Betaine

Betaine/Drug Interactions:

  • AlcoholAlcohol: Alcohol may impair folate re-methylation of homocysteine, leading to ethanol-induced elevation in homocysteine. In animal models betaine supplementation lowered homocysteine concentrations that were elevated by ethanol administration (32).
  • AntacidsAntacids: In clinical research, treatment with a dietary supplement containing melatonin, L-tryptophan, vitamin B6, folic acid, vitamin B12, methionine, and betaine promoted the regression of symptoms of gastroesophageal reflux disease (GERD) (43). According to a case report, a women being treated for gastroesophageal reflux disease using proton-pump inhibitors (PPIs) failed to develop symptoms following withdrawal of PPIs when treated with a combination of melatonin, 5-hydroxytryptophan, D,L-methionine, betaine, L-taurine, riboflavin, vitamin B6, folic acid, and calcium (87). However, the beneficial effects of betaine on gastrointestinal symptoms are unclear from these studies, as betaine was administered in combination with other supplements, and according to the case report, only minimal symptoms occurred if all ingredients except for melatonin were withdrawn.
  • AntidiarrhealsAntidiarrheals: In clinical research, reported adverse effects associated with betaine have included diarrhea, stomach upset, gastrointestinal irritation, vomiting, and nausea (66; 70; 71).
  • AntiemeticsAntiemetics: In clinical research, reported adverse effects associated with betaine have included diarrhea, stomach upset, gastrointestinal irritation, vomiting, and nausea (66; 70; 71).
  • AntilipemicsAntilipemics: In clinical research, treatment with betaine resulted in significant increases in total cholesterol, LDL-cholesterol, and triglycerides in various studies, including studies assessing the effect of betaine in patients with coronary artery disease (67; 26; 68; 69). In one study, treatment with betaine resulted in significant increase in HDL-C (69). In clinical research, treatment with bezafibrate resulted in increased excretion of betaine compared to patients who lacked fibrate treatment (88).
  • AntineoplasticsAntineoplastics: An epidemiological study reported that dietary intake of betaine was inversely associated with the risk of colorectal adenoma in women in the United States (56).
  • AntipsychoticsAntipsychotics: A 10 year-old boy with MTHFR deficiency experienced severe psychotic symptoms which disappeared upon betaine supplementation, although the dose was not specified within the report (89). According to secondary sources, betaine may cause adverse mental changes.
  • AntiviralsAntivirals: In clinical research, treatment with S-adenosyl-L-methionine (SAMe) plus betaine improved early virological response in patients with hepatitis C who were unresponsive to treatment with pegylated interferon alpha ((peg)IFNalpha) and ribavirin (44). However, the effects of betaine alone are unclear from this study.
  • BezafibrateBezafibrate: In clinical research, treatment with bezafibrate resulted in increased excretion of betaine compared to patients who lacked fibrate treatment (88).
  • Birth controlBirth control: In clinical research, a gel containing an equimolar concentration of alkyl amine oxide and alkyl betaine showed contraceptive efficacy that was considered to be non-inferior to nonoxynol-9 (42). However, the effects of betaine alone are unclear from this study.
  • Cardiovascular agentsCardiovascular agents: In clinical research, treatment with betaine resulted in significant increases in total cholesterol, LDL-cholesterol, and triglycerides in various studies, including studies assessing the effect of betaine in patients with coronary artery disease (67; 26; 68; 69). In addition, patients with coronary artery disease showed a significant decrease in flow-mediated dilation following treatment with betaine (67). A prospective cohort study has reported that individuals who were in the highest quartile of choline plus betaine intake showed a slight but statistically insignificant increase in the risk of coronary heart disease (81). However, in homocystinuric patients (those with CBS deficiency), treatment with 2-15g betaine daily reduced the risk of total cardiovascular events (3).
  • Dermatologic agents, topical steroidsDermatologic agents, topical steroids: According to a case report, systemic allergic dermatitis of the lips occurred in an individual using a contact lens solution containing cocamidopropyl betaine (CAPB); however, this effect was attributed to the presence of myristamidopropyl dimethylamine (MAPD) in the solution (74). Similarly, literature review has indicated that many allergies attributed to CAPB are actually caused by an allergy to 3-(dimethylamino)propylamine (DMAPA), a substrate used to synthesize CAPB (75). However, many case reports have indicated that allergic dermatitis may occur in individuals due to use of products containing CAPB. According to a report, contact dermatitis due to treatment with Octenisept? occurred in 11 out of 251 patients, and in at least three of these cases, the adverse reaction was attributed to cocamidopropyl betaine and phenoxyethanol (76). Similarly, according to a case series study, up to 27% of individuals with an allergy to ascaridole showed a positive skin patch test reaction to cocamidopropyl betaine (77). In another case report, allergic contact dermatitis consisting of pruriginous lesions of the cheeks and chin occurred in an individual who used a shaving gel containing CAPB (78). In vitro, exposure of TERT-1 keratinocytes to Tego? Betain, a concentrated solution of CAPB, resulted in significant reduction in cell viability (82).
  • Dental and periodontal agentsDental and periodontal agents: In clinical research, use of mouthwash containing cocamidopropyl betaine in combination with other constituents significantly reduced concentrations of volatile sulfate compounds and reduced breath malodor (33). In other clinical study, mouthwash containing betaine in combination with xylitol and sodium fluoride improved saliva flow compared to baseline (34), while treatment with dry mouth products containing olive oil, betaine, and xylitol increased salivary flow rates, reduced complaints regarding dry mouth symptoms, and improved quality of life (35). However, the effects of betaine alone are unclear from these studies.
  • Exercise performance enhancersExercise performance enhancers: In clinical research, treatment with betaine significantly improved bench training volume, back squat volume, body fat percent and lean body mass, and cross sectional area of the arm compared to placebo in individuals participating in strength training (36). In other clinical research, treatment with betaine reduced feelings of fatigue compared to placebo in individuals participating in exercise training (37). Finally, treatment with betaine has been reported to increase resting protein kinase B (Akt) and IGF-1, as well as decrease cortisol and attenuate exercise-induced reduction in Akt phosphorylation (38).
  • Fertility agentsFertility agents: In clinical research, a gel containing an equimolar concentration of alkyl amine oxide and alkyl betaine showed contraceptive efficacy that was considered to be non-inferior to nonoxynol-9 (42). However, the effects of betaine alone are unclear from this study.
  • FibratesFibrates: In clinical research, treatment with bezafibrate resulted in increased excretion of betaine compared to patients who lacked fibrate treatment (88).
  • Gastrointestinal agentsGastrointestinal agents: In clinical research, reported adverse effects associated with betaine have included diarrhea, stomach upset, gastrointestinal irritation, vomiting, and nausea (66; 70; 71).
  • H2-receptor antagonistsH2-receptor antagonists: In clinical research, treatment with a dietary supplement containing melatonin, L-tryptophan, vitamin B6, folic acid, vitamin B12, methionine, and betaine promoted the regression of symptoms of gastroesophageal reflux disease (GERD) (43). According to a case report, a women being treated for gastroesophageal reflux disease using proton-pump inhibitors failed to develop symptoms following withdrawal of PPIs when treated with a combination of melatonin, 5-hydroxytryptophan, D,L-methionine, betaine, L-taurine, riboflavin, vitamin B6, folic acid, and calcium (87). However, the beneficial effects of betaine on gastrointestinal symptoms are unclear from these studies, as betaine was administered in combination with other supplements, and according to the case report, only minimal symptoms occurred if all ingredients except for melatonin were withdrawn.
  • HepatotoxinsHepatotoxins: Alcohol-induced hepatic steatosis was reduced by betaine supplementation in animal models (90; 31). According to expert opinion, niacin-induced hepatotoxicity, likely caused by a reduction in levels of S-adenosylmethionine in the liver leading to an increase in homocysteine levels, may be reduced by co-treatment with an equimolar amount of betaine (60). However, preclinical or clinical data supporting this conclusion are lacking.
  • LaxativesLaxatives: In clinical research, reported adverse effects associated with betaine have included diarrhea, stomach upset, gastrointestinal irritation, vomiting, and nausea (66; 70; 71).
  • Photoprotective agentsPhotoprotective agents: In clinical research, treatment with a skin cream containing N-palmitoylethanolamine, N-acetylethanolamine, betaine, and sarcosine significantly reduced the development of erythema, as well as the formation of thymine dimers, when applied for at least one month prior to exposure to significant UV irradiation (48). However, the effect of betaine alone is unclear from this research.
  • Proton pump inhibitorsProton pump inhibitors: In clinical research, treatment with a dietary supplement containing melatonin, L-tryptophan, vitamin B6, folic acid, vitamin B12, methionine, and betaine promoted the regression of symptoms of gastroesophageal reflux disease (GERD) (43). According to a case report, a women being treated for gastroesophageal reflux disease using proton-pump inhibitors failed to develop symptoms following withdrawal of PPIs when treated with a combination of melatonin, 5-hydroxytryptophan, D,L-methionine, betaine, L-taurine, riboflavin, vitamin B6, folic acid, and calcium (87). However, the beneficial effects of betaine on gastrointestinal symptoms are unclear from these studies, as betaine was administered in combination with other supplements, and according to the case report, only minimal symptoms occurred if all ingredients except for melatonin were withdrawn.
  • Renally eliminated agentsRenally eliminated agents: Excretion of glycine betaine is elevated in diabetic and renal disease patients (91).
  • Weight loss agentsWeight loss agents: Betaine has reduced adipose tissue in pigs (92; 65). However, in a clinical trial of 42 obese subjects, there was no significant difference in body weight, resting energy expenditure, or fat mass between the betaine group (6g daily for 12 weeks) and controls (26).
  • Wound healing agentsWound healing agents: In clinical research, treatment of chronic wounds using a combination of betaine plus polyhexanide significantly reduced wound pH, improved the ability to decontaminate encrusted wounds, and reduced wound odor (49; 50). However, the effects of betaine alone are unclear from these studies.

    • Betaine/Herb/Supplement Interactions:

  • AntacidsAntacids: In clinical research, treatment with a dietary supplement containing melatonin, L-tryptophan, vitamin B6, folic acid, vitamin B12, methionine, and betaine promoted the regression of symptoms of gastroesophageal reflux disease (GERD) (43). According to a case report, a women being treated for gastroesophageal reflux disease using proton-pump inhibitors failed to develop symptoms following withdrawal of PPIs when treated with a combination of melatonin, 5-hydroxytryptophan, D,L-methionine, betaine, L-taurine, riboflavin, vitamin B6, folic acid, and calcium (87). However, the beneficial effects of betaine on gastrointestinal symptoms are unclear from these studies, as betaine was administered in combination with other supplements, and according to the case report, only minimal symptoms occurred if all ingredients except for melatonin were withdrawn.
  • AntidiarrhealsAntidiarrheals: In clinical research, reported adverse effects associated with betaine have included diarrhea, stomach upset, gastrointestinal irritation, vomiting, and nausea (66; 70; 71).
  • AntiemeticsAntiemetics: In clinical research, reported adverse effects associated with betaine have included diarrhea, stomach upset, gastrointestinal irritation, vomiting, and nausea (66; 70; 71).
  • AntilipemicsAntilipemics: In clinical research, treatment with betaine resulted in significant increases in total cholesterol, LDL-cholesterol, and triglycerides in various studies, including studies assessing the effect of betaine in patients with coronary artery disease (67; 26; 68; 69). In one study, treatment with betaine resulted in significant increase in HDL-C (69). In clinical research, treatment with bezafibrate resulted in increased excretion of betaine compared to patients who lacked fibrate treatment (88).
  • AntineoplasticsAntineoplastics: An epidemiological study reported that dietary intake of betaine was inversely associated with the risk of colorectal adenoma in women in the United States (56).
  • AntioxidantsAntioxidants: In clinical research, treatment with betaine attenuated the increase in urinary HCTL caused by strength training exercises (36).
  • AntipsychoticsAntipsychotics: A 10 year-old boy with MTHFR deficiency experienced severe psychotic symptoms which disappeared upon betaine supplementation, although the dose was not specified within the report (89). According to secondary sources, betaine may cause adverse mental changes.
  • AntiviralsAntivirals: In clinical research, treatment with S-adenosyl-L-methionine (SAMe) plus betaine improved early virological response in patients with hepatitis C who were unresponsive to treatment with pegylated interferon alpha ((peg)IFNalpha) and ribavirin (44). However, the effects of betaine alone are unclear from this study.
  • Birth controlBirth control: In clinical research, a gel containing an equimolar concentration of alkyl amine oxide and alkyl betaine showed contraceptive efficacy that was considered to be non-inferior to nonoxynol-9 (42). However, the effects of betaine alone are unclear from this study.
  • Cardiovascular agentsCardiovascular agents: In clinical research, treatment with betaine resulted in significant increases in total cholesterol, LDL-cholesterol, and triglycerides in various studies, including studies assessing the effect of betaine in patients with coronary artery disease (67; 26; 68; 69). In addition, patients with coronary artery disease showed a significant decrease in flow-mediated dilation following treatment with betaine (67). A prospective cohort study has reported that individuals who were in the highest quartile of choline plus betaine intake showed a slight but statistically insignificant increase in the risk of coronary heart disease (81). However, in homocystinuric patients (those with CBS deficiency), treatment with 2-15g betaine daily reduced the risk of total cardiovascular events (3).
  • CholineCholine: In clinical research, treatment with choline (dietary or supplementation) significantly increased plasma concentrations of betaine (93; 94; 95). Also, pregnant women who received dietary choline experienced increased plasma and breast milk concentrations of betaine (85).
  • Dermatologic agentsDermatologic agents: According to a case report, systemic allergic dermatitis of the lips occurred in an individual using a contact lens solution containing cocamidopropyl betaine (CAPB); however, this effect was attributed to the presence of myristamidopropyl dimethylamine (MAPD) in the solution (74). Similarly, literature review has indicated that many allergies attributed to CAPB are actually caused by an allergy to 3-(dimethylamino)propylamine (DMAPA), a substrate used to synthesize CAPB (75). However, many case reports have indicated that allergic dermatitis may occur in individuals due to use of products containing CAPB. According to a report, contact dermatitis due to treatment with Octenisept? occurred in 11 out of 251 patients, and in at least three of these cases, the adverse reaction was attributed to cocamidopropyl betaine and phenoxyethanol (76). Similarly, according to a case series study, up to 27% of individuals with an allergy to ascaridole showed a positive skin patch test reaction to cocamidopropyl betaine (77). In another case report, allergic contact dermatitis consisting of pruriginous lesions of the cheeks and chin occurred in an individual who used a shaving gel containing CAPB (78). In vitro, exposure of TERT-1 keratinocytes to Tego? Betain, a concentrated solution of CAPB, resulted in significant reduction in cell viability (82).
  • Dental agentsDental agents: In clinical research, use of mouthwash containing cocamidopropyl betaine in combination with other constituents significantly reduced concentrations of volatile sulfate compounds and reduced breath malodor (33). In other clinical study, mouthwash containing betaine in combination with xylitol and sodium fluoride improved saliva flow compared to baseline (34), while treatment with dry mouth products containing olive oil, betaine, and xylitol increased salivary flow rates, reduced complaints regarding dry mouth symptoms, and improved quality of life (35). However, the effects of betaine alone are unclear from these studies.
  • Exercise performance enhancersExercise performance enhancers: In clinical research, treatment with betaine significantly improved bench training volume, back squat volume, body fat percent and lean body mass, and cross sectional area of the arm compared to placebo in individuals participating in strength training (36). In other clinical research, treatment with betaine reduced feelings of fatigue compared to placebo in individuals participating in exercise training (37). Finally, treatment with betaine has been reported to increase resting protein kinase B (Akt) and IGF-1, as well as decrease cortisol and attenuate exercise-induced reduction in Akt phosphorylation (38).
  • Fertility agentsFertility agents: In clinical research, a gel containing an equimolar concentration of alkyl amine oxide and alkyl betaine showed contraceptive efficacy that was considered to be non-inferior to nonoxynol-9 (42). However, the effects of betaine alone are unclear from this study.
  • FolateFolate: In clinical trials, patients with renal disease experienced increases in total cholesterol, LDL, HDL, and triglycerides when betaine was taken with folic acid and vitamin B6 (69). According to observational studies, betaine is most strongly associated with lower fasting and postmethionine-loading (PML) serum homocysteine levels among patients with low serum folate levels (96; 97). In clinical research, reduced plasma levels of folate have been reported with betaine treatment (67).
  • Gastrointestinal agentsGastrointestinal agents: In clinical research, reported adverse effects associated with betaine have included diarrhea, stomach upset, gastrointestinal irritation, vomiting, and nausea (66; 70; 71).
  • HepatotoxinsHepatotoxins: Alcohol-induced hepatic steatosis was reduced by betaine supplementation in animal models (90; 31). According to expert opinion, niacin-induced hepatotoxicity, likely caused by a reduction in levels of S-adenosylmethionine in the liver leading to an increase in homocysteine levels, may be reduced by co-treatment with an equimolar amount of betaine (60). However, preclinical or clinical data supporting this conclusion are lacking.
  • LaxativesLaxatives: In clinical research, reported adverse effects associated with betaine have included diarrhea, stomach upset, gastrointestinal irritation, vomiting, and nausea (66; 70; 71).
  • NiacinNiacin: According to expert opinion, niacin-induced hepatotoxicity, likely caused by a reduction in levels of S-adenosylmethionine in the liver leading to an increase in homocysteine levels, may be reduced by co-treatment with an equimolar amount of betaine (60). However, preclinical or clinical data supporting this conclusion are lacking.
  • Photoprotective agentsPhotoprotective agents: In clinical research, treatment with a skin cream containing N-palmitoylethanolamine, N-acetylethanolamine, betaine, and sarcosine significantly reduced the development of erythema, as well as the formation of thymine dimers, when applied for at least one month prior to exposure to significant UV irradiation (48). However, the effect of betaine alone is unclear from this research.
  • Renally eliminated agentsRenally eliminated agents: Excretion of glycine betaine is elevated in diabetic and renal disease patients (91).
  • SAMeSAMe: Betaine can donate a methyl group to re-methylate homocysteine into methionine. Methionine is the precursor to S-adenosylmethionine (SAM), which is used as a methyl donor for many important pathways in the human body. In vitro, inhibition of BHMT resulted in a 50% decrease in S-adenosylmethionine levels (98). In clinical research, treatment with S-adenosyl-L-methionine (SAMe) plus betaine improved early virological response in patients with hepatitis C who were unresponsive to treatment with pegylated interferon alpha ((peg)IFNalpha) and ribavirin (44).
  • Vitamin B6Vitamin B6: In clinical trials, patients with renal disease experiences increases in total cholesterol, LDL, HDL, and triglycerides when betaine was taken with folic acid and vitamin B6 (69).
  • Weight loss agentsWeight loss agents: Betaine has reduced adipose tissue in pigs (92; 65). However, in a clinical trial of 42 obese subjects, there was no significant difference in body weight, resting energy expenditure, or fat mass between the betaine group (6g daily for 12 weeks) and controls (26).
  • Wound healing agentsWound healing agents: In clinical research, treatment of chronic wounds using a combination of betaine plus polyhexanide significantly reduced wound pH, improved the ability to decontaminate encrusted wounds, and reduced wound odor (49; 50). However, the effects of betaine alone are unclear from these studies.

    • Betaine/Food Interactions:

  • Beet sugarBeet sugar: According to expert opinion, beet sugar, which is used to prepare certain types of foods including wine, contains betaine (57). Theoretically, concomitant use of betaine and foods containing beet sugar may result in increased homocysteine-lowering effects.
  • Foods containing cholineFoods containing choline: In clinical research, treatment with choline (dietary or supplementation) significantly increased plasma concentrations of betaine (93; 94; 95). Also, pregnant women who received dietary choline experienced increased plasma and breast milk concentrations of betaine (85).
  • Foods containing folateFoods containing folate: In clinical trials, patients with renal disease experienced increases in total cholesterol, LDL, HDL, and triglycerides when betaine was taken with folic acid and vitamin B6 (69). According to observational studies, betaine is most strongly associated with lower fasting and postmethionine-loading (PML) serum homocysteine levels among patients with low serum folate levels (96; 97).
  • Foods containing vitamin B6Foods containing vitamin B6: In clinical trials, patients with renal disease experienced increases in total cholesterol, LDL, HDL, and triglycerides when betaine was taken with folic acid and vitamin B6 (69).
  • Whole grainsWhole grains: In clinical research, treatment with whole-grain foods significantly increased serum levels of betaine due to the high betaine content in whole grains (99; 100; 101; 102).
  • WineWine: According to expert opinion, an average glass of wine with beet sugar as a constituent contains approximately 3mg betaine (57). Theoretically, concomitant use of betaine and certain wines may result in increased homocysteine-lowering effects.

    • Betaine/Lab Interactions:

  • DimethylglycineDimethylglycine: In human research, treatment with betaine significantly increased urinary dimethylglycine excretion. Compared to the control meal, a significant increase in urinary dimethylglycine level was observed following treatment with a high-choline/high-betaine meal (p=0.001), betaine supplementation (p=0.011), and a high-betaine meal (p=0.030), particularly after six hours (29).
  • HomocysteineHomocysteine: In various animal studies and clinical research, betaine significantly reduced levels of homocysteine in animals or patients with methylenetetrahydrofolate reductase (MTHRF) deficiency (103; 104; 4; 5; 6; 7; 8; 9; 10; 11; 12), cystathionine beta-synthase (CBS) deficiency (105; 13; 14; 15; 5), or abnormalities related to cobalamin metabolism (17; 18; 19; 20; 21; 22; 9). Also, homocysteine concentrations have been lowered in healthy human subjects treated with betaine (27; 24; 26; 29; 28; 23; 72), although in some research this effect was lacking (68).
  • Lipid levelsLipid levels: In clinical research, treatment with betaine resulted in significant increases in total cholesterol, LDL-cholesterol, and triglycerides in various studies, including studies assessing the effect of betaine in patients with coronary artery disease (67; 26; 68; 69). In addition, patients with coronary artery disease showed a significant decrease in flow-mediated dilation following treatment with betaine (67). A prospective cohort study has reported that individuals who were in the highest quartile of choline plus betaine intake showed a slight but statistically insignificant increase in the risk of coronary heart disease (81). In one study, treatment with betaine resulted in significant increase in HDL-C (69).
  • Liver enzymesLiver enzymes: In animal research, betaine decrease alanine aminotransferase, alanine transaminase, and aspirate transaminase (90). In some clinical research, nonalcoholic steatohepatitis patients treated with betaine anhydrous showed decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (66). However, in other clinical studies, significant changes in ALT, AST, alkaline phosphatase, or glutamyl transferase was lacking (71; 26).
  • Plasma betaine levelsPlasma betaine levels: In clinical trials, betaine anhydrous increased plasma betaine levels (26; 69; 29; 106).
  • Protein synthesisProtein synthesis: In clinical research, treatment with betaine has been reported to increase resting protein kinase B (Akt) and IGF-1, as well as decrease cortisol and attenuate exercise-induced reduction in Akt phosphorylation; these effects were attributed to the ability of betaine to promote protein synthesis following exercise (38).