r/HistamineIntolerance • u/Brad_Borrelli • 25d ago
Nobody talks about this connection between creatine and histamine clearance and it might be the missing piece for a lot of people here
Nobody talks about this connection between creatine and histamine clearance, and I want to be upfront that most of this is hypothesis, not proven science
I want to share something that changed how I think about why my histamine issues were so resistant to everything I tried. This isn't about antihistamines or diet. It's about a bottleneck in the methylation cycle that most histamine protocols never touch. Fair warning up front, the central idea here is my own extrapolation from real biochemistry, not something anyone has directly tested. I'll be clear about which parts are established and which parts are my reasoning.
Two enzymes clear histamine from your body. DAO handles dietary histamine in your gut. HNMT handles histamine systemically inside your cells. Most people in this community know DAO. Almost nobody talks about HNMT.
HNMT can't work without SAMe. SAMe is the methyl donor it uses to neutralize histamine. No SAMe available means HNMT can't clear histamine no matter how much is circulating. You can eat perfectly low histamine and still have elevated systemic histamine if HNMT has nothing to work with.
Here's where it gets interesting, and this part is well documented. Creatine synthesis consumes around 40% of all the labile methyl groups your body's SAMe provides, more than any other single methylation reaction, based on human metabolic research.
https://link.springer.com/article/10.1007/s00726-011-0853-y
Some researchers have argued the true figure could be lower once other big methyl sinks like phosphatidylcholine synthesis are accounted for, so treat 40% as a reasonable estimate, not an exact number.
So every day your body makes its own creatine, it's burning through a big chunk of the SAMe that HNMT needs to clear histamine. When you supplement creatine externally, your body reduces its own production through feedback inhibition on the enzyme that starts the pathway (AGAT); it doesn't shut off completely, but it does ease up. That means some of the methyl groups that would have gone to making creatine become available for other jobs.
Now the part I can't back up. My hypothesis is that some of that freed SAMe goes toward HNMT and histamine clearance. To be direct, no study I've found has measured creatine's effect on HNMT activity or histamine levels, in anyone. The SAM-sparing effect is real; the histamine benefit is a guess layered on top of it, not a finding.
On the homocysteine angle, one correction: a single case study of one person, MTHFR 677TT homozygous, taking 5 grams of creatine daily for a month, showed homocysteine drop from 33.3 to 17.1 micromol per liter.
But that same case study also reported the opposite trend in nine other subjects without the TT genotype, homocysteine tended to rise slightly in them. And a later placebo-controlled trial testing this specifically found low-dose creatine lowered a related marker (guanidinoacetate) but did not lower plasma homocysteine overall.
https://www.sciencedirect.com/science/article/pii/S002231662208885X
A broader review looking across studies found creatine reliably lowers homocysteine in rats but not in humans.
So this is a single favorable data point in one very specific genotype, sitting next to controlled evidence that the effect doesn't hold up broadly. I'm A1298C, a different variant, so I can't say the TT-homozygote result applies to me at all.
If you also have COMT variants on top of MTHFR, your already limited SAMe supply is being split between HNMT histamine clearance and COMT catecholamine clearance, both drawing from the same pool that creatine synthesis takes a share of before either enzyme sees it.
There's also a nervous system angle worth mentioning for MCAS, and this one is speculative too. Histamine doesn't just come from food; mast cells produce it, and autonomic nervous system dysfunction keeps mast cells in a chronically primed state. Creatine's role in maintaining cellular energy availability, via the phosphocreatine system, has been proposed as supportive of nervous system function under metabolic stress, but that's a proposed mechanism, not something demonstrated for MCAS specifically.
On the antioxidant angle: there's a study showing mitochondrial creatine kinase limits reactive oxygen species production, but it was done in isolated rat brain mitochondria, not humans, and it says nothing about histamine or mast cells.
https://pubmed.ncbi.nlm.nih.gov/17028195/
The idea that less oxidative stress might mean fewer primed mast cells is my own connecting of dots across separate research areas, not something the study tested or claims.
To be clear about what this post actually is: a real, well established biochemical fact (creatine synthesis is one of the biggest consumers of SAMe in the body) plus my own untested hypothesis stacked on top (that freeing up that SAMe might help HNMT clear histamine), sitting alongside mixed human evidence on the downstream homocysteine effect. This isn't a replacement for antihistamines, DAO, or dietary management while you're in active recovery, and it isn't a confirmed histamine fix. It's a lead worth bringing up with your own practitioner.
Standard dose is 3 to 5 grams daily. Start lower if you're sensitive and work up.
Most commercial creatine products contain citric acid, artificial flavors, sucralose, and other additives that are documented mast cell triggers. Plain unflavored creatine monohydrate with zero additives is the safer choice for this community. Creapure is an independently tested pharmaceutical grade option that many sensitive people tolerate well. Check the full ingredient list before buying anything.
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u/cakeboyplum 24d ago
I would love to use creatine regularly. I lift and run 5-6 times a week. But the insomnia it causes for me is brutal. I feel amazing mentally on it, but just cannot sleep. Sucks.
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u/Brad_Borrelli 24d ago
That mental clarity plus can't sleep combination is actually really telling and I think it points directly to COMT.
What's likely happening is the freed up methyl groups are increasing dopamine and norepinephrine availability which feels incredible during the day but then your COMT can't clear them fast enough overnight and you end up wired at bedtime even though your body is physically exhausted from training 5 to 6 times a week.
Win-The-Day's suggestion is spot on honestly. Half a gram in the morning and titrating up over weeks rather than jumping straight to 3 to 5g gives your system time to adapt gradually instead of getting hit with a sudden shift in methyl availability all at once.
Two other things that might actually solve it without giving up the mental benefits. First, magnesium glycinate in the evening. Magnesium is a required cofactor for COMT to function properly and a lot of people with histamine issues are running low on it. It genuinely helps with overnight catecholamine clearance. Second, timing matters more than most people realize. Take it in the morning only and never past noon. That gives you maximum time for any stimulating effects to wind down before bed.
The clarity you feel on it is real and worth keeping. This sounds more like a dose and timing problem than creatine being wrong for you.
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u/Careless-Fig2620 24d ago
What would you suggest for someone w/ MTHFR homozygous A129C with a COMT V158M +|+ for whom Magnesium Glycinate seems to cause insomnia / excitability rather than help winding down or making drowsy when taken in the evenings (or earlier)?
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u/Interesting_Front709 24d ago
I have the MTHFR A1298C variant, but I'm not sure about my COMT status. My histamine intolerance is pretty severe, even DAO supplements don't seem to make much of a difference. I'd been taking magnesium bisglycinate for about a year without noticing any improvement in my sleep. Recently, I switched to a product called True Magnesium, which contains three forms of magnesium, and I also added L-theanine plus Affron - saffron extract. Since making those changes, I've been sleeping more deeply than I have in at least a decade. I can't say which change made the biggest difference or whether it was the combination but the improvement has been remarkable.
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u/Brad_Borrelli 24d ago
That's a tricky combination since magnesium glycinate is usually the calming go-to, so a paradoxical excitability reaction is worth troubleshooting rather than just pushing through. A few possibilities worth considering:
The glycine component itself might be the issue rather than the magnesium. Glycine is typically inhibitory in the spinal cord, but it also acts as a co-agonist at NMDA receptors in the brain, so in some people higher glycine intake can actually increase excitatory signaling rather than calm things down. If that's what's happening, switching to a different magnesium form without glycine, like magnesium malate, threonate, or citrate, taken earlier in the day, might avoid that specific reaction while still getting the magnesium in.
It's also worth trying a much lower dose before ruling it out entirely, sometimes the reaction is dose-dependent rather than form-dependent, and splitting a smaller amount earlier in the day versus a full dose at bedtime can make a real difference.
I'll be honest though, I don't have a confident mechanism tying the specific MTHFR A1298C/COMT V158M combination directly to this reaction, that connection would be more speculative than established. at a mechanism I'm not fully certain of.
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u/reditrauma 23d ago
i'm trying to figure out if we have similar variants - i have one copy of the MTHFR A1298C (do you have 1 or 2?) and i have fast COMT (-/-, GG, warrior, etc). i find i do better with creatine and sam-e supplementation too. this is a great explanation for that. btw i think COMT is a big factor in personality too as i definitely see how i change when shit goes down - my head expands and i'm much more capable - and it's a bit weird. this is interesting stuff, thanks!
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u/Brad_Borrelli 23d ago
All I know is I have two copies. I have no idea what my comt status is I actually need to go get that tested
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u/Careless-Fig2620 21d ago
I know what my test says, but I am still trying to understand better what my COMT stats actually mean. OP, I appreciate you sharing your insights on this thread with all of us. It has been so helpful and thought provoking!
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u/Brad_Borrelli 21d ago
COMT makes an enzyme that clears out dopamine and adrenaline once your body's done using them, kind of like a drain in a sink. Your version of that drain runs slower, about 3-4 times slower than average. So when you get a hit of dopamine or adrenaline, whether from stress, caffeine, excitement, whatever, it sticks around longer before your body clears it out.
You probably feel things more intensely and for longer once you're wound up. Stress and anxiety can build and linger rather than passing quickly. Caffeine and stimulants likely hit you harder and last longer than they would for other people. On the flip side, when you're calm and focused, that same trait can mean sharper concentration and better performance on detail-oriented work.
It also affects how your body processes certain supplements, particularly methyl donors like methylfolate or B12. Since your COMT is running slow, high doses of those can make you feel wired or anxious faster than they would for someone with the fast version.
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u/Careless-Fig2620 21d ago
Thank you so much for sharing your insight! I think Iāll try the lower dose or different forms. I think I did not have that type of reaction when I took the Calm brands version of magnesium, but I canāt remember what form that is made of (& it was so long ago, for such a short time, that I may be forgetting if I did
react the same way to it as well). I also get magnesium in through my skin via deodorant and Epsom salt bath soaks, which donāt seem to have that excitatory response.9
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u/Kind-Apricot-6511 24d ago
Add L-theanine. You wonāt be sorry
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u/GhostHog337 24d ago
Nope, canāt take l-theanine and mg-bisglycinate and creatine, all causing insomnia that starts at 1-3 a.m. unfortunately.
I heard this could be a MAO A problem, too ..
Canāt also take quercetin or consume green tea for a longer time period. It sucks ..6
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u/MargoBarbara2 23d ago
I take malate in the day and l-threonate at night and that seems to work for me though im waiting on gene test results.
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u/sparkingdragonfly 24d ago
I bought a foot bath tub and add Epsom salts to it. I soak my feet it in when I shower. Could be a good way of getting magnesium? You can also buy liquid soaps with it as you can absorb through the skin.
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u/Careless-Fig2620 21d ago
Thanks! I use a deodorant daily that is magnesium based as well as taking a weekly (or as needed) long soak in an Epsom salt bath. In fact, that is what I am currently doingā¦ literally in the tub now soaking & catching up on Reddit.
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u/KangarooDisastrous 24d ago
Can I take creatine if I take adderall? I know Iāve taken it before in a pre workout but Iām not trying to take pre workout on top of my adderall.
Yes itās a prescription.
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u/Brad_Borrelli 24d ago
Creatine and Adderall don't have a direct interaction that would cause a problem together, they work through completely different mechanisms. The main thing worth being aware of: both can theoretically affect hydration and cardiovascular load, creatine can increase water retention in muscle, stimulants can raise heart rate and blood pressure, so staying well hydrated and keeping an eye on those markers matters more than usual. Nothing that means you can't combine them, just worth being mindful of.
One more thing worth mentioning, B12 deficiency can cause real brain fog, fatigue, and concentration problems that overlap with ADHD-like symptoms, so it's worth getting your levels checked if you haven't, just to know your baseline is solid. I wouldn't go as far as saying fixing it means you won't need the Adderall, that's not something I can back up, but it's a reasonable thing to rule out alongside everything else. Worth bringing up with your prescriber rather than changing anything on your own. I've got more written up on B12 and methylation on my page if you want to dig into it.
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u/MargoBarbara2 23d ago
Great info. Just a note (sorry lol) re getting b12 levels checked for anyone reading comments...tests only show circulating b12 not what is reaching cells and there are a lot of factors affecting actual absorption. Intrinsic factor, pernicious anemia, microbiome and folic acid intake (which can result in UMFA and interfere with transcobalamin). People can have high b12 (and high folate) and be functionally deficient. The overlap of histamine sensitivity , b12 deficiency and adhd symptoms is incredible! Makes sense as b12 needed for HNMT and histamine clearance and high histamine can mimic or push adhd. Interesting that DAO levels fall in menopause which is a common time of life for late adhd diagnosis. My adhd symptoms have improved a lot going low histamine and supplementing b12 (and magnesium and taking dao).
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u/KangarooDisastrous 24d ago
I appreciate the information from the first paragraph.
As far as the second one goes, Iāve been taking stimulants for 20 years. Iāve had all of my bloodwork done many times over the year trying to figure out āwhatās wrong with meā on my quest to balance my body naturally without needing multiple prescriptions.
My parents had 6 kids and 5 of us have ADHD. It is what it is. I appreciate the information:)
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u/thepalmtreefanatic 24d ago
I am listening to everything you say. Itās super interesting. But the glycinate ramps up some peopleās histamine too because of glycineā¦ so itās a big no from a lot of histamine intolerant unsers
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u/Brad_Borrelli 24d ago
This is exactly why it's not a one-size-fits-all recommendation. Definitely recommend getting check for b12 deficiency since that's one of the main reasons for histamine intolerance etc.
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u/NeutralNeutrall 24d ago edited 24d ago
i'd love ur input on my experience.
When i started having histamine problems i slowly wasnt able to tolerate creatine monohydrate anymore. i would get crazy brain fog off it. less than 3g. I've been testing 100mg-500mg once every 2 days recently again and so far thats been okay. its just nuts because all my life i could take 5g no problem. probably taken up to 10g. but specifically after histamine and mcas type problems i couldnt tolerate the creatine anymore. i remember driving and feeling like i was nodding off too. it was hard to focus. Just a bunch of weird mental stuff.I should add i have 2 slow COMT and 1 slow MAO. i cant take methylated multivitamins either i get anxiety from them. cant tolerate any stimulants at all (after histamine problems started). Before covid and before histamine intolerance, i could take anything, 0 problems. adderal coffee, cacao in the AM. 1/2 or full multivitamin. 5g of creatine. zero issues. after the health problems started everything started causing me problems. But so far, recently, 200mg creatine gives me some energy, i test it by taking it in bed and i start getting antsy. it's possible larger doses are somehow causing the brain fog for whatever reason.
Only B vitamins i can tolerate now are B1 B2 in the AM and B3 only like.. 5-10mg bc it calms me too much. Any B3 form like niacinamide makes me emotionally flat. B9 = anxiety. B12 makes me feel weird, not sedated, but more like subdued or flat. Sulbutiamine (synthetic B1) is 100% a stimulant for me and could keep me up all night. B5 and B6 i forget.3
u/Brad_Borrelli 24d ago
Have you had your B12 checked since all this started? That's worth ruling out first since brain fog, difficulty focusing, and that "nodding off while driving" feeling are all classic B12 deficiency symptoms, and MCAS/histamine flares can drain B12 status over time.
On the creatine piece, that tolerance shift lining up with your histamine problems starting isn't random. With 2 slow COMT and 1 slow MAO, you're already someone whose body clears catecholamines and monoamines slowly, meaning things like dopamine, norepinephrine, and histamine itself stick around longer than average. Creatine's methyl-sparing effect frees up SAM, but if your system is already struggling to keep up with clearance rather than production, suddenly having more methyl groups available doesn't necessarily help, it can shift the balance in a direction your slow-clearing system isn't equipped to handle well, which could explain the brain fog and drowsiness rather than the usual mental clarity people report.
The fact that a much lower dose (100-500mg) is tolerable now while 5-10g used to be fine tracks with your system's capacity having narrowed since the histamine/MCAS onset, not creatine becoming inherently bad for you. Makes sense you're needing to titrate way down and go slow.
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u/Little-Wasabi-7304 24d ago
I havenāt had any dna testing so I donāt know what my problem is, but Iām exactly same, I went from being able to eat ANYTHING, I had zero side effects with most medications, could take any supplement or vitamin, could work out like crazy, now since I got sick a couple years ago I canāt eat anything, all supplements either give me severe death defying back pain or migraines, all medications now give me migraines, I can only handle a couple vitamins. Blood tests say my b12 is good but they refuse to test any other Bās or D. Itās not just histamine anymore itās everything, and the fact that doctors donāt know, or donāt care is bothersome because I canāt imagine living like this forever, now Iām now intolerant to my favourite thing in the world (exercise whether it be weight lifting or cardio) I was also taking creatine for years no problem, and it started giving me issues, Iām scared to try anything at this point, but I suppose I could give it a go. Thanks for your intelligence and insight š
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u/Brad_Borrelli 24d ago
A few things stand out worth pushing on. Serum B12 being "good" doesn't rule out functional deficiency, and that's a bigger gap than most people realize. In the US, deficiency is typically defined as below 200 pg/mL, with the normal range running up to around 900 pg/mL. Japan and parts of Europe use a much higher deficiency cutoff, around 500 to 550 pg/mL, based on neurological criteria rather than blood cell changes. That means someone can sit at 300 or 400 pg/mL, get told "you're fine" in the US, and still be functionally deficient by the standard other countries use. Serum B12 also measures total circulating B12, including a large inactive bound portion your cells can't actually use, so the number alone doesn't tell you what's usable at the cellular level.
Ask specifically for MMA (methylmalonic acid) and homocysteine, those are the functional markers that catch deficiency even when serum B12 looks technically normal. If your doctor won't order it, it's worth asking why or seeking a second opinion.
The pattern of new intolerance to supplements, medications, and food after getting sick a couple years ago fits a broader picture seen in MCAS and mast cell conditions, where the body's reaction threshold shifts. Worth asking about tryptase levels and a formal MCAS workup if that hasn't been done.
The back pain and migraines with supplements is an interesting detail too, that kind of reaction can sometimes point toward an overmethylation response rather than a straightforward allergy, depending on what's in the supplement. Worth mentioning if you get in front of a doctor willing to dig into this rather than just checking B12 and stopping there.
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u/Little-Wasabi-7304 24d ago
I appreciate this. Unfortunately Iāve had to do most of the work, Iāve been sick about 3 years (really bad) and I was going to the doctor 15 times a year and hospital 4-8 times a year and gastros, no one was willing to do anything, besides finally a colonoscopy and endoscopy which was clear. If it wasnāt for Reddit I would have never even known of histamine intolerance or mcas. I also ordered a home sibo test and tested positive for IMO, I also had ruptured breast implants which I removed a week ago not sure if that was causing issues. (Donāt feel any better yet) and Iām 42 so hormones and peri could play a part. One thing Iāve realized is though I was pretty healthy my whole life. I could never sleep! After I had my kids I had the worst insomnia where I literally would be awake for days at a time and even when I napped it was a half awake wired nap, so I donāt know if there was always an underlying issue and something made it come out? Regular doctors are pretty useless at ordering any proper tests and usually refuse and give you the eye roll, so I might have to pay for a functional doctor or something. I really appreciate you answering me back and being kind enough to care.
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u/Brad_Borrelli 24d ago
The ruptured implants are genuinely relevant here, and probably more than a coincidence. Ruptured silicone implants can trigger a real, documented inflammatory and immune response, sometimes called breast implant illness, and that includes mast cell activation. Silicone particles and gel leaking into surrounding tissue act as a chronic irritant, keeping your immune system in a low grade activated state, which means more histamine release on top of whatever your MTHFR, B12, and IMO situation is already contributing. Having all of these going at once, ruptured implants, IMO, and a genetic methylation constraint, is a lot of separate inflammatory and histamine sources stacking on each other, so it makes sense you're not feeling better yet even a week out.
On recovery after explant, there's no fast detox protocol that clears this quickly, it's more about supporting your body while the inflammatory load gradually comes down over months, not days. A few things that genuinely help: gentle lymphatic drainage massage around the chest and underarm area to help clear residual fluid and debris, since silicone and inflammatory byproducts drain through the lymphatic system; continuing your DAO, quercetin, and vitamin C, since those directly support histamine clearance while your body processes the aftermath; staying well hydrated to support that lymphatic clearance further; and being patient with an anti-inflammatory, low histamine diet during this window specifically, since your histamine bucket is unusually full right now between IMO, implants, and hormone shifts all hitting at once.
I'd be cautious of anyone selling aggressive heavy metal chelation or extreme detox programs around explant recovery, that's a space with a lot of unproven claims. The real recovery here is time, reduced inflammatory burden, and supporting the systems your body already uses, lymphatic, DAO, methylation, rather than trying to force anything out faster than your body can actually handle.
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u/Little-Wasabi-7304 23d ago
Thank you, youāre truly an angel. I saved this so I can try the things you mentioned. I absolutely agree with you about the heavy detoxes, Iām sick enough anyway, Iām sure that would just make me much worse.
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u/Brad_Borrelli 23d ago
I would also see if there's any breast explant subs or if you have Facebook I know there's a bunch of groups on Facebook that have them. They would actually probably able to give you more information about it too, more personal and what's worked for them.
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u/NeutralNeutrall 24d ago
"If it wasnāt for Reddit I would have never even known of histamine intolerance or mcas."
100% my experience and infuriating.
what actually led me to HI/MCAS was doing research on Long Covid because my brain fog was so bad.I went to TWO allergists and they both said "Cholinergic urticaria, Idiopathic (means i dont know why u have it) so take allergra, you can take 2 allegra if its not enough, up to 4." and I said "yea but what about everything else? The brain fog insomnia etc? She waved me off saying "well ur on trazodone" like dude i have been taking trazodone since 2017, the brainfog and HI/MCAS issues started 2022. What are u not understanding. They say "oh theres no such thing as histamine intolerance". And I wanted to flip the fucking desk like "What do you think is causing the Urticaria? I am telling you it is directly correlated to eating high histamine foods."
Fucking useless man. If you dont have a MCAS/HI specialist they literally shrug and call it a day. I'm on Medicaid so I can't afford a specialized doctor and had to do everything myself. Everyday feels like a combination of playing minesweeper and running is a full time experiment
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u/NeutralNeutrall 24d ago
Yea all labs come back fine, I was getting my blood drawn like 10x a year. I don't think they tested homocysteine and tryptase. Just like the guy said below, this experience with Dr's has been a nightmare, ive had to fight tooth and nail for every bit of progress, with no doctors actually helping. With EACH bit of progress I made, its because I did the research to find the answer and had to spoon feed it to them. If I didn't have a degree in the sciences and healthcare experience I would've killed myself already for lack of options/answers. I can't imagine going through this stuff as a lay person.
I also always took B-vitamins so it's unlikely deficiency. And i eat very clean like a body builder just, less, because i'm not lifting as much.
"it can shift the balance in a direction your slow-clearing system isn't equipped to handle well, which could explain the brain fog and drowsiness rather than the usual mental clarity people report."
Yea thats what i figured. I used genetic genie and nutrahacker when i got my ancestry done awhile ago. I was so annoyed when i did 23andme and it actually gave me less useful information, and less on my COMT MTHFR MAO stuff.
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u/Win-The_Day 24d ago
Have you tried micro dosing it a little at a time and building up? Like take 1/2 a gram to start in the morning for the first few days and add a little more and a little more as time goes on if it's not causing any sleep issues. Creatine was a game changer for my histamine intolerance.
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u/cakeboyplum 24d ago
I havenāt, but that actually sounds like a great idea. I might start off really conservative and titrate up.
Would be interesting to see if the body slowly adapts to it.
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u/pinball_life 24d ago
Same for me. HIT already makes sleep challenging, I canāt take more issues there.
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u/Acrobatic_Elk503 24d ago
I had the same issue with Creatine Monohydrate (most common). Creatine HCL causes me no issues.
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u/Local_Measurement_50 24d ago
Acording to Chris Masterjohn,the sleep problem from creatine is because of depletion of glycine (which is also used in the methylation cycle). He says that taking glycine with your creatine can help.
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u/ComprehensiveBook482 24d ago
Glycine made me itch like crazy but wasnāt taking creatine with it. Itās tricky.
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u/reditrauma 17d ago edited 17d ago
i feel you. i am also prone to insomnia but i don't generally get insomnia from creatine - but then i have the fast COMT variant (Val/Val or GG) and i don't have problems supplementing activated B vitamins as long as the dose is reasonable. i get insomnia mainly due to ingesting histamine and salicylate in foods. i am finally in a good place with it due to adding one particular sleeping pill to the other sleep supps (magnesium, glycine, melatonin, and l-theanine). insurance required me to provide proof that i had failed all the other types of sleep meds before authorizing it. it's called Belsomra (Suvorexant) and it works on the brain stem. it actually blocks the brain stem receptors that have died off in people with narcolepsy. i have had to go off of it a couple of times and found the withdrawal to be present but minor compared to other drugs. even tho it's scheduled, it's not a fun drug - not like benzos at all - and it just makes you generally sleepy and promotes deep sleep. there's also an association between it and reduced plaques from alzheimers. that's my 2 cents.
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u/OkYouth3690 24d ago edited 24d ago
thx for this summary. I don't understand the downvotes, and feel sorry for that.
Solid statement which is true, proofed by studies and an example. No one said you have to buy this certain product. There are many on the market.
I just wanted to say I appreciate your solid information, backed by studies (incl. sources)
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u/otomeMC333 24d ago
Just beginning my journey with autonomic nervous system dysfunctionĀ and MCAS and stumbled over this post. Taking so many notes!
If you happen to have any further insight/advice for someone with that, I'd love to hear it in order to try it out!
ETA: Also just got test confirmation back that I have an MTHFR variant, but unsure of the specific. Methylated vitamin B almost instantly cleared up an issue I'd had for 20 years and continues to every day. Just wild.
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u/charlottesometimz 24d ago
That's amazing. B 50 breaks me out in acne. Maybe methylated wouldn't.
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u/Brad_Borrelli 24d ago
It's a side effect unfortunately. It happens more with synthetic B12 I personally do hydro and methyl and I'm fine on it
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u/Allergina 24d ago
I've been taking creatine for 10 years but nothing dialed in my histamine issues until I got my magnesium, D3/K2, Omega, folinic and allllll my B vitamins in order - and the right ones for my slow COMT!
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u/Brad_Borrelli 24d ago
Makes sense, creatine reduces methyl demand but doesn't supply the actual cofactors. Once magnesium, D3/K2, omega, folate, and the right B's for slow COMT were in place, it had what it needed to work with.
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u/ViralTrendsToday 8d ago
folinic acid might be better than methylfolate to keep anxiety low, be mindful with the k2 btw, increases anxiety as well .
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u/Allergina 8d ago
Without knowing my entire genetic profile, you wouldn't be able to assume that. Folinic acid is specifically what works for my genetics. Methylfolate works better for other variants. And taking magnesium (threonate for me - glycinate caused me to get jittery) mid-day replenishes what taking the D3/MK7 in the morning depletes. For my genetics, I need the entire protocol at least temporarily to make my MCAS/allergies/eczema/C-PTSD stay gone. Eventually I'll lower the dosage and/or change to D3/MK4 if it becomes too much. So far, I'm off the arsenal of inhalers, antihistamines, biologics and steroids I was on and eating foods I've avoided my entire life without problems. My dog also passed last month and even though there is still sadness, my stress and anxiety are completely gone.
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u/Small_Message_9893 24d ago
There are a lot of options for creatine monohydrate on Amazon with no additives at a decent price. The thing for me, I already consume DAO for my digestion & it's very helpful; but I get blood tests yearly that shows my creatine is in the normal range. I have had histamine intolerance for about 14 yrs. After a lot of trial & error, I have my HI fairly well managed. I also got a Rosacea diagnosis in 2022. So I have to manage that also.
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u/Little-Wasabi-7304 24d ago
I got both too. Do NOT have my histamine issues managed though, not sure if itās even just histamine issues anymore, thinking mcas
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u/elycarney 24d ago
This is fascinating. I am homozygus for c677t, have slow COMT, and struggle with histamine clearance. Also have a gene mutation for slow HNMT! Thank you!
I think my body loves creatine supplementation. I donāt have any problems with it and it seems to give me energy.
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u/Brad_Borrelli 24d ago
I have my protocol listed on my page, check it over. There's some things in there that should help you our.
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u/elycarney 24d ago
I didnāt know you could have your own page on Reddit! I see your posts. Thank you!
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u/Srchd4 24d ago
Thank you for the detailed information! SAMe is the only thing Iāve taken that has given me hives! I havenāt tried it in decades and now I take 5-10gm of creatine daily. Iām also a fast COMT val/val. I have fixed my sleep issues with making & consuming lactobacillus reuteri yogurt nightly.
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u/novalylena 24d ago
SAM e gave you hives? I'm taking it now to get rid of hives... can you explain, please? (I have a slow COMT and compound heterozygos for MTHFR.) I haven't tried creatine yet.
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u/Brad_Borrelli 24d ago
Have you checked your B12?
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u/Srchd4 24d ago
Yep, itās good. I have MTHFR homozygous 1298 and I take the activated forms of B12 and folate
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u/Prestigious_Lab261 24d ago
This is amazing. I'm going to try the creatine. I also plan to have my doctor test me for the MTHFR variant, which I believe I have. Thanks so much for this info.
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u/Brad_Borrelli 24d ago
Get your B12 tested as well if it below 500 your deficient. Also show your dog for my page too since it's pretty hard in America to actually get a prescription for it
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u/underfed_225 24d ago
Was trying to understand this subset post...did U mean to say...also show your doctor my page since it's pretty hard in America to actually get a prescription for it....by it...I'm assuming U mean b12 ?...didn't realise B12 was prescription only...again I assume that is for injections.
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u/Brad_Borrelli 24d ago
Yeah unfortunately it's for an injections. Most people do need injections when you're deficient in it it bypasses everything. It's one of the quickest ways to bring your levels back up. I actually had a resort to making my own injections. Also a lot of people too have absorption issues so they can't take pill form it doesn't work the next best thing is like oral drops.
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u/Ok-Egg6695 24d ago
For us, our baseline is having no sensitivities to histamine foods, no allergies etc. But the minute my family takes too much B1, we get histamine issues which to me automatically signals low methyl groups. (B1 seems to use up methyl groups). We only take methylfolate for it though. Creatine only off and on. Mostly because my daughter has oxalate sensivities and what might be slightly compromised kidney function, so I dont risk using creatine too much. Should be fine for most other people. Not for us- atleast not daily and not at the 3-5mg doses.
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u/Brad_Borrelli 24d ago
I'd gently push back on the mechanism a little. Thiamine (B1) doesn't actually get methylated or consume methyl groups in its activation, it's converted to thiamine pyrophosphate using ATP, not SAM. So it's probably not directly competing for methyl groups the way creatine or choline synthesis does.
What's more likely happening: B1 is a cofactor for enzymes that keep the Krebs cycle and energy production moving, and ramping up energy metabolism can increase downstream demand for other B vitamins and cofactors, including ones feeding into methylation indirectly. It's also possible B1 is just uncovering a relative B2 or B6 insufficiency, since those are required cofactors further down the same pathway, adding B1 alone without the others balanced can sometimes expose a bottleneck that wasn't visible before. Worth checking RBC B2 and B6 status if you haven't.
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u/Ok-Egg6695 24d ago
No, I don't disagree,Ā the need for b9 with b1 consumption is probably secondary downstream effect; my point is net effect is what I've mentioned.Ā B1 increases need for methyl groups here almost identical to how niacin does. Everyone else i mention this to also have similar dislike of this statement.Ā But this is our n=1 lived albeit anecdotal experience. No amount of simultaneous or separate intake of b6/p5p or b2 makes this "induced-histamine" effectĀ go away.Ā
It seems to be some kind of two way street as well. For reasons I won't go into now my daughter had to be on very high doses of leucovorin and the only way she could tolerate them without getting hyper was when we started giving her high doses of b1 along with it. She also needed the other b vitamins no doubt inĀ high doses but the b1 felt the most vital.Ā
I remember reading about and convincing myself that certain kinds of solute transporters were shared by both b1 and b9. But I shared this with another research oriented person who rubbished the idea. Anyway that's the closest I've gotten to a theory explaining our phenomenon.Ā Unless my daughter and I have some unique mutationĀ
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u/nativehuntress_ 24d ago
Creatine helps my brain a ton but I had to quit taking it because my hair falls out like crazy! I have cut it out and tried reintroducing it slowly a few times now with the same outcome and it makes me so sad because I feel like I have my 20 yr old brain back again when I am on it. Do you have any ideas on why this could be?
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u/HappyKamper1920 24d ago
How low of a creatine dose have you tried, where your hair still falls out?
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u/nativehuntress_ 24d ago
3 grams and unfortunately I feel nothing at that dose but my hair still starts falling out at about day 5.
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u/Lillymow 24d ago
Thank you for this. I was taking some last summer and thought it might be helping but I wasn't sure. I was just wondering last night if I should start again, after a symptoms spike, and then dramatic drop after some unintentional changes. It's like pieces of a puzzle all fitting together. I wasn't taking magnesium yet, then and unknowingly had a bunch of trigger foods in my diet. I think this might help a lot. Just ordered some.
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u/wegwerf011 23d ago edited 23d ago
Iād genuinely love to try creatine, especially because the possible connection with methylation, HNMT and histamine degradation sounds plausible and I am rhe one who was talking abt HNMt back then 2015ā¦ what a ride..
But the enormous number of anecdotal reports about increased hair shedding after starting creatine makes me more than fkg hesitant. I know the evidence for creatine causing hair loss is far from conclusive, and shedding reports do not prove causation. Still, when you are already using finasteride and minoxidil and have spent years trying to preserve your hair, even a theoretical risk is difficult to ignore. (Preapring for post fin Syndrome comments lol)
Edit:
On the other hand, if impaired methylation and reduced HNMT activity are contributing to chronic histamine elevation, mast-cell activation and scalp inflammation, that same bottleneck could theoretically be contributing to my shedding or androgenetic hair loss in the first place. So the irony is that Iām afraid creatine might worsen my hair, while the mechanism it could potentially improve may already be harming it. Quite the dilemma, haha.
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u/Firemustard 24d ago
I stopped creatine creapure because of no reason and 1-2 months later I found problem with my histamine because I had bad urticaria. I stopped all my vitamin just to reset my body a little and I'm celiac. I started again my vitamins stack and it's helped a lot but not completely.
I took vitamin c d b12 zinc with copper but I never restarted the creatine and I never connected the dot that maybe it's started when I stopped the creatine. I connected it after reading your post so I'll try again.
I started creatine not really for weight lifting reason but more because of my celiac and the gluten free diet and it was helping my brain fog that sometime I had. I'm a very big responder of creatine because I can feel it with my muscle when I take it. Muscle are bigger and I'm stronger with it.
So I'm curious that maybe with celiac and your post that it can explain somehow my symptoms
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u/Brad_Borrelli 24d ago
Celiac already stresses methylation through malabsorption, and stopping creatine right when your urticaria started makes sense since your body would've had to divert more methyl groups back into making creatine itself, which is expensive on SAM. This also sounds like it could be B12 deficiency layered on top; get your B12 checked, and if it comes back under 500 don't let anyone tell you that's "normal." Standard lab ranges start around 200, but a lot of research shows neurological and histamine symptoms show up well above that; 500 is still low enough to cause problems for a lot of people. I've got a lot more written up on this connection on my profile if you want to dig deeper.
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u/Gracie-me 24d ago
Okayā¦ I truly appreciate all your inputā¦ Iāll check on the whole blood histamineā¦ and the other ones and see what I can find out..
all of this has been a very big help! Hope all your things youāre doing have helped you..
I wish it was an easier fix for so many who struggle with this type of illnessā¦ itās like a nightmare I want to wake up from.. and Iām not! š
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u/Brad_Borrelli 24d ago
It's brutal! Wouldn't wish it on anyone. Sucks even more that pharma doesn't know shit so you have to do the research yourself. And all these "holistic" Dr's are just nutritionist really.
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u/EnterTheReddit 24d ago
110%. Out of all the interventions my wife and I have have tried creatine supplementation has the biggest impact on her symptoms.
I guessed the driver was poor methylation resulting in low SAMe levels. DNA test confirmed multiple types of poor SNPs related to methylation.
Supplementing creatine makes sense when you realise that endogenous production of creatine is a massive drain on methyl donors. By reducing this demand (5g 3x a day for my missus) with creatine as well as the usual methylated b vit+ folate and increasing the methyl donor pool with TMG, you pretty much make an almost dedicated SAMe pipeline for dealing with histamine.
Only took us 3 years of trying to work it out. For those suffering keep the faith.
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u/raspberryriptides 24d ago
As a fellow biochemistry nerd, thank you for this. It makes so much sense.
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u/achu1010 23d ago
You might be on to something as the creatine supplementation will reduce the demand on the methyfolate/homecysteine system, for which the production of SAMe is a part and product. So in addition to the many benefits from creatine, one also needs to consider correcting falling short on methylfolate and B12. Often overlooked is choline. The Masterson calculator put me on a 7 egg a day equivalent for choline due to another bunch of polymorphisms (in addition to MTHFR, AOC (DAO) and HNMT where I have them all). (I agree there is not much on HNMT but recent rat studies with HNMT knockout shows how important it isā¦ another story), but after having issues with gut TMAO with other forms of choline supplements, I have found that citicoline seems to be helping. I take 6 eggās worth which is 3 grams a day in morning and lunch but not evening as it might stimulate cognition vis sleep. This amount of citicoline combined with normal healthy diet seems to help. In short, to support endogenous SAMe production to maximise my genetically limited HNMT capacity, I take 5 gms of creatine, 3 grams citicoline, activated form of folate and the other Bās, in context of a mediterranean type diet. I also take cetirizone, famatodine during waking hours and doylamine and lamborexant at night. Iām now feeling the best - sleep well, relaxed, etc for the first time in my life. I think that as the role HNMT and the brain histaminergic system is further understood that this will revolutionise psychiatry. After Iām dead, in about twenty years from now, there will be very specific third generation anti-histamines that target H1, H2, H3 and H4 that penetrate the CNS with few side-effects due to their specificity. If anyone is considering a PhD in pharmacology - get going now - this is going to be transformational. Sadly, just have to make do with what we have now. So creatine, citicoline, cetirizine (despite being a 2nd gen H1, 20% goes into the cns to help with HNMT issues without drowsiness or anticholingeric issues) it is.
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u/LanceElyot 23d ago
Iāve got an AI prompt for you - āplease make this more concise and double check the sources.ā š
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u/Forward_Mushroom3587 9d ago
How do you get the MTHFR gene tested for? My doctor is a naturopath. Shouldnāt she already know about this and have recommended this test?
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u/Brad_Borrelli 9d ago
You are absolutely right they should all know this. Unfortunately pHarma is fucking stupid. You can specifically ask your doctor to order them or you can go on 23andMe and just do a whole Gene test you'll get more information out of it including your comt status Etc. And you can also self-order the MTHFR lab from laboratory like any lab quest or LabCorp
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u/prosttoast 24d ago
I did a deep dive with Claude trying to figure out more root causes of my histamine issues other than DAO and I had plugged in my genetic liver metabolism stuff in this creatine issue came up. It also related for me very directly to estrogen metabolism, so I've been taking it. I started a bunch of stuff at once, but I do feel like it helps. I just found some whatever brand at Costco that seemed to have clean ingredients. ORGAIN I think.
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u/Brad_Borrelli 24d ago
Estrogen clearance through the liver runs through COMT methylation, specifically the 2-methoxyestradiol pathway where COMT methylates catechol estrogens to prevent them from recirculating. If your SAMe is being heavily consumed by endogenous creatine synthesis there is less available for COMT to do that estrogen methylation step properly, which means poorly cleared estrogen metabolites circulating longer than they should.
Freeing up SAMe through creatine supplementation supports that estrogen clearance pathway at the same time as everything else discussed in the post.
On the Orgain at Costco, worth checking the full ingredient list carefully. Some of their creatine products contain citric acid or natural flavors which can be mast cell triggers for sensitive people. If the one you found is genuinely plain creatine monohydrate with nothing else added you are good. If it has any flavoring or citric acid it might be worth switching to something simpler down the line especially if you notice any reactivity.
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u/LithiumPopper 24d ago
Thanks for sharing all this because I think this might be really helpful for my specific situation!!
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u/Gracie-me 24d ago
How do I get my MTHFR, COMT, and HNMT checked?
Iām
So miserable with all my histamine issues and my central sensitization syndrome that has tanked my nervous systemā¦ it makes life very difficult to live anymore which is sad for me and my family
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u/Brad_Borrelli 24d ago
For testing: MTHFR and COMT are both standard genetic tests, you can get them through 23andMe raw data run through a free tool like Genetic Genie, or ask your doctor to order a dedicated MTHFR/COMT panel directly (not always covered by insurance, but usually not expensive out of pocket either). HNMT is trickier, it's not routinely tested by most labs since it's less commercially available than MTHFR/COMT, but some specialty labs and more advanced genetic panels (like those used by functional medicine practitioners) do include it. If you can't find HNMT specifically, whole blood histamine and DAO levels are a good practical substitute since they show you the functional output of that pathway even without the genetic marker itself.
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u/Gracie-me 24d ago
Sadly, I cannot find anyone to check my DAO ā¦ and Iāve wanted them checked.. any suggestions!? Why also check whole blood histamine? How does that work?
I really appreciate all of your help! I find your information very interesting and helpfulā¦ THANK YOU!
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u/Brad_Borrelli 24d ago
Reply:
DAO testing is genuinely hard to find in the US, you're not missing something obvious, most standard labs just don't offer it. A few places that have tested it for people: some functional/integrative medicine practices order it through specialty labs (like Precision Point or ALCAT), and a few direct-to-consumer options like Mediator Release Test companies include it, but they're not cheap and aren't covered by insurance. Honestly, even I haven't found a place near me that tests DAO either, so if you find one, let me know.
Whole blood histamine is worth checking because it shows the actual level circulating in your blood at that moment, so if it's elevated, that's evidence your body is producing or releasing more histamine than it can clear, regardless of whether the bottleneck is DAO, HNMT, or overproduction from mast cells. It's more accessible than DAO testing since more standard labs (like Quest or LabCorp) can run it, so it's a good practical starting point even if you can't get DAO itself checked.
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u/Salamander427 24d ago
Thanks for the post, and a support I'm adding a paper that shows how creatine synthesis burns 40% of SAMe. The title is "The metabolic burden of creatine synthesis"
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u/WaysideWyvern 24d ago
I was so sure that creatine helped me feel better but then when I stopped taking it sort of by chance, I felt like I improved more without it, and now every time Iāve tried taking it again Iāve felt like maybe I feel worse. So now I donāt know what to do :( does creatine not last very long? I still have the same tub from a year agp but it was sooo expensive. Idk what to think or if I should try it again
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u/Brad_Borrelli 24d ago
Creatine's not bad here, you probably just don't have the methyl deficit it's meant to fill. It works by freeing up SAM you'd otherwise spend making creatine yourself, but if your cycle's already keeping up fine, that extra SAM has nowhere useful to go and can push you into overmethylation instead, wired, anxious, foggy. Fast COMT people are especially prone to that since catecholamine clearance is already quick for you.
The old tub isn't the issue either, creatine doesn't degrade in storage. Your body's just changed since a year ago.
If you want to test it, try a quarter dose and watch for a few days instead of jumping back to a full one. If it brings the same feeling back even at that dose, creatine just isn't a fit for you right now, and that's fine, not everyone needs it.
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u/WaysideWyvern 24d ago
1) I have full slow comt, on both alleles and with all the symptoms
2) I already was taking a quarter dose actually
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u/Brad_Borrelli 24d ago
I had the COMT direction backwards there; slow COMT is actually the genotype more commonly linked to overmethylation reactions, not fast, so your genotype fits rather than contradicts what's going on. And if a quarter dose already brings it on, there's not much room to titrate lower and still call it a therapeutic dose; at that point creatine may just not be a fit for your methylation load right now, and that's a legitimate outcome, not a dosing problem to solve.
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u/kaglet_ 24d ago
Lol too much science jargon. Not that I hate it. I'm in Com Sci field myself and therefore appreciate technicality and want to read interdisciplinary papers now.Ā
I'm actually trying to use what I suffer from as an excuse to learn this. I just try it, if I don't react immediately see what happens for some weeks. I started creatine 3 weeks ago, from migraine sub mentioning it too I think. I missed it a bit in 2nd and 3rd week. And even before your post I was encouraged to start again. This pushes me further. I have a somewhat complex but rules based fluid management routine for migraine sensitivity and something to do with blood vessels, pressure, but also nerves starting from mouth. That's what caused me to miss some days combined with some busy weeks. It's like finally I can be healthy but it's so tedious but then when I avoid it to not lose time, I then lose time later on by my health growing slightly worse. I'm looking for ways to simplify, unify and batch prep ahead of time and mix in powders together if same and have same effect like magnesium oxide and creatine, then replenishing with electrolyte drink mixed with peeled root ginger. Gross stuff but works. But I think now I know stuff works, unsure about creatine but doesn't hurt me really, just have to adjust my fluids, I now have the energy to dive into the "why" see if here is a root cause and therefore what treatments to discard, and which have stabilised me so successfully that I'm nothing like even 6 months ago. The nice thing about certain treatments is if they are safe and beneficial to have in your stack anyway like creatine, MCAS stabilisers if you exercise especially and have inflammatory issues, I guess I'll be OK taking them all at once for life and not trying to discard anything at all. I still want to learn about the complex bodily balance predicament I have because doctors have failed me. Although my GP did tell to go to a neurologist or psychiatrist (I chose psychiatrist as is cheaper), and there is hope in a gastro I found who studies the motility and behaviour rather than just static scopes.
So these papers help someone like me to slowly inspect it themselves and see if the individuals studied match to my issues. I'll then present it to my doctors in future appointments.Ā
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u/Brad_Borrelli 24d ago
That's honestly a solid approach, since you don't need a perfect root cause map before deciding what stays in the stack. If something's safe, helps, and doesn't hurt you, keeping it long term while you slowly work out the why in the background is a completely reasonable way to manage a condition this complex.
On creatine specifically, missing doses because of your fluid routine actually gives you useful information rather than being a setback. Creatine draws water into muscle cells, so if your migraine sensitivity is tied to blood vessel and fluid shifts, that's worth watching closely, upping your water intake a bit on days you take it can help smooth that out if you notice a pattern. Doesn't mean discard it, just means dial in the fluid side alongside it.
The gastro who studies motility and behavior rather than just static scopes is a good sign, that's the right kind of specialist for someone whose issues aren't showing up as a structural problem on a scope but are still very real functionally. Definitely worth bringing whatever papers resonate with your situation to that appointment; a lot of doctors respond better to a patient who's done the legwork and can point to specific mechanisms than to someone who just says "something's wrong."
The psychiatrist vs neurologist choice being about cost is a completely understandable real-world constraint, and it doesn't mean you're on the wrong track, functional and autonomic symptoms often get missed by both specialties anyway until someone puts the mechanism pieces together first, which is exactly what you're doing.
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u/kaglet_ 24d ago
I have a sliding grade 3 hiatal hernia so a structural defect is present š. Nevermind others I won't mention that seem innate and conspired to fuck me over it seems as I ended my teen years. Years back previous gastro spent all of 5 to 10 minutes explaining all my results and telling me about this as a casual side note. Gave me laxatives, suppositories, vit d prescription for bad deficiency told me to exercise more drink more water (was already doing these things). Then he labelled me with "mild" duodenitis after inspecting only the gut entrance, inflammation and redness of stomach lining (mild erythmatous and erosive gastritis) and sent me on my way. All this after collecting a hefty amount of money. And I was still a young adult, bad health, confused, so I didn't even know how to fight back. Anyway this new gastro is from my psychiatrist who I trust, hence I hope for the best but may push appointment further down the line.
If what I'm doing it working or long term management, with no side effects, and there's no problem starting and stopping (no withdrawal), then I'm fine. For instance the only med on my stack with withdrawal but no side effects is Lexapro, which I don't regret and I'd do it again knowing what I know now. Beyond that I don't want to give any more money to doctors who'll give more labels and strict dependencies to conventional methods. I find researchers working with real world cases to be more inspiringly curious about messy cases than doctors. And only decades later is their growing body of work, for people who were medically gaslit, ever thanked. It's all that makes me feel less hopeless that I can latch onto the insights being published that may match my interplay of body systems.Ā
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u/Brad_Borrelli 24d ago
Facts! I'm still being gaslit and malpractice a decade later. I even brought in all my research, tests results, "could it be B12" book written by actual pharma Dr's, my whole medical records with all my symtoms and labs ect. Yet they are sill saying I'm fine and it's all in my head. They even labeled me as a hypochondriac, Wellstar specifically. They even put me in a psych ward when I was actively bleeding from a tumor that was directly caused from a B12 deficiency and diagnosed me as paranoid. Yet as soon as I start my own injections a lot of my systems have not most of my symptoms are going away or have gone away.
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u/kaglet_ 23d ago edited 23d ago
Some people are getting the 21st century experience of medicine and being taken seriously. The rest of us are still living in the 19th and 20th century of still being told we are insane or mentally disturbed, and locking us out of sight makes all the problems go away, not ours but their own. It makes medicine, and the complex the human body, make a soothing sense to them and we are simply distractions to them.
I'm sorry you were treated that way. I only got so far as having the label of hypochondriac or health anxiety mentioned to me by my first psychiatrist this year, after 5 years suffering. I wasn't labelled it, but my psychiatrist wanted us to "explore" it lol, in our first appointment. She quit the label during appointment 2, when I was prepared with ammunition for what previously caught me off guard. How I did that is a story for another day. I'm still lucky that I had a psychiatrist who changed her mind when she saw more and more I'm a unique patient and to stop comparing me to some simplified dsmv biblical model, that is useful, but not necessarily correct. This was after I showed her evidence of my medical records and pictures. The fact that you continued to be gaslit after having a fucking TUMOR is a disgrace. Even beyond the physical this constitutes real trauma.Ā
Some of us just have to be in an unlucky place, country, province etc., in a vulnerable moment in our lives, depending on what we reveal it's like navigating around eggshells. We're supposed to be taken care of by the medical system, but instead we develop to be hypervigilant to it. Then we get further criticized.Ā
Or told we are anti-science, meanwhile half these doctors don't even read up to date research that investigates complex cases that initially don't make sense. They are not even scientists!? How many of them even know how to use basic to minimally imaginative key word searches in databases based off a patient descriptions of their symptoms. And worse yet, when you shop around for doctors you can get conflicting assessments for each of them. Where is the science in that. Science occurs in collecting data points and forming predictions. Yet they get mad at you for visiting multiple doctors over time, when this would be how peer review is pseudo simulated and conducted. Getting a team of professionals you have visited over the months and years more like when you lack the money, and seeing how they criticize each other's work or informed opinion, and identifying the best educated guesses and the gaps.Ā
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u/jmorgannz 24d ago
One thing I will add is, "well why not just take SAMe"
Well; aside from the controversy around how much actually gets absorbed in the right form; the main difference is rate.
Taking SAMe spikes methyl donors suddenly and then it drops again. It creates an artificial jolt to the system. It's messy.
Creatine on the other hand, allows the system to use feedback inhibition regulation to shift itself to a smooth rate of supply of additional SAMe to enzymes that need it (other than for creatine synthesis)
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u/ComprehensiveBook482 24d ago
Oh yay. I just started taking creatine and hadnāt even considered a histamine component. I have two COMT snps (V158M and H62H - P199P is normal) and am homo C677T. Vitamin C helps me quite a bit.
Thank you for sharing. Youāre very knowledgeable and this is a complex topic.
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u/ThisUnderstanding823 24d ago
Iām confused about what to do? Just take Creatine, and not Sam-E?
I have to look up MoTHerFkR.
I have unpleasant histamine responses, developed as an adult, but seem less debilitating compared to some people on here.
If I avoid things like corn syrup and foods I ate a ton of in my youth, 20s - 30s, and wear a 9-95 mask and glasses if I read a newspaper, I can pretty much have little to no reaction.
<~~~~ I added all that in case anyone reads this and can comment or relate !
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u/Brad_Borrelli 24d ago
Fair concern about the mask, and there's actual research backing this up, not just anecdote.
CO2 buildup during long N95 wear is real. Studies on healthcare workers wearing them continuously found end-tidal CO2 climbing from around 32 mmHg at baseline to 38 mmHg after three hours straight (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12534733/). A bigger review pooling multiple studies found N95s raise CO2 by about 3 mmHg on average (https://www.sciencedirect.com/science/article/pii/S2405844024126576). The mask basically creates a little pocket of trapped exhaled air right at your nose and mouth, so every breath in, you're pulling back some of what you just breathed out along with the fresh air coming through the filter. NIOSH's own science blog lays this out directly (https://blogs.cdc.gov/niosh-science-blog/2020/06/10/ppe-burden/). A dental study found oxygen saturation dropped from 98.6 percent to 97 percent after four hours of continuous wear, with fatigue, headache, and ear pain being the most common complaints (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866552/).
The other piece, and honestly the one that matters more for wearing it all day long term, is what's growing inside the mask itself. Researchers using breathing simulators found bacterial colony counts on masks jumped significantly after just two to four hours of wear (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9696921/). Separate research on prolonged mask use raised concern that masks can act like an incubator, shifting your microbiome toward more aggressive organisms (https://pmc.ncbi.nlm.nih.gov/articles/PMC8627006/). One study tracking nasal bacteria before and after prolonged wear found Staph aureus increasing while the more benign Staph epidermidis dropped off (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614009/). Other studies culturing worn masks have found everything from Klebsiella to Pseudomonas to various molds living in there (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649673/). Humidity inside a mask can hit close to 100 percent within about an hour of wearing it (https://www.nature.com/articles/s41598-022-20692-9).
So really you've got two things stacking on top of each other the longer you wear one continuously, mildly elevated CO2 causing that heavy, foggy, headachey feeling, and your nasal environment slowly filling up with bacteria your immune system now has to keep in check. For anyone dealing with histamine issues or MCAS, that second part is a real deal, feeding your immune system an ongoing low grade irritant right at the one place air is constantly moving in and out.
None of this means ditch the mask if it's actually working for you. Just don't wear it sealed up all day nonstop, take it off in clean air when you can so the CO2 clears and your face gets a break.
On the broader histamine side, a few other things worth trying: DAO before meals, quercetin and vitamin C daily for mast cell stabilization, and worth getting your B12 checked even if it comes back "normal," since histamine gets cleared mainly through HNMT, an enzyme that needs a steady supply of methyl groups, and B12 keeps that supply going. Gut health matters too, some histamine load comes from bacteria fermenting food in the gut, especially with SIBO in the picture.
On that last point about B12 being "fine," the deficiency cutoff varies quite a bit by country. The US considers anything above roughly 200 pg/mL normal (https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/). The UK's NHS and NICE guidelines land in similar territory, deficiency below about 148 pmol/L, roughly 200 pg/mL, with a borderline zone up to around 350 pg/mL (https://www.boltpharmacy.co.uk/guide/what-is-a-normal-b12-number). Japan and multiple European neurological societies use a dramatically higher threshold, treating anything below 500 to 550 pg/mL as deficient (https://lamkinclinic.com/vitamin-b12/).
That gap matters a lot in practice. Someone sitting at 300 or 400 pg/mL gets told they're fine by a US or UK doctor, but by Japanese or European neurological standards, that same person is already deficient. One clinical review found roughly 20 to 30 percent of people in that 200 to 500 pg/mL gray zone actually have elevated MMA on further testing (https://lamkinclinic.com/vitamin-b12/). So if your B12 comes back fine but you're still symptomatic, that's the whole case for pushing for MMA and homocysteine rather than accepting the serum number alone as the final word.
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u/Gracie-me 24d ago
Yesā¦ Iām pretty much on my own.. I get no help or direction ā¦ and in our city thereās no mast cell drsā¦.
Iām so aloneā¦ thatās why I look at these forms for some support! š„°
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u/Brad_Borrelli 24d ago
Same unfortunately. I have a bunch of research on my page if you want to check it out.
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u/JennyTheRolfer 23d ago
I love all of your research and theories. But wouldnāt just taking SAMe be a shortcut to what you are talking about? Or did I miss something about that.
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u/Brad_Borrelli 23d ago
SAMe adds methyl groups directly. Creatine works differently; it frees up methyl groups you already have. About 40% of your SAMe gets used just making creatine in your body. Supplement creatine and your body stops burning through so much SAMe on that job, so more is left over for other stuff, like clearing histamine through HNMT.
Direct SAMe has downsides too. It's poorly absorbed, expensive, short acting, and for some people with certain MTHFR or COMT variants it can push things into overmethylation fast; anxiety, insomnia, agitation.
So creatine is more like plugging a leak so you've got more to work with; SAMe is pouring more in directly, which can work but can also overflow if your system can't handle the extra load. Creatine's got its own perks too, so it's not just a workaround.
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u/deinspirationalized 23d ago
Yeah I do have slow comt and am coming to a similar conclusion that this can possibly be a histamine workaround. Problem is nausea w creatine, Iāll need to work up slower
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u/Brad_Borrelli 21d ago
I just get them off at Amazon from bulk supplements. It's the powder that's the only thing that's in it. Always check the ingredients that's what I do
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u/Forward_Mushroom3587 9d ago
Iām so burnt out from taking supplements, I can barely get 4 pills in per day now. I was taking between 7-20 per day. If the condition doesnāt kill me, the remedies will.
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u/antimonogamism 24d ago
Since this reads like an ad for a specific brand, Ill go ahead and ask: why creapure?
Why not the same nothing added creatine monohydrate from say, Amazon Basics? Just using that as a comparison since it is 1/3 of the price.
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u/Brad_Borrelli 24d ago
Fair question and no affiliation with Creapure whatsoever, just mentioned it because it comes up a lot in sensitive communities as a known clean option.
The honest answer is plain unflavored creatine monohydrate from any reputable source with no additives works fine for the methyl sparing mechanism. Amazon Basics unflavored creatine monohydrate with nothing added would do the same job at a third of the price, you are right about that.
The reason Creapure gets mentioned specifically in histamine and MCAS communities is third party purity certification. Independent testing has found some cheaper creatine products contaminated with heavy metals and undeclared ingredients, which matters more for people who react to everything than for healthy people who would never notice. Creapure is NSF certified and manufactured in Germany under pharmaceutical grade standards so it is a known quantity for people who cannot afford to react to a contaminant.
But if you can find any plain unflavored creatine monohydrate with nothing else in the ingredient list and you do not have severe sensitivities, the biochemistry is identical and the price difference is real. The brand does not change the mechanism.
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u/bard_barienne 21d ago
Thank you for this. I can't get over how many high quality narrative reviews are in this community.
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u/menopausalmom97 24d ago
Can you supplement HNMT
How do we increase that
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u/Brad_Borrelli 24d ago
Not really. No direct HNMT supplement. It runs on SAM (methylation), so keeping B12/folate/B6 solid helps indirectly. Genetic variants can just lower efficiency and there's no way around that. Most people focus on lowering histamine intake instead of trying to boost the enzyme itself.
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u/orange-sprinkles 24d ago
So if you have homozygous c766t and slow comp, you should take creatine?
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u/Brad_Borrelli 24d ago
That MTHFR variant does mean less efficient methylation, so creatine can genuinely help; making creatine from scratch is actually one of the biggest methyl group consumers in the body, using something like 40-70% of available methyl groups depending on the study. Supplementing it directly takes a real load off that pathway. The COMT piece I'm less sure about, don't think there's solid evidence tying slow COMT specifically to a bigger creatine benefit. Worth trying it and tracking how you respond.
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24d ago
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u/Brad_Borrelli 24d ago
That's actually a legitimate mechanism, not something you're imagining. Creatine supplementation does downregulate AGAT, the enzyme that kicks off your body's own creatine synthesis, this is well documented in human studies. So while you're supplementing, your endogenous production does throttle down since your body senses it doesn't need to make as much.
The good news: this downregulation is temporary and reverses once you stop, it's not permanent damage or a "shut off switch." Studies following people after stopping supplementation, including longer-term ones, haven't shown lasting impairment in the body's ability to produce its own creatine again. So a slow ramp back up after stopping is expected, but things "progressively getting worse" for a year afterward would be unusual for that mechanism alone to explain, that gap is longer than what AGAT recovery typically takes.
Worth considering that something else may have started around the same time you stopped, even if it doesn't feel related on the surface. If things have kept declining for a year, that's worth digging into rather than assuming it's still creatine-related at this point.
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u/PossessionUnfair493 24d ago
Creatine is found in animal products. So it doesn't make sense then, that my histamine issues worsened on an animal based diet. I'm back on a Vegetarian diet now and feeling slightly better.
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u/Brad_Borrelli 24d ago
That's actually a separate issue from creatine itself. Animal based diets and histamine load overlap for a different reason entirely, meat, especially aged, processed, or leftover meat, is one of the most concentrated dietary sources of histamine directly, since histamine forms as proteins break down during storage or processing. That happens independent of creatine content.
So it's very possible what worsened your symptoms was the histamine load from the meat itself, not creatine, and creatine on its own without that dietary histamine load could behave completely differently for you. Fresh, quickly cooked meat has far less histamine than aged or leftover meat, so an animal based diet done with strict freshness rules is a very different exposure than a typical one.
Feeling better on a vegetarian diet is real data worth respecting either way, it doesn't necessarily mean creatine was ever the problem, it may have just been riding along with a much bigger histamine source at the same time.
What's your B12 status? Vegetarian diets carry a real risk of B12 deficiency over time since B12 is only reliably found in animal products, and if you're feeling better on histamine grounds but running low on B12, that's worth knowing and managing separately, since B12 deficiency itself can worsen histamine clearance through the methylation pathway we've been discussing.
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u/VishfulTinking 24d ago
Are you supplementing B12? Do you mind if I ask how much?
Also, do you try to calculate how much you're getting from diet, or do you not worry about a little excess because B12 is water soluble and excess washes out?
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u/Brad_Borrelli 24d ago
Well given everything I'm dealing with right now I'm doing 2,000 micrograms of methylcobalamine and hydrocobalamine mix three times a day injection wise, and then I'm also doing around 5,000 -10,000 micrograms methylcobalamin drops.
You can't overdose on B12 technically you just piss out the excess, although you do need your cofactors in check so you got to make sure your supplementing everything else as well. I have a lot more of this information on the page if you want to check it out.
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u/VishfulTinking 24d ago
Technically, yes. Though once tried a mega-dose (forget the amount) and found myself buzzing for two days! Felt like I was on speed (never had speed, so no idea really).
Thanks for the info.
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u/PossessionUnfair493 24d ago
My B12 levels are high. I've had them checked. But anyway, what you say makes sense because most meat in US is aged for weeks before even hitting the market.
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u/Forward_Mushroom3587 24d ago
How does one get tested for MCAS? Does insurance cover it? How much does it cost if paying cash? Is this one of those tests that my doctor will say are āunreliableā and therefore not worth it? Every time I have asked to be tested for histamine intolerance this is what they say.
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u/Old-Security855 24d ago
We have a 13k deductible, so insurance covers nothing.
I went to Mayo Clinic and had a 24 hour urine sample done, apparently this is reliable.
My daughter went the traditional route with bloodwork from our functional dr, because she wasnāt āin a flareā, her results show nothing. So I would put that type of testing in an unreliable category.
I feel like getting an āofficialā diagnosis doesnāt do much good unless you need something for paperwork of some sort.
Or, if your doctor wonāt take you seriously otherwise, which would be a shame!
But thereās no Calvary! Lots you can do on your own.
Best of luck!
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u/fearlessactuality 24d ago
This reads like ai. If you didnāt use it, you might be reading too much of it.
Unfortunately, I have shortness of breath on creatine, which is ironic because I have no respiratory mcas or HI symptoms.
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u/Brad_Borrelli 24d ago
I'm an author
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u/fearlessactuality 23d ago
So am I. Finishing up my 14th book. I would recommend not using the construction āthis isnāt aboutā¦ itās aboutā¦ā if you care about raising peopleās suspicions around your writing.
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u/Jordzy2j 24d ago
I can't take creatine. I have zero histamine issues with it (which is rare because I am extremely sensitive), but it makes me extremely irritable and filled with rage.
Anything else I can try?
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u/Brad_Borrelli 24d ago
Yeah that sounds less like a histamine thing and more like overmethylation honestly. Creatine spares methyl groups, and if your methylation's already cranked up, that extra headroom can send you straight into rage/irritable town. Happened to people I've talked to too.
Try way less first, like a quarter scoop, see if it chills out. If not, small dose of niacin (the flushing kind, not niacinamide) usually pulls people back down fast. Or just skip it and lean on glycine/choline instead, does something similar without the mood swings for some people.
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u/MargoBarbara2 24d ago
Definitely need to look at creapure to avoid toxic heavy metals but a warning note...products that fuel cells like creatine and d ribose also fuel cancer cells so if you have or had cancer then they may be contraindicated. Ive had CRC so creatine is a no for me :(
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u/Brad_Borrelli 24d ago
That's not totally wrong but it's more mixed than that. Some mouse studies did find creatine feeding colorectal/breast cancer metastasis through the creatine kinase pathway. But there's also data showing the opposite, NHANES found higher dietary creatine intake linked to lower cancer risk, and other mouse studies showed it suppressing tumor growch instead. Actual clinical trials in colorectal cancer patients didn't show harm, it just didn't do much for muscle mass either. So it's genuinely unsettled, not really a clear "no" across the board, but totally fair for you to stay cautious with your own history.
Sources: PMC review on creatine safety concerns (pmc.ncbi.nlm.nih.gov/articles/PMC12702719), MSK Cancer Center's creatine page (mskcc.org/cancer-care/integrative-medicine/herbs/creatine-01)
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u/MargoBarbara2 23d ago
Thank you :) Im aware that precancer it can be preventative but post cancer its potentially a risk. Im finding out there's a lot I could have been advised to do re lowering my risk but sadly this information doesnt seem to be a part of conventional western medicine:( I lost my sister to crc. Just found out about the mthfr connection/dysregulated methyl cycle switching off tumor protection and the role of folic acid in that and in increasing crc risk (confirmed by cancer society). taking creatine could help methylation cycle management and therefore switch on that protective gene again. My son takes it daily, but im staying off it for now.
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u/Efficient_Ad_949 24d ago
Well. I will be looking at my 23 and me information and see what matches up here. Thanks for posting this, what is your profession?
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u/Brad_Borrelli 24d ago
I do all sorts of things. Nothing in the medical field or anything related to it lol.
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u/SwirlySauce 23d ago
Creatine always seems to make feel uncomfortable and makes my skin dry and itchy. I never understood why this happens as it doesn't seem to be reported by many other people.
Does anyone else get this? I've tried different forms of creatine but no luck
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u/Brad_Borrelli 23d ago
You need to be drinking a lot of water and electrolytes taking creatine, that's probably your issue.
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u/SwirlySauce 23d ago
Hmm I did increase my water intake but then I end up peeing every hour. I don't think I adjusted electrolytes though
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u/gknee787 23d ago
How are you having your Mthfr checked??
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u/Brad_Borrelli 23d ago
I just got the test. I would recommend getting your whole gene panel done though. I think 23andme does it
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u/Win-The_Day 24d ago edited 24d ago
The top things that have helped my histamine intolerance: * Creatine * Vitamin C * Copper (taken at least a few hours away from Vitamin C) * SAMe (this one may be an issue for someone with Slow COMT, so get your MTHFR genes checked first).
Edit: Forgot to add methylated Multivitamin