encyclopedia

Betaine

Natural Sources:    

Beets; broccoli; spinach, and certain seafood.    
     

Forms:    

Standardized Betaine capsules and tablets; Multivitamin and Mineral tablets containing betaine.    
     

Therapeutic Uses:    

– ADD (Attention Deficit Disorder)
– Aging Disorders
– Anemia
– Arthritis (rheumatoid)
– Asthma
– Athletic Performance
– Alzheimer's Disease
– Attention Deficit Disorder (ADD/ADHD)
– Brain Functioning
– Cancer
– Cardiovascular Disease
– Child Development
– Depression
– Digestive Disorders
– Electrolyte Balance
– Fatty Liver
– Fetal Development
– Gallstones
– Heartburn
– Heart Disease (Heart Attack and Stoke)
– Heart Health Maintenance
– High Homocysteine
– Indigestion
– Jaundice
– Kidney Health Maintenance
– Liver Health Maintenance
– Memory Loss
– Neural Tube Defects
– Peripheral Neuropathy
– Physical Performance
– Rheumatoid Arthritis
– Stomach Acid Deficiency
– Thyroid Disorders
– Vascular Disorders
– Vitiligo (Skin pigmentation loss)
– Weight Loss     
     
    
Overview:    

Betaine, also known as glycine betaine, trimethylglycine (TMG) or oxyneurine, is found in most microorganisms and virtually all marine and fresh water invertebrates. The best known natural sources of betaine are plants from the Chenopodiaceae family, namely, the sugar beet. Betaine is often referred to as a quasi-vitamin because although humans and other animals can synthesize it from choline, it can't be synthesized in adequate quantities and generally needs to be included in the diet. Betaine is required (as a methyl donor) for the synthesis of the amino acid methionine from homocysteine. Used since 1981 in the treatment of high homocystein levels, betaine has recently been approved by the FDA as a prescription medicine for the treatment of homocystinuria. In the kidney, choline forms betaine, which plays a special role in protecting the organ. Based on several studies, betaine also naturally increases glutathione levels within the liver, the body's most important antioxidant. Betaine works along with vitamins B6, B12 and folic acid to augment the formation of S-adenosylmethionine (SAM), an important amino acid particularly concentrated in the human brain and liver. Recent studies in children with enzyme deficiencies confirm that betaine increases S-adenosylmethionine in the brain. Betaine has also been shown to raise beneficial S-adenosylmethionine levels within the liver, which helps the liver to metabolize fat and protect against alcohol-induced cirrhosis and other conditions. Betaine also decreases bilirubin, alkaline phosphotase and several other liver enzymes related to a large variety of liver disorders. Significant liver benefits have been shown in over 20 studies with betaine. Betaine is also used in the hydrochloride form for treating digestive disorders including low levels of stomach acid, indigestion, heartburn, and to destroy pathogenic bacteria in the stomach. Betaine may also be beneficial for individuals with anemia, asthma, gallstones, thyroid conditions, rheumatoid arthritis and vitiligo.
  
    
Chemistry:    

Betaine, also called trimethylglycine or “TMG”, is technically classified as a sweet crystalline quaternary ammonium salt (C5H11NO2) occurring especially in beet juice; it is also found in the form of a hydrate (C5H13NO3) or hydrochloride (C5H12NO2Cl). Betaine can be extracted from sugar beets as a white crystal (99% pure) with a distinctive mildly sweet taste and aftertaste. The betaine pathway within living systems contributes to the breakdown of homocysteine. Betaine is a natural methyl donor and is broken down into dimethylglycine (DMG) during the synthesis of the amino acid methionine from homocysteine, the main pathway for the degradation of betaine. Choline is the precursor of betaine. Choline oxidase is a cytosolic enzyme that catalyzes the two-step oxidation of choline to betaine in the pathway for the catabolism of glycine, with betaine aldehyde as an intermediate. Molecular oxygen acts as the final electron acceptor.    
   
     
Suggested Amount:    

Betaine Hydrochloride Dosage:
The use of betaine hydrochloride as a digestion aid in capsule or tablet form is recommended with the dosage of: 325 to 650 milligrams three times daily with meals, by mouth.
 
Pure Betaine Dosage:
For general health maintenance and for preventing disease the dosage range for betaine is recommended at 500-1,000 mg daily. For increasing levels of the powerful antioxidant, glutathione, the dosage range is 500-1,500 mg daily. As an anti-depressant, by raising levels of beneficial SAM (S-Adenosyl-Methionine), the dosage range is 500-1,500 mg daily. For body building the dosage range is 500-2,000 mg daily. For general vascular protection (through the conversion of homocysteine to Methionine), the dosage range is 500-1,000 mg daily. For treating liver disorders the dosage range is 500-1,500 mg daily. For anti-aging benefits the dosage range is 500-1,000 mg daily. For increasing athletic performance the dosage range is 1,000-2,000 mg daily.
 
Note: A diet that includes lots of broccoli, spinach or beets can provide as much as a fifth or even a quarter teaspoon of betaine, just over 500mg. According to the monograph on betaine published by Medline Plus and posted on the website of the National Institutes of Health, the dosage for betaine for lowering high homocysteine levels is different for different patients. Individuals should consult with their physician prior to starting a program to lower homocystein levels with betaine. The average doses of betaine are:
 
For oral dosage form (powder for solution) to prevent buildup of homocysteine:
– Adults, teenagers, and children 3 years of age and older – The starting dose is usually 3 grams taken two times a day with meals.
– Children younger than 3 years of age – The dose is based on body weight and must be determined by a doctor. Betaine should be taken with meals.
 
Betaine powder should be mixed with 4 to 6 ounces of juice, milk, or water until completely dissolved and should be taken with meals. The solution should be used immediately after mixing and should not be used if the powder does not dissolve completely or gives a colored solution. It is recommended to follow your doctor's orders or the directions on the label.
 
Caution: Several companies have mistakenly labeled betaine HCL as pure betaine or TMG. If found in capsules, open the capsule and taste the contents – if the contents are strongly acidic, it is most likely betaine HCL. Chewing a tablet of pure betaine should leave a mild sweet taste in your mouth and should not burn your tongue.
    
   
Drug Interactions:    

None known.    
     
    
Contraindications:    

Betaine hydrochloride is contraindicated for persons suffering from ulcers and high stomach acid (a sign of high stomach acid is frequent heartburn). Studies on the effects of betaine taken during pregnancy have not been done in either humans or animals and therefore it is not recommended to take betaine as a supplement during pregnancy. It is also not known whether betaine passes into breast milk and therefore it is also not recommended as a supplement for lactating mothers. Betaine has been tested in children and, in effective doses, has not been shown to cause different side effects or problems than it does in adults. However, children may require more frequent changes in their dose than adults may. Older persons may also want to seek the guidance of a trained medical professional while taking betaine, as different dosages may be required.    
     
    
Side Effects:    

Betaine may cause a body odor. Other side effects may also occur in some patients, including diarrhea; nausea; stomach upset. Sold since the early 1980's in the United States, betaine has no reports of serious negative side-effects when used in the usual dosages. Allergic reactions are also possible for betaine hydrochloride. Allergic reactions, although rare, can include breathing problems, chest pain, skin hives, rash, or itchy skin.    
     
    
References:     
     
Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. 2001. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001 Sep; 96(9): 2711-7
 
Graf D, Kurz AK, Reinehr R, Fischer R, Kircheis G, Haussinger D. 2002. Prevention of bile acid-induced apoptosis by betaine in rat liver. Hepatology 2002 Oct; 36(4): 829-39.
 
Mar MH, Zeisel SH. 1999. Betaine in wine: answer to the French paradox?
 
Med Hypotheses. 1999 Nov; 53(5): 383-5.
 
Mehta K, Van Thiel DH, Shah N, Mobarhan S. 2002. Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev 2002 Sep; 60(9): 289-93.
 
Miglio F, Rovati LC, Santoro A, Setnikar I. 2000. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung. 2000 Aug; 50(8): 722-7.
    

Additional Information:    

Betaine for Increasing Athletic Performance and Weight Loss:
Although betaine has been used in the animal husbandry field to decrease fat and increase meat yield, human studies have only just recently started. In animals, betaine decreases very low-density lipoproteins (VLDLs), increases muscle mass, decreases fat content of the body and is also known to increase bone density. These effects are well documented although they are not well understood. In humans, it is thought that betaine also helps the body to metabolize fats, which allows the body to burn fat rather than protein or muscle during exercise. The result is less cramping, increased endurance, and better utilization of fat stores. It is estimated that a 200 pound individual with 20% body fat can expect to lose as much as 5 pounds of fat and gain as much as 12 pounds of muscle by using betaine as a supplement. Due to its bi-polar nature, betaine also helps maintain the proper osmotic pressure within cells. Betaine has been shown in human studies to help maintain normal cellular electrolyte concentrations despite water losses during exercise. The effectiveness of betaine for this purpose is even put to good use in salmon farming to protect fish against the problems of changing salt content. Betaine has also been shown to have the ability to protect cellular DNA from damage through methyl donation.

Abstracts from Medline:

Betaine for Treating Nonalcoholic Liver Disease:
OBJECTIVES: No effective therapy currently exists for patients with nonalcoholic steatohepatitis (NASH). Betaine, a naturally occurring metabolite of choline, has been shown to raise S-adenosylmethionine (SAM) levels that may in turn play a role in decreasing hepatic steatosis. Our aim was to determine the safety and effects of betaine on liver biochemistries and histological markers of disease activity in patients with NASH.
METHODS: Ten adult patients with NASH were enrolled. Patients received betaine anhydrous for oral solution (Cystadane) in two divided doses daily for 12 months. Seven out of 10 patients completed 1 yr of treatment with betaine.
RESULTS: A significant improvement in serum levels of aspartate aminotransferase (p = 0.02) and ALAT (p = 0.007) occurred during treatment. Aminotransferases normalized in three of seven patients, decreased by >50% in three of seven patients, and remained unchanged in one patient when compared to baseline values. A marked improvement in serum levels of aminotransferases (ALT -39%; AST -38%) also occurred during treatment in those patients who did not complete 1 yr of treatment. Similarly, a marked improvement in the degree of steatosis, necroinflammatory grade, and stage of fibrosis was noted at 1 yr of treatment with betaine. Transitory GI adverse events that did not require any dose reduction or discontinuation of betaine occurred in four patients.
CONCLUSIONS: Betaine is a safe and well tolerated drug that leads to a significant biochemical and histological improvement in patients with NASH. This novel agent deserves further evaluation in a randomized, placebo-controlled trial. [Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. 2001. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001 Sep; 96(9): 2711-7].
 
Betaine for Treating Nonalcoholic Liver Disease:
In a prospective, randomized, double-blind therapeutic trial, 191 patients with non-alcoholic steatohepatitis were treated for 8 weeks daily b.i.d. orally either with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate (Ietepar) (96 patients) or with undistinguishable placebo capsules (95 patients). The verum treatment effectively reduced by 25% hepatic steatosis (p < 0.01) and by 6% hepatomegaly (p < 0.05), while placebo did not significantly reduce the disorders. Verum was also more effective than placebo on discomfort in abdominal upper right quadrant. The global efficacy of treatment was rated by the doctor "very good" or "good" in 48% of verum treated patients and only in 17% after placcbo (P of difference = 9 x 10(-6)). 52% of patients self-rated efficacy as "very good" or "good" after verum and only 34% after placebo (P of difference = 0.017). The verum treatment provoked a significant reduction of the increased liver transaminases (ALT, AST and gamma-GT) while placebo was ineffective. Adverse events were recorded in 10% of verum-treated patients and in 7% under placebo (no significant difference). In both groups the adverse events were mild and transient, did not require treatment discontinuation and were undistinguishable from common symptoms of liver disorders. In conclusion, the 8-week treatment with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate was found effective in non-alcoholic steatohepatitis, a disorder for which the hitherto pharmacological interventions were poorly and inconsistently effective. [Miglio F, Rovati LC, Santoro A, Setnikar I. 2000. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung 2000 Aug; 50(8): 722-7].
 
Betaine for Treating Liver Disease:
Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The effects of betaine were studied on taurolithocholate 3-sulfate (TLCS) and glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes in vitro and in vivo. Hepatocyte apoptosis, caspase activation, and poly (ADP-ribose) polymerase (PARP) cleavage, which are normally observed in response to both bile acids, were largely prevented after preincubation of hepatocytes with betaine. Betaine uptake was required for this protective effect, which was already observed at betaine concentrations of 1 mmol/L. Betaine did not affect the TLCS-induced membrane trafficking of CD95 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 to the plasma membrane or the TLCS-induced recruitment of Fas-associated death domain (FADD) and caspase 8 to the CD95 receptor. However, betaine largely prevented cytochrome c release and oxidative stress exerted otherwise by TLCS. Inhibition of caspase 9 strongly blunted TLCS-induced caspase-8 activation. Further betaine did not prevent the TLCS-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen-activated protein kinase (p38(MAPK)) activation or TLCS-induced protein kinase B (PKB) dephosphorylation. The protective betaine effect was insensitive to inhibition of Erks by PD089059, of p38(MAPK) by SB203580, or of phosphatidylinositol 3-kinase (PI3-kinase) by LY294002. Betaine supplementation in the drinking water significantly ameliorated in vivo hepatocyte apoptosis following bile duct ligation. In conclusion, this study identifies betaine as a potent protectant against bile acid-induced apoptosis in vivo and in vitro, and its antiapoptotic action largely resides on an inhibition of the proapoptotic mitochondrial pathway. [Graf D, Kurz AK, Reinehr R, Fischer R, Kircheis G, Haussinger D. 2002. Prevention of bile acid-induced apoptosis by betaine in rat liver. Hepatology 2002 Oct; 36(4): 829-39].
 
Betaine for Treating Nonalcoholic Liver Disease:
Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver injury ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Whereas simple steatosis has a benign clinical course, steatohepatitis is a recognized cause of progressive liver fibrosis and can develop into cirrhosis. NAFLD and nonalcoholic steatohepatitis (NASH) are the two most common chronic liver diseases in United States general population with a prevalence of 20% and 3%, respectively. Hepatic steatosis is frequently associated with obesity, type 2 diabetes, and hyperlipidemia with insulin resistance as a key pathogenic factor. A two-hit theory best describes the progression from simple steatosis to NASH, fibrosis, or cirrhosis. These two hits consist of the accumulation of excessive hepatic fat primarily owing to insulin resistance, and oxidative stress owing to reactive oxygen species (ROS). Mitochondria are the major cellular source of ROS in cases of NASH. Currently, treatment is focused on modifying risk factors such as obesity, diabetes mellitus, and hyperlipidemia. Antioxidants such as vitamin E, N-acetylcysteine, betaine, and others may be beneficial in the treatment of NASH. [Mehta K, Van Thiel DH, Shah N, Mobarhan S. 2002. Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev 2002 Sep; 60(9): 289-93].
 
Betaine for Preventing Hyper- and Hypoosmolar Stress:
Organic osmolytes are used in animal and plant cells to adapt to hyper- and hypoosmolar stress. We used our RBC-membrane model to investigate the effects of the osmolytes betaine, sorbitol and myo-inositol on Na(+)/K(+)-ATPase, Ca(2+)-ATPase and calmodulin-stimulated Ca(2+)-ATPase (CaM). Our results show that betaine inhibited ATPases by more than 61%: Na(+)/K(+)-ATPase (75 +/- 5.9 vs 27 +/- 2.2), Ca(2+)-ATPase (236 +/- 18.9 vs 62 +/- 4.9), and CaM (450 +/- 18 vs 174 +/- 6.9) (&mgr;M pi/min/mg protein, control (0 &mgr;M betaine) vs 100 &mgr;mol/L betaine). Sorbitol (100 &mgr;mol/L) inhibited the Ca(2+)-ATPases by 41% (126 +/- 7.6 vs 74 +/- 4.4) and CaM by 42% (253 +/- 17.7 vs 147 +/- 10.3). Inositol (100 &mgr;mol/L) inhibited Na(+)/K(+)-ATPase strongest (37 +/- 1.9 vs 20 +/- 1.0; 47% inhibition) while it showed a lesser effect on the Ca(2+)-ATPases (136 +/- 6.8 vs 102 +/- 5.1; 25% inhibition). All osmolytes inhibited RBC membrane ATPases at concentrations above 50 &mgr;mol/L, which corresponds to high normal physiologic range for organic osmolytes in serum. Furthermore, the presence of osmolytes (250 &mgr;mol/L) decreased hypoosmotic stress induced hemolysis by 42%. Together these data indicate an important regulatory role of organic osmolytes on human RBC membrane ATPases and a protective function of osmolytes in RBCs against hypoosmotic stress. [Moeckel G, Shadman R, Fogel J, Sadrzadeh S. 2002. Organic osmolytes betaine, sorbitol and inositol are potent inhibitors of erythrocyte membrane ATPases. Life Sci 2002 Oct 4; 71(20): 2413].
 
Betaine Together with Zinc Required to Lower Homocysteine:
Betaine-homocysteine methyl transferase (BHMT) catalyzes the synthesis of methionine from betaine and homocysteine (Hcy), utilizing a zinc ion to activate Hcy. BHMT is a key liver enzyme that is important for homocysteine homeostasis. X-ray structures of human BHMT in its oxidized (Zn-free) and reduced (Zn-replete) forms, the latter in complex with the bisubstrate analog, S(delta-carboxybutyl)-L-homocysteine, were determined at resolutions of 2.15 A and 2.05 A. BHMT is a (beta/alpha)(8) barrel that is distorted to construct the substrate and metal binding sites. The zinc binding sequences G-V/L-N-C and G-G-C-C are at the C termini of strands beta6 and beta8. Oxidation to the Cys217-Cys299 disulfide and expulsion of Zn are accompanied by local rearrangements. The structures identify Hcy binding fingerprints and provide a prototype for the homocysteine S-methyltransferase family. [Evans J, Huddler D, Jiracek J, Castro C, Millian N, Garrow T, Ludwig M. 2002. Betaine-homocysteine methyltransferase. Zinc in a distorted barrel. Structure (Camb) 2002 Sep; 10(9): 1159].