• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Methylfolate SIDE EFFECTS...

dannybex

Senior Member
Messages
3,561
Location
Seattle
From Dr. Ben Lynch's website:


"Methylfolate is a remarkable nutrient yet it can create significant side effects.
Those who have MTHFR mutations (especially the C677T MTHFR mutation) learn that methylfolate is critical to take. The issue is methylfolate can cause more harm than good if not started at the right time or tapered up slowly in amount.
There appear to be three types of responses to methylfolate:
FIRST: A person who can jump on methylfolate and feel absolutely wonderful. The only down side they experience is why didn’t they know about methylfolate before?!
SECOND: A person starts methylfolate has an amazingly incredible week where they are happy, interacting and alert. Then the second week comes and they switch to wanting to hide in a room by themselves or literally throw dishes across the room out of anger. Or they may become bed ridden from muscle aches, intense headaches or joint pain.
THIRD: A person takes a small amount of methylfolate and feels all the methylfolate side effects right out the gate.

  • irritability
  • insomnia
  • sore muscles
  • achy joints
  • acne
  • rash
  • severe anxiety
  • palpitations
  • nausea
  • headaches
  • migraines"

I experienced many of the effects on the list in the third category when I was first (overprescribed) folates and b12 in late 2010, early 2011.

And I can now certainly relate to the 'second' category. Of course I'm not sure that my currrent state can be completely explained by too much methylfolate (or folinic), but I'm very close to being bedridden...can hardly walk without severe pain in my feet...so I'm cutting waaay back, if not stopping the methylfolate for now.

More at the link:

http://mthfr.net/methylfolate-side-effects/2012/03/01/
 

Lotus97

Senior Member
Messages
2,041
Location
United States
lol, definitely the third category for me. I've been taking folinic for a couple of months and now I'm trying methylfolate again. I'm considering the possibility that different brands have a different effect based on Adreno's experience that he posted in another thread. Mainly that he felt anxiety with Quatrefolic and calm with Metafolin. Since Quatrefolic is what I took initially I'm first trying Thorne's methylfolate from their b complex. It's a glucosamine salt so I wonder how similar it is to Quatrefolic. After about 5-6 days of Thorne's I'm going to try Quatrefolic again. The last time I tried it it was in a b complex with a lot of folic acid. Since I'm MTHFR another possibility I'm considering is that my reaction was due to the build up of folic acid that I'm not processing. If I don't tolerate the Quatrefolic then I'll try Metafolin and compare results. It could just be that I was sensitive, but I would like to know if anyone besides Adreno has tried both Metafolin and Quatrefolic.
 

LaurieL

Senior Member
Messages
447
Location
Midwest
When I started, I already felt so bad, that I wouldn't know how to categorize my "person" status. I already had most of the symptoms anyways. o_O But the headache, I don't think I will ever forget the intensity of the headache.

You know, what blows me away? When I was a little girl, my doctor hounded me to take B12 and folic acid. For reasons I don't care to explain in the here and now, I have been on one side of ill for many years, off and on...... And these same symptoms expounded here, and the headache I experienced, are the very same I experienced as a child. And those symptoms were the reason why, as a child, I refused to go near vitamin B anything and snub folic acid. And I maintained that aversion for over 30 years.

LaurieL
 

Lotus97

Senior Member
Messages
2,041
Location
United States
When I started, I already felt so bad, that I wouldn't know how to categorize my "person" status. I already had most of the symptoms anyways. o_O But the headache, I don't think I will ever forget the intensity of the headache.

You know, what blows me away? When I was a little girl, my doctor hounded me to take B12 and folic acid. For reasons I don't care to explain in the here and now, I have been on one side of ill for many years, off and on...... And these same symptoms expounded here, and the headache I experienced, are the very same I experienced as a child. And those symptoms were the reason why, as a child, I refused to go near vitamin B anything and snub folic acid. And I maintained that aversion for over 30 years.

LaurieL
I've heard of a few other people getting headaches from methylfolate as well. The strange thing is that they said they were able to tolerate methylfolate initially, but then got the headaches later one. It's usually the other way around. That they get the symptoms initially and then they gradually subside. Both of the people this happened to were taking very high doses of methylcobalamin (5-20 mg). This could just be a coincidence though.
 

Victronix

Senior Member
Messages
418
Location
California
My experience has been that the majority of those symptoms go away with enough potassium, like over 1000 mgs. Particularly the severe anxiety -- that's clearly a part of low potassium for me. I got it with B-12 also, the same experience. It's a mind altering level of anxiety where I literally feel dissociated and am shaking all over.

Solution? Potassium. If I take enough, and keep taking it regularly, I never even start to get that anxiety.

What I've experienced that is unique to mfolate relative to mB-12 is the specificity of the muscle pains -- highly specific and focused, not broad aching or anything, but so isolated that I often think at first that I've pulled a muscle, or a tooth must have a cavity, etc.

Also an unusual focus on the neck and shoulders in terms of the muscle pains. When I was in the first couple of weeks of mfolate I had to get a special chair at work which I could rest the back of my head against because of the neck pain. It has totally gone away now.

Getting a hoarse voice was also unique to mfolate for me, and it happened literally within minutes of taking folinic acid and also mfolate. I suspect this is connected to the vagus nerve, but that's just speculation.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Rich thought excitoxicity from methylation could also be due to a drop in glutathione in the brain (specifically the astrocytes)
Quite a few PWMEs who have tried the methylation protocol have reported that they have experienced an increase in symptoms associated with excitotoxicity when they began (anxiety, insomnia, nervousness). In the past, I have suggested trying acetyl glutathione or liposomal glutathione to counter this. One or two people reported that they thought this helped them.

Now I would like to suggest something else that I think would help with this, which is less expensive: L-cystine. Note here that I do mean L-cystine, not L-cysteine. (Cystine is the oxidized form of cysteine, consisting of two cysteine molecules bound together by a disulfide bond.) Douglas Laboratories is one producer of L-cystine, and there are at least a couple of suppliers of it on the internet advertising 60 capsules, 500 mg each, for $16.50. I would suggest starting with a dosage of 500 mg and increasing to as much as 1,500 mg, depending on the response. L-cystine should not be taken by people who have a tendency to develop cystine kidney stones, or people who suspect that they have a high body burden of mercury, because L-cystine may move mercury around. And as always, I recommend working with a physician while on this protocol.

Here is the rationale:

I believe that the increase in excitotoxicity results from a further drop in the glutathione levels in the astrocytes (helper cells) in the brain, when the protocol is begun. (We know from the recent MRS measurements of Shungu et al. that glutathione is already somewhat depleted in the brain in ME/CFS.) The further drop in glutathione lowers the production of ATP by the mitochondria of these cells, and they then have less energy for pumping glutamate out of the synapses and recycling it. When glutamate builds up, it overexcites the NMDA receptors, and that produces excitotoxicity.

If this is true, then it would seem that we may be able to lower the excitotoxicity if we can support the glutathione levels in the astrocytes as this protocol is begun.

According to the Dringen model, the astrocytes make their glutathione using cystine as their source of cysteine. Cystine is obtained from the blood, and is able to pass through the blood-brain barrier.

How does cystine normally get into the blood? The liver produces glutathione from the constituent amino acids that it receives from the diet via the intestine and the portal vein blood flow. The liver exports some of its glutathione to the circulating blood, and enzymes break down the glutathione into its constituent amino acids. The cysteine is mostly oxidized to cystine, and some of this is taken up from the blood by the brain.

When the methylation protocol is begun, the activity of the methionine synthase enzyme in the liver is increased by supplementing B12 and folate forms. This causes more of the homocysteine to be converted to methionine, so less is available to support synthesis of glutathione. One result of this is that the cystine level in the blood goes down, so that less of it is available to the brain.

It would therefore seem that if L-cystine were supplemented, it would augment the cystine in the blood and increase the supply available to the brain, and hence to the astrocytes. Hopefully, this would raise the glutathione levels in these cells, and increase their ability to remove glutamate from the synapses, lowering the excitotoxicity. Ingested cystine is not metabolized significantly by the liver, because it does not import cystine readily.

If anybody decides to try this, I would be interested to hear the results, whatever they turn out to be. Thanks.

Best regards,

Rich
I believe this is the study Rich is referring to
http://www.ncbi.nlm.nih.gov/pubmed/22281935
Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology.
Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ.
Source

Department of Radiology, Weill Medical College of Cornell University, New York, NY 10021, USA. dcs7001@med.cornell.edu
Abstract

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1)H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate; (ii) single-voxel (1)H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) (31)P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Aside from low potassium or glutathione as a cause for symptoms from methylation, Alex had another theory which he blogged about:
http://forums.phoenixrising.me/index.php?entries/is-the-fatigue-in-me-an-eicosanoid-phenomena.1320/
With respect to methylation I find that the symptoms people are ascribing to low potassium disappear on resveratrol. This implies that these symptoms are eicosanoid induced, though this is not certain. So taking potassium may be a method of altering these symptoms in a drug-like not a deficiency-like way. However I am also aware that about half of us have low intracellular potassium, so there may be subgroups. This is because both potassium and eicosanoids are very important in maintaining blood vessel tone I think.

My respiratory hyper-responsiveness also seems to disappear on resveratrol. If I get an attack while on resveratrol I guess I will have disproved that, but it hasn't happened yet. It has happened when I forgot to take resveratrol and just took antioxidants.

To be clear though I am ignoring something here, at least for now. The source of resveratrol I am using also contains grape seed extract. I think thats a good antioxidant but I am not aware its anti-eicosanoid, though it can have an impact on nitric oxide (a biphasic impact depending on dose). It also might be important that my resveratrol is grape seed sourced.
 

dannybex

Senior Member
Messages
3,561
Location
Seattle
Thanks for the replies everyone. I agree that of course these symptoms could come from anything, or a variety of things, and potassium is often the culprit -- although is it lowered from methylfolate (or folate) or b12?

And yes, Rich's theory was that excitotoxicity was due to low glutathione, but that glutathione could/would be raised by b12 and folate. He also included other supps as well (esp a multi), but tended to stress the b12 and/or folate...and I wonder in hindsight if he missed or overlooked some of the other crucial nutrients that folate or b12 might displace?

Just as one example, thiamine -- which was shown in that other study to use some of the same receptors as folate, but was blocked if folate was high. Thiamine is critical for proper krebs cycle function, whereas folate isn't. So could excessive folate worsen krebs cycle function? Also thiamine deficiency can lead to excess lactate, which Lotus mentioned in a different study above...

What I find interesting is that Lynch found these patterns repeatedly in the many patients he's seen. And the symptoms, when taken together, seemed somewhat unique -- anxiety is a pretty common symptom of course, but combined w/irritability and outright anger, and with wanting to just hide in their rooms, combined with worsening pain, so much so that one feels they're heading to a bedridden status...those seem pretty specific, and at least to me, very relatable. And he says all resolved or diminished in his practice when niacin was given, and methylation slowed down.

Methinks the B vits are more complex than we previously thought.

???
 

Jarod

Senior Member
Messages
784
Location
planet earth
If we look at the right side of the yasko chart, is it possible the homocysteine and/or methionine are low and just can't keep up with the increased demand required once methyfolate is added? This screws up the whole process because methylfolate is crammed in without all the ingredients.

I'm wondering amino acids might be lacking do to the poor supply from various receptors(orifices or however that stuff gets in) that get infected and inflamed in the gut/brain. But I know so little at this point It is kind of a wild guess.:confused:
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Thanks for the replies everyone. I agree that of course these symptoms could come from anything, or a variety of things, and potassium is often the culprit -- although is it lowered from methylfolate (or folate) or b12?

And yes, Rich's theory was that excitotoxicity was due to low glutathione, but that glutathione could/would be raised by b12 and folate. He also included other supps as well (esp a multi), but tended to stress the b12 and/or folate...and I wonder in hindsight if he missed or overlooked some of the other crucial nutrients that folate or b12 might displace?

What I find interesting is that Lynch found these patterns repeatedly in the many patients he's seen. And the symptoms, when taken together, seemed somewhat unique -- anxiety is a pretty common symptom of course, but combined w/irritability and outright anger, and with wanting to just hide in their rooms, combined with worsening pain, so much so that one feels they're heading to a bedridden status...those seem pretty specific, and at least to me, very relatable. And he says all resolved or diminished in his practice when niacin was given, and methylation slowed down.
I agree about addressing nutrient deficiencies (starting, but not limited to the basic vitamins and minerals), but supplements can get expensive so I understand why Rich only recommended a low dose multi. Also some people have certain mineral and/or vitamin toxicities and there are various contraindications such carnitine and hypothyroid.

Rich actually spoke about how overdriving the methylation cycle caused the drop in glutathione. He also addresses the potassium issue.
(from multiple posts which is why there is some duplicate information)
I have seen lab test data (methylation pathways panel and plasma amino acids panel) from three people who had been on high-dose methylfolate together with high-dose methyl B12, and they showed what seems to me to be evidence of this. Namely, they had plenty of methionine and SAMe, low cystathionine and glutathione, low glycine and high sarcosine.

The rate-limiting enzyme in the methylation cycle is methionine synthase. It requires homocysteine and methylfolate as reactants and methyl B12 as a coenzyme. Normally the cells regulate the rate of the methionine synthase reaction by several feedback mechanisms. The amounts of methylfolate and methyl B12 are normally controlled. However, when large amounts of both are supplemented, the cells no longer have control over the rate of the methionine synthase reaction, and it speeds up, raising the rate of the methylation cycle. This has the effect of tending to raise the ratio of SAMe to SAH, which would raise the rates of the many methyltransferase reactions in general and would have major effects on gene expression and the biochemistry. However, the glycine N-methyl transferase reaction is there to limit the SAMe to SAH ratio. It does so by draining off methyl groups to convert glycine to sarcosine, which is why glycine goes down and sarcosine rises. Sarcosine delivers its methyl group to tetrahydrofolate, forming methylene tetrahydrofolate. This can then either go to form thymidine for new DNA formation, or it can be converted back to methylfolate by the MTHFR reaction. If the latter occurs, methylfolate delivers the methyl group back to the methionine synthase reaction, so this forms a sort of futile cycle. Meanwhile, the flow of homocysteine into the transsulfuration pathway is deficient, because homocysteine is being rapidly converted to methionine. Thus, the synthesis of cysteine is deficient, and therefore glutathione synthesis is, as well.

Best regards,

Rich
As you know, I have suggested a somewhat different approach to treating the methylation cycle partial block than Freddd has suggested.

When high dosages of methylfolate and methyl B12 are taken together, the cells are no longer able to control the rate of the methylation cycle, and it becomes overdriven.

One result of this is a rapid buildup of folates in the cells, because of the rapid production of tetrahydrofolate by the methionine synthase reaction.

Tetrahydrofolate is readily converted to the forms of folate needed to support DNA and RNA synthesis, and this releases cells from a block at the S phase of the cell cycle.

They rapidly start dividing, and this produces a strong demand for potassium.

As Alex has noted, it has been shown that the intracellular potassium levels are low in CFS (likely because of an ATP deficit at the membrane ion pumps, due to mito dysfunction, in turn due to primarily to glutathione depletion), so there is no reserve there.

The result is that the plasma level of potassium drops

Note that another effect of overdriving the methylation cycle is a further drop in glutathione, as less homocysteine is available to go toward cysteine synthesis.

There seem to be more and more people who are exhibiting effects of overdriving the methylation cycle from taking high dosages of methylfolate and methyl B12 together. I do not recommend this approach.

Best regards,

Rich
The reason I don't recommend going much higher on methylfolate when it is combined with several milligrams of methyl B12 is that this combination takes control of the rate of the methionine synthase enzyme away from the cells and drives it too fast. The result is that too much of the homocysteine is converted to methionine, and there is not enough left to flow into the transsulfuration pathway to support synthesis of glutathione and other sulfur-containing substances that the cells need.

The result is that the methylation cycle gets going well, but glutathione does not come up, as it needs to do for full recovery. There are excess methyl groups produced because of overdriving the methylation cycle. These are shunted off to the folate metabolism by sarcosine, which is produced by the glycine N-methyltransferase reaction, and then they come back to the methylation cycle via methylfolate. It's sort of like a futile cycle, like a squirrel in a rotating cage.

This is not just based on biochemical theory, though it is supported by that. It is based on lab tests that people who have been on this regimen have sent me.

For most PWMEs, this does not work very well in the long run. In Freddd's own case, because of the genetic variations that he apparently has in the CblC complementation group and in MTHFS (not to be confused with MTHFR), it is necessary for him to use a high dosage of methyl B12 to overcome the CblC problem, and it is necessary for him to use a high dosage of methylfolate to feed his folate metabolism, since he cannot use folinic acid or folic acid. (I'm not sure why he cannot use folic acid. Perhaps he has a polymorphism in the DHFR enzyme, also). Freddd cannot tolerate raising glutathione, because it binds cobalamin to form glutathionylcobalamin, and his version of the CblC complementation group is not able to retrieve cobalamin from glutathionylcobalamin. As far as I can tell, this is a rare genetic variation. Most PWMEs are depleted in glutathione, and this is responsible for a large number of the symptoms.

There may be other PWMEs who have one or more of these genetic issues as well, since Freddd reports that there are some others who respond to these supplements in the same way he does, but most do not seem to have them, based on our clinical study and anecdotal reports from quite a few PWMEs.

Best regards,

Rich
 

Victronix

Senior Member
Messages
418
Location
California
I'm still just inching along at increasing the mfolate dosage but only by tiny amounts. And still, much is an unknown. The potassium need is currently all over the map, sometimes intense, other times not at all. There is definitely a brain chemistry effect for me since being on mfolate -- I feel a little more confident, a little more aggressive, a little sooner to notice when something isn't fair to me . . .I feel changed. But also lately my memory is AWFUL . .. could be estrogen or who knows what. My synthroid dosage is increased in the past 6 weeks and that can create confusion if it T4 goes too high, but I checked my labs about 2 weeks ago and they were perfect. Perhaps they've changed. I'll have another test soon enough.

Within the 2 week window after increasing the mfolate dosage very slightly I have mild euphoria on and off and need a lot of potassium at a fairly level amount, increased with exercise or stress or heat. Now, entering the 'after the 2 week window', I have some increasing muscle pains and muscle stiffness in the neck and lower legs that potassium does not seem to alleviate -- could that mean I need to increase my B-12? Could I need more potassium but in a different way (the overt potassium deficiency signs are far decreased now, but when I take more it doesn't really seem to change anything)? Does it mean I need more mfolate? And other questions -- what about recent mood swings? Is that just the recent life losses combined with the New Moon? Questions questions. I also started drinking some alcohol, tiny 1/2 cup per evening amounts, but then I had a headache that was happening every day and had to stop. The headache has gone away but some of the muscle stiffness remains, on and off. Alcohol has some health benefits but wipes out my ability to retain nutrients it seems, certainly for B-12.

Anyway, so, sorting through things. Today I've had almost no potassium, but I do have muscle pains and stiffness and numbness in my feet. I will just have try some things, trial and error. Fredd's word of advice was if something isn't working, just double the dosage of whatever you think may be at fault. That's actually worked in the past.
 

PhoenixDown

Senior Member
Messages
455
Location
UK
There's a 4th scenario, it did nothing (for me at least). Tried taking it with Methylb12 & L-Glutathion, still nothing.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
I'm still just inching along at increasing the mfolate dosage but only by tiny amounts. And still, much is an unknown. The potassium need is currently all over the map, sometimes intense, other times not at all. There is definitely a brain chemistry effect for me since being on mfolate -- I feel a little more confident, a little more aggressive, a little sooner to notice when something isn't fair to me . . .I feel changed. But also lately my memory is AWFUL . .. could be estrogen or who knows what. My synthroid dosage is increased in the past 6 weeks and that can create confusion if it T4 goes too high, but I checked my labs about 2 weeks ago and they were perfect. Perhaps they've changed. I'll have another test soon enough.
I seem to experience more brainfog from increasing methylation.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
dannybex
Someone actually asked Rich the same question you were asking (and also had an alternate theory which caledonia also suggested - the "CBS drain" ) This is from Gesalt
Isn't the methylation protocol supposed to increase glutathione levels....not decrease them? I am a bit confused by your logic.

I have a different theory. The increased excitotoxicity from starting a methylation protocol may come from CBS defects that become more pronounced as more stuff is getting drained down the transsulfuration pathway because the methylation cycle is pushing through more. Ammonia production increases and the excess in ammonia is what's causing the increase in excitotoxicity. In this case yucca may help more so, and or supporting the urea cycle with ornithine & citrulline malate.
Rich didn't respond to the CBS question although he has said that in the methylation study he did with Dr. Neil Nathan the CBS drain resolved itself after 6 months. Hopefully Caledonia will comment on this because she knows more than me.

This is Rich's response to the question about a drop in glutathione during methylation (it does sound like it's somewhat theoretical based on his response, but I'm sure he had good reason for his theory).
Hi, Gestalt.

Yes, ultimately the methylation protocol does increase glutathione. We have documented that with lab testing.

However, the very first thing that happens when B12 and folate are applied together, which is the real essence of this protocol, is that the activity of the methionine synthase enzyme is increased. This enzyme converts homocysteine to methionine. When that starts, there is initially less homocysteine available to enter the transsulfuration pathway, and that ends up lowering the production of cysteine and hence, glutathione.

Over time, the methylation cycle is able to fill by recycling homocysteine to methionine, and then there is more homocysteine available to enter the transsulfuration pathway.

In our clinical study, our first test point after starting the protocol was at three months, and at that point the glutathione level had increased significantly. But at early times, it makes sense that glutathione would initially drop, and that does seem to correspond to the increased excitotoxicity that many people report.

If you do try L-cystine, I'll be interested to hear how it goes.

Best regards,

Rich
 

Lotus97

Senior Member
Messages
2,041
Location
United States
It seems Rich did comment on the CBS issue in another thread
http://forums.phoenixrising.me/inde...ggestions-for-cbs-mutation.18675/#post-284941
The CBS SNPs that Dr. Yasko characterizes increase the activity of the CBS enzyme. That tends to cause a greater flow of homocysteine into the transsulfuration pathway, draining the metabolites from the methylation cycle. Dr. Yasko used to use a bathtub analogy to explain this.

The SNPs only give tendencies. They don't tell you what is actually happening in the person's biochemistry. FV's results on these two panels together are a good example of why I favor running the methylation pathways panel. She does have a heterozygous SNP on one of the CBS genes, but it is clear from her SAMe plus SAH concentrations that her methylation cycle has not been drained. The same appears to be true of yours.

The CBS enzyme requires activated B6 (P5P) for its operation. If B6 (or B2, needed to convert it to P5P) are low, this will inhibit the CBS reaction, and possibly also the CTH reaction (which also needs P5P), which is the other one in the transsulfuration pathway. If these are deficient, there will be low flow through transsulfuration, even if there are CBS SNPs.

It is necessary to have good flow down the transsulfuration pathway to make cysteine. About half the body's cysteine is normally made this way. Cysteine is usually the rate-limiting amino acid for making glutathione. So low flow into transsulfuration is consistent with inability to maintain a normal glutathione level.

I find it difficult to tell what's going on in transsulfuration from the sulfite or sulfate levels alone. Many PWMEs have depleted methionine. This is what feeds the entire sulfur metabolism, starting with the methylation cycle, into the transsulfuration pathway, sulfite and sulfate. So the levels of sulfite and sulfate will depend on other factors, which can vary.

To get the whole picture of what's going on in the sulfur metabolism, it's best to run both the methylation pathways panel and a 40 plasma amino acids panel. Having sulfite and sulfate levels will help to round out the picture. But one can tell a lot from the methylation pathways panel alone.

The best way to raise glutathione in ME/CFS is to treat to lift the partial methylation cycle block, using methylfolate and B12 (I prefer sublingual hydroxo B12, at least to start with), adding general supplementation of other vitamins and minerals to take care of deficiencies, and also adding support for the lipid membranes, which have been damaged by oxidative stress. This is what the simplified methylation protocol is designed to do. Direct boosting of glutathione is not a permanent fix for low glutathione in ME/CFS.

Best regards,

Rich
 

Lotus97

Senior Member
Messages
2,041
Location
United States
This is complicated. I assume we're talking about not really methylfolate by itself, but the combination of methylfolate and B12?

Last fall I experienced symptoms from just a little bit of methylfolate and no B12 except for a low oral dose. I was also taking a lot of betaine HCL (which is supposed to be the same as TMG). My guess is I'd still have experienced the symptoms even without any B12 or TMG/betaine.
 

caledonia

Senior Member
I had something similar happen, although I had only good effects (improved MCS). I was taking a Thorne multi with has methylfolate/folinic, and oral methylcobalamin.

There is also the possibility, that even though you're not taking a B12 supplement, that you still have some B12 stores in your body that the methylfolate could be combining with. Rich suggested this to me as a possibility.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
I had something similar happen, although I had only good effects (improved MCS). I was taking a Thorne multi with has methylfolate/folinic, and oral methylcobalamin.

There is also the possibility, that even though you're not taking a B12 supplement, that you still have some B12 stores in your body that the methylfolate could be combining with. Rich suggested this to me as a possibility.

I was taking a 200 mcg of methylcobalamin orally (just not sublingually). It was Jarrow's so I don't know if it was the good batch or bad batch since I got the b complex at the end of the summer. I think B12 taken orally has a higher absorption rate at lower doses and also if someone is deficient (which I probably was). That's interesting that those helped your MCS. I've been recommending supplements to my parents and my dad has MCS. He's taking methylcobalamin and adenosylcobalamin now. I will hopefully have him taking methylfolate soon also.
 

caledonia

Senior Member
MCS is due to lack of glutathione. For every toxin molecule you encounter, your body uses up one glutathione molecule to deal with it. If you don't have enough glutathione, you experience symptoms from very tiny amounts of toxins that you would normally experience only with very large amounts of toxins. You do folate and B12, build up some glutathione, and the MCS improves.

This is how I gauge if I'm making glutathione or not - is my MCS improving or getting worse?