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Drugs and Health Products

Monograph: Betaine / Betaine Hydrochloride - Under Consultation

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This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredient.

Notes

  • Text in parentheses is additional optional information which can be included on the PLA and product label at the applicant's discretion.
  • The solidus (/) indicates that the terms and/or the statements are synonymous. Either term or statement may be selected by the applicant.

Date

December 8, 2015

Medicinal Ingredients

Proper name(s) Common name(s) Source material(s)

1-Carboxy-N,N,N-trimethylmethanaminium inner salt (Moffat et al. 2014; O'Neil et al. 2006)

(Carboxymethyl)trimethylammonium hydroxide inner salt (Martindale 2014; O'Neil et al. 2006)

Betaine
  • Beta vulgaris root (FCC 2012)
  • Betaine (anhydrous) (DNP 2014; Moffat et al. 2014; Martindale 2014; FCC 2012; O'Neil et al. 2006)
  • Betaine hydrochloride (Allen Jr. 2014; DNP 2014; Martindale 2014; O'Neil et al. 2006)

1-Carboxy-N,N,N-trimethylmethanaminium chloride (O'Neil et al. 2006)

(Carboxymethyl)trimethylammonium chloride (O'Neil et al. 2006)

Betaine hydrochloride
  • Beta vulgaris root (FCC 2012)
  • Betaine hydrochloride (Allen Jr. 2014; DNP 2014; Martindale 2014; O'Neil et al. 2006)
Note: For products making the digestive claim, the medicinal ingredient must be represented as betaine hydrochloride. For products making only the liver function claim, the medicinal ingredient must be represented as betaine.

Route(s) of Administration

Oral

Dosage Form(s)

  • The acceptable pharmaceutical dosage forms include, but are not limited to capsules, chewables (e.g. tablets), liquids, powders, strips or tablets
  • This monograph is not intended to include foods or food-like dosage forms such as bars, chewing gums or beverages.

Use(s) or Purpose(s)

Statement(s) to the effect of

All products

Helps to support liver function (Kempson et al. 2014; Obeid 2013; Ueland 2011; Lever and Slow 2010; Purohit et al. 2007; Pajares and Perez-Sala 2006; Craig 2004; Patrick 2002; Barak et al. 1996).

Medicinal Ingredient: Betaine hydrochloride

Helps to support digestion / Digestive aid (DNP 2014; Moffat et al. 2014; O'Neil et al. 2006)

Dose(s)

Statement(s) to the effect of

Subpopulation(s)

Adults (≥ 18 years)

Quantity(ies)

Liver Function
Medicinal Ingredient Minimum
(mg/day)
Maximum
(mg/day)
References
Betaine 500 4000 Schwab et al. 2011; Atkinson et al. 2008
Betaine hydrochloride 650 mg; not to exceed 1000 mg per single dose 3500 Allen Jr. 2014; Moffat et al. 2014; Atkinson et al. 2008
Digestive Aid
Medicinal Ingredient Minimum
(mg/day)
Maximum
(mg/day)
References
Betaine hydrochloride 180 mg; not to exceed 1000 mg per single dose 3500 Allen Jr. 2014; Moffat et al. 2014

Directions for use

Products providing betaine hydrochloride (as a medicinal ingredient or as a source ingredient)

Take with food/meal (Allen Jr. 2014; Moffat et al. 2014).

Duration of Use

No statement required.

Risk Information

Statement(s) to the effect of

Caution(s) and Warning(s)

All products

If you are pregnant or breastfeeding, consult a health care practitioner prior to use.

Products providing betaine hydrochloride (as a medicinal ingredient or as a source ingredient)

If you have a peptic ulcer or excess stomach acid, consult a health care practitioner prior to use (Hendler and Rorvik 2008; O'Neil et al. 2006).

Products providing ≥ 600 mg betaine and/or ≥ 780 mg betaine hydrochloride per day

If you have high cholesterol, consult a health care practitioner prior to use (Olthof et al. 2005; Swab et al. 2002).

Contraindication(s)

No statement required.

Known adverse reaction(s)

No statement required.

Storage Condition(s)

No statement required.

Non Medicinal Ingredients

Must be chosen from the current Natural Health Products Ingredients Database (NHPID) and must meet the limitations outlined in the database.

Specifications

  • The finished product specifications must be established in accordance with the requirements described in the Natural and Non-prescription Health Products Directorate Quality of Natural Health Products Guide.
  • The medicinal ingredient must comply with the requirements outlined in the NHPID. In addition, the medicinal ingredient may comply with the specifications outlined in the Betaine monograph, published in the Food Chemicals Codex (FCC 2012), or the Betaine Hydrochloride monograph, published in the United States Pharmacopeia (USP 34).

References Cited

Allen Jr. LV (Editor). Next link will take you to another Web site Remington: The Science and Practice of Pharmacy. Philadelphia College of Pharmacy. Royal Pharmaceutical Society; 2014. [Accessed 2014 July 03].

Atkinson W, Elmslie J, Lever M, Chambers ST, George PM. Dietary and supplementary betaine: acute effects on plasma betaine and homocysteine concentrations under standard and postmethionine load conditions in healthy male subjects. American Journal of Clinical Nutrition 2008;87:577-585

Barack AJ, Beckenhauer HC, Tuma DJ. Betaine, Ethanol, and the Liver: A Review. Alcohol 1996;13(4):395-398.

Craig SAS. Betaine in human nutrition. American Journal of Clinical Nutrition 2004;80:539-549.

DNP 2014. Next link will take you to another Web site Dictionary of Natural Products, Version 17.1, CRC Press. Hampden Data Services Ltd. Taylor & Francis Group. [Accessed 2014 July 03].

FCC 2012: Food Chemicals Codex. Eighth edition. Rockville (MD): The United States Pharmacopeial Convention; 2012.

Hendler SS, Rorvik DM. PDR® for Nutritional Supplements, 2nd Edition. Thomson Reuters. Physicians' Desk References Inc., NJ; 2008.

Kempson SA, Zhou Y, Danbolt NC. The betaine/GABA transporter and betaine: roles in brain, kidney, and liver. Integrative Physiology 2014;5:1-16

Lever M. Slow S. The clinical significance of betaine, an osmolytes with a key role in methyl group metabolism. Clinical Biochemistry 2010;43:732-744.

Martindale 2014: Sweetman SC, editor. Next link will take you to another Web site Martindale: The Complete Drug Reference [Internet] London (GB): Pharmaceutical Press; Copyright 1933-2014. [Accessed 2014 July 03].

Moffat AC, Osselton MD, Widdop B, Watts J (Editors). Next link will take you to another Web site Clarke's analysis of drugs and poisons. Pharmaceutical Press. Royal Pharmaceutical Society. 2014. [Accessed 2014 July 03].

Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients 2013;5:3481-3495.

Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in health humans. PLoS Medicine 2005;2(5):e135.

O'Neil MJ, Heckelman PE, Koch CB, Roman KJ, editors. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. Fourteenth Edition. Whitehouse Station (NJ): Merck & Co. Inc.; 2006.

Pajares MA, Perez-Sala D. Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Cellular and Molecular Life Sciences 2006;63:2792-2803.

Patrick L. Nonalcoholic Fatty Liver Disease: Relationship to Insulin Sensitivity and Oxidative Stress. Treatment Approaches Using Vitamin E, Magnesium, and Betaine. Alternative Medicine Review 2002;7(4):276-291.

Purohit V, Abdelmalek MF, Barve S, Benevenga NJ, Halsted CH, Kaplowitz N, Kharbanda KK, Liu Q-Y, Lu SC, McClain CJ, Swanson C, Zakhari S. Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Americal Journal of Clinical Nutrition 2007;86:14-24.

Swab U, Alfthan G, Aro A, Uusitupa M. Long-term effect of betaine on risk factors associated with the metabolic syndrome in healthy subjects. European Journal of Clinical Nutrition 2011; 65:70-76.

Swab U, Torronen A, Toppinen L, Alfthan G, Saarinen M, Aro A, Uusitupa M. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. American Journal of Clinical Nutrition 2002;76:961-967.

Ueland MP. Choline and betaine in health and disease. Journal of Inherited Metabolic Disease 2011;34:3-15.

USP 34: United States Pharmacopeia and the National Formulary (USP 34 - NF 29). Rockville (MD): The United States Pharmacopeial Convention; 2010.

References Reviewed

Abdelmalek MF, Angulo A, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with non-alcoholic steatohepatitis: results of a pilot study. American Journal of Gastroenterology 2001;96(9):2711-2717.

Abdelmalek MF, Sanderson SO, Angulo P, Soldevila-Pico C, Liu C, Peter J, Keach J, Cave M, Chen T, McClain CJ, Lindor KD. Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology 2009;50:1818-1826.

Aigner R, Maier G, Muller R, Seitz H. Process for the preparation of aqueous betaine solutions. United States Patent 1994;5,292,942.

AMA 2010. Next link will take you to another Web site Homocysteine, Folic Acid and Cardiovascular Disease.. American Heart Association [Accessed 2014 July 11].

Atkinson W, Slow S, Elmslie J, Lever M, Chambers ST, George PM. Dietary and supplementary betaine: Effects on betaine and homocysteine concentrations in males. Nutrition, Metabolism & Cardiovascular Diseases 2009;19:767-773.

Bellis HE. Process for making aqeous betaine solutions. United States Patent 1997;5,696,287.

Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G. Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. BMC Cardiovascular Disorders 2007;7:20.

del Favero S, Roschel H, Artioli G, Ugrinowitsch C, Tricoli V, Costa A, Barroso R, Negrelli AL, Otaduy MC, da Costa Leite C, Lancha-Junior AH, Gualano B. Creatine but not Betaine supplementation increases muscle phosphorylcreatine content and strength performance. Amino Acids 2012;42:2299-2305.

Edsall JT. Raman spectra of amino acids and related compounds. VI. Sarcosine, ethanolamine, choline, betaine and betaine derivatives. Journal of the Americal Chemical Society1943;66:1767-1770.

Diekman EF, de Koning TJ, Verhoeven-Duif NM, Rovers MM, van Hasselt PM. Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurology 2014;71(2):188-194.

Eussen SJPM, Ueland PM, Clarke R, Blom HJ, Hoefnagels WHL, van Staveren WA, Groot LCPGM. The association of betaine, homocysteine and related metabolites with cognitive function in Dutch elderly people. British Journal of Nutrition 2007;98:960-968.

Filipowicz M, Bernsmeier C, Terracciano L, Duong FHT, Heim MH. S-Adenosyl-methionine and betaine improve early virological response in chronic hepatitis C patients with previous nonresponse. PLoS One 2010;5(11):e15492.

Gahl WA, Bernardini I, Chen S, Kurtz D, Horvath K. The effect of oral betaine on vertebral body bone density in pyridoxine-non-responsive homocystinuria. Journal of inherited Metabolic Disease 1988;11:291-298.

Glaze DG, Percy AK, Motil KJ, Lane JB, Isaacs JS, Schultz RJ, Barrish JO, Neul JL, O'Brien WE, Smith EO. A Study of the treatment of Rett syndrome with folate and betaine. Journal of Child Neurology 2009;25(5):551-556

Hoffman JR, Ratamess NA, Kang J, Gonzalez AM, Beller NA, Craig SAS. Effect of 15 days of betaine ingestion on concentric and eccentric force outputs during isokinetic exercise. Journal of Strength and Conditioning Research 2011;25(8):2235-2241.

Hoffman JR, Ratamess NA, Kang J, Rashti SL, Faigenbaum AD. Effect of betaine supplementation on power performance and fatigue. Journal of the International Society of Sports Nutrition 2009;6:7.

Holm PI, Bleie O, Ueland PM, Lien EA, Refsum H, Nordrehaug JE, Nygard O. Betaine as a determinant of postmethionine load total plasma homocysteine before and after B-vitamins supplementation. Arteriosclerosis, Thrombosis, and Vascular Biology 2004;24:301-307.

Innis SM, Hasman D. Evidence of choline depletion and reduced betaine and dimethylglycine with increased homocysteine in plasma of children with cystic fibrosis. Journal of Nutrition 2006;136:2226-2231.

Lawson-Yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine. Molecular Genetics and Metabolism 2006;88:201-207.

Leifer A, Lippincott ER. The Infrared Spectra of Some Amino Acids. Journal of the Americal Chemical Society 1957;79:5098-5101.

Lever M, Atkinson W, Slow S, Chambers ST, George PM. Plasma and urine betaine and dimethylglycine variation in healthy young male subjects. Clinical Biochemistry 2009;42:706-712.

Lever M, George PM, Slow S, Elmslie JL, Scott RS, Richards AM, Fink JN, Chambers ST. Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine. Cardiovascular Drugs and Therapy 2009;23:395-401.

McGregor DO, Dellow WJ, Robson RA, Lever M, George PM, Chambers ST. Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure. Kidney International 2002;61:1040-1046.

Melse-Boonstra A, Holm PI, Ueland PM, Olithof M, Clarke R, Verhoef P. Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation on betaine concentrations. Americal Journal of Clinical Nutrition 2005;81:1378-1382.

Miglio F, Rovali LC, Santoro A, Setnikar I. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis: A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung 2000;50(8):722-727. [Abstract Only].

Olthof MR, van Vliet T, Boelsma E, Verthoef P. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. Journal of Nutrition 2003;133:4135-4138.

Olthof MR, Verhoef P. Effects of betaine intake on plasma homocysteine concentrations and consequences for health. Current Drug Metabolism 2005;6:15-22.

Peters SU, Bird LM, Kimonis V, Glaze DG, Shinawi LM, Bichell TJ, Barbieri-Welge R, Nespeca M, Anselm I, Waisbren S, Sanborn E, Sun Q, O'Brien WE, Beaudet AL, Bacino CA. Double-blind therapeutic trial in angelman syndrome using betaine and folic acid. American Journal of Medical Genetics Part A;2010;152A:1994-2001.

Pizzorno JE, Murray MT, editors. Textbook of Natural Medicine, Fourth Edition. St-Louis (MI): Churchill Livingstone Elsevier Inc.; 2013.

Price RK, Keaveney EM, Hamill LL, Wallace JMW, Ward M, Ueland PM, McNulty H, Strain JJ, Parker MJ, Welch RW. Consumption of wheat aleurone-rich foods increases fasting plasma betaine and modestly decreases fasting homocysteine and LDL-cholesterol in adults. Journal of Nutrition 2010;140:2153-2157.

Schwahn BC, Hafner D, Hohlfeld T, Balkenhol N, Laryea MD, Wendel U. Pharmacokinetics of oral betaine in healthy subjects and patients with homocystinuria. British Journal of Clinical Pharmacology 2003;55:6-13.

Sharp GS, Hazlet JW. Evaluation of a new method for supplementation of gastric hydrochloric acid. American Journal of Digestive Diseases and Nutrition 1954;21(5):140-144.

Schartum-Hansen H, Ueland PM, Pedersen ER, Meyer K, Ebbing M, Bleie O, Svingen GFT, Seifert R, Vikse BE, Nygard O. Assessment of urinary betaine as a marker of diabetes mellitus in cardiovascular patients. PLoS One 2013;8(8):e69454.

Swab U, Torronen A, Meririnne E, Saarinen M, Alfthan G, Aro A, Uusitupa M. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans. Journal of Nutrition 2006;136:34-38.

Trepanowski JF, Farney TM, McCarthy CG, Schilling BK, Craig SA, Bloomer RJ. The effects of chronic betaine supplementation on exercise performance, skeletel muscle oxygen saturation and associated biochemical parameters in resistance trained men. Journal of Strength and Conditioning Research 2011;25(12):3461-3471.

Van Guldener C, Janssen MJFM, De Meer K, Donker AJM, Stehouwer CDA. Effect of folic acid and betaine on fasting and postmethionine-loading plasma homocysteine and methionine levels in chronic haemodialysis patients. Journal of Internal medicine 1999;245:175-183.

White P, Marble A, Bogan IK, Smith RM. Enlargement of the liver in diabetic children. Archives of Internal Medicine 1938;62(5):740-750.

Ziesel SH. Betaine supplementation and blood lipids: fact or artifact? Nutrition Reviews 2006;64(2):77-79.