A new paradigm for the cause and treatment of CFS

[Kimsie]

I have a new Paradigm to propose for the cause of CFS in some people (it also applies to some other illnesses):

Gut dysbiosis with organisms which make histamine in the body is the cause of CFS in some people.

This is because organisms in the gut that produce histamine can cause a chronic shortage of SAMe or S-Adenosyl methionine, and low levels of SAMe can cause extreme fatigue. One of my son's experienced extreme fatigue for over a year from this cause.

How does this happen?

The needs of the body for SAMe can vary through the day, yet the mechanism for changing the amount of SAMe produced by the body takes more than 24 hours to significantly change the amounts of the enzymes that are responsible for recycling homocysteine into SAMe: methionine synthase and methylenetetrahydrofolate reductase (MTHFR).

If the level of SAMe rises too high, then methionine synthase and MTHFR are inhibited, and CBS is increased, because SAMe inhibits its own production.1 This is how SAMe is regulated in the body. If a person has histamine producing bacteria in the gut, then the bacteria will produce more histamine during the hours after eating, and less histamine during times of sleep when the protein supplying histadine, the precursor of histamine, is less abundant.

Sometimes the person will feel better in the morning before eating, and sometimes not. The unusual fluctuations make it difficult for the body to regulate the histamine levels. As the histamine levels drop during the non-eating part of the day, SAMe level rises since less is being used by the enzyme histamine N-methyltranferase to donate a methyl group to degrade histamine. This triggers the inhibitory effect on the production of methylation cycle enzymes leading to chronically low SAMe during the part of the day when histamine levels are higher. See Low SAMe.jpg

So how do we maintain levels of SAMe that are high enough for our highest daily needs without triggering the inhibiting response during the part of the day when we need less? I would suggest that one unacknowledged function of niacin is to be a methyl sponge to keep the levels of SAMe from getting high enough to trigger the inhibition.

If free niacin floating in the blood isn't harmful, and I believe that it isn't (There have been cases of liver damage from high doses of time released niacin, but none from regular niacin or niacinamide, unless you believe that elevated liver enzyme are equivalent to liver damage.) in the amounts that are needed for the methyl sponge function (perhaps up to 2.5 grams a day for some people), then I believe that the metabolism of niacin is a sufficiently low priority job for SAMe that it does its other more important jobs first and then if there is excessive SAMe, it is used to rid of extra niacin.

So here is another new theory:

Niacin functions as a buffer for S-Adenosyl methionine (SAMe) in order to assure adequate levels of SAMe for the highest need of each day, by preventing inhibition of methionine synthase and MTHFR by high levels of SAMe during periods of lowest need of each day. See with Buffer.jpg

This niacin buffer will also prevent any “overmethylation” symptoms such as anxiety.

My suggested treatment for this problem is as follows:

Niacinamide, 1.5 grams before bed with or without food.
Methyl folate or folinic acid, 3 mg with breakfast, 3 mg with dinner.
Methyl B12, 1000-10000 mcg sublingual 3 times a day.
Edit 11/12/2013 - Methionine 1-2 grams a day for the first 3 days then gradually less to 500mg.
Added 11/14/2013 - Zinc (picolinate is good, or whatever type works for you) 30-50 mg more than you already take unless you feel that you are already taking enough. This is especially important if you have ever had problems with leaky gut.
Added 11/13/2013 - P5P (activated B6) 25-100 mg a day.

At the beginning of supplementation a surge of energy may occur for a couple of days followed by a few days where the supplements appear to have stopped working. This is because the body is lowering the amounts of enzymes in response to the sudden increase in SAMe. After 3-8 days a level of balance should occur and if there is improvement but not resolution of symptoms, more of one or more of the supplements may be needed.

If resolution has occurred then a gradual lowering of the doses of supplements may be experimented with. The amounts needed are affected by the person's gene mutations as well as environmental factors.

I am using this method with two of my sons. I will report on the results when more time has passed, but it looks promising so far.

What do you think? Do you see any flaws in my thinking? Is my explanation clear enough?

1. Eur J Pediatr. 1998 Apr;157 Suppl 2:S40-4 The metabolism of homocysteine: pathways and regulation.

 

[Hip]

Interesting hypothesis.

There is a supplement called diamine oxidase (Daosin®) which is an enzyme that breaks down histamine in the gut. Certain foods are high in histamine, so this Daosin supplement is designed to be taken with such foods to prevent histamine reactions in people who are sensitive to such things.

The intestine makes its own diamine oxidase, and interestingly, the levels of diamine oxidase generated in the intestine are 500 times higher during pregnancy. 1 Now of course, ME/CFS is known to improve during pregnancy quite often.

Apparently the following bacteria are histamine producers: Clostridium perfringens, Enterobacter aerogenes, Klebsiella pneumoniae, Proteus mirabilis, and Vibrio alginolyticus. 1

Though if histamine levels were very high, you'd expect to see some histamine-produced symptoms such as skin itching and hives.

 

[Andrew]

FWIW, SAMe is on of the supplements used in when trying to treat FM and CFS. I think it is used alone or as part of the "methylation cycle" treatment.

 

[Hip]

organisms in the gut that produce histamine can cause a chronic shortage of SAMe or S-Adenosyl methionine, and low levels of SAMe can cause extreme fatigue.

Do you have any references for:

(1) Histamine's action in reducing S-adenosyl-L-methionine levels
(2) Low levels of S-adenosyl-L-methionine causing fatigue

 

[Kimsie]

Hip, I tried DAO supplements for my son and they hardly did anything for him.

1. Here is a quote from the Wikipedia page on histamine N methyltransferase:
"Histamine N-methyltransferase catalyzes the methylation of histamine in the presence of S-adenosylmethionine (SAM) forming N-methylhistamine. HMT is present in most body tissues but is not present in serum." I admit that I haven't seen any studies that show how SAMe levels are affected by histamine, but since SAMe is the methyl donor for the histamine degradation within the cell, wouldn't large amounts of histamine reduce levels of SAMe?

2. I don't have a study for this one, but if you do a search on SAMe and fatigue you will see that some people have success treating fatigue with SAMe supplements. But SAMe supplements are expensive and not a very effective way to get more SAMe into the body. Your own methionine cycle is a better way.

My main reason for saying that a lack of SAMe can cause fatigue is from my experience with my now 17 year old son. When he was 14 he was on antibiotics several times in several months. After this he became very fatigued and a few months later I learned that he had had mono and I thought that was what was causing his fatigue and that it would go away in time.

A month later he started reacting to foods when he had never had any food sensitivities before so I knew he must have a leaky gut from the antibiotics and I thought that perhaps candida was causing his fatigue. I began many things to try to treat his gut dysbiosis along with rotating high protein foods to avoid food reaction.

This went on for about 8 months without improvement. The only thing that seemed to help was a lot of vitamin C, which I realize now is able to degrade histamine. Finally I started him on the GAPS diet and that seemed to help him somewhat. About 3 months later we found out about the MTHFR mutations and found out he had the MTHFR C677T mutation and we started him on 5 mg of methlyfolate a day. It was amazing, he felt better in 2 hours!

I realize now that it was because it jump started his methylation and all of a sudden he had a lot of SAMe to get rid of that histamine. This was great, but he was still only operating at about 85% (before he was at about 50%) But with the methylfolate his gut started to heal and in a couple of months more he got over his food reactions. He was still on GAPS. He was doing so well I took him off GAPS and let him eat potatoes and rice. Big mistake!

After a month I realized that he was gradually getting worse and so I put him back on GAPS and within 24 hours he was deeply depressed from what I thought was die off. I realize now that it was because now after feeding the bacteria all that starchy food for a month he was overloaded and since GAPS is a high protein diet the bacteria were having a hay day making histamine.

We battled the depression for months with him gradually getting better from the GAPS protocol and I started giving him vitamin C to bowel tolerance. He would be lying on his bed staring blankly up at the ceiling and I would give him 15 grams or so of vitamin C and half an hour later he would be up doing something, but he never felt very well.

Finally in the summer there he was getting closer to feeling good and he was taking the full dose of BioKult and I was wondering how long it would take to get the bacteria down when one busy day I forgot to give him any sauerkraut, which is a big deal on GAPS. The next day he felt really good for the first time in 2 years!

That was when I realized that it was histamine that the gut was producing that was giving him his symptoms, because sauerkraut is high in histamine. I have seen him go from feeling good in the morning, eating something and getting depressed, give him some vitamin C and go back to feeling pretty good. But always, the first stage in the downhill slope is that he starts feeling fatigued before feeling depressed. The top level of just being a little low on your SAMe levels seems to present the symptom of fatigue.

Now I have been following this protocol with him for 3 days and today he had no symptoms at all, with only about 1 gram of vitamin C (before he was taking 50 grams a day).

A couple of weeks ago I started giving my son larger doses of methylfolate and B12, with more B12 throughout the day and he felt fantastic for one and a half days and I thought I had found the answer. Then it just stopped working.

I was puzzling and wondering why and researching and I came upon the information that high levels of SAMe inhibit the enzymes that recycle SAMe and then I realized that the fluctuations in histamine during the day and night had caused my son's body to readjust to the new levels of supplements and bring him back to the same level of SAMe he was at before.

I thought maybe he would have to get up in the middle of the night and eat some meat to keep his histamine levels up to avoid the inhibition of methionine synthase and MTHFR, but then I remembered that niacin is degraded by SAMe also, and that it is taken by people who are "overmethylating" to stop feeling anxious or whatever symptoms they were having from not having enough niacin to make the COMT enzyme get rid of excess norepinephrine.

Then I thought that perhaps niacin would be a buffer to give the SAMe something to do at night, so that my son would have enough SAMe during the day and it looks like it is working beautifully!

This is a long explanation, so I appreciate your perseverance if you are still reading this! I hope this helps!

 

[Hip]

Kimsie, what you are saying is quite misleading.

When you stated that histamine reduces SAM-e levels, and that low levels of SAM-e causes fatigue, I initially assumed that these were both established biochemical facts that you read and quoted.

But it appears that these are not established facts at all. Rather, these two statements are purely your own speculations. So it is very misleading to present such statements as facts.

Your speculative hypothesis of ME/CFS is then not build on a foundation of fact, but is speculation built on speculation.


I am always open to any good hypotheses on the cause of ME/CFS, but a good hypothesis should really be founded on biochemical fact.

There are far too many "ifs" in the hypothesis you presented.

What you are really saying is that:

(a) If low levels of SAM-e cause fatigue (and there is no evidence available that it does)
(b) and if histamine reduces SAM-e levels (and there is no evidence available that it does)
(c) and if ME/CFS patients have high levels of gut histamine produced by bacteria (and there is no evidence available that they do)

then, if all of the above three speculations are true, this could explain ME/CFS.

With this many "ifs", there is not really much of a hypothesis here.

 

[Kimsie]

Well, certainly it is speculation. All discoveries of biochemical facts begin with speculation, based on observation.

I apologise for not making myself clear enough, I was proposing a new, not established, paradigm for CFS. If these things had already been established facts, it wouldn't be new. I am basing my speculation on the observation of my son and his pathway to recovery. I was trying to make clear that what I was saying was based on this and I am sorry that I did not make it clear enough.

If you feel that my reasoning is is error, and you are not merely complaining that there are no scientific double blind studies showing that my ideas are correct, then I wish you would tell me where my reasoning is wrong.

If you object merely because there are no scientific double blind studies showing that my ideas are wrong, then that is fine. But perhaps there are others here who are more open to new ideas and they might be interested in following my line of reasoning to see if it makes sense logically.

People who have illnesses such as CFS will have to wait a long time if they are going to insist on scientific studies proving that certain cheap vitamins can help them before they are willing to give it a try, because medical science is always reluctant to change their ideas, and there is no money to be made in treatments that you can't get a patent on so who will fund the studies?

If medical science had found the answers to CFS this forum would not be here. I got tired of waiting and going to doctors who were of no help to my sons and that is why I have been trying to find the answers on my own. I feel an obligation to share my ideas because I really think there is reason to believe that they could help a lot of people and it would be wrong not to share them. People here can take the opportunity to test my ideas or not. It is an individual choice.

I am sorry that I upset you. I didn't mean to be misleading.

Kim

 

[Hip]

I hope I am not coming across as unfriendly, Kim. I am just pointing out that it is important to be clear on what is a known fact, and what is a speculation.

It is your speculation that (a) low levels of SAM-e cause fatigue, and that (b) fluctuations in histamine levels cause low SAM-e; so these should definitely not be stated as if they are facts.

And regarding the hypothesis you presented: if it were true that (a) low levels of SAM-e cause fatigue, and if it were true that (b) fluctuations in histamine levels cause low SAM-e, then your idea (c) that variations in gut histamine production might underpin ME/CFS would carry some plausibility. But when the foundations (a) and (b) that this idea is built on are themselves speculations, then the whole thing becomes highly speculative.

 

[Kimsie]

No, I don't think you are being unfriendly. It was my mistake to write it the way I did. I am very excited about this idea, because I feel that I have strong evidence that I am on the right track, from personal experience, and I tend to speak about things I feel strongly about in a positive way instead of being more cautious.

The thing is, IF I am right, then how will we find out? So far I have posted about this on several boards and no one has even really thought through my ideas enough to critique them. Of course, I have been studying the methylation cycle for months, but I thought that there were people here who were studying the methylation cycle, too.

How does one test such an idea? I am hoping that by sharing this some people will be willing to test for a week or two to see what effect it has on them. I would think that with a group such as those on this forum, who already probably are taking B12 and folate, merely adding in a couple grams of niacinamide a day with 1 gram at bedtime would probably lead to improvements in some of them. (And now I think that methionine 1-2 grams a day should be added, at least at first.)

Besides my 2 sons, and I am not holding my breath about it helping my son who has schizophenia to completely go off his meds, but I will be delighted if it can just take away some negative symptoms and brain fog, which it seems to be helping with, but it helped my other son a lot. He had extreme fatigue for well over a year and if we had just relied on doctors, I believe that he would have ended up with CFS. Now he is feeling well, except I keep finding little changes that needs to be made and it takes a couple days to adjust to the changes.

Anyway I was saying that, besides my 2 sons with illnesses, I do have a friend with fibromyalsia who is interested in trying it. She already knows that she has gut dysbiosis and problems with histamine.

I need to add that yesterday I discovered that I need to add methionine to the protocol for my son. Pulling large amounts of homocysteine up into the cycle doesn't seem to leave enough for making glutathione through the CBS pathway, at least that is what I believe happened. He felt sick yesterday until I gave him several grams of methionine over the period of a few hours.

 

[Hip]

How does one test such an idea?

The basis of your idea is that low levels of SAM-e cause ME/CFS. However, SAM-e is a freely available supplement that many people with ME/CFS have tried, but usually don't experience much in the way of improvements. So this I am afraid is another flaw in this theory.


Changing the subject: a few years ago, I was suffering from some mild psychosis symptoms, as the result of severe anxiety disorder.

Supplements I found useful for treating this mild psychosis were:

N-acetyl-glucosamine 1000 mg (or more) twice daily — the best.
Flaxseed oil one level tablespoon (15 ml) daily (more may cause diarrhea).
Vitamin C powder 3 grams, taken three times daily — much cheaper in bulk powder.
Phosphatidylserine 300 mg once or twice daily (works best with omega 3 oil) — much cheaper if you buy in bulk powder.
Niacinamide (a form of vitamin B3) 1000 mg twice daily.

Perhaps these will be useful for your son.

I also made use of very low dose amisulpride (12.5 to 50 mg daily), a third generation atypical antipsychotic drug. Atypical antipsychotics have lower side effects that first generation antipsychotics.

The amisulpride dose for schizophrenia is 400 mg daily and higher, so my daily doses were much smaller than that, but nevertheless I found they did help treat my mild psychosis symptoms. At very low doses, amisulpride is often used for its antidepressant effects; I also suffer depression, and I seem to react very badly to SSRIs, but I do well with very low dose amisulpride.

 

[Kimsie]

I believe that taking SAMe supplements is a drop in the bucket compared to what your body can make with the methylation cycle. No, I don't have any scientific evidence, but I also tried SAMe supplements for my son who is responding to this protocol and it didn't do a thing. I have observed that a 2 gm dose of methionine gave him relief from his symptoms for about 15 minutes one day before I figured out about taking niacinamide, and if only half of that became SAMe, then a one gram dose of SAMe lasted about 15 minutes, and it would not be to absurd to believe that the methionine methylation cycle can recycle 50-100 times the amount of SAMe that you get with supplementation - and that is assuming that you absorb all of the SAMe taking it orally.

I notice that your protocol for psychosis involved taking 1 gm of niacinamide twice daily. This is very nearly the amount I suggest in my protocol, and it is the most important part. Were you also at that time taking any folate and/or B12? If you were, then I would call to your attention that you were almost following my protocol, and that taking more of some or all of those three vitamins might have brought you more benefit.

The reason these things help for psychosis is because the COMT enzyme needs niacin as either a cofactor or an integral part of the enzyme and it uses SAMe for the methyl donor to degrade dopamine. (and the other catacholamines) If you would like me to I can hunt up some references for the part about COMT needing niacin and SAMe and the fact that it degrades dopamine; those things are not speculation. SAMe is involved in so many reactions in the body that I believe a shortage can cause a variety of symptoms depending on genetic and environmental factors.

My son with schizophrenia is on Abilify, which is also a second generation atypical antipsychotic drug. He has been on Abilify for 8 years. We have had some very bad experiences trying different antipsychotic drugs, and they were all 2nd gen, and our son has tried a lot of them, so we aren't eager to try experimenting with more of them.

 

[Hip]

I believe that taking SAMe supplements is a drop in the bucket compared to what your body can make with the methylation cycle.

Well it did not take long to find this study which demonstrates that in fact oral SAM-e supplementation at 1600 mg per day causes a significantly elevation in SAM-e levels.

So I am not sure where you got your info that SAM-e supplements have negligible effects on SAM-e levels.

I notice that your protocol for psychosis involved taking 1 gm of niacinamide twice daily. This is very nearly the amount I suggest in my protocol, and it is the most important part. Were you also at that time taking any folate and/or B12? If you were, then I would call to your attention that you were almost following my protocol, and that taking more of some or all of those three vitamins might have brought you more benefit.

I have tried a methylation protocol which involved daily high sublingual doses (20 mg) of B12 methylcobalamin, and oral folinic acid 800 mg with L-5-MTHF 1000 mcg, but tis may not have been at the same time that I was taking high dose niacinamide.

Nowadays I don't take niacinamide in high doses, as I find it worsens my anhedonia symptoms.

 

[Hip]

Have you ever tried an anti-inflammatory approach as an adjunct therapy for schizophrenia? Apparently this can be helpful .When I had severe anxiety disorder which bordered on psychosis, I found anti-inflammatory supplements were quite helpful.

 

[Kimsie]

Well it did not take long to find this study which demonstrates that in fact oral SAM-e supplementation at 1600 mg per day causes a significantly elevation in SAM-e levels.

So I am not sure where you got your info that SAM-e supplements have negligible effects on SAM-e levels.

Lets take a look at what the study says:
Fifteen healthy adults (10 women, 5 men), mean ± SD age 26 ± 4.5 years, completed the 4-week study...Mean ± SD SAMe plasma levels were significantly different from baseline (0.75 ± 0.12 nmol/ml) at week 2 (0.79 ± 0.13 nmol/ml, p<0.001) and week 4 (0.78 ± 0.12 nmol/ml, p=0.002)...The supplement chosen for this study increased SAMe plasma levels significantly. Although the percentage increase in SAMe concentration was small, SAMe is highly reactive and most of a dose is not expected to be present in serum or tissue.
So some people had raised SAMe levels and some were lower after supplementation, with more being raised. If these people had been CFS sufferers then this would have been a blow to my theory, but since they were healthy people who most likely weren't having fluctuations in histamine to inhibit production of SAMe the study is irrelevant as far a disproving my theory is concerned. The people who had increased SAMe levels after taking 800 mcg of SAMe for 10 days must have had slightly low levels of SAMe due to not having enough of the substrate so giving them more of the substrate elevated the levels. The same effect could have been achieved by supplementing methionine.

When SAMe levels are inhibited, they can't be changed for more than a couple days by adding more of one of the components that helps make SAMe such as substrate (methionine or SAMe), folate and B12 because the body adjusts the levels of the enzymes to bring the SAMe levels back down to where they were before the component was added. This is how our bodies regulate SAMe. You can't get around it by supplementing the components, you can only get around it by changing the usage of SAMe during the time when the need drops lower so that the SAMe gets used up and doesn't inhibit the enzymes at a level that is too low.

Here is a table that shows which enzymes are inhibited by SAMe from The metabolism of homocysteine: pathways and regulation Eur J Pediatr (1998) 157 [Suppl 2] :S40–S44

Table

You can see in the table that SAMe inhibits both the BHMT pathway and the pathway that uses methylfolate.

 

[MonkeyMan]

Kimsie, I just came across this thread and your original post is very interesting to me. I feel fine until I eat something -- anything -- and then I feel progressively worse for the next few hours. The feelings of fatigue/brain fog/depression will always peak about 3-4 hours after the meal.

I would literally give my right arm to find a solution to whatever the hell is causing this!

Drew

 

[Wayne]

Kimsie, thanks for sharing your research and observations. Plenty to think about. Just thought I'd make a quick mention about my own SAM-e experience. When I first started on it, I would feel noticeably better within 5-30 minutes, and could feel it supporting me (significantly) throughout the day. I don't believe I ever took more than one dose/day. Unfortunately, like so many other things that help, this turned out to be temporary. For several weeks however, it was a great supplement.

I ran across a a video once which explained how various anesthesias, and I think especially dental visits that use laughing gas, cause a severe depletion of SAM-e, apparently enough to chronically alter the cycle in the body that produces it.

 

[shah78]

Bravo! Yes, IT"S ONLY A THEORY! How dare do submit such an" abomination" to us with out a million dollar double blind study. (Of cource isn't this what Richvank did for years? and we all loved him, didn't we?) Sauerkraut kicks my ass . I'm trying Yucca to deal with histamine issues, but if I can "jiggle my methylation protocol just enough to help, then I'll be in "post CFS heaven!".

 

[Wayne]

Bravo! Yes, IT"S ONLY A THEORY! How dare do submit such an" abomination" to us with out a million dollar double blind study. (Of cource isn't this what Richvank did for years? and we all loved him, didn't we?) Sauerkraut kicks my ass . I'm trying Yucca to deal with histamine issues, but if I can "jiggle my methylation protocol just enough to help, then I'll be in "post CFS heaven!".

Hey Shah78, gotta tell ya, you just spiced up my rather lackluster, holmdrum day with some good hearty chuckles. Thank you very much!

I'm not real up on this whole histamine thing yet, but I have been feeling better since gradually increasing my daily dose of Liposomal Vit. C over the last few weeks, and am now up to 10g/day. I feel it's definitely improved immune function, but I also fairly certain that it's reducing my histamine levels, which I feel is responsible for some of my improvement.

 

[shah78]

Thank you Wayne. The way I see it, we are all on this Titanic called CFS. I'm looking for any lifeboat I can find. Relying/waiting on the so called" scientific method" leads to more" cold water emersion then I deem appropriate.(and I sit in 50degree water ten hours a week ) I seek the company of Freddd, Kruse, Tim Steele and any other kook on that dry, relatively warm lifeboat!

 

[xrunner]

What do you think?
1. Eur J Pediatr. 1998 Apr;157 Suppl 2:S40-4 The metabolism of homocysteine: pathways and regulation.

Interesting idea and there may be some truth to it but I'm not expert enough to say more.
Regarding treatment wouldn't it be easier to kill such harmful micro-organisms and repopulate the gut with helpful probiotics?

In my case, one of the most effective treatment I had was the probiotic Gcmaf and one of the things it does is to help re-establish the balance of gut microbiota that one was born with.
Many of those who tried it have reported an improvement in quality of sleep and, coincidence or not, histamine appears to be involved in regulating the sleep cycle.