Copyright August 2002. Kd. last updated 8.25.05
This is a discussion which tries to outline the points of methylation and establish some relationships that will result in the practical application of the information. Special thanks to andrew who contributed many links and much understanding to this discussion.
This link has a nice picture of what this process looks like. You may want to refer to it often during the following discussion. http://www.nutriwest.com/articles/homovmsm.htm
The issue of a person being an under or over methylator can be confusing. It may not be one of the all time critically defining issues, but it may help in the general sense. Several common supplements often recommended for those with autism spectrum conditions are involved in this process (this is just one of the processes these supplements may help with).
A "methyl" group is simply one carbon connected to three hydrogen atoms. It may be written as CH3 with the 3 being a subscript.
"Methylation" is not just one specific reaction. There are hundreds of "methylation" reactions in the body. Methylation is simply the adding or removal of the methyl group to a compound or other element.
So why do we care about methylation at all? In general, when some compounds receive a methyl group, this "starts" a reaction (such as turning a gene on or activating an enzyme). When the methyl group is "lost" or removed, the reaction stops (or a gene is turned off or the enzyme is deactivated). Some of the more relevant methylation reactions would be:
1. getting methyl groups "turns on" detox reactions that detox the body of chemicals, including phenols. So if you are phenol sensitive, and you increase your methylation, then theoretically your body can process more phenols and you can eat fruits without enzymes!
2. getting methyl groups "turns on" serotonin, and thus melatonin, production. Therefore, if you are a under-methylator, you can increase your methylation and have higher more appropriate levels of serotonin and melatonin. This means you may not have to take SSRIs, or may have improved sleep.
3. if you are an over-methylator you can take certain supplements to decrease methylation and perhaps turn off reactions that need to be off. This may decrease aggression or hyperness, for example.
This is the general idea. To what extent this actually works in real life for any individual is back to "every one is different." But this is one thing that the Pfeiffer Treatment Center really looks at. I hope this explanation helps.
Something to note is that everyone is not EITHER an over OR under methylator. There are more groups than that, and you may be just fine in regards to methylation. Even if the Pfeiffer statistic is exactly correct when they say 45% are under-methylators and 15% are over-methylators, that totals 60%, so almost half the people are
Where this MIGHT be helpful would be in picking supplements. So someone may do badly on the high B6 protocol. If that person does badly on TMG or DMG too this may be a clue that they will do poorly on ALL the methylation precursors so they can steer clear of that group in high doses. And vice versa, if they did really well with one, then they may also do well with others in the group. Of course, they may not see additional benefit if the methylation process is fixed with the first supplement, but it is something that might help a person know why they or their child is consistently doing well or poorly with a group of supplements.
Is there any evidence to support this? Well, I am looking at the ARI data gathered from over 18,500 parent surveys. Let's say Pfeiffer is exactly correct and under-methylators are about 45% of the "autism" population. These are the values for the precursors for methylation:
- calcium 39% saw improvement
- DMG 43% saw improvement
- Folic acid 44% saw improvement
- B6/mag (both of these are precursors) 46% saw improvement
- Zinc 43% saw improvement
So if you look at any of the precursors, really, most are around that 45% mark of under-methylators (calcium was a little low, but it is a supporting element). So we have a mark of consistency here. SAMe, methionine, and B12 were not choices. What this does NOT point out is which came first. Was zinc low for some reason not related to methylation and because it was low, methylation dropped? or are you a genetically low-methylator to begin with and do not utilize the nutrients at hand well? Or was folic acid the bottle-neck? or
magnesium deficiency? Or an injured gut which cannot adequately absorb any of the nutrients? or....
This is how I see it, just as a general guideline that may be helpful, not a cast in stone type of thing.
Where do SAMe, methionine, folate, depression,
and all that other stuff fit in?
Please refer to the diagram at the link given:
The basic cycle works like this. Methionine is an amino acid that occurs naturally with all protein foods. Meats and dairy are especially high in Methionine (as they are higher in protein and thus, all amino acids). Methionine enters the body. Notice that this amino acid contains a methyl group as indicated in the name - METHionine.
At some point, the methionine gets in touch with some energy in the form of ATP and magnesium, and becomes SAMe. SAMe travels throughout the body delivering a methyl group to any number of reactions (at least over 400 identified ones). The methyl group allows other metabolic pathways to "go" or work properly. [We will skip the SAH part of the diagram.]
~ So, methionine + ATP/magnesium = SAMe
After SAMe delivers the methyl group, it becomes homocysteine.
~ SAMe minus methyl group = homocysteine.
Homocysteine is ready to accept another methyl group which transforms it back into methionine.
~ homocysteine + methyl = methionine
Remember that methionine + ATP/MG = SAMe. And this is how methyl groups are transported throughout the body.
However, if there are not enough methyl groups to add to homocysteine, then the homocysteine levels build-up in the body. This is bad. Very bad. Elevated homocysteine levels are associated with heart disease, poor circulation, degenerative illnesses, and other unpleasant conditions. So we must get homocysteine levels down.
Where can homocysteine get some methyl groups so it can transform into methionine? One pathway is from folate+B12. A different pathway is from TMG (or betaine, DMG). Either of these pathways can give a methyl group to homocysteine. Some people may make better use of one pathway over another so this is why several of these precursors are often recommended together. Choline is another possible methyl donor. MSM MAY be a methyl donor but research has not confirmed this.
An alternate way to keep homocysteine from building up is with B6/magnesium. This is a transsulfation pathway that converts homocysteine to cysteine.
~ Homocysteine + B6/magnesium = cysteine
Some more conversions happen in this pathway including making glutathione and taurine. One step is adding molybdenum and continuing on to convert toxic sulfite molecules to really helpful sulfate molecules. The sulfate then goes throughout the body doing both wonderful building up work, and detoxing harmful chemicals (such as heavy metals and phenols).
Cysteine is real interesting. It is a thiol (meaning it contains sulfur) and its side chain is used on enzymes and it is also responsible for the 3-dimensional stability of enzymes.
Over-methylator and Under-methylator
The Pfeiffer Treatment Center identifies two different supplement regimes depending on if you are an "over-methylator" or an "under- methylator." These are VERY rough estimations and nothing concrete...they may not be accurate either; further research is needed.
Q: How can you find out if you are over or under?
A: Histamine levels may be a good indicator of whether someone is an over or under-methylator.
Low histamine points to over-methylator: If your histamine level is low you are probably an over-methylator (according to Pfeiffer research). This means that many supplements would be detrimental to him (those containing methyl). These would include taurine, GABA [both precursors to methyl activity in the brain], folic acid, B12, B6, DMG, TMG (and SAMe) - to name a few.
Q: What test checks histamine levels?
A: There is a blood test to measure histamine. Your pediatrician can do it.
Q: How can I lower the histamine level, and the results of a histamine reaction?
A: Some people who have trouble converting sulfur to sulfate (PST issue), and who have a sensitivity to certain foods and chemicals because of this, often times develop a high histamine level. My son develops a runny nose as a reaction to this problem. Benadryl helps my son with this, and anything else that lowers histamine would help him, also. I think the Feingold Diet, No-Fenol, or avoiding certain phenolic and high salicylate foods may help the sulfation problem and subsequently lower the high histamine level. Benadryl and Pepcid AC are histamine blockers. This might explain why Pepcid AC is so effective on some kids. A few parents have reported that a histamine reaction with certain foods did not happen when No-Fenol was given with those foods. MSM or Epsom salts also supply sulfur to the system and may be helpful. Some people cannot convert the sulfur in MSM to the needed sulfate form although other people can. Epsom salts supply sulfur in the sulfate form directly. Taking MSM or Epsom salts may alleviate a histamine reaction.
Q: What amount of B6 is considered "high"?
A: From the site http://www.methylmagic.com/faq.html
Some supplements have lots of B6 (e.g. 100mg) and the author usually aims for between 20 and 50mg per day of B6. Excess niacin (B3) is metabolized by methylation and thus uses up methyl groups. Also aim for 50 mg or less. These values are likely for an adult so a child needs much less.
According to Pfeiffer, "Actually excess niacin (B3) is metabolized by methylation and thus uses up methyl groups." So if you are an over-methylator, meaning you have extra, then B3 is good because it uses them up, but if you are an under-methylator, meaning deficient, then giving extra B3 is bad because it drains an already poor supply.
Frequently Asked Questions
Q: What do we really need for methylation to prevent or treat depression? - vitamins, TMG or SAMe?
A: People need folate, B12, B6, TMG and zinc whether or not they use SAMe. SAMe will not replace all the actions of any of these. All SAMe provides are methyl groups (expensive but also direct and efficient methyl groups), adenosine and methionine. Many people who "need" SAMe actually are low in precursors (e.g. methionine, folate, B12, B6, TMG and zinc). If you take SAMe, these precursors will help you recycle it, and should reduce the amounts of SAMe you need to take. (extra methionine is probably unnecessary as long as you have good protein sources in your diet and as long as your digestion is good).
Also note that for depression several aspects of biochemistry come into play and a depressed person should want to handle all of these. Three key areas:
1. Fatty acids, e.g. fish oil for membrane fluidity this helps receptors, etc. to function.
2. Methyls, e.g. folic acid, B12, B6, zinc and TMG (and SAMe) for membrane fluidity as well as for dopamine metabolism, acetylcholine and epinephrine production etc.
3. Amino acids, e.g. protein or supplements such as 5- hydroxytryptophan (5-HTP) for the starting material for neurotransmitters including dopamine, serotonin, epinephrine etc.
Q: What about MSM (methyl-sulfonyl-methane) as a methyl donor?
A: Despite having looked in the literature, the Methyl Magic manufacturers have not yet found out if MSM acts as a methyl donor. It may be fine and just that no one has done the experiments. Some of MSM's properties may be due to methylation but we just don't know. MSM is apparently a good source of organic sulfur. TMG (betaine) is a good methyl source - TMG works and is inexpensive.
Q: How does high dose niacin (vitamin B3) fit in with methylation?
A: Actually excess niacin is metabolized by methylation and thus uses up methyl groups. One source suggests to aim for under 75mg (usually ~50mg) of niacin+niacinamide per day from supplements. If you are taking large quantities of B3, please get your homocysteine and SAM checked to make sure this niacin isn't excessively taxing the methyl metabolism. Likewise some supplements have lots of B6 (e.g. 100mg) and between 20 and 50mg per day of B6, or less, might be better.
Q: Why would someone necessarily be deficient in methylation other than a lack of the proper nutrients? Is there a genetic variation serious enough that a person with sufficient vitamins would still suffer from insufficient methylation?
A: There are genetic variations that make some people especially deficient or "slow methylators". There are several kinds of such people and variations i.e. several genes and the enzymes they produce that can be inefficient or even missing altogether. In extreme cases these can cause homocysteinuria. Usually these can be handled with a combination of folic acid, B12, B6 and TMG. With some, but not all of these variations, extra amounts of the cofactor (e.g. folate) will compensate for the inefficient enzyme. Other times you need to rely on the other pathways e.g. TMG, and B6 pathways when the folate+B12 pathway is missing. Today we know that zinc should also be in this supplement combination. For people with these more serious deficiencies very high levels of folic acid (e.g. 5 milligrams/day) and TMG (e.g. 6 grams/day) are usually needed. There are some types of genetic deficiencies where SAMe is the specific needed supplement although these are less common (according to conventional wisdom) than those needing B6, folic acid, TMG etc.
Contradiction with information from Pfeiffer Treatment Center
There is a contradiction between the majority of the information on methylation and the description on the Pfeiffer Treatment Center web site. The precursors that go into the methylation cycle for SAMe/neurotransmitters/dopamine/serotonin are methionine, folate, B12, B6, TMG and zinc, and maybe some calcium and magnesium.
So, logic follows that if the one of the precursors is limiting (low), then methylation would be limiting (low) and the neurotransmitters and resulting pathways would be limited (low). This also supports the use of SAMe and the precursors as being effective for depression (because they increase neurotransmitters which improve mood).
But the Pfeiffer information does not follow this. From the Pfeiffer site http://www.hriptc.org/BioTreatment.html in regards to depression and neurotransmitters, one sentence says: "Over- Methylation: Many persons who suffer from anxiety and depression are over-methylated which results in excessive levels of dopamine,
norepinephrine and serotonin."
Over-methylation would result in excessive levels of the neurotransmitters listed, but this is not necessarily consistent with depression (I don't know about anxiety). The other references say that under-methylation results in depression.
The next sentence from Pfeiffer says:
"Typical symptoms include chemical and food sensitivities, underachievement, upper body pain, and an adverse reaction to serotonin-enhancing substances such as Prozac, Paxil, Zoloft, St. John's Wort, and SAMe."
It would seem that over-methylation would be adversely affected by MORE serotonin, SAMe, etc, because the body already has too much of that stuff. However, I could also associate the food sensitivities and underachievement with depression.
Continuing with Pfeiffer: "They have a genetic tendency to be very depressed in folates, niacin, and Vitamin B-12, and biochemical treatment focuses on supplementation of these nutrients."
This part is the opposite of other references. The folates and vitamin B-12 would be precursors, so an over-methylator should not be deficient in precursors. A person deficient in precursors should be low in methylation. Pfeiffer may have different information...or it may be more complicated and the short summary on their web site is not conveying things right. So, either something is missing, one of these is not quite right, or something else is going on, but at least this explains the inconsistency between Pfeiffer and other sources.
Pfeiffer is saying that B6, TMG, DMG, SAMe and SSRIs (medications that increase serotonin such as Zoloft and Prozac) are good for those with low methylation, but B12 and folic acid is not (even though folic acid and B12 are precursors too). However, the other sites say that ALL of those nutrients listed are precursors or otherwise aid in increasing methylation. Pfeiffer is splitting out the folic acid and B12 from the others for some reason. Andy Cutler made a comment at one point saying that Pfeiffer may be using these terms differently and may be referring to specific aspects of the methylation cycle
I called the Pfeiffer office and the answer was that they would be happy to answer the methylation question and discuss it for $90. I explained the situation, and the receptionist said no problem, but it would cost $90 up front. If someone is currently a patient of Pfeiffer, then maybe they could ask at their next visit or conference call.
This is the question that needs to be answered by Pfeiffer:
"If folate (folic acid) and B12 are two of the precursors (as are B6, TMG, and maybe zinc, magnesium and calcium) why would a deficiency of folate and B12 indicate OVER-methylation. Wouldn't a deficiency of the precursors also mean a deficiency of the end products or low/under methylation?"
So what does this have to do with enzymes or
If you are GFCF this probably becomes much more of a concern because you loose primary sources of the B vitamins including folate and B12, amino acids and minerals; then you get into adding all that stuff back in individually as supplements. By taking enzymes, you can eat the whole grains and dairy which are excellent sources of those things plus anything you eat will likely be better digested and absorbed with enzymes. So you get more actual nutrition from your food and any supplements you take. This is not about some mythical function but taking advantage of rate limiting processes and providing a nutrient that removes the rate limit. There is quite high B12 in milk. If you have an injured gut by any means, you sharply reduce your ability to absorb B12. If you go grain and dairy free in addition to this, you are very likely to be B12 deficient.
This explains why some people do so much better on enzymes as well. Enzymes are supplying better nutrition and correcting multiple pathway hurdles throughout the body all at the same time. Many of the treatments and supplements recommended to those with autism conditions are targeted to one pathway at a time, or aim to correct a pathway by supplying all the needed precursors individually.
One technique of giving high doses of taurine (as done by Dr. Bradstreet) has an effect of improving digestion. Taurine is needed in bile production…bile improves fat digestion and digestion in general. If you take enzymes to do this digestion, then you are more directly accomplishing the same thing as the taurine supplementation. You also get the added bonus of improving all nutrient uptake at the same time, including better uptake of taurine from food. So you improve the faulty pathway in both directions.
Other commonly suggested supplements include NAC (cysteine), glutathione, molybdenum, sulfur/sulfate, melatonin, and serotonin. If you can get the methylation working properly, you may not need to add in all these components separately. The melatonin and serotonin come from SAMe function. Too much B6 may deplete this. Having a good source of methyl groups plus methionine in the diet is a good way to improve serotonin and melatonin supplies.
Why do we see the constant trend of people with phenol intolerances having bad reactions to high B6 supplements?
This seems to go back to the methylation cycle. If you look at the diagram at the link given above, you see that B6/magnesium converts homocysteine to cysteine. However, in order for the cysteine to be converted on you need sulfation to be working properly. Those with faulty sulfation processes are not able to do this well and too much cysteine accumulates. Cysteine has excitatory properties and can even be toxic in high amounts. So supplying B6 increases the cysteine supply where it gets stuck in the pathway and accumulates.
This also explains why if someone did okay with high B6 or even TMG and then started enzymes, they may start to see problems with those supplements over time. Or if they take enzymes and go off a GFCF diet (thereby adding in more B vitamins). The enzyme therapy is adding in more B vitamins, so now there is a greater supply of B6. The increase in B6 "pulls" the methylation cycle into producing more cysteine…maybe too much cysteine accumulates. So ending the high B vitamins lets this cycle settle into a more balanced state. The high cysteine levels are reduced and the adverse reactions subside. Someone may be very well on a "regular" recommended daily allowance of B6, but only sees adverse reactions at the higher doses.
Here are some links that explain the problems with too much cysteine.
What is the health risk of too much vitamin B6 ?
Too much vitamin B6 can result in nerve damage to the arms and legs. This neuropathy is usually related to high intake of vitamin B6 from supplements, (28) and is reversible when supplementation is stopped. According to the Institute of Medicine, "Several reports show sensory neuropathy at doses lower than 500 mg per day". As previously mentioned, the Food and Nutrition Board of the Institute of Medicine has established an upper tolerable intake level (UL) for vitamin B6 of 100 mg per day for all adults. "As intake increases above the UL, the risk of adverse effects increases."
[Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press. Washington, DC, 1998. ]
How does mercury toxicity affect methylation?
Mercury toxicity may disrupt this cycle making it practically unsolvable until the metals are removed.
Mercury is highly attracted to sulfur. If there is mercury floating around, it will gravitate to sulfur compounds and tie them up. Any or all of the sulfur reactions will be faulty, and it will be hard to fix unless (or until) you remove the mercury or other metals. If you are mercury toxic and you do anything to increase methylation, you may increase cysteine. So if a child responds badly to high B6, mercury toxicity is a possibility because it more directly increases cysteine. Instead of this increase being beneficial, it may very likely attract mercury, and thus increase mercury movement and cause further damage…so you just can't win. You need to increase the sulfur compounds to detox the mercury (and other things), but these same sulfur compounds also start to float the mercury and cause worse problems as it moves around....
One interpretation is if you respond well to B6 and possibly TMG then you may be an under-methylator and may not have severe mercury toxicity. This is what cysteine is about, if you are severely mercury toxic then you are caught since you need more cysteine to function since the mercury takes it out, but if you have more cysteine you mobilize the mercury and you get more doing damage.
Mercury is involved in defeating so many pathways. Mercury may lead to the problems with phenol intolerance too. The mercury disrupts the cysteine pathway, so sulfate is limited and is not supplied for detoxing the phenol compounds (or other compounds).
Selenium binds with mercury and parks it in the liver in an insoluble form, as well as aiding the manufacture of glutathione which is a mercury detox pathway. So by adding Selenium you may start making some ground in correcting the pathways. So selenium gives a lot of effect for minimal hassle provided you don't take too much. Look for the selenomethionine form (a source of selenium and methionine). This is not chelation but may help while you are looking at chelation or in the process of chelating.
This methylation stuff may be more complex than is obvious. It is an intertwined process. Remember also that amino acids such as tryptophan and tyrosine may be involved in this more directly. I don't know what the relationship is between the levels of methylation and amino acids, but that may outweigh all this other stuff. Biochemistry gets very complex very rapidly.
About B12 and Increasing Methylation
There is a "newer" interest in vitamin B12. This is supplemented in two forms. One is called Cyanocobalamin. The other is Methylcobalamin and is the methylated, coenzyme form of B-12 (cobalamin) active in the brain and central nervous system. The cyanocobalamin form needs to be converted to the methylcobalamin form, so the latter is preferable if possible. B12 is needed to work with folate (folic acid or vitamin B9). B6, B12, and folate have a synergistic effect when given together. The B12 working with the others is needed for good nervous system working and myelin integrity. High folate levels or taking high amounts of folate without B12 can mask a B12 deficiency. There is lots of information by doing a search for B12. The following is from the Vitamin Research Products site:
"For memory, some subjects improved some in memory and cognition with: 750 mcg of folate, 15 mcg of vitamin B12, and 75 mg of vitamin B6 daily for 35 days."
[New Study: B Vitamins Affect Memory, www.vrp.com]
"Recently a flurry of interesting articles from the medical newswires and lay press have focused on B vitamins--specifically vitamins B6, B12, and folic acid. Some articles are simple reiterations of research from the past. Methyl Caps includes vitamin B6, B12, folic acid, and betaine (trimethylglycine). VRP was one of the first supplement companies to recognize the damaging effects of high levels of homocysteine, and how homocysteine could be easily controlled by the simple nutrients found in Methyl Caps."
[Provocative New Findings on Vitamins B6, B12 and Folic Acid Link Discovered Between Homocysteine, Alzheimer's and Diabetes]
Besides just trying to supplement the individual precursors to increase methylation, there are a few products just for increasing methylation. They contain most of the precursors (a couple listed below). Most of the sites suggested adding the precursors rather than the SAMe or methionine as being a good corrective measure. I thought the ratios of B6 to B12 were interesting - the B6 is usually quite under 25 mg:
Here are the ingredients of Methyl Caps sold by www.vrp.com
Name: Methyl Caps, 180 capsules
Serving Size: 1 Capsule
Amount Per Serving % Daily Value
Vitamin B6 (pyridoxine HCl) 17 mg 850%
Folic Acid 267 mcg 67%
Vitamin B12 (cyanocobalamin) 17 mcg 283%
Betaine (trimethylglycine or TMG) 400 mg *
Three capsules each day of VRP's Methyl Caps provide a synergistic
mix of methyl donors which work quickly to convert homocysteine into
a harmless amino acid.
What is a 'good' amount of B12 versus a therapeutic amount. Some companies sell B12 supplements in amounts up to 1000 mcg even though the RDA value is between 2 and 6 mcg/day for an adult. That is quite
Here is a description from NOW brand used therapeutically:
Brain B-12 - 1000 mcg Methylcobalamin - 100 Lozenges
"Vitamin B12, plays an important role in the metabolism of nerve tissue, protein, fats and carbohydrates. It also aids in the production of DNA/RNA and red blood cells. It also plays a role in the health of the spinal cord. A lack of adequate levels of Vitamin B12 may lead to pernicious anemia, lack of energy, weakness, muscle soreness, mental and nervous disorders, poor reflexes, speaking difficulty and nerve degeneration. As a dietary supplement, take one lozenge 1 to 2 times daily by holding under the tongue until dissolved."
Of course there were much lower strengths of B12 too. This was at a site called GreenCanyon.com that had lots of name brand supplements discounted by 20% or more.
Some other places said that those most likely to be deficient in B12 are those "Individuals with stomach and small intestinal disorders may not absorb enough vitamin B12 from food to maintain healthy body stores" Also, vitamin B12 can not be manufactured by any plants, and therefore is only found in animal products. So, vegetarians may not consume dairy products or meat which are good sources of B12, and they need to take care not to become deficient. Older people are also likely to become deficient. B12 is getting more recent press because of how it might aid in Alzheimers. Fortified breakfast cereals or foods were suggested for vegetarians or older people. There are sublingual dots you can buy too as well as in other supplements. (one place to read quick summaries about vitamins is www.anyvitamins.com)
B12 does not come from plants, only animal products. Strict vegetarians need to be aware of this and supplement it. B12 is stored in the liver and a few other spots. B12 toxicity is very hard to achieve and the main problems have been associated with B12 injections. This has even been attributed to some of the "other stuff" in the injection and may not be the B12. Or there are a few rare conditions that the injections may be contraindicated for.
B12 is released from proteins by stomach acid and digestion. Older people and those with low stomach acid or faulty digestion may develop B12 deficiencies (along with other nutrient deficiencies) because of this. Enzymes, particularly the proteases, digest the proteins and may make more B12 available (along with other nutrients). If you take anything that inhibits digestion or stomach acid, then you are inhibiting B12 release and absorbtion: like calcium carbonate with meals, Tums, Rolaids, and certain medications which affect stomach acid.
B12 combines with something called Intrinsic Factor in order to work. The stomach acid issues can affect the Intrinsic Factor availability too.
B12 is absorbed in the ileum, the very last part of the small intestine. Most everything else is absorbed before that in earlier parts of the intestine. For this reason, people with colon problems may be B12 deficient but not as deficient in other nutrients because the ileum is followed by the colon (so when problems "backup" from the colon into the small intestine, the B12 is affected first).
B12 may be deficient in people with injured guts because something called Intrinsic Factor is necessary to bind with the B12 in the stomach to "protect" it in the upper small intestine and from the stomach acid. Then the Intrinsic Factor attaches to some receptors at the end of the small intestine in the ileum aiding the B12 uptake. So at times it is the Intrinsic Factor and the fact it cannot attach to the receptors to facilitate transport and absorption into the body that is the problem and the cause of B12 deficiency. The sublingual B12 is highly preferred for this reason because it gets the B12 into the system and bypasses the entire Intrinsic Factor mechanism.
B12 deficiency can affect the nerves (as other nutrients can). The recent popular idea of getting more folic acid in the diet can mask a B12 problem, and too much folic acid (over 800 mcg a day for an adult) can lead to B12 deficiency if it is not in balance. So when people read folic acid is necessary and run out and start wolfing down folic acid without balancing it, this can provoke a B12 deficiency.
B12 is needed in incredibly small amounts like 2-6 mcg a day for an adult, kids need less. However, the therapeutic amount is between 100-1000 or more mcg a day for an adult for a couple of months. When the therapeutic amount should be used is open for debate with no clear cut evidence except for pernicious anemia (which is chronic B12 deficiency). The Alzheimers, MS, AIDS, etc issues are speculative at the moment. Some people say it may help, but others say not.
So it appears to me that healing the gut, taking enzymes (particularly proteases), and eating at least some animal foods go a long way to resolving this issue. Additional B12 for awhile may be helpful - a "try it and see" sort of thing - for mental and nerve function. Give at least a little bit of other Bs and folic acid along with it.
Here are a few more easier to understand yet thorough explanations. One has a picture of how B12 and folic acid affect the cycle of methylation, and B6 acts on another part. The precursors are much cheaper than the SAMe. It says that methylation is enhanced by estrogen and this may point to gender differences....anyway, more to explore.
Here is a link on the interrelationships of these things. It gives different amounts of B12 and folate for increasing methylation:
This one mentions that one form of B12 may be more effective than another:
Part 2: Histamine
I spent a ton of time looking into this. Here are some of the results. Please take all of this in context of everything else, these biochemical reactions are all intertwined and complex.
I was wondering WHY would histamine levels tell you about methylation function?
Methionine is a methyl carrying amino acid + ATP/magnesium = SAMe.
SAMe goes throughout the body delivering methyl groups to over 400 different reactions.
One way histamine is de-activated (eliminated) is by receiving a methyl group from SAMe. So if there is low methylation, there is low SAMe, and the histamine levels are higher because of the lack of methyl groups to deactivate it. If there is high methylation, there is higher amounts of SAMe, and lots of histamine can be deactivated.
Where does this histamine come from?
One source is when the amino acid histidine looses a carboxyl group. Some bacteria can faciliate this conversion too. So if you have a bacteria overgrowth, it may be using up histidine and converting it to more histamine. Another big source is directly from foods. Some people may have a problem eliminating histamine from their foods and this causes reactions which LOOK LIKE allergies, but are not true IgE mediated allergies. You may see a histamine reaction which is just too high levels of histamine and not because an antigen caused an immune reaction to something.
What are histamine containing foods?
Here is a great site on what foods contain what chemicals. The first link tells about "histamine intolerance" and amine foods:
Notice that many of the foods are often considered "phenol" foods even though they are not high in salicylates or phenols. They are high in amines/histamine. There are also foods that trigger a histamine reaction. This means that they directly cause a release of histamine - in some people, this includes the natural salicylates or other common additives:
Egg, strawberries, cocoa, chocolate, bananas, citrus, pineapple, pork, soy, benzoates, sulfites, nitrates, BHA, BHT, food colors, MSG.
The similarity with this and the Feingold program is very interesting.
If someone has low methylation (maybe B12 deficiency or metal interference, etc.) then you may have high histamine levels and a problem eliminating the additional histamine from foods. You would also have more chemical running around in the body triggering histamine reactions.
What lowers histamine?
Taking an antihistamine is one way. Antihistamines typically work by either inhibiting the release of histamine (like during an immune reaction) or blocking the uptake of histamine (like from food). Magnesium and vitamin C are natural anti-histamines. Vitamin C can destroy histamine directly. This is why these supplements are recommended when you are sick for any reason.
Another way to reduce histamine levels is to supply antioxidants. Free radicals are produced from both external sources and internal natural biochemical reactions. Too many free radicals provoke histamine reactions. Natural "phenols" in foods such as polyphenols, flavenoids, bioflavenoids, beta-caroteine and all those other things that No-Fenol appears to make more available to the body act as antihistamines. These natural phenols are also the trendy "antioxidants" for eliminating free radicals in the body which many places are advertising now. They neutralize the free radicals which cause histamine reactions. Less free radicals, less histamine reaction. These phenols coming from the fruits and vegetables lower histamine by 2 or 3 different mechanisms. Again, it gets complicated and there is no ONE definitive pathway.
Salicylates occur in most foods as a mean to "protect" the plant from injury. When the surface of the fruit is damaged (disease, injury, bugs, something taking a bite out of it), the food comes into contact with oxygen, and starts to break down via oxidation. The salicylates/phenol in the food are an anti-oxidant which preserves the food. This is why if you take a bite out of an apple, the "bite-mark" starts to turn brown. The apple is ttempting to heal the injury like applying a bandaid and slow or stop the rotting oxidation.
Remember that "phenols" are a huge category of compounds. Some are beneficial from natural foods, but others may be a problem. Saying something has "phenol" is like saying something contains "nitrogen". It could be anything.
A main mechanism of lowering histamine is by an enzyme produced in the gut mucosa. So if you have an injured gut for whatever reason, less enzyme may be produced, and this may mean you have a lower ability to eliminate histamine (especially from food sources). If you have multiple chemical allergies, you may want to consider a "histamine intolerance" or that you have histamine levels that run high. Inability to get rid of too much histamine would make you reactive to many foods, and overreactive to many things in the environment. Common additives such as artificial colorings, sulfites, BHA, BHT, benzoates, etc, can all inhibit this histamine degrading enzyme. Another way these can be problematic.
see Feingold Program
What does histamine do?
Histamine is located throughout the entire body. In many instances, it causes inflammation, runny nose, itching, hives, sore throat, coughing, flushing, headache and all those other typical allergy reactions. In the gut, it signals the production of gastric acid. This is why some remedies for acid stomach are really antihistamines. In the brain, it functions like a neurotransmitter. A couple of functions include affecting hunger or feeding, and also sleep/wake cycles (the circadian rhythm). A bit more histamine keeps you awake, and lower histamine levels help you sleep. This is why many antihistamines make you drowsy. Some newer antihistamines have been developed to get around this issue.
The role of antioxidants in the immune system is multifaceted as they can serve to either suppress or enhance the immune response. Depending on the desired response, different antioxidants can play different roles in balancing the immune response effectively in an individual. Beta-carotene, selenium, vitamin C, and vitamin E are all examples of exogenous antioxidants. In addition to these that come from our diet, the body also has a system of enzymes, which form the endogenous antioxidants. Together, they work to eliminate
free radicals from the body.
As andrew pointed out, if the immune system is under-reactive, this is a problem, but if it is over-reactive it is a problem. People may have any assortment of these things going on at a time.