Metabolic Dietary supplement

TMG (Trimethylglycine)

Trimethylglycine · Betaine Anhydrous

Evidence: Approved label. Example dose: finalize with a provider. Not a fact-check stamp.

500mg – 500-1000 mg Oral Daily

TMG (trimethylglycine, also called betaine or betaine anhydrous) is a naturally occurring methyl donor found in beets, spinach, quinoa, wheat bran, and shellfish. It serves as a key substrate in the methionine cycle, donating methyl groups via the BHMT (betaine-homocysteine methyltransferase) enzyme to recycle homocysteine back to methionine. TMG is one of the body's primary backup methyl donors when SAMe and folate-dependent methylation pathways are stressed.

Quick Start

Route

Oral

Start low

500mg Oral

Frequency

Daily

Timing

Anytime

Take with breakfast or lunch. Anhydrous powder or capsules both work. If using >2g/day, split into 2 doses (morning + lunch) to reduce GI effects. Pairs naturally with NR/NMN to support methyl donor pool.

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Start here. Every protocol below is ordered lowest-first. Begin at the smallest effective dose, hold about a week to assess tolerance, and step up only if needed.

Tiered Protocols · lowest first

Conservative start

500mg · Oral · Daily

conservative starter

500mg

Daily

Standard

Methylation & Homocysteine Control

500-1000 mg · Oral · Daily

human clinical trial · Olthof et al. 2003 (J Nutr); CYSTADANE (betaine anhydrous) FDA label; Hoffman et al. 2009 PMID 19250531

TWO DIFFERENT DOSE WORLDS, AND THEY MUST NOT BE CONFLATED. 6 g/day is a PRESCRIPTION dose (Cystadane) for homocystinuria, a rare inborn error of metabolism, and its label warns that betaine can raise plasma methionine further in CBS deficiency, with cerebral oedema reported. The supplement and performance dose studied is about 2.5 g/day, where the benefit was modest - a secondary-analysis increase in bench-press repetitions, with no effect on power or squat work. Our 500 mg sits below both. Also distinguish BETAINE ANHYDROUS (TMG, this compound) from BETAINE HCl, a stomach acidifier - different compounds, different purposes.

500-1000 mg

Daily

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How it works

TMG's primary mechanism is donation of methyl groups via BHMT (betaine-homocysteine methyltransferase), which transfers a methyl group from TMG to homocysteine, regenerating methionine and producing dimethylglycine (DMG) as a byproduct. This is one of two parallel pathways that recycle homocysteine (the other is folate/B12-dependent via methionine synthase). When the folate pathway is compromised (MTHFR variants, B12 deficiency), TMG provides an independent route to maintain methionine availability.

Methionine produced via this pathway is then converted to SAMe (S-adenosylmethionine), the universal methyl donor that participates in 200+ methylation reactions including DNA methylation, neurotransmitter synthesis (epinephrine from norepinephrine, melatonin from serotonin), phosphatidylcholine production, creatine biosynthesis, and detoxification of various xenobiotics. By supporting methionine recycling, TMG indirectly supports all SAMe-dependent processes.

TMG also functions as an osmolyte - it accumulates intracellularly during osmotic stress and protects cellular proteins and DNA from osmotic damage. This osmolyte function may underlie some of the ergogenic effects (cellular hydration during high-intensity exercise) and the liver-protective effects (hepatocytes use osmolytes during oxidative stress). Additionally, TMG has been shown to reduce hepatic fat accumulation in animal models of fatty liver disease and to modestly improve insulin sensitivity in some metabolic syndrome studies.

What to expect

Early

Days 1–7

Days 1-14: Subclinical methylation support. Some report subtle energy.

Evidence

HumanStrong

AnimalPresent

In-vitroPresent

Each reference below was re-fetched from its PubMed record, and the quoted sentence was confirmed to appear in that abstract and to support the claim it sits under. Follow any of them to read the source.

Exact-molecule evidence boundary: the live abstract reports the quoted finding for TMG (Trimethylglycine); no broader inference is made.

Betaine is distributed widely in animals, plants, and microorganisms, and rich dietary sources include seafood, especially marine invertebrates ( approximately 1%); wheat germ or bran ( approximately 1%); and spinach ( approximately 0.

Betaine in human nutrition. The American journal of clinical nutrition · 2004 · PMID 15321791

Evidence scope. Exact molecule wording appears in the quoted live sentence. Only the population/model, formulation, route, and outcome expressly stated there are supported.

Claims we could not support

No abstract we checked supports these for this molecule at this route. That is not the same as saying they are false — it marks where the evidence is missing.

Dose/route: 500mg; Oral; Daily. No selected live abstract sentence verified this complete regimen.

Mechanism as written in source JSON. No selected live abstract sentence verified the complete mechanism at the card formulation/route and relevant population/model.

Primary safety claim as written in source JSON. No selected live abstract sentence verified the complete safety claim for this exact formulation and route.

Interactions & stacking

Two different questions: what is documented about running these together, and what is documented about drawing them into the same syringe. A good pharmacological partner can still have to be pinned separately.

Documented together

CreatineCreatine biosynthesis consumes SAMe; TMG indirectly supports creatine production. Compatible stacking with no interactions.

SAMeDirect methyl donor SAMe supplementation is downstream of TMG's pathway. Compatible but somewhat redundant - some users alternate.

Nicotinamide Riboside (NR)NAD+ metabolism via NNMT consumes methyl donors; TMG replenishes them. Standard pairing for chronic NR users to prevent methylation depletion.

NMNSame as NR - NAD+ pathway methyl donor consumption is replenished by TMG.

Keep separate

High-dose Niacin (>500mg flush-niacin)Niacin methylation via NNMT can consume methyl donors heavily. TMG actually mitigates this rather than conflicting - but the COMBINATION is mostly redundant in healthy adults.

High LDL cholesterol patients (caution)TMG at >3g/day can elevate LDL cholesterol. Patients with cardiovascular risk and elevated LDL should monitor lipids when starting TMG, especially at therapeutic doses.

Check any specific pair in the Stack & Interaction Checker, which answers both questions separately. Absence of a documented conflict is not evidence of safety.

Pharmacokinetics

Illustrative plasma concentration · 58 h

Half-life

~14 hours

Peak · Tmax

~1-2 hours

Oral

Elimination

~36-48 hours

Bioavailability

High oral bioavailability (~90%) - well-absorbed in small intestine.

Duration of action

Methylation cycle support sustained with daily dosing; effects accumulate over weeks rather than acute hours. Skipping doses is fine for general support; pharmaceutical use requires consistent dosing.

Clearance

Primarily metabolized via BHMT in liver and kidney to dimethylglycine (DMG). DMG further metabolized to sarcosine then glycine. Renal excretion of unchanged TMG and metabolites.

Storage. Store at room temperature (20-25C) in a cool, dry place. Anhydrous powder is hygroscopic - keep tightly sealed and dry. Capsules and tablets shelf-stable for 2+ years. Powder may clump with moisture exposure but remains potent.

Regulatory status

Classified as a dietary supplement in the US (no FDA pre-approval). Pharmaceutical version (Cystadane) is FDA-approved for homocystinuria. EU permits TMG as a food supplement. Generally Recognized as Safe (GRAS) at typical supplement doses. Available widely over the counter.

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