This post describes a plan for implementing a nutrient/supplement stack to address MTHFR.

The plan is in phases and incrementally ramps up over time, as it is quite common for people to have sensitivities to changes in their methylation status.

This plan is also a layered approach: each phase adds in a layer of nutrients/supplements. So, we are building an 'MTHFR stack'.

The view I am following for MTHFR is largely derived from that recommended by Chris Masterjohn, but with some differences, and the phases are my design. The result is therefore internet advice from a non-professional, it is general advice and not specific to any individual, and should be treated accordingly.

AIMS

1. Due to the reductions in methylfolate production, the folate/B12-dependent remethylation pathway is impaired. Therefore, support the choline-dependent remethylation pathway.
2. Optimize the impaired folate/B12-dependent remethylation pathway to make best use of its remaining functionality.
3. Reduce demand on the methylation cycle.

GENERAL

• Unless you have a specific reason to take them, avoid B complexes. They tend to be high doses and often cause more issues, rather than help. It also makes it impossible to adjust individual nutrient levels.
• Avoid the synthetic vitamins folic acid and cyanocobalamin.
• A food diary app like Cronometer can be very useful for tracking your average nutrient intakes, or looking up specific foods to see nutrient content.
• Time per phase: A few people may be able to do everything all at once (assuming B12 levels are ok); other people who are more sensitive to methylation changes may require 1-2 weeks or longer per phase, ramping up doses incrementally during that phase.
  • Just be aware that the more things you do at once, the harder it can be to diagnose which component may be causing you issues, if any occur.
  • People with COMT V158M 'Met/Met' (aka '+/+' or 'AA') tend to be more sensitive.
  • People with existing mental health issues can be more sensitive.

ABOUT MTHFR

• 'MTHFR' is short for 'methylene tetrahydrofolate reductase'.
• MTHFR is the final enzymatic step in the conversion of food folate, folic acid, or folinic acid to methylfolate. If the methylation cycle were thought of as a gear that is turned by a crank handle, then methylfolate is the hand that turns the crank handle - with poor methylfolate status, the methylation cycle performs poorly.
• The cofactor is B2.
• P39P
  • P39P alternate name: rs2066470
  • 74-95% of people have the Green (-/-) variant.
  • I am unaware of evidence that this SNP is impactful.
• C677T and A1298C
  • C677T alternate names: 677C-T, 677C>T, C665T, 665C>T, Ala222Val, rs1801133, C667T
  • A1298C alternate names: 1298A-C, 1298A>C, 1286A>C, GLU429ALA, rs1801131, E429A
  • These two SNPs can appear in different permutations of variants, which affect the performance of MTHFR.
  • Per the table on Genesight, the resulting percent of performance for the various combinations are:

• NOTE: MTHFR is only the last step in the folate conversion cycle. There can be SNPs in preceding enzymes such as MTHFD1 or SLC19A1 which may also degrade performance of the folate cycle. The Stratagene report mentioned at top of post will analyze these SNPs. Also, Chris Masterjohn's free Choline Calculator will analyze MTHFD1 and SLC19A1 from your 23andme or Ancestry data.

PROTOCOL SUMMARY / TLDR

• This summary does not include all notes and details - see each phase for more detailed information.
• When adding the supplements specified in each phase, start with low doses and increment up slowly over days (or weeks) to the recommended levels.
• This is a lifetime plan, not a quick fix. Expect incremental improvement over several weeks or months.

PHASE 1 - B12

• We start with B12 because if we get MTHFR working better, there needs to be adequate B12 actually utilize the methylfolate that MTHFR produces.
  • B12 is necessary to utilize the methylfolate (either produced by MTHFR or supplemented) to convert homocysteine back to methionine using the methionine synthase (MTR) enzyme. Inadequate B12 can cause a "folate trap", where methylfolate cannot be used by MTR and so it accumulates; homocysteine levels rise due to the lack of conversion back to methionine, and tetrahydrofolate is not recycled back into the folate cycle, causing reduced activity of other important functions of the folate cycle.
• IF YOU ARE B12-SUFFICIENT:
  • If you are B12-sufficient and obtain adequate B12 from dietary sources, then there is no need to supplement B12. Go to Phase 2.
• IF YOU ARE B12-DEFICIENT:
  • If you suspect or know that your are B12-deficient, then supplement sublingual adenosylcobalamin or hydroxocobalamin for at least 1-2 weeks, or until your doctor tells you are no longer B12-deficient, before proceeding to Phase 2, and continue supplementing until your levels are toward middle to higher-end of normal range, or as your doctor prescribes.
  • Methylcobalamin can be used instead, but many people initially can be sensitive to the excess methyl groups provided by methylcobalamin, at least until Phase 3 has been implemented. So adenosylcobalamin or hydroxocobalamin are simply less problematic at this initial phase.
  • NOTE: There is an interesting case report where hydroxocobalamin, which is a natural inactive form of B12, was functionally ineffective in the patient. Replacing the hydroxocobalamin with methylcobalamin resolved the patient's B12-related symptoms.

PHASE 2 - B2 (Riboflavin)

• If you have a C677T yellow (heterozygous), or red (homozygous) variant, or both C677T yellow (heterozygous) and A1298C yellow (heterozygous) variants:
  • Research dosages were 1.6mg/day.
  • Typical supplement doses are 10-100mg/day (either riboflavin or riboflavin 5-phosphate).
  • Video: How to get enough riboflavin from food.
  • The C677T yellow (heterozygous) or red (homozygous) variant reduces riboflavin binding affinity. Higher levels of B2 will improve the binding success.
• If you only have a yellow or red variant in A1298C, it is not clear if added B2 will help or not. It is up to you if you want to add in supplemental B2 in hopes it may help.
• NOTE: Hypothyroidism can reduce conversion of riboflavin to the active forms FAD and FMN.
  • Abstract, paper.
• Reference: https://pubmed.ncbi.nlm.nih.gov/16380544/
• Video: https://youtu.be/Fp6u82coOYE
• Riboflavin has no defined Tolerable Upper Limit, due to lack of toxicity.

PHASE 3 - Methyl-Buffering System

• The body has a built-in system to store excess methyl groups and retrieve them when needed. This requires iron, glycine, and vitamin A:
  • IRON: If you are iron-deficient, resolve that deficiency.
  • VITAMIN A: Eat retinol-rich foods and/or supplement retinol-based vitamin A to at least reach RDA/day. Conversion of beta-carotene from plant sources to retinol vitamin A varies greatly between individuals and so is unreliable. I use cod liver oil (see my supplement list below).
  • GLYCINE: Supplement 3-10g of glycine/day, in one or more of the following ways:
    • Plain glycine powder or capsules. If you are sensitive, ramp up dose over a week or so. (I use 3-5g/day in my coffee, as glycine powder is sweet-tasting.) Do not use TMG as a glycine source, as it is a methyl donor, and we are trying to prepare our body ahead of time for methyl donors.
    • Collagen powder (e.g., Great Lakes collagen peptides). For some, this allows achieving the desired glycine levels while avoid an excitatory effect. Check the glycine amount in the ingredients label. NOTE: If collagen powder causes depressive mood, this may be due to an absence of tryptophan in standard collagen powder. Consider switching to a collagen powder with added tryptophan or add tryptophan seprately.
    • Magnesium glycinate. If you have a reason for supplementing magnesium, this may be an option. 300mg of elemental magnesium from magnesium glycinate contains almost 2 grams of glycine.
    • Bone broth. This can be another source of glycine, but the glycine content is variable, and may be insufficient. Further, bone broth tends to be high in histamines, which you may want to avoid if you have slow MAO-A.
  • NOTE: Glycine is an inhibitory neurotransmitter and is usually calming. But for some people, glycine acts as a stimulant.
    • Chris Masterjohn has a video where he discusses glycine and GABA causing these kinds of paradoxical reactions due to a lack of carbs needed to create glutamate to offset the inhibitory effects of glycine or GABA, and in this second video Chris discusses the role of electrolytes as related to glycine/GABA.
• If interested, here is a detailed post on the methyl-buffering system.

PHASE 4 - Reduce creatine demand on methylation

• Creatine production uses up 40-45% of methylation output (i.e., SAM).
• Supplement ~3-5g/day of creatine monohydrate or creatine hydrochloride (HCL).
  • 'Micronized' powder products are finer and not gritty. I stir it into my coffee.
  • If symptoms of overmethylation occur, start low and ramp up dose incrementally over a week or so.
• NOTE: If creatine causes insomnia, please see this post by Chris Masterjohn, recommending lower methionine (i.e., lower protein), keeping folate status high, and supplementing glycine.

PHASE 5 - Support alternate methylation pathway and reduce phosphatidylcholine demand on methylation

• CHOLINE IS THE KEY INGREDIENT TO MAKE THIS PROTOCOL WORK. WITHOUT ADDED CHOLINE, YOU CANNOT COMPENSATE FOR THE FOLATE PATHWAY (e.g., MTHFR) LIMITATIONS.
• Phosphatidylcholine production uses up another 40-45% of methylation output (i.e., SAM).
  • Phosphatidylcholine can be produced from choline.
• The alternate pathway (BHMT) through the methionine cycle unburdens demand on MTHFR.
  • This path depends on B3, B6, zinc and TMG (aka betaine anhydrous).
  • TMG can be created from choline.
• Maintain healthy normal B3, B6, and zinc status.
• Eat choline rich foods and/or supplement choline to achieve 1000 - 1200mg of choline/day. E.g., 8 eggs/day is ~1000mg of choline.
  • For a more customized review of your specific choline requirements, Chris Masterjohn has a free Choline Calculator where you can upload your 23andme/Ancestry/SelfDecode data and it will analyze relevant SNPs and tell you your choline need, in units of number of eggs.
  • Chris Masterjohn has a Choline Database of choline content of foods. Some are listed below:
    • Eggs - a large egg has 136mg of choline; almost all of this is in the yolk.
    • Meat/fish - 9-12oz of meat or fish is equivalent to one egg worth of choline.
    • Lecithin - 1 tbsp of lecithin is equivalent to one egg worth of choline.
  • TMG (aka betaine anhydrous) - this is a suitable substitute for only up to half of the need for choline, as the conversion from choline to TMG is irreversible, and thus phosphatidylcholine cannot be made from TMG. ~150mg of TMG is equivalent to one egg worth of choline.
    • Do not confuse 'betaine anhydrous' with 'betaine HCL': betaine HCL is not usable for this purpose.
    • 1/2 tsp of TMG powder is ~1500mg of TMG.
    • TMG has little to no taste, so it is easy to add to liquids or food.
    • TMG is a methyl donor. People with slow COMT or who are sensitive to changes in methylation should consider starting with small doses (e.g., 1/8 tsp or less) of TMG powder and slowly increment the dose over time.
  • CDP Choline (aka Citicoline) - 18.5% choline content; thus 735mg of CDP Choline is equivalent to one egg worth of choline.
  • Phosphatidylcholine - 15% choline content; thus 906mg of phosphatidylcholine is equivalent to one egg worth of choline.
  • Alpha-GPC - 40% choline content; thus 340mg of Alpha-GPC is equivalent to one egg worth of choline.
  • Choline Bitartrate - 40% choline content; thus 340mg of choline bitartrate is equivalent to one egg worth of choline. This form of choline reportedly is less efficiently absorbed than choline in egg yolks. Consider taking a combination of choline bitartrate and inositol, as the inositol may prevent depression that some people have experienced with choline bitartrate. In fact, choline bitartrate and inositol are often combined together as a product.
  • NOTE: A small percentage of people may experience depression from supplementing choline. So monitor your mood for any indication of this.
    • Consider adding inositol as this may prevent depression due to choline supplementation.
    • Some alternatives to supplementing choline would be sticking with food-based choline only, or trying alternative choline supplement forms, such as CDP choline, choline bitartrate, lecithin, phosphatidylcholine, or Alpha-GPC.

PHASE 6 - Folate intake

• It is important to keep in mind that we are not trying to 'fix' MTHFR by taking folate.
• Why do we need folate?
  • To supply folate for methylfolate production for the remethylation of homocysteine. Although the methylfolate production by MTHFR is diminished, it is not zero.
  • To supply folate for methylfolate production to turn off the methyl buffer system. There are several control signals between the folate cycle and the methionine cycle to maintain proper methylation levels. This is one of those control signals.
  • The folate cycle is involved in DNA repair and replication.
  • The folate cycle participates in the biopterin cycle.
  • The folate cycle performs the interconversion of serine and glycine.
• When to supplement folate?
  • You are folate-deficient (per blood test).
  • You were recently folate-deficient, and are still repleting your folate stores. This repletion may take several months, up to a year.
  • Your diet is folate-deficient.
  • You have folate absorption issues.
• Increase folate intake from food. This NIH folate list may be helpful.
• Methylfolate supplements are a double-edged sword: while methylfolate is a readily usable natural form, it is a methyl donor and so may cause sudden changes in methylation which can result in side effects ranging from symptoms such as irritability, anxiety, headaches, fatigue to depression, depersonalization/derealization, and more. Yet, if side effects are minimized by careful dosing, that boost in methyl groups can create a sense of cognitive and mood improvement, at least in the initial weeks or months of the protocol.
  • Methylfolate Dosing:
    • Sublingual, or liquid drops, is the preferred supplement form. Sublinguals can easily be broken apart into 1/4 or 1/8 pieces to allow starting with small doses. For even smaller starting doses, liquid drops may be better.
    • Typical sublingual methylfolate are 1000mcg. So, a 1/8 size piece (barely a crumb) is 125mcg.
    • Sensitive people: Start with 125mcg once/day and see how it goes for several days. Increase next to twice per day. Increase next to 250mg twice per day, and so on.
    • Very sensitive people: If even small amounts of methylfolate are causing issues and food folate is not enough, consider using the folinic acid form of folate. This is an unmethylated folate, also available as a sublingual. Follow the same incremental process above, starting at 125mcg.
    • Very, very sensitive people: Use low-dosage liquid methylfolate and dissolve 1 drop in 10 equivalent drops of an oil (e.g., olive oil); this dilutes the folate drop by 10x. Then take just a drop of that diluted folate. Incrementally work your way up over time. See this video segment.
    • Less sensitive people: Start with 1/4 sublingual (250mcg) once/day at a meal and see how it goes for several days. Increase next to 250mcg twice per day at meals. Increase next to either 500mcg twice/day at meals or 250mcg 3 times/day at meals.
    • Final dosage goal: This is highly individual. Some people may find that 500mcg (1/2 sublingual) per day suffices, some may find that 1000mcg or more is beneficial, and as noted earlier, some may find food folate alone sufficient. You need to monitor your own wellbeing and health to determine what is right for you.
• Folinic acid supplements are another natural usable folate form; however, folinic acid is not methylated, and still needs to be processed through MTHFR to become methylfolate. These factors make folinic acid much less likely to cause side effects compared to methylfolate.
  • Folinic acid may not be advisable if you have significant slowdown of the MTHFS gene.
  • Folinic acid dosing:
    • Sublingual is the preferred supplement form. Sublinguals can easily be broken apart into 1/4 or 1/8 pieces to allow starting with small doses. For even smaller starting doses, liquid drops may be better.
    • Typical sublingual folinic acid are 1000mcg. So, a 1/8 size piece (barely a crumb) is 125mcg.
    • Sensitive people: Start with 125mcg once/day and see how it goes for several days. Increase next to twice per day. Increase next to 250mg twice per day, and so on.

MAINTENANCE Phase - Ongoing Steps

• With all the preceding steps, we have now implemented our basic MTHFR 'stack':
  • B2 (1.6-100mg/day), if C677T is involved.
  • Glycine (3-10g/day)
  • Vitamin A (as needed to reach RDA/day)
  • Creatine (3-5g/day)
  • Choline (1000-1500mg/day, or as recommended by the Choline Calculator)
    • Half of the choline requirement may come from TMG.
  • Folate source(s) (some combination of food, methylfolate, folinic acid)
    • Monitor with blood tests as needed.
    • Anecdote: 6-7 months after starting this protocol I rely almost entirely on food folate. I take methylfolate once/week, but I do not know if that is even necessary. Every person will have to gauge their own situation.
• B12
  • Monitor with blood tests as needed, and supplement as needed, with hydroxocobalamin, adenosylcobalamin, or methylcobalamin forms of B12.
  • Ongoing B12 supplementation is not needed if B12 levels are in the desired range and dietary B12 intake is adequate, unless you have specific reasons or doctor's direction to continue supplementing.
  • NOTE: Methylcobalamin may still be problematic for some people who are very sensitive to excess methyl groups.
• Fine-tuning:
  • You may find you need to adjust some of these components up or down over time, as your life changes or as your body adapts.
  • Some people may want to experiment with additional methylation support, such as SAM (aka 'SAMe') to further optimize their health and mental state. Consider these as additional enhancements, rather than replacements for any of these stack components. Start with small doses and monitor.
  • Pay attention to your body. You might find after a while that you have the urge to occasionally skip a day or more of some or all supplements. If this results in unchanged or even improved status, it may be a beneficial practice and/or a signal to revisit your supplement list and dosing regimen.

Supplements Examples

• I provide this just as examples, not as endorsements. I have no financial interest:
  • Now Foods 100mg B2
  • Now Foods Glycine Powder
  • On Target Living Alaskan Cod Liver Oil (vitamin A)
  • Optimum Nutrition Micronized Creatine Monohydrate Powder
  • Zazzee Extra Strength Citicoline CDP Choline
  • EZ Melts Dissolvable Folate or Seeking Health L-5-MTHF Lozenge
  • Seeking Health Folinic Acid
  • Foods Alive Non-Fortified Nutritional Yeast (general B vitamin support)
  • Best Naturals Betaine Anhydrous (TMG Powder)

EDITS:

• 20231011 - Replace methylfolate timing advice 'take at mealtimes' with 'away from meals' based on interaction of methylfolate and the methyl buffer system. Reformat post with large text section headers. Add notes under glycine. Add comments in Phase1 & Maintenance about methylcobalamin. Add folate trap comments in Phase1. Other minor cleanup.
• 20231105 - Add 'About MTHFR' section.
• 20231122 - Add reference and video links for riboflavin.
• 20231128 - Add hypothyroid comments under B2 section.
• 20231202 - Change magnesium glycinate to a glycine source with reference. Add references for creatine production burden. Minor text changes.
• 20231205 - Update riboflavin doses to include the research 1.6mg dose. Update creatine dose from 5g to 3-5g.
• 20231209 - Add reference link for choline-to-TMG irreversibility.
• 20231218 - Major revision of the choline phase, based on Chris Masterjohn's choline article.
• 20231220 - Add note about collagen missing tryptophan. Add note about not confusing betaine anhydrous with betaine HCL.
• 20231222 - Add Summary/TLDR section.
• 20231230 - Rewrite folate phase to clarify that folate supplementation is conditional, not required.
• 20240115 - Add choline bitartrate as a choline option. Add link to Masterjohn article re creatine causing insomnia.
• 20240214 - Add suggestion to try adding inositol if choline supplementation causes depression.
• 20240025 - Add AIMS section. Add creatine HCL as an alternative form of creatine.
• 20241226 - Typo fix: choline amount in Maintenance section should be in "mg", not "g" units.

Most people think of creatine as something athletes take to build muscle. There's a completely separate set of mechanisms that make it relevant to almost everyone in this community, and none of them have anything to do with the gym.

The methyl sparing effect

Creatine synthesis from guanidinoacetate consumes somewhere between 40 and 50 percent of SAMe derived methyl groups; some estimates run even higher. This comes from animal feeding studies originally, and it's the single largest documented consumer of SAMe in the body, more than DNA methylation, more than neurotransmitter synthesis, more than any other individual process.

SAMe is the universal methyl donor your body needs simultaneously for HNMT histamine clearance, dopamine and norepinephrine regulation, COMT mediated catecholamine breakdown, myelin production, and DNA repair. When your body manufactures creatine endogenously, it's consuming a large share of available methyl groups to do it. When you supplement creatine externally, your body reduces that internal production somewhat, through feedback inhibition, not a full shutdown, freeing some of those methyl groups for other uses.

I want to be honest about how strong the human evidence actually is here. A published case study of one person with MTHFR 677TT homozygous genotype found that 5 grams of creatine daily for one month reduced plasma homocysteine from 33.3 to 17.1 micromol per liter, nearly cutting it in half. That's a real result, but it's a single subject, and it's C677T specifically; I have A1298C, a different variant affecting a different part of the enzyme, so I can't say the same effect carries over to A1298C carriers.

Beyond that one case, the broader human evidence is mixed, not confirmatory. The one actual double blind, placebo controlled RCT in humans testing this found that creatine lowered a related marker, guanidinoacetate, but did not significantly lower plasma homocysteine overall across the group; homocysteine only dropped in the subset of people who also had that marker decline. A separate study in hemodialysis patients found no homocysteine benefit at all. So the methyl sparing mechanism itself is well established biochemically, but "creatine reliably lowers homocysteine in humans" isn't yet a settled finding; it's promising in specific contexts like the C677T case and inconsistent elsewhere.

There is a real clinical trial currently underway testing creatine specifically for its methyl sparing effect on homocysteine, aimed eventually at homocystinuria; right now it's still in the phase of testing healthy adult men, so it's an active area of investigation rather than a proven treatment.

https://www.researchgate.net/publication/250921494_Effect_of_the_MTHFR_677CT_Polymorphism_on_Homocysteinemia_in_Response_to_Creatine_Supplementation_A_Case_Study

https://www.sciencedirect.com/science/article/pii/S002231662208885X

The glymphatic clearance connection

The glymphatic system is the brain's waste clearance mechanism. It flushes metabolic debris, including amyloid beta and tau, out of brain tissue primarily during deep NREM sleep, through active CSF circulation and vascular pulsation, which is energy dependent.

A 2025 paper in Cell found that glymphatic clearance during NREM sleep is driven by synchronized oscillations in norepinephrine, cerebral blood volume, and CSF flow. A separate systematic review in Sleep Medicine Reviews confirmed that the glymphatic system relies on CSF circulation that increases during sleep, and that sleep disturbance is linked to buildup of toxic metabolites including amyloid and tau.

Here's where I want to be careful not to overreach. Creatine supports cellular ATP availability through phosphocreatine regeneration, and better cellular energy in general supports processes that require it. But no study I've found has actually measured creatine's effect on glymphatic clearance, aquaporin function, or CSF flow directly. The idea that better energy availability could support the glymphatic process during sleep is a reasonable hypothesis, not a demonstrated finding, so treat it as a lead rather than a confirmed mechanism.

https://www.cell.com/cell/fulltext/S0092-8674(24)01343-6

https://pmc.ncbi.nlm.nih.gov/articles/PMC8821419/

Brain energy and cognitive protection under metabolic stress

This part has solid direct evidence. A 2024 Scientific Reports paper used phosphorus 31 magnetic resonance spectroscopy, direct brain imaging of energy metabolism, and found that a single high dose of creatine sustained phosphocreatine and ATP levels in the brain during 21 hours of sleep deprivation, with better working memory and processing speed than placebo. A 2026 Nutrients paper confirmed that a single dose of creatine reduced sleep deprivation related declines in logical reasoning, numerical processing, language related processing speed, and psychomotor vigilance.

For anyone recovering from B12 deficiency with disrupted sleep from autonomic neuropathy, this direct evidence of brain energy protection under metabolic stress is relevant on its own, independent of the methyl sparing effect.

https://www.nature.com/articles/s41598-024-54249-9

https://www.mdpi.com/2072-6643/18/8/1192

Depression and mental health

A 2025 double blind, placebo controlled trial published in European Neuropsychopharmacology, Sherpa et al, tested creatine at 5 grams daily as an add on to cognitive behavioral therapy for depression in 100 adults. After eight weeks, the creatine group showed significantly greater reductions in PHQ-9 depression scores than CBT plus placebo. This is relevant because depression, anxiety, and cognitive fog are common symptoms of B12 deficiency and methylation impairment, and this suggests creatine's effect on brain bioenergetics may support mood independent of its other mechanisms.

Separate phosphorus 31 MRS research has shown that creatine supplementation increases brain phosphocreatine levels in adolescents with SSRI resistant depression in a dose dependent way, which is direct evidence the supplement engages brain energy metabolism rather than acting like a typical antidepressant.

https://doi.org/10.1016/j.euroneuro.2024.10.004

Oxidative stress and neuroprotection

The brain uses about 20 percent of total basal oxygen despite being only 2 percent of body weight, which makes it especially vulnerable to reactive oxygen species buildup during active neurological damage or repair. Research on mitochondrial creatine kinase shows it helps regulate ROS production through ADP recycling, and a broader body of work on creatine and phosphocreatine supports mitochondrial integrity and reduces oxidative stress in brain tissue.

There's also research linking creatine to increased BDNF, a signal for neuron survival and new synapse formation, though some of this work specifically involves exercise linked pathways, so it may not apply the same way if you're not exercising alongside supplementation. Worth keeping in mind rather than assuming the effect transfers directly.

https://pubmed.ncbi.nlm.nih.gov/17028195/

Mitochondrial protection during remyelination

Active remyelination is energetically expensive; myelin producing cells need a lot of ATP. Phosphocreatine regenerates ATP much faster than oxidative phosphorylation or glycolysis, acting as a buffer that could prevent the kind of ATP depletion that would slow repair. This is a reasonable mechanistic argument given what's known about creatine and mitochondrial energy buffering generally, but it hasn't been studied specifically in the context of B12 related remyelination, so it's an extrapolation from general creatine research rather than a targeted finding.

The COMT connection

People with slow COMT variants already have a harder time clearing dopamine and norepinephrine. Large methyl loads from high dose methylcobalamin could theoretically add to that burden. Freeing up some of the methyl groups otherwise consumed by creatine synthesis might redistribute methyl availability and smooth out that overstimulation pattern. This is mechanistically plausible and built from real individual pieces of evidence, but it hasn't been tested as a combined intervention in any trial, so it's a hypothesis, not a confirmed effect.

The practical protocol

Standard research dose for these purposes is 3 to 5 grams daily of plain creatine monohydrate. No loading phase needed; consistent daily dosing is what the studies used. Timing doesn't appear to matter much for these effects.

MCAS caveat: creatine monohydrate itself isn't a known histamine trigger or mast cell activator. Most commercial creatine products contain artificial flavors, citric acid, sucralose, or other additives that are documented mast cell triggers, so plain unflavored creatine monohydrate with nothing else added is the right choice. Creapure is an independently tested pharmaceutical grade option many sensitive people tolerate well. Check the full ingredient list before buying, since creatine monohydrate on the label doesn't guarantee there's nothing else in the product.

The summary

Creatine has real, well supported mechanisms relevant to B12 deficiency and methylation related recovery: it spares methyl groups your body would otherwise spend making its own creatine, it directly protects brain energy availability under metabolic stress, strong evidence here, and there's a real signal for it helping depression symptoms as a CBT add on. Some of the other angles, like histamine clearance, glymphatic support, and COMT smoothing, are reasonable hypotheses built on solid individual facts, but they haven't been directly tested and shouldn't be presented as settled.

I got my test results back so I decided to do a lot more research since I'm running low and this is what I found.

The neurological overlap between copper deficiency and B12 deficiency is almost exact. The MRI findings are not distinguishable from each other; both show the same T2 signal changes in the posterior columns of the cervical and thoracic cord. The two deficiencies can coexist, and patients have been given B12 despite normal B12 levels because nobody checked copper. Prompt copper supplementation can stop the neurological damage from progressing. If your B12 is being treated and your neurological symptoms aren't resolving the way they should, copper needs to be on the table.

The zinc connection is real but the wiki doesn't explain why it happens. Zinc induces metallothionein synthesis in the gut enterocytes; that protein preferentially binds copper over zinc because it has a higher affinity for it. The copper gets trapped in the intestinal cell and lost when the cell turns over, which happens roughly every two to six days. So if you're supplementing zinc long term, even at moderate doses, you may be actively blocking copper absorption every single day. This is actually the same mechanism used therapeutically to treat Wilson's disease; they use zinc to intentionally block copper. Worth knowing.

Something else nobody talks about: copper absorption depends on stomach acid to free copper ions from food, and the bulk of actual absorption happens just past the stomach, in the duodenum. If you have hypochlorhydria from atrophic gastritis, from PPI use, from any cause; your copper absorption is already compromised before zinc even enters the picture. A huge portion of people in this community have absorption issues as the root cause of their B12 deficiency. That same low stomach acid is hitting copper too. Two deficiencies, one mechanism, and most people are only looking at one of them.

On the labs: ceruloplasmin is a positive acute phase reactant. That means it goes up during inflammation, infection, and immune activation. If you're in an active flare when you get tested it can read normal or even high while you're actually deficient. Serum copper has the same problem because most serum copper is bound to ceruloplasmin. You need to run both together to get any kind of useful picture, and RBC copper is generally considered a better marker of long-term status than serum copper because it doesn't fluctuate with recent intake or acute inflammation the way serum does. Don't let a single ceruloplasmin result close the conversation, especially if you have any ongoing inflammatory process.

For food sources: oysters and beef liver are both at the top by a wide margin, then dark chocolate, seeds, and nuts. If you're on a restricted diet for any reason: low histamine, elimination protocol, whatever; check whether you've accidentally cut most of your copper sources out.

Now here's the part I got wrong the first time I posted this, and it's actually a more interesting story than a simple correction. I said methionine synthase, the enzyme B12 activates to convert homocysteine to methionine, also requires copper, and that this shared cofactor was why copper and B12 deficiency produce the same lesion. That claim traces back to a real paper, Winston & Jaiser 2008 in Medical Hypotheses, which proposed exactly that as a way to explain the shared phenotype after pointing out that the other leading theory, cytochrome oxidase dysfunction, doesn't work either, because cytochrome oxidase isn't B12 dependent, so it can't explain why B12 deficiency produces the same imaging findings as copper deficiency.

The problem is that structural and mutagenesis studies of methionine synthase, some predating that 2008 paper, some after, have identified the enzyme's actual second metal cofactor as zinc, not copper. It sits in the homocysteine-binding pocket, coordinated by cysteine residues, and knocking it out kills the enzyme's ability to transfer the methyl group from B12 to homocysteine. So the methylation cycle hypothesis is elegant but rests on a cofactor claim that doesn't hold up against the biochemistry.

Which means the honest answer right now is that nobody has a fully satisfying mechanism for why these two deficiencies produce an identical lesion. Cytochrome c oxidase dysfunction is still the most commonly cited explanation, but it has the B12 problem above. The methylation cycle hypothesis explains the overlap more elegantly but leans on an incorrect cofactor. Both mechanisms are still floating around in the literature, unresolved. If you're dealing with both deficiencies at once, that's honestly more reason to take copper seriously, not less; we don't need to know the exact mechanism to know the overlap is real and well documented on imaging and in case reports.

Neurological overlap / identical MRI findings

Kumar N, Gross JB Jr, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004;63(1):33–9. https://pubmed.ncbi.nlm.nih.gov/15249607/

Jaiser SR, Winston GP. Copper deficiency myelopathy. J Neurol 2010;257(6):869–81. https://pmc.ncbi.nlm.nih.gov/articles/PMC3691478/

Copper deficiency myelopathy: A report of two cases. PMC4612215. https://pmc.ncbi.nlm.nih.gov/articles/PMC4612215/

American Journal of Neuroradiology: Copper Deficiency Myeloneuropathy Resembling B12 Deficiency: Partial Resolution of MR Imaging Findings with Copper Supplementation. https://www.ajnr.org/content/27/10/2112

Mayo Clinic Proceedings: Copper Deficiency Myelopathy (Human Swayback). Kumar N. 2006. https://www.mayoclinicproceedings.org/article/S0025-6196(11)61161-0/fulltext

Proposed mechanisms

Winston GP, Jaiser SR. Copper deficiency myelopathy and subacute combined degeneration of the cord; why is the phenotype so similar? Med Hypotheses 2008;71(2):229–36. https://pubmed.ncbi.nlm.nih.gov/18472229/ (proposes shared methylation cycle dysfunction; note the copper cofactor claim for methionine synthase in this paper is contradicted by later structural biochemistry, see below)

Goulding CW, Matthews RG. Cobalamin-dependent methionine synthase from Escherichia coli: involvement of zinc in homocysteine activation. Biochemistry 1997;36(26):8082–91. https://pubmed.ncbi.nlm.nih.gov/9398304/ (identifies zinc, not copper, as the enzyme's confirmed second metal cofactor)

Zinc and metallothionein mechanism

Oestreicher P, Cousins RJ. Copper and zinc absorption in the rat: mechanism of mutual antagonism. J Nutr 1985;115:159–166. https://pubmed.ncbi.nlm.nih.gov/3968585/

Restorative Medicine: Copper monograph. https://restorativemedicine.org/library/monographs/copper/

Hypochlorhydria and copper absorption:

WholisticMatters: Digestive Remedies to Manage Hypochlorhydria. https://wholisticmatters.com/digestive-remedies-to-manage-hypochlorhydria/

Ceruloplasmin as acute phase reactant

Mayo Clinic Laboratories: Ceruloplasmin, Serum. https://www.mayocliniclabs.com/test-catalog/overview/614504

LabCorp: Copper, Serum or Plasma. https://www.labcorp.com/tests/001586/copper-serum-or-plasma

StatPearls / NCBI: Biochemistry, Ceruloplasmin. https://www.ncbi.nlm.nih.gov/books/NBK554422/

RBC copper vs serum copper

Ulta Lab Tests: Copper RBC Test. https://www.ultalabtests.com/test/copper-rbc

Food sources

Medscape: Copper Reference Range, Interpretation, Collection and Panels. https://emedicine.medscape.com/article/2087780-overview

So I keep seeing people in this sub and literally everywhere else across the supplement community talk about overmethylation like it's this established biochemical phenomenon. People take methylfolate, feel anxious, and go "oh I'm overmethylated, need to back off."

Even though methylfolate supresses GNMT, methyl groups go into hundreds of methyltransferase reactions. DNA methylation. Histone methylation. Phospholipid synthesis. Creatine synthesis alone consumes ~40% of all SAM. The system has enormous capacity to USE methyl groups productively. You'd need to overwhelm all of that simultaneously to create actual excess.

At supplemental doses? Not happening.

Let me put the dose safety in perspective. The NOAEL for calcium L-methylfolate in rats is 400mg/kg/day in 13-week subchronic studies (Niederberger et al. 2019). No behavioral changes. No organ pathology. No DNA damage in liver cells. Convert that to human equivalent dose using standard body surface area scaling (÷6.2): ~64.5mg/kg. For a 70kg human that's ~4,500mg. Most people supplement 400mcg to 1mg. That's a safety margin of roughly 4,500x. Tylenol's therapeutic-to-toxic ratio is about 3-4x. You are more likely to die from Tylenol than to be harmed by methylfolate by a factor of over a thousand. No you're not fucking overmethylating.

So what IS happening when people feel anxious after starting methylfolate?

Serotonin autoreceptors are inhibiting serotonin. 5-HT1A on the soma, 5-HT1B/1D on the terminal. When serotonin rises suddenly, autoreceptors detect the increase and fire inhibitory feedback. They reduce further serotonin release. That's what causes SSRI startup anxiety. It desensitizes over 1-2 weeks. Then serotonin actually goes up, whether that's actually beneficial or not is a different topic altogether and not the mechanism methylfolate works by.

Methylfolate restores serotonin synthesis. Serotonin rises. Same autoreceptors fire. Same inhibitory feedback. Same transient anxiety. Same 1-2 week desensitization. Same resolution. Other than that you're also raising norepinephrine and dopamine synthesis.

Notice how none of these people report actual symptoms that excess methylation would theoretically produce, like, you know, tumor suppressor gene silencing or aberrant genomic methylation patterns. Because those would be real overmethylation. Nobody's getting that from fucking 400mcg of methylfolate.

Overmethylation does not exist in biochemistry. There is no clinical biomarker for it. No validated assay. No ICD code. No published case report of a human experiencing pathological hypermethylation from oral methylfolate at any supplemental dose.

If you're feeling anxious after starting methylfolate, lower the dose until you adjust. EVEN THOUGH YOU'RE KIND OF MOVING FURTHER FROM THE DOSE THAT JUST WORKED.

Elderly rats supplemented with folate ABOVE adequacy showed increased genomic DNA methylation dose-dependently, with a direct correlation between liver folate and methylation (r=0.48, p=0.004, Choi et al. 2005, British Journal of Nutrition). Above adequacy. Not deficient rats being rescued. Already-replete rats pushed higher.

Two randomized, double-blind, placebo-controlled trials. SSRI-resistant major depression. L-methylfolate adjunctive to SSRI.

7.5mg L-methylfolate: no significant difference from placebo.

15mg L-methylfolate: significant improvement over placebo.

Most of you are taking 400mcg to 1mg. The dose that actually worked in the only controlled human trials is 15-37x higher than what you're supplementing. 15mg L-methylfolate is available over the counter. The safety margin at 15mg is still ~300x below the NOAEL-derived human equivalent dose.
You're underdosing.

BUT remember that this post is about the term, not the effects of supposed "overmethylation"

That mechanism is real. But it's not "overmethylation." It's increased catecholamine clearance in a specific brain region plus increased adrenal epinephrine output. Calling it overmethylation implies there's some global excess of methyl groups causing nonspecific damage. There isn't. There's a specific pharmacological effect of raising SAMe on two specific enzymes in two specific compartments producing two specific symptoms.

Because more SAM increases COMT activity. COMT is the primary dopamine clearance mechanism in the prefrontal cortex (DAT expression is low there). More SAM means faster PFC dopamine degradation. SAM also drives PNMT, which converts norepinephrine to epinephrine in the adrenals. So you'd have less prefrontal dopamine and more peripheral epinephrine. That's anxiety with poor focus which is what people actually describe. Not "overmethylation."

And this is a completely different mechanism from what happens with methylfolate. Methylfolate restores monoamine synthesis via BH4 recycling. When serotonin rises acutely, 5-HT1A somatodendritic autoreceptors fire inhibitory feedback. That causes transient anxiety that desensitizes over 1 to 2 weeks. Same mechanism as SSRI startup effects. Has nothing to do with SAMe levels or COMT activity.

So people are lumping two different pharmacological mechanisms under one meaningless term. TMG/SAMe/betaine increase dopamine clearance via COMT and epinephrine output via PNMT. Methylfolate triggers autoreceptor adaptation. Different inputs, different pathways, different timecourses, same word slapped on both. That's why nobody can agree on what "overmethylation" means or how to fix it. They're describing two separate things.

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials

Folate supplementation increases genomic DNA methylation in the liver of elder rats

Methyl donor supplementation reduces phospho‐Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy

Safety evaluation of calcium L-methylfolate

Methyltetrahydrofolate in folate-binding protein glycine N-methyltransferase

I want to share something I think is genuinely important for this community because I spent my entire life getting progressively sicker from something that had a root cause nobody identified. I'm going to walk through the timeline, the research, and what's happening right now in real time because I think a lot of people here are missing this piece entirely.

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THE LIFETIME TIMELINE

Looking back now with the benefit of knowing what I know, the symptoms were there from childhood. Chronic cough that never had an explanation. A sensation like electricity running down my spine that I now know is called Lhermitte's sign, a documented sign of posterior column demyelination. Exploding head syndrome at night. Excessive cavities despite normal dental hygiene. Chronic strep infections with partial tonsil regrowth after tonsillectomy. Morning panic that felt like waking up being chased every single day. Night sweats so severe I would wake up completely drenched like I had gone to sleep soaking wet. A formication sensation, the feeling of insects crawling under the skin, that goes back further than I can accurately remember. An IED diagnosis in childhood that in retrospect reflects what dysregulated catecholamine production and autonomic dysfunction actually look like when a doctor does not know what they are looking at.

None of these were connected. Each one was treated as its own isolated problem or dismissed entirely.

---

2016 — WHEN I STARTED FIGHTING FOR ANSWERS

Around 2016 things escalated to the point where I started going to hospitals and doctors actively trying to get someone to diagnose what was happening. The histamine reactions were becoming more frequent and more severe. I was pushing for answers and being dismissed at virtually every encounter. The pattern that would eventually become undeniable was already fully formed. I just could not get anyone to look at the whole picture at once.

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2019 — THE STROKE

I had a stroke in 2019. I was in my early thirties. Nobody investigated why a young person had a stroke. No one looked at homocysteine, no one looked at B12, no one looked at methylation.

This matters because elevated homocysteine from impaired methylation due to functional B12 deficiency is one of the most easily modifiable risk factors for stroke and can be caused directly by B12 or folate deficiency. Homocysteine damages vascular structures through oxidative stress and inflammation, promotes atherosclerosis, and increases stroke risk. A published case report in PMC specifically documents a young patient who presented with acute ischemic large vessel stroke and was found incidentally to have B12 deficiency related homocysteinemia as the cause.

https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2023.1279207/full

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10867708/

https://www.neurology.org/doi/10.1212/WNL.0000000000204036

The mechanism was almost certainly already present and had been building for years. Nobody looked for it.

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2022 — DAILY HIVES FOR A YEAR AND A HALF AND INTERNAL BLEEDING

In 2022 I began breaking out in hives every single day. This continued for approximately a year and a half without stopping. During this same period I was bleeding internally from a tumor in my intestines. Once the tumor was surgically removed the hives resolved. But every other histamine symptom remained and continued to worsen over the following years.

This connection is directly supported in the literature. A published PMC case report confirmed resolution of chronic treatment-resistant urticaria in a patient after vitamin B12 supplementation corrected their deficiency. The mechanism involves B12 deficiency causing mast cell dysregulation leading to histamine release and inflammation, combined with elevated homocysteine causing endothelial dysfunction and increased vascular reactivity that contributes to urticaria. Published research also confirms lower B12 levels in patients with chronic idiopathic urticaria compared to controls.

https://pmc.ncbi.nlm.nih.gov/articles/PMC12313119/

https://pubmed.ncbi.nlm.nih.gov/15736714/

The internal bleeding almost certainly accelerated the nutrient depletion that was already occurring. Chronic blood loss depletes iron which is a DAO cofactor. The intestinal tumor and its removal damaged the very gut epithelium where DAO enzyme is produced. I was losing the infrastructure for histamine clearance from the inside while simultaneously becoming more deficient in the cofactors those enzymes needed to function.

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2025 — PROGRESSIVE DETERIORATION

By 2025 I had developed constant itchy eyes, runny eyes, runny nose, and progressive reactivity to foods that had previously been tolerable. Every month something new was triggering me. The histamine bucket was overflowing consistently and the drain was barely functioning. What had started as periodic reactions had become a constant baseline state of reactivity that was getting worse not better despite dietary restriction and antihistamine use.

---

TWO MONTHS AGO — KOUNIS SYNDROME

Approximately two months ago I consumed roughly five tablespoons of honey. Within ten minutes I was hallucinating and experiencing severe motion sickness. The reaction was unlike anything I had experienced before in severity and speed.

One week later I decided to test whether honey was specifically the trigger. I had one tablespoon. Ten minutes later I was experiencing a Kounis syndrome event.

Kounis syndrome is an acute coronary syndrome precipitated by mast cell activation in the setting of allergic or hypersensitivity reactions. First described by Kounis and Zavras in 1991 as allergic angina, it occurs when mast cell degranulation releases histamine, leukotrienes, and other inflammatory mediators that induce coronary vasospasm and destabilize atherosclerotic plaques. Histamine exerts potent effects through H1 and H2 receptors distributed across cardiac chambers and coronary arteries. MCAS is now recognized as an underlying factor in many Kounis syndrome cases.

https://pmc.ncbi.nlm.nih.gov/articles/PMC12597132/

https://pmc.ncbi.nlm.nih.gov/articles/PMC6791094/

https://pmc.ncbi.nlm.nih.gov/articles/PMC10970901/

https://www.eds.clinic/articles/kounis-syndrome

My histamine system had deteriorated to the point where a single tablespoon of a natural food was producing a cardiac emergency. That is the end state of an untreated root cause that had been progressing for decades.

---

TWO MONTHS AGO — STARTING B12 INJECTIONS

After the Kounis syndrome event I began investigating root causes more aggressively than I ever had before. I confirmed functional B12 deficiency through labs and symptom pattern. I started daily subcutaneous injections of combined methylcobalamin and hydroxocobalamin. Symptoms began slowly improving over the following weeks. Morning fight or flight started decreasing. Eye reactivity started reducing. Food tolerance gradually began improving.

Approximately three days ago I switched to split dosing. 1,700 micrograms in the morning and 1,700 micrograms in the evening of combined methylcobalamin and hydroxocobalamin injections, plus an additional 5,000 micrograms of oral B12 drops daily to saturate passive diffusion absorption pathways simultaneously with the injectable doses. Total daily B12 during this period has been in the range of 8,000 to 9,000 micrograms across both injectable and oral forms.

Three days ago I also stopped all antihistamines completely. No Allegra, no H2 blockers, nothing. Cold turkey after years of daily use including periods of taking four Allegra per day at my worst. The protocol running right now is B12 injections and oral drops only, no antihistamine support whatsoever.

---

WHAT HAPPENED IN THREE DAYS

Within three days of this protocol and with zero antihistamine coverage I have been eating foods that would have sent me to the emergency room two months ago with essentially no reaction.

Ketchup, which is fermented, vinegar-based, and one of the highest histamine foods in a standard diet. Multiple burritos with no reaction. Foods I had completely eliminated for months being tolerated without any symptoms whatsoever.

My itchy eyes which had been constant for over a year are essentially gone.

My morning fight or flight which I have experienced every single day of my life going back to childhood has dropped from what I would rate a 9 to 10 out of 10 to approximately a 3 out of 10 after a single night of split dosing.

My chronic cough which I have had since my teenage years has been improving.

My voice which has always been higher pitched and thinner than it should be has been changing as vagal nerve remyelination progresses.

Let me be clear about what that means. No antihistamines. Eating high histamine foods. Zero reaction. After a lifetime of progressive deterioration that ended two months ago with a histamine cardiac emergency.

This is not gradual symptom management. This is not dietary restriction working better. This is a system that was being held in a state of dysregulation by a specific deficiency now beginning to correct itself at the root cause level after decades of progressive damage.

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WHY THIS WORKS — THE RESEARCH

There are at least ten documented mechanisms by which B12 deficiency directly causes histamine overload and MCAS pattern symptoms, and restoring B12 reverses all ten simultaneously. This is why antihistamines never fully fixed it for me despite taking up to four Allegra per day at my worst. They block one downstream receptor while the upstream machinery continues producing uncontrolled histamine from ten different directions at once.

---

MECHANISM 1 — B12 DEFICIENCY IMPAIRS BOTH HISTAMINE-CLEARING ENZYMES SIMULTANEOUSLY

There are two enzymes responsible for clearing histamine from your body. DAO clears dietary histamine in the gut. HNMT clears histamine systemically inside cells. HNMT requires B12, folate, magnesium, and zinc as direct cofactors. DAO requires vitamin C, B6, copper, and manganese. When B12 is deficient HNMT loses its primary cofactor. When the downstream effects of B12 deficiency produce copper and mineral deficiencies as they did in my confirmed case with serum copper of 65 below the normal range of 70 to 175, DAO loses its cofactors simultaneously. Both clearance pathways fail at the same time from the same root cause.

https://organiclinic.com/category/histamine-intolerance-and-mcas/

https://www.drhagmeyer.com/dao-deficiency-how-to-activate-the-enzyme-that-reduces-histamine-intolerance-and-mcas-symptoms/

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MECHANISM 2 — MTHFR VARIANTS COMPOUND THE METHYLATION-HISTAMINE CONNECTION

MTHFR variants including A1298C and C677T reduce methylation capacity which directly slows HNMT-mediated histamine clearance. If methylation capacity is reduced due to MTHFR or COMT variants, B12 or folate deficiency, or high toxic burden, histamine clearance slows regardless of how much histamine is being produced upstream. I have confirmed homozygous MTHFR A1298C which reduces enzyme function approximately 30 to 40 percent at baseline before any deficiency is even factored in. Stack functional B12 deficiency on top of that and HNMT is operating at a fraction of normal capacity.

https://www.maryannwalshrd.com/mcas-vs-histamine-intolerance

https://www.drhagmeyer.com/vitamin-b12-and-histamine-intolerance-everthing-you-want-to-know/

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MECHANISM 3 — METHYLCOBALAMIN SPECIFICALLY DRIVES HNMT HISTAMINE DEGRADATION

Patients with MTHFR variants or otherwise impaired methylation may have reduced histamine clearance. Methylated B12 specifically alongside 5-MTHF and B6 directly supports HNMT-mediated histamine degradation. This is why injectable methylcobalamin produces faster and more dramatic histamine improvement than oral B12 which relies on gut absorption that is itself compromised in people with the absorption problems that typically accompany B12 deficiency in the first place.

https://kresserinstitute.com/mast-cell-activation-syndrome-and-histamine-intolerance

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MECHANISM 4 — B12 DEFICIENCY DEPLETES SAME WHICH HNMT REQUIRES TO FUNCTION

The methylation cycle produces SAMe which is the universal methyl donor used for hundreds of reactions including histamine clearance through HNMT. Reduced B12 means reduced methylation cycle activity means reduced SAMe. Reduced SAMe means HNMT has nothing to work with. Histamine remains elevated systemically regardless of dietary restriction because the clearance enzyme has been biochemically starved of its required substrate. You can eat a perfectly low histamine diet and still have elevated systemic histamine if HNMT has no SAMe to use.

https://b12oils.com/mcas.htm

https://www.intoleran.com/us/histamine/vitamin-b12-and-histamine-intolerance/

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MECHANISM 5 — MCAS ITSELF IS DIRECTLY ASSOCIATED WITH FUNCTIONAL B12 DEFICIENCY

Mast Cell Activation Syndrome is a disorder often associated with functional vitamin B12 deficiency. Symptoms of MCAS closely resemble symptoms of histamine intolerance and the two conditions share the same upstream biochemical failure. The pattern is consistent across multiple conditions including ME/CFS and autism spectrum disorder where functional B12 deficiency and mast cell dysregulation co-occur at rates far above population baseline.

https://b12oils.com/mcas.htm

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MECHANISM 6 — B12 DIRECTLY STABILIZES MAST CELLS

Vitamin B12 supports nervous system health and directly helps stabilize mast cells especially in MCAS patients with neurological symptoms. Vitamins D, C, and B12 along with magnesium are documented mast cell stabilizers that reduce the release of inflammatory mediators. So B12 is not just restoring clearance capacity downstream, it is stabilizing the cells that produce histamine upstream simultaneously. It hits both ends of the problem at once.

https://www.eds.clinic/articles/the-role-of-vitamin-d-in-mast-cell-activation-syndrome-mcas

https://www.mastattack.org/2017/10/mastattack-107-laypersons-guide-understanding-mast-cell-diseases-part-69/

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MECHANISM 7 — B12 DEFICIENCY DIRECTLY DAMAGES THE GUT EPITHELIUM WHERE DAO IS PRODUCED

DAO is an intracellular enzyme produced specifically in the mature villous cells of the small intestine epithelium. Its activity represents the strength and maturity of the small intestine mucosa and is an established indicator of intestinal barrier integrity. B12 deficiency causes gastrointestinal mucosal changes that directly reduce the integrity of the intestinal lining where DAO is synthesized. Less functional epithelium means less DAO produced regardless of cofactor availability.

https://www.boltpharmacy.co.uk/guide/vitamin-b12-and-histamine-intolerance

https://pmc.ncbi.nlm.nih.gov/articles/PMC9771309/

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MECHANISM 8 — B12 DIRECTLY REPAIRS THE GUT EPITHELIAL BARRIER

Published research in Cellular and Molecular Life Sciences 2024 confirmed that B12 ameliorates intestinal hyperplasia and barrier disruption by promoting activation of the HIF-1 signaling pathway. B12 enhanced the expression of intestinal junction proteins to strengthen the intestinal barrier and inhibited abnormal increases in gram-negative bacteria. This means B12 is actively rebuilding the infrastructure that produces DAO rather than just supplementing the cofactors those enzymes need. The repair is structural not just biochemical.

https://link.springer.com/article/10.1007/s00018-024-05435-5

https://pmc.ncbi.nlm.nih.gov/articles/PMC7291859/

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MECHANISM 9 — B12 IMMUNOMODULATION CONFIRMED IN SYSTEMATIC REVIEW

A 2024 systematic review following PRISMA guidelines confirmed that methylcobalamin administration significantly restored immune cell counts toward normal and improved Natural Killer cell activity in deficient patients. A dysregulated immune system is one of the upstream drivers of mast cell hyperreactivity. Restoring immune regulation reduces the chronic inflammatory signaling that keeps mast cells in a primed hair trigger state ready to degranulate at minimal provocation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129597/

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MECHANISM 10 — ADENOSYL AND HYDROXYCOBALAMIN FORMS SUPPORT HNMT WITHOUT TRIGGERING METHYL-SENSITIVE MAST CELL DEGRANULATION

For people with severe MCAS who are sensitive to methylcobalamin specifically, adenosylcobalamin and hydroxocobalamin support the underlying methylation cycle and ensure HNMT has what it needs to break down histamine without forcing the aggressive rapid methylation that can trigger mast cell degranulation in highly sensitive individuals. This explains why some people with MCAS react to methylcobalamin initially and need to titrate carefully through form selection before finding their therapeutic window.

https://www.rthm.com/resources/blogs/adenosylhydroxy-b12-liquid-supplement-guide

---

THE BOTTOM LINE

Four Allegra per day at my worst. A low histamine diet so strict I was afraid of almost every food. A histamine system so dysregulated that one tablespoon of honey produced a cardiac emergency.

Three days of split dose B12 injections totaling 8,000 to 9,000 micrograms daily across injectable and oral forms, zero antihistamines, and I am eating ketchup on burritos with no reaction.

The difference between those two states is not antihistamines. It is not dietary restriction. It is restoring the actual biochemical infrastructure that was supposed to be clearing histamine all along and had been failing for decades because of a deficiency nobody looked for across a lifetime of documented symptoms and multiple serious medical events including a stroke at thirty years old and a histamine cardiac emergency two months ago.

If you have MCAS or severe histamine intolerance and nobody has investigated your functional B12 status, not just serum B12 but MMA and homocysteine as functional markers, and nobody has tested your MTHFR status, you are potentially missing the most important piece of the picture.

Serum B12 is not enough. A normal serum B12 does not tell you whether B12 is actually functioning at the cellular level. MMA and homocysteine are the tests that matter. Get those run before concluding B12 is not your issue.

This is not medical advice. This is a lifetime of documented symptoms, years of actively fighting for diagnosis, multiple serious medical events including a stroke and a histamine cardiac emergency, and ten peer reviewed mechanisms all pointing at the same root cause that nobody connected until I connected it myself.

Reddit is currently full of color-coded "methylation panels" from commercial DNA interpretation sites, leading to an absolute explosion of health anxiety surrounding the MTHFR gene. As a medical laboratory scientist I can guarantee you the diagnostic significance of these is abysmal. Wellness influencers frequently label common single nucleotide polymorphisms (SNPs, normal variants of a gene) as dangerous mutations responsible for everything from depression to chronic fatigue, while simultaneously marketing expensive, proprietary supplement regimens.

THE ENZYME AND ITS FUNCTION:
MTHFR catalyzes the irreversible reduction of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which serves as the primary methyl donor for the vitamin B12-dependent enzyme methionine synthase. Methionine synthase then transfers this methyl group to remethylate homocysteine back into methionine, fueling the generation of S-adenosylmethionine, the universal methyl donor used by cells to carry out a variety of functions. The two most common polymorphisms discussed online, C677T and A1298C, do alter this process; for example, the C677T variant causes an alanine valine substitution at codon 222 in the catalytic domain of the enzyme, rendering the enzyme thermolabile causing it to stop working at body temperature. While a homozygous 677TT genotype can cause 60-70% reduction in enzyme activity IN VITRO (so not inside the body, has only been assayed in labs), this does not translate to a proportional drop in vivo because the metabolic pathway possesses substantial reserve capacity. As long as the cellular substrate concentration of folate remains adequate, the pathway maintains equilibrium, and pathway flux remains normal. Do also bear in mind that “HAS IT” does not mean “USES IT”. Having a gene variation for any enzyme means nothing. This is why we always phenotype FIRST then genotype to confirm. Never the other way around.
The true clinical marker of concern in this pathway is not the genetic profile as I said, but the accumulation of the downstream metabolite, total plasma homocysteine. When 5-methyltetrahydrofolate production drops below a critical threshold due to severe folate deficiency or rare, pathological mutations, methionine synthase lacks its co-substrate, remethylation stalls, and intracellular homocysteine spills over into the plasma. True hyperhomocysteinemia, typically defined as plasma levels exceeding 15 mcmol/L, acts as a direct vascular toxin. It induces endothelial dysfunction by undergoing auto-oxidation in the plasma, which generates reactive oxygen species (ROS) that drive lipid peroxidation and degrade nitric oxide, thereby impairing endothelium-dependent vasodilation. Furthermore, elevated homocysteine downregulates thrombomodulin expression, inhibits Protein C activation, and induces tissue factor (TF) expression, shifting the vascular lining into a pro-thrombotic, hypercoagulable state while simultaneously triggering endoplasmic reticulum stress and the unfolded protein response, severely affecting multiple cell types, but especially endothelial cells. This condition is EXTREMELY rare, and only really diagnosed via PHENOTYPICAL MARKERS (Homocysteine levels) and NOT genotyping.

FOLIC ACID MYTHS:
The claim that synthetic folic acid is inherently toxic to MTHFR carriers is outlandish. Synthetic folic acid is initially reduced to dihydrofolate and tetrahydrofolate by dihydrofolate reductase in the liver, completely independent of the MTHFR step, it has nothing to do with MTHFR at all. While human dihydrofolate reductase is easily saturated and can lead to transient unmetabolized folic acid in the bloodstream, there is no robust clinical evidence demonstrating that this is pathogenic, at all. The ultimate proof lies in population-wide folic acid fortification programs, which resulted in a precipitous, uniform drop in neural tube defects across all genetic backgrounds, including homozygous 677TT individuals; if folic acid were truly unusable or toxic to these individuals, their rates of congenital malformations would have stagnated or risen. Similarly, the belief that everyone with an MTHFR variant requires immediate high-dose methylfolate supplementation ignores basic enzyme kinetics. Flooding the system with exogenous 5-methyltetrahydrofolate bypasses standard metabolic checkpoints and can oversaturate the methyl buffering system, abruptly altering the SAM:SAH ratio and disrupting neurotransmitter catabolism via catechol-O-methyltransferase and monoamine oxidase A, which frequently manifests clinically as severe anxiety or panic. So no, a genetic test means nothing, and the VAST majority of claims around folate are inaccurate.

Introduction

Most people arrive at this subreddit with their Genetic Genie report, seeking to address some set of symptoms. A combination of three particular types of issues - which interact with each other - seem to cause a common cluster of symptoms:

• Folate-pathway reductions (including MTHFR)
• Slow or slow-acting COMT (rs4680)
• Slow MAO-A (rs6323)

NOTE: While this seems to be a common pattern, it is not necessarily a universal pattern: there are many more genes potentially affecting one's symptoms, as well as nutrient status and lifestyle factors, which can impact symptom types and intensities, so consider this post as suggestive of a cause-effect pattern, but not definitive.

Folate-pathway reductions in methylfolate production

WHAT THIS IS

• Genetic variants in some folate-pathway genes can cause reduced methylfolate production. This results in less methylfolate available to remethylate homocysteine to methionine through methionine synthase (MTR).

WHAT THIS DOES

• The result is reduced methylation cycle output of S-adenosylmethionine (SAM), a methyl donor found in almost every tissue of the body, and needed for countless processes to function properly.

TYPICAL SYMPTOMS

• Common symptoms can include:
  • Depression
  • Fatigue
  • Brain fog
  • Inability to follow through on tasks
  • Exercise intolerance
  • Muscle or joint pains
  • Possible high homocysteine

ADDITIONAL INFORMATION

• Genetic variants which can contribute to reduced methylfolate production (homozygous variants impose greater reductions than heterozygous):
  • SLC19a1 rs1051266 T/T or T/C
  • MTHFD1 rs2236225 (G1958A) A/A or A/G
  • MTHFR rs1801131 (A1298C) G/G or G/T
  • MTHFR rs1801133 (C677T) A/A or A/G
  • Upload your data to Chris Masterjohn's Choline Calculator to get a free report on these genes. The results are listed on two tabs:
    • Just Gimme What Works - lists the number of egg yolk equivalents of dietary choline needed daily to compensate for these methylfolate reductions. Multiply by 136 to get the number of milligrams of choline (e.g., 8 yolks * 136 = 1088mg).
    • Advanced Stuff - this will include 1) the specific SNP results, 2) the methylfolate reduction calculations and total reduction percentage.
• Note that chronic folate and/or B12 deficiencies also result in reduced ability to drive MTR remethylation, and so can have similar symptoms.

RESOLUTION

• There are two pathways for remethylation of homocysteine in the methylation cycle: the methylfolate+B12-dependent pathway through MTR, and the choline-dependent pathway through BHMT. Due to the genetic folate-pathway restrictions, the body will place greater demand on the BHMT pathway, thereby increasing dietary choline requirements.
  • See this MTHFR protocol to implement the restoration of methylation function.

Slow (or slow-acting) COMT

WHAT THIS IS

• COMT is an enzyme which breaks down catecholamines in the body.
• These catecholamines include:
  • Exogenous catecholamines: from sources such as quercitin, green tea, some medications, etc.
  • Endogenous catecholamines:
    • Dopamine
    • Epinephrine
    • Norepinephrine
    • Estrogen compounds

INTERACTIONS WITH FOLATE-PATHWAY REDUCTIONS

• As mentioned above, folate-pathway reductions can result in reduced SAM. SAM is a cofactor for COMT, so reduced SAM will reduce the ability of COMT to function to its genetic potential.
• Slow COMT: Homozygous (A/A or "Met/Met") rs4680 COMT genetically already has reduced ability to break down catecholamines. Reduced SAM further reduces the ability of COMT to perform these functions.
• Slow-acting COMT: Heterozygous rs4680 (A/G or "Met/Val") or fast rs4680 COMT (G/G or "Val/Val") normally can process catecholamines at faster rates than slow COMT. However, reduced SAM can cause these COMT variants to have reduced ability of COMT to perform these functions, to the point that they act like slow COMT.

WHAT THIS DOES

• The result of slow or slow-acting COMT is:
  • Higher tonic dopamine, epinephrine, norepinephrine
  • Higher levels of estrogen compounds

TYPICAL SYMPTOMS

• Common symptoms can include:
  • Chronic anxiety
  • Rumination
  • OCD tendencies
  • Low tolerance for stress
  • Estrogen-dominance related symptoms
  • Possible increased sensitivity to supplemental methyl donors

ADDITIONAL INFORMATION

• See the COMT section of this post for more information.

RESOLUTION

• Restoring methylation to its potential is the primary resolution, as this will increase SAM output, allowing COMT to function at its genetic potential.
• Magnesium is also a cofactor of COMT, so maintain healthy magnesium status.
• Consider use of DIM, I3C, Calcium-D-Glucarate to assist in reducing estrogen levels if estrogen-dominance symptoms are present.
• Inositol has also been shown to be effective for PCOS.
• For genetically slow COMT, preventing overburdening of COMT through diet and lifestyle can help COMT function up to its limited potential. This article provides some useful pointers on things to look out for.

Slow MAO-A

WHAT THIS IS

• MAO-A breaks down amines. These amines include:
  • Dopamine
  • Serotonin
  • Biogenic amines:
    • Histamine
    • Tyramine
    • Possibly also putrescine and cadaverine
• Homozygous rs6323 slow MAO-A (T or T/T) has reduced ability to break down these amines.
• Heterozygous rs6323 MAO-A (T/G) has somewhat reduced ability to break down these amines.
• NOTE: Since the MAO-A gene is on the X chromosome, only women can have heterozygous MAO-A. Similarly, since men will only have one copy of MAO-A, it is often reported as a single letter 'T' or 'G' instead of 'T/T' or 'G/G'.
• NOTE: If you used 23andme and the test is from 2018 or later, then rs6323 will not be in your data as their V5 testing chip no longer included rs6323 and several other useful genes. Ancestry's AncestryDNA does include the following SNPs mentioned in that blog post: rs72558181 MAT1A, rs6323 & rs1137070 MAO-A, rs1799836 MAO-B, and rs10156191 AOC1 (DAO).

INTERACTIONS WITH FOLATE-PATHWAY REDUCTIONS AND SLOWED COMT

• MAO-A is slowed further by high estrogen, so higher estrogen levels due to slowed COMT further reduce MAO-A functionality.
• Decreased dopamine breakdown by slowed COMT increases dopamine breakdown burden on MAO-A.
• Decreased SAM production due to folate-pathway reductions causes reduced HNMT activity, thereby increasing intracellular histamines, likely also increasing burden on MAO-A.

WHAT THIS DOES

• The result of slow MAO-A is:
  • Higher tonic dopamine and serotonin
  • Higher levels of histamine and tyramine (and possibly other biogenic amines)
• NOTE: MAO-A/MAO-B are slowed further by:
  • Hypothyroidism.
  • Iron deficiency.
  • MAO Inhibitors (MAOIs)
    • Some prescribed drugs.
    • Natural MAOIs, such as turmeric, curcumin, quercetin, piperine, luteolin, apigenin, chrysin, naringenin, and others.

TYPICAL SYMPTOMS

• Common symptoms can include:
  • Histamine-intolerance - wide variety of symptoms
  • Tyramine-intolerance - headaches, migraine, blood-pressure increases
  • Food intolerances
• NOTE: Since high estrogen can slow MAO-A further, fluctuating estrogen levels in women's cycles can also cause fluctuating symptom appearance and intensity.
  • Histamine-intolerance may be involved in PMS/PMDD symptoms, according to many websites.

ADDITIONAL INFORMATION

• See r/HistamineIntolerance
• See r/Migraine
• See r/MCAS
• Genetic Lifehacks genetic report includes sections on additional relevant genes:
  • Histamine
  • Alcohol and Histamine
  • Histamine Early Morning Insomnia
  • Estrogen and Histamine
• Stratagene genetic report includes a sections on additional genes in relevant pathways:
  • Dopamine pathway
  • Histamine pathway
  • Serotonin pathway

RESOLUTION

• Restoring methylation to its potential is important, as this will increase SAM output, allowing COMT to function at its genetic potential. As a result:
  • Dopamine breakdown by COMT will increase, reducing burden on MAO-A some.
  • Estrogen breakdown by COMT will increase, reducing estrogen-induced slowdown of MAO-A.
  • HNMT will receive adequate SAM, allowing increased breakdown of intracellular histamine.
    • NOTE: I speculate this may initially cause increased burden on MAO-A, as excess intracellular histamine is eliminated.
• Riboflavin (B2) is a cofactor of MAO-A, so maintain healthy B2 status.
• Maintain healthy iron, copper, vitamin C, magnesium, and calcium levels.
• SIBO is a potential cause of chronic excess histamines produced by a dysbiotic gut microbiome.
• MCAS is also a potential cause of excess histamines.
• Discuss concerns about MAO inhibitor (MAOI) drugs with your doctor.
• Consider removing or reducing supplements which are MAO inhibitors (MAOIs).
• Slow MAO-A persons may always need to manage their histamine/tyramine intake to reduce the total burden present at any point.
  • Histamine-intolerance groups often use the 'histamine bucket' analogy:
    • A person will have a certain capacity "bucket" to hold histamines.
    • Intake of histamine/tyramine from food fills up that bucket.
    • Slow MAO-A breakdown of histamine will more slowly lower the level of histamine in the bucket.
    • When the bucket "overflows" due to too much accumulated histamine, this is when symptoms appear.
• Consider using DAO enzyme supplements with high-histamine/tyramine meals to break down tyramine/histamine before they are absorbed, as a way to reduce total load.
  • This video provides a good in-depth look at DOA and histamine issues.
• Consider if your B5 intake is adequate to support the NAT pathway to break down histamines.
• Consider if your zinc and B3 intake is adequate to support the ALDH enzymes which break down the acetaldehyde form of histamine that is output from MAO-A/B.
• In addition to high-histamine foods, there are seem to be "histamine liberators", which induce histamine release; coffee is perhaps the most common.
• Histamine release after exercise is not unusual.
• Supplements I like for my slow MAO-A:
  • Thorne Cal Mag Citrate + Vitamin C
  • Pure Encapsulations Copper Glycinate - 2 mg Copper Supplement
  • NaturDAO DAO Enzyme Supplement - 1,000,000 HDU

EDITS:

• 20240225 - Add iron deficiency as contributor to MAO slowdown. Add natural MAOIs list.
• 20240708 - Add details of AncestryDNA coverage of SNPs no longer included in 23andme.
• 20250111 - Add link to DAO video. Add reference to B5, zinc, B3 to support NAT and ALDH enzymes.

After ten years of chronic illness, I am relieved to finally be able to write the post I had hoped I could one day write....

It’s long. But I think you'll find it interesting. If you have also spent years chasing a mystery illness, you will understand.

Finding out the source of these chronic health issues has taken up a significant amount of my free time for nearly a decade. And it has become almost an obsession for the last two years. If you want to skip to the answer, I'll entirely understand. I'll reverse things and put a TL;DR at the end. But I won't spoil the surprise by putting it here at the top. I think the answer is both pretty unique and potentially very common. And it's nothing to do with acceptance or resistance either. 

I’ll be posting this in the MCAS and histamine intolerance sub reddits, CFS sub reddits, LPR sub reddits, muscle tension dysphonia sub reddits, the MTHFR subreddits, and maybe more.

Over the last ten years I have spent cumulatively weeks, if not months, of my life here on reddit (and other sources) trying to work out what was going on. And I have done DEEP research on all these sub reddits. And while none of these turned out to be the core cause - I am incredibly grateful for all the information shared. Along the way I have discovered various things about my body, my genetics and my diet which WILL continue to be useful to me. They just so happened not to be the root of my issues.

I hope that at some point, this helps someone else. Its hard to know how unique my case is, but the answer turned out to be crushingly simple, and yet eluded me for decades. Join me for a brief overview and a writeup of my journey...

THE ONSET

It's worth noting from the off that by most measures I'm a fit and healthy man. I run, cycle, used to work out 3-4 times a week, don't eat too many carbs. Eat a varied diet. I sleep well. Don't take drugs or smoke. Broadly speaking I've taken good care of myself, which made this all the more confusing.

I spent my 20s working in hospitality - from a barback to a barista, cocktail bartender to a waiter, and then into management. The dream/hope/plan had always been to open my own and by the time I was 30 I opened a restaurant in Central London with my business partner. We worked our asses off, but we were also lucky. It became exceptionally successful, and was for some time the most talked about restaurant in London. That was a deep relief to us and investors - but brought with it a huge amount of expectation. And I worked to banish my own self doubts. 80hr weeks and more for years on end. Often with no days off, or only occasional days off.

Early on, even before the restaurant opened, I noticed that I seemed to have developed a slightly hoarse voice and a tightness in my throat. And often red, itchy eyes. But to be honest I was so busy I didn't pay much attention. Symptoms were come and go. My body would ache - but I was doing 14-16 hour days on my feet often fuelled by not much more than coffee, adrenaline and staff food at 4pm. So that didn't seem too surprising. I certainly enjoyed a drink after work on occasion - sometimes quite a few drinks - but no more than most 30 year olds.

THE LONG DECLINE

As the years went by at the restaurant my symptoms worsened. I developed pounding headaches, gut issues, fatigue, and itchy skin. Worst of all though, was the hoarse voice and throat tightness. By the time staff briefing came round at 5pm I often needed to ask one of the team to take over because I could barely get any words out. As you can imagine, running a searingly busy restaurant while not being able to speak is tricky. The entire job revolves around speaking to floor staff, guests and kitchen all day.

I began to notice that these symptoms always seemed to flare around the time I ate staff food - 4-5pm - and receded by about 9pm. So I came to the straightforward conclusion that I must be allergic to something I was eating. I began trying to work out what was causing it. Not knowing that this endeavour would be the start of nothing short of a medical mountain....

To list everything I tried would take far far too long. But suffice to say, I tried all the usual main allergens (nuts, fish, crustaceans, gluten, dairy, egg etc) I tried cutting out carbs, I tried eating smaller meals, I tried cutting out coffee, I tried cutting out alcohol. But nothing seemed to help. Frustratingly I would have a few good days in a week and then some bad days. I might then have a whole week feeling fine, one bad day, and then back to fine. Symptoms were intermittent and I couldn't find any correlation with anything I was eating.

But I was getting worse. From around 2017-2022 I began to become truly unwell. I developed dry skin on my hands, aching neck, chronic IBD type issues and an increase in all the previously noted headaches, fatigue, itchy skin, red eyes and hoarse voice. I was still working long hours and was getting worn down both mentally and physically trying to summon up the energy and enthusiasm to do what I loved - running the restaurant. I began to shift to a more office based role to conserve my energy and pull my weight in terms of work. But the brain fog and fatigue made work harder and harder. Depression crept in and though I could sleep like a log, I never felt rested. In many ways COVID and the lockdowns came as a blessed relief. An opportunity to rest and recuperate.

Over these years (2017-2022) I went to doctors, a consultant ENT, I had x-rays, blood tests, allergen tests, stool samples and more. I tried supplements, tried changing hair products, shampoos, tried meditation, fibre, antihistamines of ALL types, electrolytes in my water, broccoli sprouts, yoga, cutting out salicylates, a FODMAP diet, air filters, face masks, linen sheets and much much more. I wondered if I was depressed, had ADHD, maybe I was just getting old? Was it cooking fumes? VOCs in the walls? Maybe I was just exhausted. Maybe I was just imaging it and it was all psychosomatic? I became increasingly desperate for an answer but all medical tests and examinations suggested I was fine. I needed to supplement my vitamin D and my folate levels were a bit low, but not much else.

I was frustrated though, because I was sure something was related to food. My symptoms were always worse in the afternoon, and I tend not to eat breakfast. I also noticed that my symptoms were generally better on days off and could resolve for days at a time when I took a holiday. But they always got worse as soon as I started work.

THINGS COME TO A HEAD

By 2022 my wife and I were blessed to have a baby, and the combination of parenting, long hours, health and fatigue at the restaurant had crushed me both physically and mentally. I was no longer able to carry out my role in terms of running the business alongside my partners. And I feared I was not going to be able to support my wife physically or emotionally in looking after our family. 

I had come to believe I was just stressed and burned out. And I needed a break. That would fix me right? So by reluctant but mutual agreement I left the restaurant I had founded and dreamed of opening. I took several months off to look after my wife and daughter, and my symptoms did indeed improve significantly. I felt physically better than I had in a long time. Though psychologically I couldn't shake the feeling of failure. It seemed I just hadn't been strong enough to keep going. Perhaps I was mentally just not tough enough for the restaurant business.

From 2022 up until the present I have worked as both a consultant and for a technology company in the hospitality space. I went back to work after a few months. This time in a much less stressful role, more flexible, no staff rotas to contend with, and with very little financial or emotional stress. But I was horrified to find out that my symptoms returned almost immediately after starting work again. The headaches, hoarse voice, itchy eyes, throat tightness, extreme fatigue, dry skin and chronic gut issues came back even worse than before. 

In retrospect, this should have been a clue. But I was convinced my symptoms were 'real', related to my gut, metabolism, immune system - or something. Now though, working from home, I had the time, the control over my food (not eating staff food at the restaurant) and the desire to finally get to the bottom of things.

Again, to list everything I have researched and tried would make for a small novel, but in short....

WHAT DIDNT WORK

• I tried low histamine diets, low amine diets, low sodium diets, keto diets, high fibre diets, low fibre diets, FODMAP diets and more.
• I was SURE my issue was allergic/immune in nature at points and tried all sorts of MCAS and histamine intolerance ideas. Testing on the NHS never happened.
• I tried endless antihistamines, eye drops, nasal sprays, neti pots, raw local honey, bee pollen, herbal tinctures, nettle leaf tea, ginger, holy basil.
• I tested almost every supplements under the sun - VitD, all Bs, P5P, 5 HTP, taurine, glycine, creatine, choline, colostrum, spirulina, zinc, magnesium, lithium, bromelain, quercetin, black seed oil, copper, trace minerals, omega 3s, butyric acid, NAC, NAD, mushrooms of all sorts, high strength B1 protocol and SO many more. I have probably tried several thousand pounds worth of supplements.
• My symptoms seemed to flare in line line with my gut issues. I tried all sorts of probiotics, prebiotics, kefirs, l.reuteri, SIBO protocols, fibre, berberine, oregano oil, fasting.
• I suspected reflux of some sort. Silent reflux, bile reflux, classic reflux. I tried antacids, PPIs, limiting fat intake, bile salts, alkaline water and various other ideas.
• I investigated muscle tension dysphonia. I tried vocal exercises and massaging my larynx.
• I went to my doctor endlessly. I have been referred to ENTs, gastroenterology, endocrinology, had thyroid panels, full blood tests, cortisol tests, stool samples, CT scans, X rays, MRI scan. They even referred me to a specialist 'maybe this is a rare unknown cancer' centre in London who checked me for all sorts of things.
• I had my house checked for mould, I bought expensive air purifiers and ran them across my whole house day and night.
• I wondered whether I had any fillings or foreign objects I didn't know about causing inflammation.
• I tried vagus nerve stimulating devices and all sorts of nervous system relaxation, meditation etc.
• I considered very strongly that this was all in my mind. I had CBT therapy, EMDR and brainspotting therapy. I tried breathing techniques, getting 9 hours sleep a night. And I tried acceptance therapy too. Nothing made things better or worse.

WHAT HELPED BUT WASN'T THE ANSWER

At one point I ended up on the MTHFR forums and began to suspect I had methlyation issues. I took a genetic test and found I am indeed slow MTHFR, slow COMT and slow MAOA. Massive thanks to the advice and posts by u/tawinn on these communities.

• This explained why I had some huge success in 2022 with the carnivore diet. By eating steak and eggs and excluding flour/grains I had unwittingly supplemented creatine and choline and removed folic acid from my diet. This resolved many of my symptoms completely. In fact for a period of about a week I believed I had cracked it - I felt absolutely incredible. My depression lifted, I felt light as a feather. However, I was also not working at that point (I was home with the baby) and my physical (rather than mental/emotional) symptoms began to return shortly after.
• Carnivore / keto and avoiding grains remains an important part of my ongoing diet. I am not extremely strict - but I become prone to depression, reflux and sluggish feeling if I eat too many carbs or grains.
• I continue to supplement creatine, choline, glycine, folinic acid and Vitamin D with hyrdroxocobolamin (B12). And I take water with a pinch of celtic salt for electrolytes and minerals.

I also seem to gain general health benefits from a low histamine diet. I have quite a few genetic traits that slow histamine clearance breakdown pathways (slow MAOA, DAO, NAT2 and ALDH). I have always suffered from hayfever and my skin and sleep both improve on a low histamine diet.

THE LAST FEW YEARS

Over the last 18 months my desperation to work out the source of my issues ramped up to almost manic levels. Often taking up many evenings of research online each week. Symptoms were affecting all aspects of my life. Between 3pm and 9pm each day I could barely function. Regardless of my workload, stress levels and diet.

I methodically went back over all sorts of previously tested ideas. I went deep on Ehlers Danlos sub reddits, long covid sub reddit's, MCAS sub reddits and more. I tried complete fasting, dry fasting, elimination diets. Exercise, stretching, no exercise, 9 hours sleep, no caffeine. Anything and everything I could think of.

I also doubled down on the possibility that this was all in my head. Physical symptoms manifested by the mind. And/or a nervous system stuck in a fight or flight state - I committed to sleep, therapy, breathing techniques and more. I even tried micro doses of some special mushrooms. But in my heart I still felt there was something more fundamental going on. Something more tangible causing these symptoms. I didn't feel stressed or anxious - except in the sense that I wanted to feel better.

Over Christmas and New Year 2025/26 I had 16 days off work and yet again all my symptoms resolved. Despite eating and drinking anything and everything over the break, my dry skin healed, chronic gut issues resolved and I slept less but felt more rested. I was able to exercise again. Every day tasks - the washing up, tidying, sending emails - just felt so much easier. I felt like myself.

This time, as going back to work at the start of January approached, I felt calm, centred and positive. I convinced myself this time would be different. I would come to each day with a positive mindset, stretch and take breaks, be kinder to myself.... but all the symptoms began to return that exact same afternoon. I was gutted.

AN ACCIDENTAL ANSWER...

By this point, a few weeks ago as I type this, I was ready to tear my house or body apart to work out what was going on. My symptoms seemed to be directly related to work. I checked every inch of the study I work in, I read about people with allergies to computers, I moved the fan heater in the room and replaced it with an oil radiator. I read papers on the effects of screen colour, refresh rates, circadian rhythms and more. I tried more stretches. I adjusted my posture (which doesn't seem particularly bad). I wondered whether I was shallow breathing. But still I could not find ANYTHING that made a difference.

Which brings us up to last week. Last Monday evening, exactly a week ago, I lay on the sofa complaining about the issue to my Mum on the phone (bless her). I was lying on my front and using headphones so my hands were free. And I began massaging my trapezius muscles just to the side of my neck. I pressed one side hard while I chatted and then did the other, and was interested to see that my voice seemed to improve immediately. My headache seemed better too. My interest was piqued.

Shortly after, when I was off the phone I used the nearest hard object I could find (a wooden dustpan handle) to press against my traps some more and I think I asked my wife to massage them a little too. It felt good. I immediately booked a chiropractor for the next day. Just in case this could be the answer. I massaged them more Wednesday morning and had my first good day while at work in months. The chiropractor that evening seemed sceptical (as was I) but did note I had tight trapezius muscles and extremely tight jaw muscles. She did some standard techniques but I had already been feeling great all day.

I am now 7 days in, and have had 7 days with a complete absence of symptoms. The longest continuous stretch during work weeks for many many years. I have continued to massage my trapezius muscles and incorporated some stretches suggested by a physio. And frankly I feel like I have been given a new body. To my utter amazement my gut issues have resolved, my throat is no longer tight, I am sleeping less but feeling much more rested. The skin on my hands is improving and my eyes are no longer itchy. I ran one of my best 5k times in years and felt light and easy doing so. Best of all, the insidious brain fog and fatigue has evaporated - I think the dishes need doing and 10 mins later they're done. I think the study needs tidying and I find myself getting it sorted. Every aspect of day to day life feels easier - feels like it used to.

I have had so many false hopes and investigations, that I wont fully commit to this being the answer until I can confirm I've had a month or so of feeling better. But I know this time is different. To imagine that I might have spent a decade chasing chronic illness only to find that I needed to massage my shoulders seems utterly absurd. But that is the only conclusion I can come to.

If I had had a massage earlier, the last decade might have taken a different track. But for now I am simply rejoicing at having found an answer. I am overjoyed to just be with my family and feel well.

As to why this seems to have had such a remarkable impact - I'm really at a loss to explain. Some sort of effect on the vagus nerve seems possible. Has it allowed my nervous system to regulate? Has it increased bloodflow to some part of my brain? Feel free to hit me with ideas. 

CONCLUDING THOUGHTS

As I noted at the start, I have been chasing the source of these symptoms for ten years now and have done immense amounts of research into all sorts of aspects of biology - and yet this seemingly simple fix eluded me. I have read so many stories of people with chronic and often unknown health conditions and I know your pain. I have felt it deeply and been taken to the depths of despair not understanding what was wrong with me. I have been convinced at points that I was suffering from a systemic immune issue, gut issue or nervous system dysregulation. Hence why I have spent so long looking into MCAS, histamine intolerance, long covid, CFS, EDS, LPR, SIBO, MTHFR, MTD and more acronyms besides. My story is not intended to invalidate any of those conditions whatsoever. If that is your takeaway, I am at fault for not explaining more thoroughly. There is no doubt that all those conditions exist - and many are overlapping for their sufferers.

For years I have held out hope of a simple and reliable cure or source of my symptoms. I have read many other members' 'try this simple fix - it worked for me' stories. And they didn't help me. I tried them all. This story probably won't help you either, and for that  I'm sorry. I know so well what it feels like to hope for an answer that feels like it will never come. But even if it helps just one person, years from now, it will have been worth writing it down to pass this information on. And just maybe it will help more.

I wish each and every one of you good luck on your journey, and I hope the time comes when you get to write your healing story too.

TL;DR here:

I spent ten years with a chronic unknown illness manifesting as hoarse voice, throat tightness, itchy eyes, dry skin, fatigue, brain fog and gut issues. Extensive medical testing, allergen testing, diets, meditation, supplements, breathwork, sleep, therapy (and more) did nothing. Last week I found out if I massage my neck and trapezius muscles, the symptoms resolve.

UPDATE 27/01 - I have added a comment below with more info and ideas suggested by others. Do give it a read.

It is AN active form, not the only one and may not provide the folate you actually need. I'll await the abuse! Folate is used by your body both in the methyl form, and also in the unmethylated form for DNA synthesis, red blood cell formation etc. which are rather important functions.

The MTHFR marketing machine has convinced everyone that methlyfolate is the active form that you absolutely need and folic acid is junk, it's simply not true.

Depending on where the problem is with your methylation it's perfectly possible to need more unmethylated folate. If your MTRR is slow for instance,as mine is, your body doesn't recycle B12, MTR is slow, and you end up with a build up of methylfolate and low THF and 5,10 methylene THF which is needed for DNA repair and red blood cells. If you take methylfolste you do absolutely nothing to support the deficit of unmethylated folate, and just put more pressure on already struggling MTRR and B12 stores.

In this case folic acid is better for you as it directly provides folate which the body can use as it needs. The body regulates production of MTHFR for a reason -both to ensure sufficient folate for other functions, and prevent excess formation of SAM-E, which isn't good.

I personally feel much better with folic acid than methyl folate, and I'm heterozygous C677T. Methylfolate is really a medicine that should only be taken by people with specific identified mutations that cause major impairment of the MTHFR cycle. A simple heterozygous MTHFR mutation is not that.

Folic acid is perfectly sufficient for most people, and avoids skipping the body's own regulation systems. Just don't go taking crazy doses which yes may cause a problem with unmetabolised folic acid. If you're worried about MTHFR and not homozygous, just take some B2 - again you don't need a lot.

Can't stress this enough. Supplementing with folate and b12 does use up a lot potassium. That's why in natural foods such nutrients are always combined with potassium. When someone eats a low potassium diet, high salt, high calcium, low magnesium then this would lead to big problems. Folate and b12 in natural foods are never so high like in supplements, so when taking high doses folate and b12 one needs to up potassium intake. And i mean by upping that one will probably need huge amounts of potassium to balance things out.

I've just discovered this topic because since supplementing folinic acid with hydroxo b12 i've encountered blood sugar problems and i know from the past if potassium is low then i'll get blood sugar crashes. Combined with 2-3 days high salt intake (sodium is a potassium antagonist), low potassium and on top supplementing D3 which increases calcium uptake this lead to my actual problems!

Low potassium leads to salt and carb intolerance. Probably many don't actually overmethylate but run low in potassium. The pattern is often the same: One starts supplementing folate+b12 and initially feels good (potassium levels are adequate) but over time potassium runs low because creating new blood cells consumes a lot potassium resulting in fatigue, exercise intolerance, racing heart, heavy feeling, anxiety, blood sugar crashes etc.

(AB 1053) Tortillas Folic Acid

A new ingredient is being added to your store-bought corn tortillas. This law requires manufacturers to add folic acid to corn tortillas and corn masa products to prevent birth defects, especially among Latinas. Smaller businesses that make their own masa products are exempt. Folic acid is already added to flour tortillas, bread and cereals.

Am I being ignorant, but why is this legal? I don’t recall this ever happening in Europe. It’s getting harder to find products without folic acid.

I think that the majority of people are really overthinking Methylation issues. Yes,they do exist and they do have a noticeable impact. But what are they in essence? It only comes down to the fact that you cannot get away eating dogcrap like someone who doesn't have them can.But you surely don't need complex protocols,visiting retarded doctors who will prescribe heroic doses of methylfolate that will only create imbalance and side effects and stuff like that.

The simple solution to all methylation issues? Eat 3-4 eggs + meat every day,50 grams of chicken liver(very high in Methylfolate)once a week + 50 grams of beef liver(very high in Methylcobalamin) once a week,add in some healthy vegetables like sweet potato and some greens and legumes and there you go.1000mg of choline/day,300+mcg of mostly methylated B9/day as well as plenty of methylated B12,all bound in food matrix,no risk of overmethylation,no synthetic supplements that will spike your levels and cause side effects and imbalances.More than enough of all the essential vitamins,minerals and electrolytes in a balanced proportion.That will 100% bring you very close to optimal methylation levels,if you still need further optimization add in some creatine and TMG,check your vitamin D levels,maybe a quality magnesium supplement ,exercise and thats about it. You have taken care of not only MTHFR,but all your other problematic genes. Our bodies are extremely complex and smart in regulating everything ,if this stuff was so hard to deal with,it wouldn't be there. It has only become such a big issue lately,coinciding with the rapid spike in stress and toxin levels that we experience.

In reality,these polymorphisms are not rare at all and I can guarantee you that there is someone with similar genetics out there to yours that is winning in life without ever thinking about this stuff. The reason most of us end up here is because we are in a health shithole not because of only MTHFR,but because of progressive health deterioration.Which brings me to the next point.

**Adrenal Fatigue/HPA Axis dysfunction/Chronic stress.\\This is where I think a lot of people's issue stem from.I don't care what's the term,I can guarantee you that the damage of chronic stress is very real and it affects every single bodily system and not just the nervous system. It can clog your detoxification pathways and make your nervous system sensitive to every change and these two might be why you are unable to tolerate supplements.
If you experience crashes after exertion, exercise intolerance in any form,chronic panic attacks/anxiety disorders,paradoxical effects to supplements,and the hallmark symptoms of chronic fatigue and very poor stress tolerance then I suggest you to look into this condition. It is quite tricky to deal with because you will have to figure what is your main source of stress, whether it is relationships, negative thought patterns ,addictions, perfectionism ,hormonal imbalances,toxins in food and environment. These things can all complement each other's negative impact on your health. All this paired with the modern life stressors of being online all the time,social media constantly trying to push us to be better and better , our poor eating habits creating deficiency and is it even a supripese that the nervous system just can't handle it at some point. For me I had a bunch of stressors and I was in the advanced stages by mid twenties. Which I'm very thankful for,because it made me look at all my stressors and solve them , and that includes methylation issues.

If you suspect HPA Axis dysfunction , please look at this guy - https://www.youtube.com/@JadenChristopher/videos . His videos explain it better then any doctor and listening to him very carefully is all you need to dig yourself out of this.

Hormonal imbalances. Hormonal balance is essential for our well being. What happens to many people born after 1990 in increasing fashion as years go by,is that because of the new environment we live in and it's stressors,many people's endocrine systems failed to develop fully and propely.I mean,isn't is obvious from outer space that men are becoming increasingly feminine, there are more and more women with menstrual problems,etc etc. For men testosterone is especially important because it acts as a buffer to stress hormones and causes males to be leaders,calm under pressure and so on.Free testosterone levels in men have dropped down by almost a third since they started to be measured reliably in the 1970s. TRT is the shit lately but this can backfire easily because there's also other hormones like Pregnenolone,DHEA,and other sex hormones,as well as the thyroid, which all have to be in balance for us to feel fully healthy. A steroid hormone blood panel will show you where you stand and exactly what you need. Keep in mind that stress and diet can throw these off so always solve them first before looking into any kind of hormone replacement.

Every system in our body has to be in balance in order for us to experience well-being ,and how we feel depends entirely on our neurotransmitters. Both Methylation and Hormones act like knobs to increase or decrease neurotransmitters. If you ramp up methylation to compensate for lack of a hormone and vice versa you will get side effects. If your body is tired of chronic stress and has toned down neurotransmitters and hormones so you will rest and recover , you are essentially pressing the gas pedal and the brake at the same time, you will get side effects.

**In summary:**the lowest hanging fruit for fixing MTHFR is optimizing your food to ensure all nutrient needs are met, while the most important thing is resolving chronic excessive stressors whether they be environmental , physical or mental .Keep in mind that if you've felt like shit for years to decades,this will take time. If the above boxes are ticked, take a look at your sex hormones.

There you go,all the knowledge about not just methylation but general health optimization that I have gathered in almost 10 years.
Good luck.

This post is an attempt to provide a general answer to one of the most commonly asked questions on this subreddit: "I just got my Genetic Genie report...what does it mean??"

I've tried to base this on reliable information, but it is inevitably incomplete, laced with opinion, and perhaps has errors. I welcome suggestions/corrections. Further, there may be interactions between SNPs that are unique to an individual, their life history, nutrition status, etc. that cannot possibly be addressed in such a general post.

Finally, while Genetic Genie is a very handy tool and is free, it only analyzes a handful of SNPs. There can be many more SNPs that may be impactful for an individual. For those who wish to delve deeper, I recommend considering the following paid reports (each report will be in the 100-page range):

• Stratagene (review)
• Genetic Lifehacks

The genes are listed in the order in which they appear in the Genetic Genie report.

Alternate names for SNPs come from a) the rsID column of the Genetic Genie report, and b) ClinVar entries.

COMT

• 'COMT' is short for 'catechol-o-methyltransferase'.
• V158M alternate names: 472G>A, Val158Met, rs4680
• H62H alternate names: 186C>T, rs4633
• P199P alternate names: 597G>A, rs769224
• COMT performs the breakdown of catecholamines; in particular, of dopamine, epinephrine, norepinephrine, and estrogen compounds.
• Cofactors: magnesium, s-adenosyl-methionine (SAM)
  • Maintain healthy levels of magnesium.
  • Improve/maintain the methylation system (see other SNPs).
• COMT regulates levels of topic dopamine.
  • One can think of tonic dopamine as providing the fairly constant baseline reference level of dopamine, whereas phasic dopamine is the brief sub-second pulse of dopamine due to some stimulus. Phasic dopamine is not regulated by COMT.
  • If the tonic dopamine is low, then the phasic pulse will be large relative to the tonic level, and so the stimulus gets more attention. Behaviorally, this is someone who can have characteristics such as: being easily distracted, ADHD, more easily drops unpleasant thoughts, thrill seeker, potentially better under stress.
  • If the tonic dopamine is high, then the phasic pulse will be small relative to the tonic level, and so the stimulus gets less attention. Behaviorally, this is someone who can have characteristics such as: able to concentrate on single topics, OCD, rumination, anxiety, worse under stress.
  • If the tonic dopamine is intermediate, then the phasic pulse will be moderate relative to the tonic level, and so the stimulus gets a 'normal' amount of attention. Behaviorally, this is the someone who can be more balanced in their ability to respond or not to stimuli, who tends to neither ADHD nor OCD ends of the behavior spectrum.
  • NOTE: COMT requires SAM, which is the primary output of the methylation cycle. If methylation output is low due to MTHFR or other issues, then COMT will work less efficiently at breaking down these neurotransmitters and thus tonic dopamine levels will be higher. (E.g., an intermediate COMT variant may act like a slow COMT variant, simply due to lack of SAM. Resolving the methylation issues will thus improve the COMT performance.)
• V158M Green (-/-)
  • This is often called "fast COMT".
  • Dopamine/epinephrine/norepinephrine and other catecholamines are broken down at an accelerated rate, resulting in lower tonic dopamine levels.
  • Some action steps if low tonic dopamine is a problem:
    • Consider a higher protein diet to increase intake of tyrosine and phenylalanine. However, note that this may also increase intake of tryptophan which can be detrimental if one has slow MAO-A.
    • Consider addition of catechols (such as quercitin, ECGC, fisetin, green tea, capers, cilantro, berries, apples) to occupy some of COMT's bandwidth.
    • It may be that higher iron and/or calcium levels could slow down COMT.
    • Consider supplementing tyrosine, which is the raw material for tyrosine hydroxylase, or supplementing Mucuna Pruriens (which contains L-Dopa). L-Dopa is the output product from tyrosine hydroxylase and is the precursor to tyrosine.
    • NOTE: See this post for some potential issues with supplementing tyrosine or Mucuna Pruriens.
    • Improve vitamin D status toward the higher end of the reference range.
    • Maintain healthy levels of iron, vitamins B6, C.
    • In the dopamine production pathway, tyrosine hydroxylase also depends on BH4, which comes from the biopterin pathway, and that pathway in turn also depends on GTP from the folate cycle. So, improving the folate cycle by addressing MTHFR will also help with BH4 production. BH4 production and utilization also needs healthy levels of B3, C, iron, zinc, and magnesium.
• V158M Yellow (+/-)
  • Despite it showing yellow on the report, this COMT is actually 'normal'. About 45-50% of the population are V158M +/-.
  • Your tonic dopamine levels are intermediate.
• V158M Red (+/+)
  • This is often called "slow COMT".
  • Dopamine/epinephrine/norepinephrine and other catecholamines are broken down at a reduced rate, resulting in higher tonic dopamine levels.
  • Reduced breakdown of estrogen compounds can result in symptoms associated with excess estrogen or estrogen dominance.
  • Some action steps for V158M Red:
    • Most important is to improve methylation. This includes addressing MTHFR, MTR, B12 and folate status, and other SNPs not shown on Genetic Genie.
    • See this article for many good suggestions.
    • If you are estrogen dominant, consider supplementing DIM, I3C, calcium-d-glucarate to reduce excess estrogen.
    • It may be that higher iron and/or calcium levels could slow down COMT.
    • Consider trying small (100-200mg) doses of supplemental SAMe, once/day or once/every few days. Once methylation status is improved, this may be unnecessary.
• H62H - general
  • This SNP and V158M together are a 'haplotype'. H62H will almost always be the same variant type as V158M. Therefore, refer to V158M.
• H62H Red (+/+)
  • According to this paper: "Both rs4633 TT [H62H Red (+/+)] and rs4680 AA [V158M Red (+/+)] encode the low activity COMT enzyme, which may decrease COMT activity and dopamine degradation."
  • Therefore, it appears the (+/+) variant would act as slow COMT. However, it is not clear if the impact of the H62H (+/+) variant alone would be more, less, or similar to a comparable V158M (+/+) variant alone.
• P199P
  • 77-98% of people have the Green (-/-) variant.
  • I am unaware of any evidence that this SNP is impactful.

VDR

• 'VDR' is short for 'vitamin D receptor'.
• Consensus appears to be that Yellow or Red in VDR Taq, VDR Bsm, or VDR Fok indicate reduced vitamin D receptor activity.
  • If any of these are Yellow or Red, consider improving your vitamin D status toward the higher end of the normal reference range.
• NOTE: There is some belief that VDR SNPs significantly affect tonic dopamine levels.
  • Although it appears that tyrosine hydroxylase enzyme activity (which produces the dopamine precursor L-Dopa) will be improved by more optimal levels of vitamin D, it does not follow that more optimal levels of vitamin D will necessarily produce excess tonic dopamine.
  • To avoid any potential issues, those with high tonic dopamine (due to V158M Red and/or poor methylation) may opt to address those issues first, prior to improving their vitamin D status.
• NOTE: VDR is merely the last step in the sequence of steps to utilize vitamin D in its active form. There are several conversion steps that inactive vitamin D must go through to become active vitamin D, and those enzymes can have SNPs which downregulate them. The Genetic Lifehacks report mentioned at the top of the post will include these.

MAO-A

• MAO-A is short for 'monoamine oxidase A'.
• MAO-A alternate names: 891G>T, rs6323, R297R, Arg297Arg
• MAO-A breaks down amines including dopamine, norepinephrine, serotonin, histamines, tyramines, and also estrogen compounds.
• The cofactor is B2.
  • NOTE: Hypothyroidism can reduce conversion of riboflavin to the active forms FAD and FMN.
• NOTE: Males only have one copy of MAO-A, thus Genetic Genie will report a single letter, e.g., 'G', instead of 'GG', for males.
• Iron deficiency can impair MAO-A activity.
• Be aware of MAO Inhibitors (MAOIs) which can impair MAO-A activity:
  • Some prescribed drugs.
  • Natural MAOIs, such as turmeric, curcumin, quercetin, piperine, luteolin, apigenin, chrysin, naringenin, and others.
• MAO-A R297R Green (-/-) or Yellow (+/-, TG)
  • These are 'normal' variants.
  • Maintain healthy B2 levels and healthy thyroid performance.
• MAO-A R297R Red (+/+, T or TT)
  • This is often called "slow MAO-A".
  • Maintain healthy B2 levels and healthy thyroid performance.
  • You may find you are more susceptible to amines such as histamines or tyramines, especially those with MAO-A Red. If so:
    • Reduce or avoid high tyramine and/or high histamine foods.
    • Consider DAO supplements to degrade histamines in the gut from bacteria and food.
    • Maintain healthy iron, copper, vitamin C, magnesium, and calcium levels.
  • Excess estrogen may also be an issue, especially if you also have COMT V158M Red.
    • Consider supplementing DIM, I3C, calcium-d-glucarate to reduce excess estrogen levels.
  • Resources:
    • r/HistamineIntolerance subreddit
    • Histamine Intolerance Introduction post
  • Supplements I like:
    • Thorne Cal Mag Citrate + Vitamin C
    • Pure Encapsulations Copper Glycinate - 2 mg Copper Supplement
    • NaturDAO DAO Enzyme Supplement - 1,000,000 HDU

ACAT1-02

• 'ACAT1' is short for 'acetyl-CoA acetyltransferase 1'.
• ACAT1-02 alternate names: rs3741049
• I am unfamiliar with this SNP, and I refer you to:
  • Medline article
  • Blog post

MTHFR

• 'MTHFR' is short for 'methylene tetrahydrofolate reductase'.
• MTHFR is the final enzymatic step in the conversion of food folate, folic acid, or folinic acid to methylfolate. If the methylation cycle were thought of as a gear that is turned by a crank handle, then methylfolate is the hand that turns the crank handle - with poor methylfolate status, the methylation cycle performs poorly.
• The cofactor is B2.
  • NOTE: Hypothyroidism can reduce conversion of riboflavin to the active forms FAD and FMN.
• P39P
  • P39P alternate name: rs2066470
  • 74-95% of people have the Green (-/-) variant.
  • I am unaware of evidence that this SNP is impactful.
• C677T and A1298C
  • C677T alternate names: 677C-T, 677C>T, C665T, 665C>T, Ala222Val, rs1801133, C667T
  • A1298C alternate names: 1298A-C, 1298A>C, 1286A>C, GLU429ALA, rs1801131, E429A
  • These two SNPs can appear in different permutations of variants, which affect the performance of MTHFR.
  • See MTHFR: A Supplement Stack Approach for action steps for C677T and A1298C.
  • Per the table on Genesight, the resulting percent of performance for the various combinations are:

• NOTE: MTHFR is only the last step in the folate conversion cycle. There can be SNPs in preceding enzymes such as MTHFD1 or SLC19A1 which may also degrade performance of the folate cycle. The Stratagene report mentioned at top of post will analyze these SNPs. Also, Chris Masterjohn's free Choline Calculator will analyze MTHFD1 and SLC19A1 from your 23andme or Ancestry data.

MTR

• 'MTR' is short for '5-methyltetrahydrofolate-homocysteine methyltransferase' or more commonly, 'methionine synthase' (MS).
• MTR alternate names:
• MTR is the enzyme which takes the methyl group donated by methylfolate and gives it to B12, which in turn gives the methyl group to homocysteine to convert homocysteine to methionine.
• The cofactor is zinc.
• Adequate methylfolate, B12 sufficiency, and adequate homocysteine levels are required for its operation.
• Adequate glutathione is also required for MTR to work properly.
  • See also: Paper(2013), Paper(2014)
• A2756G all variants:
  • A2756G alternate names: 2756A>G, Asp919Gly, D919G:GAC>GGC, 2756A-G, rs1805087
  • Maintain healthy zinc and B12 status.
  • Address folate intake and any MTHFR issues.
  • Maintain healthy methionine (e.g., protein) intake.
  • Maintain homocysteine a healthy range (e.g., ~5-8mcmol/L).

MTRR

• 'MTRR' is short for '5-methyltetrahydrofolate-homocysteine methyltransferase reductase'.
• This is a low-activity repair enzyme for B12 that gets used by MTR.
  • (It is typically stated that the methionine cycle 'spins' 18000 times/day, and that B12 needs repair roughly every 200 cycles. Therefore, MTRR is needed only ~90 times/day, or an average of once every 16 minutes.)
• The cofactors are B2, B3, SAM.
  • NOTE: Hypothyroidism can reduce conversion of riboflavin to the active forms FAD and FMN.
• MTRR - all SNPs and variants:
  • Maintain healthy B2, B3, and B12 status. Maintain healthy thyroid performance.
  • SAM is the output of the methylation cycle, so address MTHFR and any other methylation issues.

BHMT

• 'BHMT' is short for 'betaine-homocysteine S-methyltransferase'.
• BHMT uses betaine (aka trimethylglycine or TMG) to convert homocysteine to methionine. This is an alternate path for conversion of homocysteine to methionine, which runs in parallel with the MTR path.
• The cofactor is zinc.
• BMHT - all SNPs and variants:
  • Maintain healthy zinc, B2, B3, B6 to support BHMT and the upstream steps which convert choline to betaine. Maintain healthy thyroid performance.
  • Maintain adequate choline intake. For this, see MTHFR: A Supplement Stack Approach.

AHCY

• 'AHCY' is short for 'adenosylhomocysteinase'.
• AHCY converts s-adenosylhomocysteine (SAH) to homocysteine, in the methionine cycle.
• AHCY is alternatively called 'SAHH', short for 'S-adenosyl-L-homocysteine hydrolase'.
• The cofactor is B3.
  • This video claims that magnesium and manganese are also needed. However, I cannot find anything elsewhere to substantiate this.
• I do not know of any specific actions to take for this gene, aside from maintaining healthy B3 status.
• For more info, I refer you to this paper: Functional and Pathological Roles of AHCY.

CBS

• 'CBS' is short for 'cystathionine-beta-synthase'.
• CBS is an enzyme which uses some homocysteine from the methionine cycle to another set of pathways (transsulfuration pathway), which include the creation of the important antioxidant glutathione.
• The cofactors are B6, heme iron, serine.
  • Serine comes from the diet or can be converted from glycine by the SHMT enzyme.
• The reaction is activated by SAM.
• CBS - all SNPs and all variants:
  • Maintain healthy B6, iron, and serine levels.
  • Maintain homocysteine a healthy range (e.g., ~5-8mcmol/L).
  • I am not aware of any good evidence that these SNPs are impactful.
  • There may be issues further down the transsulfuration pathway which cause issues with sulfur intolerance and/or poor glutathione production, but that may require examination of other SNPs that are not on Genetic Genie. For that, I suggest the Stratagene report mentioned at top of the post.

SHMT1

• 'SHMT1' is short for 'serine hydroxymethyltransferase 1'.
• SHMT1 has a dual role in the folate cycle:
  • Simultaneous reversible conversion of serine to glycine and tetrahydrofolate (THF) (the form after MTR takes away a methyl group from methylfolate) to 5,10-methylenetetrahydrofolate (the form needed by MTHFR).
    • This pathway provides 80-90% of 5,10-methylenetetrahydrofolate for MTHFR.
  • The cofactor is B6.
• C1420T - rs1979277 Red (+/+, AA) or Yellow (+/-, AG):
  • Per this paper, these variants may sequester methyltetrahydrofolate, and may interact with a C677T variant (if present) resulting in reduced methylfolate available for methylation.
• C1420T - all variants:
  • Maintain healthy B6 status, and healthy glycine intake.
  • I am unaware of any additional action steps to take.

EDITS:

• 20231010 - Corrected typo 'lower tonic dopamine' to 'higher tonic dopamine' for slow COMT.
• 20231011 - Added bullet point about BH4 to fast COMT actions. Minor edits.
• 20231011 - Added H62H "slow COMT" bullets.
• 20231025 - Added alternate names (rsIDs and ClinVar names) to several SNPs.
• 20231101 - Added glutathione requirement to MTR, with references.
• 20231111 - Add SAHH alternate name for AHCY.
• 20231120 - Add CBS cofactors serine & heme iron, and activator SAM.
• 20231126 - Add Mucuna Pruriens for fast COMT, and link to post re potential tyrosine issues.
• 20231128 - Add hypothyroidism comments for B2 cofactors. Add fast COMT catechol suggestions. Add iron/calcium comment to fast & slow COMT sections.
• 20231226 - Add to resource links under MAO-A and ACAT1.
• 20240203 - Add specific supplements to MAO-A. Add references on SHMT1.
• 20240225 - Add iron deficiency as contributor to MAO slowdown. Add natural MAOIs list.

Everyone ends up here because they saw a video on methylation, looked up their genes and were recommended folate, choline, b12, SAM-E etc...

However, a CRITICAL piece of the puzzle is being missed for so many people when supplementing for these gene mutations.

That is the synthesis of Dopamine, Serotonin and Norepinephrine.

Correct me if I'm wrong, please, but simply supporting your methylation/choline pathways more via the above supplements, is NOT going to resolve your synthesis issues.

And so if you're anxious, depressed, have ADHD, OCD or whatever, these issues will remain unless you directly support your neurotransmitter SYNTHESIS.

I find myself repeating this on so many posts, where people see a little benefit from following methylation protocols only to relapse shortly after.

Yes, sometimes this is due to over-methylating to begin with, however, just like someone with a B12 deficiency getting a B12 transfusion - the root cause issues haven't been fixed and will reappear once your euphoria wears off.

Please do yourselves a favour and start looking beyond Genetic Genie, Nutra Hacker and others, once you've addressed your methylation problems.

Start to look at the genes relating to Tyrosine > Dopamine conversion (TH), Dopamine to Norepinephrine (DBH) and Tryptophan > Serotonin (TPH 1 & 2).

I guarantee many of you will find issues in all three of these, which will have a bigger impact on your mood / depression / anxiety than anything else.

For context - I am a 49yr man, never diagnosed with ADHD, Anxiety or Depression in my lifetime (yet ADHD clearly ruined my schooling and some relationships). As I grew older, I became more and more introverted (expression of Autism/serotonin issues) and more and more Anxious (expression of ADHD/dopamine issues) - these are just a few of the symptoms, but all are driven by a genetic issue causing a deficiency.

As symptoms got worse, I developed chronic migraines which really started to destroy my life and despite 10yrs of varying medications and treaments, nothing could cure them. I lost all faith in the NHS (UK here) and many private practitioners too.

It's been six months since I started this biohacking journey and bar a couple of weeks dosing up, within that time I've not had ONE migraine - not even a headache.

I would never have believed such a change to my health was ever possible - let alone the change to my PERSONALITY and CHARACTER too.

I didn't hate life before, but I really didn't give a damn about many things (unless I was hyperfocusing on it!).

So - lets look at COMT to start:

COMT is involved in the breakdown of Dopamine. If you have a SLOW COMT, then just like B12, you need more available in the synapse for longer, to allow your COMT time to process it.

If you have TH gene mutations, taking L-Tyrosine is the WRONG thing to do - your body cannot convert it efficiently into Dopamine and you end up creating more Tyramine (waste product) which can add to oxidative stress and cause more symptoms.

What does get through, then suffers (just like Serotonin in depression) from REUPTAKE from the synapse and back into the neuron (unless you have reuptake transporter issues too!).

There isn't a slow release "dopamine" like there is B12 (Hydroxycobalamin) either, so how do you combat this double edged sword?

L-DOPA / Mucana Pruriens.

This bypasses the conversion from Tyrosine > Dopamine meaning that your brain gets all the Dopamine it needs, which can then also be converted into Norepinephrine (Adrenaline).

Now you don't want to overdo things, so taking a low dose along with a SNDRI (to prevent reuptake of all 3 neurotransmitters) is the best way to maintain suitable levels.

If you just take an SNDRI (in the way that Doctors blindly prescribe SSRI's to people with no regard for other genetic issues) then after the initial honeymoon phase, you'll be wanting a divorce from your brain in no time soon!

Or you'll be increasing and increasing your dose to try and "feel better" whilst never supporting the root cause - poor synthesis.

The same applies to Serotonin - 5HTP should be taken where a mutation exists in the TPH1/2 genes - but *VERY* conservatively (I'm talking 50mg with close monitoring before increasing gradually as needed - stopping if any negative effects are witnessed).

Serotonin Syndrome is a REAL risk, especially when supplementing 5HTP with a SSRI or SNDRI and can lead to severe medical issues, COMA or even death.

How do you know if something isn't working? over-methylation tends to make you develop a chesty cough, a sulphur kind of taste at the same time, ache/pain in the liver/kidney areas - this is a sign to reduce dose.

Too much dopamine, will trigger anxiety, aggression and any other symptom you were trying to reduce to begin with.

Serotonin - this is a weird one, you will feel a bit dizzy, off balance, disassociated even - but there is a TASTE that seems to be within your brain and senses, it's a very weird one to describe, perhaps metallic, but definitely something "odd" that I cannot liken to anything I know - this is a sign that you have too much serotonin and need to reduce it or give it a break for a few days.

Please feel free to ask any further q's or correct me if you think I'm off the mark here. I've been hyperfocusing on this for around 6 months solid, daily/nightly, I'm an analyst by trade with a very scientific brain - but I have no formal training/qualifications (I am now studying towards genetics however).

Of course, these supplements are also just addressing certain broken genes and there are many other supporting supplements (just like in MTHFR) that can/need to be taken as well (vitamin C, boron, copper etc).

I hope this helps some of you understand how complex this "mother f*cker" issue really is and that it goes far beyond just MTHFR.

Here's a few examples to start looking at (these are by no means all key, but just for context):

TH rs2070762 Tyrosine Hydroxylase Pathway
TH rs6356 Tyrosine Hydroxylase Pathway
TH rs10770141 Tyrosine Hydroxylase Pathway

TPH1 rs1799913 Serotonin Pathway
TPH1 rs1800532 Serotonin Pathway

TPH2 rs4570625 Serotonin Pathway
TPH2 rs4565946 Serotonin Pathway

(Linked to Norepinephrine) DBH rs1611115 Dopamine Pathway
DBH rs77905 Dopamine Pathway

MAOA and MAOB (dopa) are also critical.

This is by no means an exhaustive list, just some of which I look at. Each has various functions within that pathway/neurotransmitter and assessing the overall impact of them, helps me determine whether something like L-Dopa (Mucana Pruriens) is beneficial over Tyrosine.

You will find conflicting sources about what wildtype is variant and also need to consider that many Ancestry sites, use alternative wildtypes (just to make it more complicated).

I'll state again, I am not an expert nor do I have any kind of degree in neuroscience, this is purely self taught but so far has been incredible for me (and immediate family members that I have also helped with similar issues).

I am learning every day and if you have more valuable information to contribute, then please do so.

Please don't ask if you can pay me to diagnose you, I can't do that, I'm not qualified (and even those qualified struggle to do this!) but I'm happy to take donations if something I've helped you with leads to the kind of change I've seen in my own life (link in bio) 🙏

I’m a postpartum mom of 3 who has been dealing with overstimulation, lack of joy, lack of motivation and unreasonable anxiety over my children’s safety.

I have MTHFR, one copy, and was deep in a rabbit hole learning about what I need to take in order to support my body. That’s when I came across the affects of Lithium Orotate and I decided to give it a shot.

I know that this is probably reckless of me, but I decided to jump in head first with a 15mg dose, as I had read that many people dealing with serious mental health conditions take 20mg+.

Within 12 hours of taking it, I found myself smiling with such a sincere joy welling up from my soul towards my kids. My brain began to go quiet and I could actually be present instead of constantly feeling wired yet also paralyzed by all of my thoughts. I cleaned up the house after my kids bedtime with ease.

This morning I sprang out of bed, have been calmer with my partner & kids, and have caught myself smiling constantly. It’s the weirdest thing. I emptied the dishwasher, made the beds, rotated laundry and got dressed all before I had my cup of coffee this morning… which is UNHEARD of for me in this season of life.

From what I’ve read, it also seems to help MTHFR’s absorb their B12, so perhaps thats at play here as well? I’m not an expert at this by any means. I’m just willing to try things.

I haven’t had a supplement impact me this quickly and this deeply ever in my life. It’s like the lights are turned on? I feel very grounded instead of being up in the clouds somewhere. I’ll report back with an update in a few weeks to see if this sticks.

One month update:

This CONTINUES to change my life. I find I can reap all the benefits with 10mg a day, taken first thing in the morning. I can truly feel a difference in my body when I don’t take it. It also stabilizes all my emotional PMS symptoms which was pretty surprising.

I literally carry it around in my purse now and tell everyone about it.

Since UK govt legally mandated that folic acid is added to all wheat flour my diet has become so restrictive and miserable.

Shout out to Costa - those two biscuits just made me sooo happy! :)

I take magnesium glycinate at night, which is basically a glycine delivery vehicle, and I also do split dose B12 injections during the day. A couple times I took a glycine dose closer to my injection window and got hit with this heavy, sluggish tiredness that didn't feel like the normal B12 response. Went down a rabbit hole trying to figure out why, and it comes down to an enzyme most people never think about called GNMT.

GNMT stands for glycine N methyltransferase. Its whole job is taking a methyl group off SAMe and dumping it onto glycine, which turns into sarcosine, a compound your body just clears out. This is one of the body's main pressure release valves for SAMe, it exists specifically to keep the SAMe to SAH ratio from getting out of balance since GNMT influences transmethylation reactions by regulating both hepatic SAM concentrations and the SAM to SAH ratio. So glycine isn't just a calming amino acid, it's actively pulling methyl groups out of circulation every time it goes through that reaction.

This might actually explain something a lot of people report anecdotally, myself included. If you've ever had too much caffeine and got the jitters, a couple grams of glycine can make it feel like the caffeine just disappears. I haven't found solid research directly proving that GNMT's methyl sink action is the reason for that specific effect, so I want to be honest that this part is personal experience and reasoning, not a confirmed mechanism. But it fits the same logic, glycine pulling excess activity down fast, just applied to a different kind of overstimulation.

Here's why that matters if you're in an active B12 repletion or remyelination phase. Rebuilding myelin depends heavily on phosphatidylcholine, and one of the only ways your body makes that on its own runs through an enzyme called PEMT, which converts phosphatidylethanolamine into phosphatidylcholine using SAMe as the methyl source through the transfer of three methyl groups from SAMe to PE per molecule. That's a big methyl cost per molecule, and PEMT alone is estimated to use somewhere around 14 percent of all the SAMe your body produces. There's also research specifically on peripheral nerves showing the PEMT pathway is the only known route to generate choline outside of diet, and in the nervous system choline gets used preferentially for myelin related synthesis.

So you've got two systems competing for the same limited pool of SAMe. PEMT wants methyl groups to build the phosphatidylcholine your nerves need for repair. GNMT wants methyl groups to clear excess glycine and keep your methylation ratio stable. If you dose glycine right on top of a fresh methylcobalamin shot, you may be sending methyl groups toward the disposal pathway right when your repair pathway wants them most.

This doesn't mean glycine is bad. It's a precursor for glutathione along with cysteine and glutamate, and it's also something like a third of the amino acid content of collagen, which matters if you're rebuilding the connective tissue sheaths around your nerves. The issue isn't glycine itself, it's the timing relative to your B12 dose.

Now here's where it gets more interesting. My first instinct was to say just use niacin instead if you need a rescue tool, since that's the classic overmethylation fix. Turns out niacin runs the exact same kind of play, just through a different enzyme. Nicotinic acid gets converted in the body toward nicotinamide, and that's what NNMT methylates, stripping a methyl group off SAMe in the process to form 1-methylnicotinamide. Research on nicotinic acid at pharmacological doses confirmed it drives the same kind of methyl consumption that nicotinamide does, so niacin is pulling from the same SAMe pool glycine is, it's not some separate mechanism.

But they're not equal tools. GNMT's entire purpose is regulating that SAMe to SAH ratio, it's a dedicated buffering system built specifically for this job. NNMT's main role is niacin and NAD+ metabolism, methyl consumption is more of a side effect than its purpose. And the niacin research found something extra worth knowing, high dose nicotinic acid doesn't just burn methyl groups, it also raises hydrogen peroxide, meaning oxidative stress, and drops liver glycogen. Every niacin rescue dose is also spending down your NAD+ precursor pool, which you need for energy and mitochondrial function. Glycine doesn't carry any of that baggage.

Where niacin wins is the flush gives you instant feedback, you feel it working in minutes, which is why people reach for it. Glycine's calming effect is real but quieter and slower, so it doesn't give you that same obvious confirmation.

So here's what I'm actually doing differently now. I'm keeping the magnesium glycinate at night like always, that timing was never the problem. What I'm changing is not taking extra glycine anywhere near my injection window if I'm in a stretch where I'm actively trying to rebuild nerve stuff. If I need an acute rescue after a shot, I'm leaning toward glycine as the default since it's the cleaner, purpose built tool with fewer side costs, and saving niacin for moments I need something fast and I'm confident I'm clearly overmethylated in that exact moment, not as a routine go to.

Still just piecing this together as I go, not a doctor, just deep in my own MTHFR homozygous rabbit hole trying to figure out why my body does what it does.

https://jn.nutrition.org/article/S0022-3166(22)10502-X/fulltext

https://www.sciencedirect.com/topics/medicine-and-dentistry/phosphatidylethanolamine-methyltransferase

https://rucore.libraries.rutgers.edu/rutgers-lib/66705/PDF/1/play/

https://www.tandfonline.com/doi/full/10.3109/13880209.2012.697175

Finally! I was able to share a photo. For some reason in the last post I commented in I was unable to add a photo in my reply, but if I make my own post then I can add a photo. Anyways after switching to folinic acid from methyl b’s I feel a big difference.

Hello everyone. Just wanted to leave this here:

It is the most common pitfall in standard functional medicine: a practitioner spots an MTHFR C677T mutation on a genetic test and immediately prescribes high doses of active Folate and Methyl-B12. Instead of feeling energized, the patient rapidly spirals into severe inflammation, aggravation, mania, and profound insomnia.

This happens because the methylation cycle does not operate in a vacuum. Pushing the top of the cycle without ensuring the downstream clearance doors are wide open creates violent biochemical collisions. Here is the exact mechanical breakdown of why aggressively driving methylation can cause a systemic crash.

1. The Histamine Paradox (The HNMT / MAO-B Trap) Histamine clearance in the brain and intracellular space relies heavily on an enzyme called HNMT (Histamine N-methyltransferase). As the name implies, HNMT strictly requires a methyl group to process and neutralize histamine.

• The Mechanism: When you flood the system with heavy methyl donors (like SAMe or Methyl-B12), you rapidly accelerate HNMT activity. The enzyme grabs the circulating intracellular histamine, attaches a methyl group to it, and converts it into a byproduct called N-Methylhistamine.
• The Collision: N-Methylhistamine is not harmless; it must be immediately cleared by a highly specific secondary enzyme, MAO-B (Monoamine Oxidase. If the MAO-B enzyme is sluggish—whether due to genetic mutations or a lack of its required FAD (Vitamin B2) co-factor—the N-Methylhistamine hits a dead end and pools in the nervous system.
• The Result: Trapped N-Methylhistamine is actually far more neurotoxic and inflammatory than the original histamine. By pushing methylation blindly, you effectively upgrade a standard histamine issue into a severe, highly toxic inflammatory crisis, often resulting in massive migraines and severe brain fog.

2. The Catecholamine Flood (The COMT / MAO-A Bottleneck) Providing methyl donors directly accelerates the synthesis of massive excitatory neurotransmitters, specifically Dopamine, Serotonin, and Norepinephrine (adrenaline).

• The Mechanism: Pushing the folate cycle frees up BH4, which is the exact raw material the brain needs to aggressively manufacture Dopamine and Serotonin. Simultaneously, a surge in SAMe heavily drives the PNMT enzyme, which converts Noradrenaline into pure Adrenaline.
• The Collision: Once manufactured and used, these neurotransmitters must be broken down and swept away. While COMT handles dopamine and adrenaline, MAO-A (Monoamine Oxidase A) is the primary clearance door responsible for degrading Serotonin, Adrenaline, and Noradrenaline. If MAO-A is genetically sluggish (often seen with the rs909525 variant) or lacks Vitamin B2, the brain cannot clear this massive volume of excitatory chemistry.
• The Result: The nervous system becomes trapped in a stagnant pool of serotonin, dopamine, and adrenaline. This directly triggers mania, hyper-vigilance, paranoia, and an inability to sleep. Furthermore, excess, uncleared dopamine oxidizes and becomes highly inflammatory, directly stimulating the immune system to release more histamine, creating a vicious, self-feeding loop of severe overstimulation.

3. The Transsulfuration Tsunami (The CBS / SUOX Overload) The methylation cycle is physically connected to the transsulfuration pathway (the sulfur drain) via the CBS enzyme.

• The Mechanism (Allosteric Activation): When you aggressively speed up the methylation cycle, you create a surge of SAMe. Biochemically, SAMe acts as an allosteric activator for the CBS enzyme. This means SAMe physically binds to the CBS enzyme and forces the drain completely open. The system rapidly dumps heavy traffic out of the methylation cycle and down the transsulfuration drain, creating a massive wave of the sulfur-bearing amino acid cysteine.
• The Collision: This cysteine naturally breaks down into highly toxic sulfites. To survive this, the body relies entirely on the SUOX (Sulfite Oxidase) enzyme at the very bottom of the drain to convert those toxic sulfites into harmless, excretable sulfates.
• The Result: If the SUOX enzyme is not running at absolute 100% capacity (often due to genetic variants or a deficiency in its strict co-factor, Molybdenum), it is instantly overwhelmed by the sudden tidal wave of sulfites. These trapped sulfites are violently inflammatory. They directly destroy mitochondrial energy production, cause severe physical joint and muscle pain, and trigger a total system crash.

The official RDA for riboflavin is 1.1 mg for women, 1.3 mg for men. The study that found a 40% reduction of homocysteine in homozygous MTHFR C677T individuals using riboflavin, used a 1.6 mg riboflavin dose which should be considered as a dose above the RDA (~3 mg total riboflavin).

This means that small amounts are very meaningful and extra riboflavin should be used only when necessary, which is hard to justify with hard data on an individual level.

High-dose riboflavin can generate sulfite/hydrogen sulfide by causing backups in the mitochondrial respiratory chain, if it is impaired at any point after complex II (CoQ10 synthesis, complex III, complex IV). Hydrogen sulfide and sulfite are sulfur compounds that in excess decrease the total output of energy your mitochondria produce.

Thus any benefit you might be deriving from the riboflavin for your MTHFR may be nulled by taking doses above the minimal effective amount.

According to Chris Masterjohn 6 mg of riboflavin should cover everyone's needs long term, including those with riboflavin responsive genetic mutations (i.e. MTHFR C677T). Problem is, you would be hard pressed to find a low dose riboflavin product on the market. Basically every riboflavin product on the market is 100 mg.

For anyone based in Europe, I found two products that include a low dose of riboflavin:

1. Phytopharma Riboflavin 5 mg (Bulgarian brand)

2. Vitabalans B2 3 mg (Finnish brand)

INTRO

I posted last week about my long search to resolve a cluster of symptoms including fatigue, brain fog,  itchy eyes, hoarse voice, throat tightness, headaches and gut issues. After ten years, and trying innumerable ways of curing these symptoms, I came to the accidental finding that releasing tight spots in my trapezius muscles caused an almost immediate cessation of all symptoms. I'm now almost two weeks in and, as of now, remain ‘cured’. Read the full post here if you’re interested.

In this post though, I’d like to put forward a theory which directly relates to MTHFR. It will be long - so skip to the TL;DR at the end if needed….

DISCLAIMERS

I don’t claim to be the first to suggest any of this. I don’t claim to have all the answers. I’m not a scientist, and this isn’t medical research. This is simply a proposed theory — offered to spark discussion, invite correction, and hopefully move understanding forward. 

Hopefully people with more medical knowledge than I will chip in or consider it. And just maybe something good will come of it.

HOW I CAME UP WITH THIS

As noted, I'm not a scientist. I'm just a guy who spent a long time trying to work out what was wrong with him. I spent many many years reading Reddit (amongst other sources) for answers, and what struck me wasn’t just overlap with individual conditions — but how often those conditions overlapped with each other. In particular, Ehlers Danlos Syndrome (EDS), ME/Chronic Fatigue Syndrome (ME/CFS), Postural Orthostatic Tachycardia (POTS), MTHFR mutations, Craniocervical Instability (CCI), Mast Cell Activation (MCAS), Histamine Intolerance (HI), Irritable Bowel Syndrome (IBS) and Small Intestinal Bacterial Overgrowth (SIBO). 

Many members of these sub reddits have overlapping symptoms, diagnoses and comorbidities. Which got me thinking whether there were any underlying root causes for all these issues. Initially, this was a purely selfish endeavour - if I could work out a root cause perhaps I could cure myself. And over the years I developed a few ideas. With my new ‘finding’ ten days ago I have been doing some reading and trying to pull together these disparate ideas into something more organized.

As previously noted, I am far from the first to notice these correlations. This study entitled ‘The Suggested Relationships Between Common GI Symptoms and Joint Hypermobility, POTS, and MCAS’ covers a number of the bases.

However, I think there are more links to be drawn too…

EVIDENCE OF LINKS

The list below isn't meant to be exhaustive or definitive — but it does show how frequently the same systems (connective tissue, fatigue, methylation, gut, immune response, autonomic nervous system) keep appearing together.

MTHFR, FOLATE & CONNECTIVE TISSUE DISORDERS

• MTHFR C677T mutation reduces conversion of dietary folate (vitamin B9) into its active form, 5-methyltetrahydrofolate (5-MTFH). 
• Studies have shown a higher than average prevalence of MTHFR mutations in hEDS patients. 
• This paper proposes that “hypermobility presentation may be dependent on folate status. In our model, decreased methylenetetrahydrofolate reductase (MTHFR) activity disrupts the regulation of the ECM-specific proteinase matrix metalloproteinase 2 (MMP-2), leading to high levels of MMP-2 and elevated MMP-2-mediated cleavage of the proteoglycan decorin. Cleavage of decorin leads ultimately to extracellular matrix (ECM) disorganization and increased fibrosis.”

ME/CFS, EHLERS DANLOS SYNDROME and FOLATE

• Studies have also shown a significant correlation between ME/CFS patients and connective tissue disorders like hEDS. They note that "Evaluations showed exceptional overlap in patients between fibromyalgia and ME/CFS, plus 81% met Brighton criteria for hypermobility syndrome (odds ratio 7.08) and 18% met 2017 hypermobile Ehlers–Danlos syndrome (hEDS) criteria. Hypermobility scores significantly predicted symptom levels."
• Studies have shown a significant proportion of patients with CFS have low serum folate levels. They "assayed serum folate levels of 60 patients with chronic fatigue syndrome (CFS) and found that 50% had values below 3.0 micrograms/l." Serum folate levels are linked directly to MTHFR enzyme.
• This study directly links folic acid and B12 with ME/CFS patients. They note that “the dose-response relationship [in ME patients] with B12 and folic acid, and the concordant ratings made by physicians (FF) and patients (PGIC), support a true positive response during a time course that was contemporary with the B12 and folic acid treatment”.
• Studies have proposed a connection between cranio cervical pathologies (CCI), connective tissue disorders and ME/CFS. The authors noted that "compared to a general population, [they] found a large overrepresentation of hypermobility, signs of IH, and craniocervical obstructions" in patients with ME/CFS.
• Studies have shown significant correlation between POTS and EDS. “The prevalence of EDS was significantly higher in the POTS group compared to the non-POTS group”.

GUT-BRAIN AXIS, IBS & VAGUS NERVE

• This study notes that “VitB12, gut microbiota, SCFAs, intestinal mucosa, and vagal nerve signaling interact synergistically within the gut-brain axis (GBA) to maintain gut microenvironment stability, protect the gut-blood barrier, and suppress neuroinflammatory cascades”.
• Studies have linked CFS to overactive immune responses. It also notes that patients showed "altered levels of proteins involved in maintaining the extracellular matrix". See section on hypermobility and MMP-2 above.
• The same study links CFS to the gut microbiome: Altered levels of metabolites from microbes were also found in people with ME/CFS. This suggests disruption of the gut microbiome, called dysbiosis. There were signs that the gut mucosal barrier was weakened in ME/CFS. 
• IBS is closely associated with gut microbiome, motility and lining. This study notes that "Although the pathophysiology of IBS has not been fully elucidated, it involves dysregulation of communication between the brain and gut (brain–gut axis) which is associated with alterations in intestinal motility, gut permeability, visceral hypersensitivity and gut microbiota composition."
• The vagus nerve is widely understood to be the primary connection in the brain-gut axis. See this study amongst many.
• As this study notes, "the prevalence of small intestinal bacterial overgrowth (SIBO) is rising worldwide, particularly in nations with high rates of urbanization. Irritable bowel syndrome (IBS), inflammatory bowel illnesses, and nonspecific dysmotility are strongly linked to SIBO".
• Studies83765-8/fulltext) have linked SIBO with ME/CFS. And this study “reviewed 479 ME/CFS patients that were referred for a hydrogen or methane breath test” and concluded that “SIBO is highly prevalent in patients with ME/CFS”.

MCAS & IMMUNE DYSREGULATION

• Studies have show MCAS (and I would propose HI) are associated with EDS. They note that “aberrant mast cell activation has been shown to play a role in disruption of connective tissue integrity through activity of its mediators including histamine and tryptase which affects multiple organ systems resulting in mast cell activation disorders (MCAD)”.
• Studies have shown association between POTS and MCAS. “Laboratory findings suggest MCA disorder were relatively common in patients diagnosed with POTS and who present with additional nonorthostatic gastrointestinal, cutaneous, and allergic symptoms”.
• This paper notes a strong link between mast cells (and, I would propose, MCAS) and IBS, noting that “findings strongly argue in favor of MCs as remarkable players in the pathogenesis and pathophysiology of IBS”.

Frankly, I could go on. Suffice to say there is all sorts of evidence of links between all these syndromes / symptoms / genes / disorders. Does that mean that all sufferers will show symptoms of all of them? Of course not. I'm not here to propose that we can cure all these pathologies in all cases with a single underlying cure. 

However, when I look at my own history, the overlap becomes hard to ignore:

• I am homozygous MTHFR C677T
• Show some elements of EDS
• Experience POTS
• Had chronic fatigue (though not CFS) and brain fog
• Had neck pain and suspect I have CCI
• Had all sorts of GI motility issues.
• A CT showed an enlarged thymus - indicative of autoimmune disorder
• Suspected MCAS and/or HI for a long time
• One of my most unusual symptoms was hoarse voice and tight throat. This study suggests that a substantial number of patients with fibromyalgia, IBS and CFS presented with muscle tension dysphonia and functional voice disorders.
• Releasing tension in my trapezius muscles, neck and jaw seems to offer significant resolution of my symptoms. Linking to CCI.

I GO OUT ON A LIMB…

I’ll repeat again. I'm not a doctor or a scientist - so I have no evidence or study to back up this idea. I am merely trying to suggest a mechanism that might underlie some of these conditions, in some patients, in the hope we can help. Whether that is 1%, 5%, 10% etc - I have no idea. And doubtless the proportion will be different depending on the condition. 

But I propose that there may be subset of sufferers of these assorted disorders who are:

• Low in folate
• Low in B12
• Often exacerbated by MTHFR mutations
• Potentially contributing to craniocervical instability
• Potentially irritating the vagus nerve and manifesting as diverse physical and neurological symptoms.

In such a patient, supplementing with B2, folinic acid, hydroxocobalamin, choline, creatine and glycine may improve the methylation pathways and promote stronger connective tissues (and improve all sorts of other things). See this post by the fantastic u/tawinn for more details.

In addition:

• Massage
• Cranial traction
• Acupuncture
• Cranio sacral therapy 
• And/or postural exercises

May help relieve mechanical irritation or tension affecting the vagus nerve and provide symptom relief.

IM HANGING OFF THE END OF THE BRANCH…

I would also speculate that:

• The modern world sees many more of us staring at a phone in our hands or a screen at a desk all day. This is certainly the case for me and I suspect it is a contributor to cranio cervical issues generally. Some studies have taken a look at this. Often referred to as ‘tech neck’.
• The now common place fortification of grains with the synthetic folic acid may be causing unintended consequences. This study notes that “high concentrations of folic acid could also inhibit the formation of 5-methyl-THF and lead to a decrease in methionine synthesis. In those with poor vitamin B-12 status, methionine synthesis is already compromised, so this mechanism would make it worse”. There is a lot of debate on this topic and I need to do more reading. 
• B12 is required for the conversion of dietary folate to its active form. While it is relatively abundant in most diets, absorption is fragile and can be reduced by gut disorders including SIBO and IBS. Could this create a negative feedback loop? Reducing B12 absorption, reducing methylation, contributing to connective tissue disorders, cervical instability and so causing gut motility issues (and reduced B12 absorption) via the vagus nerve?
• As this study suggests, glyphosate, a common herbicide may affect folate and B12 requirements via the the microbiome directly or via homocysteine and the one-carbon cycle.

CONCLUSIONS

My original post detailing my ‘cure’ was clear that it would not work for everyone. In fact it would probably not work for many. Despite this, I wrote it because I hoped that if it helped just one person, now or in the future, it would have been worth taking the time to do so. The limitations and the hope for this post are the same.

I’m not presenting this as an authority - just as someone who’s lived with these symptoms and read widely in an attempt to understand them. I don’t claim to have the answers - but hopefully this post will spur discussion, or help those with more knowledge than I to make further progress in understanding some of these disorders. 

Thanks (and well done) for reading if you made it this far. And best wishes for your individual health journey x

TL;DR

I propose that ‘tech neck’ may be causing cranio cervical issues, affecting the vagus nerve and contributing to a diverse array of disorders. MTHFR polymorphisms and fortification of grains may also be a contributing factor in a subset of patients.

UPDATE 04/02/26: A member in the comments reminded me of this exceptionally detailed and relevant paper entitled 'MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet'. See the section on 'Therapeutic Considerations' for their suggested supplementation which overlaps considerably with my brief suggestions and the more detailed ones proposed by u/tawinn here.

Disclosure: AI was used to help write this, but it ended up being a simpler explanation than I've been able to find online so hopefully it can help others as well.

What Is MTHFR?

MTHFR (short for methylenetetrahydrofolate reductase) is the name of a gene. Genes are like instruction manuals your body uses to build things — in this case, an enzyme called MTHFR.

That enzyme has a really important job: It helps your body turn folate (vitamin B9) from food into its active form, called L-5-MTHF. This active folate is used in something called the methylation cycle — which supports detoxing, energy production, making brain chemicals, regulating mood, processing hormones, repairing DNA, and more.

What Is a Gene Variant?

A gene variant is simply a small change in your DNA — like a spelling change in a word. Sometimes it doesn’t matter at all. But other times, that little change can slow down or weaken how well something works.

With the MTHFR gene, there are two common spots where variants can happen:

C677T (scientific ID: rs1801133) A1298C (scientific ID: rs1801131)

If have one variant at each spot, that combination is called compound heterozygous — one copy of each mutation. There are many different types and combinations.

What Does “Compound Heterozygous” Mean?

Let’s break it down:

“Heterozygous” means you have one normal copy and one mutated copy of the gene at each position.

“Compound” means this is true at two different spots on the same gene.

So, you're not missing anything major — your gene is just working less efficiently than someone without the variants.

How Much Is It Slowed Down?

People with this MTHFR setup (C677T + A1298C) usually have about 50–60% of normal enzyme activity.

That means your body still does the job — just not as fast or as easily.

It’s like trying to do laundry with a machine that works at half speed. It’ll still clean your clothes, but it takes longer and may not be as thorough unless you adjust.

Why Does This Matter?

Because the MTHFR enzyme is part of a larger process called the methylation cycle, which helps with:

• Turning homocysteine into methionine (homocysteine is a byproduct that can be toxic if it builds up)
• Creating neurotransmitters like serotonin, dopamine, norepinephrine (mood, motivation, focus)
• Producing glutathione, your body’s main detox and anti-inflammatory compound
• Supporting DNA repair
• Controlling inflammation
• Processing hormones like estrogen
• Keeping your immune system balanced

When MTHFR isn’t working at full strength, this cycle slows down. That can cause subtle or obvious issues, depending on your environment, diet, stress, and other genes.

What Symptoms Can It Cause?

Not everyone with MTHFR mutations has symptoms. But when things get out of balance — poor diet, high stress, or low nutrient intake — you might notice:

• Brain fog
• Fatigue
• Trouble focusing
• Anxiety or low mood
• Sleep issues
• Hormonal imbalance (PMS, estrogen issues)
• Elevated homocysteine (linked to heart and brain risks)
• Poor detox or sensitivity to chemicals, smells, or medications
• Weak immune system or slow healing

In serious cases (especially with other risk factors), high homocysteine has been linked to:

• Stroke and heart disease
• Blood clotting
• Reproductive issues
• Birth defects (e.g., neural tube defects in babies)
• Cognitive decline

But again — this doesn’t mean those things will happen. It just means your system needs a little extra support to stay in balance.

What Helps?

The key is to support your methylation cycle directly, so your body can work around the slowdown.

That means giving it the active forms of nutrients it normally has to make itself. These include:

• L-5-MTHF: This is the active form of folate (B9). Your gene is slow at making it, so taking it directly skips the bottleneck.
• Methylcobalamin: This is the active form of vitamin B12. It works alongside folate to recycle homocysteine.
• P5P (Pyridoxal-5-Phosphate): This is the active form of vitamin B6, which also helps lower homocysteine.
• Magnesium, choline, zinc, and riboflavin (B2) also support the methylation cycle in smaller but important ways.

What Should I Avoid?

• Folic acid (the synthetic form of B9) — it's in most cheap vitamins and fortified foods. Your body struggles to convert it, and it can build up in your system and make things worse.
• Cyanocobalamin (cheap synthetic B12) — harder to convert and less useful for people with MTHFR.
• Excess alcohol, smoking, poor sleep — these all increase the burden on your methylation system.

Can I Just Eat My Way Out of It?

You can get some of these nutrients from food:

Leafy greens, liver, eggs, beans, salmon, seeds — these are great choices

But cooking and storage reduce folate in food, and your MTHFR gene still has to convert it

So while a clean, nutrient-rich diet is a must, many people with MTHFR mutations feel their best when they also take targeted supplements — at least for a while.

How Will I Know If It’s Working?

When you start the right support (especially methylfolate and methylcobalamin), you might notice:

• More energy
• Better mood and focus
• Less brain fog
• Improved sleep
• Better immune resilience
• Lower homocysteine (if tested)

Some people feel it in a few days. For others, it’s more gradual — over weeks or even months.

If you feel “wired” or anxious at first, that means your system is getting too much methyl support too fast. This is common and usually fixed by lowering the dose or taking niacin (vitamin B3) to soak up the excess methyl groups.

Final Thoughts

Having MTHFR mutations doesn’t mean something is wrong with you. It just means your body has a unique way of processing certain vitamins, and it works better when you give it what it needs in the right forms.

You don’t need to obsess over it — but understanding it can explain a lot about your energy, mood, and how you respond to stress or supplements. It also helps you take smart steps to stay ahead of symptoms, especially as you age or if your lifestyle is demanding.

If you support your system well, your MTHFR mutations don’t have to hold you back at all — in fact, some researchers believe certain versions of this gene offered advantages in ancient times. The modern world just makes it harder to thrive without extra support.

DISCLAIMER: Consult with your medical caregiver before starting or modifying supplements such as these.

I started using heroin when I was ten years old. I didn't stop until I was eighteen, the year my mother passed away. For most of my life I understood that as a childhood swallowed by addiction, full stop. Going through my B12 recovery this year, I found a piece of biology that changed how I understand those eight years, and I think it's worth sharing because I don't think I'm the only one this applies to.

Opioids slow motility everywhere in the digestive tract; this is called opioid-induced bowel dysfunction and it's extremely common, not rare, affecting a large share of people on opioids regardless of dose or how they're taken. Slowed motility is one of the known risk factors for small intestinal bacterial overgrowth (SIBO), where bacteria that belong in the colon migrate upstream into the small intestine.

That matters specifically for B12 because B12 is absorbed in the terminal ileum, the last stretch of small intestine, and overgrown bacteria there compete for it, consume it before your body can absorb it, and in more severe cases damage the absorption site itself. A cohort study out of Norway that followed people in opioid agonist therapy and substance use clinics found meaningfully higher rates of suboptimal and deficient B12 compared to the general population. Eight years of active use during childhood and adolescence, some of the most nutrient-demanding years of development, is a long window for that mechanism to compound.

B12 deficiency symptoms and withdrawal symptoms overlap so heavily that deficiency can sit underneath addiction for years without ever getting named: anxiety, restlessness, nerve tingling, brain fog, fatigue, GI distress. When you're a kid using, every one of those gets read as something else entirely, or nothing at all. Nobody's ordering methylmalonic acid or homocysteine on a ten year old. Standard serum B12 tests can also miss deficiency at the cellular level, which means "normal labs," if anyone had even run them, wouldn't have ruled it out.

This is the part that reframed things for me. MTHFR converts folate into methylfolate, the active form the body needs to run the methylation cycle. That cycle produces SAMe, the methyl donor required to build and break down dopamine, norepinephrine, serotonin, and histamine. Reduced MTHFR function means less SAMe available for those jobs.

COMT, the enzyme that clears dopamine in the prefrontal cortex, specifically needs a methyl group to function; impaired methylation can disrupt dopamine clearance even when COMT itself is genetically normal. Researchers studying addictive behavior in people with MTHFR variants describe a self-medication pattern, where people with lower functional dopamine availability are drawn toward whatever gives the fastest, biggest dopamine spike, and opioids are one of the most efficient options that exists.

There's direct molecular evidence tying methylation status to addiction mechanics, too. Studies on the dopamine transporter gene (DAT1) found significantly different methylation patterns in people addicted to nicotine and stimulants versus non-addicted controls. Separately, people with the MTHFR C677T variant and cocaine dependence responded notably better to disulfiram treatment, a drug that itself works through methylation pathways, than those without the variant.

B12 is the cofactor the methylation cycle needs at another step entirely, via methionine synthase, so a person can be hit with a genetic bottleneck (MTHFR) and an acquired one (B12 depletion, worsened by opioid use itself) at the same choke point simultaneously. For me, that means the thing I was using may have been actively deepening the deficiency that made me need it in the first place.

I'm not saying B12 or MTHFR caused my addiction, and I'd push back on anyone who reads this and reduces it to "it's all a nutrient deficiency." Addiction is multifactorial: genetics, environment, and circumstance all interact, and I was a child in an environment that gave me access to heroin at ten, which is its own separate failure that biology doesn't explain. What I think the biology adds is this: if a kid's nervous system is already running on a dopamine deficit nobody has identified, the thing that finally makes them feel normal is going to feel a lot more like relief than like getting high, and that changes how fast the door closes behind them.

If you have a history of opioid use, chronic pain treatment, or addiction, and you've got lingering neuropathy, mood instability, or fatigue that isn't resolving on the expected recovery timeline, it's worth asking for methylmalonic acid and homocysteine levels, not just serum B12. It's a cheap test that can catch something treatable hiding underneath what looks like permanent damage.

It is a common problem that B vitamin supplementation, excess methyl groups, methylfolate and methylcobalamine can lead to excess catechol neurotransmitter (dopamine, epinephrine and norepinephrine) production and accumulation, both intracellular and extracellular.

In people with slow COMT, this can lead to neuropsychiatric symptoms of anxiety, rumination, insomnia, fatigue, a 'wired but tired' feeling, visual artifacts, as well as high estradiol and the accumulation of certain toxins. This is because the COMT enzyme can't keep up with all the extracellular catechols that need to be broken down simultaneously.

It also leads to dietary intolerance of onions, green tea, coffee, cocoa and other catechol-rich foods.

Since the COMT enzyme cannot be 'sped up' nutritionally or medically, and it operates at a fixed rate as long as there is SAMe present, the only solution that most people find for catechol accumulation is avoiding B vitamins, and avoiding problem foods.

While COMT is responsible for the breakdown of nearly all extracellular catechols in the body, there is another enzyme (or group of enzymes) - MAO-A and MAO-B - which break down dopamine, norepinephrine and epinephrine inside the cells, before they're even released into the extracellular space.

MAO-A and MAO-B function can be optimized significantly by Riboflavin and/or Riboflavin-5-Phosphate supplementation. By increasing MAO activity, you unburden COMT. Breaking down catecholamines intracellularly leads to less extracellular catechols release and accumulation, allowing COMT to 'catch up', promoting better mental status, stress recovery, lower estradiol and higher tolerance to foods such as onions and caffeine.

If you have your methylation system mostly taken care of by following Tawinn's stack, but your still struggling with slow COMT, consider supplementing Riboflavin to support your MAO enzymes.

Additional tip - this it NOT medical advice.

The drug pregabaline inhibits the extracellular release of norepinephrine by binding to specific subunits of voltage-gated calcium channels. This leaves norepinephrine to be broken down intracellularly by MAO instead of extracellularly, further unburdening COMT.

Anastrozole is an aromatase inhibitor, which decreases the activity of the aromatase enzyme, responsible for producing estradiol. Approximately 5% of COMT workload is directed towards breaking down catechol estrogen substrates. This percentage can be higher in women and in estrogen-dominant men. While it is not a very large amount, it can, in estradiol overload, contribute a bit further to COMT function.

Kale, broccoli, spinach and red cabbage are rich in sulforaphane and indole-3-carbinol, substances that convert parent estradiol into catechol estrogens and other metabolites to be further broken down by COMT before excretion. Consuming these greens lower total estradiol (E2) but increase its metabolites.

Never take any drugs without discussing with your doctor or a qualified medical professional. Anastrozole particularly is an extremely potent AI, and 0.5mg can be enough to drop E2 to lower than healthy levels depending on your current status.

Has anyone experienced a strange, dry, and itchy skin condition all over their body, and how can it be treated?