 10 days and was gone by the time I got into my doctor at a hastily made appointment. It started about 4 hours after I started L-carnitine fumarate. That first day I dumped about 4 pounds of excess water. My stomach was swollen taut and hard like a basketball. My breathing was impaired and breathing while reclining was very difficult. By the time the smell returned to normal I had dumped 20 pounds of water and my stomach was soft.

I had started the adnosylb12 a few months earlier to good effect. When I added the l-carnitine suddenly my energy level went through the roof and immediately I was able to do 34 minutes on the Nordic Trak at my usual settings instead of 17 minutes as on the day before. I made no other changes. It was a one time occurrence that started to fade after a week and was gone after 10 days. I also started rebuilding my muscles that hadn’t been normal in more than 20 years by that point and had faded away to mere shadows of their former mass.

I have no specific theory about it other than it was related to decreasing edema. By the end of the water dump period I had lost about 80 pounds in all of water weight. My tissues are no longer waterlogged and my blood pressure came down about 50 points.

Is there an emotional impact one may expect with active B12 protocol?

Rapidly changing, volatile, emotions. Also, for me when my neurology started working again I started feeling all the emotions that were so flattened for decades. Also, unprocessed experiences from 30 years back even, all started hitting at once. After recovering to an extent I went through a period of mourning for my life that was long gone. I still have some of that cropping up. The decades of illness and disability cost me everything in my life I used to care about, my wife, my young children, my business, my sports, my interests, even my ability to read for a while. Right now, I am about 2/3 through the first novel I have read in maybe 15 years. I used to read at least 100 books per year, many of therm novels. As I have come back and the neurology has healed I have changed. My wife divorced me and when she remarried she said that he was “a lot like you used to be”. I am not remotely the guy she had married 33 years before.

After several NDEs I was a complete stranger to her and she was a complete stranger to me. After the divorce she didn’t see me in person for about 9 months. When she came over one day, knocked on the door and I let her in. She looked at me and then at the other person there and asked “Where is Fred, I was supposed to meet him here?”. I had changed visually that much in 9 months of healing. The changes were internal as well as external. Dying would have been easier. I’m appreciating being alive again.

What’s the best ratio of the adb12 to mb12?

The only other issue I’ll address before having that answer is in regards to the ratio of the adb12, mb12 and methylfolate. The suggested ratios of mb12 to adb12 that I have come across is in the neighborhood of 3x – 10x as much mb12 as adb12. When another person tried precise injections of adb12 and mb12, when he tried the large doses of adb12 mood and personality changes similar to those of mb12-CSF deficiency occurred. In my injection series of adb12 I approached from a titration point of view. The peak effect of adb12 was reached with 1mg of adb12 injected at the same time as 10mg of mb12. I achieve exactly the same effect with 6-9mg of sublingual adb12 taken at time of injection with mb12 10mg SC. I find that I only need 18mg of adb12 about once a week, whether in divided or single dose as long as taken at same time as the mb12 injection to provide the CSF penetrating diffusion gradient. Several people have needed somewhat larger daily doses of adb12, but not larger than the mb12 to maintain an equilibrium state with the adb12. My daughter does best on a single adb12 daily plus the mb12.

After a complete recovery with active B12’s, my wife changed to a multivitamin and began exercising. Then, she has had a pretty significant “crash”. She is very restless in her sleep, severe fatigue, muscle pain, she is back to going to sleep at 6pm. Any ideas?

A multivitamin has far less of things especially minerals than the individuals because of bulk. So there is less calcium, magnesium, potassium and zinc most likely. There would also be much smaller doses of b-complex items, fewer of them and likely no active versions such as p-5-p or pantethine. I also don’t see Metafolin listed and that is a critical cofactor for both kinds of b12.

The way this crash sounds it could be one or more of several things; a running out of a cofactor which is unable to keep healing going, or a change in the minerals balance causing the problems or both. Also another angle is the exercising. IN my case, after 17 years of inability to exercise or even walk very far for a lot of it, I started the cardio exercise at 1 minute and worked up by a minute every other day as able to.

I hit a wall at 17 minutes (Nordic track) until I started the l-carnitine fumarate but didn’t crash, just could go past it. 24 hours after starting the carnitine I effortlessly went to 34 minutes and then had to start working up again. So maybe it has to do with exercise. One possibility is D-ribose which helps restore the ATP after exercise and turns out to be a critical cofactor for some.

It feels as though the b12 stimulates my system until my system becomes exhausted after a few weeks and then shuts down, why is that?

B12 is not a stimulant. It doesn’t act like one. It does largely 3 things; it causes the mitochondria to produce more energy, and there can be holdups on cofactors in that, it causes all sorts of cells to heal which rapidly depletes resources, for example potassium, zinc, C, magnesium, A, E and everything else needed to build cells which is subject to sudden holdups by exhaustion of resources and it improves performance of the nervous system and brightens all the senses. That appears to many people as “over-driven” at first but can rapidly fade to “normal” for the present equilibrium and definitely does not maintain that enhanced brightening for long. You may be one of those who has trouble getting enough b12 into the CNS/CSF.

Am I the only one experiencing more benefits from mb12 than adb12?

Be careful of misinterpreting what you perceive. Adb12 is very different from mb12. Typically a person feels mild startup for the first dose or two only and nothing at all on an ongoing basis as long as equilibrium is maintained. If one doesn’t take adb12 for a month, then mild startup might be perceived. You see, adb12 does two things, occupies the mitochondria which produces energy and helps form myelin. The adb12 stays in the mitochondria once it is there so there is not a regular turnover. Deficiency symptoms of adb12 only come back very slowly, especially the only noticeable effects, the energy producing function. Mb12 on the other hand circulates and is dumped out of the body rapidly, so some people can feel an effect from each tablet until they get to a high body equilibrium. When you can’t feel the adb12 that means it is doing it’s job. You may find that taking one adb12 per week is quite sufficient to maintain body/mitochondria equilibrium. It gets more questionable when it comes to myelin and CNS equilibrium. I have experimented with adb12 from quite a bit per day timed for CNS penetration with my mb12 injections to once per week. Some people say “I need 5 per day” every day to banish brainfog. Some find 1 per day to 1 per week entirely satisfactory.

Why do some people get sicker when they take folic acid or folinic acid?

I have recently performed another test which I decided I needed to do after the experience with Folinic acid. Guess what, more folic acid at the same times as the Metafolin dose with my b12 dose, taken in the form of adb12 with folic acid (Country Life Dibencozide) causes my leading edge folate deficiency symptoms to start coming back in 6-7 days. It BLOCKS the metafolin when taken at the same time (peaks coincide) from being effective. It causes folate deficiency symptoms just slightly slower than glutathione, in sufficient quantity. The Folinic acid at just 1 x 800mcg per day caused leading edge folate deficiency symptoms in 30 days. “. . . I’m 3 days into no folic acid at all. My central nervous system is starting to show more signs of starting to heal again, IBS is gone and cheilitis is healing faster than usual. Very interesting.”

What form of magnesium would you recommend?

Rich: Generally, PWCs are found to be low in intracellular magnesium, so I would tend to go for the higher ratios of magnesium to calcium, like 1:1. For a normal, healthy person, the 2:1 ratio is appropriate, but PWCs need more Mg, in my opinion. Magnesium glycinate is the best absorbed form. Epsom salt baths (magnesium sulfate) are helpful for many, but not tolerated by some, I think because they have sulfate-reducing bacteria in the gut, which convert sulfate to hydrogen sulfide. Magnesium malate has been helpful for many, because it also supplies malate, used in the Krebs cycle. Dr. Cheney for years has used magnesium sulfate combined with taurine as an injection. The taurine counters the pain from the magnesium sulfate, and this gets magnesium into the blood in larger amounts.

What’s better when starting out, one whole 1,000 mcg sublingual or four quarters spread out over the day?

A 1000 mcg tablet is a good place to start. To start out, 1/4 4 times in a day will probably work out better giving a more even serum level than taking the whole 1mg at once. After a few day if you are not having too much start up responses you might start increasing by another quarter each day, going to half tablets per dose when you get to 6 quarters and then up from there. Watch for sudden changes like muscle spasms, mood changes other than improvement, fatigue, weakness, muscle weakness and other signs of potassium levels falling.

Has anyone else had increased inflammation from restarting the methylation cycle?

The Carmen Wheatley “Scarlett Pimpernel” papers I, II and III deal with this very issue. That with b12 there is first an increase in inflammation and then a neutralizing of the nitric oxide leading to a decrease in inflammation. This appears to happen as cell formation picks up with methylation starting up. There is no need to take prednisone. The inflammation will run it’s course and inflammation and pain will decrease. I had a lot of pain which wasn’t controlled by multiple medications. The pain decreased perhaps 90% allowing all but one medication to be discontinued. I had been taking 2400mg/day of ibuprofen. 9 months after starting mb12 the inflammation was gone and ibuprofen made no difference any more. 9 months after starting mb12 I was able to discontinue/taper Dilantin (for neurological pain and some spasm control). 9 months after starting mb12 I was able to start tapering benzos. 9 months after starting mb12 I was able to discontinue albuterol, Compazine suppositories, antihistamines, theophyllin, an anti-narcolepsy med and probably a few more in there. It took about 9 months to reach that point. However, some specific pains started fading by year 10.

What is a reasonable goal for folate dose? I’m currently at 1.1 mg…

That is a reasonable starting dose. Since it is by titration, not “goal” one is doing it by reduction of deficiency symptoms or improvement in healing.. It really depends on whether the person has significant blocking by folinic acid, folic acid or veggie folates or takes too much b1, b2 and/or b3. Anywhere from 1600mcg to 30mg might be what is needed. In the Deplin studies in regards to depression the most effective doses were 15mg and 30mg. The 7.5 mg wasn’t enough for most. I have listed it several times at something like this.

  1. Donut hole paradoxical folate deficiency or insufficiency, up to 2 mg to 6 mg
  2. Folic Acid blockade – 8 mg to 12 mg
  3. Folic acid, folinic acid and veggie folates blockade, 16 mg to 30 mg

And all the above might be increased or decreased by adjusting B1, B2 and B3. Too much of one or more increases the need for methylfolate and potassium and can decrease healing. . . . Several doses of methylfolate work better than one dose for most people. With MeCbl and AdoCbl in the body, and l-carnitine, by the time equilibrium is reached and the folate deficiency symptoms are on the mend no single dose makes any noticeable difference. CHRONIC FATIGUE

What CFS symptoms have been corrected with methylation treatment? What side effects have been experienced during treatment? The following symptoms of CFS have been reported to have been corrected by various PWCs on this treatment. Note that these are gathered from reports from many PWCs, so that not all have been reported by a single person.

1. Improvement in sleep (though a few have reported increased difficulty in sleeping initially).
2. Ending of the need for and intolerance of continued thyroid hormone supplementation.
3. Termination of excessive urination and night-time urination.
4. Restoration of normal body temperature from lower values.
5. Restoration of normal blood pressure from lower values.
6. Initiation of attack by immune system on longstanding infections. 7. Increased energy and ability to carry on higher levels of activity without post-exertional fatigue or malaise. Termination of “crashing.”
8. Lifting of brain fog, increase in cognitive ability, return of memory. 9. Relief from hypoglycemia symptoms 10. Improvement in alcohol tolerance 11. Decrease in pain (though some have experienced increases in pain temporarily, as well as increased headaches, presumably as a result of detoxing).
12. Notice of and remarking by friends and therapists on improvements in the PWC’s condition.
13. Necessity to adjust relationship with spouse, because not as much care giving is needed. Need to work out more balanced responsibilities in relationship in view of improved health and improved desire and ability to be assertive.
14. Return of ability to read and retain what has been read.
15. Return of ability to take a shower standing up.
16. Return of ability to sit up for long times.
17. Return of ability to drive for long distances.
18. Improved tolerance for heat.
18. Feeling unusually calm.
19. Feeling “more normal and part of the world.”
20. Ability to stop steroid hormone support without experiencing problems from doing it.
21. Lowered sensation of being under stress.
22. Loss of excess weight.

The following reported symptoms, also gathered from various PWCs trying this simplified treatment approach, are those that I suspect result from die-off and detox:

1. Headaches, “heavy head,” “heavy-feeling headaches”
2. Alternated periods of mental “fuzziness” and greater mental clarity
3. Feeling “muggy-headed” or “blah” or sick in the morning
4. Transient malaise, flu-like symptoms
5. Transiently increased fatigue, waxing and waning fatigue, feeling more tired and sluggish, weakness
6. Dizziness
7. Irritability
8. Sensation of “brain firing: bing, bong, bing, bong,” “brain moving very fast”
9. Depression, feeling overwhelmed, strong emotions
10. Greater need for “healing naps.”
11. Swollen or painful lymph nodes
12. Mild fevers
13. Runny nose, low grade “sniffles,” sneezing, coughing
14. Sore throat
15. Rashes
16. Itching
17. Increased perspiration, unusual smelling perspiration
18. “Metallic” taste in mouth
19. Transient nausea, “sick to stomach”
20. Abdominal cramping/pain
21. Increased bowel movements
22. Diarrhea, loose stools, urgency
23. Unusual color of stools, e.g. green
24. Temporarily increased urination
25. Transiently increased thirst
26. Clear urine
27. Unusual smelling urine
28. Transient increased muscle pain”

How does methylation disfunction cause Chronic Fatigue Syndrome (CFS)?

Rich: 1. To get an isolated case of CFS (I’m not talking here about the epidemics or clusters), you have to have inherited some genetic variations from your parents. These are called polymorphisms or single-nucleotide polymorphisms. We know what some of the important ones are, but we don’t know all of them yet. This is a topic that needs more research.

2. You also have to have some things happen in your life that place demands on your supply of glutathione. Glutathione is like a very small protein, and there is some in every cell of your body, and in your blood. It protects your body from quite a few things that can cause problems, including chemicals that are toxic, and oxidizing free radicals. It also helps the immune system to fight bugs (bacteria, viruses, fungi) so that you are protected from infections by them.

3. Oxidizing free radicals are molecules that have an odd number of electrons, and are very chemically reactive. They are normally formed as part of the metabolism in the body, but if they rise to high levels and are not eliminated by glutathione and the rest of the antioxidant system, they will react with things they shouldn’t, and cause problems. This situation is called oxidative stress, and it is probably the best-proven biochemical aspect of chronic fatigue syndrome.

4. There are a variety of things in your life that can place demands on your glutathione. These include physical injuries or surgery to your body, exposure to toxic chemicals such as pesticides, solvents, or heavy metals like mercury, arsenic or lead, exposure to infectious agents or vaccinations, or emotional stress that causes secretion of a lot of cortisol and adrenaline, especially if it continues over a long time. Just about anything that “stresses” your body or your mind will place a demand on glutathione. All people experience a variety of stressors all the time, and a healthy person’s body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed. However, if a person’s body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low. When glutathione is properly measured in most people with CFS (such as in the Vitamin Diagnostics methylation pathways panel), it is found to be below normal.

5. One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins. If left unprotected, vitamin B12 is very reactive chemically. If it reacts with toxins, it can’t be used for its important jobs in your body. A routine blood test for vitamin B12 will not reveal this problem. In fact, many people with CFS appear to have elevated levels of B12 in their blood, while their bodies are not able to use it properly. The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with CFS.

6. When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins. Also, the levels of toxins rise in the body when there isn’t enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low.

7. The most important job that B12 has in the body is to form methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.

8. When there isn’t enough methylcobalamin, methionine synthase has to slow down its reaction. Its reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles.

9. The methylation cycle is found in all the cells of the body (not counting the red blood cells, which are unusual in a lot of ways). The methylation cycle has some important jobs to do. First, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body. It is not a coincidence that these substances are found to be low in CFS, so that people try taking them as supplements. Not enough of them is being made because of the partial block in the methylation cycle. The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns. The “reading” of DNA is referred to as “gene expression.” Methyl groups prevent or “silence” gene expression. Over-expression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression.

10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with CFS.

11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.

12. That’s the basic biochemical mechanism of CFS. I believe that everything else flows from this. As you know, there are many symptoms in CFS. I won’t discuss all of them in detail here, but here’s how I believe the fatigue occurs: The cells have little power-plants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells. For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.

When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the “machinery” in the little power-plants, lowering their output of ATP. So the muscle cells then experience an energy crisis, and that’s what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances. These have been observed in the ATP Profiles and Translocator Protein test panels offered by Acumen Lab in the UK.

13. There are explanations that flow from this basic mechanism for other aspects of CFS. I haven’t figured out explanations for all of the aspects of CFS, but I do think I understand a large number of them in some detail, and I’ve been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.

14. The involvement of infections by bacteria, viruses and fungi appears to have two aspects in CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of CFS (such as at Incline Village in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.

15. Second, when a person’s glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the observation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.

16. Third, when the immune system’s defenses are down, a person can catch new infections from others or from the environment, and the immune system is not able to defeat them, so they accumulate over time. Dr. Garth Nicolson has found that the longer a person has been ill, the more infections they have, on the average.

17. Other things that accumulate over time are various types of toxins, because the detox system depends to a large extent on the sulfur metabolism, and it will not be operating properly as long as the person has CFS. The body stores much of these toxins in fat, but as the levels get higher, they begin cause problems throughout the biochemistry of the cells. Many people with CFS have been tested for toxins (most commonly the heavy metal toxins, which are the most easily tested) and they are commonly found to be elevated.

18. The longer a person is chronically ill with CFS, the more toxins and infections accumulate in their body, and the more symptoms they experience. This explains why the disorder changes over time, and why some people become extremely debilitated after being ill for many years.

19. The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified treatment approach is designed to do, and so far, the evidence is that it does do these things in most people who have CFS. I recommend that people with CFS have the Vitamin Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment. This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery.

20. The main question I’m working on now is what else needs to be done to bring people to recovery? I don’t have complete answers to this question yet. Many people may recover from this treatment alone, but it is proving to be a slow process, and we will need more time to see how this will work out. It does appear that people who suffer from illness due to toxic molds do need to remove themselves from environments where these are present. The small amount of evidence I have so far suggests that people who have Lyme disease will need to have that treated in addition. I’m not sure about certain viral infections. They may also need to be treated. We still have a lot to learn, but I’m convinced that the mechanism I have described above is the core of the abnormal biochemistry in CFS, and correcting it needs to be cornerstone of the treatment.


Is there a certain amount of vegetables that’s okay to eat (to avoid consuming too much folic acid)?

As to vegetable consumption, I am experimenting. I know of no way to eliminate them and have any kind of a healthful and pleasurable diet. Total quantity makes a difference. Possibly even frequency during the day makes difference. Pre-loading with Metafolin makes a difference. As I have some symptoms that come and go in days, I can experiment and back off before things get severe.

The b-complex might be better off breakfast and dinner, more like 10-12 hours apart. The sleep will normalize after a bit. Good luck in your experiments and keep us posted with what works, now that you have some rapidly responding symptoms that can alert you.

Freddd: I have this [paradoxical folate deficiency] from folic acid, folinic acid and vegetable food source folate. I happen to have what I think is a very nice organic garden. When I started eating a lot of greens a couple of months ago the folate deficiency symptoms started popping up again. I have to be careful how much how often I eat the greens and timing with respect to metafolin. Freddd: I have to take 1600mcg of Metafolin with each meal as well as 1600-2400mcg 3 other times per day to get barely enough Metafolin to reverse folate deficiency from vegetable food source folates.

Freddd: What comes out in the urine clearly isn’t delivered to the cells. So, on the very first dose of Metafolin the just noticeable amount visible in urine of mb12 doubled. Each time I go into paradoxical folate deficiency the amount of b12 in the urine goes up a lot, some multiples of a just noticeable difference. When I took glutathione with 30mg of mb12 unchanged, the amount of b12 in my urine went up to a level approximating that of 160mg with metafolin. So clearly folic acid, folinic acid, vegetable folate, glutathione and NAC all increase urine output of b12 a lot thereby decreasing the amount available to cells.

Freddd: Based on my own and similar experiences of others, 400mcg of folic acid can block 4000mcg of methylfolate in some people, paradoxical folate deficiency 1. If they also have a folinic problem, paradoxical folate deficiency 2 the vegetable folate in food could block another 8000-12,000mcg of methylfolate. Either of these as well as both of these could block all the methylfolate in the diet and 4000-16000mcg of additional Metafolin. These would also induce b12 deficiencies no matter how much was taken of any kinds.

As a vegetarian, would my requirement for B12 be higher than average?

For a vegetarian, I would also suggest that l-carnitine fumarate may make a knock your socks off difference. That teamed with adb12, mb12 and Metafolin will get the mitochondria back to work for most people with CSF/FMS, restore exercise tolerance, allow muscle repair and building, decrease multiple forms of muscle pain and in general restore the muscles to normal function whereas hydroxycbl does no such thing. 2/3s of b12 deficiency symptoms will get worse and worse the longer a person takes hydroxycbl as it has no effects on them. When the energy starts coming back as the mitochondria are restored to functionality and the nerves start working better a person might feel rather stimulated. That passes. If you back away from it every time it starts, it appears to get worse and worse.

There is something in red meat that has a beneficial effect on me and if I don’t regularly consume it my symptoms get worse. What is it?

Red meat contains mostly adb12 and a little mb12. It also contains carnitine which works with the adb12 for energy in the mitochondria. A single small steak dinner can increase your blood serum level of cobalamin by 400pg/ml (2-4 mcgs). It is this variability with food that is one of the factors of making serum [testing for] cobalamin, or bound cobalamin (since adb12 eaten and digested becomes bound) for that matter reliable only as an instantaneous snapshot of cobalamin.


How does B12 effect thyroid issues?

Hypothyroid is perhaps the most frequent co-correlate of b12 deficiency and B12 deficiency is directly linked to causing Hashimotto’s. There have been a number of people operating on the “thyroid” hypothesis based on the direct effects of increased energy (increased ATP production because that is one of the major jobs of b12). They tested and retested and changed doses and all sorts of things and just screwed it all up. The changes from b12 happen much faster than the the T3 and t4 and tsh tests can catch. You are feeling the most common startup effect of b12, an increase in energy. Generally people who don’t over-interpret do better getting through the startup. People who have all sorts of specific explanations tend to get themselves all anxious and that complicates everything. A good percentage of what happens with b12 is that it causes faster nervous signal transmission and more signal gets through with increased performance. Whether something actually intensifies or if its appearance intensifies or some combination should be considered. Mostly it isn’t what people jump on and the thyroid hypothesis has caused considerable trouble for some. Many of these changes in symptoms are phantoms that one can chase after endlessly and fruitlessly.

I don’t know if your application of thyroid hypothesis on this is correct this time for you or not. All I know is that most who make changes based on the thyroid hypothesis end up not being happy with having made the changes. I am hypothyroid and have been since 8-9 years old. I had lot’s of stimulation from startup with methyb12 and a lesser startup with adb12 and no real changes in thyroid at all.

How does active B12 affect adrenal issues?

Rich: One of the central issues in the treatment of CFS that several of the clinicians and researchers are debating is, where do you start? It’s true that most PWCs have HPA axis dysfunction, and many have Hashimoto’s thyroiditis. It’s generally agreed that support for the adrenal axis should come before (or concurrently with) support for the thyroid axis. But should the adrenal axis be supported first, before anything else? And if so, should the support be things like vitamin C and vitamin B5, which the adrenals are known to need, or should it be adrenal glandular extract, or things like ginseng or licorice? Or should low-dose glucocorticoids be used?

People seem to respond differently to these various treatments. One school of thought is that adrenal and thyroid hormones should be given in an attempt to normalize these levels. Another school of thought is that there is a more fundamental metabolic problem, and that the body is compensating for it by lowering the adrenal and thyroid output, so that if they are supported first, this will cause more harm than good. Dr. Cheney has emphasized to me that if a person is in heart failure (as are many of his patients), it is not a good idea to support the thyroid first, because this will place a greater load on the heart.

I have proposed the hypothesis that a chronic partial methylation cycle block is the fundamental biochemical abnormality in CFS, and that glutathione depletion is tied to it in a vicious circle mechanism. I’ve suggested that the HPA axis dysfunction results from improper synthesis of ACTH by the pituitary, owing to glutathione depletion in it. I’ve suggested that the Hashimoto’s results from damage to proteins in the thyroid by its own hydrogen peroxide, as a result of glutathione depletion in the thyroid gland, also. I’ve suggested that the diastolic dysfunction causing heart failure is due to glutathione depletion in the mitochondria of the heart muscle cells, lowering the rate of production of ATP. If all of this is true, then treating the partial methylation cycle block should be one of the first things to do. Perhaps 3 or 4 people have reported that their thyroid function has recovered after they started the Simplified Treatment Approach for lifting the partial methylation cycle block, in a couple of cases quite soon after starting. One person has reported that her diurnal cortisol plot returned to normal from being low after a few months on this treatment. I don’t have a lot of measured data yet on this.

I recommend approaching the treatment of the methylation cycle block slowly, so that all the organs will have a chance to respond and make changes gradually. Some people have started with much smaller dosages than those suggested in the protocol of the Simplified Treatment Approach, and have been able to increase the dosages over time. The longest time anyone has been on this treatment now is nearly 3 years. For some, it has taken this long to begin to experience significant improvement, while others experienced significant improvement in a few months.

I understand the desire of people to get well as soon as possible, but I think it takes time to restore the body’s function to normal if the methylation cycle has been partially blocked for an extended time. In particular, I think this has caused the detox and immune systems to be dysfunctional, and the result is accumulation of toxins and infections over time. The rate at which these can be eliminated is limited, and I think that is a major factor in slowing the recovery.

Does B12 stress the adrenal glands? Rich: I just joined the Yahoo adrenal fatigue group and did a search on B12. I didn’t find any comments there suggesting that B12 stresses the adrenals. There were suggestions about supplementing B12 or making sure there is enough in the diet.

A search of PubMed likewise did not reveal any suggestion that B12 stresses the adrenals.

So far, I haven’t found any hard evidence for this suggestion.

Frankly, it doesn’t seem very plausible to me. Vitamin B12 is an essential nutrient. Every cell in the body needs it, including those in the adrenals. In the hierarchy of treatments for just about any disorder, I would place adequate nutrition near the beginning.

garcia: If you have adrenal fatigue and you detox too fast, additional stress is created for the adrenals.

I feel wired and tired – is that an adrenal problem?

There is a subgroup of persons with “wired and tired”. The lack of ATP for powering the cycle is why I suggest AdoCbl at the same time to ATP going. That often alleviates the the “tired” except that there is no more capacity. Both AdoCbl and L-Carnitine Fumarate appear necessary to cause the mitochondria to grow new ones. I would propose that the sustained effect would be by partial mitochondria startup, because most other MeCbl effects are gone in a few days. The sustained “energy” appears to be ATP startup. One can top off with AdoCbl and that often has a energy startup that fades slowly. L-Carnitine Fumarate is sometimes the one that causes a huge startup requiring titration. Some people have a far more extreme startup and can try a micro-tititration from below any effectiveness. Often people sensitive in a certain way are very bothered by ATP startup and call it over-methylation. This is a difficulty in language when this occurs because if the words don’t convey what is happening. Also, if one is taking only 100mcg or so of MeCbl that is enough to sustain most healing but just doesn’t provide much methyl. AdoCbl doesn’t supply any methylation unless methylation was stalled on ATP block.

How does the partial methylation cycle block affect the digestive system?

Rich: We know from the experience of many PWCs using the baking soda–burp test and salutary results of betaine-HCl supplementation that there is low stomach acid in many cases of CFS. According to the GD-MCB hypothesis, this is due to mitochondrial dysfunction in the parietal cells, which in turn results from glutathione depletion and the partial methylation cycle block.

We also know that digestion is often poor in PWCs. According to the GD-MCB hypothesis, this results from deficient secretion of pancreatic enzymes and/or bile. These in turn result from the lack of sufficient stomach acid to signal the need for the pancreatic enzymes and bile, and from deficiency of glutathione, which is necessary for bile production in the liver.

We also know that there is dysbiosis in most cases of CFS, as revealed by comprehensive stool testing. The lack of stomach acid allows pathogens that come in with the food to survive passage through the stomach and into the gut. In addition, there are abnormalities in peristaltic transport and cleaning of the gut, which allows small intestinal bacterial overgrowth (SIBO). These abnormalities are likely due to deficiencies in production of serotonin and acetylcholine by the gut, which in turn are due to the partial methylation cycle block.

We also know that there is leaky gut, which results from damage to the wall of the gut. The gut does not have its normal protection against oxidative stress, toxins and pathogens as a result of glutathione depletion. Also, the lack of folate inhibits the production of new DNA and RNA, which are needed for making new cells to replace those that die and are sloughed off the lining of the gut. Finally, the immune system is dysfunctional because of the lack of glutathione and folates, which are needed to support cell-mediated immunity in particular. Glutathione is also needed to control the oxidative stress generated by the immune system when it produces inflammation to attack pathogens.

In the other direction, problems in the digestive system can impact the methylation cycle, folate metabolism, and glutathione. For example, if the digestive system is unable to absorb enough B12, such as because of pernicious anemia or because of celiac disease, the methylation cycle will not have enough methylcobalamin as a cofactor for methionine synthase. If the digestion and absorption of other nutrients is poor, the other vitamins, minerals, amino acids and fatty acids needed by these parts of the metabolism can also become deficient. If dysbiosis is present, the gut flora may not be able to produce nutrients that it normally supplies for the body, including active folates. If there is leaky gut, the immune system will be occupied producing antibodies against food proteins, and this will take supplies and energy that may be needed for these other parts of the metabolism.

As a result of this two-way interaction, if the digestive system has serious issues, it will likely be necessary to deal with them directly, while treating to lift the partial methylation cycle block. I note that Dr. Amy Yasko emphasizes this in her full treatment program, in which gut support is one of the early interventions.

Should I fix my digestive issues before starting methylation?

velha508: I have gut issues – which I am currently working on. I worked on my methylation cycle first because

1) I could not think clearly prior to getting my methylation cycle going

2) The methylation block is likely the reason for the gut issues in the first place – that is, contributes to the cascade of events that leads one to end up with dysbiosis (I think anyway). While some may think the opposite is true – once you are in a CFS state your body will not have the energy needed to heal and maintain a healthy gut if you have a methylation block.

3) Getting it going helped and is helping with clearing up my gut issues. With little effort on my part my digestive system has started to come around on it’s own after 4 months on Freddd’s protocol.

I read Myhill’s whole approach about building a house from the ground up and I felt that the foundation was lifting the ‘methylation block’, not fixing my gut… Sunday: I’ve been on the methylation protocol for about 4 months. A few weeks ago, my constant nausea stopped. (Warning: it did get much worse on the B12s before it went away. This seems to be a pattern with my B12 reactions; a symptom gets worse for some weeks, then disappears or is reduced drastically. I still have the occasional bout of nausea, but it isn’t constant. So nice.)

Also, I have started digesting foods more normally, absorbing more of their nutrients. How do I know without extensive testing? Well, for the last year I lost weight no matter what I ate. Now I have started to gain it (never thought I’d be happy about that!). I’m also responding to foods and supplements more as I used to (e.g., I feel a boost of energy after eating protein; my mind clears when take a ginkgo biloba supplement), although I’m nowhere near back to my pre-CFS responses. And my elimination, which used to swing between diarrhea and constipation, is now easy and normal (that got more extreme, too, before it healed).

My experience is that methylation IS the basis of at least a lot of my gut issues. I agree with velha, you might want to consider doing this as the basis of your gut healing, or along with other gut-healing stuff. Or at least just keep it in mind as you proceed. richvank: The best treatment sequence is not easy to determine even if one knows the sequence in the pathogenesis, because there can be interactions.

For example, the development of a partial methylation cycle block may be what leads to the gut dysfunction in many cases. However, when the gut dysfunction has developed, it can lead to poor digestion and absorption of substances that are important to get the methylation cycle running again, such as amino acids. So even though the methylation cycle block may have led to the gut dysfunction, it may be necessary in some cases to work on the gut first. In other cases, the gut may still be working well enough to bring in enough of the essential nutrients, and in those cases, of which yours might be two, fixing the methylation first works well.

Yesterday I had a conversation with Dr. Richard Kunin, the president of the Orthomolecular Health-Medicine Society, a person who has studied methylation issues for many years. He pointed out to me that when methylation goes down, one of the first things to suffer is the exocrine pancreas function, i.e. the part of the pancreas that normally produces digestive enzymes. I did a little literature searching, and he appears to be right. That might be one way (or maybe it’s THE way) that a partial methylation cycle block leads to gut dysfunction.

When you can’t digest food for lack of digestive enzymes, I think the bacteria are going to respond by consuming the food and overgrowing. This may account for low chymotrypsin or pancreatic elastase in some of the stool tests from PWCs that I’ve seen. In the past, I’ve suspected that this might be due to low stomach acid production, which would lead to lack of a signal to excrete the digestive enzymes from the pancreas when the food moves into the duodenum. But maybe the problem really is with the pancreas itself, because of the methylation cycle block. velha: My gut shut down at the same time I became very ill – July/August 09. Digestion just stopped. So, mine has been short term also.

It is hard to say what has helped my gut the most. I can say the I noticed no effect with increasing doses of mB12 and methylfolate (at least not immediate). My gut began to improve in late December. I did a number of things at that time, two being increasing my adB12 (to daily) and carnitine dosages (~4g/day). Suzy: I just wanted to share another possible reason for improvement of gut function on Rich’s or Freddd’s protocol. This abstract shows that oxidative stress can lead to pancreatitis and Rich’s protocol has been shown to raise glutathione in his study.

Superoxide dismutase and catalase: a possible role in established pancreatitis.
Guice KS, Miller DE, Oldham KT, Townsend CM Jr, Thompson JC.

The mechanism of cerulein-induced acute pancreatitis may involve the production of free radicals in excess of the capacity of endogenous intracellular scavengers. These radicals destroy the cellular membranes, releasing digestive enzymes and cellular proteins into the interstitium. Thereafter, a cascade of events, including polymorphonuclear infiltration and complement activation, leads to pancreatic destruction.

The present study demonstrates that superoxide dismutase and catalase reduce the ultrastructural and biochemical injury associated with cerulein-induced acute pancreatitis in rats. Pretreatment with superoxide dismutase and catalase 30 minutes before injury did not appear to be protective, presumably because the half-life of intravenous superoxide dismutase is only 6 minutes. This and similar studies suggest a potential clinical role for free radical scavengers in acute established pancreatitis.


Does B12 methylate mercury causing more damage?

Nicola: The answer you will get on the Cutler list is that B12 doesn’t methylate mercury to any meaningful extent, and that some people need lots of B12. I did over 100 rounds of DMSA / ALA before starting this protocol to reduce body burden, but have still had 3 big herxes since September, and have felt much better since. I could barely tolerate the folate either – even 1/4 tablet made me feel unbearably tired and draggy. I have now worked up to 2 tablets and have much more energetic and optimistic. In my experience the things you react most to are the things you need the most.

Freddd: If you were to read Dr. Cutler on the hypothetical methylation of mercury he says that it happens very readily in a test-tube full of high purity substances but almost not at all in the body with everything in a very dilute living system. In vivo can be very different from in vitro.

He also expresses the idea that if it did methylate the mercury easily it would be to a less toxic form such as in fish and that it would be more easily flushed from the body and would be a good thing, an exactly opposite view of what it does from some other people. Everything I can find research wise in vivo is that there is a slight possibility of methylation.

The indirect research, such as the form of the b12 being excreted in the urine being almost totally unchanged and 99% of total dose excreted unchanged in 2 days indicates that there is actually very little interaction. With something like cyanide, or glutathione that reacts almost instantly and strongly with all the mb12 available the changed b12 pours from the system very visibly in urine almost immediately. So whatever is going on if it is b12 and mercury is something that happens at the extreme low end of the scale equivalent to a tuna-fish sandwich. Whether it has a perceivable effect or not I can’t say.

Is there any point in trying active B12 protocol with 6 amalgam fillings still in my mouth?

Rich: I don’t think the issue of whether to remove amalgams before or after treating the partial methylation cycle block in CFS has been resolved, at least to my satisfaction. I will give you the pros and cons as I understand them.

First, it is kind of a basic principle of toxicology that when you are treating a toxicity, the first thing to do is to remove the source of the toxins. That is sort of common sense, and it’s a good idea in general.

However, the toxicity of mercury from amalgam fillings is a unique situation in that the removal of the source of the toxin tends to expose the person even more to the toxin, because drilling heats the filling and raises the vapor pressure of the mercury, which evaporates and is easily inhaled, because the fillings are located in the mouth.

Precautions such as a good vacuum in the mouth and a separate supply of air to the nose are helpful, but there is probably still some additional exposure to the patient from the evaporating mercury.

This situation is compounded by the fact that often the person’s glutathione level has been depleted, partly by having to detox mercury in the past, as well as due to other causes, so if there is additional exposure to mercury, the person is not in a good status to deal with it, because of their low glutathione, and the result can be more serious toxicity, including neurotoxicity due to entry of mercury into the brain. So all of this argues to lift the partial methylation cycle block and thus bring glutathione up before removing the amalgams.

On the other hand, the continued presence of the amalgam fillings will cause continued intake of mercury, which will have to be dealt with by the detox system, so that in a sense one is working against oneself by leaving the amalgams in while trying to increase the rate of removal by the detox system.

Another factor is that mercury can inhibit the activity of several enzymes in the methylation cycle and related pathways, so that it may be difficult to lift the partial methylation cycle block in some cases unless some sort of chelation treatment is done first to lower the mercury levels.

So the situation is somewhat complicated. I guess I find the first argument most compelling, especially since I have read several reports from people who had their fillings removed initially, even with precautions, and suffered because of it. So I guess I think that generally speaking there is merit in trying to lift the partial methylation cycle block and thus raise glutathione before disturbing the amalgams. But I can’t say that I have proof that this is the best approach in all cases.

If active B12 protocol starts heavy-metal detoxification, is there something I can take to neutralize the metals when they are mobilized?

As well as taking the active B12s I also take DMSA on the Cutler protocol to mop up the mercury that is mobilised by getting methylation going. For me, this makes a day / night difference in how I feel. Without DMSA – fluey, fatigued, crabby, depressed: with DMSA – functional, brighter, clear head. Also with DMSA you know that the mercury is being taken OUT of the body, rather than just redistributed as in the case of other binders. I know that some people are against chelation, for reasons I don’t understand, but it has made the difference to me of being able to tolerate this protocol and not.

What is Freddd’s personal experience with Mercury?

The question itself was of personal interest. I had lots of decalcified areas under braces and ended up with lots of amalgams. As the child of a dentist I also played with mercury. I was likely as contaminated as anybody here except those eating a lot of contaminated fish. What was my danger? Since I went through the first few years of mb12 with increasing doses of mb12 and no adverse reactions, though lots of startup symptoms, there wasn’t anything that wasn’t transitory or caused increased impairment.


327 thoughts to “Active B12 therapy and methylation FAQ”

  1. Hello sir,
    I am having digestive issues, indigestion, gas since 3 years. Last year, one day i suddenly started feeling a rocking, swaying sensation in my body and i felt as if my body is unstable always. Then after 3 months, i got a weird pulsating feeling in my head as if it is vibrating rhythmically when i used to keep my head on pillow trying to go for sleep in complete silence. Although i don’t notice this when i am busy while sitting or walking. In last 3 years, i have visited more than 20 doctors, got MRI of brain, multiple blood tests, endoscopy, colonoscopy etc. Everything came normal except i was found to have gastritis and h.pylori infection. I took antibiotics for 14 days and after that doctors said that my gastritis is now fine and prescribed me PPI for 2 months. I got tested my Vitamin b12 level in last october and it was 158. I got 10 injections 500 mcg each in 20 days and tablets of b12 and folic acid. Still my symptoms didn’t improve and i started suffering from insomnia. In May this year, i found your website and after reading that sublingual b12 are more effective, i ordered Jarrow’s mb12 5000 mcg and took half tablet daily for 4 months. I didn’t get even a little startup symptoms and i didn’t feel any change at all. Now yesterday,my blood test has shown b12 level 1123 which is high but still my digestive, neurological symptoms like pulsating head, imbalance and extreme insomnia persist. Yesterday i also got tested for folic acid and it came extremely low. Now, is it possible that all these Jarrows b12 sub lingual which i took for 4 months remained ineffective only because i had low folate level. Does the deficiency of folate cause all the symptoms which i have mentioned ? Should i start folate now and how much. Is Jarrows methyl folate good ? Is it possible that once i start folate along with mb12, then only b12 will start having its effect and my symptoms will start to heal. Have you ever heard of any such case where taking mb12 for long didn’t help due to low folate level but once intake of folate was started, healing took place. When i visit Doctors, they tell that i am completely fine and treat me for depression and tell me that everything is in my head. I am suffering a lot. Please guide me. You and your website are my last hope.

    1. Sounds like the folate might be worth a try-but start with a very low dose. Any possibility you have mercury toxicity? that’s one that causes a lot of neurological problems that many doctors will miss. A candida infection is another. wishing you well!

  2. Hi Eric,

    I did read the blog on b12 protocol above. When I first started the b12 on Dr. Yasko program, I notice great improvement in my mood and my muscles stopped burning. Years of depression was lifted in 2 days. It worked like a miracle. I notice my liver swelling went down, and i could tolerate little more sulphur food than before. However with continuous use for 1 month on it now, I am noticing depression coming on again with anger. I notice my blood sugar start to go down. Perhaps, that is because i stopped active form of B6. I experienced heart palpitations and gallbladder attack again. I don’t know if this is a healing crisis again with a rollar coaster ride. My worst symptoms are coming back again: gallbladder and low blood sugar dips in the 2 am and then, i go back to sleep at 6 am. Any thoughts?

    1. well, if you started with P5P and then switched to B6, I’d probably go back to the P5P to see what happens!

  3. I keep reading all over that B12 and also folate can make ocd worse… Im very confused. I have tried to educate myself in order to try and treat my severe ocd. I don’t know who to believe, they all so many different things.
    I want to heal the leaky gut and brain, detox both, then take the correct supplementation to balance the brain again. Im so overwhelmed with info, no idea who is right and where to start.
    I also live in the UK (manchester) and there doesn’t seem to be anyone specialising in this area anywhere within my reach. Any advice please? Id really appreciate it. Thanks

    1. Anne, you know Pyroluria is a very common affliction associated with OCD. You might just ask your doctor for plasma zinc and b6 bloodwork. If they’re low, you’re on the right track and might find relief quite easily with zinc and vitamin B6 supplementation…

  4. Supplements are not working, I believe I am not absorbing them due to leaky gut/brain. If you believe this ([please dont slam me if you dont, Im tired of ‘experts’ calling it quackery and replying with arrogant emails… thanks)
    I want to know how to cleanse, heal and then introduce the right supplements to cure my extremely disabling ocd; I am desperate as nothing works (CBT, medication). I am fighting suicidal depression because my life is a living hell and cannot afford private treatment.

    1. What have you tried? Tried SAMe?

      There are a couple of inexpensive treatments that seem to work for a wide array of illness like liver flushing, chlorine dioxide and hydrogen peroxide…

      hang in there Anne!

  5. I’d be remiss not to mention that by far the best form of B12 I’ve come across – in terms of ease of use and uptake/effectiveness – is the transdermal oil made by in Australia.

    It’s $AU40 per bottle. You get 80% uptake, so can drop the dose from the sublingual. The effect is much ‘smoother’. And no more rotting teeth.

    It comes in methyl or adenosyl or both.

  6. Hi, I have low b12 , ate mostly fish diet, and took cyanocobalamin. Experienced nerve pain, vision issues and palpitations. In doing some research I determined it was cobalt poisining. Your article seems to say that it’s the body adjusting to the b12. But no specific mention of cyanob12. I’m afraid to try again. Dont want to poisoin myself. Any comments?

    1. I don’t have the time to go back and search right now but I am certain Fred warns against using the cyano version. I think there’s some relation with cyanide which obviously doesn’t sound good does it?

  7. Hello what about pure enscapsulations they are gmo free but B12 is derrived corn dextrose fermented please answer.
    Do you recommend this supplement? B12 as methycobalalamine?

    They are hypoallergenic but i dont know will they help? what is YOur opinion about pure enscapsulations B complex and which one would you use for B12?

    1. hi Adam, yes, we use the pure encapsulations B complex in my house… and I use the Jarrow for mb12.

      1. 1. I think zinc picolinate is one of the best forms. His opinion about picolinates is negative i dont know… Please read this article.

        2. Do you use B complex plus with b12 from pure enscapsulations? This B complex already contain B12.

        3. Life extansion supplement contain stereates what is your opinon about life enxtansion supplements?
        Please check this What Ya think?
        4. So B12 from pure ensacpsulations is OK? it is corn derived form fermented dextrose althought gmo free corn and it is already labeled.

        Thank You Very much for sharing the info.

        1. Pure encapsulations B complex does contain vitamin B12 but the amounts are very small so I would add additional MB12. Generally speaking I like Life Extension – their research is great. I have not researched stearates but do think it would be extremely difficult to avoid them.

          1. the dose is very small but is 6,667% really small?
            Are you swallowin the pure ensc capsule or under tongue? I have red that under tongue absorbtion is just 5%, so what about the best method to take the supplements

  8. Just discovered this. After a long journey (Hashimoto’s, adrenal fatigue syndrome), I think B12 deficiency might be one of my major remaining issues. I’m taking MB12 and AB12, but not sure I’m doing everything right. Is there anyone out there available for personal advising, consultation, etc.?

    1. mB12 & Ado B12 are not much use swallowed. You get about 5% uptake if you take them sublingually. And transdermal (rubbing on the skin) gives you ~80% uptake. Most people need to ensure they get enough B2 to make the B12 work – “It’s not a B12 problem: it’s a B2 and B12 problem.” (“It” being CFS & a host of other illnesses.) Plus enough C, Se & iodine (cooking with iodised salt is enough).

      The most effective transdermal B12 is sold by the Australian company B12Oils. The chief scientist (& owner) there, Dr Greg Russell-Jones, has studied B12 & CFS for 25 years, & is very generous with information by email.

      1. hello it is best to take B12 sublingually
        B complex are water soluble
        so it does not really matter when you take it
        it does not have to be with a meal
        just needs a good amount of water

        do you agree with this person who wrote this above?

  9. Hi Eric. I have been using this page a lot to find information, as I was clueless about many things regarding methylation. I have learned a lot from you, so thank you for that!!
    I have started the B-complex from Pure Encapsulations with very good effect. I want to start higher doses of Methyl B12, what I dont understand is this:
    The B-complex already contains 800 mcg (if taken twice a day), do I also need to take an additional 800 mcg on top of the B-complex, when I have reached the higher doses of Methyl B12?

    1. sorry, I don’t understand your question. I don’t take the B complex myself since I take individual B vitamins. The amount contained in the B complex is very low compared to the 5 mg MB12 that I take daily.

      1. So you take 5mg?
        Why so much and how long will you take?

        16000percent of the recommended dose labeled on the package (b complex) is this not much?

        1. I just reduced my dosage from 5 mg to 1.25 after several years. I believe it was contributing to my gut infection has be 12 feeds bacterial and fungal overgrowth… I’m hoping that even over-driving methylation was a good thing for a toxic person like me.

  10. OK, I’ve been doing really great! So . . . I decided to try to add in a small amount of adenocobalamin. The pills are from Seeking Health. 4000 mcg of Methylcobalamin and 1000 of adenocobalamin. All was fine for a day or so and then suddenly I’m back to getting very intense hot flushes all over my body, which have gotten worse. Also getting a weird tightening in my throat and feeling that I can’t get a full breath. I’m ready to stop and go back to the just the Methyl . . . but do you think I should try to weather this out? Been on these for 2 weeks. It’s getting very uncomfortable! Thanks for any advice you can give!

    1. if it were me I would probably try to cut the adb12 in half and try to ride it out that way… good luck!

  11. Eric
    I’m sure I read SOMEWHERE HERE that Adenosylcobalmin helped brain function in some small way, but I cannot find it now and maybe I just dreamed it. I have an elderly friend who could use some help in that department but I can’t send it to him if I can’t find it.
    Does that sound familiar to you?
    He is taking a lot of MethylB12 but that is all.

    When you have the time, will you let me know?

  12. Are you available for private consultations? It sounds like I’m a strong candidate for this therapy, but I’m sometimes overwhelmed by the sheer volume of information. I wonder if I could hire you, or prevail upon you for a bit of your time by telephone, to answer questions about how best to proceed.

    1. Sorry I’m not, struggling to just stay afloat with my own illness, my wife’s and my daughters lol…

      1. What about pure enscapsulations B complex, the best way to take?
        Before meal or after meal? 1 or 2 hours? Or put under your tongue?

        What ya think about to put into yoghurt the yellow B complex powder from pure enscapsulation capsule and after 12 hours eat the yoghurt?

        The same with zinc from pure ensca. the best way to use? With meal or seperated?

        Please answer as fast as possible 🙂

        1. We take those with meals… why would you put it in yogurt and let it sit? I also take zinc with meals – believe it’s hard on the stomach otherwise.

  13. Hi: I appreciate all the information you’ve gathered here. I’m looking into a low sulfur diet and your list will be helpful. I was sad though because there’s not much on there I normally eat so it is a bit step for me. I had a question on the B complex you mentioned. You said it had all the active forms of vitamin b (Pure Encapsulations) but I can’t find this one on the label: AdenoslyB12 also known as adb12 or adenosylcobalamin or dibencozide Do you get that in another supplement? Thanks.

  14. Thanks for the precious summary. I’ve been following your advices and now taking Active folate, mb12 with Potassium, Zinc, Magnesium and Calcium without any problem and little side effect.
    Introduced today 3mg sublingual abd12 and got severe side effects (nausea, extreme tiredness…). I know the dose could be high for the first adb12 pill i’m taking but I’m wondering if this side effect doesn’t mean that I don’t need it and should stop taking it? Reducing the dose might improve side effects, but those side effects are really a sign that there is a lack of adb12 in the body?
    I’m really worried to continue taking it if this could be harmful and the side effect is a sign that I don’t need it. Any advice?

    1. the adb12 side effects only lasted a few days for me and my understanding is that’s fairly normal. I think ADB 12 is considered the easiest to get through. I had very strange effects from it, but all gone and I take it every day now.

  15. Eric, thank you for all of the valuable help you gave me a few months back. I’m now 7 months into supplementing and my body has improved beyond my highest hopes. It is a journey though, and what I love about this page – the best on the internet IMO – is that it tells the truth. If someone is deficient you WILL get worse before you get better.

    Your symptoms will be triggered and if we can just power through them the light is on the other side. After reading this I learned to be thankful as my symptoms worsened. It felt like my body is a computer and the B12 was going through each and every file and rebooting them. I still have a few remaining symptoms, I wonder if some may be permanent. But I went from over 50 active symptoms to less than 10 minor ones. Feels like a miracle and I thank you for posting this. I hope that people read it over and over again, do what it says. Maintain high potassium levels, expect worse symptoms and have patience. It is worth it!

    1. wow, congrats JB!! reading your note gave me goosebumps, very happy for you… – Eric

  16. Hi,

    What a thing to read – thanks for compiling this informative article. I have a question, though.

    I have suffered with vague and mysterious symptoms for practically all my life, certainly the last two decades (Im 35 now). After going through every test I could imagine and being declared clinically healthy (yet feeling like crap), I identified b12 deficiency as the most likely culprit. My serum b12 measured recently was 205 micromol/l, which was just within the lab limits, but I read that you can have problems similar to mine at this near-low level.

    I have all the b12 def symptoms – fatigue, poor sleep and recovery, gastrointestinal problems, occasional twitches and spasms, paresthesias in limbs and tongue, not to mention my unhealthily pale skin.

    A month ago my GP started me on weekly b12 injections (1000 mcg cyanocobalamin – I couldn’t get shots in any other form). Apart from that I use 2×1000 mcg methyl b12 oral tablets from Jarrow formulas daily. I later also ordered 3000 mcg adenosyl b12 tablets, but they have not yet arrived.

    I was expecting to see a rapid and significant change, but after 4 shots and about 50 tablets I can barely say Im feeling better. A little better, maybe, but not anything like what I expected. Im starting to think that b12 def is not my issue after all and I need to look further.

    Having read the article, I realize that this is not a very aggressive therapy and maybe higher doses could yield better results. But still, how soon would you expect improvement with this regimen? The only thing I can say is that my paresthesias are getting more noticeable, from occasional transient pricking to almost constant pins-and-needles sensation on my palms and soles of my feet. Im not sure if this is a good thing or not. Though after what I read from various sources Im not worried that b12 supplementation in the doses I use could do me any harm.

    Thank you in advance for any advice,

    1. you might try doing solgar methyfolate 1000s sublingually together with the jarrow 5mg mb12s, split up a couple times a day to see what happens…

    2. I had b12 deficiency, anemia, and neuropathy with levels in the 300s. It took me several months for my weekly cyano shots to kick in. I had neuropathy for a year prior to shots and it mostly improved around month 9 of shots. It’s still iffy if I stop the shots.

      I don’t know how you will react to more aggressive treatment, but for me 1000 mcg methylfolate and 5000 mcg methylcobalamin was majorly destabilizing. It’s definitely high dose. I cannot tolerate anything methyl. I like hydroxocobalamin.

      That said, some people like it. You may tolerate it, just beware of the potential for side effects and keep an eye out.

      Have you been checked for PA or malabsorption? Are your other nutrients like iron and magnesium, etc, ok? Thyroid function? My doctor says those affect b12. Is your non-fasting blood sugar healthy? That was a big contributor to my neuropathy.

      It’s probably a good idea to recheck with your doctor and a neurologist in the meantime.

      Good luck.

  17. Eric, I would like to thank you for this extremely professional and hard work you putted on this article. It sheds the lights on what could be the reasons of my unexplained CFS since 12 years.
    In your opinion, what are the best lab tests (serum,urines) that could be done to justify the start of such treatment? (knowing I already have seen in my DNA that I have homozygous MTHFR (C677T, CBS (+/-) & MTRR (+/-) mutations.)
    I would not want to start this natural treatment and create further imbalance that would lead to further damages.

    Thanks a lot

    1. Michael, you’re asking the wrong guy – I’m not a big fan of lab testing. I remember reading very often about people who are clearly B12 deficient that have very high B12 lab levels – probably serum. I think the DNA testing is enough to experiment. But that’s just me and it’s partly because my funds are limited. If money was no object, I would know a lot more about the testing aspects. It just seems that the tests covered by insurance are often the ones that are considered unreliable.

  18. Great resource Eric- I have landed on this blog a few times in my searches and come back to this page in particular a few times.
    I think the mental reframe of healing/ startup symptoms vs detox is a very useful one. The approach of titrating and staying with a dose through the symptoms rather than stopping and starting over sounds good.
    I have had a few disastrous attempts at B12 and /or MTHF supplementation but have since found a great practitioner and have had a few months of stabilising/ inflammatory control . Starting again on MTHF this week, then eventually B12 so very timely, thanks

  19. Hey man! I just read this article for the second time in two days. Trying to absorb as much info as possible. Exactly one month ago, due to a suspicion of methylation issues, I began supplementing a product from Seeking Health called Active b12 w/MethylFolate. Before then I had been using TMG for months and was really focusing on my liver. Within the first week of starting active b12’s and continuing my daily regime I felt great and then, as described in your article, I hit a wall. Mood decreased, constantly wanted to sleep, had absolutely no energy and isolated myself from my family and friends. This went on for about a week and then got better. My question is since I’m seeing success with this particular supplement should I stick with it or should I transition into the supplements you recommend and experiment with higher dosages? If so what should I start out by taking? I’m not in terrible condition, but I’m by no means heathy either. Thanks!

    1. if it were me I would want to experiment with higher doses… I don’t know anything about the supplement you are taking but generally speaking I try to avoid multivitamins because you want to know what impact each component is having on you.

      1. Hi, how long the tirednes period is about to last? I think mine has lasted some weeks already. I started around Christmas time and first weeks it was fine, but recently things have turned around;

        Taking one per day of this:

        One half per day or two quaters per day of this:

        Every second day one of these:

        So it’s the basic set.

        I also experienced those symptoms Brad described about isolating oneself due to tirednes. Is it dangerous to stop taking the supplements? And if on the other hand if raising the dose, when one should finish?

        1. You probably shouldn’t be taking that country life dibencozide… if I remember correctly it has folic acid. if you’re having a hard time, you can always reduce your doses and titrate up more slowly. Everyone is different and there are no hard and fast rules.

    1. yes but I can’t do it by email, as emails get lost in my firehose stream of email. If you post questions here they won’t get lost.

      1. Hi sir, 8 months ago in May 2015, one day i suddenly felt like having a brain fog. in next 2-3 days, i used to feel shaky all the time, it felt like the ground is shaking. i was not able to sleep for 2 days. i went to neurologists and got a mri of brain and cervical spine, thyroid and blood glucose test. everything came normal. i also got ecg and other heart tests and everything came normal. they gave me escitalopram and some other sleep medicines. in 2-3 days symptoms lessened and i became normal except having unstable feeling while i was standing or changing sides while sleeping. Then, suddenly after 4 months in august, i again started feeling unstable while resting or relaxing. i went for a B12 test and it came as 158. doctor sggested 10 mecobalamin injections on alternate days i.e 10 injections over 20 days. then, continuous methyl cobalmin tablets 1500 mcg for 4 months. i took all the 10 injections and after that i have taken tablets for 4 months continuously. my brain fog has simproved but that shaky and unsteady feeling while sitting, relaxing and sleeping is still there. it causes a lot of problem in falling asleep and also my sleep gets disturbed after 3-4 hours. my vitamib b12 level is 520 now. so, now i am very confused whether my symptoms are indeed due to vitamin b12 or anything else because vitamin b12 level has increased still my symptoms have not improved. i have extreme poor digestion and other abdominal problems, discomfort, high sgpt since 2 years. when i go to neurologists, they say i am perfectly fine but from inside i know how much suffering i am going through. my symptoms are such mysterious that i am also unable to explain it properly. when i go to sleep i telaxed state , whole body feels like shaking and floating. doctors think it is pyschological problem and send me back prescribibg anti depressants. plz help me.

        1. If you have poor digestion and abdominal problems, that’s where I would start! first with a bowel cleanse like bentonite and psyllium, then antiparasitic’s like humaworm and maybe after that some kind of juice cleanse… If you can get a hair test, that’s also a good thing to do. Often heavy-metal problems lead to digestive problems.

          If your brain fog improved with methylation therapy, you probably want to continue in some form. You may want to get some of the Jarrow 5 mg sublinguals and start out with one quarter in the morning and one quarter in the afternoon.

        2. Shaiesh, Have you considered testing for heavy metal poisoning or bacterial infections such as lyme and other tick bite Co-infections?

  20. Hello! I received my bloodworm and it shows large red blood cells, anemia… yet my iron was high and my b12 was EXTREMELY high. They ran more tests and can’t figure out why my cells are large. I also have b12 deficiency symptoms. My doctor just called and said try a sublingual under my tongue, once a week…. Do you recommend anything else? I don’t see on this website people with high b12 serum…. i think i have an absorption issue. My blood test definitely didnt show I was deficient but i don’t think its getting into the cell. Any thoughts>

    1. my recollection is that it’s very common for people with b12 deficiency/methylation problems to have high serum b12…

  21. Hi there,
    Thanks for a wealth of info here. I’ve stated Freddd’s basic protocol. I’m two weeks in and struggling to know if I have startup symptoms or folate insufficiency. How can you tell? I drink tons of coconut water for potassium. I attempted higher 5mthf today and just felt really yucky . It doesn’t speak to me as being helpful or not. Any suggestions would be great? I can’t find a right methylcobalamin to methyl folate ratio at all. Thanks so much!

    1. it’s not one or the other. if you have folate insufficiency, you will get startup symptoms… so you probably have both.

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