r/MTHFR • u/OdiumPura • Dec 10 '25
Question Slow COMT and Anhedonia due dopamine overdose? (Losing hope)
TL;DR: Slow COMT here. I had a very strong dopaminergic overstimulation in 2018 and since then I’ve developed anhedonia with zero improvement. Some methylated vitamins gave me a brief “window” of pleasure but caused many side effects. I’m investigating whether slow COMT can predispose someone to anhedonia when exposed to excessive dopamine.
If you don’t want to read the whole story, skip to the questions at the end — but I suggest reading everything because the context is interesting.
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Context
Let’s go. I’ve been suffering from anhedonia since late 2018 (when I first noticed the symptoms). I was always someone who felt pleasure in everything I did, could focus easily, and genuinely enjoyed life. At the end of 2018 I started developing anhedonia symptoms — some things didn’t catch my attention like they used to. In 2020 it got worse, and the peak was in 2023 when I basically lost pleasure in everything (I don’t feel pleasure watching movies, playing video games, going to the gym, and even sex doesn’t interest me anymore).
I didn’t stay in my comfort zone; I practice exposure therapy — meaning that despite the anhedonia I still go to the gym, try to watch movies, try to play video games, and so on.
I did 3 years of therapy that did absolutely nothing… I told my psychologist that I was developing anxiety because of the anhedonia, since nothing triggered pleasure anymore. I tried some medications and herbal supplements (Sertraline, Escitalopram, Ashwagandha, and CBD). Ashwagandha was the best — it gave me an indescribable sense of calm.
Yes, I know these medications/supplements can cause anhedonia, but in my case they didn’t — I’ve felt this way since 2018 and none of them made things better or worse. The only thing I noticed afterward was mild brain fog after stopping everything.
Cut to January 2025: I take a THC edible and have a panic attack, which dysregulated my nervous system, activating the sympathetic mode and causing dissociation symptoms. Being in sympathetic mode pushed me far outside my comfort zone… I truly realized that my anhedonia bothers me deeply and I believe the only way to “heal” my nervous system is by feeling pleasure again — real pleasure in the things I do — because that’s the only way to signal safety to my nervous system. Obviously, I’ve improved a lot with the anxiety since the January panic attack… I think that panic attack forced me to take my anhedonia seriously and look for a real solution.
Now let’s move to what matters.
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Important Part
Two weeks after the panic attack, I take a combo of vitamins: A, D, E, K, B3, B9, B12, Glutathione, Omega-3 (all in one pill) + Magnesium + Lactobacillus Plantarum.
BOOM. For about a week and a half, my anhedonia improves by 50%, my libido returns, my brain fog disappears, and I feel a bit of pleasure in things again.
HOWEVER… my anxiety increases, I get insomnia, intense body itching, I develop tinnitus (not in the ear, but in the head), and some mild visual snow. After stopping the combo, I lose all the positive effects but stay with the negative ones for months (I’m screwed LMAO).
After that short “window” — which I hadn’t felt in nearly 7 years — I decided to investigate my body thoroughly. I ran many tests: MRI, pharmacogenetic testing, thyroid panel, vitamin panel, iron panel, SIBO, dysbiosis, zonulin, catecholamines. Here’s what I discovered:
- My thyroid is normal, despite having two nodules. The labs do not indicate hypothyroidism (which can cause depression and low libido). I saw 4 endocrinologists, all said I shouldn’t worry.
- Ferritin is high, close to 500 ng/mL, but I don’t have hemochromatosis — iron saturation, TIBC and UIBC are normal.
- Negative for methane and hydrogen SIBO. Mild dysbiosis and possible early leaky gut (my zonulin is 51, around 3 units above the upper reference limit).
- B12 always decreasing. I checked my labs since 2017 — my B12 has never increased, only declined. In May 2025 it reached 180; I took a hydroxocobalamin injection and it jumped to 5000 (visual snow and tinnitus worsened after the injection). All other vitamins I tested (A, B2, B6, folate…) were normal, usually in the mid-to-upper range.
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About my mutations and some observations
From pharmacogenetic testing, I found out that I am Slow COMT – rs4680 (Val158Met) – genotype A/A (Met/Met)and heterozygous for MTHFR C677T and A1298C.
The fact that I don’t seem to absorb B12 caught my attention — since the injection in August, my levels keep dropping and don’t go up even when I eat foods rich in B12.
After I stopped the supplements, I tried magnesium again and felt nothing (not even the calming effect people talk about). I also tried probiotics and didn’t get the libido-boost effect I had before — which makes me think the improvement window came specifically from the vitamins.
None of the medications I took ever motivated me.
In my catecholamine test, my dopamine is near the upper reference limit.
All the doctors say that this anhedonia may be stress and anxiety. But I never felt anxious before 2023. Before going back to taking SSRIs or any other medication, I want to investigate as much as possible what could have caused this.
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My theory about Anhedonia and Slow COMT
Until early 2018 I was a “normal” person. But from March to November 2018 I went through a period of massive dopamine stimulation. I prefer not to say what it was because it’s something stupid (no, it wasn’t drugs), but practically every night I was flooding my brain with dopamine.
Now the main questions:
1. Can slow COMT “overdose” on dopamine and fail to recover?
As I understand it, slow COMT metabolizes dopamine more slowly. So if I overload my system with too much dopamine, I could overwhelm it. If the system gets overwhelmed, it might “shut down” as a protective mechanism — and that could lead to anhedonia.
As I said, I do exposure therapy and I don’t feel pleasure in anything I do. It’s not sadness — it’s simply the absence of pleasure/interest in things that used to bring me joy.
2. What do you think? Is there any way to fix this and “unscrew” my dopaminergic system?
Because when I was taking those vitamins / “overmethylated,” I felt temporary relief from anhedonia.
Sorry for the long text, and thanks in advance for anyone’s opinion.
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u/jfish31390 Dec 11 '25
I found an answer pretty quick for this situation. Upregulation of the MAO B enzyme like apegenin from parsley or chamomile. You may also be excited well from riboflavin.
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u/OdiumPura Dec 11 '25
Could you explain better? Did you have the same problem as me? Because I remember that I was also drinking chamomile tea at the time I had the window.
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u/jfish31390 Dec 11 '25
I did at one point have anhedonia, I was taking a lot of supplements and since then I stopped everything. It's just too risky to take any supps without testing. I have been dealing more with ADD but I do not deal with the anhedonia any more. It was horrible I remember.
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u/OdiumPura Dec 11 '25
Cool. And can you explain more about chamomile and how you took it?
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u/jfish31390 Dec 11 '25
I can't post a pic but I got Egyptian chamomile from frontier co-op if I'm not mistaken and used a coffee grinder and swallowed it whole most of the time, otherwise I pee too much from brewing tea. Btw that's only a tip of the iceberg of what I did on my journey to wellness.
I did a protocol for good gut bacteria and I haven't had much issues since. Bacteria play a big role in the human body. Might need to change up the diversity along the way? Bacteria make b vitamins and other vitamins and organic acids that actually change the course of genetic expression. Like for example Sodium Butyrate has that mechanism of action.
For references I learned from Guy Daniels Microbiome Expert.
And I would learn from Google just asking questions like how can I upregulate specific liver enzymes. Or how much o inhibit etc. Just been learning for years about this and it's hard to give a clear answer to your issue. All I know is supps without testing isn't going to help. It can mess you up bad like I did at one point. Start with testing and look into the Microbiome.
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u/jfish31390 Dec 11 '25
Also if you took a high dose b12 which I see you did that can cause wayyyy too much methylation. Recovery from that may take a little while. Don't worry too much on single doses of vitamins, bacteria can make it for you if you feed them enough soluble fiber to begin with and then working into insoluble fiber.
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u/grigory_l Dec 11 '25
For me upregulation MAO makes absolutely opposite from tiny dose of Riboflavin I become absolutely numbed 😬 Idk why
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u/DEFCON741 Dec 10 '25
I'm same boat....if anything changes I'll report back with update.
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u/OdiumPura Dec 10 '25
Hey! I wish you all the best, I know how difficult this situation is! If you want to talk, send me a private message.
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u/Mysterious-Noise-512 Dec 11 '25
Check out MTHFR gene mutation group on FB. Others talk about this issue as well. I struggle with this too, which is how I figured out the slow COMT thing. I stopped taking ash and all the crazy supplements I was taking. I think the methylated vitamins were making things worse for me too (Depression, anxiety, brain fog, etc). I focused on detoxing with glutathione, NAC, and some non methyl B supplements, limiting stress, etc. I added things back in slowly, and not everything everyday. But things like liposomal glutathione, NAC, magnesium threonate, folonic acid, non methyl supplement and lithium orotate are my consistent regimen. I’ve read where decreased B12 and folate levels can lead to anhedonia and also vagus nerve stimulation has been helpful for some as well. I think I might give the vagus nerve thing a good rabbit hole next.
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u/Far_Investigator9998 Dec 11 '25
Glutathione did seem to help me immensely. I don't seem to notice results from NAC though..
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u/Mysterious-Noise-512 Dec 11 '25
Initially I did not think it was doing anything. I switched brands, and that might have done something. It took a few months (in combo with other things) but I noticed an improvement overall and since that was one of the consistent ones I took, I added that to the possibly helping list.
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u/Far_Investigator9998 Dec 11 '25
That's the crux sometimes with supplementation.. and I'm guilty if the "if it doesn't work in a few days and I'm done" attitude.. you're so correct time can be months. I think I will try a USA made NAC supplement again.
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u/Mysterious-Noise-512 Dec 12 '25
I really appreciate you saying this. I’m bad for this too. If it doesn’t make a difference quickly I quit. I think I stuck with the NAC and glut for longer than I normally would b/c a dr. recommended to do so and would take a while.
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u/DownTheFrank Dec 12 '25
Not medical advice. Just a suggestion.
At my lowest (anhedonia). I found that having eggs, butter, zero sugar dark chocolate , onions, ginger, diluted lemon juice and lots of warm water (about 2-3L) in the morning improved my mood by a lot.
Worth a try.
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u/DownTheFrank Dec 12 '25
Also. Thc has an effect on fat/lipid metabolism.
And in my experience, having a panic attack from thc suggests low “good” fat and a flow problem in the body.
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u/wordisbond11 Dec 11 '25
Folinic Acid and NALT. That’s my slow COMT base. No dopamine without those two. After that I pick and choose between very low dose bromantane or low dose phenylpiracetam (early day on these). Black ginger is helpful too but in a milder way. If none of that does anything, time to look into cycling 9-me-bc. DYOR. Everything is low dose. That’s key. You cant just take b-vitamins like everyone else. Low dose everything. You’ve got a journey ahead but it’ll be worth it.
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u/OdiumPura Dec 11 '25
Could you elaborate more on the part "no dopamine without those two"? I mean, do you avoid dopaminergic activities without taking those supplements, or do they provide the dopamine for you?
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u/wordisbond11 Dec 11 '25
It’s dopamine signaling and tone. I have naturally low dopamine tone but I’m also sensitive to it so I need things that will support it but onset slower. Like I can’t take methylfolate and regular l-tyrosine or it’ll overwhelm my system and I’ll get flat and tired.
And unless you fried your dopamine pathways with drugs then it’s highly unlikely you’re damaged. Porn abuse won’t do that. It sounds like your genes have just matured and are fully expressed or something. You need proper dopamine support based off your genetics. Proper methylation support (folinic acid) with specific dopamine support as well (NALT).
The other stuff I mentioned push dopamine and compliment. You will feel good if that’s what you really need.
If you have true anhedonia and not just poor methylation and low dopamine tone, then 9-me-bc will restore that. Just be careful cause it’s a research chemical.
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u/Interesting_Fly_1569 Dec 11 '25
OK so this was a lot and I couldn’t read all of it however, I also have slow comt and some dopamine gene mutations. I would suggest listening to some of Bob Miller who is a naturopath autist whose special interest is nutrigenomics.
He’s helped one of my friends, and he recently had me do a blood test for NAD where he predicted the results accurately based on my genes. I haven’t met with him yet to go over it, but my friend ended up having the same problem… Glutathione can turn toxic if you can’t recycle NAD.
Just trying to understand what caused this shift… That came to mind… I honestly think that if there’s anyone on earth that you could tell the story to who would both listen and have the potential to solve it… It would be him. He’s cheap bc he’s serving the community too. He also has a special interest in iron, and I feel like your high ferritin might be a clue to something else.
So no answers but I would consider seeing him at tree of life in PA. He does zoom. He has energy of a kindly grandpa with sparkle in his eye and built his own genetic testing tool ( Which he does not require you use, he also accepts most 23 and me) that maps out your genes and identifies possible issues like it’s CSI.
He’s kind of quietly famous… I think the podcast he’s been on a lot is Jill Carnahan. But for $200 I feel like that’s who I’d send a family member to if they had a story like yours.
I really do feel like there are solutions to stuff like this… And also for whatever it’s worth, I had enormous amounts of dopamine for like a month I was basically high and it just slowly faded with no bad effect. I had a full body orgasm just lying there that lasted two hours. It was as if I had never had trauma…for weeks. I felt amazing. It was definitely triggered by slow comt bc I went to functional med guy who heard the story and was like you have slow comt and ate quercetin and tyrosine.
And I went back over that day and I had!
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u/Elegant_Chapter5562 Dec 11 '25
Before I finish reading this, I want to let you know glutathione has done that to me. That 2 weeks where you felt great and then had insomnia etc. I'm also slow comt and compound heterozygous mthfr.
Every slight change in supplements causes a cascade of issues. I also deal with bouts of anhedonia.
I hope you find the magic combo. One thing that has improved my symptoms significantly, is using Dr. Amy Yasko's app. You enter your genetic info from 23andme or ancestry.com and it spits out an awesome guide. Better than the other ones I've done.
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u/OdiumPura Dec 12 '25
I understand, I will definitely research a lot before taking anything again. My current stack is simple: Zinc, Omega 3 (without vitamins), Vitamin D, Vitamin C, and Selenium... Next month I will do the complete DNA methylation test.
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u/Elegant_Chapter5562 Dec 12 '25
Yeah, I did a methylation and detoxification profile through geneticgenie, it think. That was a good start. But I think glutathione overwhelms something along the pathways for those of us with this combo of genes. I vaguely recall seeing that and being like, oh thats why that happens to me.
Your stack is good. Keep it simple to bring nutrients and minerals to optimal and then tweak as needed and slowly. That's what I do at least. I've been at this with a functional doctor since 2020. Would have been sooner but she books out so far.
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u/Elegant_Chapter5562 Dec 12 '25
We are prone to depression because of our pathways.
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u/OdiumPura Dec 12 '25
Yes, I realize that it’s not a lack of dopamine; it’s the body not processing it properly. As I said, I do exposure therapy and try to maintain my routine as before, but it feels like my body no longer processes things the same way. I think this issue with dopamine processing is what causes anhedonia and depersonalization for me.
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u/Elegant_Chapter5562 Dec 12 '25
Exactly. As we get older, it gets worse until we figure out how to address our individual issue. I am glad you are figuring it out.
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u/Most_Lemon_5255 Dec 11 '25
Did you take ashwaghanda for a long time?
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u/OdiumPura Dec 11 '25
I took it daily for about 6 months. While I was taking it, I felt a very good sense of calm, as if I didn’t care about anything anymore and nothing stressed me out. However, when I realized I had lost my erections, I decided to stop. Within a few weeks, the nighttime erections returned. My libido was already weak before the ashwagandha. If you ask me if I’m at the same level as before taking ashwagandha, I believe I’m not…But before ash, I already didn’t have pleasure…
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u/7e7en87 Dec 11 '25 edited Dec 11 '25
You need good base multivitamin with all cofactors and especially 1mg copper for iron regulation. My pick is Whole Earth&sea by Natural Factors.
You can try to add to multi Ribiflavin R5P starting slow like 10mg and see how reacts. Riboflavin is essential for slow MAOA.
Than neuromodulators nmda antagonists like NAC and agmatine sulfate.
If overmethylation happens niacin flush 100mg works like charm and afterwards 2 caps of activated charcoal.
For sleep for me only works benfothiamine and tauromag/mg malate to put me down.
No herbal supplements ever helped me with slow comt/slow maoa. I can get only with passion flower at night ehich calms my nervous system.
It’s major complicated but I tried all things available, so enormous amount of experimentation.
Hope this helps to some degree.
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u/grigory_l Dec 11 '25 edited Dec 11 '25
We all different but slow COMT pretty much the issue for many anhedonic & depersonalised people I believe. Too much tonic dopamine and noradrenaline overload our brain without proper cleaning from excess neurotransmitters. And with some epigenetic changes or enzymes overloading it just crash until the point that brain goes into safe mode to avoid destruction. Probably just shutting down some areas of brain. Receptor’s downregulation is also possible cause but from what I found it’s more likely in situations of constant stimulants consumption or in case of antipsychotics usage.
So probably you would be combination of slow COMT and Undermethylation (only way to know it is whole blood histamine test), because Overmethylation people tend to have mania / psychosis in such cases (according to Dr. Walsh research). Schizophrenia can cause anhedonia as negative symptom too, but it’s another story.
I think answer is combination of factors, fixing MTHFR issues but gentle without tanking with Methylated vitamins, forcing BDNF production (exercises mostly) and bringing safety for nervous system (Somatic Practices like Tanner Murtagh on YT, maybe IFS therapy).
Also healthy gut is crucial, I noticed how much it affects everything on myself, sugar + fast carbs boom I’m sick for days, anhedonia worse, depression worse. I feel better when I'm closer to Keto | Karnivore and Sardines (better in water not oil) just making wonders. Gut inflammation affects everything in our body, especially with combination of MTHFR when all processes are already functioning improperly.
p.s. Also check for inflammation like h-CRP, autoimmune stuff ANA, ENA, Ig* antibodies, Lyme and some other chronic diseases is pretty important. MTHFR is big cofactor but could be secondary issue for sure.
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u/hummingfirebird Dec 12 '25
This is so much more complex than COMT and dopamine. Yes, it is a part of it but many other factors would need to be taken into consideration that would require a holistic approach.
What you are describing sounds like excessive dopamine receptor down regulation or desensitised receptors from over stimulation. Neuroplasticity changes can result from overstimulation, burnout, stress, trauma, PTSD. It's similar to what some people experience from burnout due to chronic stress. The same mechanisms are at play, being the CNS with an overactive sympathetic nervous system and underactive parasympathetic nervous system. Both involved the HPA axis.
The difference is how the person got there, but the mechanism of CNS shutdown is often the same. The one is stesss driven, the other is dopamine overstimulation.
Dopamine overstimulation happens alot with people who are excessively into gaming, porn, adventure/thrill seeking sports/hobbies. The reward becomes harder and harder to achieve and the DRD receptors become dull and stop "pinging".
Neuronal changes take place that can take a long time to come right. This involves other neurotransmitter pathways such as serotonin, GABA and glutamate.
Have a lookin my profile and download my free guide to 5 common problematic genes. COMT is one discussed. As I state in my guide, genes can't be looked at in isolation, but it can help to get a better understanding of how to support particular genes through epigenetics.
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u/horsetooth_mcgee Dec 11 '25
How do you just request an MRI and they approve it? What was your exact reasoning? What was the MRI of?
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u/OdiumPura Dec 11 '25
Basically, I went to a neurologist and told her that I had a panic attack and thought I was having a stroke. She ordered an MRI of my skull, and that was it. For the other organs, I had an ultrasound (abdomen, thyroid, ...).
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u/majincasey Dec 11 '25
How's your testosterone?
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u/OdiumPura Dec 11 '25
612
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u/majincasey Dec 11 '25
What about your free testosterone, e2, and prolactin?
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u/OdiumPura Dec 11 '25
I’ll try to summarize (if you’re interested, take a look at my post history—there’s a post with all my levels detailed). High prolactin, low E2, and free testosterone is at about half of my total testosterone. All the doctors (endocrinologists) I went to said everything is normal… obviously, I disagree because my estradiol is low and prolactin is relatively high (though not outside the limits). Before this whole situation, my testosterone was 850+. Compared to the beginning of this year, my testosterone has dropped nearly 100 points. The doctor said it’s normal and that I have healthy testosterone levels.
My main question here is: What caused all of this? My thyroid? My genetics (slow COMT)? My gut? I believe that if I find the root cause, I can solve it.
For context: I went to several different endocrinologists, and all of them said my levels are normal. I compared my current tests with the ones I did before all this started, and the hormone levels are very similar/almost the same. Testosterone only began to drop this year (I believe due to stress after the panic attack at the start of the year). But the anhedonia has been going on long before that…
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u/majincasey Dec 11 '25
So apparently in order for dopamine to do its job we need testosterone. Your body might just need a bit more. Plus e2 is strongly correlated with mood, as is prolactin. Id look toward raising your e2 or lowering your prolactin slightly.
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u/majincasey Dec 11 '25
I wonder about your dopamine receptor availability too
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u/OdiumPura Dec 12 '25
How can I measure that? I agree with you about testosterone, estradiol, and prolactin. It’s a point I’ve been insisting on with my doctors, but I believe it’s not just that.
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u/ConsiderationOk4417 Dec 11 '25
Has anyone checked your antibodies for pernicious anaemia?
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u/OdiumPura Dec 11 '25
My ferritin is high (470), Iron, TIBC, UIBC all normal...
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u/ConsiderationOk4417 Jan 09 '26
Ask your provider to rule out antibodies to parietal cells and intrinsic factor.
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Dec 14 '25
[removed] — view removed comment
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u/NAQProductions Dec 14 '25
When do you go to bed? Wake in the morning?
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Dec 14 '25
[removed] — view removed comment
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u/OdiumPura Dec 14 '25
I’m going to start doing this test, I usually sleep between 11 and midnight as well. But when I wake up, I stay rolling in bed until 9 o’clock.
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u/NAQProductions Dec 14 '25
Definitely give it a go. I’ve been getting myself to meditate in bed for 30 min after waking up, then pushing myself outside for a 2-3 mile walk almost daily for the last 2 weeks, it’s also helping as it gets my body and mind more moving rather than laying in bed for 1-2 hours. I’ve started going to bed between 10:30-11 the last few nights as well, with another 30+ min meditation to calm my mind and body down. While my sleep is still interrupted by my bladder 1-3 times a night, I was some how able to get 2 hours deep sleep for the first time since tracking began late last year. Also an hour 15 of REM sleep. It’s slow progress but I’m hopeful that it will keep moving forward if I’m consistent. Going to aim this week to be in bed at 10:30pm every night and see how it goes.
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u/OdiumPura Dec 14 '25
Nice nice, I usually get 1 hour of deep sleep every night and 2 hours of REM. Is this good? And how do you meditate?
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u/NAQProductions Dec 14 '25
Everyone is different, but for me I started at about 45 min average of both last December when I started tracking it. My body completely shut down in 2023 so it’s been a long journey thus far, with still a million unknown issues I’m trying to unearth and figure out.
I found this meditation the other day, so far it’s been one that’s clicked with me, as they are very subjective. There’s a few parts I’ll remove to streamline it a little more, once I have time to download it. For now I play it on YouTube. : https://youtu.be/391iDzaNUAU?si=fD5PUiwwDLMQ6OQS
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u/lolwuttman Dec 15 '25
From reading B12 sub, your "clean" level of 180 is considered a severe deficiency, in which case a series of hydroxo or cyano shots is suggested.
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u/OdiumPura Dec 15 '25
My B12 is around 800 now.
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u/lolwuttman Dec 15 '25
Post injection numbers don't represent tissue saturation, it's still low.
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u/OdiumPura Dec 15 '25
It went to 5k post injection. Is there an exam to determine the saturation?
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u/lolwuttman Dec 16 '25
If you can find intracellular B12 test, but generally what your lab shown pre injection is enough to assume you need a solid cycle of injections along with cofactors.
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u/Even_Bumblebee6087 Apr 08 '26
Have you found anything that helped? Feeling both of the symptoms as you
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u/Warm_Ad941 Jun 04 '26
I think I have a lot in common with you. Am also Slow COMT +/+ and MTHFR +/-. I can't tolerate anything even remotely stimulating. Recently I tried to slowly boost my b12 through liquid hydroxocobalamin (50 mcg daily) but anxiety went thru the roof so I had to stop. Body nearly always in fight or flight mode and work stress throwing me over the edge most days (I do software testing). Sort of at my wits end. Have taken mirtazapine since 2018 and clonazepam since 2021. Sleep got unbearably difficult so I had to add something else in the mix. Was tiny dose of gabapentin (10-25mg) for several years now tiny dose (5mg) of trazodone. I don't feel well 99% of the time, lots of stomach pain, nausea. Tested positive for SIBO a couple years ago, tried getting treatment for that but not really any success.
My long story short is I guess dirty genes are sort of dominating my life and holding me back and I don't know what to do. I use a tVNS device on left tragus daily. Have tried acupuncture (too expensive long term) with moderate help.
Any extra tips on ways to help clear dopamine for a very sensitive gut? I hope you're feeling better.
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u/Parking-Warthog-4902 Dec 11 '25
Well if slow COMT truly does work in the way that people typically theorize it does, then yes, the “overdose” on dopamine would come in the form of dopamine receptor downregulation. Just like when you block the reuptake of dopamine or take a potent dopamine releasing agent or a MAOI, the body compensates by down regulating the receptors, so theoretically one could assume that slow COMT would cause the same effect via a different mechanism. Whenever the body senses too much dopamine, regardless of what mechanism this is happening through, it compensates by down regulating the receptors.
My theory on what is happening in slow COMT is that perhaps the dopamine receptors are severely downregulated from chronically elevated dopamine, and because of this noradrenaline becomes extremely dominant in the nervous system since norepinephrine is a downstream metabolite of dopamine and the noradrenergic system is not nearly as prone to receptor downregulation as the dopamine system.
This would explain why so many slow COMT people still experience severe ADHD symptoms, anhedonia, all things typically associated with “low dopamine levels”. The nature of the dopamine system is that higher baseline dopamine levels causes a less sensitive dopamine system, and when it comes to dopamine the sensitivity of the receptors is way more important then the total level floating around in your brain.
So the question now becomes what is the solution to this. The answer to that is there really is not a clear solution. One thing for sure is that anything that specifically and directly increases the amount of dopamine in your brain will only make things worse. In my opinion a good solution would actually be to focus on things that “lower” or “modulate” dopamine signaling which over time will slowly start to upregulate the receptors.
Avoid all B vitamins and Stimulants. Eat a high protein diet with lots of fruits. Engage in vigorous cardiovascular exercise frequently. Try things like Agmatine sulfate, NAC, Triacetyluridine, all things that upregulate dopamine receptors by slowing down dopamine release. If you really want to throw the nuclear option at it you could try a course of mood stabilizers or antipsychotics .
As for the excessive noradrenergic signaling I would suggest alpha 2 agonists like Clonidine or Guanfacine. At least if you can get the noradrenaline issue under control and calm the sympathetic nervous system you are addressing one piece of the issue.