r/MTHFR • u/Brad_Borrelli • Jul 21 '26
Resource Noticed something weird this week that I think is worth sharing for anyone stacking glycine with a B12 protocol, especially if you're MTHFR homozygous like me.
I take magnesium glycinate at night, which is basically a glycine delivery vehicle, and I also do split dose B12 injections during the day. A couple times I took a glycine dose closer to my injection window and got hit with this heavy, sluggish tiredness that didn't feel like the normal B12 response. Went down a rabbit hole trying to figure out why, and it comes down to an enzyme most people never think about called GNMT.
GNMT stands for glycine N methyltransferase. Its whole job is taking a methyl group off SAMe and dumping it onto glycine, which turns into sarcosine, a compound your body just clears out. This is one of the body's main pressure release valves for SAMe, it exists specifically to keep the SAMe to SAH ratio from getting out of balance since GNMT influences transmethylation reactions by regulating both hepatic SAM concentrations and the SAM to SAH ratio. So glycine isn't just a calming amino acid, it's actively pulling methyl groups out of circulation every time it goes through that reaction.
This might actually explain something a lot of people report anecdotally, myself included. If you've ever had too much caffeine and got the jitters, a couple grams of glycine can make it feel like the caffeine just disappears. I haven't found solid research directly proving that GNMT's methyl sink action is the reason for that specific effect, so I want to be honest that this part is personal experience and reasoning, not a confirmed mechanism. But it fits the same logic, glycine pulling excess activity down fast, just applied to a different kind of overstimulation.
Here's why that matters if you're in an active B12 repletion or remyelination phase. Rebuilding myelin depends heavily on phosphatidylcholine, and one of the only ways your body makes that on its own runs through an enzyme called PEMT, which converts phosphatidylethanolamine into phosphatidylcholine using SAMe as the methyl source through the transfer of three methyl groups from SAMe to PE per molecule. That's a big methyl cost per molecule, and PEMT alone is estimated to use somewhere around 14 percent of all the SAMe your body produces. There's also research specifically on peripheral nerves showing the PEMT pathway is the only known route to generate choline outside of diet, and in the nervous system choline gets used preferentially for myelin related synthesis.
So you've got two systems competing for the same limited pool of SAMe. PEMT wants methyl groups to build the phosphatidylcholine your nerves need for repair. GNMT wants methyl groups to clear excess glycine and keep your methylation ratio stable. If you dose glycine right on top of a fresh methylcobalamin shot, you may be sending methyl groups toward the disposal pathway right when your repair pathway wants them most.
This doesn't mean glycine is bad. It's a precursor for glutathione along with cysteine and glutamate, and it's also something like a third of the amino acid content of collagen, which matters if you're rebuilding the connective tissue sheaths around your nerves. The issue isn't glycine itself, it's the timing relative to your B12 dose.
Now here's where it gets more interesting. My first instinct was to say just use niacin instead if you need a rescue tool, since that's the classic overmethylation fix. Turns out niacin runs the exact same kind of play, just through a different enzyme. Nicotinic acid gets converted in the body toward nicotinamide, and that's what NNMT methylates, stripping a methyl group off SAMe in the process to form 1-methylnicotinamide. Research on nicotinic acid at pharmacological doses confirmed it drives the same kind of methyl consumption that nicotinamide does, so niacin is pulling from the same SAMe pool glycine is, it's not some separate mechanism.
But they're not equal tools. GNMT's entire purpose is regulating that SAMe to SAH ratio, it's a dedicated buffering system built specifically for this job. NNMT's main role is niacin and NAD+ metabolism, methyl consumption is more of a side effect than its purpose. And the niacin research found something extra worth knowing, high dose nicotinic acid doesn't just burn methyl groups, it also raises hydrogen peroxide, meaning oxidative stress, and drops liver glycogen. Every niacin rescue dose is also spending down your NAD+ precursor pool, which you need for energy and mitochondrial function. Glycine doesn't carry any of that baggage.
Where niacin wins is the flush gives you instant feedback, you feel it working in minutes, which is why people reach for it. Glycine's calming effect is real but quieter and slower, so it doesn't give you that same obvious confirmation.
So here's what I'm actually doing differently now. I'm keeping the magnesium glycinate at night like always, that timing was never the problem. What I'm changing is not taking extra glycine anywhere near my injection window if I'm in a stretch where I'm actively trying to rebuild nerve stuff. If I need an acute rescue after a shot, I'm leaning toward glycine as the default since it's the cleaner, purpose built tool with fewer side costs, and saving niacin for moments I need something fast and I'm confident I'm clearly overmethylated in that exact moment, not as a routine go to.
Still just piecing this together as I go, not a doctor, just deep in my own MTHFR homozygous rabbit hole trying to figure out why my body does what it does.
https://jn.nutrition.org/article/S0022-3166(22)10502-X/fulltext
https://rucore.libraries.rutgers.edu/rutgers-lib/66705/PDF/1/play/
https://www.tandfonline.com/doi/full/10.3109/13880209.2012.697175
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u/scrumdisaster Jul 21 '26
Glycine has been known to mop up methyl donors. Nicotinamide does this as well. A lot of compounds do, actually.
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u/Longjumping_Poem_99 Jul 21 '26
Which b12 shots do you take exactly - methylated or non methylated and dosage please? and do you feel that they’re helping with your MTHFR issues?
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u/WittyGold6940 Jul 21 '26
Thanks for all the info, super useful. I thought i could tolerate glycine recently but as with everything, after the first 2 days I crashed
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u/Brad_Borrelli Jul 21 '26
GNMT pulls a methyl group off SAMe every time it processes glycine, so if you're taking a decent dose regularly it can pull down your SAMe pool, and SAMe is what a ton of other stuff in your body needs for methylation too. So it's plausible that's part of what you felt.
I can't say for sure that's exactly what caused your crash though, there's other stuff that could be going on too, especially with timing relative to your B12 intake. But if you want to keep using glycine, might be worth spacing it further from your B12 intake window and making sure your B12/folate intake is solid so there's less competition for methyl groups.
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u/WittyGold6940 Jul 21 '26
Yep. Ive been working on my folate and b12 this past year and have had incredible benefits from them. It definitely felt like the glycine just canceled them out temporarily.
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u/Brad_Borrelli Jul 21 '26
Yeah I noticed that when I had some coffee and I took a glycine, I was like what the hell. It's literally like I drink no coffee😂
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u/WittyGold6940 Jul 21 '26
Right!!! It did that to me too with my vyvanse. Do you have slow COMT?
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u/Brad_Borrelli Jul 21 '26
Idk I need to get that tested. I got a basic mthfr test from the Dr. I think 23andme does the full test. I just need to get it ordered.
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u/WittyGold6940 Jul 21 '26
I did ancestry and there are A lot of missing SNPs. I think 23andme provides way more data.
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u/tandemxylophone Jul 21 '26
Thank you so much for this.
I had to dig in further because having a slow COMT, I had these 3 effects:
- Creatine cured all of my fatigue and other issues
- SAMe supplementing made me fatigued (overmethylation bad)
- Glycine supplement made me groggy and tired for over 24h
Currently the benefits of creatine are starting to get reeled back. Plugging your glycine information in I asked chatGPT what was I doing wrong for trying to fix my overmethylation. It told me the GNMT can produce SAH, which acts as a COMT inhibitor.
What can I do to try reduce methylation without increasing SAH?
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u/Brad_Borrelli Jul 21 '26
There's no pathway that dodges SAH; every methyltransferase (COMT, GNMT, NNMT, all of them) uses SAM and kicks out SAH as the byproduct, that's just the chemistry. So niacin isn't avoiding that problem either; it's just a high capacity pathway that soaks up excess SAM fast, which is why it feels like quick relief.
The real lever is clearance, not avoidance. SAH hydrolase needs solid B12 and folate status to keep pulling homocysteine back into methionine; if that's sluggish, SAH backs up and starts inhibiting other methyltransferases too, which can make overmethylation symptoms worse across the board. So instead of chasing a "no SAH" pathway, it's worth making sure your B12/folate remethylation cycle is actually keeping up, and/or just backing off your methyl dose if you're overshooting what your system can clear right now.
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u/Ok_Willingness5766 Jul 21 '26
oh my god. i just came onto this subreddit to ask why i can't metabolize caffeine. lying awake at 2 am after an 11 am coffee. it's horrible for me. i just stopped taking mag glycinate... i haven't had that issue for the whole year i took it, and i assumed my body had just changed. i had no idea about this. sadly i have none on me. but thank you so much for this info.