SAMe plus betaine is a safe and effective tool to counteract mild depression

BACKGROUND: S-adenosyl-L-methionine (SAMe), a safe, endogenous, pleiotropic methyl donor well known for its antidepressant role, has been assumed to have a possible role in increasing plasma levels of compounds known to be able to raise cardiovascular risk. Although the issue is still being debated, betaine (trimethylglycine), a specific methyl donor involved in the homocysteine circuit, may be able to reduce such a risk and/or, by determining a sparing effect on endogenous SAMe, may be able to improve the clinical efficiency of SAMe itself. Indeed, preliminary results have shown clinical improvement determined by an add-on therapy with betaine administered along with SAMe, versus SAMe alone, to patients affected by mild/moderate depression. AIM: To evaluate the safety and antidepressant role played by the association of SAMe plus betaine versus amitriptyline administered in untreated individuals with a recent diagnosis of mild depression. METHODS: This small, open-label, randomized, observational study enrolled 64 individuals with a diagnosis of mild depression according to the Zung Self-Rating Depression Scale. After randomization, they were treated with either Laroxyl((R)) (amitriptyline, 75 mg/day) or DDM Metile((R)) (enteric-coated SAMe, 500 mg/day, plus betaine, 250 mg/day) for 12 months. Assessment of clinical scores and tolerability was performed at T=0 and after 3, 6, and 12 months. RESULTS: After 3 months, both treatments showed a small and not statistically significant improvement. After 6 and 12 months, both treated groups demonstrated a more noticeable improved response, although the group treated with SAMe plus betaine showed better results in terms of score, number of individuals in remission, and side effects. Compliance was overlapping in both treatments. CONCLUSION: The association of SAMe plus betaine seems to be a safe and effective tool to counteract mild depression and also when used as monotherapy in subjects with a recent diagnosis.

Di Pierro, F. and R. Settembre, Preliminary results of a randomized controlled trial carried out with a fixed combination of S-adenosyl-L-methionine and betaine versus amitriptyline in patients with mild depression. Int J Gen Med, 2015. 8: p. 73-8

Lower seasonal maternal dietary betaine intake and resultant lower blood levels correlates with previously reported reduced DNA methylation in offspring

BACKGROUND: Animal models show that periconceptional supplementation with folic acid, vitamin B-12, choline, and betaine can induce differences in offspring phenotype mediated by epigenetic changes in DNA. In humans, altered DNA methylation patterns have been observed in offspring whose mothers were exposed to famine or who conceived in the Gambian rainy season.

OBJECTIVE:The objective was to understand the seasonality of DNA methylation patterns in rural Gambian women. We studied natural variations in dietary intake of nutrients involved in methyl-donor pathways and their effect on the respective metabolic biomarkers.

DESIGN:In 30 women of reproductive age (18-45 y), we monitored diets monthly for 1 y by using 48-h weighed records to measure intakes of choline, betaine, folate, methionine, riboflavin, and vitamins B-6 and B-12. Blood biomarkers of these nutrients, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), homocysteine, cysteine, and dimethylglycine were also assessed monthly.

RESULTS:Dietary intakes of riboflavin, folate, choline, and betaine varied significantly by season; the most dramatic variation was seen for betaine. All metabolic biomarkers showed significant seasonality, and vitamin B-6 and folate had the highest fluctuations. Correlations between dietary intakes and blood biomarkers were found for riboflavin, vitamin B-6, active vitamin B-12 (holotranscobalamin), and betaine. We observed a seasonal switch between the betaine and folate pathways and a probable limiting role of riboflavin in these processes and a higher SAM/SAH ratio during the rainy season.

CONCLUSIONS:Naturally occurring seasonal variations in food-consumption patterns have a profound effect on methyl-donor biomarker status. The direction of these changes was consistent with previously reported differences in methylation of metastable epialleles. This trial was registered at www.clinicaltrials.gov as NCT01811641.

Dominguez-Salas, P., et al., DNA methylation potential: dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women. Am J Clin Nutr, 2013

Deletion of murine betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinoma

Betaine-homocysteine S-methyltransferase (BHMT) uses betaine to catalyze the degradation of homocysteine (Hcy). There are common genetic polymorphisms in the BHMT gene in humans. To model the phenotype of mice with a loss of BHMT function, we generated the first Bhmt-/- mouse. Deletion of the gene resulted in a 6-fold increase in hepatic and an 8-fold increase in plasma Hcy concentrations, suggesting the importance of BHMT in Hcy removal. Deletion of the gene resulted in a 43% reduction in hepatic S-adenosylmethionine (AdoMet) and a 3-fold increase in hepatic S-adenosylhomocysteine (AdoHcy) concentrations, resulting in a 75% reduction in methylation potential (AdoMet:AdoHcy). Bhmt-/- mice accumulated betaine in most tissues, including a 21-fold increase in the liver concentration compared to wildtype (WT). These mice had lower concentrations of choline, phosphocholine, glycerophosphocholine, phosphatidylcholine and sphingomyelin in several tissues. At 5 weeks of age, Bhmt-/- mice had 36% lower total hepatic phospholipid concentrations and a 6-fold increase in hepatic triacyglycerol concentrations compared to WT, which was due to a decrease in the secretion of very low density lipoproteins. At 1 year of age, 64% of Bhmt-/- mice had visible hepatic tumors. Histopathological analysis revealed that Bhmt-/- mice developed hepatocellular carcinoma (HCC) or carcinoma precursors. These results indicate that BHMT has an important role in Hcy, choline and one-carbon homeostasis. A lack of BHMT also affects susceptibility to fatty liver and HCC. We suggest that functional polymorphisms in BHMT that significantly reduce activity may have similar effects in humans.

Teng, Y.W., et al., Deletion of murine betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinoma. J Biol Chem, 2011. 286: p. 36258-67

Betaine has a hepatoprotective effect by increasing glutathione levels and glutathione-related enzyme activities in rats

The effects of betaine supplementation on D-galactosamine-induced liver injury were examined in terms of hepatic and serum enzyme activities and of the levels of glutathione and betaine-derived intermediates. The rats induced with liver injury showed marked increases in serum enzyme activity, but those receiving dietary supplementation of 1% betaine showed enzyme activity levels similar to a control group without liver injury. Administration of betaine also increased both hepatic and serum glutathione levels, even following D-galactosamine injection. The activity of glutathione-related enzymes was markedly decreased following injection of D-galactosamine, but remained comparable to that of the control group in rats receiving 1% betaine. The concentrations of hepatic S-adenosyl methionine and cysteine showed similar trends to that observed for hepatic glutathione levels. These results indicate that 1% betaine has a hepatoprotective effect by increasing hepatic and serum glutathione levels along with glutathione-related enzyme activities in rats.

Okada, T., et al., Amelioration of D-galactosamine-induced acute liver injury in rats by dietary supplementation with betaine derived from sugar beet molasses. Biosci Biotechnol Biochem, 2011. 75(7): p. 1335-41.

Effect of Betaine on GAA-induced homocysteinemia

Setoue et al (2008). "Hyperhomocysteinemia induced by guanidinoacetic acid is effectively suppressed by choline and betaine in rats." Biosci Biotechnol Biochem 72(7): 1696-703.

Guanidinoacetic acid (GAA), a precursor of creatine:

- raised plasma homocysteine
- raised liver homocysteine and s-adenosylhomocysteine (SAH)
- lowered liver s-adenosylmethionine (SAM)

Betaine and choline significantly suppressed these effects.