NiaCel 400 [Discontinued] by Thorne

EFFECTIVE

• Homocystinuria. Oral betaine anhydrous is effective at reducing plasma homocysteine levels in patients with homocystinuria associated with cystathionine beta-synthase (CBS) deficiency, 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency, or cobalamin cofactor metabolism (cbl) defect. Details: Clinical research shows that taking oral betaine anhydrous reduces plasma homocysteine levels by 20% to 30% when compared with placebo in adults and children with several types of homocystinuria, including CBS deficiency, MTHFR deficiency, and cbl defect (698). Observational studies have also found that betaine anhydrous reduces plasma homocysteine levels as monotherapy, in combination with other treatments, such as pyridoxine, folate, and cobalamin, and in patients refractory to pyridoxine treatment (145,698,34956). A specific betaine anhydrous product (Cystadane, Recordati Rare Diseases Inc.) is approved by the US FDA for homocystinuria. Oral betaine anhydrous is initiated at a dose of 100 mg/kg daily in children under 3 years of age and a dose of 3 grams twice daily in children 3 years and older, then titrated to effect. Although some patients have taken up to 20 grams daily, some clinical research suggests that doses above 150 mg/kg daily do not provide additional benefit (698).

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral betaine anhydrous decreases plasma homocysteine levels in people with hyperhomocysteinemia; however, any effects on cardiovascular sequela and other clinical outcomes are unclear. Details: Most clinical research in adults with normal or mildly elevated plasma homocysteine levels (<25 micromol/L) shows that taking betaine anhydrous 3-6 grams daily orally for up to 12 weeks can modestly decrease plasma homocysteine levels by 5.5% to 15% when compared with control (6810,16451,16452,34894,34896,34902,34904,34925,34936). Some research indicates that oral doses of betaine anhydrous up to 4 grams daily can lower plasma homocysteine levels without an adverse effect on lipid levels (105813). However, it is not clear whether any reduction in plasma levels of homocysteine results in a decreased risk for cardiovascular disease. In patients with kidney failure, clinical research shows that taking betaine anhydrous 4 grams daily lowers levels of plasma homocysteine after methionine loading, but does not affect fasting levels, when compared with control (16455). However, taking this dose of betaine anhydrous in combination with folate 5 mg daily does not seem to have additive homocysteine-lowering effects in patients with kidney failure when compared with folate alone (34885,34957,34963). A very small clinical study in children with hyperhomocysteinemia secondary to pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) or cobalamin C (cblC) deficiencies shows that taking betaine anhydrous 100 or 250 mg/kg daily in divided doses for one month leads to similar reductions in total plasma homocysteine concentrations, suggesting that an increased dose is not beneficial in the setting of pediatric pnrCBS and cblC deficiencies. The researchers noted that increased doses of betaine anhydrous cause proportional increases in methionine concentrations, which can induce severe hypermethioninemia in patients with pnrCBS, possibly leading to increased intracranial pressure and cerebral edema. In contrast, increases in methionine and S-adenosylmethionine concentrations are desirable in patients with cblC deficiency since low concentrations of both are implicated in the pathology of cblC deficiency (111374).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angelman syndrome. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with Angelman syndrome shows that taking betaine anhydrous (Cystadane, Recordati Rare Diseases, Inc.) 100-200 mg/kg daily or betaine anhydrous 6-12 grams daily for 12 months, in combination with folate, folic acid derivatives, creatine, and/or vitamin B12, does not prevent seizures or improve cognitive, motor, or language development, when compared with placebo or baseline (34932,34945).
• Athletic performance. It is unclear if oral betaine anhydrous improves athletic performance; small clinical trials have yielded conflicting findings that may be related to age, training status, and biological sex. Details: Small clinical trials in males with and without strength training experience shows that taking betaine anhydrous 2-2.5 grams daily for 10-15 days, either alone or in combination with resistance training or blood flow restriction, does not improve muscle power, strength, or performance on bench press, leg press, or squat exercises when compared with placebo (34940,34941,34947,34954,111373). In aerobic exercise training, a small clinical study in healthy untrained males shows that taking betaine anhydrous 1.25 grams twice daily with 300 mL of a sports beverage for 2 weeks does not improve aerobic capacity or performance during exhaustive endurance exercise when compared with placebo (105550). Similarly, a small clinical study in trained male runners shows that taking betaine anhydrous 5 grams once with 1000 mL of a sports beverage after becoming dehydrated does not improve long-distance running or sprinting after rehydration when compared with placebo (34916). Additional clinical research in males and females who have undergone at least 6 months of CrossFit training shows that taking betaine anhydrous 1.25 grams twice daily for 6 weeks while continuing to train does not improve muscle strength, body composition, aerobic capacity, or anaerobic performance when compared with placebo (105549). However, other research shows that betaine anhydrous benefits certain aspects of athletic performance in particular subgroups. One small clinical study in healthy, active males shows that taking betaine anhydrous 2.5 grams daily for 2 weeks improves subjective fatigue scores during exercise when compared with placebo (34941). Another small clinical study in active but untrained young females shows that taking betaine anhydrous (BetaPower, Finnfeeds) 2.5 grams daily for 8 weeks in combination with a structured resistance training program reduces body fat percentage and body fat mass, but does not improve muscle strength, when compared with placebo (98525). Another small clinical study in active females shows that taking betaine anhydrous 1.2 grams twice daily for 2 weeks improves power output during sprinting, but not oxygen uptake, when compared with placebo (107950). Betaine anhydrous has also been studied in adolescents. Preliminary clinical research in trained adolescent soccer players shows that taking betaine 1 gram twice daily orally with 300 mL water for 14 weeks improves muscle power, agility, and sprint time, but not muscle strength, when compared with placebo (108654).
• Colorectal adenoma. It is unclear if oral betaine anhydrous reduces the risk of colorectal adenoma. Details: Preliminary population research has found that high dietary betaine intake is not associated with a reduced risk of colorectal adenoma when compared with low dietary betaine intake (14845).
• Depression. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with major depression shows that taking a specific combination product (DDM Metile, Omeopiacenza) containing betaine anhydrous 125 mg and S-adenosyl-L-methionine (SAMe) 250 mg orally twice daily for 12 months improves depression symptoms when compared with amitriptyline 75 mg daily. After 12 months, patients treated with the combination product showed an average improvement in depression scores of 38%, compared with 18% in patients treated with amitriptyline (90107). It is unclear if this effect is due to betaine anhydrous, SAMe, or the combination.
• Dry mouth. It is unclear if topical betaine anhydrous is beneficial in patients with dry mouth. Details: Applying betaine anhydrous 4% topically twice daily in a toothpaste for 2 weeks reduces symptoms of dry mouth when compared with baseline (6812). Other preliminary clinical research in adults with dry mouth shows that using a specific mouthwash product (Xeros Dentaid) that contains betaine anhydrous 1.33%, xylitol 3.3%, and sodium fluoride 0.05%, each evening for 4 weeks improves dry mouth symptoms when compared with baseline (34944). It is unclear if this effect is due to betaine anhydrous, other ingredients, or the combination. Additionally, the validity of the findings from these studies is limited by the lack of a comparator group.
• Fibrocystic breast disease. Although there has been interest in using oral betaine anhydrous for fibrocystic breast disease, there is insufficient reliable information about the clinical effects of betaine anhydrous for this purpose.
• Gastroesophageal reflux disease (GERD). Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of betaine anhydrous 100 mg, melatonin 6 mg, L-tryptophan 200 mg, vitamin B6 25 mg, folic acid 10 mg, vitamin B12 50 mcg, and methionine 100 mg daily for 40 days reduces symptoms of GERD in more patients when compared with omeprazole 20 mg daily. Symptom improvement occurred in 100% of patients who took this combination supplement, compared with only 66% of patients taking omeprazole (16011). It is unclear if this effect is due to betaine anhydrous, other ingredients, or the combination.
• Gingivitis. Topical betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of patients with gingivitis shows that brushing with a toothpaste containing a combination of extra virgin olive oil, xylitol, and betaine anhydrous daily for 4 months decreases gingival bleeding and improves markers associated with gingival health when compared with placebo and commercial toothpaste (111372).
• Hepatitis C. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking pegylated interferon alpha and ribavirin in combination with betaine anhydrous (Cystadane, Recordati Rare Diseases, Inc.) and S-adenosyl-L-methionine (SAMe) daily for 12 months induces early virological response in approximately 60% of patients with hepatitis C who were previously unresponsive to treatment with pegylated interferon alpha and ribavirin. However, sustained virological response only occurred in 10% of these patients (20465). The validity of this study is limited by the lack of a comparator group. Also, it is unclear if this effect is due to betaine anhydrous, SAMe, or the combination.
• Metabolic Syndrome. It is unclear if oral betaine anhydrous is beneficial in patients with metabolic syndrome. Details: A large observational study in older adults with overweight or obesity and metabolic syndrome has found that increased dietary intake of betaine for 1 year is associated with reduced body weight, waist circumference, glycated hemoglobin (HbA1c), body weight, and triglycerides and increased levels of high-density lipoprotein (HDL) cholesterol (111375).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral betaine anhydrous is beneficial in patients with NASH. Details: Preliminary clinical research shows that taking betaine anhydrous 10 grams twice daily orally for 12 months improves NASH scores when compared with placebo (34928). Taking betaine anhydrous also normalizes liver enzyme levels and reduces inflammation and fibrosis when compared with baseline (10631,34928).
• Obesity. It is unclear if oral betaine anhydrous is beneficial in patients with obesity. Details: Preliminary clinic research in obese adults on a reduced-calorie diet shows that taking betaine anhydrous 3 grams orally twice daily for 12 weeks does not reduce body weight or fat mass or improve resting energy expenditure when compared with placebo (16452). A meta-analysis of small randomized controlled trials that studied the effects of betaine anhydrous on body composition also shows that taking betaine 1.5-20 grams daily for 2-52 weeks does not reduce body mass, fat mass, or fat-free mass when compared with control. However, the validity of this study is limited by inclusion of obese, non-obese, and healthy patients (108653).
• Osteoarthritis. Although there has been interest in using oral betaine anhydrous for osteoarthritis, there is insufficient reliable information about the clinical effects of betaine anhydrous for this purpose.
• Rett syndrome. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in female children with Rett syndrome shows that taking a combination of folate 15 mg and betaine anhydrous 6-12 grams orally daily for 12 months does not improve motor function, growth, or development when compared with placebo. In addition, one subgroup analysis suggests that taking the combination product may reduce head circumference growth rate (34922).
• Sunburn. Topical betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy adults shows that applying a specific cream (Physiogel AI), which contains betaine anhydrous 0.36%, N-palmitoylethanolamine 0.3%, N-acetylethanolamine 0.21%, and sarcosine 0.24%, daily for one month prior to ultraviolet (UV) light exposure can reduce UV-induced redness when compared with placebo. However, application of this cream only once 20 minutes prior to UV exposure does not have any effect (34905). It is unclear if any benefits are due to betaine anhydrous, other ingredients, or the combination. More evidence is needed to rate betaine anhydrous for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Although there is interest in using oral nicotinamide riboside for AMD, there is insufficient reliable information about the clinical effects of nicotinamide riboside for this condition.
• Alzheimer disease. Although there is interest in using oral nicotinamide riboside for Alzheimer disease, there is insufficient reliable information about the clinical effects of nicotinamide riboside for this condition.
• Ataxia telangiectasia. It is unclear if oral nicotinamide riboside improves ataxia telangiectasia. Details: Preliminary clinical research in adults and children with ataxia telangiectasia shows that taking nicotinamide riboside orally 25 mg/kg daily for 4 months improves ataxia scores by 11% to 17% when compared with baseline. Ataxia scores also worsened after treatment withdrawal. The validity of this study is limited by the lack of a comparator group (107703).
• Athletic performance. It is unclear if oral nicotinamide riboside improves athletic performance in healthy adults. Details: One small study in young, healthy males shows that taking a specific nicotinamide riboside product (NAD+ Cell Regenerator, Life Extension) 500 mg two hours before exercise does not improve measures of muscle strength, muscle fatigue, or oxygen consumption when compared with placebo (102036). Given the small sample size, this study is limited by a lack of adequate power to detect significant differences between groups.
• Diabetes. Although there is interest in using oral nicotinamide riboside for diabetes, there is insufficient reliable information about the clinical effects of nicotinamide riboside for this condition.
• Heart failure. It is unclear if oral nicotinamide riboside is beneficial for heart failure. Details: Preliminary clinical research in patients with heart failure and a left ventricle ejection fraction of less than 40% shows that taking nicotinamide riboside 250 mg orally twice daily, titrated weekly by 250 mg to a final dose of 1000 mg orally twice daily, for 12 weeks does not improve 6-minute walk test distance or quality of life scores when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110506).
• Hyperlipidemia. It is unclear if oral nicotinamide riboside improves lipid levels. Details: One small clinical study in sedentary males with obesity and elevated blood lipids shows that taking nicotinamide riboside (Niagen, ChromaDex) 1000 mg twice daily for 12 weeks does not improve total cholesterol or low-density lipoprotein (LDL) cholesterol when compared with placebo (94745).
• Hypertension. It is unclear if oral nicotinamide riboside reduces blood pressure. Details: One small clinical study in patients with and without hypertension shows that taking nicotinamide riboside (Niagen, ChromaDex) 500 mg twice daily for 6 weeks non-significantly reduces systolic and diastolic blood pressure by around 4 mmHg and 2 mmHg, respectively, when compared with placebo. The effect seems to be more pronounced in patients with elevated blood pressure at baseline (94744).
• Nonalcoholic fatty liver disease (NAFLD). Oral nicotinamide riboside has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with NAFLD shows that taking a combination product containing nicotinamide riboside 125 mg and pterostilbene 25 mg (Basis, Elysium Health), 2-4 tablets orally daily for 26 weeks does not improve liver function test levels or liver fat content when compared with placebo (110508).
• Obesity. It is unclear if oral nicotinamide riboside improves weight loss. Details: Two small clinical studies in adults with obesity shows that taking nicotinamide riboside (Niagen, ChromaDex) 1000 mg once or twice daily for 6-12 weeks does not reduce body weight or improve insulin sensitivity, glucose metabolism, or lipid levels when compared with placebo (94745,104935).
• Parkinson disease. It is unclear if oral nicotinamide riboside improves Parkinson disease. Details: Very preliminary clinical research in adults with newly diagnosed Parkinson disease shows that taking nicotinamide riboside 500 mg orally twice daily for 4 weeks does not improve Parkinson disease scores when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110504).
• Physical performance. It is unclear if oral nicotinamide riboside improves physical performance in older adults. Details: One small clinical study in healthy, elderly males shows that taking a specific nicotinamide riboside product (NAD+ Cell Regenerator, Life Extension) 500 mg two hours before exercise seems to improve some measures of muscle strength and fatigue, but not oxygen consumption, when compared with placebo. Additionally, muscle strength, as measured by isometric peak torque, was improved in these older patients when compared with younger males taking the same product (102036). More evidence is needed to rate nicotinamide riboside for these uses.

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LIKELY SAFE ...when used orally and appropriately in doses of up to 6 grams daily (698,10631). However, some patients have used up to 20 grams daily with apparent safety (698). Betaine anhydrous is available as an FDA-approved prescription product (Cystadane) (698), and also as a supplement. The European Food Safety Authority states that betaine anhydrous is safe to use in doses up to 6 mg/kg daily, in addition to usual dietary intake (105548). There is insufficient reliable information available about the safety of topical betaine anhydrous.

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses up to 150 mg/kg daily (698). However, some patients have used up to 20 grams daily with apparent safety (698). Prescription betaine anhydrous (Cystadane) is approved by the US FDA for use in infants and children (698).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when nicotinamide riboside chloride is used orally and appropriately. The European Food Safety Authority has set a tolerable upper intake level (UL) of 300 mg daily for nicotinamide riboside chloride (104937,107706). In clinical research, higher doses have been used for up to 12 weeks (110504,110506). A specific nicotinamide riboside branded ingredient (Niagen, ChromaDex) 1000 mg has been used twice daily for 12 weeks with apparent safety (94744,94745,94746,102035).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when nicotinamide riboside chloride is used orally and appropriately. The European Food Safety Authority has determined that taking nicotinamide riboside chloride in doses of up to 230 mg daily is safe when pregnant or breastfeeding (104937,107706).

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(Read more about BETAINE ANHYDROUS)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, nicotinamide riboside may have additive effects with antihypertensive drugs, potentially increasing the risk for hypotension.  Details One small clinical study suggests that nicotinamide riboside can modestly reduce blood pressure in hypertensive patients (94744). However, other clinical research did not find a reduction in blood pressure when compared with control (104935).

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General ...Orally, betaine anhydrous is generally well tolerated.
Most Common Adverse Effects:
Orally: Body odor, diarrhea, elevated cholesterol levels, GI distress, nausea, vomiting.
Serious Adverse Effects (Rare):
Orally: Cerebral edema.

Cardiovascular ...Betaine anhydrous might have adverse effects on the plasma lipid profile. Some studies have reported a 3% to 4% increase in total and low-density lipoprotein (LDL) cholesterol levels with betaine anhydrous 6 grams daily (16452,16455,16456,34904). A meta-analysis of 6 studies in adults, some with obesity and/or prediabetes, shows that taking betaine anhydrous 4-6 grams daily for 6-24 weeks is associated with a mean increase in total cholesterol of 4 mg/dL, with no significant change in LDL cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels (105814). Another meta-analysis of 12 studies, some in healthy adults and others in adults with various disease states, shows that taking betaine anhydrous 1.5-20 grams daily for 2-52 weeks is associated with a mean increase in total cholesterol of 14 mg/dL, and a mean increase in LDL cholesterol of 10 mg/dL, with no change in triglyceride or HDL cholesterol levels (105813).

Gastrointestinal ...Orally, betaine anhydrous can cause vomiting, nausea, GI distress, and diarrhea (698,10631,34888,34928,111374).

Neurologic/CNS ...When used orally to treat homocystinuria due to cystathionine beta-synthase deficiency, elevated plasma methionine concentrations can occur following use of betaine anhydrous, which might lead to cerebral edema (698,111374).

Other ...Orally, betaine anhydrous can cause body odor (698,10631).

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General ...Orally, nicotinamide riboside seems to be well tolerated.
Most Common Adverse Effects:
Orally: Bloating, muscle pain, nausea, pruritus, sweating, and transient changes in stools.

Dermatologic ...Orally, mild cases of flushing, skin rash, pruritus, and excessive sweating have been reported in clinical trials for some patients taking nicotinamide riboside (Niagen, ChromaDex) (94744,94745). However, flushing and skin rash were reported at the same rate in patients receiving placebo (94744).

Gastrointestinal ...Orally, mild cases of nausea, bloating, and transient changes in stools have been reported in clinical trials for some patients taking nicotinamide riboside (Niagen, ChromaDex) (94744,94745,102035).
Other gastrointestinal adverse effects such as abdominal discomfort, diarrhea, and dyspepsia have been reported with oral use of a combination product (Basis, Elysium Health) containing nicotinamide riboside and pterostilbene (94747). It is unclear if these effects were due to nicotinamide riboside, pterostilbene, or the combination.

Hematologic ...Orally, increased bruising was reported in one clinical trial for one patient taking nicotinamide riboside (Niagen, ChromaDex) (94744).

Musculoskeletal ...Orally, leg cramps were reported in one clinical trial for one patient taking nicotinamide riboside (Niagen, ChromaDex) (94744). Some patients taking this specific nicotinamide riboside product in another clinical trial have reported mild muscle pain or soreness (102035).

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