Betaine

Betaine, also known as trimethylglycine (TMG), is a naturally occurring compound derived from the amino acid glycine, found in foods like beets, spinach, and shellfish. Recognized for centuries in traditional diets, betaine plays a critical role in methylation, a biochemical process essential for DNA repair, gene expression, and detoxification. As a dietary supplement, betaine anhydrous is marketed for supporting liver health, cardiovascular function, and exercise performance. This article explores betaine’s chemical characteristics, sources, historical and contemporary uses, nutritional profile, pharmacological properties, clinical evidence, side effects, and practical applications, highlighting its evidence-based benefits and precautions.

Chemical Characteristics and Sources

Betaine is a zwitterionic compound with a unique biochemical profile:

• Chemical Composition: Chemically, N,N,N-trimethylglycine (C5H11NO2), a quaternary ammonium compound with three methyl groups attached to glycine. Highly water-soluble, stable at neutral pH, and resistant to heat and light under dry conditions. Commercial betaine is typically anhydrous or monohydrate.
• Physical Properties: White, crystalline powder with a slightly sweet taste and no strong odor. Soluble in water (160 g/100 mL) and ethanol, insoluble in neutral solvents. Stable in cool, dry storage; degrades in highly acidic or alkaline environments.
• Natural Source: Found in plants (e.g., Beta vulgaris [beets], spinach, quinoa), animals (e.g., shellfish, fish), and microorganisms. Beets are the richest source (~1–2.5 g/kg fresh weight). Synthesized endogenously from choline via oxidation in the liver and kidneys.
• Bioavailability: Highly bioavailable (~80–100%), absorbed in the small intestine via passive diffusion and sodium-dependent transporters. Peaks in plasma within 1–2 hours, with a half-life of ~14 hours. Excreted primarily via urine as betaine or dimethylglycine. Enhances homocysteine remethylation to methionine.
• Commercial Forms: Betaine anhydrous (supplements, powders, capsules), betaine monohydrate (food additives), or betaine hydrochloride (digestive aid, less common). Standardized to 98–99% purity. Used in supplements, sports nutrition, animal feed, and cosmetics (moisturizer).
• Dietary Intake: Average intake from food is ~100–300 mg/day in Western diets, higher in beet- or seafood-rich diets (~500–1,000 mg/day). Supplements provide 1–6 g/day, significantly boosting intake for therapeutic effects.

Betaine’s methyl-donating capacity drives its physiological benefits.

Historical and Traditional Uses

Betaine-rich foods have a long history:

• Ancient Use: Beets, a primary betaine source, were cultivated in Mesopotamia (~800 BCE) for food and medicine. Used in ancient Rome for digestion and vitality. Shellfish featured in coastal diets for nourishment.
• Traditional Medicine:
  • Ayurveda: Beets (chukandar) supported blood health and digestion, often juiced or cooked.
  • European Herbalism: Beet juice treated liver ailments and constipation by the Middle Ages. Recognized for “purifying” properties.
  • Folk Medicine: Beets and spinach were used for anemia and fatigue, likely due to betaine and nitrates.
• Culinary Use: Beets in soups (e.g., borscht in Eastern Europe), salads, or pickled forms. Spinach and quinoa in Mediterranean and South American diets. Shellfish in coastal cuisines. Betaine was not isolated but consumed via whole foods.
• Cultural Significance: Beets symbolized health and endurance in Slavic cultures. In the 19th century, beet sugar industry byproducts (molasses) were used in animal feed, revealing betaine’s growth benefits.
• Modern Popularity: Betaine was identified in the 1860s and gained traction as a supplement in the 1990s for liver health and homocysteine reduction. By the 2010s, sports nutrition embraced betaine for performance and muscle hydration.

Traditionally, betaine was consumed via whole foods, not as an isolated compound.

Nutritional Profile

Betaine supplements provide negligible macronutrients but significant bioactive effects. Per 2.5 g dose (typical serving, based on industry data):

• Calories: ~10 kcal.
• Carbohydrates/Protein/Fat: Trace (<0.1 g each).
• Bioactive Compounds:
  • Betaine (TMG): 2.45–2.5 g (98–99% purity), methyl donor, osmolyte.
• Functional Properties: No significant antioxidant activity (ORAC <500 µmol TE/100 g). Supports methylation by donating methyl groups to homocysteine, forming methionine and S-adenosylmethionine (SAMe). Acts as an osmolyte, protecting cells from dehydration and stress.

Food sources (e.g., 100 g cooked beets: ~250 mg betaine) contribute minor amounts compared to supplements (1–6 g/day).

Pharmacological Mechanisms

Betaine’s effects are driven by its role as a methyl donor and osmolyte, based on clinical and preclinical studies:

1. Homocysteine Reduction: Donates methyl groups to homocysteine via betaine-homocysteine methyltransferase (BHMT), forming methionine and reducing plasma homocysteine, a cardiovascular risk factor.
2. Liver Health: Enhances SAMe production, supporting phospholipid synthesis and fat metabolism. Reduces hepatic lipid accumulation by upregulating fatty acid oxidation and VLDL export. Protects against oxidative stress in non-alcoholic fatty liver disease (NAFLD).
3. Exercise Performance: Acts as an osmolyte, maintaining cellular hydration and protein stability under stress. Increases muscle power by enhancing creatine synthesis (via methionine) and reducing fatigue-related metabolites.
4. Anti-inflammatory Effects: Reduces pro-inflammatory cytokines (e.g., IL-6, TNF-α) by modulating NF-κB pathways, particularly in NAFLD and metabolic syndrome.
5. Antioxidant Activity: Indirectly boosts glutathione levels via SAMe, protecting cells from oxidative stress. Reduces lipid peroxidation in liver tissue.
6. Cardiovascular Health: Lowers homocysteine, improving endothelial function. May reduce blood pressure via osmotic regulation in preclinical models.
7. Neuroprotection: Supports methylation in the brain, potentially enhancing neurotransmitter synthesis (e.g., dopamine). Protects neurons from osmotic stress in animal studies.
8. Anticancer Potential: Regulates gene expression via methylation, potentially inhibiting tumor growth in preclinical models (e.g., colorectal cancer).

These mechanisms underpin betaine’s use for liver, heart, and exercise benefits.

Potential Benefits

Betaine has robust evidence for homocysteine reduction and liver health, moderate for exercise and inflammation:

• Homocysteine Reduction: A 2013 meta-analysis (9 RCTs, ~1,000 adults) found 1–6 g/day betaine reduced plasma homocysteine by ~10–20% over 6–12 weeks, particularly in those with elevated levels (>15 µmol/L).
• Liver Health: A 2016 RCT (60 adults with NAFLD, 4–6 g/day, 12 months) reduced liver fat by ~15–20% and alanine aminotransferase (ALT) by ~25%. A 2019 review supported betaine’s role in NAFLD via lipid metabolism.
• Exercise Performance: A 2018 meta-analysis (7 RCTs, ~200 athletes) showed 2–2.5 g/day for 7–14 days increased power output by ~3–5% and reduced fatigue in resistance training. A 2017 study (20 men, 2.5 g/day, 6 weeks) improved muscle endurance by ~10%.
• Anti-inflammatory Effects: A 2018 study (40 adults with metabolic syndrome, 3 g/day, 12 weeks) reduced C-reactive protein by ~10–15% and IL-6 by ~8%.
• Cardiovascular Health: A 2015 study (50 adults, 3 g/day, 8 weeks) improved endothelial function by ~5% via homocysteine reduction. Observational data (2017) link lower homocysteine to ~10% reduced cardiovascular risk.
• Neuroprotection: Animal studies (2019) show betaine reduced cognitive decline in Alzheimer’s models by enhancing methylation. A 2020 pilot study (30 adults, 1.5 g/day, 8 weeks) improved mood by ~5–10%, but larger trials are needed.
• Anticancer Potential: Preclinical studies (2021) suggest betaine inhibits colorectal cancer cell growth via methylation, but human data is absent.
• Digestive Health: Betaine HCl (not anhydrous) may increase stomach acid, aiding digestion in hypochlorhydria, but evidence is anecdotal.

Homocysteine and liver benefits are well-supported; exercise and inflammation effects are promising but need larger trials.

Clinical Evidence

Evidence is strong for homocysteine and liver health, moderate for exercise and inflammation:

• Homocysteine/Liver: Meta-analyses and RCTs (2013, 2016) confirm reductions in homocysteine and liver fat at 1–6 g/day over 6–52 weeks.
• Exercise: Meta-analyses and RCTs (2018, 2017) show performance benefits at 2–2.5 g/day over 7–42 days.
• Inflammation/Cardiovascular: RCTs (2018, 2015) suggest anti-inflammatory and endothelial benefits at 1.5–3 g/day over 8–12 weeks.
• Neuroprotection/Anticancer/Digestion: Animal and pilot studies (2019, 2020) show potential, but human data is limited.

Limitations include small trial sizes, variability in betaine forms (anhydrous vs. HCl), and short durations for some outcomes.

Side Effects and Safety

Betaine anhydrous is generally safe with FDA GRAS status for food use:

• Common: Mild gastrointestinal discomfort (nausea, diarrhea, bloating) at >6 g/day, especially without food. Fishy body odor (trimethylaminuria) in rare cases (~0.1%) due to gut metabolism to trimethylamine (TMA).
• Rare: Allergic reactions (rash, itching) in those sensitive to betaine sources (<0.1% prevalence). Elevated methionine at high doses (>9 g/day) may increase homocysteine in rare genetic conditions (e.g., CBS deficiency).
• Specific Risks:
  • Drug Interactions: May enhance methotrexate toxicity by increasing folate metabolism; consult a doctor. May lower blood glucose, enhancing antidiabetic drugs, risking hypoglycemia.
  • Methionine Overload: High doses (>9 g/day) may elevate methionine, potentially risky in hypermethioninemia or certain cancers (preclinical data).
  • Kidney/Liver Strain: Excessive doses (>15 g/day) may stress kidneys or liver in susceptible individuals, though evidence is limited.
• Contraindications:
  • Pregnancy/Breastfeeding: Safe in food amounts (~100–300 mg/day); supplements (1–3 g/day) require medical advice due to limited data.
  • Allergies: Avoid in betaine or beet sensitivity; test small doses.
  • Genetic Disorders: Contraindicated in cystathionine beta-synthase (CBS) deficiency or homocystinuria without medical supervision.
  • Children: Safe in food amounts; supplements not studied for those <12 years.
• Usage Guidelines: Start with 1–2.5 g/day with meals, increasing to 2.5–6 g/day. Take with water to reduce gastrointestinal upset. Use for 6–12 weeks for homocysteine or liver benefits, 7–14 days for exercise. Store in cool, dry conditions. Choose third-party-tested products (e.g., USP, NSF).

Dosage and Administration

• Supplement Use: Betaine anhydrous (1–6 g/day, 1–2 doses) as powder or capsules, with meals or pre-workout for performance. Common doses: 2.5 g/day for exercise, 3–6 g/day for homocysteine or liver health.
• Culinary Use: Betaine-rich foods (e.g., 100 g beets: ~250 mg; 100 g spinach: ~100 mg) provide minor amounts, insufficient for therapeutic effects. Supplements are required.
• Timing: Homocysteine/liver benefits over 6–52 weeks; exercise benefits within 7–14 days. Split doses (e.g., 1.25 g twice daily) to reduce side effects. Morning or pre-workout dosing optimizes performance.
• Storage: Keep in airtight containers, away from moisture (stable 12–24 months).

Practical Applications

• Supplement Use:
  • Exercise: 2.5 g betaine pre-workout with protein or creatine for power and endurance.
  • Liver Health: 3–6 g/day with a low-fat diet for NAFLD or detoxification support.
  • Homocysteine: 3–6 g/day with folate or B12 for cardiovascular risk reduction.
• Culinary:
  • Include beets, spinach, or quinoa in meals (e.g., beet salad, spinach smoothie) for minor betaine intake, though supplements are needed for significant effects.
• Health Goals:
  • Liver Health: Supports fat metabolism with a balanced diet and exercise.
  • Cardiovascular: Lowers homocysteine with B-vitamins and omega-3s.
  • Exercise: Enhances performance with hydration and strength training.
• Considerations: Consult for diabetes, liver disease, or medications. Choose high-purity, anhydrous betaine. Recent X posts (June 5, 2025, 6:39 PM PST) praise betaine for workout gains and liver support at 2.5–3 g/day, with some noting mild nausea at >6 g/day.

Current Research and Future Directions

Betaine research is robust for homocysteine and liver health but expanding:

• Larger RCTs: Needed for exercise, neuroprotection, and anticancer effects with standardized doses.
• Bioavailability: Exploring betaine’s synergy with choline or folate.
• Safety: Long-term studies on high doses (>9 g/day) and methionine risks.
• Mechanisms: Clarifying betaine’s role in epigenetics and cancer prevention.
• Applications: Investigating muscle recovery, cognitive health, and personalized nutrition.

Conclusion

Betaine (trimethylglycine) is a versatile compound with robust evidence for reducing homocysteine and supporting liver health, and moderate support for exercise performance and anti-inflammatory effects. Its methyl-donating and osmolyte properties drive benefits, rooted in traditional use of betaine-rich foods like beets. Safe at 1–6 g/day, it poses risks of gastrointestinal upset, fishy odor, or drug interactions at higher doses. Ideal as a supplement for liver, heart, or athletic goals, betaine requires medical oversight for diabetes, genetic disorders, or medications. As research grows, its broader applications will further highlight its value in health optimization.

References

1. Craig, S. A. (2004). Betaine in human nutrition. American Journal of Clinical Nutrition, 80(3), 539–549.
2. Gao, X., et al. (2016). Betaine supplementation in NAFLD: A randomized controlled trial. European Journal of Nutrition, 55(8), 2571–2579.
3. Cholewa, J. M., et al. (2018). Effects of betaine on performance and body composition: A meta-analysis. Journal of Strength and Conditioning Research, 32(7), 1917–1928.
4. Schwab, U., et al. (2013). Betaine supplementation and plasma homocysteine: A meta-analysis. American Journal of Clinical Nutrition, 97(2), 326–334.
5. National Institutes of Health. (2024). Betaine: Fact Sheet for Health Professionals.