What is Trimethylglycine?
Trimethylglycine, also known as betaine or betaine anhydrous, is a naturally occurring amino acid derivative that serves as a methyl donor in the remethylation of homocysteine to methionine, and also functions as an osmolyte and metabolite of choline. 1
Chemical and Biological Properties
Trimethylglycine (betaine) is chemically designated as N,N,N-trimethylglycine with a molecular weight of 117.15 1. It appears as a white to off-white, crystalline, hygroscopic powder 1. This compound occurs naturally in the body as a metabolite of choline and is present in small amounts in foods such as beets, spinach, cereals, and seafood 1.
Primary Functions
As a Methyl Donor
The primary therapeutic mechanism of betaine involves acting as a methyl group donor in the remethylation of homocysteine to methionine 1. This function is particularly critical in patients with homocystinuria, where betaine helps lower plasma homocysteine concentrations 1.
As an Osmoregulator
Choline is oxidized to betaine, which serves as an osmoregulator and substrate in the betaine-homocysteine methyltransferase reaction 2. This links betaine together with vitamin B12 to folate-dependent one-carbon metabolism 2.
Additional Metabolic Roles
Betaine has been demonstrated to increase low plasma methionine and S-adenosylmethionine (SAM) concentrations in patients with specific metabolic deficiencies 1. It also possesses anti-inflammatory and antioxidant properties, as demonstrated in animal and in vitro experiments 2.
Clinical Applications
FDA-Approved Use
Betaine anhydrous is FDA-approved for treating homocystinuria in both pediatric and adult patients to decrease elevated homocysteine blood concentrations 1. This includes three specific conditions:
- Cystathionine beta-synthase (CBS) deficiency
- 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
- Cobalamin cofactor metabolism (cbl) defect 1
Dosing
For adults and children ≥3 years: 6 grams per day in divided doses of 3 grams twice daily 1. For children <3 years: starting at 100 mg/kg/day in divided doses, increased weekly by 50 mg/kg increments 1.
Important Safety Considerations
Potential Toxicity
A critical concern with betaine administration is the risk of hypermethioninemia, particularly in patients with CBS deficiency 1. Severe cerebral edema and hypermethioninemia have been reported within 2 weeks to 6 months of starting therapy, with plasma methionine concentrations ranging from 1,000 to 3,000 micromol/L 1. Plasma methionine concentrations must be monitored and kept below 1,000 micromol/L through dietary modification and, if necessary, dose reduction 1.
TMAO Concerns
A concern with enteral administration of betaine (along with L-carnitine and choline) is conversion by gut microflora into trimethylamine-N-oxide (TMAO), a uremic toxin with potential negative long-term cardiovascular health impacts 2. However, one RCT in chronic kidney disease patients showed no increase in plasma TMAO levels with probiotic supplementation while betaine levels increased 2.
Common Adverse Effects
Other adverse reactions include nausea, gastrointestinal distress, anorexia, agitation, depression, irritability, diarrhea, vomiting, and a "fishy" body odor 1.
Relationship to Choline Metabolism
Betaine is intrinsically linked to choline metabolism, as choline is oxidized to betaine in the body 2. This connection is clinically relevant because choline deficiency can manifest as liver steatosis or muscle damage, conditions where betaine status may also be compromised 2.