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POSSIBLY INEFFECTIVE

• Athletic performance. Taking oral choline before exercise does not improve athletic performance. Details: Clinical research in trained athletes shows that taking oral choline 2.43 grams as a single dose does not delay fatigue during endurance sports when compared with placebo (5164). Other clinical research in untrained adults shows that taking oral choline 8.425 grams or 50 mg/kg once prior to participating in exhaustive, load-carrying exercise does not improve dexterity, upper or lower body strength, grip strength, or run time-to-exhaustion following exercise when compared with placebo (42229,42237).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral choline is beneficial in patients with age-related cognitive decline. Details: Small clinical studies in adults with memory loss shows that taking choline 2 grams four times daily orally for 21 days does not improve memory when compared with placebo (5170). Observational research in adults over 60 years of age has found that intake of choline 187-399.5 mg daily is associated with a 33% to 42% reduced odds of low cognitive function when compared with intake of less than 187 mg daily. Intake of more than 399.5 mg daily was not associated with low cognitive function when compared with less than 187 mg daily (109100).
• Allergic rhinitis (hay fever). It is unclear if oral choline is beneficial in patients with allergic rhinitis. Details: Preliminary clinical research shows that taking oral choline, as tricholine citrate, 500 mg three times daily for 8 weeks is less effective than intranasal budesonide 200 mcg twice daily for reducing symptoms of allergic rhinitis (42252).
• Alzheimer disease. Although there has been interest in using oral choline for Alzheimer disease, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Asthma. Small clinical studies suggest that oral choline may modestly improve symptoms in patients with asthma. Details: Preliminary clinical research shows that taking choline 500-1000 mg orally three times daily for 3-4 months decreases the severity of symptoms, the number of symptomatic days, and the need to use bronchodilators in patients with asthma when compared with placebo (5165,5166). Preliminary data also shows that choline 3 grams daily might be more effective than 1.5 grams daily (5165).
• Autism spectrum disorder. Oral choline has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of donepezil 2.5-5 mg daily and choline bitartrate 350 mg daily for 12 weeks improves receptive language skills, but no other outcomes, for up to 6 months after treatment when compared with placebo in children aged 5-10 years with autism spectrum disorder. Also, adolescents aged 11-16 years experienced no benefits, and some experienced an increase in behavioral symptoms, such as irritability (103571). It is unclear if this effect is due to choline, donepezil, or the combination.
• Breast Cancer. It is unclear if dietary intake of choline reduces the risk of breast cancer. Details: A meta-analysis of 6 low to moderate-quality observational studies suggests that neither high nor low dietary intake of choline is associated with breast cancer risk. This finding is largely influenced by inclusion of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort study, which analyzed data from over 300,000 subjects. However, subanalysis of 3 case-control studies suggests that high dietary intake of choline may be associated with a decreased risk of breast cancer when compared with low choline intake (111416). The interpretation of these findings is limited by the heterogeneity of the included studies, self-reported data, and a small number of studies.
• Bronchitis. Although there has been interest in using oral and inhaled choline for bronchitis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Cancer. It is unclear if dietary choline intake reduces the risk for cancer. Details: A meta-analysis of 11 low-quality population studies has found that high dietary intake of choline is associated with an 18% lower risk of cancer when compared with low choline intake. High dietary intake of both choline and betaine was associated with a 40% lower risk of cancer (97390).
• Cardiovascular disease (CVD). It is unclear if dietary choline intake reduces the risk of CVD or improves outcomes in patients with CVD. Details: A meta-analysis of population research has found that high intake of dietary choline is not associated with a lower risk of coronary artery disease, stroke, or mortality when compared with a diet low in choline (97388). A more recent population study has found that energy-adjusted total choline intake is not associated with the incidence of CVD over ten years. However, the highest intake of free choline is associated with a 34% reduced risk of CVD when compared with the lowest intake (109104).
• Cerebellar ataxia. It is unclear if oral choline is beneficial in patients with cerebellar ataxia. Details: Despite some anecdotal reports suggesting that taking choline improves motor function, preliminary clinical research shows that taking choline 4-5 grams orally daily for 4 days to 6 weeks does not reduce cerebellar ataxia (5161,5173,23679).
• Cognitive function. It is unclear if oral choline is beneficial for improving cognitive function in healthy adults. Details: Preliminary clinical research shows that taking a single dose of choline 50 mg/kg orally prior to participating in an exhaustive, load-carrying task does not improve reaction time, reasoning, memory, or serial addition and subtraction ability following the task when compared with placebo (42237). Also, preliminary clinical research in patients requiring long-term total parenteral nutrition (TPN) shows that adding choline chloride 2 grams daily to TPN for 24 weeks might improve delayed visual memory, but does not improve other measures of cognitive performance, when compared with TPN alone (42232).
• Cirrhosis. Although there has been interest in using oral choline for cirrhosis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Complex partial seizures. Although there has been interest in using oral choline for complex partial seizures, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Dementia. Although there has been interest in using oral choline for dementia, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Depression. It is unclear if oral choline is beneficial for the treatment or prevention of depression. Details: Observational research has found that dietary choline intake of at least 198 mg daily is associated with a 32% to 43% decreased risk of depressive symptoms when compared with intakes of less than 198 mg daily (109106). It is unclear if choline supplementation is beneficial for depression.
• Diabetes. It is unclear if oral choline is beneficial for the treatment or prevention of type 2 diabetes; the available research is conflicting. Details: Preliminary clinical research shows that taking oral choline bitartrate 1000 mg daily for 2 months does not affect coagulation parameters or levels of triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol in patients with type 2 diabetes (103569). Choline has also been evaluated for the prevention of type 2 diabetes. In Finnish males, observational research has found that dietary intake of total choline at levels of more than 482 mg daily, especially as phosphatidylcholine, is associated with a 25% lower risk of developing type 2 diabetes over the following 19.3 years when compared with intakes of less than 382 mg daily (103567). However, in males and females in the US, additional observational research has found no association between dietary choline and risk of type 2 diabetes over a mean of 9 years (103570). In addition, a sub-analysis found that the highest intakes of choline (a median of 487 mg daily) were associated with a 54% higher risk of type 2 diabetes among females, but not males, when compared with the lowest intakes (a median of 175 mg daily) (103570). Population research in patients with diabetes has found that an intake of dietary choline in amounts of at least 279 mg daily is associated with a 2.1-fold increased odds of diabetic retinopathy in females, but not males, when compared with an intake less than 206 mg daily (109102). It is unclear if choline itself is responsible for the increased odds of diabetic retinopathy in this population.
• Fetal alcohol spectrum disorders (FASD). It is unclear if oral choline improves cognition in children with fetal alcohol spectrum disorders (FASD). Details: Clinical research in children aged 2.5-5 years with FASD shows that taking oral choline bitartrate, providing choline 500 mg, daily for 9 months does not improve global cognitive development or hippocampal-dependent memory when compared with placebo. However, a subgroup analysis of only children aged 2.5-4 years suggests that choline may improve hippocampal-dependent memory (92112). Follow-up of this study at 7 years shows that choline improves motor speed and suggests a trend towards improved color naming, which are components of executive functioning testing, when compared with placebo (111745). The validity of these findings is limited by the high rate of patient discontinuation which limits statistical power. A small clinical trial in children 5-10 years old with FASD shows that taking oral glycerophosphocholine, providing choline 625 mg, daily for 6 weeks does not improve cognitive function, executive function, attention, or hyperactivity when compared with placebo (97389).
• Hepatitis. Although there has been interest in using oral choline for hepatitis, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Huntington disease. Although there has been interest in using oral choline for Huntington disease, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Hypertension. It is unclear if oral choline is beneficial for the prevention or treatment of hypertension. Details: Population research has found that every 100-mg increase in daily dietary choline intake is associated with a 15% decreased risk of developing hypertension over the next 4.6 to 9.1 years (109098). However, it is unclear if any benefits are specifically related to dietary choline or whether choline supplementation is beneficial.
• Infant development. It is unclear if oral choline intake during pregnancy is beneficial for infant development; the available research is conflicting. Details: Two observational studies have found that higher intake of choline during the second and third trimesters of pregnancy is associated with improvement in offspring cognitive development and visual memory at the age of 18 months and 7 years, respectively, when compared with lower choline intake (94654,94657). One of these studies found that each 1 mcmol/L increase in maternal blood levels of choline at 16 weeks' gestation was associated with a 2.23-point increase in cognitive skill score based on the Bayley Scales of Infant Development (BSID-III) at 18 months of age (94657). Also, some observational research has found that higher plasma levels of choline during pregnancy are associated with higher processing speed and decreased social withdrawal at 4 years of age in the offspring (109101). In contrast, 3 observational studies have found that higher intake of choline during pregnancy, as well as higher maternal and cord blood levels of choline, are not associated with improved offspring intelligence at 5 years of age or cognitive performance at 3 or 7 years of age (94654,94655,94656). However, many of these observational studies, including those with positive findings, included populations with a mean intake of choline that was below the recommended adequate intake of 450 mg daily (94654,94656). It's possible that higher intake of choline is needed to observe a benefit; however, research on the effects of choline supplementation is limited. One small clinical trial shows that taking choline 930 mg daily during the third trimester modestly improves sustained attention in the child at 7 years of age when compared with taking 480 mg daily (109105).
• Metabolic syndrome. It is unclear if oral choline is beneficial in patients with metabolic syndrome. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking oral choline 400 mg daily for 4 weeks does not decrease body weight, blood pressure, plasma glucose levels, or low-density lipoprotein (LDL) cholesterol levels, or increase high-density lipoprotein (HDL) cholesterol levels, when compared with baseline (105731).
• Neural tube birth defects. It is unclear if oral choline intake is beneficial for preventing neural tube defects. Details: Population research has found that females who have a high dietary choline intake around the time of conception have a lower risk of having offspring with a neural tube defect when compared to those with lower intake (13134).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral choline is beneficial in patients with nonalcoholic fatty liver disease (NAFLD). Details: A cross-sectional analysis of results from observational and clinical research shows that low dietary intake of choline is associated with increased fibrosis in postmenopausal adults with NAFLD, but not in children, males, or premenopausal adults with NAFLD. Dietary choline intake was not associated with steatosis severity in any patient subgroup (92109).
• Schizophrenia. Although there has been interest in using oral choline for schizophrenia, there is insufficient reliable information about the clinical effects of choline for this purpose.
• Tourette syndrome. Although there has been interest in using oral choline for Tourette syndrome, there is insufficient reliable information about the clinical effects of choline for this purpose.
• TPN-associated hepatic steatosis. It is unclear if intravenous choline is beneficial in patients with TPN-associated hepatic steatosis. Details: In patients receiving long-term total parenteral nutrition (TPN), plasma levels of choline can decrease. Small, low-quality clinical studies show that administering intravenous choline 1-4 grams daily for 24 weeks improves some markers of TPN-associated hepatic steatosis when compared with baseline or placebo (5174,42235). More evidence is needed to rate choline for these uses.

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POSSIBLY EFFECTIVE

• Metabolic syndrome. Oral inositol seems to modestly improve lipid parameters, blood pressure, and insulin resistance in patients with metabolic syndrome. Details: Some clinical research in postmenopausal adults with metabolic syndrome following a low-calorie diet shows that taking myo-inositol 2 grams twice daily for one year reduces total cholesterol by 29 mg/dL, triglycerides by 64 mg/dL, systolic and diastolic blood pressure by 9 mmHg and 6 mmHg, respectively, increases high-density lipoprotein (HDL) cholesterol by 6 mg/dL, and improves insulin resistance when compared with placebo. It did not reduce body mass index or waist circumference in these patients (91554). A meta-analysis of clinical studies in a mixed population shows similar effects on blood pressure, especially among postmenopausal adults with metabolic syndrome, at durations exceeding 8 weeks, and at doses of at least 4 grams (108820). Another clinical study in postmenopausal adults with metabolic syndrome and at risk for breast cancer shows that taking a combination of inositol and alpha-lipoic acid daily for 6 months, in combination with a low-calorie diet, reduces insulin resistance (HOMA-IR) by at least 20% when compared with a low-calorie diet alone. Also, taking inositol and alpha-lipoic acid seems to increase HDL cholesterol by about 6% and reduce triglycerides by 5% when compared to baseline (91543). It is unclear if these effects are due to inositol, alpha-lipoic acid, or the combination.
• Polycystic ovary syndrome (PCOS). Oral inositol, often in combination with folic acid, seems to improve some glycemic, lipid, metabolic, hormonal, and reproductive parameters in patients with PCOS. However, research is conflicting. Details: Oral inositol, most frequently in the forms of myo-inositol or D-chiro-inositol, has been evaluated for efficacy in a wide range of outcomes associated with PCOS including reproductive and pregnancy outcomes, metabolic parameters, and anthropomorphic measures. Often, inositol is taken in combination with folic acid or metformin. Inositol has been investigated for its effect on metabolic parameters that are often altered in PCOS. A meta-analysis of 9 studies in patients with PCOS shows that taking myo-inositol or D-chiro-inositol with or without folic acid marginally decreases body mass index (BMI) by about 0.5 kg/m2 when compared with placebo (111670). Inositol has also been evaluated for its effect on glucose metabolism in adults with PCOS. Meta-analyses of about 10 studies show that taking myo-inositol or D-chiro-inositol with or without folic acid reduces fasting plasma glucose by 1-4 mg/dL (98944,111670). However, evidence is conflicting on the effect of inositol on insulin levels and measures of insulin resistance (98944,111670). Additionally, most studies show that inositol does not improve measures of glucose metabolism more than metformin. The effect of inositol on lipid profiles has also been studied. A meta-analysis of 2 clinical studies and other small clinical studies show that taking inositol as D-chiro-inositol with or without folic acid modestly reduces total cholesterol and triglycerides when compared with control (2028,98944,91552). Some studies have also investigated the effect of inositol on hormone levels. Meta-analyses show that inositol modulates androgen levels as shown by reduced total and free testosterone, androstenedione, and increased sex-hormone binding globulin when compared with placebo. (2028,91552,98944,111670). The validity of these effects is limited by high heterogeneity in terms of inclusion and exclusion criteria, dose, and treatment duration within the included studies. Myo-inositol has also been compared with metformin in some clinical research, with some evidence of benefit (95085,95086). Meta-analyses of small clinical studies show that taking myo-inositol 2-4 grams daily, with or without folic acid, for 12-24 weeks does not improve fasting blood glucose, fasting insulin, insulin resistance (HOMA-IR), BMI, waist-hip circumference, or androgen levels when compared with metformin 1.5-2.5 grams daily (100705,108823,111670,111670). However, inositol seems to have a lower risk of adverse effects than metformin. These analyses are limited due to the small size, methodological issues, and high heterogeneity of the included studies. In combination with metformin, small clinical studies show that taking metformin, myo-inositol 550 mg, and D-chiro-inositol 150 mg twice daily is associated with improved lipid parameters and postprandial insulin levels when compared with metformin alone (108822). Meta-analyses and clinical studies have investigated the effect of inositol on ovulation, reproduction, and pregnancy outcomes. Some research suggests that inositol increases ovulation rate, promotes cycle normalization, and improves ovarian function in patients with PCOS (2028,91552,98944,111670). A small clinical study shows that taking myo-inositol 4 grams and folic acid 400 mcg (Inofolic, Lo.Li.Pharma) daily for three spontaneous cycles induces ovulation in about 62% of individuals with anovulatory PCOS and insulin resistance. Adding clomiphene citrate with myo-inositol induces ovulation in about 72% of the patients who remain anovulatory after treatment with myo-inositol alone (91547). Another clinical study shows that taking a combination of inositol 2 grams, folic acid 200 mcg, and N-acetyl cysteine 600 mg (Ovaric HP, Just Pharma) twice daily for 12 months improves ovulation rates in PCOS patients with oligomenorrhea, regardless of insulin sensitivity at baseline (91553). Despite evidence that inositol improves ovulation rates, it does not appear to impact pregnancy rates (111670). Some research has also investigated the effects of taking both isomers of inositol concomitantly. Taking myo-inositol 550 mg plus D-chiro-inositol 13.8 mg (Inofolic Combi, Lo.Li.Pharma) twice daily, beginning 12 weeks before ovarian hyperstimulation and continuing throughout pregnancy, improves oocyte quality when compared to treatment with D-chiro-inositol alone. The combination appears to increase fertilization rate in patients aged 35 years or younger, but not those older than 35 years (91544). Other clinical research shows that taking myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily for 12 weeks improves pregnancy rates and live birth rates by an additional 10% and 11%, respectively, when compared with myo-inositol 550 mg plus D-chiro-inositol 13.8 mg. The higher-dose combination also resulted in a 15% lower rate of ovarian hyperstimulation syndrome when compared with those taking the lower dose of D-chiro-inositol (102317). Lastly, other research shows that taking myo-inositol and D-chiro-inositol together may improve metabolic parameters faster than taking myo-inositol alone (91550). Research has also evaluated the effects of inositol on other pertinent clinical outcomes in PCOS. Several small clinical studies show that taking the combination of myo-inositol and D-chiro-inositol, alone or in combination with metformin, improves menstrual cycle irregularity when compared with metformin alone, but not as much as a taking a combined hormonal contraceptive (108822,108824). The validity of these findings is limited by the unblinded nature of the studies. Also, a small clinical study shows that taking metformin with myo-inositol 550 mg and D-chiro-inositol 150 mg twice daily is associated with improved acne, but not hirsutism, at 6 months, when compared with metformin alone (108822). The validity of these findings is limited by the unblinded nature of the study. More research is needed to clarify the effect of inositol on anthropometric, metabolic, and endocrine outcomes in patients with PCOS.
• Preterm labor. Oral inositol in combination with folic acid seems to prevent preterm labor in individuals at risk for gestational diabetes. Details: A meta-analysis of five clinical trials in individuals at risk for gestational diabetes shows that taking myo-inositol plus folic acid daily, beginning during the first trimester and continuing throughout pregnancy, decreases the risk of preterm delivery by 64% when compared with folic acid alone. Patients in all but one study included in this analysis took myo-inositol 2 grams plus folic acid 200 mcg twice daily, while patients in the other study took myo-inositol 1100 mg plus D-chiro-inositol 27.6 mg and folic acid 400 mcg daily (100706). It's unclear if these results are generalizable to individuals with a low risk for gestational diabetes.

POSSIBLY INEFFECTIVE

• Acute respiratory distress syndrome (ARDS). Oral or intravenous inositol does not seem to prevent ARDS in preterm infants and may be associated with worsened outcomes. Details: Historically, small clinical trials in infants with or at risk for ARDS have suggested that myo-inositol, given parenterally and enterally for 5-10 days, might improve survival and reduce the risk of death and serious complications (2191,2192,91546). However, a large, high-quality clinical study in infants born at less than 28 weeks' gestation at risk for ARDS shows that myo-inositol 40 mg/kg given intravenously and then enterally every 12 hours for up to 70 days does not reduce the risk of death or retinopathy of prematurity (ROP). In fact, the rate of death or type 1 ROP increased by 7% in the myo-inositol group when compared to the control group, and a higher incidence of adverse events in the myo-inositol group, including poor perfusion, hypotension, and infections, led to early trial discontinuation (98946). Long-term follow-up until 24 months corrected age confirms that the initial increase in mortality rate in the myo-inositol group remained stable; however, there was no difference in a composite outcome of death or survival with moderate or severe neurodevelopmental impairment, as well as no difference in the risk of ROP, between the treatment and control groups (108819). The most recent meta-analysis, which incorporates this large clinical study, concludes that inositol supplementation does not reduce the risk of death in infants at risk for ARDS (102319).
• Anxiety. Oral inositol does not seem to be beneficial for patients with anxiety. Details: A meta-analysis of four clinical trials shows that taking inositol orally does not improve anxiety severity in patients with anxiety disorders, including obsessive-compulsive disorder, panic disorder, or post-traumatic stress disorder, when compared with placebo (91549).
• Depression. Oral inositol does not seem to be beneficial for patients with depression. Details: Guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that inositol in doses up to 12 grams daily is not currently recommended as monotherapy or adjunctive use for major depressive disorder due to a lack of evidence for efficacy (110318). Additionally, a meta-analysis of seven clinical trials shows that inositol does not significantly improve symptoms of depression in patients with bipolar depression, major depressive disorder, or premenstrual dysphoric disorder (PMDD) (91549). While limited research shows that patients receiving inositol for 4 weeks may improve, patients initially responding to inositol seem to relapse rapidly upon discontinuation of treatment (2026,2185). Additionally, taking inositol with a selective serotonin reuptake inhibitor (SSRI) doesn't appear to improve the effectiveness of SSRI therapy or improve depression in SSRI treatment failures (2025,10851).
• Diabetic neuropathy. Oral inositol does not seem to be beneficial for patients with diabetic neuropathy. Details: Most preliminary clinical research shows that taking inositol orally doesn't improve the symptoms of diabetic neuropathy (2193,2194,2195).
• Retinopathy of prematurity. Oral or intravenous inositol does not seem to prevent retinopathy of prematurity (ROP) in preterm infants. Details: A meta-analysis of six clinical trials shows that myo-inositol, given parenterally and/or enterally, does not seem to reduce the risk of ROP when compared with placebo in preterm infants (100704). A large, high-quality clinical study included in this meta-analysis shows that myo-inositol 40 mg/kg given intravenously and then enterally every 12 hours for up to 70 days does not reduce the risk of death or ROP in infants born at less than 28 weeks' gestation. In fact, the rate of death or type 1 ROP increased by 7% in the myo-inositol group when compared with placebo and a higher incidence of adverse events in the myo-inositol group, including poor perfusion, hypotension, and infections, led to early trial discontinuation (98946). Long-term follow-up until 24 months corrected age confirms that the initial increase in mortality rate in the myo-inositol group remained stable; however, there was no difference in a composite outcome of death or survival with moderate or severe neurodevelopmental impairment, as well as no difference in the risk of ROP, between the treatment and control groups (108819).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related testosterone deficiency. It is unclear if oral D-chiro-inositol is beneficial in patients with age-related testosterone deficiency. Details: A very small clinical study in males aged 65-75 years with low-normal morning testosterone levels and signs and symptoms of androgen deficiency shows that taking D-chiro-inositol 600 mg twice daily for 30 days improves sexual function and physical strength when compared with baseline (108821). The validity of these findings is limited by the lack of a comparator group.
• Bipolar disorder. It is unclear if oral inositol is beneficial in patients with bipolar disorder. Details: Evidence is conflicting on whether inositol helps treat bipolar disorder in children. One very small preliminary study in children aged 5-12 years with bipolar disorder not on concomitant mood-stabilizing medications shows that taking inositol 80 mg/kg (maximum 2 grams) daily for 12 weeks reduces manic symptoms when compared to baseline. Additionally, taking a combination of inositol 80 mg/kg and high eicosapentaenoic acid omega-3 fatty acid capsules (EPA; Nordic Naturals) 1650-3000 mg daily for 12 weeks reduces manic and depressive symptoms when compared to baseline (95092). However, another more recent study with the same intervention and protocol shows that the combination of inositol and high eicosapentaenoic acid omega-3 fatty acid reduces symptoms of depression, but does not improve manic symptoms, when compared with either ingredient taken alone (111676).
• Chemotherapy-induced leukopenia. Oral inositol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults undergoing breast cancer surgery and adjuvant chemotherapy shows that taking inositol orally 390 mg twice daily and applying IP-6 gel 4% twice daily to the surgical site, starting 2 weeks before adjuvant chemotherapy and stopping 2 weeks after the last cycle, attenuates reductions in white and red blood cell counts when compared with no intervention. Using inositol and IP-6 also improves breast and arm symptom scores and some quality of life scores; however, these improvements were not consistent over time.
• Diabetes. It is unclear if oral inositol is beneficial for the treatment of type 1 diabetes or the prevention of gestational diabetes. Details: Preliminary clinical research in patients with type 1 diabetes and a body mass index of at least 25 kg/m2 shows that taking a specific combination product containing D-chiro-inositol and folic acid (Chirofol 500, LJ Pharma) daily for 6 months, along with insulin therapy, decreases glycated hemoglobin (HbA1c) by approximately 0.5% when compared to taking folic acid alone with insulin therapy. However, there was no difference between groups with respect to insulin resistance or body mass index (95088). Most research shows that taking inositol during pregnancy prevents gestational diabetes. However, most studies conducted to date are of low quality and it is unclear if the results are generalizable. Meta-analyses of 4-7 clinical studies in pregnant adults, some with overweight and obesity, shows that taking myo-inositol 200-4000 mg daily may reduce the risk of gestational diabetes and gestational hypertension, improve 1- and 2-hour glucose tolerance test results, and reduce insulin requirements. Inositol may also be associated with improved infant outcomes such as increased gestational age at birth and reduced preterm delivery but does not seem to influence birth weight, NICU admission rate, neonatal hypoglycemia, the incidence of shoulder dystocia, macrosomia or cesarian delivery when compared with control (111664,111667,111671,111677). The validity of these effects is limited by significant heterogeneity within the included studies, concerns about blinding, and overall low-quality evidence. Most clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg twice daily (usually as Inofolic, Lo.Li. Pharma International), beginning during the first trimester and continuing throughout pregnancy, decreases the incidence of gestational diabetes by 57% to 92% when compared with folic acid alone in patients at risk for gestational diabetes. Myo-inositol seems to be more effective than D-chiro-inositol (91545,91548,95083,95084,100706,103750,104688). However, supplementation with lower doses of inositol, mimicking natural inositol occurring in the body, may not be effective. Other evidence is conflicting about whether inositol prevents gestational diabetes. One clinical study shows that taking a combination of myo-inositol 1.1 grams, D-chiro-inositol 27.6 mg, and folic acid 400 mcg (Inofolic Combi, Lo.Li. Pharma International) daily during pregnancy does not decrease the incidence of gestational diabetes when compared with folic acid alone in patients with a family history of diabetes (95082,103750). In patients eventually diagnosed with gestational diabetes, one small clinical study shows that taking myo-inositol 2 grams reduces the number of patients requiring insulin by at least 50% (104688), although another small clinical study shows that adding D-chiro-inositol, myo-inositol, or both to folic acid does not affect insulin resistance when compared with placebo (98945).
• Dyslipidemia. Although there has been interest in using oral inositol for hypercholesterolemia and hypertriglyceridemia, there is insufficient reliable information about the clinical effects of inositol for these conditions.
• Hypertension. Although there has been interest in using oral inositol for hypertension, there is insufficient reliable information about the clinical effects of inositol for this condition.
• Hypothyroidism. It is unclear if oral inositol is beneficial for subclinical hypothyroidism. Details: Clinical research in females aged 18 to 50 years with or at risk for subclinical hypothyroidism in Slovakia shows that taking myo-inositol 600 mg and selenium 83 mcg daily for 6 months modestly reduces thyroid stimulating hormone (TSH) and thyroid auto-antibody titers when compared to baseline. Myo-inositol and selenium supplementation also reduces patient-reported hypothyroid symptoms including fatigue, menstrual cycle irregularity, and intolerance to heat or cold (110591). The interpretation of these results is limited by the lack of a control group. In addition, it is unclear if these effects are due to myo-inositol, selenium, or the combination.
• Infertility. It is unclear if oral inositol is beneficial in patients undergoing intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF). Details: Several small studies in patients undergoing ICSI show that taking a specific combination product containing myo-inositol 4 grams and folic acid 400 mcg (Inofolic, Lo.Li. Pharma International S.r.l) daily, starting 1-3 months before ICSI and continuing until ovulation, improves fertilization rate, but does not improve implantation or pregnancy rates, when compared with taking folic acid alone (103752,108825). However, another moderate-sized clinical study in adults with infertility undergoing ICSI and IVF shows that taking the same combination of myo-inositol 4000 mg and folic acid 400 mcg daily for 2 months starting on the third day of the cycle improves mean number of oocytes, meiosis II oocytes, 2 pronuclear embryos, and clinical pregnancy and live birth rates when compared with taking folic acid alone (111672). The effects of inositol on fertility have been studied in patients with specific comorbidities. A case-control study in long-term survivors of lymphoma suggests that taking myo-inositol 400 mg and D-chiro-inositol 45 mg (Ovofert Fast, CRL Pharma) three times daily for 12 months is associated with reductions in follicle stimulating hormone (FSH), luteinizing hormone (LH), dyspareunia, and dysmenorrhea and a modest increase in antral follicle count of the right ovary when compared with control (111673). The validity of these effects is limited by a lack of blinding. Inositol has also been evaluated in females with polycystic ovary syndrome (PCOS). A meta-analysis of clinical studies in adults with PCOS undergoing IVF or ICSI shows that inositol does not improve pregnancy rates when compared to no treatment. However, inositol may increase clinical pregnancy rates when compared with metformin (111675). Inositol has also been evaluated in combination with other ingredients. A large clinical study in females planning to conceive shows that taking a combination product containing myo-inositol 4 grams, vitamin D, riboflavin, vitamin B6, vitamin B12, zinc, and probiotics does not improve time-to-conception, clinical pregnancy rates, or live birth rates when compared with a standard micronutrient supplement. However, the supplement shortens time-to-conception in adults with overweight to durations equivalent to patients who are not overweight, but lengthens time to conception in adults with obesity when compared with placebo (111665). It is unclear whether these effects are due to inositol, other ingredients, or the combination.
• Insomnia. It is unclear if oral inositol is beneficial for improving sleep during pregnancy. Details: Clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg (Inofolic, Lo.Li. Pharma International) before bed for 10 weeks, starting at 14 weeks gestation, improves overall measures of sleep quality by a small amount when compared with folic acid alone. However, this improvement was not maintained until 37-38 weeks' gestation. Also, the study was not limited to patients with poor sleep quality during pregnancy, but to any healthy pregnant individual (104687).
• Lithium-induced side effects. It is unclear if oral inositol is beneficial for reducing lithium-induced side effects. Details: A small clinical study suggests that taking inositol 6 grams daily for 10 weeks may improve psoriasis associated with lithium therapy when compared with baseline (11972). However, taking inositol orally does not seem to improve other lithium-induced adverse effects, such as tremor, thirst, and changes in thyroid and adrenal function (2027).
• Lung cancer. It is unclear if oral inositol is beneficial for slowing the rate of bronchial dysplasia. Details: Preliminary clinical research in smokers with bronchial dysplasia considered at high risk for lung cancer shows that taking myo-inositol (Tsuno Food Industries Co., Ltd.) 9 grams orally once daily for 2 weeks then twice daily for 6 months, does not increase the rate of complete or partial response when compared with placebo (95090).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral inositol is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD and obesity shows that taking myo-inositol powder 4 grams daily for 8 weeks does not improve liver health markers, such as liver function test levels or liver steatosis, but does improve some components of lipid profiles, glycemic indices, and anthropometric measures when compared to baseline (111304) However, this study may have been inadequately powered to detect differences in some of the outcomes.
• Obesity. It is unclear if oral inositol is beneficial in patients with overweight or obesity. Details: A meta-analysis of 15 clinical studies in adults shows that taking inositol 600-4450 mg daily for 6-48 weeks decreases body mass index (BMI) by about 0.4 kg/m2. Subgroup analysis suggests that myo-inositol may be beneficial at a dosage less than 1000 mg for less than 12 weeks, especially in patients with polycystic ovary syndrome (PCOS) and overweight or obesity, with higher baseline BMI, and above 40 years of age (111666). However, the validity of this finding is limited by significant heterogeneity in the included studies.
• Obsessive-compulsive disorder (OCD). It is unclear if oral inositol is beneficial in patients with OCD. Details: One preliminary clinical study in adults with OCD shows that taking inositol 18 grams daily for 6 weeks improves Yale-Brown Obsessive Compulsive Scale scores when compared with placebo (2186). However, taking inositol does not seem to improve the severity or type of OCD symptoms in patients already taking a selective serotonin reuptake inhibitor (91556). Both of these studies were small, and treatment was administered for only 6 weeks.
• Panic disorder. Oral inositol seems to improve symptoms of panic disorder. Details: A very small clinical study shows that taking inositol 12 grams daily reduces the severity and rate of panic attacks and the severity of agoraphobia over 4 weeks of treatment when compared with placebo (2184). Another very small clinical study shows that taking inositol 18 grams daily for one month may be as effective as fluvoxamine 150 mg daily for treatment of panic disorder (10387). However, the one-month duration may not have provided adequate time to see the full effects of fluvoxamine.
• Post-traumatic stress disorder (PTSD). It is unclear if oral inositol is beneficial in patients with PTSD. Details: Preliminary clinical research shows that taking inositol 12 grams daily for 4 weeks does not improve distress when compared with placebo in patients with PTSD (91557).
• Pregnancy-induced hypertension. It is unclear if oral inositol is beneficial for preventing hypertension during pregnancy. Details: In patients with a body mass index (BMI) between 25-29.9 kg/m2, preliminary clinical research shows that taking myo-inositol 2 grams plus folic acid 200 mcg (Inofolic, Lo.Li. Pharma International) twice daily, beginning during the first trimester and continuing throughout pregnancy, decreases the incidence of pregnancy-induced hypertension by 66% when compared with folic acid alone (104688).
• Psoriasis. It is unclear if oral or topical inositol is beneficial for improving symptoms of psoriasis. Details: One small clinical study shows that taking inositol 6 grams daily for 10 weeks does not improve symptoms of psoriasis in a small group of patients when compared to baseline. However, taking this dose of inositol has a moderate effect on overall symptoms in patients with psoriasis related to lithium use (11972). Preliminary clinical research also shows that topical use of D-chiro-inositol is unlikely to be beneficial for reducing overall symptoms of psoriasis. Topical application of inositol 0.25% or 1% for 6 weeks improves overall symptoms when compared with baseline. However, the inositol-containing creams were no more effective than the control cream (104686). Inositol has also been evaluated in combination with other ingredients. A small prospective observational study in adults with mild plaque psoriasis suggests that applying amino-inositol and urea 40% cream (Inosit U40, Biogena) 1-2 times daily for 4 weeks is associated with reductions in the severity and extent of psoriasis symptoms and improvements in quality of life measures when compared to baseline (111668). The validity of these effects is limited by a small sample size, a lack of a comparator group, insufficient blinding, and the observational study design.
• Trichotillomania. It is unclear if oral inositol is beneficial for reducing hair pulling. Details: Preliminary clinical research shows that taking inositol in doses ranging from 6-18 grams daily over a period of 10 weeks is no more effective than placebo in reducing subjective or clinician-documented symptoms of hair pulling in patients with trichotillomania (95089). More evidence is needed to rate inositol for these uses.

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EFFECTIVE

• Imerslund-Grasbeck disease. Intramuscular vitamin B12 is effective for patients with this condition. Details: Administering intramuscular vitamin B12 (hydroxocobalamin) 1 mg daily for 10 days, followed by monthly injections for the remainder of a patient's life, is effective for treating familial selective vitamin B12 malabsorption (Imerslund-Grasbeck disease) (15,82862).
• Vitamin B12 deficiency. Administering vitamin B12 orally, intramuscularly, or intranasally is effective for preventing and treating vitamin B12 deficiency. Details: Vitamin B12 deficiency has varying definitions but is often defined as vitamin B12 (cobalamin) levels less than 180-200 pmol/L (or 240 pg/mL). Some believe that only intramuscular vitamin B12 is effective for treating vitamin B12 deficiency. However, clinical research shows that oral therapy increases cobalamin levels similarly to intramuscular administration, even in patients with pernicious anemia or malabsorption, if a high enough dose is given (2909,2911,2915,9335,82832) (82836,82949,82860,103976,103972,107141,107144). Some evidence suggests that the most effective oral dose is between 647-1032 mcg daily (13106). However, in certain situations, intramuscular treatment might be more appropriate. Guidelines by the British Committee for Standards in Hematology recommend only intramuscular vitamin B12 for initial treatment of severe vitamin B12 deficiency in patients with pernicious anemia, malabsorption disorders, or neurological involvement (94722). Intramuscular vitamin B12 is also appropriate in patients with diarrhea or vomiting and those likely to be nonadherent (103972). Vitamin B12 deficiency is especially common in older adults, primarily due to lack of intrinsic factor and malabsorption (2915,2919,9335). Daily supplementation with vitamin B12 50-100 mcg might be needed to correct deficiency (10126), while daily doses of 25-37.5 mcg help to maintain normal levels over time (9335). In addition to supplements, foods such as milk and bread fortified with vitamin B12 can be used and are approximately 55% to 60% absorbed by people over 60 years of age (10124). Vitamin B12 deficiency is also common in patients that have had gastric surgery, including gastrectomy and bariatric surgery (107144,107145). Taking vitamin B12 in the doses found in multivitamins or generic vitamin B supplements does not seem to prevent vitamin B12 deficiency following bariatric surgery (107145). However, taking methylcobalamin 500 mcg daily is beneficial for treating vitamin B12 deficiency associated with a total gastrectomy and taking cyanocobalamin 5000 mcg daily is beneficial for preventing vitamin B12 deficiency following gastric bypass (107144). Other people at risk for vitamin B12 deficiency include strict vegetarians who eat no animal products (vegans) and people with increased vitamin B12 requirements associated with pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, and hepatic and kidney disease. Moderate consumption of animal products may not be sufficient to restore and maintain vitamin B12 levels, especially in adolescents who had consumed macrobiotic (vegan type) diets for the first 6 years of life. High dietary intake of vitamin B12 or supplements is usually needed in order to restore and maintain optimal vitamin B12 levels in these adolescents (10125).

LIKELY EFFECTIVE

• Cyanide poisoning. Intravenous hydroxocobalamin (Cyanokit) is likely effective as an antidote for patients with suspected or known cyanide toxicity due to inhalation, ingestion, or skin exposure. Details: Treatment of cyanide poisoning with hydroxocobalamin (Cyanokit) up to 10 grams has been approved by the US Food and Drug Administration (FDA) and recommended by the Australian Resuscitation Council (82870,82905,82906). Hydroxocobalamin is also FDA-approved for treating cyanide toxicity during pregnancy (82904).

POSSIBLY EFFECTIVE

• Canker sores. Sublingual or topical vitamin B12 seems to reduce canker sore symptoms. Details: Clinical research in patients with canker sores shows that applying a topical ointment containing vitamin B12 500 mcg in four divided doses daily for 2 days reduces pain levels by 80% when compared with a control ointment not containing vitamin B12 (96176). Other preliminary clinical research shows that taking vitamin B12 1000 mcg sublingually daily for 6 months reduces the duration of canker sore outbreaks, the number of ulcers, and level of pain when compared with placebo in patients with normal vitamin B12 levels (17242).
• Hyperhomocysteinemia. Oral vitamin B12 in combination with folic acid, and sometimes with vitamin B6, reduces homocysteine levels. Details: While folic acid 0.5-5 mg daily lowers fasting homocysteine levels by an average of 25%, adding vitamin B12 0.5 mg daily produces an additional decrease of about 7% on average (6883,9400,9401,9405,9409,50145,107136). Vitamin B12 in combination with folic acid and other vitamins also reduces homocysteine levels in patients with kidney failure, sickle cell disease, and those receiving nitrous oxide general anesthesia (1489,6883,6884,7289,7881,9324,9414,9415,9416,9481,82941). Some researchers recommend routine use of vitamin B12 with homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Using vitamin B12 alone has a limited effect on homocysteine levels, and probably only in those people with vitamin B12 deficiency (2147,9410,9512). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,2147,3323,9402,9405,9408,9409). Clinical research suggests that supplementation with folic acid, pyridoxine, and vitamin B12 decreases homocysteine levels and reduces the atherosclerosis progression in patients at risk for atherosclerosis when compared with placebo (50133,50056,82806). However, other research suggests that elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50%, and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9400,9405,9409,96417). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem improve endothelial function or help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50373,50314,97619). There is also some debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136).
• Postherpetic neuralgia. Subcutaneous injections of vitamin B12 seem to reduce postherpetic neuralgia symptoms. Details: Clinical research in patients with subacute herpetic neuralgia shows that subcutaneous injection of vitamin B12 (methylcobalamin) 1000 mcg six times weekly for 4 weeks reduces pain when compared with oral vitamin B12 or subcutaneous lidocaine (90394). Another clinical study shows that administering local subcutaneous injections of methylcobalamin 1000 mcg plus lidocaine up to 20 mg daily for 12 injections over 14 days, starting within 7 days of the onset of subacute ophthalmic herpetic neuralgia, decreases the mean pain score by 63% to 79% when compared with intravenous lidocaine and intramuscular methylcobalamin. Less than 2 patients need to be treated to achieve a pain reduction to ≤3 out of 10. Healing of rash, itching, numbness, and tingling were also improved (96175). Additional clinical research in patients with postherpetic pain and itching shows that this same dosing regimen of subcutaneous vitamin B12 reduces pain and analgesic requirements when compared to baseline (90396).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B12 does not seem to improve cognitive function in older adults when used alone or in combination with other B vitamins. Details: Taking vitamin B12 100-1000 mcg plus folic acid 400-2000 mcg, with or without vitamin B6 3-50 mg, daily for up to about 2 years does not seem to improve tests of cognitive function in adults aged 65 or older, most of whom do not report cognitive impairment at baseline (14392,50225,50510,90392,107140). Also, supplementation with vitamin B12 does not seem to improve cognitive function in elderly individuals with low vitamin B12 levels (12305).
• Alzheimer disease. Oral vitamin B12, when used in combination with other B vitamins, does not seem to improve cognitive function in patients with Alzheimer disease. Details: Clinical research in patients with probable Alzheimer disease using routine medication shows that taking vitamin B12 1 mg, folic acid 5 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, a meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). Observational research has also found that higher vitamin B12 intake over 3 years in a population consuming a folate-fortified diet is not associated with a decreased risk of developing Alzheimer disease (15270). In contrast, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). More research is needed to determine if any changes in this latter study are clinically relevant.
• Cataracts. Oral vitamin B12 does not seem to reduce cataract development. Details: Clinical research in women with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg daily, vitamin B6 50 mg daily, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts and seems to increase the risk of cataract extraction by 28% when compared with placebo (96149).
• Circadian rhythm sleep disorders. Oral vitamin B12 does not seem to improve sleep disorders. Details: Oral vitamin B12 (methylcobalamin) does not seem to be effective for treating delayed sleep phase syndrome. Methylcobalamin 0.5-1 mg three times daily, with or without bright light therapy, also does not seem to help people with primary circadian rhythm sleep disorders (1344,1345,1346,1347,1348).
• Cognitive impairment. Oral vitamin B12 does not seem to be beneficial for older adults with cognitive impairment. Details: A meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374).
• Fall prevention. Oral vitamin B12 does not seem to reduce the risk of falls. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Osteoporosis. Oral vitamin B12 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly patients or patients with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral vitamin B12 does not seem to improve physical performance in older adults. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not increase hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B12 1000 mcg, folic acid 2.5 mg, and vitamin B6 50 mg daily, reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or at least three risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if high-dose intramuscular vitamin B12 improves the prognosis of ALS. Details: A clinical study in patients with ALS symptoms for 3 years or less shows that intramuscular vitamin B12 (methylcobalamin) 25-50 mg twice weekly for 3.5 years does not slow functional decline or increase the time until ventilation or death when compared with placebo. However, other clinical research in patients with early-stage ALS shows that intramuscular methylcobalamin 50 mg twice weekly for 16 weeks is associated with slower functional decline and a longer period of time until death or full ventilation when compared with placebo (104947,111556). These effects seem to be particularly notable in fine and gross motor skills, but not bulbar or respiratory functions. Furthermore, vitamin B12 and riluzole slowed clinical progression of ALS more than riluzole alone (111556).
• Angioplasty. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B12 400 mcg, folic acid 1 mg, and vitamin B6 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412,34540). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, pyridoxine, and vitamin B12 followed by oral administration of folic acid 1.2 mg, pyridoxine 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151,34540). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B12, other ingredients, or the combination.
• Anxiety. Although there is interest in using oral vitamin B12 for anxiety and panic attacks, there is insufficient reliable information about the clinical effects of vitamin B12 for these uses.
• Asthma. Although there is interest in using oral vitamin B12 for asthma, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Atherosclerosis. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with intermediate risk for coronary heart disease shows that taking vitamin B12 100 mcg, aged garlic extract 250 mg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if topical vitamin B12 reduces the severity of eczema. Details: Preliminary clinical research shows that applying a specific topical vitamin B12 0.07% cream (Regividerm) twice daily reduces the extent and severity of atopic dermatitis when compared with placebo (15765).
• Attention. Although there is interest in using oral vitamin B12 for improving attention and focus, there is insufficient reliable information about the clinical effects of vitamin B12 for this use.
• Cancer. It is unclear if oral vitamin B12 reduces overall cancer risk when used in combination with other B vitamins. Details: An ancillary clinical study in middle-aged and elderly adults with cardiovascular disease shows that taking a combination of vitamin B12 (cyanocobalamin) 0.02 mg, folic acid 0.56 mg, and vitamin B6 3 mg, with or without eicosapentaenoic acid (EPA) 400 mg plus docosahexaenoic acid (DHA) 200 mg, for a median of 4.7 years does not reduce the risk of cancer when compared with placebo (90666). An additional secondary analysis of clinical research in patients recovering from stroke or transient ischemic attack shows that taking vitamin B12 500 mcg, folic acid 2 mg, and vitamin B6 25 mg daily for around 3.4 years does not reduce the risk of cancer when compared with placebo (90378). The validity of these findings is limited because the studies were not designed nor adequately powered to test for cancer risk.
• Cardiovascular disease (CVD). Oral vitamin B12, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly reduce the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B12 in combination with folic acid and/or vitamin B6 does not seem to reduce the risk for secondary death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, other research shows that taking vitamin B12 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). It is unclear which specific combination of B vitamins, if any, might be optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cervical cancer. It is unclear if oral vitamin B12 reduces cervical cancer risk. Details: Some epidemiological evidence has found that increasing vitamin B12 intake from dietary and supplement sources, along with folic acid, thiamine, and riboflavin, might decrease the risk of precancerous cervical lesions (11074). Also, an analysis of two case control studies has found that increased intake of vitamin B12 is associated with a 75% reduced odds of cervical cancer (34609).
• Chemotherapy-induced peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients receiving chemotherapy shows that a combination of B vitamins that includes vitamin B12 (cyanocobalamin) 1000 mcg, taken daily starting one week prior to treatment and finishing 12 weeks after treatment is completed, does not prevent peripheral neuropathy when compared with placebo (96173).
• Child development. It is unclear if oral vitamin B12 is beneficial for child development. Details: Population research has found that daily dietary intake of less than 2.26 mcg vitamin B12 in the third trimester of pregnancy is associated with an increased risk of poorer outcomes in the offspring for some measures of speech and mathematics ability, including vocabulary at 24 months, combining words at 38 months, speech intelligibility at 6 years, and math comprehension between ages 8-11 years, when compared with dietary intakes of at least 2.26 mcg daily. There was no association between prenatal vitamin B12 intake and reading or spelling abilities, vocabulary at other ages, or full-scale Intelligence Quotient (IQ) at ages 8 or 15 (107143). Furthermore, a very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve neurodevelopment as measured by language, motor, socioemotional, or cognitive scores at 12 months old and may worsen early motor performance at 8-12 weeks when compared with placebo. However, the negative effects on motor performance resolved by 6 and 12 months of age (112431).
• Child growth. Oral vitamin B12 taken by pregnant adults does not seem to be beneficial for infant growth. Details: A very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve the infant's linear growth, length, or weight at 12 months of age (112431).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin B12 reduces the risk of COPD. Details: Clinical research in patients with COPD shows that taking vitamin B12 500 mg daily for 8 weeks modestly improves endurance on the cycle ergometer, but does not improve oxygen consumption, when compared with placebo (96172).
• Cognitive function. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing vitamin B12, other B vitamins, bacopa, and gingko biloba twice daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B12 reduces colorectal cancer risk. Details: Some epidemiological evidence has found that increased dietary intake of vitamin B12 is associated with a reduced risk of developing colorectal cancer (90383). However, preliminary clinical research shows that taking vitamin B12 1 mg, folic acid 2.5 mg, and vitamin B6 50 mg daily for up to 7.3 years does not reduce the risk of colorectal adenoma in females at high risk for cardiovascular disease (90389). Furthermore, a secondary analysis of clinical research in elderly patients suggests that taking vitamin B12 500 mcg and folic acid 400 mcg daily for 2 years might increase the risk of colorectal cancer when compared with placebo (90393).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin B12 is beneficial for patients with COVID-19. Details: A small observational study in hospitalized patients with COVID-19 pneumonia has found that higher plasma vitamin B12 levels may be associated with an increased risk of transfer to intensive care or death than lower plasma levels. However, when multivariate regression was conducted, only patient age was associated with worsened outcomes. Additionally, the total study population was small, with only nine of 49 patients experiencing the worsened outcomes (107138).
• Dementia. It is unclear if oral vitamin B12 reduces the risk of developing dementia. Details: A large cohort of Danish adults has found that vitamin B12 levels or intake does not seem to impact the risk of developing Alzheimer disease or other dementias (104922). However, vitamin B12 might be beneficial in specific patient populations. A small observational study in patients with Parkinson disease has found that higher vitamin B12 levels (648.5 ng/L) are associated with a lower risk of developing dementia when compared with lower vitamin B12 levels (452 ng/L) (103975). It is not yet known if supplementation with vitamin B12 reduces the risk for dementia in these patients.
• Depression. It is unclear if oral vitamin B12 is beneficial for reducing depression risk. Details: A meta-analysis of epidemiological research has found that the highest dietary intake of vitamin B12 is associated with a 14% reduced risk of depression. However, in a sub-analysis, this association was not significant in males (107133). In contrast, one epidemiological study in older males included in the analysis has found that daily dietary intake of at least 4.79 mcg vitamin B12 is linked with a 58% lower risk of depression when compared with daily intake of less than 3.16 mcg. In this study, this inverse association was not observed in females (96168). Other observational research has found that low-normal serum vitamin B12 levels are associated with a 3.8 times increased risk for depression during pregnancy when compared with normal vitamin B12 levels (102384). It is unclear if increased intake of vitamin B12 through the diet or supplements reduces the risk for depression or is beneficial for treating symptoms of depression in any population. However, a meta-analysis of clinical research in elderly populations shows that supplementation with vitamin B12 100-1000 mcg daily, usually in combination with folic acid 400-2000 mcg daily, does not reduce symptoms of depression. Most individuals in these studies were not specifically diagnosed with depression (107140).
• Diabetes. It is unclear if oral vitamin B12 improves glycemic indices or prevents loss of skeletal muscle in patients with diabetes. Details: A small clinical study in patients with diabetes in India who are stabilized on metformin and/or a sulfonylurea shows that taking vitamin B12 (methylcobalamin) 500 mcg with or without folic acid 5 mg daily for 8 weeks seems to reduce glycated hemoglobin (HbA1C) by 1.3% to 1.5%, compared with a 0.3% increase with placebo (104917). This study is limited due its small sample size and lack of blinding. In elderly adults with type 2 diabetes, population research has found a lower dietary intake of vitamin B12 (average of 11.2 mcg daily) in individuals with a loss of skeletal muscle mass of at least 1.2%, compared with an average intake of 13.4 mcg daily in those with a skeletal muscle mass loss of less than 1.2%. However, further analysis determined that any relationship between vitamin B12 intake and loss of skeletal muscle mass was only significant in individuals with insufficient energy intake overall (107151).
• Diabetic neuropathy. Small clinical studies suggest that oral vitamin B12 may modestly improve pain in patients with diabetic neuropathy. Details: Two small clinical studies in patients with diabetic peripheral neuropathy show that taking vitamin B12 (methylcobalamin) 1-1.5 mg for 4-12 months modestly improves pain when compared with baseline or placebo (82841,104923). Some research also shows that vitamin B12 may be beneficial in combination with other ingredients. Studies have evaluated products containing vitamin B12 (methylcobalamin or cyanocobalamin), benfotiamine, and vitamin B6 daily for 9-12 weeks (82931,82939); and vitamin B12 (methylcobalamin) 2 mg, folic acid (L-methylfolate) 3 mg, and vitamin B6 (pyridoxal-5'-phosphate) 35 mg (Metanx; Pamlab) daily for 24 weeks (90375).
• Diarrhea. It is unclear if oral vitamin B12 is beneficial for reducing diarrhea in children. Details: Preliminary clinical research in children aged 6-30 months from low- and middle-income countries shows that taking vitamin B12 at twice the recommended dietary allowance, with or without folic acid, does not reduce the risk for diarrhea when compared with placebo (90391).
• Fatigue. It is unclear if intramuscular vitamin B12 is beneficial for improving well-being in those with fatigue or tiredness. Details: A small crossover trial in patients complaining of tiredness or fatigue shows that receiving intramuscular injections of vitamin B12 (hydroxocobalamin) 5 mg twice weekly for 2 weeks seems to improve general well-being and happiness, and has a trend toward improving fatigue, when compared with placebo (10127). The validity of this study is limited by a large drop-out rate and unstandardized outcome measures.
• Hearing loss. Oral vitamin B12 has only been evaluated in combination with adenosine triphosphate; its effect when used alone is unclear. Details: A small observational study in adults with idiopathic sudden sensorineural hearing loss has found that taking vitamin B12 1.5 mg with adenosine triphosphate 300 mg daily for 8-16 weeks is associated with modestly reduced hearing loss at 4-6 months after starting treatment when compared with taking the combination for less than 8 weeks (104924). This finding is limited due to its observational nature and lack of a control group.
• Hepatitis C. It is unclear if intramuscular vitamin B12 is beneficial for sustaining viral response in patients with chronic hepatitis C infection. Details: A small clinical study in patients with chronic hepatitis C infection shows that intramuscular vitamin B12 (cyanocobalamin) 5000 mcg every 4 weeks along with standard care improves sustained viral response when compared with standard of care alone (90386).
• Hypertriglyceridemia. It is unclear if oral vitamin B12 is beneficial for reducing triglyceride levels. Details: Some evidence shows that taking vitamin B12 7.5 mcg with fish oil 5 grams might be superior to fish oil alone when used daily to reduce total serum cholesterol and triglycerides. This suggests vitamin B12 might have an independent effect in lowering serum cholesterol and triglycerides, but further investigation is needed to confirm this effect (8694).
• Hypotension. It is unclear if oral vitamin B12 is beneficial for treating hypotension. Details: A meta-analysis of 3 observational studies in patients hospitalized with hypotension secondary to cardiac surgery vasoplegia suggests that administration of intravenous vitamin B12 (hydroxocobalamin) is associated with an 8 mmHg higher mean arterial pressure (MAP) at 1 hour but no change in vasopressor dosage at 1 hour or mortality rate when compared with methylene blue (112264). The validity of these findings is limited by the inclusion of only retrospective studies.
• Infant development. It is unclear if taking oral vitamin B12 during pregnancy is beneficial for improving infant development. Giving oral vitamin B12 to infants does not seem to be beneficial. Details: Clinical research shows that supplementation with vitamin B12 50 mcg daily from less than 14 weeks gestation until 6 weeks postpartum does not improve cognitive development in infants by 9 months of age when compared with placebo (96174). When these children were evaluated at 30 months of age, a very small benefit of vitamin B12 on expressive language was identified; however, there was no effect on cognition, receptive language, fine motor skills, or gross motor skills (100169). It is unknown whether a longer duration of postpartum supplementation or supplementation in specific populations might be beneficial. Vitamin B12 supplementation in infants has also been evaluated. A large clinical trial in marginally stunted Nepalese infants aged 6-11 months shows that giving vitamin B12 (cyanocobalamin) 2 mcg daily for 12 months reduces homocysteine levels, but does not improve motor or cognitive development, when compared with placebo (104926).
• Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin B12 for IBD, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Lung cancer. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: The association between vitamin B12 and lung cancer is unclear. Some population research found no relationship between blood levels of vitamin B12 and lung cancer (9454). However, other observational research involving over 5,000 case-control pairs found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of lung cancer.
• Male infertility. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing vitamin B12 1.5 mcg, L-carnitine, acetyl L-carnitine, citric acid, selenium, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility in patients with idiopathic infertility when compared to baseline. However, improvement in sperm morphology was lacking. Furthermore, patients with more severe varicocele seem to benefit most, especially with regard to progressive motility (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to vitamin B12, other ingredients, or the combination.
• Mastalgia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin B12 as methylcobalamin 100 mg, gamma-linolenic acid, and vitamin C daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Multiple sclerosis (MS). Although there is interest in using oral vitamin B12 for MS, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B12 is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking vitamin B12 1000 mcg daily for 12 weeks reduces serum levels of homocysteine but has no effect on serum aminotransferases, measures of steatosis, fibrosis scores, fasting blood glucose, serum insulin, measures of insulin resistance, triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with placebo (111555).
• Pancreatic cancer. It is unclear if oral vitamin B12 is beneficial for reducing the risk of pancreatic cancer. Details: Most population research has found that increased intake of vitamin B12, as a supplement or in the diet, is not associated with a reduced risk of pancreatic cancer (9327,104927). However, a small, retrospective population study in which smoking and non-smoking adults recalled past eating habits found that increased dietary intake of vitamin B12 is associated with a 33% reduction in pancreatic cancer risk (97976). These conflicting findings may be related to study methodology, as well as the age, gender, or smoking status of the included patients.
• Periodontitis. Although there is interest in using oral vitamin B12 for periodontitis, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product containing vitamin B12 3 mcg, folic acid 400 mcg, and uridine monophosphate 50 mg (Keltican) daily for 60 days reduces pain by 44% and decreases analgesic use by over 75% when compared to baseline in patients with peripheral neuropathy, including those with lumbar/lumbosacral radiculopathy, sciatic pain, and cervical radiculopathy (90384). The validity of this finding is limited by the lack of a control group. Furthermore, it is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Psoriasis. Topical vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific cream containing vitamin B12 and avocado oil (Regividerm, Regeneratio Pharma AG) reduces symptoms of psoriasis as effectively as calcipotriol ointment (Psorcutan) after 12 weeks of therapy. The vitamin B12 combination cream also causes less irritation than calcipotriol (14909). It is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Respiratory tract infections. A small study suggests that oral vitamin B12 does not reduce the rate of respiratory tract infections in children. Details: Preliminary clinical research in children aged 6-30 months from low-and middle-income countries suggests that taking vitamin B12 at twice the recommended dietary allowance with or without folic acid does not reduce the risk for lower respiratory tract infections when compared with placebo (90391).
• Schizophrenia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of vitamin B12 400 mcg and folic acid 2 mg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral vitamin B12 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B12, either alone or with other B vitamins, is beneficial for stroke prevention. Details: Epidemiological research has found that people with a higher intake of vitamin B12 from dietary sources do not have a reduced risk of ischemic or hemorrhagic stroke (14316). A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50420,50423,83050,90379,90380,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis suggests that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Another meta-analysis suggests that exposure to low, but not high, amounts of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tinnitus. It is unclear if intramuscular vitamin B12 is beneficial in patients with tinnitus. Details: A small clinical study shows that intramuscular vitamin B12 2500 mcg weekly for 6 weeks reduces tinnitus severity by 22% when compared to baseline in patients with chronic tinnitus and vitamin B12 deficiency, but not in patients with normal levels of vitamin B12. Vitamin B12 does not improve pitch or volume in either group of patients (96170). The validity of this finding is limited by the lack of a control group.
• Venous thromboembolism (VTE). It is unclear if oral vitamin B12 is beneficial for preventing VTE. Details: Epidemiological research has found that low levels of vitamin B12 are associated with an increased risk for VTE. However, clinical trials evaluating the use of B vitamins for prevention of VTE have shown conflicting results (90398). More evidence is needed to rate vitamin B12 for these uses.

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LIKELY SAFE ...when used orally and appropriately. Choline is safe in adults when taken in doses below the tolerable upper intake level (UL) of 3.5 grams daily (3094) ...when used intravenously and appropriately. Intravenous choline 1-4 grams daily for up to 24 weeks has been used with apparent safety (5173,5174).

POSSIBLY UNSAFE ...when used orally in doses above the tolerable upper intake level (UL) of 3. 5 grams daily. Higher doses can increase the risk of adverse effects (3094).

CHILDREN: LIKELY SAFE
when used orally and appropriately (3094). Choline is safe in children when taken in doses below the tolerable upper intake level (UL), which is 1 gram daily for children 1-8 years of age, 2 grams daily for children 9-13 years of age, and 3 grams daily for children 14-18 years of age (3094).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL. High doses can increase the risk of adverse effects (3094).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Choline is safe when taken in doses below the tolerable upper intake level (UL), which is 3 grams daily during pregnancy and lactation in those up to 18 years of age and 3.5 grams daily for those 19 years and older (3094,92114). There is insufficient reliable information available about the safety of choline used in higher doses during pregnancy and lactation.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Inositol has been used with apparent safety in doses up to 18 grams daily for up to 6 weeks or 6 grams daily for 10 weeks (2184,2185,2187,95089). Myo-inositol 4 grams daily has also been used with apparent safety for 6 months (95085). There is insufficient reliable information available about the safety of inositol when used topically.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Inositol 80 mg/kg (maximum 2 grams) has been taken daily for up to 12 weeks in children aged 5-12 years (95092). ...when used enterally or intravenously and appropriately in premature infants for treating acute respiratory distress syndrome for up to 10 days (2191,2192,91546,91551).

CHILDREN: POSSIBLY UNSAFE
when used enterally or intravenously for extended durations in premature infants. A large clinical study in infants born at less than 28 weeks' gestation found that myo-inositol 40 mg/kg, given intravenously and then enterally every 12 hours for up to 10 weeks, was associated with a small increased risk of death (98946). Long-term follow-up until 24 months corrected age confirms that the initial increase in mortality rate in the myo-inositol group remained stable; however, there was no difference in a composite outcome of death or survival with moderate or severe neurodevelopmental impairment, as well as no difference in the risk of retinopathy of prematurity, between those who received myo-inositol or control (108819).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. Myo-inositol has been used with apparent safety in amounts up to 4000 mg daily during pregnancy (91548,95082,104688).

LACTATION:
Insufficient reliable information available; avoid using. Breast milk is rich in endogenous inositol (2138); however, the effects of exogenously administered inositol are not known.

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LIKELY SAFE ...when used orally, topically, intravenously, intramuscularly, or intranasally and appropriately. Vitamin B12 is generally considered safe, even in large doses (15,1344,1345,1346,1347,1348,2909,6243,7289,7881)(9414,9416,10126,14392,15765,82832,82949,82860,82864,90386)(111334,111551).

PREGNANCY: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B12 during pregnancy is 2.6 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA of vitamin B12 during lactation is 2.8 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 while breastfeeding.

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ATROPINE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, choline might decrease the effects of atropine in the brain.  Details Animal research shows that administering choline one hour before administering atropine can attenuate atropine-induced decreases in brain levels of acetylcholine (42240). Theoretically, concomitant use of choline and atropine may decrease the effects of atropine.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, taking inositol with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research shows that inositol lowers blood glucose levels and glycated hemoglobin (HbA1c) levels in patients with diabetes (95083,95084,95088).

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General ...Orally, choline is well tolerated when used appropriately. Adverse effects have been reported with doses exceeding the tolerable upper intake level (UL) of 3.5 grams daily.
Most Common Adverse Effects:
Orally: Fishy body odor. At high doses of at least 9 grams daily, choline has been reported to cause diarrhea, nausea, salivation, sweating, and vomiting.

Cardiovascular ...Orally, doses of choline greater than 7. 5 grams daily may cause low blood pressure (94648).

Gastrointestinal ...Orally, large doses of choline can cause nausea, vomiting, salivation, and anorexia (42275,91231). Gastrointestinal discomfort has reportedly occurred with doses of 9 grams daily, while gastroenteritis has reportedly occurred with doses of 32 grams daily (42291,42310). Doses of lecithin 100 grams standardized to 3.5% choline have reportedly caused diarrhea and fecal incontinence (42312).

Genitourinary ...Orally, large doses of choline greater than 9 grams daily have been reported to cause urinary incontinence (42291).

Neurologic/CNS ...Orally, high intake of choline may cause sweating due to peripheral cholinergic effects (42275).

Oncologic ...In one population study, consuming large amounts of choline was associated with an increased risk of colorectal cancer in females, even after adjusting for red meat intake (14845). However, more research is needed to confirm this finding.

Psychiatric ...Orally, large doses of choline (9 grams daily) have been associated with onset of depression in patients taking neuroleptics. Further research is needed to clarify this finding (42270).

Other ...Orally, choline intake may cause a fishy body odor due to intestinal metabolism of choline to trimethylamine (42285,42275,42310,92111,92112).

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General ...Orally and intravenously, inositol seems to be well tolerated. Topically, no adverse effects have been reported, although a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Diarrhea, gas, and nausea.

Gastrointestinal ...Orally, inositol may cause nausea, diarrhea, gas, and gastrointestinal discomfort (10387,11972,91547,91549,95089,95090,95092).

Immunologic ...Orally, inositol in combination with omega-3 fatty acids has been associated with reports of cold and allergy symptoms in children in clinical research (95092).

Musculoskeletal ...Orally, inositol in combination with omega-3 fatty acids has been associated with reports of tics and other musculoskeletal side effects in children in clinical research (95092).

Neurologic/CNS ...Orally, inositol may cause dizziness, tiredness, insomnia, agitation, and headache (10387,11972,95089,95092). In combination with omega-3 fatty acids, inositol has been associated with reports of feelings of thirst in children in clinical research (95092).

Psychiatric ...In one case report, a 36-year-old male with adequately controlled bipolar disorder was hospitalized with symptoms of mania after consuming several cans of an energy drink containing inositol, caffeine, taurine, and other ingredients (Red Bull Energy Drink) over a period of 4 days (14302). It is not known if this is related to inositol, caffeine, taurine, a different ingredient, or a combination of the ingredients.

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General ...Orally, intramuscularly, and topically, vitamin B12 is generally well-tolerated.
Most Common Adverse Effects:
Intramuscular: Injection site reactions.
Serious Adverse Effects (Rare):
Intramuscularly: Severe hypokalemia has been rarely linked with correction of megaloblastic anemia with vitamin B12.

Cardiovascular ...In human clinical research, an intravenous loading dose of folic acid, vitamin B6, and vitamin B12, followed by daily oral administration after coronary stenting, increased restenosis rates (12150). Hypertension following intravenous administration of hydroxocobalamin has been reported in human research (82870,82864).

Dermatologic ...Orally or intramuscularly, vitamin B12 can cause allergic reactions such as rash, pruritus, erythema, and urticaria. Theoretically, allergic reactions might be caused by the cobalt within the vitamin B12 molecule (82864,90373,90381,103974). In one case report, oral methylcobalamin resulted in contact dermatitis in a 59-year-old Japanese female with a cobalt allergy (103974). In another case report, a 69-year-old female developed a symmetrical erythematous-squamous rash for 5 years after oral vitamin B12 supplementation for 10 years. A patch test confirmed that the systemic allergic dermatitis was due to vitamin B12 supplementation, which resolved 3 months after discontinuation (114578).
Vitamin B12 (intramuscular or oral) has also been associated with at least 19 cases of acneiform eruptions which resolved upon discontinuation of vitamin B12 (90365,90369,90388). High-dose vitamin B12 (20 mcg daily) and vitamin B6 (80 mg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may last up to four months after the supplement is stopped and can be treated with systemic corticosteroids and topical therapy (10998,82870,82871).

Gastrointestinal ...Intravenously, vitamin B12 (hydroxocobalamin) 2. 5-10 grams can cause nausea and dysphagia (82864).

Genitourinary ...Intravenously, vitamin B12 (hydroxocobalamin) 5-15 grams has been associated with chromaturia in clinical research (82870,82871,112282,112264).

Hematologic ...According to case report data, the correction of megaloblastic anemia with vitamin B12 may result in fatal hypokalemia (82914).

Musculoskeletal ...According to case report data, correction of megaloblastic anemia with vitamin B12 has precipitated gout in susceptible individuals (82879).

Neurologic/CNS ...Treatment with vitamin B12 has been rarely associated with involuntary movements in infants with vitamin B12 deficiency (90370,90385,90397). In some cases these adverse reactions were misdiagnosed as seizures or infantile tremor syndrome (90370,90385). These adverse reactions presented 2-5 days after treatment with vitamin B12 and resolved once vitamin B12 was discontinued (90370,90385,90397).

Oncologic ...Although some epidemiological research disagrees (9454), most research has found that elevated plasma levels of vitamin B12 are associated with an increased risk of various types of cancer, including lung and prostate cancers and solid tumors (50411,102383,107743). One study found, when compared with blood levels of vitamin B12 less than 1000 ng/mL, plasma vitamin B12 levels of at least 1000 ng/mL was strongly associated with the occurrence of solid cancer (107743). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of cancer. It is possible that having cancer increases the risk of vitamin B12 elevation. However, one observational study has found that the highest quintile of dietary intake of vitamin B12 is associated with a 75% increased incidence of developing esophageal cancer when compared with the lowest quintile in never drinkers, but not drinkers (107147).

Renal ...There is a case report of oxalate nephropathy in a 54-year-old male which was determined to be related to the use of intravenous hydroxocobalamin as treatment for cyanide poisoning. Intermittent hemodialysis was started 5 days after admission, along with a low-oxalate diet, oral calcium acetate, and pyridoxine 5 mg/kg daily (107148). A review of the use of intravenous hydroxocobalamin for suspected cyanide poisoning in 21 intensive care units in France between 2011 and 2017 resulted in a 60% increased odds of acute kidney injury and a 77% increased odds of severe acute kidney injury in the first week. However, biopsies were not conducted and a direct link with use of hydroxocobalamin could not be made (107139).

Other ...Several studies have found that higher vitamin B12 levels may be associated with increased mortality or decreased survival rates in hospitalized elderly patients (82889,82812,82857,82895). Human research has also found a positive correlation between vitamin B12 status and all-cause mortality in Pima Indians with diabetes (82863).

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