Glycine has been a big improvement in our fatigue, sleep, and general health.
I wonder if we have an underlying B1 deficiency but will also consider folate moving forward. We try things slowly so it will be a while before I get to folate.
I think I totally had this. I ramped down my use and it got better. I now only take half the dose and if I start having trouble I dial it back. Nice to know about the glycine. Thanks
Chris do you have a methyl cycle/metabolism biochem chart you refer to? It would help a lot to have something to help visualize if one metabolite backs up how it could affect everything else, etc
whenever i hear all the benefits of creatine i wonder if they are actually true.. i am 58 year old endurance athelete, i tried supplementing with creatine many times and i never felt any difference in my performance , i only gained weight.. wish you can dedicate one podcast for creatine good and bad.. Thanks
Can you give in layman’s terms exactly what to do here? My 18 year old baseball player son takes Creatine (not every day) & definitely has insomnia. He does have the single mthfr c677t gene mutation as well (o have the double). Thx!
I`ve been experiencing some uncommon and unpleasant effects on Creatine this Christmas. The first day (21st of December) I took 1 gram with the breakfast and it gave me euphoria all day and the next too. Then I took 0,5 g with breakfast, lunch and for a couple of evenings. I did notice a difficulty to get asleep or a need of less sleep, but the worst effect was by the 3-4th day of starting with it, is that it produced me a congested nose for a while, maybe for 1-2 hours and then went away. But by the 10th day or so, it didn't go away. And I had a congested nose with which I couldn't breath through even after stopping the creatine intake after the 10th day of the start. Now I am having anti-inflammatory medicines and is getting better by the 6th day. I have subclinical Hypothyroidism with Hashimoto. By the time of taking creatine, I was also taking 250 mg TMG for breakfast and for lunch. Glycine and TMG gives me insomnia, which I can only compensate taking tryptophan. I thought that glycine, TMG and maybe creatine would lower my tryptophan like collagen does.
I've found some publications talking about the phenomenon of the airway inflammation:
- Effect of Creatine Supplementation on the Airways of Youth Elite Soccer Players (Simpson AJ et al. 2019)
- Creatine supplementation impairs airway inflammation in an experimental model of asthma involving P2 × 7 receptor (Garcia et al. 2019)
- Creatine Supplementation Augments Chronic Allergic Airway Inflammation and Remodelling: from Mice to Human Evidence (Garcia et al. 2019)
I take creatine as part of my migraine treatment stack. One feature of my migraines is extreme brain fog, identical to what I get if I take too long of a nap in the afternoon. In researching I found that the fog is likely caused by a buildup of adenosine (this also makes you sleepy at night.) I found out that creatine forces [edit: facilitates] the conversion of adenosine to ATP, thereby lowering the level of adenosine. Sure enough, taking creatine helps significanly reduce brain fog when I have a migraine. So in otherwise healthy people, the creatine may be simply reducing adenosine and therefore interfering with sleep. For that reason, if I don't have a migraine, I only take creatine in the morning (and never more than 500 mg)
(by the way, the other supplements in my migraine stack besides 500 mg of creatine are riboflavin 100mg, COQ10 100mg, and pantothenic acid 500mg. It works well to stop a migraine for me).
In perusing pubmed briefly the other day, creatine activates some adenosine receptors. It definitely can't force the adenosine to become ATP, but it could prevent cytosolic ATP from being broken down into adenosine by keeping it phosphorylated, which would reduce the production of adenosine and its export from the cell.
I believe your experience, but I doubt your mechanistic explanation is true. I don't see how creatine would be able to "force the conversion of adenosine to ATP."
Yes, poor wording on my part. Maybe it would be more accurate to say "creatine facilitates the conversion of adenosine to ATP". Thanks for sharing your knowledge and research Dr Masterjohn.
Interesting. I've kind of noticed this, but creatine makes me feel like I need less sleep. I usually sleep about 8 hours, but on creatine I was getting around 6 hours, but I felt the same. I didn't have trouble falling asleep but I was waking up earlier.
There's some support for creatine reducing sleep need in animals. I feel like so little is known about it that I'd want to measure lots of things to prove to myself I only needed 6h sleep if that's what I was getting.
Feeling fantastic on creatine, 3 g daily with breakfast 40 minutes before any caffeine (started taking it 4 months ago) - mood, energy, cognition, lifting weights, can handle things without taking a nap midday, falling asleep very fast, but waking up early, like hour or hour and a half earlier, not feeling tired from it but on a purely psychological level worrying that this can't be good if it affects sleep...
I've experienced this effect as well -- thanks for tackling it!
The SHMT reaction discussed here is the one shown on most one-carbon diagrams, but the glycine cleavage system runs in parallel to it, and it moves glycine in the opposite direction. That is, as SHMT normally synthesizes glycine from serine+THF, the GCS uses glycine+THF to create 5,10-methylene-THF. I've seen sources say the GCS moves 40% of "overall glycine flux", which makes it sound like it rivals SHMT for throughput. (My notes say I got this from a textbook called "Folate in Health & Disease", and it seemed supported by PMC2666368, a paper in which they used computer modelling to study one-carbon flow in the context of B6 deficiency.)
But I've never heard this outside of these sources -- all the attention is on SHMT --so I've wondered if I'm misinterpreting something. Otherwise, it seems like the GCS would counteract the above effect (to some degree) when 5,10-methylene-THF builds up?
It does not run in the opposite direction. It destroys glycine.
I think it’s pretty clear that GCS disposes of excess glycine. It’s also mitochondrial rather than cytosolic so they aren’t really running in parallel as the pools of substrates are not equilibrated.
Even if you were looking at it correctly and everything was equilibrated with all movements being linearly proportional to the substrates being discussed, you’d still be shutting down nearly all of your glycine synthesis and 40% of your glycine breakdown which is still a massive loss of glycine, though I don’t think that’s in any case the right way to look at it.
I think it would be useful to look at figure 2 in the “folic acid” chapter of Modern Nutrition in Health and Disease.
There you’ll see that GCS operates in the the mitochondria and everything discussed in my article is cytosolic, and that the only pools that equilibrated between compartments are amino acids and formate. So the carbon from GCS is destined to become, if anything cytosolic, cytosolic formate.
The cytosolic pool of 5,10-methylene-THF is directly equilibrated between SHMT1 and MTHFR.
It isn’t directly equilibrated with GCS.
Further, there are four substrates to convert THF to 5,10-methenyl-THF in mitochondria, the others being serine, sarcosine, and dimethylglycine, so these are all competing with GCS. As such the abundance of glycine rather than the abundance of THF is going to drive the proportion fulfilled by GCS, because the carbon can so easily be gotten from the others.
In fact, were the concentrations of carbon sources similar, buildup of 5,10-methenyl-THF in mitochondria would slow glycine synthesis from mSHMT as much as it would slow down glycine cleavage from GCS.
Meanwhile the direction of synthesis in cytosol is glucose —> serine —> glycine and the activity of MTHFR will directly influence the cytosolic ratio of THF/5,10-CH2-THF which will directly control the flow of the serine —> glycine step.
I am 68 yo F supplementing with Creatine to help with bone density and increased muscle mass. I have added muscle and feel I have less saggy skin and some bone improvements, so I don’t want to stop. I have also read there are cognitive benefits for older people. But I do suffer from insomnia (waking up early or after a few hours of sleep). I take collagen at the same time as the creatinine, and then again later in the day, so I think I’m getting glycine already. Any other suggestions? Should I perhaps only take Creatinine on my workout days?
FWIW, I always have insomnia from creatine, as well as methyl folate (400mcg or more). Interestingly, these side effects were gone for a period when I was very defficient in molybdenum. The reactions to creatine and folate came back after I began supplementing it. We know that molybdenum deficiency can cause accumulation of methionine, therefore, there would not be enough SAMe, which would also explain why I was very depressed at the time and had complete erectile dysfunction and would explain why creatine or folate did not have any negative effect on me at the time.
A few years ago, I have tried experimenting with glycine at night when I was experiencing insomnia from creatine. It didn't help at all, so at least for me, it's something else.
I think that something else is *maybe* a kind of... compensatory response from adrenal glands, provoked by an imbalance between breakdown (SAMe) and synthesis of neurotransmitters. So the usual suspects.. oxidative stress (BH4), infections, yada yada.
Or alternatively/additionally, if I understand correctly, the shutting off of MTHFR could potentially cause a reduction in 10 formyl THF, which could contribute to lower synthesis of BH4, therefore explaining why some seemingly healthy people get this side effect. Maybe some kind of combination of SNPs related to folate and methylation predispose to this.
It would be interesting to see if specifically folinic acid might help with this. I haven't tried it myself for insomnia, but have, interestingly, experienced improvement in irritability caused by methylfolate, after taking folinic acid.
"We know that molybdenum deficiency can cause accumulation of methionine"
How do we know this? Why does it do that?
"the shutting off of MTHFR could potentially cause a reduction in 10 formyl THF"
How would it do that?
If you are molybdenum deficient, the most proximate difference that would occur to SAMe metabolism is that sulfite would not be able to deliver its electrons to complex IV of the respiratory chain, so the most obvious thing to look at is if you are backing up the respiratory chain.
I doubt you can rule out glycine. You didn't say anything about how much you took, but I doubt you took enough to completely rule it out.
I have no idea why it does that, but I'm going by the study that you have mentioned yourself in various contexts, the one on a Crohn's patient with molybdenum deficiency.
I don't remember the exact dose of glycine that I took at night, but it was most likely 5g. I have also tried more during the day for general uncomfortable side effects from methylfolate, as per your suggestions of glycine as a buffer and it also didn't help. I think this theory is insufficient to explain both situations, be it insomnia or anger/irritability.
In terms of reduction of 10 formyl THF:
From your article:
"Thus, an accumulation of 5,-10-methylene-tetrahydrofolate without MTHFR- and methionine synthase-mediated release of tetrahydrofolate will strongly inhibit the synthesis of glycine and will strongly favor the conversion of glycine to serine"
At first I thought 5, 10 methylene THF would be trapped, but I looked again, and now I see that it can actually be converted back to THF via TYMS and DHFR, I missed that before.
Still, I would guess that this may not be the most efficient and optimal way and could contribute somewhat, but that's only my layman speculation. As everything else is..
I don't see where you are getting the methionine accumulation from my description.
The glycine buffering issue cannot be tested just using glycine as there are numerous factors that regulate the function and expression of GNMT.
Thymidylate synthesis will likely be regulated by the need for thymidylate, so SHMT1 is likely to act as the release valve for spillover of extra 5,10-CH2-THF.
Sorry, maybe I wasn't clear. You didn't mention the methionine itself, but I think you did mention this case study, which talks about elevated methionine levels:
I see, looks like the inability to clear the sulfite generated by the methionine is backing up its upstream metabolism. (Of course he was on methionine in the TPN, but they do not that reducing it left his methionine levels still higher than normal).
Your articles are like having a personal coach at my side! So grateful.
It gives me non-restful dreams. In the morning, I feel like I've been up all night.
Glycine has been a big improvement in our fatigue, sleep, and general health.
I wonder if we have an underlying B1 deficiency but will also consider folate moving forward. We try things slowly so it will be a while before I get to folate.
I think I totally had this. I ramped down my use and it got better. I now only take half the dose and if I start having trouble I dial it back. Nice to know about the glycine. Thanks
Chris do you have a methyl cycle/metabolism biochem chart you refer to? It would help a lot to have something to help visualize if one metabolite backs up how it could affect everything else, etc
Great article, thanks!
Does creatine alter the cognitive effects of caffeine?
I don't know, I would think that would be incredibly individual, like the cognitive effects of caffeine are.
whenever i hear all the benefits of creatine i wonder if they are actually true.. i am 58 year old endurance athelete, i tried supplementing with creatine many times and i never felt any difference in my performance , i only gained weight.. wish you can dedicate one podcast for creatine good and bad.. Thanks
This might help:
https://chrismasterjohnphd.substack.com/p/047-alex-leaf-answers-a-question
Can you give in layman’s terms exactly what to do here? My 18 year old baseball player son takes Creatine (not every day) & definitely has insomnia. He does have the single mthfr c677t gene mutation as well (o have the double). Thx!
See the last paragraph.
I`ve been experiencing some uncommon and unpleasant effects on Creatine this Christmas. The first day (21st of December) I took 1 gram with the breakfast and it gave me euphoria all day and the next too. Then I took 0,5 g with breakfast, lunch and for a couple of evenings. I did notice a difficulty to get asleep or a need of less sleep, but the worst effect was by the 3-4th day of starting with it, is that it produced me a congested nose for a while, maybe for 1-2 hours and then went away. But by the 10th day or so, it didn't go away. And I had a congested nose with which I couldn't breath through even after stopping the creatine intake after the 10th day of the start. Now I am having anti-inflammatory medicines and is getting better by the 6th day. I have subclinical Hypothyroidism with Hashimoto. By the time of taking creatine, I was also taking 250 mg TMG for breakfast and for lunch. Glycine and TMG gives me insomnia, which I can only compensate taking tryptophan. I thought that glycine, TMG and maybe creatine would lower my tryptophan like collagen does.
I've found some publications talking about the phenomenon of the airway inflammation:
- Effect of Creatine Supplementation on the Airways of Youth Elite Soccer Players (Simpson AJ et al. 2019)
- Creatine supplementation impairs airway inflammation in an experimental model of asthma involving P2 × 7 receptor (Garcia et al. 2019)
- Creatine Supplementation Augments Chronic Allergic Airway Inflammation and Remodelling: from Mice to Human Evidence (Garcia et al. 2019)
Interesting, thanks for sharing.
I take creatine as part of my migraine treatment stack. One feature of my migraines is extreme brain fog, identical to what I get if I take too long of a nap in the afternoon. In researching I found that the fog is likely caused by a buildup of adenosine (this also makes you sleepy at night.) I found out that creatine forces [edit: facilitates] the conversion of adenosine to ATP, thereby lowering the level of adenosine. Sure enough, taking creatine helps significanly reduce brain fog when I have a migraine. So in otherwise healthy people, the creatine may be simply reducing adenosine and therefore interfering with sleep. For that reason, if I don't have a migraine, I only take creatine in the morning (and never more than 500 mg)
(by the way, the other supplements in my migraine stack besides 500 mg of creatine are riboflavin 100mg, COQ10 100mg, and pantothenic acid 500mg. It works well to stop a migraine for me).
In perusing pubmed briefly the other day, creatine activates some adenosine receptors. It definitely can't force the adenosine to become ATP, but it could prevent cytosolic ATP from being broken down into adenosine by keeping it phosphorylated, which would reduce the production of adenosine and its export from the cell.
I believe your experience, but I doubt your mechanistic explanation is true. I don't see how creatine would be able to "force the conversion of adenosine to ATP."
Yes, poor wording on my part. Maybe it would be more accurate to say "creatine facilitates the conversion of adenosine to ATP". Thanks for sharing your knowledge and research Dr Masterjohn.
Interesting. I've kind of noticed this, but creatine makes me feel like I need less sleep. I usually sleep about 8 hours, but on creatine I was getting around 6 hours, but I felt the same. I didn't have trouble falling asleep but I was waking up earlier.
There's some support for creatine reducing sleep need in animals. I feel like so little is known about it that I'd want to measure lots of things to prove to myself I only needed 6h sleep if that's what I was getting.
Feeling fantastic on creatine, 3 g daily with breakfast 40 minutes before any caffeine (started taking it 4 months ago) - mood, energy, cognition, lifting weights, can handle things without taking a nap midday, falling asleep very fast, but waking up early, like hour or hour and a half earlier, not feeling tired from it but on a purely psychological level worrying that this can't be good if it affects sleep...
It could have reduced your sleep need, judge by how you feel and objective measures of health.
I've experienced this effect as well -- thanks for tackling it!
The SHMT reaction discussed here is the one shown on most one-carbon diagrams, but the glycine cleavage system runs in parallel to it, and it moves glycine in the opposite direction. That is, as SHMT normally synthesizes glycine from serine+THF, the GCS uses glycine+THF to create 5,10-methylene-THF. I've seen sources say the GCS moves 40% of "overall glycine flux", which makes it sound like it rivals SHMT for throughput. (My notes say I got this from a textbook called "Folate in Health & Disease", and it seemed supported by PMC2666368, a paper in which they used computer modelling to study one-carbon flow in the context of B6 deficiency.)
But I've never heard this outside of these sources -- all the attention is on SHMT --so I've wondered if I'm misinterpreting something. Otherwise, it seems like the GCS would counteract the above effect (to some degree) when 5,10-methylene-THF builds up?
It does not run in the opposite direction. It destroys glycine.
I think it’s pretty clear that GCS disposes of excess glycine. It’s also mitochondrial rather than cytosolic so they aren’t really running in parallel as the pools of substrates are not equilibrated.
Even if you were looking at it correctly and everything was equilibrated with all movements being linearly proportional to the substrates being discussed, you’d still be shutting down nearly all of your glycine synthesis and 40% of your glycine breakdown which is still a massive loss of glycine, though I don’t think that’s in any case the right way to look at it.
I think it would be useful to look at figure 2 in the “folic acid” chapter of Modern Nutrition in Health and Disease.
There you’ll see that GCS operates in the the mitochondria and everything discussed in my article is cytosolic, and that the only pools that equilibrated between compartments are amino acids and formate. So the carbon from GCS is destined to become, if anything cytosolic, cytosolic formate.
The cytosolic pool of 5,10-methylene-THF is directly equilibrated between SHMT1 and MTHFR.
It isn’t directly equilibrated with GCS.
Further, there are four substrates to convert THF to 5,10-methenyl-THF in mitochondria, the others being serine, sarcosine, and dimethylglycine, so these are all competing with GCS. As such the abundance of glycine rather than the abundance of THF is going to drive the proportion fulfilled by GCS, because the carbon can so easily be gotten from the others.
In fact, were the concentrations of carbon sources similar, buildup of 5,10-methenyl-THF in mitochondria would slow glycine synthesis from mSHMT as much as it would slow down glycine cleavage from GCS.
Meanwhile the direction of synthesis in cytosol is glucose —> serine —> glycine and the activity of MTHFR will directly influence the cytosolic ratio of THF/5,10-CH2-THF which will directly control the flow of the serine —> glycine step.
I am 68 yo F supplementing with Creatine to help with bone density and increased muscle mass. I have added muscle and feel I have less saggy skin and some bone improvements, so I don’t want to stop. I have also read there are cognitive benefits for older people. But I do suffer from insomnia (waking up early or after a few hours of sleep). I take collagen at the same time as the creatinine, and then again later in the day, so I think I’m getting glycine already. Any other suggestions? Should I perhaps only take Creatinine on my workout days?
Does the creatine worsen your insomnia?
I guess I have to try going without it. It never occurred to me that it could be the issue till I saw this. I will test it out.
Chris your grasp of these matters is second to none.
However your only one man, and there’s appears so many edge cases.
Will we get to a stage of having a ‘ChrisGPT’? That would be the ultimate fix it seems.
Thanks.
Workin on it
You will save so many, good luck with everything.
FWIW, I always have insomnia from creatine, as well as methyl folate (400mcg or more). Interestingly, these side effects were gone for a period when I was very defficient in molybdenum. The reactions to creatine and folate came back after I began supplementing it. We know that molybdenum deficiency can cause accumulation of methionine, therefore, there would not be enough SAMe, which would also explain why I was very depressed at the time and had complete erectile dysfunction and would explain why creatine or folate did not have any negative effect on me at the time.
A few years ago, I have tried experimenting with glycine at night when I was experiencing insomnia from creatine. It didn't help at all, so at least for me, it's something else.
I think that something else is *maybe* a kind of... compensatory response from adrenal glands, provoked by an imbalance between breakdown (SAMe) and synthesis of neurotransmitters. So the usual suspects.. oxidative stress (BH4), infections, yada yada.
Or alternatively/additionally, if I understand correctly, the shutting off of MTHFR could potentially cause a reduction in 10 formyl THF, which could contribute to lower synthesis of BH4, therefore explaining why some seemingly healthy people get this side effect. Maybe some kind of combination of SNPs related to folate and methylation predispose to this.
It would be interesting to see if specifically folinic acid might help with this. I haven't tried it myself for insomnia, but have, interestingly, experienced improvement in irritability caused by methylfolate, after taking folinic acid.
"We know that molybdenum deficiency can cause accumulation of methionine"
How do we know this? Why does it do that?
"the shutting off of MTHFR could potentially cause a reduction in 10 formyl THF"
How would it do that?
If you are molybdenum deficient, the most proximate difference that would occur to SAMe metabolism is that sulfite would not be able to deliver its electrons to complex IV of the respiratory chain, so the most obvious thing to look at is if you are backing up the respiratory chain.
I doubt you can rule out glycine. You didn't say anything about how much you took, but I doubt you took enough to completely rule it out.
I have no idea why it does that, but I'm going by the study that you have mentioned yourself in various contexts, the one on a Crohn's patient with molybdenum deficiency.
I don't remember the exact dose of glycine that I took at night, but it was most likely 5g. I have also tried more during the day for general uncomfortable side effects from methylfolate, as per your suggestions of glycine as a buffer and it also didn't help. I think this theory is insufficient to explain both situations, be it insomnia or anger/irritability.
In terms of reduction of 10 formyl THF:
From your article:
"Thus, an accumulation of 5,-10-methylene-tetrahydrofolate without MTHFR- and methionine synthase-mediated release of tetrahydrofolate will strongly inhibit the synthesis of glycine and will strongly favor the conversion of glycine to serine"
At first I thought 5, 10 methylene THF would be trapped, but I looked again, and now I see that it can actually be converted back to THF via TYMS and DHFR, I missed that before.
Still, I would guess that this may not be the most efficient and optimal way and could contribute somewhat, but that's only my layman speculation. As everything else is..
I just reread my description here:
https://chrismasterjohnphd.substack.com/p/molybdenum
I don't see where you are getting the methionine accumulation from my description.
The glycine buffering issue cannot be tested just using glycine as there are numerous factors that regulate the function and expression of GNMT.
Thymidylate synthesis will likely be regulated by the need for thymidylate, so SHMT1 is likely to act as the release valve for spillover of extra 5,10-CH2-THF.
Sorry, maybe I wasn't clear. You didn't mention the methionine itself, but I think you did mention this case study, which talks about elevated methionine levels:
https://pubmed.ncbi.nlm.nih.gov/3141849/
I see, looks like the inability to clear the sulfite generated by the methionine is backing up its upstream metabolism. (Of course he was on methionine in the TPN, but they do not that reducing it left his methionine levels still higher than normal).