In plain terms: TMG (Trimethylglycine / Betaine) shows early signals in human research but the evidence is limited -- small trials, surrogate endpoints, or not yet independently replicated. It is an emerging area, not yet a proven one.
TMG (Trimethylglycine / Betaine)
The evidence as the record states it
Olthof et al. (J Nutr, 2003; PMID 14652361): four parallel groups of 19 healthy adults, placebo or betaine 1.5, 3 or 6 g/day for 6 weeks; fasting homocysteine 12, 15 and 20 percent lower than placebo, with post-methionine rises also blunted. Steenge et al. (J Nutr, 2003; PMID 12730412): 6 g/day for 6 weeks in adults with mildly raised homocysteine, 1.8 micromol/L lower than placebo. Schwab et al. (Am J Clin Nutr, 2002; PMID 12399266): 42 obese adults on a reduced-energy diet, 6 g/day for 12 weeks; homocysteine fell against placebo, and total and LDL cholesterol were higher on betaine. Alfthan et al. (Br J Nutr, 2004; PMID 15522136): dose-response in 34 healthy adults; 1 g/day lowered homocysteine 1.1 percent (not significant), 3 and 6 g/day by 10 and 14 percent. Pooled: McRae (J Chiropr Med, 2013; PMID 23997720), 5 placebo-controlled trials at 4 g/day or more, homocysteine 1.23 micromol/L lower; Ashtary-Larky et al. (Crit Rev Food Sci Nutr, 2022; PMID 33764214), homocysteine 1.30 micromol/L lower, total cholesterol 14 mg/dL and LDL 10 mg/dL higher, the lipid rise at 4 g/day or more; Zawieja et al. (J Diet Suppl, 2021; PMID 31809615), 6 trials, total cholesterol 0.34 mmol/L higher. NULL FINDINGS: Schwab et al. (Eur J Clin Nutr, 2011; PMID 20978525), 63 healthy young adults, 4 g/day for 6 months, homocysteine unchanged; Olthof et al. (PLoS Clin Trials, 2006; PMID 16871332), crossover in 39 adults aged 50 to 70, 6 g/day lowered homocysteine 12 percent but did not improve flow-mediated dilation. Combination, not graded: Lu et al. (Eur J Nutr, 2023; PMID 36717385), 100 Chinese adults with hyperhomocysteinemia, folic acid 400 micrograms, B6, B12 plus 1 g betaine for 12 weeks lowered homocysteine 10 percent; the folate alone could account for it, so it cannot support a betaine grade, and the study products were made by a supplement manufacturer that employs one author, a relationship the paper's no-conflict statement does not mention. Neither cited trial studied TMG alongside NMN or NR or measured S-adenosylmethionine. Grade C: homocysteine lowering replicates across independent groups and pooled trials at 1.5 to 6 g/day, but homocysteine is not an established stand-in for a clinical outcome.
Why Grade C and not Grade B
Grade C reflects early or limited human evidence -- small trials, surrogate endpoints, or preliminary findings not yet independently replicated. The evidence points in a promising direction but does not yet meet the standard for Grade B. A single well-powered, independently replicated trial with a meaningful endpoint would move this to Grade B or higher.
What this grade covers and what it does not
What would move this grade
A well-powered randomized trial with an objective, clinically meaningful primary endpoint and at least one independent replication would support Grade B or higher.