Methylation & MTHFR Support Protocol

One Billion Times Per Second

Right now, inside your body, a single carbon atom bonded to three hydrogens — a methyl group (CH3) — is being transferred from one molecule to another. This happens roughly one billion times per second. Methylation is the most ubiquitous biochemical reaction in human physiology, and most people have never heard of it.

What methylation does:

• Epigenetics: turns genes on and off. DNA methylation silences gene expression. This is how identical twins with the same genome can develop different diseases — their methylation patterns diverge over a lifetime based on diet, toxins, stress, and lifestyle.
• Neurotransmitter production: synthesizes serotonin, dopamine, norepinephrine, epinephrine, and melatonin. If you cannot methylate, you cannot make the molecules that govern mood, motivation, focus, and sleep.
• Detoxification: Phase II liver conjugation. Methylation neutralizes toxins, medications, hormones, and heavy metals for excretion. Poor methylation means poor detox — a backed-up garbage truck.
• Histamine clearance: histamine is degraded by histamine N-methyltransferase (HNMT). Undermethylators often have histamine intolerance — hives, headaches, runny nose, anxiety, insomnia.
• Estrogen metabolism: catechol-O-methyltransferase (COMT) methylates estrogen metabolites. Poor methylation of 4-OH estrone (the “dangerous” metabolite) is linked to estrogen-dependent cancers.
• Myelin production: the insulating sheath around nerves requires SAMe-dependent methylation. MS and peripheral neuropathy connect here.
• CoQ10 and creatine synthesis: both require methylation. These are not just supplement ingredients — they are endogenously produced molecules that depend on a functioning methyl cycle.
• Immune function: T-cell differentiation, antibody production, and viral defense all require adequate methylation.

The Methylation Cycle — A Brief Map

The methylation cycle is an interconnected web of biochemical pathways. Here is the simplified version:

1. Folate (B9) enters the cell and is converted through several steps to 5-MTHF (methylfolate) by the enzyme MTHFR.
2. Methylfolate donates its methyl group to homocysteine (via the enzyme MTR, which requires B12), converting it to methionine.
3. Methionine is activated by ATP to become SAMe (S-adenosylmethionine) — the body’s universal methyl donor.
4. SAMe donates its methyl group to DNA, neurotransmitters, hormones, toxins, and hundreds of other substrates.
5. After donating its methyl group, SAMe becomes SAH (S-adenosylhomocysteine), then converts back to homocysteine, completing the cycle.

When this cycle runs smoothly, methylation proceeds at its billion-per-second pace. When it stalls — due to genetic variants, nutrient deficiencies, or toxic burden — the downstream effects ripple across every system.

Key Genes and SNPs

MTHFR — The Gatekeeper

MTHFR (methylenetetrahydrofolate reductase) converts folate to its active form, 5-MTHF (methylfolate). This is the rate-limiting step.

• C677T variant: 30-40% of the general population carries at least one copy. Heterozygous (one copy) = approximately 35% reduced enzyme activity. Homozygous (two copies, T/T) = up to 70% reduced enzyme activity. More prevalent in Mediterranean, Hispanic, and East Asian populations.
• A1298C variant: affects BH4 (tetrahydrobiopterin) recycling rather than folate metabolism directly. BH4 is required for the synthesis of serotonin, dopamine, and nitric oxide. Compound heterozygous (one C677T + one A1298C) can be clinically significant.

MTHFR is the most well-known methylation gene, but it is not the only player.

COMT — The Speed Controller

COMT (catechol-O-methyltransferase) metabolizes catechols: dopamine, norepinephrine, epinephrine, and catechol estrogens.

• Val158Met (rs4680): Val/Val = “fast COMT” — rapid catechol clearance. These individuals tend to be calm under pressure but may have lower baseline dopamine (need stimulation, may benefit from coffee and green tea). Met/Met = “slow COMT” — sluggish catechol clearance. Higher baseline dopamine and estrogen levels. These individuals tend to be more creative and detail-oriented but also more prone to anxiety, insomnia, pain sensitivity, and estrogen dominance. They do poorly with excess methyl donors, caffeine, and catechol-rich supplements (quercetin, green tea extract).

Other Key Genes

• MTR/MTRR: Methionine synthase and its reductase. B12-dependent enzymes that convert homocysteine back to methionine. SNPs here increase B12 requirements.
• CBS (cystathionine beta-synthase): Upregulations (gain-of-function) push the transsulfuration pathway, rapidly clearing homocysteine but generating excess sulfur metabolites (sulfite, taurine, ammonia). These individuals may be sensitive to sulfur-containing supplements (NAC, MSM, alpha-lipoic acid, garlic) and high-sulfur foods (cruciferous vegetables, eggs, onions). Homocysteine may appear falsely normal or low.
• AHCY: converts SAH to homocysteine. SNPs here cause SAH to accumulate, which inhibits all methyltransferases — a global methylation brake.
• MAT: converts methionine to SAMe. SNPs reduce SAMe production even when methionine is adequate.
• BHMT: an alternative pathway that converts homocysteine to methionine using TMG (betaine) instead of methylfolate/B12. A backup route that can be upregulated therapeutically.

Testing

Blood Markers

• Homocysteine: The single most important functional marker of methylation status. Optimal: 6-8 μmol/L. Standard lab range goes up to 15, but cardiovascular and neurological risk begins rising above 8. Elevated homocysteine = undermethylation, B12 deficiency, folate deficiency, or B6 deficiency. Note: CBS upregulations can push homocysteine falsely low.
• Methylmalonic acid (MMA): The functional marker of B12 status. Elevated MMA means B12 is deficient at the cellular level, even if serum B12 appears normal. More sensitive than serum B12 alone.
• Folate — serum and RBC: Serum folate reflects recent intake. RBC folate reflects tissue stores over 3-4 months — a better long-term marker. Optimal RBC folate: >800 ng/mL.
• B12 (serum): Optimal >600 pg/mL (the standard lower limit of 200 pg/mL allows significant functional deficiency). Japanese and European guidelines set the lower limit at 500-550.
• Histamine (whole blood): Undermethylators often have elevated whole blood histamine (>70 ng/mL). The Walsh Research Institute uses histamine as a methylation proxy. High histamine + high homocysteine = classic undermethylation pattern.

Genetic Testing

• 23andMe raw data → upload to interpretation platforms: Genetic Genie (free, basic), StrateGene (Dr. Ben Lynch, detailed pathway mapping), Opus23 (practitioner-level, Dr. Peter D’Adamo)
• Focus on: MTHFR, COMT, MTR, MTRR, CBS, AHCY, MAT, BHMT, VDR, MAOA, MAOB, GAD, DAO

Hormone Methylation

• DUTCH test (Dried Urine Test for Comprehensive Hormones): Shows estrogen metabolism pathways (2-OH, 4-OH, 16-OH estrogens) AND their methylation status. The 4-OH pathway produces genotoxic metabolites; methylation converts them to the safer 4-MeO-E1. If 4-OH is elevated and 4-MeO is low, methylation of estrogen is impaired — a cancer risk factor.

Protocol for MTHFR and Undermethylation

Start Low, Go Slow

The cardinal rule of methylation support. Flooding the cycle with methyl donors when it has been stalled can cause a surge of neurotransmitter production, detox mobilization, and gene expression changes — experienced as anxiety, insomnia, irritability, headaches, or worsening of existing symptoms.

Core Supplements

• Methylfolate (5-MTHF / L-methylfolate): Start at 100-400mcg — not milligrams. Increase by 100mcg every 1-2 weeks based on tolerance. Therapeutic range: 1-5mg for most individuals with MTHFR variants. Some require up to 15mg (under supervision). This bypasses the MTHFR enzyme entirely — you are providing the already-converted end product. Quality brands: Thorne (5-MTHF), Seeking Health (L-methylfolate), Pure Encapsulations. Avoid folic acid (the synthetic form) — it competes with natural folate for receptors and is poorly converted in MTHFR variants, potentially accumulating as unmetabolized folic acid (UMFA) which may inhibit natural folate metabolism.
• Methyl-B12 (methylcobalamin): 1000-5000mcg sublingual daily. Sublingual bypasses GI absorption issues. Methylcobalamin is the active coenzyme form that directly participates in the MTR reaction. Adenosylcobalamin is the mitochondrial form — some practitioners use both.
• B6 as P5P (pyridoxal-5-phosphate): 25-50mg/day. The active form of B6, required by over 150 enzymatic reactions including transsulfuration (CBS pathway), neurotransmitter synthesis (serotonin, GABA, dopamine), and histamine degradation. P5P form bypasses the liver conversion step needed for pyridoxine.
• B2 (riboflavin): 25-50mg/day. The MTHFR enzyme itself requires riboflavin (as FAD) to function. B2 supplementation has been shown to lower homocysteine in MTHFR C677T carriers independent of folate status. An underappreciated cofactor.
• TMG (trimethylglycine / betaine): 500-1500mg/day. Feeds the BHMT pathway — an alternative route to convert homocysteine to methionine that does not require methylfolate or B12. A useful backup, especially when methylfolate is not tolerated. Found naturally in beets (hence “betaine”).
• SAMe (S-adenosylmethionine): 200-400mg/day on an empty stomach. The direct methyl donor. Use when methylfolate is not tolerated or when a more immediate methylation boost is needed. Well-studied for depression (comparable to SSRIs in several trials), liver support, and joint health. Enteric-coated, away from food. Can cause mania in bipolar individuals — use with caution.
• Cofactors: Magnesium (400mg glycinate), Zinc (15-30mg with copper balance) — both are essential cofactors for multiple methylation cycle enzymes.

Overmethylation — When You Push Too Hard

Too much methylfolate, methyl-B12, or SAMe can overshoot the target. Signs of overmethylation:

• Anxiety, restlessness, racing thoughts
• Insomnia (especially difficulty falling asleep)
• Irritability, agitation
• Headaches
• Muscle tension, jaw clenching
• Heart palpitations

Immediate intervention: Niacin (vitamin B3, nicotinic acid) 50-100mg. Niacin is a methyl buffer — it requires a methyl group for its own metabolism, effectively soaking up excess methyl groups. The “niacin flush” (vasodilation, warmth, redness) is harmless and subsides in 15-30 minutes. Niacinamide works as a methyl buffer too but does not cause the flush.

Adjustment: Reduce methylfolate dose. Switch from methylcobalamin to hydroxocobalamin (a non-methylated B12 form that gently supports B12 status without adding methyl groups). Reassess in 1-2 weeks.

Slow COMT Considerations

Individuals with Met/Met COMT (slow clearance of catechols) need special consideration:

• Avoid excess methyl donors: Slow COMT means dopamine and norepinephrine already accumulate. Flooding the system with methyl groups increases catecholamine production further — driving anxiety and insomnia.
• Limit catechol-containing foods and supplements: Coffee (catechol), green tea extract (EGCG is a catechol), quercetin (catechol structure). These are healthy for most people but problematic for slow COMT.
• Support COMT function: Magnesium (COMT’s essential cofactor), SAMe with caution (feeds COMT but also produces more methyl donors — it is a double-edged sword).
• Exercise: moderate exercise helps clear catecholamines through MAO and physical metabolism. Intense exercise can spike catecholamines beyond COMT’s clearance capacity.
• Estrogen dominance: Slow COMT means slow estrogen clearance. These individuals benefit from DIM (diindolylmethane), calcium-D-glucarate, and fiber for estrogen metabolism support.

Lifestyle Foundations

Supplements tune the methylation engine. Lifestyle provides the raw materials and the terrain:

• Leafy greens: Spinach, kale, collards, romaine, arugula — rich in natural folate (the word “folate” derives from “folium,” Latin for leaf). Two cups of dark leafy greens daily provides 200-400mcg of natural food folate.
• Reduce alcohol: Alcohol depletes B vitamins across the board — B1, B6, folate, B12. Even moderate drinking impairs methylation. The liver prioritizes alcohol detoxification over methylation.
• Manage stress: Stress burns through methyl groups at an accelerated rate. Cortisol and catecholamine production require methylation. Chronic stress is a methylation drain. Meditation, breathwork, adequate sleep, and nature exposure are not luxuries — they are methylation preservation strategies.
• Avoid folic acid fortification: Since 1998, the US has mandated folic acid fortification of grains. For MTHFR variants, this synthetic folate may do more harm than good. Read labels. Choose products without added folic acid. Seek methylfolate-containing supplements and prenatal vitamins.

The Clinical Pattern

When you see a patient with depression plus anxiety plus histamine intolerance plus estrogen dominance plus chemical sensitivity plus fatigue — and nothing in conventional medicine connects these dots — think methylation.

One cycle. One billion reactions per second. When it falters, the ripple effects cross every system: neurological, hormonal, immunological, detoxification, cardiovascular. The beauty is that supporting methylation is biochemically straightforward — the right forms of B vitamins, the right cofactors, the right dose titration, and respect for individual genetics.

Start low. Go slow. Listen to the body’s response. The methylation cycle has been running since before you were born — it knows what it needs. Your job is to remove the obstacles and provide the raw materials.