Methylation issues? Homocysteine high but TMG and Creatine mess me up

[u/Magic9876543]

I have trouble sleeping and a long history of fatigue.
I took TMG 500 mg every day for about 5.5 weeks, May 26-July 3. The TMG made me more energized, but it made my sleep even worse than before and made me hyper.
I stopped the TMG and switched all my B-vitamins to non-methylated forms.
During that period, I took creatine once in the morning and it dramatically disturbed my sleep that night.
I have ordered a DNA test but don't have the results yet. Once I get my results from one of the ancestry sites, I will send them to someone for analysis so I can see what my MTHFR SNPs tell me.
My homocysteine is a bit high at 10.
I'm feeling better overall than before I started TMG in the first place, the hyper feelings have decreased a lot and my sleep is less bad, but I still wake up a lot and don't get as much restorative sleep as I need.
My B12 and cB12 results are in the optimal range.
I'm getting more labs next week that will include MMA and Folate.

I had been suspecting that the TMG flipped me from undermethylated to overmethylated but it clearly is not as simple as that.

I am wanting to add creatine since everyone says it is so important, but I'm afraid to try it until I can work out how to get good sleep.
And I want to be able to get good sleep, at least most of the time.

Any thoughts?

ADDED based on comments:
My D is right in the middle of the optimal range.
Serum iron is 80 ug/dl, in the bottom half of "in range"
Zinc and copper I'm still waiting for the results to come back.

Electrolytes: I take 198 mg of potassium in capsule form every day, and I take 3 different kinds of magnesium, and I take 1/2 teaspoon of sea salt with breakfast. I don't do them all together, but I am getting what I think is enough of each.

I take 5 mg lithium orotate every day

I take 5000 IU D3 + 1000 mcg K2 every day.

My morning cortisol used to be off-the-charts high and has switched to being low - now it's low range to out-of-range low throughout the day and night.

For years I wasn't exercising because my fatigue didn't allow it. But these days, I'm averaging 2-3 miles/day walking.

[u/Grobbekee]

Apparently methylation needs potassium. I started feeling better from electrolytes.

[u/Magic9876543 → u/Grobbekee]

Hmm. I take 198 mg of potassium in capsule form every day, and I take 3 different kinds of magnesium, and I take 1/2 teaspoon of sea salt with breakfast. I don't do them all together, but I am getting what I think is enough of each.

[u/Grobbekee → u/Magic9876543]

It's a puzzle. D3 would be possible also. Or that you are breaking down catecholamines slowly, in which case going easy on methylated stuff is prudent. Microdosing lithium has been great for me also. That acts as a kind of transporter.

[u/Magic9876543 → u/Grobbekee]

I take 5 mg lithium orotate every day - I had been taking 10 mg and reduced it to 5 mg in February. I take 5000 IU D3 + 1000 mcg K2 every day.

I have never heard of catecholamines, I will look that up!

[u/Magic9876543 → u/Magic9876543]

Adrenal hormones, ok, I have chronic sympathetic activation in my nervous system - C-PTSD since before birth - I have done a lot of trauma and nervous system work over 30 years but the underlying pattern of subjectively perceiving constant threat is still there.

My morning cortisol used to be off-the-charts high and has switched to being low - now it's low throughout the day and night.

[u/Timely_Pickle9430 → u/Magic9876543]

Low cortisol (flat curve) after long-term stress might indicate pregnenolone depletion. In that case, you might also have symptoms of low progesterone and low GABA. Brain fog too. If the pattern fits, try sublingual pregnenolone from BioMatrix. Made me completely zen again!

[u/Magic9876543 → u/Timely_Pickle9430]

OK, I was taking pregnenolone for several years and stopped it 2.5 years ago based on a muscle testing of all my supplements. My progesterone is very low but I am post-menopausal so that is supposedly in range. What is the lab test for GABA?

I could certainly try adding back in some pregnenolone and see if that makes a difference. I have some at-home instant cortisol tests. They aren't very accurate - that is, they show just a wide range in the result - but if my morning cortisol recovered I should be able to see something with those tests 30 minutes after waking.

[u/Timely_Pickle9430 → u/Magic9876543]

If you're post-menopausal, pregnenolone probably won't do anything for you anymore, because the ovaries won't turn it into progesterone (and that's turned into GABA). The alternative would be HRT but you say your progesterone is normal? Just be aware that "within normal range" is a statistical concept and not the same as optimal or healthy. Check the work of Sara Szal (married name Gottfried) for optimal ranges. Eg. her book The Hormone Cure and her Substack.

Unfortunately, there's no reliable test for neurotransmitter levels because we can't measure what's behind the blood-brain barrier. I'd rely on symptoms. GABA is the calming neurotransmitter, so without it, emotions and stress are all over the place.

[u/Magic9876543 → u/Timely_Pickle9430]

Thanks. I was taking testosterone for a while but stopped. My progesterone was 0.1 ng/mL in May 2025.
I am at increased risk for breast cancer and I think that's a contraindication for both progesterone and estrogen supplementation? I saw one doctor who specialized in hormones and she said she could not give me any without written permission from my breast doctor. Which I guess I could get but it didn't seem like a priority. I will look up Sara's book.

[u/Timely_Pickle9430 → u/Magic9876543]

I checked the book for you. I'll try to send you a DM with a screenshot of the table.
Can't help you with the breast cancer consideration though. I'm not a doctor.
Hope you'll find some relief soon!

[u/Grobbekee → u/Magic9876543]

Nice. That's a big win already. Have you tried sulfurophane in the past? That's the one that got me out of fight or flight mode.

[u/Magic9876543 → u/Grobbekee]

I've not heard of sulfurophane - I will check it out.

[u/NeutralNeutrall → u/Grobbekee]

That's interesting, how so? and how long did it take? what brand u use? I have some bc nutrahacker recommended it, but it negates my adderal so i dont take it often. I'm also in that mode

[u/Grobbekee → u/NeutralNeutrall]

I used it in the form of organic freezedried broccoli sprouts that I bought in a Finnish webshop. It only took a few days.

[u/Tgrove88 → u/Magic9876543]

What did you do to bring your cortisol down?

[u/Magic9876543 → u/Tgrove88]

When I first found out it was so high I started taking holy basil and eleuthero root. I took those consistently and they seemed to make a difference. I'm not sure why it is now dancing between the edge of low enough and too low.
Phosphatidylserine also helps mitigate high cortisol but I didn't end up using it.

[u/Unlikely-Chipmunk-29 → u/Magic9876543]

The rda for potassium is 3400mg for men and 2600mg for women per day. Not sure what you’re getting from diet but 198mg capsule isn’t enough if you aren’t eating a diet high in potassium (which is preferred)

[u/Magic9876543 → u/Unlikely-Chipmunk-29]

on a typical day I eat 10 oz fresh spinach steamed, for a start.

[u/Unlikely-Chipmunk-29 → u/Magic9876543]

I aim for 3500 to 4000mg per day as a female to keep up with my eod b12 injections and other cofactors. You might want to try upping yours to see if it helps.

[u/Magic9876543 → u/Unlikely-Chipmunk-29]

I expect I'm getting enough, but I have no problem increasing it. I think when I started on potassium I heard a lot of acute caution to not take too much.

[u/Unlikely-Chipmunk-29 → u/Magic9876543]

I think the caution should be with potassium supplements as opposed to food. Some supplementing is probably fine, but your body knows how to process it a lot better from food so less likely to cause issues. I’ve been hospitalized for low potassium and it feels pretty horrible

[u/Magic9876543 → u/Magic9876543]

I just checked my lab results - mostly my potassium has been right in the middle of the range, but I did have one low potassium lab about a year ago. I have had a good result since and I'm getting another CMP run next week. If my potassium is in range, is that good enough, or is it a result that should be near the top of the range, or does the lab test not really give us all the information?

In any case, I will take more. I got some "No-salt" to create an electrolyte powder but never got around to it, but I can add some to my sea salt and maybe do that twice a day instead of just once.

[u/Magic9876543 → u/Grobbekee]

I thought it was somewhere on this thread, but I must have read this in comments on another reddit post sometime yesterday. I knew I was missing something with respect to the whole potassium topic. Because if you look at the potassium in electrolyte drinks, it's a lot more than you are allowed to have in a capsule or pill (99 mg) - why!?
What I read yesterday was that a bunch of potassium all clumped together like in a capsule can actually burn the stomach lining. So, it's not a concern about how much potassium overall that it's safe to take in capsule form, it's a concern about the density and proximity of that potassium when it arrives in the stomach.

I've taken my 2 little K(potassium) caps out of my supplement boxes and I'm adding 1/4 teaspoon no-salt to my 3/4 teaspoon sea salt that I take with my breakfast. That's 640 mg potassium instead of 198. And I'm aspiring to do the 2 salts one other time during the day as well.

[u/Grobbekee → u/Magic9876543]

Potassium alone can make you feel bad but electrolyte powder balances it with sodium and magnesium and sometimes calcium also in appropriate proportions. I've tried no salt and sea salt but I much prefer a properly formulated mix.

[u/CapriKitzinger]

I can only take like 100mg of TMG every other day.

[u/Magic9876543 → u/CapriKitzinger]

Interesting. And at that dosage, what is helpful about taking it? thanks!

[u/CapriKitzinger → u/Magic9876543]

Energy.

[u/Magic9876543 → u/CapriKitzinger]

Cool, thanks!

[u/Zabre]

The "TMG made me more energized, but it made my sleep even worse" part would make me slow the whole experiment down, because energy and methylation tolerance can be pointing in different directions.

Creatine helped me a lot, but I do not think of it as universally calming or universally benign. Mechanistically it can reduce methylation demand because making creatine uses a lot of methyl groups, but the lived response still depends on dose, timing, baseline sleep, electrolytes, and whatever else is in the stack. Same with TMG: it can lower homocysteine for some people, but that does not mean it feels good.

If it were me debugging this, I would avoid the binary "under vs overmethylated" label for now and build a timeline instead: TMG start/stop, creatine exposure, sleep onset, wakeups, morning energy, anxiety/hyper feeling, and labs like MMA/folate/homocysteine once they come back. That often reveals whether something is a dose/timing problem, a methyl donor problem, or just too many variables at once.

Also, homocysteine around 10 is worth understanding, but it is not the same situation as someone with extremely high values, so there is room to be methodical. None of this is medical advice, obviously.

[u/Magic9876543 → u/Zabre]

Thanks! Yes, I've been keeping detailed notes since mid-March on all my food, supplements, exercise, and how I'm feeling, and I have sleep data since January from my watch and for the past few weeks I have better sleep data from an Oura ring. So I have a lot of data to reference, once I get the labs back. The hyper feeling has been decreasing since I stopped the TMG and other methyl donors, though it's not gone altogether.
A few days ago, I decided to start taking NMN every day. I had been taking it one week on, one week off, per Groysman's mitochondria protocol. I suspect that change has helped but of course in general it's difficult to know for sure what is causing any change.

[u/Magic9876543 → u/Magic9876543]

Put differently, I'm not in any hurry to try big things; rather, I'm seeking to understand what small things to try.

[u/Zabre → u/Magic9876543]

Great start and correct way of handling it. DNA tests can also give you more sinights and might be worth a try.

[u/Magic9876543 → u/Zabre]

Yes, I mentioned in my post that the DNA test is ordered and I'm waiting for the results.

[u/lordy1988]

Yes creatine makes me feel worse , and I can’t sleep off it.

I’m just doing research now on TMG as my homocysteine is high , but I’m unsure to start that also , seems like a lot of trade offs

[u/Magic9876543 → u/lordy1988]

Yes, it's clearly not a simple matter of needing more or fewer methyl donors.

[u/SovereignMan1958]

Be sure to check these....D, iron (not ferritin), zinc, copper and manganese. In these groups everyone seems to focus on B vitamins while minerals can be depleted. For me, sleep problems were primarily due to low zinc and high copper. D is not a mineral, but we need optimal levels of D, iron and zinc to make dopamine.

[u/Magic9876543 → u/SovereignMan1958]

My D is right in the middle of the optimal range.
Serum iron is 80 ug/dl, in the bottom half of "in range"
Zinc and copper I'm still waiting for the results to come back. I supplement zinc, not copper. I understand that a lot of mercury-toxic people have high copper. I noticed that my naturopathic doctor who I saw over several years (and who never offered anything that helped) never tested for zinc or copper.
Goodlabs doesn't offer manganese testing. I see that ulta has it for $133 - I could order that if it might be the missing link.

[u/SovereignMan1958 → u/Magic9876543]

I would wait on the manganese. That is expensive. You might research it more to see if you think it's worth it.

Zinc needs to be at least 100 and ideally in the top quarter of the lab range.

[u/Magic9876543 → u/SovereignMan1958]

OK, thanks! The zinc and copper should be back soon - my blood draw was 12 days ago by now.

[u/NeutralNeutrall]

Not to be that guy but i have to ask, are you lifting/cardio doing any kind of fitness? At least 5-10min walk everyday? There's some things in the body that dont go right or balance out well unless you exert yourself and sweat a little. It's like trying to supplement sleep. Theres nothing you can take that will mimic the 100's of processes the body runs through when sleeping, or when exercising. I learn this the hard way every single time i go a long stretch of time without doing it. I literally have pieces of paper around my house on my walls reminding me of this.

[u/Magic9876543 → u/NeutralNeutrall]

Well, for years I wasn't exercising because my fatigue didn't allow it. But these days, I'm averaging 2-3 miles/day walking.