Methylation, Detoxification & Depression: The Hidden Biochemical Block

Deep inside every cell in your body, a process called methylation is happening right now. Methylation is the addition of a small chemical group (a methyl group) to DNA, proteins, and other molecules. It's one of the most fundamental biochemical processes in your body—so fundamental that it controls whether genes are turned "on" or "off."

When your methylation is working properly, you're clearing stress chemicals, hormones, and toxins efficiently. Your brain chemistry stays balanced. Your mood is stable.But when methylation becomes dysregulated—when you have too much or too little methylation happening—you accumulate stress chemicals in your bloodstream, your neurotransmitters don't get cleared properly, your oestrogen backs up, and you feel anxious, depressed, and wired but exhausted.

This is one of the most overlooked drivers of depression in midlife women, and it requires functional lab testing to identify. Most doctors have never heard of it.

The Two-Problem Scenario: Over-Methylation vs. Under-Methylation

Methylation dysregulation comes in two opposite forms, and both can cause depression:

Under-Methylation ("Overmethylator" Problem)

When you under-methylate, you don't have enough methyl donors being produced, so:

• You can't effectively break down adrenaline, norepinephrine, and dopamine

• These stress neurotransmitters accumulate in your bloodstream

• You feel wired, anxious, and unable to calm down

• You can't clear Oestrogen effectively, so it backs up

• You accumulate toxins and heavy metals

• You can't produce adequate serotonin (methylation is part of serotonin synthesis)

The result: you feel simultaneously anxious and depressed, wired but tired, with racing thoughts and lack of motivation.

Over-Methylation ("Undermethylator" Problem)

When you over-methylate:

• You have excessive methyl donors being produced

• This dysregulates neurotransmitters in a different way

• You may have depleted B12, folate, and choline

• You can't properly regulate dopamine and serotonin

• You feel depressed, unmotivated, and scattered

The result: you feel depressed, unmotivated, and unable to focus.

The key point: Both scenarios cause depression, but the interventions are opposite. If you take the wrong approach, you feel worse.

How Methylation Creates Stress Chemical Accumulation

Here's the mechanism that causes depression:

The Oestrogen & Stress Neurotransmitter Connection

Your liver has an enzyme called catechol-O-methyltransferase (COMT). This enzyme's job is to break down stress neurotransmitters (adrenaline, norepinephrine, dopamine) so they don't accumulate and poison your mood.

COMT requires methylation to work.

When you have impaired methylation, COMT can't function properly. So:

• Adrenaline and norepinephrine accumulate → you feel anxious, panic-prone, wired

• Dopamine accumulates → you feel overstimulated initially, then burnt out as your dopamine receptors down-regulate

• These excess catecholamines cause neuroinflammation → depression

Additionally, your Oestrogen can't be properly broken down and excreted. Excess Oestrogen backs up, which:

• Further dysregulates neurotransmitters

• Increases inflammation

• Worsens mood dysregulation

This is why many women with methylation issues feel anxious, panicky, depressed, and say they feel "off" or chemically dysregulated.

The Detoxification Bottleneck

Your liver has two main detoxification phases:

• Phase 1: Breaks down toxins into intermediate forms (requires various enzymes)

• Phase 2: Adds water-soluble groups to make toxins excretable through urine/stool (requires methylation)

When methylation is dysregulated, Phase 2 backs up. Toxins and hormones that should be excreted accumulate. This toxic load creates neuroinflammation, which is a primary driver of depression.

This is particularly relevant for midlife women because:

• We've accumulated toxins over decades

• Our detoxification capacity naturally declines with age

• Hormone dysregulation during perimenopause further impairs detoxification

• We often take more supplements and medications, adding to the detoxification burden

 Why Midlife Women Become Dysregulated in Methylation

Nutrient Depletion

Methylation requires several B vitamins and nutrients as cofactors:

• B12 (cobalamin): Critical for methylation; many midlife women are deficient

• Folate (not folic acid): Essential for methylation; folic acid can actually worsen methylation if you have genetic variants

• Choline: Needed for methylation; often deficient

• Betaine: Methylation cofactor; deficient in many

• Magnesium: Cofactor for multiple methylation enzymes; many women are deficient

Many midlife women are depleted in multiple methylation cofactors due to:

• Years of restrictive dieting

• Stress-induced nutrient depletion

• Poor nutrient absorption from gut dysbiosis

• Lack of nutrient-dense foods

Without these nutrients, methylation simply can't happen.

Genetic Variations (MTHFR, COMT, etc.)

You may carry genetic variants that affect methylation:

• MTHFR variants: Affect folate metabolism and methylation capacity

• COMT variants: Affect how quickly you break down stress chemicals

• MAO variants: Affect dopamine and serotonin breakdown

These variants don't determine your fate, but they do mean your body requires more nutritional support to optimize methylation.

Oestrogen Dominance & Perimenopause

As oestrogen fluctuates during perimenopause, the burden on methylation increases. Your body has to clear more oestrogen. If methylation is already compromised, oestrogen backs up, creating a vicious cycle. Read more in our blog post: Progesterone & Oestrogen Imbalance: The Hormonal Depression Trap in Midlife Women

Chronic Stress

Stress hormone excess (see 'Cortisol Dysregulation and Depression: How Chronic Stress Rewires Your Brain') depletes B vitamins and methylation cofactors. Additionally, the metabolic demand of chronic stress dysregulates methylation itself.

Gut Dysbiosis

Your gut bacteria help produce B12, folate, and choline. When your microbiome is dysbiotic, you can't produce or absorb adequate methylation cofactors, even if you're eating them. You may also want to read more in The Gut-Brain Depression Axis: How Dysbiosis Inflames Your Brain

How to Recognize Methylation Dysregulation

Signs of under-methylation (impaired clearing of stress chemicals):

• Anxiety or panic attacks

• Feeling "wired" or "overstimulated"

• Racing thoughts, difficulty sleeping

• Sensitivity to stimulants (caffeine, medications)

• Perfectionism and obsessive thinking patterns

• Irritability and rage

• Difficulty relaxing

• Depression mixed with anxiety

• Feeling chemically dysregulated

Signs of over-methylation (excessive methylation consuming resources):

• Depressed mood

• Lack of motivation or drive

• Scattered thinking, difficulty focusing

• Fatigue despite adequate sleep

• Feeling emotionally flat

• Difficulty with ambition or goal-setting

• Low dopamine symptoms

Both can show:

• Depression

• Hormone dysregulation

• Difficulty clearing medications

• Sensitivity to supplements

• Accumulation of toxins (heavy metals, mold)

• Chronic health issues that don't respond to treatment

The Bottom Line

Your depression may not be a serotonin problem. It may be a methylation problem—your body can't properly clear stress chemicals, toxins, and excess hormones. As a result, neuroinflammation and neurotransmitter imbalance create depression.

The good news? Methylation is highly responsive to nutritional support. By providing your body with the nutrients it needs to methylate effectively, and reducing the toxin burden, you allow your brain chemistry to rebalance.

The key is knowing whether you're under- or over-methylating, and personalizing your approach accordingly.

If you’d like to understand more about your methylation type and how your genetics may be influencing your depression, book a call today so we can explore this in a personalised, evidence-informed way.

Book call today to find out more

Next up: We explore neuroinflammation and the gut-brain connection—how your gut dysbiosis is literally inflaming your brain.

Reference Research:

- Functional Medicine Research Foundation - MTHFR and methylation

- NCBI/PMC - "Methylation and Mental Health"

- Lynch, B. & Pedre, C. "Dirty Genes" (comprehensive methylation reference)

- Journal of Psychiatric Research - COMT gene variants and depression

- American Journal of Clinical Nutrition - folate, methylation, and mood