Some people do well on folinic supplementation, some react badly. The reasons for this are unknown but presumably it has something to do with difficulties in processing folinic, and therefore possibly with the two enzymes which act on it, MTHFS or SHMT1. Accumulation of folinic will act to inhibit other pathways and so there could be a cascading effect.
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TMG makes me very depressed why?
- Thread starter wiltedflower77
- Start date
Some people do well on folinic supplementation, some react badly. The reasons for this are unknown but presumably it has something to do with difficulties in processing folinic, and therefore possibly with the two enzymes which act on it, MTHFS or SHMT1. Accumulation of folinic will act to inhibit other pathways and so there could be a cascading effect.
Great contribution @alicec
Too unwell to fully follow today but what is becoming apparent is the more I know the less I know lol. I am homo for MTR & MTRR (just hetero for a1298c). Perhaps there lies a clue.
I may have neglected folate & potassium and TMG is not ready to be introduced.
I was low in cellular potassium before embarking on this journey. I noticed after I started mb12 I would become extremely pale, cold, weak and nauseas with my period. Never been iron deficient in my life. After reading some other threads, flagging potassium.
Too unwell to fully follow today but what is becoming apparent is the more I know the less I know lol. I am homo for MTR & MTRR (just hetero for a1298c). Perhaps there lies a clue.
I may have neglected folate & potassium and TMG is not ready to be introduced.
I was low in cellular potassium before embarking on this journey. I noticed after I started mb12 I would become extremely pale, cold, weak and nauseas with my period. Never been iron deficient in my life. After reading some other threads, flagging potassium.
Thanks @alicec for filling in some more of the blanks in my understanding! 
Intriguing. Didn't know that. Pretty odd though, wouldn't it be a different thing and have a different name then? Or does it have to do with charge and thus amount of electrons etc? What am I missing here?!
While I still have to look a bit deeper that is one of the main possibilities for me as well; burning amino acids for energy production. I'm pretty close to being underweight and have been for close to ten years. I'm wondering if that is where my bad response to Carnitine Fumarate comes in since that is related to burning fatty acids, possibily because those aren't available. But that's just conjecture on my end without knowing more on how the Krebs cycle and Carnitine Fumarate function.
Well I'm interested in how this is going to turn out as well! I'm positive there are still (many) roadblocks left but at least I now understand why TMG and Phosphatidylcholine were having negative effects. And that gives me new pointers and tools to improve my situation.
With regards to that: the 9 aminos and SAMe definitely have a positive impact on my mood and general well-being. But the 'I-feel-great' effect only lasts half an hour to an hour. After that I still feel better than without them but it's obvious more things need to be added, or the dose needs to be upped.
Did try Methionine separately today but too short after a 9 amino's dose to make meaningful conclusions. Initial conclusion would be that it did nothing. That could mean that taking Methionine quickly resolves the low Homocysteine situation but that I then quickly shift to another blocking thing (initial guess would be B2, since the Methionine I took comes with B6). Or that the other amino's are having a synergistic effect. Doing the same but with SAMe might answer a few questions. And taking it further away from the 9 amino's or SAMe.
Things I did notice though: I need to drink more when taking those 9 amino's. A lot more. Possibly related to Creatine production? Who knows. Too many variables.
One other thing that's throwing a wrench into interpreting everything correctly is that I'm back to having to increase magnesium again. Will need to test if SAMe directly impacts negative symptoms from that.
Interesting!
alicec said:
Intriguing. Didn't know that. Pretty odd though, wouldn't it be a different thing and have a different name then? Or does it have to do with charge and thus amount of electrons etc? What am I missing here?!
While I still have to look a bit deeper that is one of the main possibilities for me as well; burning amino acids for energy production. I'm pretty close to being underweight and have been for close to ten years. I'm wondering if that is where my bad response to Carnitine Fumarate comes in since that is related to burning fatty acids, possibily because those aren't available. But that's just conjecture on my end without knowing more on how the Krebs cycle and Carnitine Fumarate function.
Well I'm interested in how this is going to turn out as well! I'm positive there are still (many) roadblocks left but at least I now understand why TMG and Phosphatidylcholine were having negative effects. And that gives me new pointers and tools to improve my situation.
With regards to that: the 9 aminos and SAMe definitely have a positive impact on my mood and general well-being. But the 'I-feel-great' effect only lasts half an hour to an hour. After that I still feel better than without them but it's obvious more things need to be added, or the dose needs to be upped.
Did try Methionine separately today but too short after a 9 amino's dose to make meaningful conclusions. Initial conclusion would be that it did nothing. That could mean that taking Methionine quickly resolves the low Homocysteine situation but that I then quickly shift to another blocking thing (initial guess would be B2, since the Methionine I took comes with B6). Or that the other amino's are having a synergistic effect. Doing the same but with SAMe might answer a few questions. And taking it further away from the 9 amino's or SAMe.
Things I did notice though: I need to drink more when taking those 9 amino's. A lot more. Possibly related to Creatine production? Who knows. Too many variables.
One other thing that's throwing a wrench into interpreting everything correctly is that I'm back to having to increase magnesium again. Will need to test if SAMe directly impacts negative symptoms from that.
Interesting!
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Hi @MacGyver thank you so much for your insight into all this mind boggling stuff!!! I have been meaning to reply for ages but been having a bad time with depression this last week or so. I would love to say that after reading your posts the coin has dropped but my brain is in a real scramble!! I am going to try and go over it all with a diagram of the metabolic cycles in front of me and maybe then it might sink in a bit. Basically it's way over my little head but I'm willing to try supplements to see if they have a beneficial effect or not. I took 400mcg of methylfolate on Friday along with 1000mcg methylb12 and my mood became better again but only lasted that day and am now back down the black hole!!! I have some l-carnitine so I might try that?
Keep us posted with any updates.
Thanks again
Keep us posted with any updates.
Thanks again
No problem, thanks for making this thread in the first place. It's an issue that I've read about several times but no-one seems to know the answer.
That said there are a few more possibilities, besides low Methionine/Homocysteine/Methylfolate/Methylcobalamin, why TMG can cause a problem.
This will definitely make things even more complicated/overwhelming but we need to consider them.
It's possible the glycine is the actual one 'causing' or rather revealing another deficiency or problem.
A quick test with glycine would be able to rule that out/confirm that. If you feel the same with glycine as you did with TMG you know the problem is not the methyl donation but the amino acid.
In my last post I mentioned I was experiencing issues with magnesium. In fact I was getting magnesium deficiency symptoms but taking magnesium, while resolving some of the symptoms, caused more pain and depression. I'm happy to have figured this out (again...).
Upping B2 in FMN form resolved that problem. I went over my notes and noticed that about three weeks ago I had lowered my FMN dose and had switched from using it between gum and lip to using it as a sublingual. Turns out that was a double whammy causing massive issues with magnesium. I'm in the process of figuring out an optimal amount in relation to enough magnesium.
So don't expect the same dose from them if you actually use them as a sublingual compared to using them between lip and gum which yields a much higher effective delivered dose (I know, obvious, but I thought I the lower dose would still have been enough, guess not)
After that, probably in a few weeks, I'll try the TMG and Phosphatidylcholine again to see if enough B2 (and magnesium) has changed anything to my response to those. I wanted to throw that out in case you have that (FMN) on hand now and are willing to try that out. That would help you and me (and anyone having the same problem) as well
On the 9 amino acids and SAMe; I've added them to my regime, since they yielded benefits even with the above problems with B2 and magnesium, though I'm holding off on ramping those up until the B2 and magnesium stabilize.
I did notice the positive effect tapered off when the magnesium/B2 became a big problem, so there's going to be a link between the two. But then what process in the body wouldn't be affected by a B2 or magnesium deficiency?!
Still, seems paramount to resolve those first to get maximum benefit from the amino's and SAMe.
That said there are a few more possibilities, besides low Methionine/Homocysteine/Methylfolate/Methylcobalamin, why TMG can cause a problem.
This will definitely make things even more complicated/overwhelming but we need to consider them.
It's possible the glycine is the actual one 'causing' or rather revealing another deficiency or problem.
A quick test with glycine would be able to rule that out/confirm that. If you feel the same with glycine as you did with TMG you know the problem is not the methyl donation but the amino acid.
In my last post I mentioned I was experiencing issues with magnesium. In fact I was getting magnesium deficiency symptoms but taking magnesium, while resolving some of the symptoms, caused more pain and depression. I'm happy to have figured this out (again...).
Upping B2 in FMN form resolved that problem. I went over my notes and noticed that about three weeks ago I had lowered my FMN dose and had switched from using it between gum and lip to using it as a sublingual. Turns out that was a double whammy causing massive issues with magnesium. I'm in the process of figuring out an optimal amount in relation to enough magnesium.
So don't expect the same dose from them if you actually use them as a sublingual compared to using them between lip and gum which yields a much higher effective delivered dose (I know, obvious, but I thought I the lower dose would still have been enough, guess not
)After that, probably in a few weeks, I'll try the TMG and Phosphatidylcholine again to see if enough B2 (and magnesium) has changed anything to my response to those. I wanted to throw that out in case you have that (FMN) on hand now and are willing to try that out. That would help you and me (and anyone having the same problem) as well
On the 9 amino acids and SAMe; I've added them to my regime, since they yielded benefits even with the above problems with B2 and magnesium, though I'm holding off on ramping those up until the B2 and magnesium stabilize.
I did notice the positive effect tapered off when the magnesium/B2 became a big problem, so there's going to be a link between the two. But then what process in the body wouldn't be affected by a B2 or magnesium deficiency?!
Still, seems paramount to resolve those first to get maximum benefit from the amino's and SAMe.
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Hi @MacGyver I have tried glycine and to start with it helped my anxiety a lot and mood then after a few days I noticed my mood get worse about an hour after taking it and gave me dizzyness too so stopped it. Took between 500mg - 2 grams daily in divided doses.
Could you explain what b2 has to do with magnesium? If you already have then just point me to the post. I have run out of FMN but got active b2 capsules. What dosage of FMN did you take?
Could you explain what b2 has to do with magnesium? If you already have then just point me to the post. I have run out of FMN but got active b2 capsules. What dosage of FMN did you take?
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- 66
Hi @MacGyver just wondered how you were getting on? Had any luck at all? I haven't yet. Have found a Nutrigenomics practitioner here in the uk so hopefully will get some help solving these puzzles soon. Will let you know. Annie
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- 30
MacGyver wrote:
So that would mean anything that increases Homocysteine would help here which means:
Hi MacGyver,
Thanks for a very interesting post!
I just want to check if I got you right:
• If one responds positively to TMG and/or choline, the methionine (folate/B12) pathway is working correctly and it’s safe to use TMG/choline as desired without worrying about diverting the methylation flow away from the B12/folate pathway.
If so, I wonder what you would make of my story:
• At first, I had a wild and overwhelming reaction to low dose methylfolate in conjunction with high dose B12. My methylation was so over the top that I even induced a textbook serotonin syndrome with these two supplements alone.
• After a few months I started requiring megadoses of methylfolate just to stay away from undermethylation, and sometimes even that didn’t do the trick.
• I ended up in some kind of middle ground where B12/folate (mega mega doses) keeps me reasonably methylated and functional, but no way near the initial bursts of energy that I experienced and not enough to make me feel like myself.
• Adding TMG to this mix gives me a nice, subtle sense of well-being and increased physical stamina, but it doesn’t increase my potassium need—and it seems to decrease the half life of B12, suggesting that TMG induces a folate deficiency (since folate increases B12 half life according to Freddd)
• Adding moderate to large amounts of choline or lecithin gives me back that WILD overmethylation feeling with elation, crazy energy bursts, and insatiable hypokalemia. Thus, lecithin initially seemed like a life saver but turned out to cause the same trouble as TMG: it made B12 much less effective.
So, I’m seeing positive ”primary” effects from both TMG and lecithin/choline, but that seems to happen at the expense of the folate/B12 pathway (deficiency symptoms of both vitamins surface).
This would contradict your hypothesis, even though it makes total sense to me in theory.
* * *
Finally, I've just tried SamE for the first time. 200 mg made me quite agitated but it definitely potentiates and works synergistically with folate/B12—sort of brings them back to life—and does induce some hypokalemia (which for me is always a sign of fine methylation), so I will stick to it, possibly in half the dose. After adding SamE I’ve also been able to reduce my 30 mg methylfolate dosage to 25 mg.
Does this give you any clue as to what’s going on?
Grateful for input!
So that would mean anything that increases Homocysteine would help here which means:
- Taking Methionine
- Taking things that spare Methionine:
- Cysteine (might increase urea excretion so not the best idea initially) (hello NAC btw, although that would contradict your experience, maybe exactly because it increases the urea burden EDIT: NAC lowers homocysteine, see my post below)
- Carnitine which is methionine + lysine
- Taking SAMe
- Taking things that spare SAMe:
- Creatine
- Increasing absorption of Methionine from food via a properly working digestive system:
- Digestive enzymes to break down protein
- Stimulate bile so endogenous enzymes are released
- Increasing stomach acid if low since bile is released in response to correct acidity of food
- SAMe is know to increase bile...
- Eating a protein rich diet, preferably meat
- Making the CBS pathway function normally since it otherwise might be a drain on homocysteine as well
Hi MacGyver,
Thanks for a very interesting post!
I just want to check if I got you right:
• If one responds positively to TMG and/or choline, the methionine (folate/B12) pathway is working correctly and it’s safe to use TMG/choline as desired without worrying about diverting the methylation flow away from the B12/folate pathway.
If so, I wonder what you would make of my story:
• At first, I had a wild and overwhelming reaction to low dose methylfolate in conjunction with high dose B12. My methylation was so over the top that I even induced a textbook serotonin syndrome with these two supplements alone.
• After a few months I started requiring megadoses of methylfolate just to stay away from undermethylation, and sometimes even that didn’t do the trick.
• I ended up in some kind of middle ground where B12/folate (mega mega doses) keeps me reasonably methylated and functional, but no way near the initial bursts of energy that I experienced and not enough to make me feel like myself.
• Adding TMG to this mix gives me a nice, subtle sense of well-being and increased physical stamina, but it doesn’t increase my potassium need—and it seems to decrease the half life of B12, suggesting that TMG induces a folate deficiency (since folate increases B12 half life according to Freddd)
• Adding moderate to large amounts of choline or lecithin gives me back that WILD overmethylation feeling with elation, crazy energy bursts, and insatiable hypokalemia. Thus, lecithin initially seemed like a life saver but turned out to cause the same trouble as TMG: it made B12 much less effective.
So, I’m seeing positive ”primary” effects from both TMG and lecithin/choline, but that seems to happen at the expense of the folate/B12 pathway (deficiency symptoms of both vitamins surface).
This would contradict your hypothesis, even though it makes total sense to me in theory.
* * *
Finally, I've just tried SamE for the first time. 200 mg made me quite agitated but it definitely potentiates and works synergistically with folate/B12—sort of brings them back to life—and does induce some hypokalemia (which for me is always a sign of fine methylation), so I will stick to it, possibly in half the dose. After adding SamE I’ve also been able to reduce my 30 mg methylfolate dosage to 25 mg.
Does this give you any clue as to what’s going on?
Grateful for input!
TMG, DMG, and SAM-e all seem to have significant positive effects on me... Since you know more than me about stomach acid and betaine hcl, maybe you can tell me if this is related?
some relevant info
- have BHMT-02 and BHMT -08 homozygous BUT I've read that these are not clinically relevant, so maybe something else is causing me to require more TMG/DMG/SAM-e/Glycine?? This brings me to stomach acid, liver, gallbladder... hoping that you can explain something to me or add insight... e.g. I have low stomach acid and that's caused a cascade of problems, but not sure
- all of these supps seem to poop out at some time... my hypothesis is that i'm using up a co-factor after a couple of months and if I understood better, then I could add something or adjust the protocol, but i'm totally in the dark..
- TMG really made my head / cognition better for a couple of hours today - which is great!
- these supps do not CAUSE depression, or cure it, but they do help brain fog - one of my most intractable symptoms
- no excess homocysteine, either
I'm sorry @ebethc, I'm not up to speed on the SNPs. I still have low stomach acid, and think it may be an overall bacterial imbalance thing, but not sure. I got my ubiome results back last week, and had ZERO bifido bacteria and almost no lactobacillus and no f. prausnitzii which was low in the Lipkin studies.
And I just saw @Hip's mention of the connection to depression, which I have at low levels, but not sure if there's a connection in my case. I do think though that if targeted probiotic therapy (probably high dose) helps w/digestion and inflammation, that it might help w/stomach acid production as well.
And I just saw @Hip's mention of the connection to depression, which I have at low levels, but not sure if there's a connection in my case. I do think though that if targeted probiotic therapy (probably high dose) helps w/digestion and inflammation, that it might help w/stomach acid production as well.
juniemarie
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TMG makes me depressed as well
I'm coming around to believe almost everything about our health is connected to microbiome imbalances. Several nutrient deficiencies are connected to low stomach acid:
https://en.wikipedia.org/wiki/Achlorhydria#Causes
Me too
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I feel great taking TMG. Been taking about 2.4 grams twice a day. Hetero for MTHFR and 1 Copy of C677T. No depression or fatigue.
do you think it makes sense to always take folate w TMG or SAM-e?
I've never noticed much of a difference taking M-B12, but playing around w TMG or SAM-e + Folate and maybe P5P, Zinc, Magnesium might be a good idea
EDIT: any preference for L-Methylfolate w calcium salt VS L-Methylfolate w glucosamine salt (I believe the marketing names are metafolin vs quatrefolic)? thx
Hip
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I am not sure that I understand the question.
Hip
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I don't know, I guess it's worth trying.
I have the same problem. I came across this thread https://www.longecity.org/forum/topic/93984-the-reason-why-choline-causes-depression/
I haven't found any solution except to take benedryl.
I haven't found any solution except to take benedryl.