TMG (Trimethylglycine)
TMG is a methyl donor derived from beets that lowers homocysteine via the BHMT pathway and replenishes the methyl groups consumed during NMN/NR metabolism. A foundational co-supplement in any NAD+ longevity stack.
What Is TMG?
Trimethylglycine (TMG), also known as betaine anhydrous, is a naturally occurring compound found in high concentrations in sugar beets, spinach, quinoa, and wheat germ. Structurally, it is the amino acid glycine with three methyl groups (–CH₃) attached to its nitrogen atom. These methyl groups are the functional currency of TMG — they are donated to biochemical reactions that regulate gene expression, detoxification, neurotransmitter synthesis, and cardiovascular health.
TMG was originally isolated from sugar beets (Beta vulgaris), which is why it carries the name "betaine." It should not be confused with betaine HCl (betaine hydrochloride), which is used as a digestive acid supplement and does not provide methylation support.
Mechanism — How TMG Works
TMG's primary biochemical role is as a methyl donor in the BHMT (betaine-homocysteine methyltransferase) pathway. This reaction occurs primarily in the liver and kidneys:
- Homocysteine + TMG → Methionine + DMG: TMG donates one of its three methyl groups to homocysteine, converting it back to methionine. The byproduct is dimethylglycine (DMG).
- Methionine → SAMe: Methionine is then converted to S-adenosylmethionine (SAMe), the body's universal methyl donor used in over 200 methylation reactions.
- SAMe → SAH → Homocysteine: After SAMe donates its methyl group, it becomes S-adenosylhomocysteine (SAH), which is hydrolysed back to homocysteine — completing the cycle.
This BHMT pathway is independent of the folate/B12 pathway (which uses methyltetrahydrofolate and methylcobalamin to remethylate homocysteine via the MTR enzyme). TMG provides a parallel route for homocysteine clearance, which is why it is effective even when B12 and folate are adequate.
The NMN Methylation Drain — Why TMG Matters for NAD+ Stacks
This is the primary reason TMG has become standard in longevity protocols. The connection works as follows:
- NMN → NAD+ → Nicotinamide: When NAD+ is consumed by sirtuins, PARPs, and CD38, it releases nicotinamide (NAM) as a byproduct.
- Nicotinamide recycling: NAM is either recycled back to NMN via the salvage pathway (NAMPT enzyme) or methylated by NNMT (nicotinamide N-methyltransferase) to form methyl-nicotinamide for excretion.
- Methylation cost: The NNMT reaction consumes a methyl group from SAMe for every molecule of nicotinamide it processes. High-dose NMN supplementation increases NAD+ turnover, which increases nicotinamide production, which increases methylation demand.
- The drain: If methyl donors are insufficient, the increased methylation demand can deplete SAMe, reduce methylation capacity, and cause homocysteine to accumulate.
The NMN methylation drain is mechanistically sound and widely accepted in the longevity community, but direct human RCT evidence quantifying the exact degree of methyl depletion from NMN supplementation is limited. Some practitioners report elevated homocysteine in patients taking NMN without TMG. The precautionary approach — taking TMG alongside NMN — is low-risk and biochemically rational.
Evidence Quality
TMG's evidence base spans two distinct use cases:
| Use Case | Evidence Level | Key Data |
|---|---|---|
| Homocysteine reduction | Strong (multiple RCTs) | 1,500–6,000 mg/day reduces homocysteine 10–20% in hyperhomocysteinemia; effective as adjunct to folate/B12 |
| NMN methylation support | Moderate (mechanistic + clinical observation) | Biochemically sound; NNMT pathway well-characterised; clinical reports of homocysteine rise on NMN without TMG |
| Exercise performance | Mixed | Some studies show improved power output and body composition at 2,500 mg/day; others show no effect |
| Liver health (NAFLD) | Moderate | Betaine reduces hepatic fat accumulation in animal models; human data is limited but directionally positive |
Dosing & Practical Use
For NMN/NR stacking: 500–1,000 mg/day. This is the most common longevity use case. Take alongside your NMN or NR dose in the morning.
For homocysteine reduction: 1,500–3,000 mg/day, split into two doses. Higher doses (up to 6,000 mg) have been used in clinical settings for severe hyperhomocysteinemia.
For exercise performance: 2,500 mg/day, typically taken pre-workout.
Form: Betaine anhydrous powder or capsules. TMG powder has a mildly sweet taste and dissolves easily in water. Capsules are more convenient but may require multiple pills at higher doses.
Timing: Morning, with or without food. TMG is well-absorbed regardless of meal timing. No known interactions with common medications.
Side effects: Generally well-tolerated. High doses (>3,000 mg) may cause mild GI discomfort, fishy body odour (from trimethylamine production), or diarrhoea. Start low and titrate up.
Biomarker Connections
TMG directly influences several measurable biomarkers:
- Homocysteine: The primary target. Optimal range is <10 µmol/L. TMG lowers homocysteine via the BHMT pathway independent of B12/folate status. Test every 3–6 months when starting TMG or NMN.
- Vitamin B12: TMG does not replace B12 — both pathways (BHMT and MTR) work in parallel. Ensure B12 is adequate (>500 pg/mL) alongside TMG supplementation.
- Folate: Similarly, methylfolate (5-MTHF) drives the MTR pathway. TMG complements but does not substitute for adequate folate status.
- SAMe/SAH ratio: Not routinely tested but reflects methylation capacity. TMG supports SAMe production by recycling homocysteine to methionine.
The standard NAD+ methylation-support stack: NMN 500–1,000 mg + TMG 500–1,000 mg + Methylcobalamin (B12) + Methylfolate. This covers both the BHMT and MTR remethylation pathways, ensuring homocysteine stays controlled while NAD+ turnover is elevated.
Frequently Asked Questions
Why should I take TMG with NMN?
NMN metabolism increases methylation demand. When NAD+ is recycled, nicotinamide is methylated by NNMT for excretion — consuming SAMe-derived methyl groups. Without adequate methyl donors, homocysteine can rise. TMG donates methyl groups via the BHMT pathway, replenishing the methyl pool and keeping homocysteine in check. It is now considered standard practice in NAD+ longevity protocols.
What is the correct dose of TMG?
For NMN stacking: 500–1,000 mg/day. For homocysteine reduction: 1,500–3,000 mg/day. Clinical trials have used up to 6,000 mg/day safely. Start at 500 mg alongside your NMN dose and increase if homocysteine remains elevated on blood work. Most people do well at 1,000 mg/day.
Is TMG the same as betaine?
Yes. TMG (trimethylglycine) is the chemical name for betaine anhydrous — the same molecule. However, betaine HCl (betaine hydrochloride) is a different product used for stomach acid support and does not provide methylation benefits. When purchasing for methylation or NMN stacking, look for "betaine anhydrous" or "TMG" on the label.
Can TMG lower homocysteine without B12 and folate?
TMG lowers homocysteine via the BHMT pathway, which is independent of B12 and folate. Clinical trials show 10–20% homocysteine reduction with TMG alone. However, the body uses both pathways (BHMT and MTR) for optimal homocysteine clearance. For best results, ensure adequate B12 (>500 pg/mL) and folate alongside TMG — covering both remethylation routes.
Further reading: TMG & homocysteine on PubMed →